Geographic, Sociodemographic, and Clinical Factors Associated With Parental Self-Efficacy in Pediatric Patients With Hearing Loss.

OBJECTIVE: To identify geographic, sociodemographic, and clinical factors associated with parental self-efficacy in a diverse cohort of deaf or hard-of-hearing (DHH) children. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary children's hospital. METHODS: Four hundred forty parents of DHH children aged 0 to 17 completed the 25-item Scale of Parental Involvement and Self-Efficacy (SPISE) survey from 2014 to 2022. Residential addresses were geocoded and assigned Area Deprivation Index and Social Vulnerability Index rankings, and univariable and multivariable analyses were conducted using sociodemographic and clinical variables, including sex, race/ethnicity, insurance type, survey language, age at the survey, comorbidities, newborn hearing screening results, and hearing loss laterality and severity. RESULTS: Compared to English and Spanish-speaking parents, Chinese-speaking parents were associated with overall lower parental self-efficacy and involvement (regression coefficient = -0.518, [-0.929, -0.106]), Cohen's d = 0.606) and lower scores on items related to their ability to affect multiple aspects of their child's development and expression of thoughts as well as competency in checking and putting on their child's sensory device. Across univariable and multivariable analyses, besides Chinese language, all other sociodemographic, clinical, and geographic variables were not associated with SPISE score. CONCLUSION: To achieve the best patient outcomes, care teams can use the SPISE to evaluate parental self-efficacy and provide targeted support to parents at risk for having lower knowledge and confidence scores about critical skills necessary to facilitate their child's auditory access and language development. Notably, this study found similar reports of parental efficacy across various sociodemographic, clinical, and geographic variables but significantly lower SPISE scores in Chinese-speaking families.

Risk Factors Associated with Delays in Hearing Loss Identification in Pediatric Patients.

OBJECTIVE: To identify sociodemographic factors associated with pediatric late-identified hearing loss (LIHL) and classify novel subgroups within the LIHL population. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary children's hospital. METHODS: Our cohort included children with permanent hearing loss (HL) between 2012 and 2020 (n = 1087). Patients with early-identified HL were compared to patients with LIHL (>6 months of age at diagnosis), and 3 subgroups: (1) late-identified congenital HL: failed NHS but had a diagnostic audiogram >6 months old; (2) late-onset HL: passed NHS and identified with HL after 6 months old; (3) late-identified, unknown-onset: unknown NHS results, identified after 6 months old. Geospatial analysis was performed using ArcGIS Pro. RESULTS: Compared with early-identified children, children with LIHL were more likely to have more comorbidities (odds ratio [OR] = 1.12, [1.01, 1.23]), be an under-represented minority (URM) (OR = 1.92, [1.27, 2.93]) and have a higher social vulnerability index (SVI) (adjusted odds ratio [AOR] = 2.1, [1.14, 3.87]). However, subgroups in the LIHL cohort had variable associations. Children with late-identified unknown onset hearing loss were uniquely associated with a primarily non-English speaking household (AOR = 1.84, [1.04, 3.25]), whereas children with late-onset hearing loss were less likely to have public insurance (AOR = 0.47, [0.27, 0.81]. There were no significant associations for children with late-identified congenital hearing loss. Neighborhood disadvantage, as measured by SVI, had an increased association with late-identified unknown onset HL (AOR = 4.08, [2.01, 8.28]) and a decreased association with late-onset HL (AOR = 0.40, [0.22, 0.72]). CONCLUSION: Sociodemographic factors serve as proxies for health care access, and these factors vary across LIHL pathways. Understanding the risk factors associated with each LIHL subgroup may help address disparities in pediatric HL identification.

Understanding Barriers to Timely Diagnosis and Intervention Among Immigrant Children With Hearing Loss.

