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.

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.

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.

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.

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.

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.

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.

Maternal immunization with pneumococcal 9-valent conjugate vaccine and early infant otitis media.

A randomized trial of an investigational 9-valent pneumococcal conjugate vaccine (PCV-9) or placebo given to pregnant women during the last trimester to prevent early infant otitis media (OM) was conducted. All infants received Prevnar(®) at 2, 4, 6, and 12 months. Clinic and adverse event records were reviewed to identify OM. Variables significantly related to acute OM by age 6 months (p<0.05) were: vaccine group (9 valent or placebo), sibling history of tympanostomy tubes, upper respiratory infection, and number of clinic visits by 6 months. Infant OM rates were similar between 6 and 12 months (58% and 56%). Results suggested that immunizing pregnant women with PCV-9 increased infants' risk of acute OM in the first 6 months of life, and this correlated with decreased infant antibody responses to their infant Streptococcus pneumoniae vaccine serotypes, but did not influence antibody responses to 3 other serotypes two of which were in maternal vaccine (types 1 and 5) and one was a control (type 7F). Explanations for these results include dampening of infant antibody production by high levels of passively acquired maternal pneumococcal antibodies and/or altered B lymphocyte immune responses in infants exposed to these specific polysaccharide antigens in utero.

Evaluation of replication of variants associated with genetic risk of otitis media.

The first Genome Wide Association Study (GWAS) of otitis media (OM) found evidence of association in the Western Australian Pregnancy Cohort (Raine) study, but lacked replication in an independent OM population. The aim of this study was to investigate association at these loci in our family-based sample of chronic otitis media with effusion and recurrent otitis media (COME/ROM). Autosomal SNPs were selected from the Raine OM GWAS results. SNPs from the Raine cohort GWAS genotyped in our GWAS of COME/ROM had P-values ranging from P = 0.06-0.80. After removal of SNPs previously genotyped in our GWAS of COME/ROM (N = 21) and those that failed Fluidigm assay design (N = 1), 26 SNPs were successfully genotyped in 716 individuals from our COME/ROM family population. None of the SNP associations replicated in our family-based population (unadjusted P = 0.03-0.93). Replication in an independent sample would confirm that these represent novel OM loci, and that further investigation is warranted.

A genome-wide association study of chronic otitis media with effusion and recurrent otitis media identifies a novel susceptibility locus on chromosome 2.

Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with P < 10(-4) and 12 imputed SNPs with P < 10(-4) on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P = 1.30 × 10(-5)) on chromosome 2 in the independent otitis media population (P = 4.7 × 10(-5); meta-analysis P = 1.52 × 10(-8)). Three additional SNPs had replication P values < 0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P = 3.4 ×10(-7)) in KIF7 intron 7 (P = 0.072), and rs10775247, a non-synonymous SNP in TICRR exon 2 (P = 0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P = 0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.

Experiencing community: perspectives of individuals diagnosed as having serious mental illness.

OBJECTIVE: Community integration is recognized as a crucial component of recovery from serious mental illness. Although the construct of community integration can be measured with structured instruments, little is known about the subjective and experiential meaning of community and community involvement for persons with serious mental illness. METHODS: In 2010, 30 individuals with serious mental illness treated in two public mental health clinics completed semistructured interviews that elicited the places and people that they associate with the experience of community and the larger meaning of community in their lives. RESULTS: Participants described four experiences as integral to their concepts of community: receiving help, minimizing risk, avoiding stigma, and giving back. Participants looked for communities that provide reliable support, and they described the need to manage community contact in order to protect themselves and others from their symptoms and from discrimination. Most participants experienced communities centered on mental health treatment or mentally ill peers as providing opportunities for positive engagement. CONCLUSIONS: The experience of having a serious mental illness shapes preferences for and perceptions of community in pervasive ways. Participants described community involvement not as a means to move away from illness experiences and identities but as a process that is substantially influenced by them. Mental health communities may help individuals with serious mental illness to both manage their illness and recognize and enjoy a sense of community. The findings indicate the need for further research on the relationship between community integration and outcome in serious mental illness.

Panel 1: Epidemiology, natural history, and risk factors.

BACKGROUND: The First International Symposium on Recent Advances in Otitis Media (OM) with Effusion was held in Columbus, Ohio, in 1975. The symposium has been organized in the United States every 4 years since, followed by a research conference to (a) assess major research accomplishments, (b) identify important research questions and opportunities, (c) develop consensus on definitions and terminology, and (d) establish priorities with short- and long-term research goals. One of the principal areas reviewed quadrennially is Epidemiology, Natural History, and Risk Factors. OBJECTIVE: To provide a review of recent literature on the epidemiology, natural history, and risk factors for OM. DATA SOURCES AND REVIEW METHODS: A search of OM articles in English published July 2007 to June 2011 was conducted using PubMed and related databases. Those with findings judged of importance for epidemiology, public health, and/or statistical methods were reviewed. RESULTS: The literature has continued to expand, increasing understanding of the worldwide burden of OM in childhood, complications from treatment failures, and comorbidities. Novel risk factors, including genetic factors, have been examined for OM susceptibility. Population-based studies in Canada, the United States, and other countries confirmed reductions in OM prevalence. Although most studies concentrated on acute OM (AOM) or OM with effusion (OME), a few examined severe chronic suppurative OM (CSOM), a major public health problem in developing countries and for certain indigenous populations around the world. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Recent publications have reinforced earlier epidemiological findings, while extending our knowledge in human population groups with high burden of OM.

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.

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.

Evaluation of 15 functional candidate genes for association with chronic otitis media with effusion and/or recurrent otitis media (COME/ROM).

DNA sequence variants in genes involved in the innate immune response and secondary response to infection may confer susceptibility to chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). We evaluated single nucleotide polymorphisms (SNPs) in 15 functional candidate genes. A total of 99 SNPs were successfully genotyped on the Sequenom platform in 142 families (618 subjects) from the Minnesota COME/ROM Family Study. Data were analyzed for association with COME/ROM using the Generalized Disequilibrium Test (GDT). Sex and age at exam were adjusted as covariates, relatedness was accounted for, and genotype differences from all phenotypically discordant relative pairs were utilized to measure the evidence of association between COME/ROM and each SNP. SNP rs2735733 in the region of the mucin 5, subtypes A/C gene (MUC5AC) exhibited nominal evidence for association with COME/ROM (P = 0.002). Two additional SNPs from this region had P values<0.05. Other variants exhibiting associations with COME/ROM at P<0.05 included the SCN1B SNP rs8100085 (P = 0.013), SFTPD SNP rs1051246 (P = 0.039) and TLR4 SNP rs2770146 (P = 0.038). However, none of these associations replicated in an independent sample of COME/ROM families. The candidate gene variants examined do not appear to make a major contribution to COME/ROM susceptibility, despite a priori evidence from functional or animal model studies for a role in COME/ROM pathology.

Epidemiology, natural history, and risk factors: panel report from the Ninth International Research Conference on Otitis Media.

The 2007 Recent Advances in Otitis Media Research Conference Panel Report provides an update on otitis media (OM) research published from 2003 to 2007. This report summarizes important trends in disease incidence and prevalence, describes established and newly identified risk factors for acute and chronic OM and OM with effusion, and conveys information on newly discovered genetic factors. In this report, researchers have described declining rates of OM diagnosis, antibiotic prescriptions, offices visits for OM, and middle ear surgery since the licensure and routine use of pneumococcal conjugate vaccine in infants. The panel report also recommends short and long term goals for current and future OM research.

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.

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.