Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants.

BACKGROUND: Otitis media (OM) susceptibility has significant heritability; however, the role of rare variants in OM is mostly unknown. Our goal is to identify novel rare variants that confer OM susceptibility. METHODS: We performed exome and Sanger sequencing of >1000 DNA samples from 551 multiethnic families with OM and unrelated individuals, RNA-sequencing and microbiome sequencing and analyses of swabs from the outer ear, middle ear, nasopharynx and oral cavity. We also examined protein localisation and gene expression in infected and healthy middle ear tissues. RESULTS: A large, intermarried pedigree that includes 81 OM-affected and 53 unaffected individuals cosegregates two known rare A2ML1 variants, a common FUT2 variant and a rare, novel pathogenic variant c.1682A>G (p.Glu561Gly) within SPINK5 (LOD=4.09). Carriage of the SPINK5 missense variant resulted in increased relative abundance of Microbacteriaceae in the middle ear, along with occurrence of Microbacteriaceae in the outer ear and oral cavity but not the nasopharynx. Eight additional novel SPINK5 variants were identified in 12 families and individuals with OM. A role for SPINK5 in OM susceptibility is further supported by lower RNA counts in variant carriers, strong SPINK5 localisation in outer ear skin, faint localisation to middle ear mucosa and eardrum and increased SPINK5 expression in human cholesteatoma. CONCLUSION: SPINK5 variants confer susceptibility to non-syndromic OM. These variants potentially contribute to middle ear pathology through breakdown of mucosal and epithelial barriers, immunodeficiency such as poor vaccination response, alteration of head and neck microbiota and facilitation of entry of opportunistic pathogens into the middle ear.

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154∗) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202∗) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10-5) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154∗) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10-7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154∗, and p.Arg202∗-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

Evaluation of an outreach programme for patients with COVID-19 in an integrated healthcare delivery system: a retrospective cohort study.

OBJECTIVES: In the first year of the COVID-19 pandemic, health systems implemented programmes to manage outpatients with COVID-19. The goal was to expedite patients' referral to acute care and prevent overcrowding of medical centres. We sought to evaluate the impact of such a programme, the COVID-19 Home Care Team (CHCT) programme. DESIGN: Retrospective cohort. SETTING: Kaiser Permanente Northern California. PARTICIPANTS: Adult members before COVID-19 vaccine availability (1 February 2020-31 January 2021) with positive SARS-CoV-2 tests. INTERVENTION: Virtual programme to track and treat patients with 'CHCT programme'. OUTCOMES: The outcomes were (1) COVID-19-related emergency department visit, (2) COVID-19-related hospitalisation and (3) inpatient mortality or 30-day hospice referral. MEASURES: We estimated the average effect comparing patients who were and were not treated by CHCT. We estimated propensity scores using an ensemble super learner (random forest, XGBoost, generalised additive model and multivariate adaptive regression splines) and augmented inverse probability weighting. RESULTS: There were 98 585 patients with COVID-19. The majority were followed by CHCT (n=80 067, 81.2%). Patients followed by CHCT were older (mean age 43.9 vs 41.6 years, p<0.001) and more comorbid with COmorbidity Point Score, V.2, score ≥65 (1.7% vs 1.1%, p<0.001). Unadjusted analyses showed more COVID-19-related emergency department visits (9.5% vs 8.5%, p<0.001) and hospitalisations (3.9% vs 3.2%, p<0.001) in patients followed by CHCT but lower inpatient death or 30-day hospice referral (0.3% vs 0.5%, p<0.001). After weighting, there were higher rates of COVID-19-related emergency department visits (estimated intervention effect -0.8%, 95% CI -1.4% to -0.3%) and hospitalisation (-0.5%, 95% CI -0.9% to -0.1%) but lower inpatient mortality or 30-day hospice referral (-0.5%, 95% CI -0.7% to -0.3%) in patients followed by CHCT. CONCLUSIONS: Despite CHCT following older patients with higher comorbidity burden, there appeared to be a protective effect. Patients followed by CHCT were more likely to present to acute care and less likely to die inpatient.

