La primo-infection est un moment critique de l’établissement du réservoir justifiant de l’initiation d’un traitement précoce. Nous avons initié un essai randomisé évaluant l’impact de deux ans d’un traitement antirétroviral intense (essai ANRS147 OPTIPRIM, trithérapie versus pentathérapie) sur le réservoir et avons initié des études physiopathologiques au cours de cet essai. Nous montrons ainsi la faible diversité génétique des virus en primo-infection dans les compartiments sanguins et rectaux. Le réservoir s’établit dès le premier mois de l’infection par diffusion d’un cluster viral homogène au sein des lymphocytaires T CD4 naïfs (TN) et mémoires centrales (TCM), transitionnelles (TTM), effectrices (TEM) quiescents. Il en résulte une perturbation de l’homéostasie lymphocytaire associée à une faible contribution au réservoir des cellules peu différenciées à longue demi-vie, TN et TCM. Par ailleurs nous montrons que la majorité des patients au moment de leur primo-infection n’ont pas la capacité de développer des réponses T CD8 à même de supprimer la réplication virale comme chez les patients HIV Controllers. Après deux ans de traitement, nous observons que la diversité virale n’a pas évolué, par contre la taille du réservoir est fortement réduite. Les anomalies de l’homéostasie lymphocytaire T CD4 persistent, par contre le traitement très précoce a permis de protéger les TN et TCM. Il n’y a pas de bénéfice additionnel d’une pentathérapie mais nous avons validé le concept qu’un traitement précoce permet d’induire un contrôle virologique au long cours après arrêt de traitement. Nos résultats indiquent qu’un traitement plus long que deux ans permettrait de renforcer la diminution du réservoir. Ces résultats seront à prendre en compte pour l’élaboration de futurs essais en primo-infection visant à réduire le réservoir pour une rémission au long cours. / HIV primary infection is a critical period in the establishment of the reservoirs that justifies the initiation of an early treatment. We started a randomised trial to assess the impact of a two-year intense HAART (ANRS147 OPTIPRIM trial: five-drug therapy versus. three-drug therapy) on the blood reservoir; within this this trial, we included some pathophysiological studies. Thus, we show that during the primary infection, viruses have a low genetic diversity in blood and rectal compartments. The reservoir establishes itself as early as the first month of the infection by spreading a homogeneous viral cluster in CD4 T cells subsets, naive T cells (TN), central memories (TCM), transitional memories (TTM), effector memories (TEM), and resting T cells. This results in a disruption of the lymphocyte homeostasis, linked to the low contribution to the reservoir of TN and TCM, which are little differentiated cells with long half-lives. Moreover, we show that, at the time of the primary infection, the majority of patients do not have the ability to develop CD8 T cells responses that could suppress the viral replication, as HIV Controllers patients do. After two years of treatment, we observe that there is no evolution of the viral diversity, but the size of the reservoir is significantly reduced. The abnormalities of the CD4 T cells lymphocyte homeostasis remain, but the very early treatment was able to protect the TN and TCM. The five-drug therapy does not have any additional benefit, but we confirm the idea that early treatment can induce long-term virological control after the discontinuation of the treatment. Our results show that a treatment lasting more than two years would be able to reinforce the reduction of the reservoir. These results should be taken into account in the development of future trials aiming to reduce the reservoir in patients treated at the time of primary infection for a sustainable remission.

