Three-dimensional simulations of six treatment maneuvers for horizontal canal benign paroxysmal positional vertigo canalithiasis.

BACKGROUND AND PURPOSE: Horizontal canal benign paroxysmal positional vertigo (BPPV) is the second most common variant of BPPV after posterior canal BPPV. Various liberatory maneuvers are recommended for the treatment of horizontal canal BPPV canalithiasis (hc-BPPV-ca). The aim of this study was to show how three-dimensional (3D) dynamic simulation models visualize the movement of the clot of otoconia within the canal for a better understanding of the theoretical efficacy. METHODS: Based on reconstructed magnetic resonance imaging and fluid dynamics, a 3D dynamic simulation model (as a function of time) was developed and applied. Thereby, six treatment maneuvers for hc-BPPV-ca were simulated: two types of the roll maneuver (the original 270° and the modified 360°) as well as two Gufoni and Zuma maneuvers (for geotropic and apogeotropic nystagmus). RESULTS: The simulations showed that the 360° roll maneuver and Zuma maneuver are effective treatment options for hc-BPPV-ca for debris in all locations within the canal. However, the original 270° roll maneuver will not be effective if the clot is in the ampullary arm of the horizontal canal. The Gufoni maneuver for geotropic hc-BPPV-ca is effective, whereas for apogeotropic hc-BPPV-ca there is a risk of treatment failure due to insufficient repositioning of the debris. CONCLUSIONS: The 3D simulations for movement of the otoconia clots can be used to test the mechanism of action and the theoretical efficacy of existing maneuvers for the different BPPV variants. For hc-BPPV-ca, the modified 360° roll maneuver and Zuma maneuver are theoretically efficient for all subtypes, whereas Gufoni maneuver is effective for geotropic nystagmus only.

Extended spectrum ß-lactamase producing uropathogenic Escherichia coli and the correlation of biofilm with antibiotics resistance in Nepal.

BACKGROUND: Urinary tract infection (UTI) is one of the frequently diagnosed infectious diseases which is caused mainly by Escherichia coli. E. coli confers resistance against the two major classes of antibiotics due to the production of extended spectrum ß-lactamase enzymes (ESBL), biofilm, etc. Biofilm produced by uropathogenic E. coli (UPEC) protects from host immune system and prevent entry of antimicrobial compounds. The main objective of this cross-sectional study was to determine the correlation of biofilm production and antibiotic resistance as well as to characterize the pgaA and pgaC genes responsible for biofilm formation among uropathogenic ESBL producing E. coli. METHODS: A total of 1977 mid-stream urine samples were examined and cultured for bacterial strain identification. ESBL was detected by combined disc method following CLSI whereas biofilm formation was analyzed by semi-quantitative method. Furthermore, the pgaA and pgaC genes responsible for biofilm formation in UPEC were detected by multiplex PCR. All the statistical analyses were done via IBM SPSS Statistics 21 where Pearson's correlation test were used to determine correlation (-1 ≥ r ≤ 1). RESULTS: E. coli was the predominant causative agent, which accounted 159 (59.3%) of the Gram-negative bacteria, where 81 (50.9%) E. coli strains were found to be ESBL producers. In addition, 86 (54.1%) E. coli strains were found to be biofilm producers. Both the pgaA and pgaC genes were detected in 45 (93.7%) the UPEC isolates, which were both biofilm and ESBL producers. Moreover, there was a positive correlation between biofilm and ESBL production. CONCLUSION: The analyses presented weak positive correlation between biofilm and ESBL production in which biofilm producing UPEC harbors both pgaA and pgaC genes responsible for biofilm formation.

Understanding V(D)J recombination initiator RAG1 gene using molecular phylogenetic and genetic variant analyses and upgrading missense and non-coding variants of clinical importance.