Intravenous Opioid Administration During Mechanical Ventilation and Use After Hospital Discharge.

Importance: Guidelines recommend an analgesia-first strategy for sedation during mechanical ventilation, but associations between opioids provided during mechanical ventilation and posthospitalization opioid-related outcomes are unclear. Objective: To evaluate associations between an intravenous opioid dose received during mechanical ventilation and postdischarge opioid-related outcomes in medical (nonsurgical) patients. Design, Setting, and Participants: This retrospective cohort study evaluated adults receiving mechanical ventilation lasting 24 hours or more for acute respiratory failure and surviving hospitalization. Participants from 21 Kaiser Permanente Northern California hospitals from January 1, 2012, to December 31, 2019, were included. Data were analyzed from October 1, 2020, to October 31, 2023. Exposures: Terciles of median daily intravenous fentanyl equivalents during mechanical ventilation. Main Outcomes and Measures: The primary outcome was the first filled opioid prescription in 1 year after discharge. Secondary outcomes included persistent opioid use and opioid-associated complications. Secondary analyses tested for interaction between opioid doses during mechanical ventilation, prior opioid use, and posthospitalization opioid use. Estimates were based on multivariable-adjusted time-to-event analyses, with death as a competing risk, and censored for hospice or palliative care referral, rehospitalization with receipt of opioid, or loss of Kaiser Permanente plan membership. Results: The study included 6746 patients across 21 hospitals (median age, 67 years [IQR, 57-76 years]; 53.0% male). Of the participants, 3114 (46.2%) filled an opioid prescription in the year prior to admission. The median daily fentanyl equivalent during mechanical ventilation was 200 µg (IQR, 40-1000 µg), with terciles of 0 to 67 µg, more than 67 to 700 µg, and more than 700 µg. Compared with patients who did not receive opioids during mechanical ventilation (n = 1013), a higher daily opioid dose was associated with opioid prescriptions in the year after discharge (n = 2942 outcomes; tercile 1: adjusted hazard ratio [AHR], 1.00 [95% CI, 0.85-1.17], tercile 2: AHR, 1.20 [95% CI, 1.03-1.40], and tercile 3: AHR, 1.25 [95% CI, 1.07-1.47]). Higher doses of opioids during mechanical ventilation were also associated with persistent opioid use after hospitalization (n = 1410 outcomes; tercile 3 vs no opioids: odds ratio, 1.44 [95% CI, 1.14-1.83]). No interaction was observed between opioid dose during mechanical ventilation, prior opioid use, and posthospitalization opioid use. Conclusions and Relevance: In this retrospective cohort study of patients receiving mechanical ventilation, opioids administered during mechanical ventilation were associated with opioid prescriptions following hospital discharge. Additional studies to evaluate risks and benefits of strategies using lower opioid doses are warranted.

Characterization and Genome Sequence of Arthrobacter Phage Iter.

Arthrobacter phage Iter was isolated in North Georgia. Its genome is 43,963 bp with 70 open reading frames (ORFs) and a GC content of 67.4%. It shares 89.11% nucleotide identity with Arthrobacter phage Phives. Actinobacteriophages that share over 50% nucleotide identity are sorted into clusters, with Iter in cluster AZ.

Evaluation of newborn screening bloodspot-based genetic testing as second tier screen for bedside newborn hearing screening.