Abstract Radiographic oral and maxillofacial findings were recorded in a cohort of 293 home living elderly, in Helsinki, Finland, derived from a random sample of 8035 subjects, , born in 1904, 1909, and 1912, who participated in the Helsinki Ageing Study. They were 76, 81, and 86 years old at the commencement of the radiographic study. The relationships of potentially infectious findings with increased all-cause mortality over four years were studied. During the four-year follow-up, 18.5% of the subjects died. Of the 124 edentulous subjects, 17% had condylar findings, 13% radiopaque intraosseous findings, 9% retained roots, 6% maxillary sinus findings, 4% impacted teeth and 3% radiolucent findings. Edentulous women had more arthrotic condylar findings than men. The mean number of teeth in the 169 dentate subjects was 13.9, 15.5 in men and 13.2 in women. Carious teeth were found in 75%, radiolucent findings in 41%, teeth with vertical infrabony pockets in 51%, furcation lesions in 28%, calculus in 40%, and condylar findings in 25%. Periodontal attachment loss was slight in 18%, moderate in 31%, and advanced in 46%. 21% of the teeth had been endodontically treated. Periapical lesions were found in 17% of these teeth, and in 4% of the other teeth. 75% of the rootfillings were inadequate, exhibiting periapical lesions twice as often as the adequate ones. Men had more carious teeth, periapical lesions and furcation lesions than women, indicating better oral hygiene and/or utilisation of dental services in women. Compared with the previous studies carried out in Finland, slightly more teeth and less tooth-associated pathology were found in the present subjects. In contemporary Scandinavian studies, only a slightly better oral health status in the elderly has been reported. During the four-year follow-up, mortality was higher in the subjects with moderate to advanced infrabony pockets, OR 2.2, 1.0-4.7. In the previous studies, similar associations have been found in larger study cohorts including younger subjects. Our results indicate that oral foci may be more dangerous for the elderly than it has been previously thought, as the subjects who died had poorer dental health than those who survived.

The asexual life cycle of Plasmodium falciparum parasites takes only 48 hours, allowing for rapid replication. The continuous infection, rupturing and re-infection of erythrocytes results in the pathogenicity of this disease. Schizogony (nuclear division) in P. falciparum parasites occurs via alternation between the S and M phases of the cell cycle where DNA synthesis occurs in the mature trophozoite and schizont stages, followed by mitosis to form daughter merozoites. Merozoites then give rise to ring stages after they have infected erythrocytes and the ring stages continue their development to trophozoites. This cyclic development, known as the intraerythrocytic developmental cycle, has a unique transcriptional regulation, which is closely linked to cell cycle regulation. However, the intricacies that these mechanisms are controlled by are still unidentified. One of the means in which the P. falciparum parasite’s complex life cycle is controlled is by means of epigenetics. Epigenetics refers to the heritable changes on a phenotypic level, which are independent of changes on a genetic level. One group of enzymes that participates in the parasite’s epigenetic control is the Plasmodium histone deacetylases. Inhibition of histone deacetylases (HDACs) results in hyperacetylation, which causes aberrant gene transcription and eventually results in parasite death. Comparative analyses of three histone isolation methods and analysis of P. falciparum parasite histones and their post-translational modifications (PTMs) by mass spectrometry techniques identified both epigenetically relevant and novel PTMs in P. falciparum parasite histones and led to the discovery of an adapted histone isolation method for investigation of histone PTM landscapes. When this modified method was used for the investigation of histones that were isolated from P. falciparum parasites treated with HDAC inhibitors compared to untreated parasites, differences were seen in the PTM landscape. Subsequent in silico screening strategies were used to identify ten compounds from the Medicines for Malaria Venture (MMV) Malaria Box, which target the active site of the zinc-requiring PfHDAC1. From these, eight compounds showed inhibition of proliferation of cultured P. falciparum parasites. Ensuing, the adaptation of an HDAC assay to investigate histone deacetylase inhibition was used to validate these compounds as possible PfHDAC1 inhibitors, with at least two of the compounds showing significant inhibition of PfHDAC1 activity, comparable to that of the known HDAC inhibitor, suberoylanilide hydroxamic acid, SAHA. The use of in silico screening of a large library of compounds, such as the MMV Malaria Box, successfully narrows down candidates for possible anti-malarials with drug-like properties by identification of their cellular targets. This work is method-based and facilitates the investigation of the epigenetic landscape of histones, and the identification of novel HDAC inhibitors. / Dissertation (MSc)--University of Pretoria, 2014. / gm2014 / Biochemistry / unrestricted