The recombination-activating genes (RAGs) encode for V(D)J recombinases responsible for rearrangements of antigen-receptor genes during T and B cell development, and RAG expression is known to correlate strictly with the process of rearrangement. There have been several studies of RAG1 illustrating biochemical, physiological and immunological properties. Hitherto, there are limited studies on RAG1 focusing molecular phylogenetic analyses, evolutionary traits, and genetic variants in human populations. Hence, there is a need of a comprehensive study on this topic. In the current report, we have shed light into insights of evolutionary traits and genetic variants of human RAG1 gene using 1092 genomes from human populations. Syntenic analyses revealed that two RAG genes are physically linked and conserved on the same locus in head-to-head orientation from sea urchin to human for about 550 MY. Spliceosomal introns have been in invaded in fishes and sea urchin, whereas gene structures of RAG1 gene from tetrapods remained single exon architecture. We compiled 751 genetic variants in human RAG1 gene using 1092 human genomes; where major stockholders of variant classes are 79% single nucleotide polymorphisms (SNPs), 12.2% somatic single nucleotide variants (somatic SNVs) and 6.8% deletion. Out of 267 missense variants, 140 are deleterious mutations. We identified 284 non-coding variants with 94% regulatory in nature.

Expression analysis of octopamine and tyramine receptors in Drosophila.

The monoamines octopamine and tyramine, which are the invertebrate counterparts of epinephrine and norepinephrine, transmit their action through sets of G protein-coupled receptors. Four different octopamine receptors (Oamb, Octß1R, Octß2R, Octß3R) and 3 different tyramine receptors (TyrR, TyrRII, TyrRIII) are present in the fruit fly Drosophila melanogaster. Utilizing the presumptive promoter regions of all 7 octopamine and tyramine receptors, the Gal4/UAS system is utilized to elucidate their complete expression pattern in larvae as well as in adult flies. All these receptors show strong expression in the nervous system but their exact expression patterns vary substantially. Common to all octopamine and tyramine receptors is their expression in mushroom bodies, centers for learning and memory in insects. Outside the central nervous system, the differences in the expression patterns are more conspicuous. However, four of them are present in the tracheal system, where they show different regional preferences within this organ. On the other hand, TyrR appears to be the only receptor present in the heart muscles and TyrRII the only one expressed in oenocytes. Skeletal muscles express octß2R, Oamb and TyrRIII, with octß2R being present in almost all larval muscles. Taken together, this study provides comprehensive information about the sites of expression of all octopamine and tyramine receptors in the fruit fly, thus facilitating future research in the field.

Surveying genetic variants and molecular phylogeny of cerebral cavernous malformation gene, CCM3/PDCD10.

The three cerebral cavernous malformations (CCMs) genes namely CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 have been identified for which mutations cause cerebral cavernous malformations. However, the protein products of these genes involved in forming CCM signaling, are still poorly understood imposing an urgent need to understand these genes and their signaling processes in details. So far involvement of CCM3/PDCD10 in the cavernous angioma has been characterized from biochemical and biophysical analyses. However, there is no comprehensive study illustrating the phylogenetic history and comprehensive genetic variants of CCM3/PDCD10. Herein, we explored the phylogenetic history and genetic variants of CCM3/PDCD10 gene. Synteny analyses revealed that CCM3/PDCD10 gene shared same genomic loci from Drosophila to human and the gene structure of CCM3/PDCD10 is conserved from human to Branchiostoma floridae for about 500 MYs with some changes in sea urchin and in insects. The conserved CCM3/PDCD10 is characterized by presence of indels in the N-terminal dimerization domain. We identified 951 CCM3/PDCD10 variants by analysis of 1092 human genomes with top three variation classes belongs to 84% SNPs, 6.9% insertions and 6.2% deletions. We identified 22 missense mutations in the human CCM3/PDCD10 protein and out of which three mutations are deleterious. We also identified four stop-codon gaining mutations at the positions E34*, E68*, E97* and E140*, respectively. This study is the first comprehensive analysis of the CCM3/PDCD10 gene based on phylogenetic origin and genetic variants. This study corroborates that the evolution of CCM proteins with tubular organization evolvements by endothelial cells.

Revising angiotensinogen from phylogenetic and genetic variants perspectives.