OBJECTIVE: Identify the age at diagnosis and intervention of immigrant and/or non-English-speaking children with hearing loss (HL) and risk factors associated with delays. Identify barriers for non-English-speaking caregivers of deaf/hard-of-hearing children. STUDY DESIGN: Sequential mixed methods. SETTING: Tertiary care center in an urban city. METHODS: The analysis includes descriptive statistics, and 1-way and 2-way analysis of variance of the retrospective chart review. The quantitative study demonstrated foreign-born experienced disparities, so we conducted semistructured interviews on a subset of non-English-speaking families in the cohort that was then thematically analyzed using a human-centered design strategy. RESULTS: We divided 532 children into 3 groups: US-born with English as the preferred language (N = 294), US-born and non-English language preferred (N = 173), and foreign-born (N = 67). The laterality of HL and pure-tone averages were similar among the groups (p = .972 and .071, respectively). Age at diagnosis and time to the intervention were significantly different (39.7, 31.5, 75.8 months, p < .001 and 24.6, 29.2, 48.9 months, p = .001, respectively). Ages at diagnosis and intervention were associated with birthplace (p = .005, p = .0005, respectively) but not preferred language (p = .667, p = .343, respectively). Included in the qualitative interviews were Mandarin- (n = 5), Arabic- (n = 4), and Spanish-speaking families (n = 3). Insights revealed participants' quest for anticipatory guidance and social support, the consequences of cultural stigma, and the complexity of caring for a child with HL in an immigrant family. CONCLUSION: Foreign-born children with HL have significant delays in diagnosis and intervention compared to US-born children. For non-English-speaking parents, the diagnosis of HL presents challenges beyond that of the immigrant experience.

Impact of Sociodemographic Disparities on Language Outcomes After Cochlear Implantation in a Diverse Pediatric Cohort.

OBJECTIVE: We examined how sociodemographic and audiologic factors affect receptive and expressive language outcomes in children with cochlear implantation. STUDY DESIGN: Retrospective cohort study. SETTING: A hearing loss (HL) clinic at a tertiary center. METHODS: Sociodemographic variables, HL characteristics, age at implantation, and receptive language scores (Preschool Language Scale and the Clinical Evaluation of Language Fundamentals) were collected from patients with congenital HL who received their first implant by 4 years old after January 1, 2007. t Tests, linear regression, Mann-Whitney, Cohen's d, and mediation analysis were used for descriptive statistics and hypothesis testing. RESULTS: Among 79 patients, 42 (53%) were females, 44 (56%) under-represented minorities, and 56 (71%) had public insurance. At least 1 year after implantation, the median receptive language score was 69 (range 50-117). Females (p = .005), having private insurance (p = .00001), having a Cochlear Implant Profile score below 4 (p = .0001), and receiving their implant at or before 12 months of age (p = .0009) were significantly associated with improved receptive language outcomes. Insurance type had a significant effect on receptive language outcomes, independent from age at first implantation (total effect: coef = -13.00, p = .02; direct effect: coef = -12.26, p = .03; indirect effect: coef = -0.75, p = .47). Sociodemographic variables had large effect sizes, with the Cochlear Implant Profile score having the largest effect size (d = 1.3). CONCLUSION: Sociodemographic factors have a large impact on receptive language outcomes. Public insurance is associated with worse receptive language, not mediated by later age at implantation, suggesting that other factors primarily impact language outcomes in publicly insured children with cochlear implants.

Factors associated with congenital cytomegalovirus infection detected by dried blood spot testing in children with hearing loss.

