Chronic rhinosinusitis is a common disorder of chronic inflammation of the upper respiratory tract. It is associated with significant symptoms and impairment of the quality of life of sufferers. Despite recent advances in the medical and surgical management of chronic rhinosinusitis, there remains a population of patients who fail to obtain relief from their symptoms. Chronic inflammation of the mucosa of the nasal cavity and paranasal sinuses is one of the hallmarks of chronic rhinosinusitis. This inflammation is demonstrated by an increased number of chronic inflammatory cells, elevated levels of pro-inflammatory cytokines, increased expression of adhesion molecules and metaplastic changes in the epithelium. The current medical treatments for chronic sinusitis aim to reduce this inflammation and consequently improve symptoms. In recent years, evidence has emerged that macrolide antibiotics have an anti-inflammatory effect that is separate from their anti-bacterial effect. This effect was first described in the treatment of diffuse panbronchiolitis, a disorder of chronic inflammation of the lower respiratory tract. Following the success of macrolides in treating this condition it was trialed in chronic rhinosinusitis. Several open-label trials have subsequently demonstrated a beneficial effect. Laboratory studies have investigated the mechanism of the anti-inflammatory effect of macrolides. These have shown that macrolides effect cytokine production, inflammatory cell apoptosis, expression of adhesion molecules, neutrophil oxidative burst, bacterial virulence and mucociliary function. In this thesis we report a series of experiments designed to further investigate the mechanism of action and clinical effect of macrolides. In vitro studies using whole sections of chronic rhinosinusitis mucosa cultured for 24 hours in macrolide, prednisolone or control showed that macrolide and prednisolone produced significant reductions in the production of interleukin-5, interleukin-8 and granulocyte-macrophage colony stimulating factor. The same cultured specimens also showed a reduction in expression of transforming growth factor-?. No reduction was seen in the expression of the key pro-inflammatory nuclear transcription factor Nuclear factor-?B. In our in vivo experiments, biopsies were taken from chronic rhinosinusitis patients who had received a 3-month course of macrolide. These biopsies showed a reduction in the number of neutrophils present following treatment. There was no reduction in the number of other inflammatory cells or in the expression of TGF-? and NK-?B. We have performed the first ever double-blinded, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Patients receiving macrolide showed significant improvements in saccharine transit time, nasal endoscopic scoring and symptom scores following a 12 week course. Patients with low levels of serum immunoglobulin E showed significantly improved outcomes compared to those with high levels. Interleukin-8 levels in nasal lavage fluid were significantly reduced in the patients with low levels of IgE following macrolide treatment. No improvements in any of the objective or subjective outcome measures were seen in the placebo-treated patients. We have performed a series of experiments investigating the anti-inflammatory effect of macrolide antibiotics from 'the bench to the bedside'. These experiments have provided insight into the mechanism of action of macrolides in the laboratory setting and evidence of a beneficial effect in the treatment of chronic rhinosinusitis patients.

Upper Respiratory Tract Disease (URTD), caused by the pathogens Mycoplasma agassizii and M. testudineum, has been documented in the desert tortoise (Gopherus agassizii). Although URTD was identified as a putative agent that led to federal listing of the Mojave population of the desert tortoise, little is known about this disease in the Sonoran population of the desert tortoise. The purpose of this study was to determine: 1) the prevalence of URTD across an urban gradient in Greater Tucson, Arizona, 2) the relationship between URTD and captive and free-ranging tortoises in Mohave, Maricopa, and Pima counties in Arizona, and 3) the effects of URTD on desert tortoise home range size and winter temperature selection.