Angiotensinogen (AGT) belongs to the serpin superfamily. It acts as the unique substrate of all angiotensin peptides, which generates a spectrum of angiotensin peptides in the renin-angiotensin system and regulates hypertension. This serpin belongs to the multiple member group V2 of the intron encoded vertebrate serpin classification. Despite huge advancements in the understanding of angiotensinogen based on biochemical properties and its roles in the RAS, phylogenetic history of AGT remains forgotten. To date, there is no comprehensive study illustrating the phylogenetic history of AGT. Herein, we investigated phylogenetic traits of AGT gene across vertebrates. Gene structures of AGT gene from selected ray-finned fishes varied in exon I and II with insertions of two novel introns in the core domain for ray-finned fishes at the position 77c and 233c. We that found AGT loci is conserved from lampreys to human and estimated to be older than 500 MY. By comparing AGT protein in 57 vertebrate genomes, we illustrated that the reactive center loop (RCL) of AGT protein became from inhibitory (in lampreys, GTEAKAETVVGIMPI†SMPPT) to non-inhibitory (in human, EREPTESTQQLNKPE†VLEVT) during period of 500 MY. We identified 690 AGT variants by analysis of 1092 human genomes with top three variation classes belongs to SNPs (89.7%), somatic SNVs (5.2%) and deletion (2.9%). There are 32 key residues out of 121 missense variants, which are deleterious for AGT protein, computed by combination of SIFT and PolyPhen V2 methods. These results may have clinical implications for understanding hypertension.

Molecular phylogeny of C1 inhibitor depicts two immunoglobulin-like domains fusion in fishes and ray-finned fishes specific intron insertion after separation from zebrafish.

C1 inhibitor (C1IN) is a multi-facet serine protease inhibitor in the plasma cascades, inhibiting several proteases, notably, regulates both complement and contact system activation. Despite huge advancements in the understanding of C1IN based on biochemical properties and its roles in the plasma cascades, the phylogenetic history of C1IN remains uncharacterized. To date, there is no comprehensive study illustrating the phylogenetic history of C1IN. Herein, we explored phylogenetic history of C1IN gene in vertebrates. Fishes have C1IN with two immunoglobulin like domains attached in the N-terminal region. The RCL regions of CIIN from fishes and tetrapod genomes have variations at the positions P2 and P1'. Gene structures of C1IN gene from selected ray-finned fishes varied in the Ig domain region with creation of novel intron splitting exon Im2 into Im2a and Im2b. This intron is limited to ray-finned fishes with genome size reduced below 1 Gb. Hence, we suggest that genome compaction and associated double-strand break repairs are behind this intron gain. This study reveals the evolutionary history of C1IN and confirmed that this gene remains the same locus for ∼450 MY in 52 vertebrates analysed, but it is not found in frogs and lampreys.

Prevalence of drug resistant Enterobacteriaceae in a Nepalese tertiary care hospital.

Antimicrobial resistance in Enterobacteriaceae is an emerging global public health problem. Numerous studies have reported community-acquired AmpC beta-lactamase and extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae in Nepal. However, there are limited data on community-acquired Metallo-beta-lactamase (MBL) producing Enterobacteriaceae. A hospital-based descriptive cross-sectional study was conducted using 294 Enterobacteriaceae isolates from a total of 2,345 different clinical specimens collected from patients attending a tertiary care hospital in Nepal. Bacteria were isolated using standard microbiological growth media and identified using biochemical tests. For antimicrobial susceptibility testing, Kirby-Bauer disc diffusion technique was used. AmpC, ESBL, and MBL productions were detected by using combined disc method. AmpC, ESBL, and MBL productions were detected in 19.4%, 29.6%, and 8.5% of total Enterobacteriaceae isolates respectively. Higher rates of beta-lactamases production were seen among the isolates from in-patients in comparison with those from out-patients. However, 11.6%, 25%, and 3.7% of the total isolates from out-patients were AmpC, ESBL, and MBL producers respectively. The co-production of the beta-lactamases was also detected, with two Klebsiella pneumoniae isolates producing all three beta-lactamases. One MBL producing Proteus vulgaris isolate that was pan-resistant with no remaining treatment options was also isolated. Prevalence of drug resistant Enterobacteriaceae in our study was very high. Detection of AmpC, ESBL, and MBL positive isolates from out-patients, who did not have recent history of hospital visit, indicated the community dissemination of the drug resistant bacteria. This is a matter of great concern and an immediate attention to formulate strategies to prevent further development and spread of antibiotic resistance is required.

Sequence, phylogenetic and variant analyses of antithrombin III.