OBJECTIVE: Congenital cytomegalovirus (cCMV) infection in infants leads to an increased risk of developing sensorineural hearing loss (SNHL), even if they are asymptomatic at birth. There are currently no national guidelines for universal screening for CMV, placing children with cCMV at a high risk for unidentified and untreated HL, which in turn places them at greater risk for lasting impacts on quality of life and cognitive and behavioral abilities. We sought to describe the sociodemographic and hearing loss characteristics of children with HL due to cCMV. DESIGN: We performed a retrospective cohort study of patients 0-18 years of age who completed CMV dried blood spot (DBS) testing in our HL clinic before April 1, 2022. Home ZIP codes were entered into the Healthy Places Index (HPI) database to quantify the health of the community in which the patient lived. Severity of HL was determined by pure tone averages (PTA) of hearing thresholds for frequencies of 500Hz, 1000Hz, 2000Hz, and 4000Hz. Progression was defined as those who referred on newborn hearing screen and then had a >15 dB increase in PTA, and those who passed newborn hearing screen and were found to have HL later in life. Logistic regression was used to compare variables. RESULTS: Of 365 children who received a CMV DBS test, 15 (4%) had a positive test, indicating the presence of cCMV infection, and 350 (96%) had a negative test. 192 (53%) were male, 212 (58%) were URM, 202 (55%) had public insurance, the median number of ICD-10 codes was 2 (range 0-53), and the median HPI percentile score was 71.2 (range: 3.4-99.9). Although CMV DBS testing was ordered for those with suspicion of SNHL, ultimately diagnostic testing found 333 (91%) with SNHL, 4 (1%) with CHL, 13 (4%) with mixed HL, 9 (3%) with auditory neuropathy spectrum disorder, and 5 (4%) with unspecified HL, and 11 (3%) without HL. Of the 353 patients with HL, 126 (36%) had unilateral, 156 (44%) had symmetric bilateral, and 71 (20%) had asymmetric bilateral HL; 183 (52%) had progressive and 138 (39%) had stable HL. In children with SNHL (n = 333), we tested the association of socio-demographic and audiologic factors with cCMV. Those with asymmetric bilateral SNHL (OR 5.19, 95% CI 1.81-14.90) or profound SNHL (>90 dB) in either ear (OR 13.91, 95% CI 3.82-50.67) had higher odds of having cCMV. Those with symmetric bilateral SNHL had lower odds of a positive CMV DBS test result (OR 0.17, 95% CI 0.02-0.76). All sociodemographic variables, medical comorbidities, and other audiologic variables were not associated with CMV DBS test results. CONCLUSION: Congenital CMV infection is associated with asymmetric bilateral and profound SNHL. More research is warranted to determine best practices for universal screening for cCMV to identify these children.

Predictors of successful natural sleep MRI for sensorineural hearing loss in infants.

OBJECTIVES: Cochlear implantation (CI) in children with sensorineural hearing loss (SNHL) before 12 months of age (mo) improves language outcomes. MRI is important to assess CI candidacy. Anesthesia before 3 years old may increase risk of neurocognitive delay. Natural sleep MRI (NS-MRI) is an emerging technique to avoid anesthesia in infants, but relies on successful sleep for adequate imaging. Our multidisciplinary team hypothesized the following predictors of successful NS-MRI for CI evaluation: age, distance travelled, comorbidities, primary language, insurance type, HL characteristics, time and duration of MRI. METHODS: We performed retrospective review of children 0-12mo who attempted NS-MRI. The NS-MRI was successful if imaging was sufficient for definitive clinical management per the managing otolaryngologist. RESULTS: Among 26 patients (29 scans), the median age was 3.2mo (range: 1.2-6.8mo), distance travelled was 16.3 miles (range: 0.9 to 365 miles), 12 (46%) children had medical comorbidities. 8 (31%) had public insurance. 10 (38%) had bilateral HL. 52% (15/29) of scans were successful. Patients with comorbidities had significantly lower odds of successful NS-MRI (OR 0.09; 95% CI 0.01-0.54). Success was not associated with age, distance travelled, insurance type, primary language, HL characteristics, time or duration of MRI on univariable analysis. All 11 children who failed NS-MRI underwent hearing-aid fitting and/or imaging with sedation and CI as clinically indicated before 12mo. CONCLUSION: NS-MRI was successful in 52% of infants, regardless of age, demographics, HL or MRI characteristics. Unsuccessful NS-MRI did not result in delayed intervention. NS-MRI is an effective consideration for a broad range of infants with SNHL.

Impact of Genetic Testing on Hearing Interventions.

OBJECTIVE: Clinical guidelines recommend genetic testing when evaluating congenital and late-onset sensorineural hearing loss (SNHL). Genetic diagnoses can provide parents additional information regarding anticipated hearing loss progression, comorbid conditions, and family planning. Additionally, obtaining a genetic diagnosis may increase parental acceptance of hearing loss and subsequent pursuit of intervention. This study evaluates the association between genetic diagnoses and hearing loss intervention. METHODS: We included children ages 0-18 years with SNHL who were hearing aid or cochlear implant candidates but non-users and underwent hearing-loss gene panel testing prior to initiating intervention. Univariate analyses were performed to identify predictors of hearing aid fitting or cochlear implantation. Multivariate logistic regression evaluated the impact of demographic and clinical factors on subsequent intervention. RESULTS: Of the 385 children with SNHL who underwent hearing loss gene panel testing, 111 were included. Median age was 7.5 years. 56% were underrepresented minorities, 71% were non-White, and 71% were publicly insured. Those found to have a genetic diagnosis were 4.6 times as likely to subsequently undergo intervention (p = 0.035). Additionally, bilateral hearing loss and earlier age of genetic testing were associated with increased likelihood of intervention. CONCLUSION: Up to half of children with SNHL are suspected to have an underlying genetic etiology. Children diagnosed with a genetic diagnosis are significantly more likely to subsequently utilize hearing aids or cochlear implantation. This provides additional support for clinical guidelines recommending genetic testing not only due to the impact of prognostication but also on treatment decision-making. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:1982-1986, 2023.