Nepagrįstas antibiotikų vartojimas gydant ūmine viršutinių kvėpavimo takų infekcija (ŪVKTI) sergančius pacientus ne tik sąlygoja atsparių antimikrobiniams vaistams bakterijų padermių vystymąsi, bet ir didina nepageidaujamo vaistų poveikio dažnį bei išlaidų sveikatos priežiūrai kaštus. Lietuvoje iki šiol nebuvo analizuotos priežastys, lemiančios gydytojų sprendimą skirti bei pacientų norą sulaukti antibiotikų ŪVKTI gydymui. Darbo tikslas – nustatyti ir įvertinti antibiotikų vartojimo ŪVKTI gydymui dažnį ir priežastis Kauno apskrities PSP įstaigose. Darbo uždaviniai - nustatyti antibiotikų skyrimo ŪVKTI gydymui dažnį ir priklausomybę nuo ŪVKTI išraiškos; įvertinti paciento lūkesčius sulaukti antibiotikų ŪVKTI gydymui bei jų ryšį su gydytojo sprendimu skirti antibiotikų ŪVKTI gydymui; įvertinti ligos eigos, gydytojo amžiaus, specialybės bei darbo aplinkos ir sprendimo skirti antibiotikų ŪVKTI sergantiems pacientams sąsajas. Išvados: Sulaukti recepto antibiotikams tikisi trečdalis į PSP įstaigą atvykusių pacientų. Pacientų lūkestis gauti antibiotikų ŪVKTI gydymui susijęs su gydytojo sprendimu skirti šių vaistų. Kauno apskrities PSP įstaigų gydytojai antibiotikų ŪVKTI gydymui skiria 40,2 proc. atvejų. Nepagrįstai daug (32,8 proc.) antibiotikų skiriama “paprastam peršalimui” gydyti. Persikvalifikavę į šeimos gydytojus terapeutai bei vyresnio amžiaus gydytojai antibiotikų ŪVKTI gydymui skiria dažniau lyginant su stacionarią rezidentūrą baigusiais bei jaunesniais šeimos gydytojais. / Most commonly AURTI are caused by viruses, and since antibiotics are ineffective against viral infections, researchers in a number of countries have concluded that the rates of antibiotic prescription for AURTI are unjustifiably high. The aim of the study was to determine and evaluate the reasons and rate of antibiotic use for the treatment of AURTI in primary healthcare units of Kaunas County. The objectives of the study were to determine the rate of prescribing antibiotics for AURTI; to evaluate the patients’ expectations to receive antibiotics for AURTI and to assess the relationship of these expectations with the physicians’ decision to prescribe antibiotics for this disorder; to evaluate the associations of the phy¬sician’s age, specialty and working environment with the decision to prescribe antibiotics for patients with AURTI. Conclusions: One-third of patients who visited PHC institutions expected to receive prescriptions for antibiotics. The patients’ expectations to receive antibiotics for the treatment of AURTI was related to the physicians’ decision to prescribe antibiotics. Physicians of PHC institutions of Kaunas County prescribe antibiotics for AURTI in 40.2% of cases. With unjustified rate (32.8%) antibiotics are prescribed for “common cold”. Internists who had re-qualified as family physicians and older physi¬cians prescribed antibiotics more frequently, compared to those who had comple¬ted full-time residency in family medicine and younger physicians.

Background: Antibiotics are prescribed frequently for upper respiratory tract infections (URTIs) despite the fact that most of them do not require antibiotics. This over-prescription contributes to antibiotic resistance which is a major health problem. Physicians perceive that patients’ expectations influence their antibiotic prescribing practice. Methods: As the first phase of the thesis, we conducted a systematic review to determine the effectiveness of patient-oriented interventions to reduce unnecessary use of antibiotics for URTIs. As the second phase, we conducted a qualitative descriptive study to explore patients’ views about URTIs and identify ways they manage them by using semi-structured interviews based on Common Sense-Self-Regulation Model (CS-SRM). Results: Our systematic review included 14 studies which based on their interventions were classified into two major categories: delayed prescriptions and patient/public information and education interventions. Our meta-analysis revealed that almost all studies with delayed prescription significantly reduced use of antibiotics for URTIs. Our subgroup analysis showed that prescriptions that were given at a later time and prescriptions that were given at the index consultation had similar effects regarding antibiotic use. The small number of included studies in the patient/public information and education group did not allow us to make a definite conclusion on their effectiveness. For the qualitative study, 15 individuals were interviewed. almost all participants mentioned that they only visited their doctor if their symptoms got progressively worse and they could no longer self-manage URTI symptoms. When visiting a doctor, most participants reported that they expected to receive an examination and an explanation for their symptoms. Discussion: Patient-oriented interventions (especially delayed prescriptions) may be effective in reducing antibiotic use or prescription for URTIs in patients. Further research is needed to investigate the costs and feasibilities of implementing these interventions as part of routine clinical practice. Our participants reported good knowledge regarding the likely lack of benefit from antibiotics for URTIs. The results suggest a discrepancy between our participants’ reported reasons for visiting doctors and doctors’ perceptions about patients’ reason for their visit identified in previous studies. Focusing on interventions that facilitate the communication between patients and doctors, instead of providing more education to public may help in reducing the use of unnecessary antibiotics.