Antithrombin III (ATIII) performs a critical anticoagulant function by precluding the activation of blood clotting proteinases, aided by its two cofactors, heparin and heparan sulfate. Though several studies have been carried out on physiological, biochemical and structural perspectives on ATIII, so far there are limited studies on the molecular evolution of ATIII. Herein, we carried out molecular phylogenetic analyses of ATIII genes, combining gene structures, synteny and sequence-structural features for ATIII spanning 50 vertebrate genomes. ATIII is maintained over 450 MY on same genomic loci in vertebrates with few changes in ray-finned fishes and lost one intron 262c in tetrapods and coelacanth. In ray-finned fishes, ATIII gene has additional intron at the position 262c, which shared by group V1 members, corroborating that it is lost in other vertebrates and also in lobed-finned fish coelacanth (Latimeria chalumnae). We found that heparin binding basic residues, hD helix, three pairs of Cys-Cys salt bridges, N-glycosylation sites, serpin motifs and inhibitory reactive center loop (RCL) of ATIII protein are highly conserved. Using 1092 human genomes available from 1000G project, we also compiled 1997 ATIII variants, which reveals 76.2% single nucleotide polymorphisms (SNPs), 11.8% deletions and 8.1% insertions as three major classes of gene variations. These understandings may have medical importance as well.

Biomarkers in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a complex disorder secondary to gene-environment interactions, and is the commonest chronic lung disease in infancy. There is no specific or effective treatment available to date for BPD. Since the aetiopathogenesis of BPD is multifactorial, involving diverse molecular signaling pathways, a variety of biomarkers detected in biological fluids have been proposed for early identification of infants predisposed to BPD. This review will be restricted to biomarker studies in human infants, conducted mostly in the last decade. The majority of the studies have been conducted using blood, urine or tracheal aspirate samples. Despite the multitude of biomarkers proposed, most studies have been conducted in small numbers of infants, with few being replicated by independent investigators. Confirmatory studies with adequate sample sizes and assessment of the role of putative biomarkers in the aetiology of BPD in developmentally appropriate animal models and human lungs with BPD will enhance the potential for therapeutic interventions. Genomic and proteomic approaches have the greatest potential to significantly advance the field of biomarkers in BPD.

Outpatient management of established bronchopulmonary dysplasia: An update.

As the incidence of infants with bronchopulmonary dyspasia (BPD) has continued to rise, so has their rate of survival. Their medical management is often complex and requires the use of numerous therapies such as steroids, bronchodilators, diuretics and modalities to deliver supplemental oxygen and positive pressure. It also requires multi-disciplinary care to ensure adequate growth and to optimize neurodevelopmental outcomes. This review aims to discuss the most widely used therapies in the treatment of patients with established BPD. The focus will be on ongoing outpatient (post-neonatal intensive care) management of children with BPD. Since many of the mentioned therapies lack solid evidence to support their use, more high quality research, such as randomized controlled trials, is needed to assess their effectiveness using defined outcomes.

Diagnostic Delay in Pediatric Vestibular Disorders.

BACKGROUND: Vertigo and dizziness in children can be multi-factorial. Vestibular function tests allow an improved differential diagnosis and treatment. Delay in diagnosis of the diverse etiologies causing dizziness can adversely affect the health of children and is a matter of concern for their families. This study analyzes the delay in diagnosis and the importance of establishing a diagnosis with detailed history and neuro-otological evaluation. METHODS: A total of 241 children presenting with vertigo to a tertiary otoneurology clinic between January 2019 and April 2022 were analyzed for the duration between the onset of symptoms and diagnosis, presenting complaints, and characteristic findings. RESULTS: Two hundred and forty-one patients with a mean age of 12.5 ± 3.02 years (range, 5-16 years) were evaluated. About 39.4% of patients were diagnosed after over a year (with some over 5 years) of suffering from vertigo and only 18.7% of patients were diagnosed correctly within 1 month of symptom onset. The presenting features were variable with 174 (72.2%) complaining of spinning, unsteadiness, and falls seen in 36+10+37 (34.4%). Vestibular migraine was the most common diagnosis (63.39%), followed by benign paroxysmal positional vertigo (24.48%), of which the posterior canal was most affected (50.85%) followed by horizontal (40.68%) and anterior canal (8.47%). Other etiologies noted were central (14.10%) and peripheral vestibulopathy (17.42%) and variable other causes (6.19%). CONCLUSION: Many pediatric vertigo and dizziness patients do not reach the correct diagnosis for long durations and are treated as "unspecified dizziness." A detailed examination with a multidisciplinary approach including vestibular evaluation is advocated to give definitive treatment to these children.