PURPOSE: : Bedside newborn hearing screening is highly successful in identifying deaf or hard-of-hearing infants. However, newborn hearing screening protocols have high loss to follow-up rates. We propose that bloodspot-based genetic testing for GJB2 alleles can provide a means for rapid confirmation in a subset of infants who fail bedside newborn hearing screening. METHODS: : We performed a case-control study comparing the prevalence of common GJB2 mutations from deidentified bloodspots designated as "refer" by newborn hearing screening and contemporaneously selected randomly chosen controls designated as "pass." Between March 2006 and December 2007, 2354 spots were analyzed for common alleles, c.35delG, c.167delT, c.235delC, and p.V37I in GJB2 with a subset reanalyzed by conventional Sanger sequencing to search for additional alleles. RESULTS: : The prevalence of biallelic GJB2 mutations in bloodspots from infants who referred by newborn hearing screening is approximately 1 in 50 (23/1177). In contrast, one bloodspot from an infant who passed newborn hearing screening was identified to harbor biallelic GJB2 mutations. CONCLUSIONS: : These findings show that when a newborn refers by newborn hearing screening, there is a significant chance that GJB2-related hearing loss is present. Bloodspot-based genetic testing for common GJB2 alleles should be considered as second tier testing for bedside newborn hearing screening.

Significant linkage at chromosome 19q for otitis media with effusion and/or recurrent otitis media (COME/ROM).

BACKGROUND: In previous analyses, we identified a region of chromosome 19 as harboring a susceptibility locus for chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our aim was to further localize the linkage signal and ultimately identify the causative variant or variants. We followed up our previous linkage scan with dense SNP genotyping across in a 5 Mb region. A total of 607 individuals from 139 families, including 159 affected sib pairs and 62 second-degree affected relative pairs, were genotyped at 1,091 SNPs. We carried out a nonparametric linkage analysis, modeling marker-to-marker linkage disequilibrium. RESULTS: The maximum log of the odds (LOD) score increased to 3.75 (P = 1.6 × 10(-5)) at position 63.4 Mb, with a LOD-1 support interval between 61.6 Mb and 63.8 Mb, providing significant evidence of linkage between this region and COME/ROM. The support interval contains over 90 known genes, including several genes involved in the inflammasome protein complex, a key regulator of the innate immune response to harmful exogenous or endogenous stimuli. Parametric linkage analysis suggests that for a sib of an affected individual, the recurrence risk of COME/ROM due to this linkage region is twice the recurrence risk in the population. We examined potential associations between the SNPs genotyped in this region and COME/ROM, however none provided evidence for association. CONCLUSION: This study has refined the 19q region of linkage with COME/ROM, and association results suggest that the linkage signal may be due to rare variants.

Multi-omic studies on missense PLG variants in families with otitis media.

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

American Indian breastfeeding attitudes and practices in Minnesota.

OBJECTIVES: We examined the breastfeeding attitudes and practices in an American Indian population in Minnesota. METHODS: We interviewed women prenatally (n = 380), at 2-weeks (n = 342) and at 6-months postpartum (n = 256). We conducted multivariable analyses to examine the demographic, behavioral, and attitudinal correlates of breastfeeding initiation and duration. RESULTS: Factors positively associated with breastfeeding initiation included positive breastfeeding attitudes and social support for breastfeeding from the woman's husband/boyfriend and her mother. Factors positively associated with breastfeeding at 2-weeks postpartum were support from the woman's mother and positive attitudes about breastfeeding. The prenatal use of traditional American Indian medicines and cigarette smoking were both significantly associated with breastfeeding at 6-months postpartum. CONCLUSIONS: Programs to encourage breastfeeding in American Indian communities may be strengthened with protocols to encourage social support, recognition of the perceived health, developmental, and practical benefits of breastfeeding, and a focus on traditional American Indian health practices.

Presence of otitis media with effusion and its risk factors affect serum cytokine profile in children.

UNLABELLED: Otitis media with effusion (OME) is a condition that has significant impact on the quality of life of children. Although the etiology is multi-factorial, certain risk factors such as an allergic predisposition, daycare, and cigarette smoke exposure contribute to its pathogenesis. OBJECTIVE: (1) To determine whether there is a tendency for children with chronic or recurrent OME (cases) to have higher serum levels of the T-helper 2 cell (Th-2) allergenic-type cytokines, interleukin-4 (IL-4), and IL-5, or the T-helper 1(Th-1) infectious-type cytokines, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha), compared to children without a history of recurrent OME (controls) and (2) to determine any possible correlations between the cytokine levels and risk factors associated with OME. METHODS: We analyzed serum levels of these four cytokines by enzyme-linked immunosorbent assays of 19 cases and 17 controls. RESULTS: Cases, independent of age, had increased levels of serum IL-5 compared to controls (p=0.014). While a significant difference in serum IL-4 levels did not exist between cases and controls, children exposed to cigarette smoke had significantly higher levels of serum IL-4 (p=0.003). While serum levels of IFN-gamma were statistically significantly higher in cases than controls with univariate analysis (p=0.011), when controlling for age and smoke exposure with multivariate analyses, the difference did not reach significance (p=0.086). CONCLUSION: These results suggest that patients with chronic or recurrent OME and those exposed to cigarette smoke mount a Th-2 allergic-like response, as demonstrated by their serum cytokines.