Upper airway endoscopy at rest has been the diagnostic method of choice for diagnosing equine upper respiratory tract (URT) disease since its development in the 1970´s. The development of high-speed treadmill endoscopy (HSTE) improved the sensitivity of URT endoscopy by allowing the examiner to observe the horse’s nasopharynx and larynx during exercise. However, the level of exertion achieved during HSTE may not always represent that achieved during normal exercise as surface, rider, tack, and environmental variables are altered. Recently, the development of dynamic overground endoscopy (DOE) has addressed some of those shortcomings. A retrospective study was undertaken to describe the upper airway abnormalities detected during DOE in horses presenting with poor performance and/or abnormal respiratory noise in South Africa. Patient records of Thoroughbred racehorses undergoing DOE from November 2011 to August 2012 by the Onderstepoort Veterinary Academic Hospital were reviewed. Data collected included signalment, primary complaint, distance exercised, maximum speed attained, and dynamic airway abnormalities detected. XIII A second study was carried out to evaluate agreement within and among examiners of three grading systems for laryngeal function at exercise. The grading systems assessed were an existing system for grading axial deviation of aryepiglottic folds (ADAF), a modified system for grading recurrent laryngeal neuropathy (RLN) at exercise, and a proposed system for grading vocal cord collapse (VCC). For investigation of intra-observer variability, recordings were watched by two of the investigators at the same time, on two different occasions, in real time, slow motion, and at frame-by-frame speed. To evaluate inter-observer variability, recordings were watched by four investigators on one occasion, as described for investigation of intra-observer variability, and scoring sheets completed. Kappa agreement was calculated for both intra- and inter-observer sessions. Fifty-two horses that underwent DOE for investigation of poor performance and/or abnormal respiratory noise were identified. The main abnormalities detected included dorsal displacement of the soft palate (DDSP) (13/52 horses, 25%); recurrent laryngeal neuropathy (RLN) (17/52 horses, 33%); axial deviation of the aryepiglottic folds (ADAF) (21/52 horses, 40%) and vocal cord collapse (VCC) (18/52 horses, 35%). A total of 40 horses presented one or more abnormalities of the URT (77%). Fifteen horses (29%) had a single abnormality, and 25 horses (48%) had multiple abnormalities. Results at frame-by-frame speed from the intra-observer evaluations for all the conditions showed substantial agreement for RLN by both observers (K = 74 - 80). Intra-observer evaluations for VCC were moderate to substantial (K 53 – 63). ADAF was the most difficult URT abnormality to assess for both observers, and agreement within observers was only fair to moderate (K = 36 - 52). Inter-observer evaluations for RLN showed substantial to moderate agreement (K = 62). Inter-observer evaluations for VCC showed moderate agreement (K = 47 – 54), and inter-observer evaluations for ADAF showed only slight to fair agreement and were the lowest for all the conditions (K = 14 – 22). This study showed that DOE is a useful technique for providing valuable information about disease of the URT. Finding multiple abnormalities in 48% of horses examined using DOE suggests that DOE may be indicated even for those horses with an obvious abnormality found during resting endoscopy. The intra-observer evaluations showed that RLN had higher agreement values than those for ADAF and VCC at all speeds, and that ADAF had lower agreement values than those for VCC and RLN at all speeds. Inter-observer agreement was less than intra-observer agreement, presumably because more observers were involved in the inter-observer assessment. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Companion Animal Clinical Studies / unrestricted