Using a human-centered, mixed methods approach to understand the patient waiting experience and its impact on medically underserved Populations.

PURPOSE: To use a mixed methods approach to investigate the patient waiting experience for a medically underserved population at an outpatient surgical clinic. METHODS: We used lean methodology to perform 96 time-tracked observations of the patient journey in clinic, documenting the duration of activities from arrival to departure. We also used human-centered design (HCD) to perform and analyze 43 semi-structured interviews to understand patients' unmet needs. RESULTS: Patients spent an average of 68.5% of their total clinic visit waiting to be seen. While the average visit was 95.8 minutes, over a quarter of visits (27%) were over 2 hours. Patients waited an average of 24.4 minutes in the waiting room and 41.2 minutes in the exam room; and only spent 19.7% of their visit with an attending provider and 11.8% with a medical assistant. Interviews revealed that patients arrive to their visit already frustrated due to difficulties related to scheduling and attending their appointment. This is exacerbated during the visit due to long wait times, perceived information opacity, and an uncomfortable waiting room, resulting in frustration and anxiety. CONCLUSIONS: While time tracking demonstrated that patients spend a majority of their visit waiting to be seen, HCD revealed that patient frustrations span the waiting experience from accessing the appointment to visit completion. These combined findings are crucial for intervention design and implementation for medically underserved populations to improve the quality and experience with healthcare and also address system inefficiencies such as long wait times.

Using Architectural Mapping to Understand Behavior and Space Utilization in a Surgical Waiting Room of a Safety Net Hospital.

OBJECTIVE: To use architectural mapping to understand how patients and families utilize the waiting space at an outpatient surgery clinic in a safety-net hospital. BACKGROUND: The waiting period is an important component of patient experience and satisfaction. Studies have found that patients value privacy, information transparency and comfort. However, approaches common in the architecture field have rarely been used to investigate interactions between patients and the built environment in a safety-net healthcare setting. METHODS: This was a prospective observational study in a general surgery outpatient clinic at a safety-net hospital and level 1 trauma center. We used a web-based application generated from the design and architecture industry, to quantitatively track waiting space utilization over 2 months. RESULTS: A total of 728 observations were recorded across 5 variables: time, location, chair selection, person/object, and activity. There were 536 (74%) observations involving people and 179 (25%) involving personal items. People most frequently occupied chairs facing the door (43%, n = 211), and least frequently occupied seats in the hallway (5%, n = 23), regardless of the time of their appointment (p-value = 0.92). Most common activities included interacting with personal phone, gazing into space, and talking face to face. Thirteen percent of people brought mobility devices, and 64% of objects were placed on an adjacent chair, indicating the desire for increased personal space. CONCLUSION: Architectural behavioral mapping is an effective information gathering tool to help design waiting space improvement in the safety-net healthcare setting.

Outcomes of Gene Panel Testing for Sensorineural Hearing Loss in a Diverse Patient Cohort.