Trends in Outpatient Visits and Hospital and Intensive Care Unit Admissions of Adults With COVID-19 in an Integrated US Health Care System, March 2020 to January 2022.

This cohort study of patients at a single integrated health system examines trends in COVID-19­related treatment location and mortality.

Early otitis media among Minnesota American Indians: the Little Ears Study.

OBJECTIVES: We examined relationships between otitis media risk factors, sociodemographic characteristics, and maternal knowledge and attitudes and early onset of otitis media. METHODS: Pregnant women from Minnesota American Indian reservations and an urban clinic were enrolled in our study between 1998 and 2001. Follow-up was performed on enrollees' infants until the children were 2 years old. Research nurses collected data by ear examination, from interviews and questionnaires given to enrolled mothers, and otitis media episodes that were abstracted from medical records. RESULTS: Sixty-three percent of infants had experienced an otitis media episode by 6 months of age. Logistic regression analyses showed that maternal otitis media history, infant history of upper respiratory infection, and compliance with study visits were significantly related to early otitis media onset. Although high percentages of infants were exposed to cigarette smoke and other children and were formula fed, these factors were not related to otitis media. Mothers' prenatal awareness of otitis media risks associated with environmental tobacco smoke exposure and formula feeding did not predict their postpartum behaviors. CONCLUSIONS: We found that infant history of upper respiratory infection and maternal otitis media history are risk factors for early otitis media in American Indian infants. Mothers' prepartum knowledge and attitudes regarding otitis media did not predict their postpartum avoidance of risk behaviors.

Hearing screening and middle ear measures in American Indian infants and toddlers.

UNLABELLED: American Indian children have three times the rate of otitis media compared to the general population, yet prospective cohort studies of OME and hearing loss have not been previously reported in American Indian infants. Between 1997 and 2003, a cohort of 421 infants was enrolled at birth from Minnesota American Indian reservations and an urban clinic and followed to age 2 years. This study reports OAE hearing screening results related to OME diagnoses, as well as risk for recurrent hearing screening failure and OME in American Indian infants and children. METHODS: Infants were prospectively assessed at regular intervals with pneumatic otoscopy, distortion product otoacoustic emissions, and tympanometry by nurses who were trained in all procedures and validated on pneumatic otoscopy. RESULTS: In the newborn period, 23.5% of infants failed hearing screening in at least one ear. Hearing screening failures increased to 29.9% from 2 to 5 months of age. Technical fail results due to excessive noise occurred frequently in infants 6-24 months of age, making interpretation of true pass and fail rates questionable in older infants. OAE test result was associated with OM diagnosis, and this relationship strengthened with age, with the strongest association above 6 months of age. CONCLUSIONS: A high rate of hearing screening failures occurred among American Indian infants in the first 5 months of age, and was significantly associated with a correspondingly high rate of otitis media. Only one infant out of 366 was identified with sensorineural hearing loss, thus essentially all of the hearing screening failures reflected either a middle ear origin or other temporary problems. OAE screening provided a valuable hearing screening measure in this population at high risk for recurrent otitis media, but due to excessive noise in infants 6 months and older, practical use of OAE screening is limited. Use of behavioral assessment is needed after 6 months of age, when high rates of OME persist in this population. Increased efforts to develop public and medical education, as well as screening, diagnosis and treatment programs are needed to detect and decrease recurrent OME in American Indian infants and children.