Superior Ethmoidal Breadth (SEB = the maximum breadth between the left and right frontoethmoidal sutures) has been widely employed by anthropologists as a proxy for internal nasal airway dimensions since it is easily measured without imaging. SEB is also commonly argued to evince climatic adaption in modern humans, as populations living in cold-dry environments predictably exhibit narrower SEB dimensions than those inhabiting tropical environments. However, given uncertaintiy regarding its relationship with internal nasal anatomy, the accuracy of SEB as a proxy for airway dimensions remains questionable. Here, I evaluate the correlation between SEB and internal airway dimensions using linear measurements collected on CT scans from a mixed-sex sample of human crania (n=215) ancestrally derived from sub-Saharan Africa, the Arctic Circle, East Asia, and Europe. My results demonstrate that SEB is often located superior to the anatomcial roof of the nasal passages but is highly correlated (R= 0.8119, p<0.0001) with ethmoidal breadth taken at the functional level of the upper airways (i.e., functional airway breadth [FEB]). ANOVA results indicate, in addition to significant differences in SEB (χ2 = 82.20, p<0.0001), regional differences also exist for FEB (χ2 = 54.21, p<0.0001) and its components: the combined superior and superior common meatal breadths (χ2 = 19.03, p< 0.0001) and ethmoid air cell (EAC) breadth (χ2 = 27.67, p<0.0001). Further, following theoretrical expecations, the African-derived sample generally exhibits the widest internal nasal dimensions and the Arctic-derived sample the narrowest. Specifically, the Arctic sample exhibits significantly narrower airway breadths compared to all other groups. Conversely, the African sample possesses significantly wider EAC breadths comapred to all other groups. Cumulatively, these results empirically support use of SEB as proxy for upper nasal airway breadth and bolster claims that clinal variation in internal airway dimensions across human populations is likely attributable to climatic factors.

Thesis advisor: Babak Momeni / Diseases of the upper respiratory tract encompass a plethora of complex multifaceted etiologies ranging from acute viral and bacterial infections to chronic diseases of the lung and nasal cavity. Due to this inherent complexity, typical treatments often fail in the face of recalcitrant infections and/or severe forms of chronic disease, including asthma. Thus, in order to provide improved standard of care, the mechanisms at play in hard-to-treat etiologies must be better understood. More recently, research has demonstrated a significant association between microbiota and many URT diseases. Previous work has also identified species capable of directly inhibiting standard treatments used to control asthma exacerbations. Despite an exhaustive collection of data characterizing microbiota composition in states of both health and disease, our knowledge of what microbiota profiles are observed in what specific disease etiologies is severely lacking. Yet, gaining these insights is crucial for the translation of such data into application. In this thesis I sought to: 1) identify gut microbiota profiles associated with severe and treatment resistant forms of childhood asthma, and 2) formulate a predictive model to facilitate the restructuring of microbiota for desired therapeutic outcomes. To identify gut microbiota and metabolites enriched in severe and treatment resistant childhood asthma, I looked to an ongoing longitudinal human study on vitamin D and childhood asthma. In this study, I find several fecal bacterial taxa and metabolites associated with more severe (i.e., higher wheeze proportion) and treatment resistant asthma in children at age 3 years. Specifically, several Veillonella species were enriched in children with higher wheeze proportion and in children that responded poorly to inhaled corticosteroid treatment (ICS) (i.e., non-responders). Haemophilus parainfluenzae, a species previously identified as enriched in the airway of adults with ICS-resistant asthma, was also uniquely enriched in children considered ICS non-responders in this study. Several metabolic pathways were also distinctly enriched: histidine metabolism was enriched in children with higher wheeze proportion while sphingolipid metabolism was enriched in ICS non-responders. Both metabolic pathways have been previously identified in association with asthma, further corroborating their role in this disease. Yet, this study is the first to identify these taxa and metabolites in children with preexisting and treatment resistant asthma. In the pursuit of improved treatment outcomes for recalcitrant URT diseases, recent efforts have turned towards microbiota-based therapies. While such treatments have proven successful in the treatment of gastrointestinal infections, these methods have not yet been extended to other conditions. Considering this, I ask whether a predictive model describing microbial interactions can facilitate the restructuring of microbiota for desired therapeutic outcomes. For this, I use a community of nasal microbiota to determine when a simply Lotka-Volterra-like (LV) model is a suitable representation for microbial interactions. I