Importance: A genetic diagnosis can help elucidate the prognosis of hearing loss, thus significantly affecting management. Previous studies on diagnostic yield of hearing loss genetic tests have been based on largely homogenous study populations. Objectives: To examine the diagnostic yield of genetic testing in a diverse population of children, accounting for sociodemographic and patient characteristics, and assess whether these diagnoses are associated with subsequent changes in clinical management. Design, Setting, and Participants: This retrospective cohort study included 2075 patients seen at the Children's Communications Clinic, of whom 517 completed hearing loss gene panel testing between January 1, 2015, and November 1, 2021, at the University of California, San Francisco Benioff Children's Hospital system. From those 517 patients, 426 children with at least 2 audiograms were identified and analyzed. Data were gathered from November 2021 to January 2022 and analyzed from January to February 2022. Main Outcomes and Measures: The measures of interest were sociodemographic characteristics (age at testing, gender, race and ethnicity, primary language, and insurance type), hearing loss characteristics, and medical variables. The outcome was genetic testing results. Variables were compared with univariate and multivariable logistic regression. Results: Of the 2075 patients seen at the Children's Communications Clinic, 517 (median [range] age, 8 [0-31] years; 264 [51.1%] male; 351 [67.9%] from an underrepresented minority [URM] group) underwent a hearing loss panel genetic test between January 1, 2015, and November 1, 2021. Among those 517 patients, 426 children (median [range] age, 8 [0-18] years; 221 [51.9%] male; 304 [71.4%] from an URM group) with 2 or more audiograms were included in a subsequent analysis. On multivariable logistic regression, age at testing (odds ratio [OR], 0.87; 95% CI, 0.78-0.97), URM group status (OR, 0.29; 95% CI, 0.13-0.66), comorbidities (OR, 0.27; 95% CI, 0.14-0.53), late-identified hearing loss (passed newborn hearing screen; OR, 0.27; 95% CI, 0.08-0.86), and unilateral hearing loss (OR, 0.04; 95% CI, 0.005-0.33) were the only factors associated with genetic diagnosis. No association was found between genetic diagnosis yield and other sociodemographic variables or hearing loss characteristics. Patients in URM and non-URM groups had statistically similar clinical features. A total of 32 of 109 children (29.4%) who received a genetic diagnosis received diagnoses that significantly affected prognosis because of identification of syndromic or progressive sensorineural hearing loss or auditory neuropathy spectrum disorder relating to otoferlin. Conclusions and Relevance: This cohort study's findings suggest that genetic testing may be broadly useful in improving clinical management of children with hearing loss. More research is warranted to discover and characterize diagnostic genes for those who have been historically underrepresented in research and medicine.

Congenital aural atresia and first branchial cleft anomalies: Cholesteatoma and surgical management.

Objectives: To describe the prevalence and significance of first branchial cleft anomalies in children with congenital aural atresia. Methods: Retrospective cohort study and case series. Patients were included if they had ICD-10 code Q16.0, Q16.1, Q16.9, Q17.2, or Q17.9 in their medical record and were seen at UCSF Benioff Children's Hospital from 2012 to 2020 for aural atresia. Children were categorized as having aural atresia and first branchial cleft anomalies if the presence of a first branchial cleft anomaly was noted in otolaryngology provider notes; otherwise, they were categorized as aural atresia alone. Patients with aural atresia and first branchial cleft anomalies were included in the case series. Results: Among 125 children with congenital aural atresia, 5 (4%) were identified with first branchial cleft anomalies. In all cases, an epithelialized tract was noted to originate from the inferior aspect of the middle ear cleft, exiting the temporal bone in an inferomedial position adjacent to the stylomastoid foramen, with a cutaneous exit point inferior to the expected location of the native ear canal. There was no association with sex, microtia grade, or laterality of atresia; however, children with aural atresia and first branchial cleft anomalies were significantly more likely to have syndromes such as Goldenhar and Treacher Collins (p = .04) than those with aural atresia alone.3/5 (60%) children with aural atresia and first branchial cleft anomalies presented with cholesteatoma compared with 1/120 (0.8%) children with aural atresia alone, a significant difference (p < .001). All four children over the age of two have undergone surgical management. In two of these, excision of the branchial cleft anomaly could be combined with atresiaplasty, with normal hearing results in both cases. Conclusions: Aural atresia can be associated with comorbid anomalies of the head and neck. First branchial cleft anomalies can be suspected based on characteristic clinical appearance and confirmed with computed tomography showing a typical course through the temporal bone. When present in the context of congenital aural atresia, first branchial cleft anomalies are associated with a significantly increased risk for cholesteatoma, often necessitating surgical management with favorable hearing outcomes. Level of evidence: 4.

Detection of protein-protein interactions at the septin collar in Saccharomyces cerevisiae using a tripartite split-GFP system.

