Panel 7 - Pathogenesis of otitis media - a review of the literature between 2015 and 2019.

OBJECTIVE: To perform a comprehensive review of the literature from July 2015 to June 2019 on the pathogenesis of otitis media. Bacteria, viruses and the role of the microbiome as well as the host response are discussed. Directions for future research are also suggested. DATA SOURCES: PubMed database of the National Library of Medicine. REVIEW METHODS: PubMed was searched for any papers pertaining to OM pathogenesis between July 2015 and June 2019. If in English, abstracts were assessed individually for their relevance and included in the report. Members of the panel drafted the report based on these searches and on new data presented at the 20th International Symposium on Recent Advances in Otitis Media. CONCLUSIONS: The main themes that arose in OM pathogenesis were around the need for symptomatic viral infections to develop disease. Different populations potentially having different mechanisms of pathogenesis. Novel bacterial otopathogens are emerging and need to be monitored. Animal models need to continue to be developed and used to understand disease pathogenesis. IMPLICATIONS FOR PRACTICE: The findings in the pathogenesis panel have several implications for both research and clinical practice. The most urgent areas appear to be to continue monitoring the emergence of novel otopathogens, and the need to develop prevention and preventative therapies that do not rely on antibiotics and protect against the development of the initial OM episode.

GFAP mutations, age at onset, and clinical subtypes in Alexander disease.

OBJECTIVE: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. METHODS: We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. RESULTS: LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. CONCLUSIONS: AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.

Involvement of a membrane-bound class III adenylate cyclase in regulation of anaerobic respiration in Shewanella oneidensis MR-1.

Unlike other bacteria that use FNR to regulate anaerobic respiration, Shewanella oneidensis MR-1 uses the cyclic AMP receptor protein (CRP) for this purpose. Three putative genes, cyaA, cyaB, and cyaC, predicted to encode class I, class IV, and class III adenylate cyclases, respectively, have been identified in the genome sequence of this bacterium. Functional validation through complementation of an Escherichia coli cya mutant confirmed that these genes encode proteins with adenylate cyclase activities. Chromosomal deletion of either cyaA or cyaB did not affect anaerobic respiration with fumarate, dimethyl sulfoxide (DMSO), or Fe(III), whereas deletion of cyaC caused deficiencies in respiration with DMSO and Fe(III) and, to a lesser extent, with fumarate. A phenotype similar to that of a crp mutant, which lacks the ability to grow anaerobically with DMSO, fumarate, and Fe(III), was obtained when both cyaA and cyaC were deleted. Microarray analysis of gene expression in the crp and cyaC mutants revealed the involvement of both genes in the regulation of key respiratory pathways, such as DMSO, fumarate, and Fe(III) reduction. Additionally, several genes associated with plasmid replication, flagellum biosynthesis, and electron transport were differentially expressed in the cyaC mutant but not in the crp mutant. Our results indicated that CyaC plays a major role in regulating anaerobic respiration and may contribute to additional signaling pathways independent of CRP.

Epidemiology of human blastomycosis in Vilas County, Wisconsin. II: 1991-1996.

PURPOSE: A previous report identified Vilas County, Wisconsin, as an area highly endemic for blastomycosis based on a case series 1979-90. This study was done to compare the epidemiologic features of persons with this disease over the following six years. METHODS: Compilation of data from the 47 mandatory physician/laboratory case reports of blastomycosis, disease onset 1991-96, received at the Vilas County Health Department; case mapping by site visit; and statistical comparison to the previous series. RESULTS: The estimated mean annual incidence rate for Vilas County during 1991-96, 40/100,000, remains unchanged from 1984-90. Cases were again disproportionately represented in the southeast corner of the county, and 36/46 lived within 1/4 mile of water. There was a trend toward a higher proportion of female cases in this study (27/47) compared to the prior report (28/73; P = 0.06); the mean age, 47 years, did not differ. Among 32 patients whose activities were recorded, a minority engaged in hunting (4), fishing (4) and gardening (12) prior to disease onset; but 19/32 recalled excavation prior to exposure compared to 17/60 in 1979-90 (P < 0.01). Among cases with a pulmonary presentation, winter onset cases (3/40) were significantly fewer than in 1979-90 (19/55). However, over the entire 18 years there was no disproportionately represented season. CONCLUSIONS: In highly endemic Vilas County, the mean annual incidence of human blastomycosis appears stable over the past 13 years. A combined case series of 18 years reveals no predilection by gender or season of onset.

Distribution of mucus and sperm in bovine oviducts after artificial insemination: the physical environment of the oviductal sperm reservoir.

There is a sperm reservoir in the caudal oviduct of cattle and other mammals. We had observed trapping of sperm by mucus produced by explants of bovine oviductal epithelium in vitro; therefore, we used techniques designed for preserving mucus and luminal dimensions to determine whether mucus is associated with the reservoir in vivo. Heifers were synchronized by prostaglandin injections and inseminated during estrus. Oviducts on the side of ovulation were surgically removed either 8-10 h after insemination (preovulatory) or 50-55 h after insemination (postovulatory). Segments (1 cm) taken from the uterotubal junction (UTJ), caudal 3 cm of isthmus, and mid ampulla were snap frozen. Frozen sections were coated with collodion and postfixed in phosphate-buffered formaldehyde containing cetyl-pyridinium chloride. Sections were alternately stained with periodic acid-Schiff stain (PAS) or alcian blue/PAS. Most of the oviductal lumen was highly branched with passages that measured only a few microns across and were filled with mucus. In limited areas, the lumen opened to 100 microm across and was only lightly stained for mucus. Overall, the lumen was much narrower than in sections prepared by standard fixation and paraffin embedding. Sperm were found scattered throughout the lumen of the UTJ and isthmus, in both the narrow, deeply stained luminal areas and the wider, lightly stained areas. The numbers tapered off cranially, especially prior to ovulation. In conclusion, the combination of narrow passages and mucus would appear to impede sperm progress, contributing to the creation of a reservoir.