Safety and tolerability of serial home infusions of nesiritide for advanced heart failure.

Although the therapeutic strategy of serial 6-hour intravenous infusions of nesiritide for advanced chronic heart failure (HF) is currently under investigation, frequent hospital or clinic visits may present logistical challenges for many patients with HF. Therefore, a pilot study was conducted to evaluate the safety and tolerability of serial nesiritide infusions administered at home in this patient population. Twenty patients with advanced HF were enrolled into a protocol for the administration of 12 weekly intravenous infusions of nesiritide (2 microg/kg bolus, 0.01 microg/kg/min for 6 hours) at home. Blood samples and weights were obtained weekly, and clinical assessments were made at 4 and 12 weeks. During the 12-week study period, there were 3 deaths unrelated to nesiritide therapy. Six patients required >or=1 hospitalization for HF. Two of 204 infusions resulted in symptomatic hypotension, and there were no adverse renal events. Mean body weight decreased at week 4 but returned to baseline by week 12. Antibodies to nesiritide were not detected in any patient. In conclusion, serial home infusions of nesiritide in patients with advanced HF appear to be safe and well tolerated, but the efficacy of this therapeutic strategy requires definition in a larger, randomized trial.

Predictors for resident success in otolaryngology.

BACKGROUND: This study aimed to determine predictors for otolaryngology resident success using data available at the time candidates are interviewed (eg, medical school attended, letters of recommendation, test scores) and data that emerge during residency. STUDY DESIGN: We performed a retrospective cohort study of 36 residents who entered our program between 1983 and 1993. RESULTS: Seventy percent of Alpha Omega Alpha (AOA) members and 13% of nonmembers were in the highest tertile based on faculty ranking (p<0.01), and candidates with an exceptional trait were more likely than those without an exceptional trait to rank in the highest tertile (57% versus 10%, p<0.01). AOA membership was also related to current academic appointment (p=0.02). Significant correlations included United States Medical Licensing Examination (USMLE) I score, year 2 in-training score (0.48, p=0.03), and years 3 and 4 in-training score and faculty ranking (minus 0.39, minus 0.50, respectively, p50% of the interviewers (p<0.05 for both). CONCLUSIONS: In our program designed to train academic otolaryngologists, postresident success was strongly predicted by having an exceptional trait and AOA membership. Success during residency was predicted by interviewer's impression of the candidate and a USMLE I score>570. Knowledge of these factors at the time of the resident interview could increase the likelihood of selecting the most appropriate candidates for academic otolaryngology. Resident success is a complex outcome, and other unmeasured and unexamined characteristics can provide additional insight into choosing successful residents.

Association of the FBXO11 gene with chronic otitis media with effusion and recurrent otitis media: the Minnesota COME/ROM Family Study.

OBJECTIVE: The FBXO11 gene is the human homologue of the gene mutated in the novel deaf mouse mutant jeff (Jf), a single gene model of otitis media. We have evaluated single nucleotide polymorphisms (SNPs) in the FBXO11 gene for association with chronic otitis media with effusion/recurrent otitis media (COME/ROM). DESIGN: A total of 13 SNPs were genotyped across the 98.7 kilobases of genomic DNA encompassing FBXO11. Data were analyzed for single SNP association using generalized estimating equations, and haplotypes were evaluated using Pedigree Disequilibrium Test methods. PATIENTS: The Minnesota COME/ROM Family Study, a group of 142 families (619 subjects) with multiple affected individuals with COME/ROM. MAIN OUTCOME MEASURES: Genetic association of COME/ROM with polymorphisms in FBXO11. RESULTS: The FBXO11 SNPs are contained in a single linkage disequilibrium haplotype block. Ten of the 13 SNPs were sufficiently polymorphic in the sample to permit analysis. In univariate genetic analysis, 1 reference SNP (hereinafter rs) (rs2134056) showed nominal evidence of association to COME/ROM (P = .02), and 2 SNPs approached significance (rs2020911, P = .06; rs3136367, P = .09). In multivariable analyses, including known risk factors for COME/ROM (sex, exposure to smoking, attending day care centers, no prior breastfeeding, and having allergies), the evidence of independent association was reduced for each SNP (eg, rs2134056, from P = .02 to P = .08). In subsequent analyses using the Pedigree Disequilibrium Test, the association of FBXO11 SNP rs2134056 (P = .06) with COME/ROM was confirmed. Incorporating multiple SNPs in 2- and 3-locus SNP haplotypes, those haplotypes containing rs2134056 also exhibited evidence of association of FBXO11 and COME/ROM (P values ranging from .03 to .10). CONCLUSION: We have observed evidence consistent with an association between polymorphisms in FBXO11, the human homologue of the Jeff mouse model gene, and COME/ROM.