Class of 2015 Abstract / Objectives: Stenotrophomonas maltophilia is considered one of the most intrinsically resistant opportunistic infections in the hospital setting. Immunocompromised patients are at a significant risk for nosocomial S. maltophilia infection. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry can quickly identify S. maltophilia. This study sought to determine the median and range of time to appropriate therapy of S. maltophilia infections after implementation of MALDI-TOF-MS for rapid species identification. Methods: A retrospective electronic medical record review of patients admitted to UAMC-UC during the study period was utilized to determine time to appropriate therapy. Positive cultures for S. maltophilia were identified by the microbiology laboratory database and assessed for inclusion in the study. Demographic information, time of culture, time to appropriate therapy, and isolate susceptibilities were collected using a data extraction tool. Variables were assessed with medians and ranges. Results: The average time to appropriate therapy was 3.4 days with a median of 3 days (range 0-21). Most isolates were susceptible to sulfamethoxazole-trimethoprim and levofloxacin and resistant to ceftazidime. Of the 20 isolates resistant to sulfamethoxazole-trimethoprim, 14 were susceptible to levofloxacin. Only one isolate was resistant to all four drugs. Immunocompromised patients accounted for only 12% of the study population. Conclusions: After implementation of MALDI-TOF MS, the median time to appropriate therapy in S. maltophilia infection was 3 days. Rapid species identification can lead to a quicker time to appropriate therapy, which is essential for effective treatment of S. maltophilia infection.

Class of 2015 Abstract / Objectives: In 2011, the American Academy of Pediatrics released an updated urinary tract infection guideline that addressed diagnosis, antibiotic treatment, and duration of therapy in children ages 2-24 months. The objectives of this study were to evaluate the appropriateness of antibiotic prescribing and compare outcomes between age groups. Methods: This retrospective chart review included patients aged 1 month through 12 years admitted to a regional academic medical center from January through July 2014 and diagnosed with UTI or pyelonephritis. Patients were identified using ICD-9 codes. Demographic information, antibiotic treatment, length of stay, and complications were collected and the chi square statistical test was used to compare results between age groups. Results: There were 104 patients included in this study. The most common bacteria cultured were Escherichia coli (85%). Ceftriaxone (71%) and cephalexin (30%) were the most commonly prescribed empiric and discharge antibiotic, respectively. Based on guideline recommendations and culture results, inappropriate antibiotic selection only occurred with 7% of the orders while inappropriate prescribing occurred 35% of the time. Readmission within 90 days occurred in 15% of patients aged 2-24 months (guideline age group) and in 14% of all other patients (P>0.05). Conclusions: There was no difference between age groups with respect to inappropriate antibiotic prescribing or complications for pediatric UTI treatment and inappropriate antibiotic dosing occurred more frequently than inappropriate selection. More research is necessary to assess the impact of the guidelines on prescribing practices and factors associated with inappropriate prescribing.

Class of 2011 Abstract / OBJECTIVES: To evaluate the appropriateness of discharge antimicrobial medications for UTI in an adult population based on therapy prescribed. METHODS: In this retrospective chart review study the appropriateness of discharge antimicrobial therapy for patients admitted to an academic medical center during 3 weeks in 2010 was assessed based on culture results, estimated renal function, reported drug allergies, route of administration, and change in UTI from in-house to discharge prescribed therapy. RESULTS: A total of 35 patients with discharge UTI antimicrobials within the study period met inclusion criteria and were evaluated. According to available urinary culture and susceptibility data, 22 of 35 (62.8%) of received an appropriate antimicrobial therapy. Based on reported gastrointestinal function, all 35 patients could take oral medications but two patients with an appropriate oral therapy option received intravenous therapy. All patients were discharged with antimicrobials that were appropriate according to patients’ reported drug allergies and only one patient received an antimicrobial agent that was inappropriately adjusted based on the patient’s estimated renal function. UTI antimicrobial therapies were the same at 24 hours prior to discharge and as the discharge antimicrobial in 100% of patient cases evaluated CONCLUSION: The antimicrobial UTI discharge therapy was evaluated for appropriateness based on urine culture results, patients’ allergies, and patients’ estimated renal function. Overall, antimicrobial therapy was only appropriate in 22 of 35 (62.8%) of patients based on the available culture results.