Clinical and biomechanical measures of balance as fall predictors in ambulatory nursing home residents.

BACKGROUND: We evaluated the capacity of biomechanical and clinical measures of balance to predict future risk of recurrent falls in a cohort of frail, elderly ambulatory residents of 12 Tennessee community nursing homes. METHODS: Baseline measurements of balance and other potential fall risk factors were obtained in 303 ambulatory nursing home residents. Balance measures included biomechanics force platform measurements of postural sway (area ellipse and mean velocity) and clinical measures, which included functional reach, Tinetti balance subscale (adapted from Tinetti's Performance Oriented Mobility Index), timed chair stands, and 10-foot walk. Residents who fell two or more times during follow-up (mean of 11 months) were identified from nursing home incident reports and nursing notes. The predictive value of the balance measures was evaluated by the incidence density ratio (IDR) estimated from proportional hazards models. RESULTS: There were 118 recurrent fallers (54.2 per 100 person-years). Rates of recurrent falls increased with increasing quintiles of both the biomechanical and clinical measures of balance, with unadjusted IDRs (95% CI) per quintile change of 1.22 (1.07-1.39) for area ellipse, 1.12 (0.98-1.27) for mean velocity of postural sway, 1.29 (1.13-1.47) for the Tinetti balance subscale, 1.24 (1.08-1.41) for timed walk, 1.24 (1.09-1.42) for timed chair stands, and 1.12 (0.98-1.28) for functional reach. Controlling for age, gender, height, and weight did not materially affect the linear relationship between the balance measure quintiles and subsequent recurrent falls. However, after controlling for additional fall risk factors, only area ellipse of postural sway and the Tinetti balance subscale remained independently predictive of subsequent recurrent fall rates, with IDRs of 1.16 (1.02-1.36) and 1.17 (1.01-1.34), respectively. In an analysis where subjects were stratified by tertiles of each of these two measures, each measure appeared to independently predict future rates of recurrent falls. The independent predictive capacity of each measure persisted after controlling for other fall risk factors in a multivariate analysis with IDRs of 1.15 (1.00-1.32) for area ellipse and 1.15 (1.00-1.32) for the Tinetti balance subscale. Inclusion of both balance measures in a model with other fall risk factors to evaluate their relationship did not materially alter IDR point estimates of these risk factors. CONCLUSIONS: In this cohort of frail, nursing home residents, both area ellipse of postural sway and the Tinetti balance subscale independently predicted risk of future recurrent falls. However, the predictive value of other independent fall risk factors on risk of future recurrent falls persisted and was not explained by these two measures. Thus, assessment of patient fall risk based on surrogate endpoints, for either research or clinical practice, may need to include multiple measurements.

Injurious falls in nonambulatory nursing home residents: a comparative study of circumstances, incidence, and risk factors.

OBJECTIVE: To determine the circumstances of, incidence of, and risk factors for falls resulting in serious injuries in nonambulatory nursing home residents compared with those for ambulatory residents. DESIGN: Prospective cohort study with 1-year follow-up. SETTING: Twelve community nursing homes in Tennessee. SUBJECTS: A total of 1228 residents, 65 years of age or older, of whom 725 (59%) were nonambulatory and 503 (41%) were ambulatory. MEASUREMENTS: Baseline data were obtained for potential risk factors for injurious falls. These included demographic characteristics, mental and physical function, vision, hearing, incontinence, and use of mechanical restraints and psychotropic drugs. Data were obtained from direct resident assessment, care provider interview, and the nursing home Minimum Data Set (MDS) (validated in a sample of residents). OUTCOME: There were 111 first falls resulting in serious injury (head injury with altered consciousness, fracture, joint dislocation or sprain, or sutured laceration) that received medical treatment (hospitalization, emergency room visit, physician visit, or on-site radiological examination), ascertained from facility incident reports and nursing home charts. RESULTS: Nonambulatory residents had a substantially greater prevalence of mental and physical impairment. Circumstances of injurious falls in nonambulatory (n = 39 falls) and ambulatory (n = 72 falls) residents differed; those in the former groups were more likely to involve equipment (87% vs 45%, P < .0001), occur while seated or during transferring (82% vs 21%, P < .0001), and from a chair/bed level (54% vs 6%, P < .0001). The incidence of injurious falls in nonambulatory residents (6.7 per 100 person-years) was less than half that in ambulatory residents (17.0 per 100 person-years, P < .0001). After controlling for other factors, the nonambulatory residents at highest risk were those not bed-bound and with capacity for independent transfer (incidence density ratio (IDR) = 2.02, 95% CI = 1.07-7.99); the ambulatory residents at highest risk were baseline users of psychotropic drugs (IDR = 2.49, 95% CI = 1.43-4.33). CONCLUSIONS: In the study cohort, nonambulatory residents had 35% of injurious falls. Because the circumstances and risk factors of these events were substantially different from those for ambulatory residents, separate prevention strategies may be needed for this group. These data suggest that increasing the safety of transferring and of equipment are appropriate targets for interventions.