Tympanometry of a diverse group of preschool aged children.

OBJECTIVE: Ethnicity has been previously described as a risk factor for middle ear disease. Little data exist on the presence of middle ear disease based on tympanometry screening comparing Asian children and children of other races. METHODS: Two hundred and seventy children aged 3-5 were screened with tympanometry at six Head Start sites in St. Paul, Minnesota during the months of September and October of 2004. Gender, age, and race/ethnicity was recorded and entered into a database, along with values for canal volume, static admittance, peak pressure, and tympanometric width. RESULTS: Criteria for abnormal tympanometry were based on American Speech-Language Hearing Association (ASHA) recommendations for a failed tympanogram for 1-5 year olds (admittance <0.3 mmho or width >200 daPa). There were no statistically significant differences in failure rates between males and females. There were, however, more failures for Asian (predominantly Hmong) children compared to children of other races/ethnicities after adjusting for age and gender differences (OR=6.39, CI 3.65-11.2, p<0.001) and for children <4-years-old compared to children 4-5-years-old after adjusting for race and gender differences (OR=1.99, CI 1.03-3.84, p<0.05). CONCLUSIONS: Asian children were more than six times as likely to fail tympanometry as children of other races/ethnicities. The explanation for this difference is likely to be multifactorial, and further research is needed to characterize this difference.

Rare A2ML1 variants confer susceptibility to otitis media.

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

Quantitative EEG Correlates of Outcome in Older Psychiatric Patients: Part II: Two-Year Follow-Up of Patients With Depression.

The authors examined quantitative electroencephalographc (QEEG) coherence in 37 depressed elderly patients and performed 2-year follow-up evaluations. All subjects had equivocal cognitive impairment, but none had delirium or dementia. More than 40% (16/37) recovered from depression, and 38% (14/37) remained well for 2 years. Twenty-four percent (n = 9) had died within 2 years, most from cardiac causes. Low trans-Rolandic coherence from the left hemisphere was strongly associated with mortality: 44% (7/16) of those with low coherence died, and 78% (7/9) of those who died had low coherence. Among survivors (n = 28) at follow-up, low coherence was significantly associated with lower functional status. These findings suggest that the coherence variable measures actual neurophysiology differences between groups of depressed patients and these differences are associated with the heterogeneous outcomes of depression in elderly patients.

Quantitative EEG Correlates of Outcome in Older Psychiatric Patients: Part I: Cross-Sectional and Longitudinal Assessment of Patients With Dementia.

Using quantitative electroencephalographic coherence (a measure of synchronized electrical activity between brain regions) the authors examined heterogeneity in clinical presentation and outcome inpatients with dementia. Patients (N = 114) with mild-to-moderate dementia of the Alzheimer's type (DAT) or multi-infarct dementia (MID) were examined for coherence from the left hemisphere. More than 70% diagnostic accuracy in distinguishing between DAT and MID subjects was achieved using coherence measures alone. Also, decreased coherence measured across the Rolandic fissure in the left hemisphere was significantly associated with poorer functional status of subjects at 2-year follow-up, despite similar levels of cognitive impairment at baseline. These findings suggest that coherence is a useful measure for assessment and for prediction of the course of illness inpatients with dementia.