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Coming theses from other universities

  • Unresolved Controversies in Child Pneumonia in low and middle income Countries. Author: Nick Brown Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-439329 Publication date: 2021-05-04 12:09

    There has been a fall globally in pneumonia-related fatality in children during the Millennium Development and early Sustainable Development Goal era.

    However, pneumonia remains the single largest contributor to mortality with issues including antibiotic resistance, pollution, a change in infective epidemiology, equipoise over effects of adjunctive treatments and identification of sick, decompensating children. 

    This thesis examines 4 of these controversies as original research.

    Theme 1; two papers, 1 and 2: The first discusses the background motivation. The second a large randomized, non-inferiority controlled trial undertaken (‘RETAPP’) in a suburban slum area of Karachi, Pakistan. Oral amoxicillin treatment was compared with placebo, in the treatment of WHO-defined, uncomplicated, fast breathing pneumonia.

    Theme 2 (paper 3) The role of indoor air pollution and poverty in recurrent fast breathing pneumonia: a nested case control study.

    Theme 3 (paper 4). The role of adjunctive use of zinc to standard treatment in children with severe pneumonia: a systematic review and meta-analysis of randomised controlled trials.

    Theme 4 (paper 5). Recognition of the child with severe respiratory illness using the Clinical Respiratory Score in the emergency department 

    Results: In the RETAPP study, 4,002 randomised children were enrolled. There was a significant difference in treatment failure rates in the amoxicillin and placebo groups (2.6 % vs 4.9 %). The number needed to treat was high at 44, and mortality very low and similar in both groups, discussion points for policy makers.

    There does not appear to be an enhanced risk with Indoor Air Pollution in recurrence of pneumonia. The only predictor was household poverty: external pollution could be a factor.

    Adjunctive zinc confers no additional advantage to children with severe pneumonia.

    The clinical respiratory score is a highly sensitive, but non-specific marker for severe illness.

    Conclusions: The small, though significant, differences in treatment failure rates in fast breathing pneumonia are likely to have implications for setting of management.

    The role of environmental predictors needs to turn to poverty and external pollution.

    Zinc has no role as an adjunctive treatment. The clinical respiratory score has excellent predictive value for severe illness.

  • The role of HMG-coenzyme A reductase (HMGCR) and statin medication in the Central Nervous System : Cognitive Functions, Metabolism, Feeding and Sleep Behaviour Author: Ahmed Alsehli Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-439049 Publication date: 2021-04-29 10:25

    Millions of people are currently on statin medications (HMGCR inhibitors) to prevent cardiovascular diseases. Despite considerable central nervous system expression, little is known about HMGCR function in the brain. In Paper I, we used Drosophila and rodent models and found that inhibiting Hmgcr expression in the insulin-producing cells of the Drosophila hypothalamus equivalent, known as the pars intercerebralis (PI), throughout development, significantly reduces the expression of Insulin–like peptides 2 and 3 (ILP2 and ILP3), severely decreasing insulin signalling. This reduction causes decreased body size, hyperglycemia, increased lipid storage, and hyperphagia. We also discovered that Farnesyl pyrophosphate synthase (Fpps), an enzyme downstream of Hmgcr in the mevalonate pathway, is required for ILP2 expression in the PI. In rodents, acute inhibition of hypothalamic Hmgcr stimulates food intake as well. Furthermore, in rats, we found two regions within the hypothalamus that had significantly increased neural activity, the paraventricular nucleus and arcuate nucleus, which are known to regulate food intake. In Paper II, we explored the effects of statins on cognition and performed an observational study on a population-based sample from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups. Subjects were classified depending on age (up to 65 and over 65 years). The effect of statin use differed between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. In Paper III, we examined association of single nucleotide polymorphisms within the HMGCR gene, rs17238484 and rs12916, with self-reported insomnia symptoms. We found that statin users are associated with a higher risk for self-reported insomnia. The HMGCR genetic variants were also associated with self-reported insomnia, but in different manner. Carriers the rs12916-T risk allele had a protective effect from insomnia symptoms. No associations were found for either statin takers or carriers of these HGCMR risk alleles and late evening chronotype. The increased risk of insomnia noted with statins is partially explained by a mechanism that might be independent of HMGCR inhibition. In Paper IV, we discovered a novel role for Hmgcr in sleep regulation in Drosophila, where lacking of pan-neuronal Hmgcr expression causes sleep-promoting effects. We also found that loss of Hmgcr expression specifically in the PI insulin-producing cells, recapitulates the effect of pan-neuronal Hmgcr inhibition. Conversely, inhibiting Hmgcr in only six PI DH44 expressing neurons has the opposite effect on sleep, increasing sleep latency and decreasing sleep duration. This bi-functional property of Hmgcr in the fly brain underlies its importance in sleep regulation. Furthermore, loss of Hmgcr showed no effect on circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock.

  • Atypical femoral fractures: Another brick in the wall : On aspects of healing, treatment strategies and surveillance Author: Hans Peter Bögl Link: http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-175309 Publication date: 2021-04-26 15:44

    Atypical femoral fractures are stress fractures of the femoral subtrochanteric and diaphyseal region. It is a common notion that these fractures heal poorly, if at all. In this thesis we show that patients with atypical femoral fractures have a good capacity to generate bone and therefore heal fractures. In daily practice, these patients have a higher risk for reoperation when compared with patients with a normal femoral fracture. However, this risk is less likely to be dependent on the type of fracture than other factors such as age, gender, comorbidities and survival. Using an implant that protects the fragile proximal femur, the risk for reoperations can be attenuated dramatically. An intramedullary nail with fixation of the femoral neck protects the femur from subsequent hip fractures – the most common complication in elderly patients with any type of femoral shaft fracture.

    Atypical femoral fractures are difficult to identify in the population. Erroneous diagnosis coding, poor reporting of adverse drug reactions and low accuracy of radiology reports make the identification and surveillance a difficult task. The Swedish Fracture Register has provided the option to register this special fracture since 2015. With its physician-based registration process, it enables researchers and treating physicians to identify and follow these rare fractures longitudinally.

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