then utilize our LV-like model to examine whether environmental fluctuations have a major influence on community assembly and composition. For this, I looked specifically at pH fluctuations. In this study, I found that LV-like models are most suitable for describing community dynamics in complex low nutrient conditions. I also identified simple in vitro experiments that can reliably predict the suitability of a LV-like model for describing outcomes of a two-species community. When our LV-like model was applied to an in silico community of nasal species to determine the impact of environmental fluctuations, I find that nasal communities are generally robust against pH fluctuations and that, in this condition, facilitative interactions are a stabilizing force, and thus, selected for in in silico enrichment experiments. Overall, this thesis further corroborates the association of microbiota with URT diseases and treatment outcomes while also providing unique insight into their association with specific etiologies in childhood asthma. This thesis also provides a framework for developing models able to facilitate the development of future microbiota-based therapies while also determining how, and when, environmental factors impact community assembly and composition. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

[Truncated abstract] Pneumococcal exposure is high and life-long in developing countries including Papua New Guinea (PNG), with children under 2 years of age being at most risk for early upper respiratory tract pneumococcal carriage and infection. Deaths from pneumococcal diseases such as pneumonia and meningitis are common and likely the result of an absence of vaccination programmes. The need for effective and affordable pneumococcal vaccines has led to the testing of protein antigens including pneumolysin (Ply) and pneumococcal surface protein A (PspA) as novel vaccine antigens. Little is known on the immune responses to these proteins in humans, particularly in high-risk populations where such vaccines will be of most benefit. In this study, we examined the roles of naturally acquired antibody and cellular immune responses in mothers and newborns to Ply and PspA family 1 (PspA1) and family 2 (PspA2) in protection against or risk for early carriage in a high-risk PNG population. Antibodies to Ply, PspA1 and PspA2 were measured in plasmas of 241 mothers and 115 newborns (cords) from PNG, and 50 Australian mothers using an enzyme-linked immunosorbent assay (ELISA). Pernasal swabs were collected from PNG mothers at the time of delivery, one month post-partum, and weekly within the first month of life from their newborns to determine pneumococcal carriage. Cellular immune responses to Ply, PspA1 and PspA2, the TLR2/TLR4 ligands, LTA and LPS and to PHA were measured in cord blood mononuclear cells (CBMC) of 84 PNG versus 33 Australian newborns. Innate and T-cell cytokine responses in the PNG newborns were then analysed to determine their effect on infant pneumococcal carriage. ... No protective effect against infant pneumococcal carriage was observed with maternal and cord IgG levels for all antigens. Maternal carriage at time of delivery increased the risk for infant pneumococcal carriage in the first month of life (HR: 1.93, 95% CI 1.36 – 2.73, p = 0.001) with 70% of infants being colonised. Papua New Guinean newborns produced higher innate IL-10 and IFN-¿ (p = 0.003) and TNF-a (p < 0.001) to Ply compared to Australian newborns with no significant differences observed for IL-6 or IL-12. IFN-¿ responses to LPS and LTA (p = 0.005 and p < 0.001) were higher in PNG than Australian newborns, while IL-6, IL-10 (p < 0.001) and TNF-a (p = 0.002) to LPS with LTA-induced IL-6 and IL-10 (p < 0.001) were higher in Australian newborns. T-cell IL-5, IL-10, IL-13, IFN-¿, IL-6 and TNF-a response levels to PspA and PHA stimulation were significantly high in PNG newborns. No differences were observed for cytokine responses to Ply and PspA between PNG infant pneumococci carriers and non-carriers. Papua New Guinean infants are colonised by pneumococci very early in life and this may be influenced by high maternal carriage rates. PspA- and Ply-IgG levels are high in PNG mothers and undergo cross placental transfer but do not appear to be protective against early pneumococcal carriage. In PNG newborns, PspA elicits T-cell responses, while Ply drives more innate cellular responses, neither were demonstrated to have a protective effect against early carriage though further work is required to better define these and their relation to immune development in early childhood.