Large Variability of Head Angulation During the Epley Maneuver: Use of a Head-Mounted Guidance System with Visual Feedback to Improve Outcomes.

BACKGROUND: The aim of this study was to show the variability in head angulation during the canalolith repositioning maneuvers to treat benign paroxysmal positional vertigo and to describe a head-mounted benign paroxysmal positional vertigo guidance system to measure the head orientation. METHODS: A guidance system for benign paroxysmal positional vertigo was developed by NeuroEquilibrium Diagnostic Systems to measure head orientation and provide visual feedback and instructions to examiners during various maneuvers for benign paroxysmal positional vertigo. Twenty-five experienced examiners and 25 healthy volunteers (aged 21-35 years) were recruited. Each examiner applied the Epley maneuver twice in 1 volunteer: without and with the use visual feedback from a guidance system. Head orientation in both procedures was measured and compared. RESULTS: The trained examiners demonstrated a large variability in head orientation during the Epley maneuver, which was reduced by using the benign paroxysmal positional vertigo guidance system. There was a variability of 39-65° in head orientation measured without the guidance system. The use of the guidance system reduced the variation range to a sixfold decrease in variability. CONCLUSION: There is a large variability in head orientation when performing repositioning maneuvers, which could compromise the efficacy of benign paroxysmal positional vertigo treatment. Treatment for benign paroxysmal positional vertigo can be optimized by reducing this variability with a benign paroxysmal positional vertigo guidance system. It might also be a useful tool for teaching.

Prevalence of Horizontal Canal Variant in 3,975 Patients With Benign Paroxysmal Positional Vertigo: A Cross-sectional Study.

Background and Objectives: Current understanding based on older studies is that pc-BPPV is far more common than hc-BPPV. Such studies are limited by small sample sizes, and often the supine roll test for hc-BPPV is not performed. To better estimate the prevalence of hc-BPPV, we studied a large cross-section of patients with VOG-diagnosed BPPV. Methods: Using a cross-sectional study of patients with BPPV, we investigated patients referred to NeuroEquilibrium specialty clinics throughout India between January 1, 2021, and December 31, 2021. All patients were evaluated with video oculography (VOG) during positional tests, and all diagnoses were confirmed by a neurotologist and neurologist. Results: Of 3,975 patients with VOG-confirmed and specialist-diagnosed BPPV (median age, 51 years; 56.6% women), pc-BPPV accounted for 1,901 (47.8%), hc-BPPV was seen in 1,842 (46.3%), and anterior canal BPPV was found in 28 (0.7%) patients. Discussion: This study found that hc-BPPV is far more common than previously reported. It is important to perform the supine roll test in addition to the Dix-Hallpike in all patients suspected with BPPV. Better training to diagnose patients with BPPV and to accurately recognize the nystagmus pattern of hc-BPPV should be a priority.

Cervical Papanicolaou Smear Test Screening among Patients Visiting the Outpatient Department of Gynaecology of a Tertiary Care Centre.

Introduction: Carcinoma cervix is the second most common cause of death in women worldwide and the most common cause in developing countries. Cervical cancer is considered a preventable gynaecological problem as it has a long premalignant stage which can be detected by exfoliative cytology like papanicolaou smear test. The papanicolaou smear test is a simple, safe, non-invasive, and low-cost effective method for screening cervical cancer in developing countries like Nepal. The aim of the study was to find out the prevalence of cervical papanicolaou smear test screening among patients visiting the Outpatient Department of Gynaecology of a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among patients visiting the Department of Gynaecology of a tertiary care centre after obtaining ethical approval from the Institutional Review Committee. Data from 14 April 2021 to 22 October 2022 were collected between 11 May 2023 to 26 May 2023 from the hospital records. Papanicolaou smear tests among the age group of 21 years up to 70 years were included in the study. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Results: Among 11,173 patients, papanicolaou smear test was done in 572 (5.12%) (4.71-5.53, 95% Confidence Interval). Negative for intraepithelial lesion was the most common cytological pattern seen in 518 (90.55%) patients. The low-grade squamous intraepithelial lesion was the most common among abnormal epithelial cells seen in 29 (5.07%). Conclusions: The prevalence of cervical papanicolaou smear test among patients visiting the Outpatient Department of Gynaecology was found to be similar to other studies done in similar settings. Keywords: cervical cancer; cytology; papanicolaou smear.