There is a need for understanding the stories behind domestic violence and HIV/AIDS in women. Many research studies focus on the interaction between domestic violence and risky behaviours for HIV/AIDS infection and have ignored the experiences of women who are caught up in these situations. This study aims at exploring the experiences of HIV-positive women who are victims of domestic violence and tries to understand their feelings regarding their HIV status and the violence. Factors that contribute to the spread of HIV in women are also explored. It is argued that domestic violence and other socio-cultural factors are the driving forces behind the high incidence of HIV/AIDS in women. These factors also contribute to the continuation of dominant themes of domestic violence. The emerging stories further indicate that cultural factors situate women in positions that limit their ability to make decisions in the relationship, including sexual decisions. In the context of domestic violence, it not only becomes difficult for women to cope with their HIV diagnosis, but their positive HIV status also leads to the continuation of domestic violence. Copyright / Dissertation (MA)--University of Pretoria, 2010. / Psychology / unrestricted

Maternal tolerance during pregnancy increases the risk of infection with certain intracellular pathogens such as Salmonella enterica serovar Typhimurium (S.Tm). Systemic S.Tm infection during pregnancy in normally resistant 129X1/SvJ mice, with a functional natural resistance-associated macrophage protein-1 (Nramp1), leads to severe placental infection followed by fetal and maternal death. We hypothesized infection-induced inflammatory trophoblast cell death contributes to adverse pregnancy outcomes. We therefore investigated the kinetics of systemic and oral S.Tm infection in wild-type and gene deficient mice with defects in specific inflammatory pathways. Systemic infection with S.Tm resulted in preferential placental replication compared to other tissues in Nramp1+/+ mice. At 24 hours, <25% of individual placentas per mouse were infected, progressively increasing to >75% by 72 hours which correlated with a steady increase in resorption rates. Moreover, placental infection was associated with increased neutrophils, macrophages and natural killer cells whereas neutrophil numbers in the spleen remained unchanged, suggesting dichotomous modulation of inflammation in the systemic compartment compared to the feto-maternal interface. Oral infection resulted in systemic dissemination of the bacteria, substantial placental colonization and fetal loss five days post-infection in C57BL/6J mice. Systemic infection in pregnant cell death deficient Rip3-/-Nramp1+/+ mice (with defective necroptosis) resulted in decreased fetal demise relative to Nramp1+/+ and Caspase-1,11-/-Nramp1+/+ mice (with defective pyroptosis) suggesting a role for necroptotic inflammation. This study provides insight into the kinetics and mechanism of inflammation and cell death during placental S.Tm infection. Such studies may assist in the rational management of foodborne pathogens contracted during pregnancy.

Introduction. Infection prevention and control is both a national and international priority, with compliance with precautions being sub-optimal. One of the reasons suggested for poor compliance is a lack of appropriate education for health care professionals. There is a limited body of research available which considers infection prevention and control education for nursing students, particularly in clinical placements and no identified research in this area in midwifery. Aim. A body of research was undertaken with the overall aim of exploring and analysing the experiences and learning needs of nursing and midwifery students in relation to infection prevention and control in their clinical placements. Methods. An interpretivist approach was utilised to undertake semi-structured interviews with 32 nursing students, 15 midwifery students and 31 nurse mentors within a body of research comprising of three related studies. Date were analysed using Framework Analysis. Results. Several themes emerged from the body of work including the nature of infection prevention and control practice that is perceived as good or poor practice; attitudes towards infection prevention and control; barriers and motivators to learning about infection prevention and control; attitudes towards the infection prevention and control nurse and barriers to reporting poor practice. Conclusions. The body of work presented has several implications for future practice and research. New knowledge has been developed in particular in relation to perceptions of the role of the infection prevention and control nurse, barriers to reporting poor practice, the infection prevention and control education of midwifery students and the acceptance of poor practice as the norm. By triangulating findings from three separate but related studies, the research has been strengthened, providing additional support for the conclusions reached.