Orientador: Aramis Augusto Pinto / Banca: Mitika Kuribayashi Hagiwara / Banca: Tânia de freitas Raso / Resumo: O presente trabalho, primeiro estudo sobre clamidiose felina no Brasil, teve o objetivo de pesquisar a presença direta e indireta de Chlamydophila (elis em gatos domésticos provenientes de cinco municípios da região nordeste do estado de São Paulo. Adicionalmente, correlacionar os dados de ficha clínica com os resultados positivos obtidos nos três testes laboratoriais utilizados, ou seja, reação em cadeia pela polimerase (PCR), reação de imunotluorescência indireta (RI FI) e reação de fixação do complemento (RFC). O grupo experimental final foi constituído de 151 animais, dos quais 73 eram provenientes de gatis, 18 de clínica/hospitais veterinários e 60 de abrigos públicos para animais. Das 151 amostras de suabes de conjuntiva submetidas à PCR, em 6,0% (9/151) foi encontrado DNA de C. (elis. Anticorpos anti-Chlamydiaceae foram detectados em 72,1% (106/147) das amostras de soros submetidas à RIFI. Em somente 9,4% (10/106) dos soros positivos à RIFI, foram detectados anticorpos fixadores do complemento, revelando que a RFC, embora específica, apresenta baixa sensibilidade quando utilizada na pesquisa de anticorpos anti-Chlamydiaceae em gatos domésticos. Foi também observado que gatos provenientes de gatis, animais com idade maior que um ano e inferior a seis anos, bem como as fêmeas, estão mais predispostos a soroprevalência para C.felis pela RIFI. Entretanto, tais resultados não foram observados nos animais PCR positivo. Ademais, pode-se verificar uma estreita relação entre as presenças de DNA clamidial e de anticorpos anti-Chlamydiaceae em gatos domésticos brasileiros aos dados das fichas clínica relacionados à doença do trato respiratório superior, a secreção ocular e a conjuntivite. / Abstract: This work, first study about feline chlamydiosis in Brazil, had the objective to evaluate the direct and indirect presence to Chlamydophila felis in domestic cats coming trom tive cities of northeast of São Paulo state. Additionally, relate informations of clinical records with positives results get in the three laboratories tests used, whatever, complement fixation test (CFT), immunofluorescende assay (IFI) and Polymerase Chain Reaction (PCR). Experimental group had 151 animais, witch 73 coming from catteries, 18 coming trom veterinary clinicallhospital and 60 coming from public animal shelters. From 151 samples of conjunctival swabs submitled to PCR, in 6% (9/151) were detect DNA of C.felis. Anti-Chlamydophila antibodies were detect in 72,1%(106/147) of samples of serum submitted to IFI. In just 9,4% (10/106) of the positive serums in IFI, had complement fixation antibodies, detected by CFT. The CFT, although specific, presented low sensibility when to use to research of anti-Chlamydiaceae antibodies in domestic cats. In cats from catteries, animais between one and six year, and female were more predispose to a presence of antibodies anti-Chlamydophila by IFI. However, these results were not observed in animais PCR positive. Thus, was observed a relationship between the presence of chlamydial DNA and antibodies anti-Chlamydiaceae in Brazilian domestic cats, added with informations of clinical records, like with upper respiratory tract disease, ocular discharge and conjunctivitis. / Mestre

Cílem této diplomové práce je vytvořit 3D model horních dýchacích cest podle originálního modelu segmentovaného z CT dat, aplikovat různé podmínky na průtok vzduchu v modelu, a poté hodnotit změnu charakteristik rychlosti a tlaku. Model horních dýchacích cest byl vytvořen v prostředí softwaru ANSYS, který využívá výpočetní dynamiku tekutin, a byly použity Navier-Stokesovy rovnice pro modelování průtoku vzduchu v modelu. Nejprve byl vytvořen jednoduchý 2D model za účelem seznámení se s prostředím ANSYS. Dále byl zkonstruován 3D model horních dýchacích cest a byly modelovány charakteristiky rychlosti a tlaku za různých podmínek. Tyto podmínky zahrnují různé umístění a množství míst pro odběr vzorků v modelu a výběr různých kombinací vstupů. Nakonec byly prezentovány a hodnoceny výsledky spolu s ilustracemi modelů modelovaných za různých podmínek. 3D model lze považovat ze kompromis mezi výpočetní náročností a složitostí modelu a lze jej použít jako základ pro další výzkum.