Various methods can provide a readout of the physical interaction between two biomolecules. A recently described tripartite split-GFP system has the potential to report by direct visualization via a fluorescence signal the intimate association of minimally tagged proteins expressed at their endogenous level in their native cellular milieu and can capture transient or weak interactions. Here we document the utility of this tripartite split-GFP system to assess in living cells protein-protein interactions in a dynamic cytoskeletal structure-the septin collar at the yeast bud neck. We show, first, that for septin-septin interactions, this method yields a robust signal whose strength reflects the known spacing between the subunits in septin filaments and thus serves as a "molecular ruler." Second, the method yields little or no spurious signal even with highly abundant cytosolic proteins readily accessible to the bud neck (including molecular chaperone Hsp82 and glycolytic enzyme Pgk1). Third, using two proteins (Bni5 and Hsl1) that have been shown by other means to bind directly to septins at the bud neck in vivo, we validate that the tripartite split-GFP method yields the same conclusions and further insights about specificity. Finally, we demonstrate the capacity of this approach to uncover additional new information by examining whether three other proteins reported to localize to the bud neck (Nis1, Bud4, and Hof1) are able to interact physically with any of the subunits in the septin collar and, if so, with which ones.

Coordinate action of distinct sequence elements localizes checkpoint kinase Hsl1 to the septin collar at the bud neck in Saccharomyces cerevisiae.

Passage through the eukaryotic cell cycle requires processes that are tightly regulated both spatially and temporally. Surveillance mechanisms (checkpoints) exert quality control and impose order on the timing and organization of downstream events by impeding cell cycle progression until the necessary components are available and undamaged and have acted in the proper sequence. In budding yeast, a checkpoint exists that does not allow timely execution of the G2/M transition unless and until a collar of septin filaments has properly assembled at the bud neck, which is the site where subsequent cytokinesis will occur. An essential component of this checkpoint is the large (1518-residue) protein kinase Hsl1, which localizes to the bud neck only if the septin collar has been correctly formed. Hsl1 reportedly interacts with particular septins; however, the precise molecular determinants in Hsl1 responsible for its recruitment to this cellular location during G2 have not been elucidated. We performed a comprehensive mutational dissection and accompanying image analysis to identify the sequence elements within Hsl1 responsible for its localization to the septins at the bud neck. Unexpectedly, we found that this targeting is multipartite. A segment of the central region of Hsl1 (residues 611-950), composed of two tandem, semiredundant but distinct septin-associating elements, is necessary and sufficient for binding to septin filaments both in vitro and in vivo. However, in addition to 611-950, efficient localization of Hsl1 to the septin collar in the cell obligatorily requires generalized targeting to the cytosolic face of the plasma membrane, a function normally provided by the C-terminal phosphatidylserine-binding KA1 domain (residues 1379-1518) in Hsl1 but that can be replaced by other, heterologous phosphatidylserine-binding sequences.

The Carboxy-Terminal Tails of Septins Cdc11 and Shs1 Recruit Myosin-II Binding Factor Bni5 to the Bud Neck in Saccharomyces cerevisiae.

UNLABELLED: Septins are a conserved family of GTP-binding proteins that form heterooctameric complexes that assemble into higher-order structures. In yeast, septin superstructure at the bud neck serves as a barrier to separate a daughter cell from its mother and as a scaffold to recruit the proteins that execute cytokinesis. However, how septins recruit specific factors has not been well characterized. In the accompanying article in this issue, (Finnigan et al. 2015), we demonstrated that the C-terminal extensions (CTEs) of the alternative terminal subunits of septin heterooctamers, Cdc11 and Shs1, share a role required for optimal septin function in vivo. Here we describe our use of unbiased genetic approaches (both selection of dosage suppressors and analysis of synthetic interactions) that pinpointed Bni5 as a protein that interacts with the CTEs of Cdc11 and Shs1. Furthermore, we used three independent methods-construction of chimeric proteins, noncovalent tethering mediated by a GFP-targeted nanobody, and imaging by fluorescence microscopy-to confirm that a physiologically important function of the CTEs of Cdc11 and Shs1 is optimizing recruitment of Bni5 and thereby ensuring efficient localization at the bud neck of Myo1, the type II myosin of the actomyosin contractile ring.Related article in GENETICS: Finnigan, G. C. et al., 2015 Comprehensive Genetic Analysis of Paralogous Terminal Septin Subunits Shs1 and Cdc11 in Saccharomyces cerevisiae. Genetics 200: 841-861.