The impact of obstructive sleep apnea in children with sickle cell disease and asthma.

INTRODUCTION: Asthma and obstructive sleep apnea (OSA) are chronic diseases that disproportionately affect children with sickle cell disease (SCD). The literature describes the negative impact that both conditions have on children with SCD separately; however, the effect of OSA on asthmatic children with OSA is less specific. We hypothesized that the presence of OSA in children with SCD and asthma is associated with specific hematologic markers, worse clinical outcomes, and greater healthcare utilization. METHODS: We retrospectively evaluated children with both SCD and asthma who underwent polysomnography (PSG). We assessed their demographic information, PSG data, hematologic indices, and healthcare utilization based on the concurrent presence of OSA. RESULTS: Fifty-nine percent of the cohort had OSA with a lower oxygen saturation (SpO2 ) nadir (87% vs. 93%, p < 0.001) and a lower median daytime SpO2 (96.5% vs. 98.5%, p < 0.05); those with OSA were more likely to have the hemoglobin SS genotype (86% vs. 46.5%, p = 0.03). Additionally, those with OSA had a higher mean corpuscular volume (87 vs. 77.2 fL, p = 0.03) and reticulocyte count (10.1% vs. 5.5%, p < 0.01). There was no difference in asthma severity or healthcare utilization between those with OSA and those without OSA. DISCUSSION: Overall, children with SCD and asthma might be at increased risk for developing OSA, and screening for sleep-disordered breathing should be incorporated as part of their routine care.

Characterization of the flavonoid-responsive regulator FrrA and its binding sites.

Previous microarray analyses revealed that in Bradyrhizobium japonicum, about 100 genes are induced by genistein, an isoflavonoid secreted by soybean. This includes the three genes freC, freA, and freB (systematic designations bll4319, bll4320, and bll4321), which are likely to form a genistein-, daidzein-, and coumestrol-inducible operon and to encode a multidrug efflux system. Upstream of freCAB and in the opposite orientation, FrrA (systematic designation Blr4322), which has similarity to TetR-type regulators, is encoded. A deletion of frrA leads to increased expression of freB in the absence of an inducer. We identified the correct translational start codon of frrA and showed that the gene is inducible by genistein and daidzein. The protein, which was heterologously expressed and purified from Escherichia coli, binds to two palindrome-like DNA elements (operator A and operator B), which are located in the intergenic region between freC and frrA. The replacement of several nucleotides or the insertion of additional spacer nucleotides prevented binding. Binding of FrrA was also affected by the addition of genistein. By mapping the transcription start sites, we found that operator A covers the transcriptional start site of freC and operator B is probably located between the -35 regions of the two divergently oriented genes. Operator A seems to be conserved in a few similar gene constellations in other proteobacteria. Our data indicate that in B. japonicum, besides NodD1 (the LysR family) and NodVW (a two-component response regulator), a third regulator type (a TetR family member) which responds to the plant signal molecules genistein and daidzein exists.

Modified Interpretations of the Supine Roll Test in Horizontal Canal BPPV Based on Simulations: How the Initial Position of the Debris in the Canal and the Sequence of Testing Affects the Direction of the Nystagmus and the Diagnosis.

Background and Objectives: The aim of this study was to show with three-dimensional simulations how the diagnostic supine roll test (SRT) is affected by the initial position of the debris within the horizontal canal (hc) and study the nystagmus patterns on changing the sequence of testing and its impact on the diagnosis of the side of involvement in hc-BPPV. Methods: A 3D dynamic simulation model was developed and applied based on reconstructed MRI images and fluid dynamics. Each semicircular canal was linked to the respective extraocular muscles to visualize nystagmus generated on stimulation of the canal. Results: The simulations of hc-canalithiasis showed that the nystagmus pattern seen with the SRT is changed by the initial position of the otolith debris within the canal and the sequence of testing. The debris changes position during SRT so that sequential steps do not start at the initial position as previously assumed. The sequence of performing the SRT steps from the right or left side influences the nystagmus pattern generated: bilateral direction-changing, bilateral direction-fixed, and unilateral nystagmus can be seen in different test conditions. The SRT itself may even reposition the debris out of the canal. Conclusions and Clinical Implications: Simulations provide a dynamic tool to study the diagnostic SRT in hc-canalithiasis. Starting the SRT from right or left has a major impact on the test outcome (unlike the Dix-Hallpike maneuver). The findings provide a new interpretation for the results of the SRT. The simulations explain the phenomenon of direction-fixed nystagmus as a logical consequence of starting the SRT with the head turned toward the non-affected side in hc-canalithiasis with debris in the ampullary arm. They also show that unilateral nystagmus seen on SRT indicates canalithiasis of the non-ampullary arm of the side opposite to the side of nystagmus. The generation of bilateral direction-changing, bilateral direction-fixed, and unilateral nystagmus can be the cause of misdiagnoses in terms of the affected side and underlying mechanisms. Finally, a recommendation for a standardized protocol for the sequence of positional tests should be established to ensure uniform interpretation of test results.