Introduction: Emerging pathogens (EP) in cystic fibrosis (CF) include organisms that have infected individuals with CF for many years e.g. Burkholderia multivorans and Mycobacterium abscessus and more recently identified potential pathogens in CF e.g. Pneumocystis jirovecii and Pandoraea spp. The clinical implications of infection with these organisms are emerging but much remains unknown. Current evidence suggests that infection with some EP is associated with a worse prognosis. This thesis aimed to investigate the epidemiology, prevalence and clinical impact of EP in adults with CF.Methods: (1) The prevalence of P. jirovecii was determined in adults attending Manchester Adult Cystic Fibrosis Centre (MACFC) who were clinically stable versus those experiencing an acute pulmonary exacerbation (PEx). (2) The prevalence of M. abscessus at MACFC was determined, isolates of M. abscessus were strain typed, and cross infection risk was assessed. The clinical impact of Gram-negative EP was assessed by: (3) assessing their prevalence and determining if any patients attending MACFC harboured identical strains and had opportunities for cross infection to occur, and by (4) following these patients longitudinally and comparing outcome with age, gender and FEV1 matched Pseudomonas aeruginosa infected controls. Results: (1) P. jirovecii was detected via sputum PCR in 10 (4.4%) of 226 samples tested from 111 patients. P. jirovecii was more likely to be detected in samples taken from an acute pulmonary exacerbation compared with samples taken from stable patient visits (7 (9.2%) of 76 exacerbations samples versus 3 (2%) of 150 stable visit samples, p = 0.033). (2) Prevalence of M. abscessus was stable at ≤3.6% from 2010 to 2015. 21 patients (91.3%) with a positive culture for M. abscessus since 2010 were infected with M. abscessus subsp abscessus. 2 clusters of 7 and 6 patients harboured strains with identical variable number tandem repeat profiles and some of these patients had opportunities for cross infection to occur. 28.6% of patients developed M. abscessus pulmonary disease, 38.1% were persistently culture positive with no related pulmonary disease, and 33.3% spontaneously cleared M. abscessus from their sputum. (3) Prevalence of Gram-negative EP ranged from 1.9% (Ralstonia spp.) to 6.2% (B. multivorans). Small numbers of patients shared strains of B. multivorans; Stenotrophomonas S. maltophilia and Achromobacter; Ralstonia and Pandoraea species. Epidemiological connections consistent with possible cross infection were found in patients infected with Pandoraea and Ralstonia species. (4) Patients with B. multivorans; S. maltophilia; Ralstonia spp. and Pandoraea spp. had higher antibiotic requirements than P. aeruginosa infected matched controls. B. multivorans; Achromobacter spp.; Ralstonia spp. and Pandoraea spp patients had median FEV1 (% predicted) values ≥10% (absolute) lower than the overall median FEV1.Conclusion: Prevalence of all EP investigated at MACFC was low. P. jirovecii was approximately 5 times more likely to be detected in patients with acute PEx compared with stable patients suggesting it may be a cause of PEx. Results suggest that some patients attending MACFC may have acquired infection with M. abscessus subsp abscessus, Pandoraea spp. or Ralstonia spp. through cross infection. Patient numbers are too small to establish this with certainty and a common environmental source is possible. Gram-negative EP other than Achromobacter spp. were associated with higher acute antibiotic requirements than P. aeruginosa matched controls suggesting these EP are associated with an increased risk of PEx. The fact that many Gram-negative EP were associated with lower median lung function may indicate that these EP cause accelerated lung function decline or that patients with more advanced disease are at most risk of acquiring EP.