Benefit of pulmonary subspecialty care for children with sickle cell disease and asthma.

OBJECTIVE: Asthma is a recognized comorbidity in children with sickle cell disease (SCD). It increases the risk of acute chest syndrome (ACS), vaso-occlusive episodes, and early mortality. We aim to determine whether evaluation and management of children with SCD and asthma by a pulmonologist reduce rate of asthma exacerbation and ACS. METHODS: The study included 192 patients with SCD (0-21 years) followed at Children's Hospital of Philadelphia Hematology between January 1, 2015, and December 31, 2018, with a diagnosis of asthma, wheeze, or cough. Patients were placed in two groups: those evaluated by a pulmonologist (SCD-A-P) and those not (SCD-A). Rates of emergency department (ED) visits and hospitalizations for asthma exacerbation and ACS were compared between groups and over time. RESULTS: SCD-A-P patients (n = 70) were predominantly SCD type SS with lower hemoglobin and hematocrit compared to SCD-A patients (n = 122). SCD-A-P started with a higher average rate of hospital visits for asthma exacerbation and ACS per year (2.69 [1.02-4.37]) compared to SCD-A (0.43 [0.24-0.63]), (p < 0.001). For SCD-A-P patients with at least one hospital visit (n = 48), the average rate decreased from 3.93 (1.57-6.29) to 0.85 (0.48-1.23) following pulmonary consultation (p = 0.014) and was comparable to the SCD-A rate by study end. CONCLUSION: SCD-A-P was mainly SCD type SS and had higher ED/hospitalization rates for asthma exacerbation and ACS compared to SCD-A, but the rates significantly decreased following pulmonology consultation. These findings support the pulmonologist's role in the multidisciplinary care of SCD patients and highlight the need for evidence-based asthma guidelines for children with SCD.

Diagnostic and Therapeutic Maneuvers for Anterior Canal BPPV Canalithiasis: Three-Dimensional Simulations.

Background and Objectives: Anterior canal BPPV is a rare BPPV variant. Various diagnostic and therapeutic maneuvers have been described for its management. The aim of this study was to use three-dimensional simulation models to visualize otoconial debris movement within the anterior canal during diagnostic tests and different liberatory maneuvers. This can help to optimize existing treatment maneuvers and help in the development of better management protocols. Methods: Based on reconstructed MRI images and fluid dynamics, a 3D dynamic simulation model (as a function of time) was developed and applied. Simulations of the supine head-hanging test for diagnosis of ac-BPPV were studied. Three repositioning maneuvers were simulated: 1) the Yacovino maneuver and its modifications, 2) the reverse Epley maneuver and 3) the short canal repositioning (CRP) maneuver. Results: The simulation showed that the supine head-hanging test is a good test for diagnosis of ac-BPPV affecting both labyrinths and demonstrated why there is no inversion of nystagmus on sitting up. The Yacovino maneuver was seen to be an effective treatment option for ac-BPPV without having to determine the side involved. However, simulations showed that the classical Yacovino maneuver carried a risk of canal switch to the posterior canal. To overcome this risk, a modified Yacovino maneuver is suggested. The reverse Epley maneuver was not an effective treatment. Short CRP is useful in ac-BPPV treatment; however, it requires determination of side of involvement. Conclusion: The 3D simulator of the movement of the otoconial debris presented here can be used to test the mechanism of action and the theoretical efficacy of existing diagnostic tests and maneuvers as well as to develop new treatment maneuvers to optimize BPPV treatment.