Using intracerebral microdialysis to probe the efficacy of repurposed drugs in Alzheimer′s disease pathology

All disease-targeting drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer′s disease patients. Even the recently approved drug Aducanumab, has proven effective in removing amyloid-β, but does not reduce cognitive decline. This emphasizes the urgent need for novel therapeutic approaches that could reduce several AD neuropathologies simultaneously, eventually leading to improved cognitive performance. To validate whether our mouse model replicates AD neuropathology as observed in patients, we characterized the 3xTg AD mouse model to avoid premature translation of successful results. In this study we have repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting the Wnt signaling and endosomal-lysosomal pathway respectively, to test their potential to attenuate AD pathology. Using intracerebral microdialysis, we simultaneously infused these disease-targeting drugs between 1-2 weeks, separately and also in combination, while collecting cerebrospinal fluid. We found that Fasudil reduces intracellular amyloid-β in young, and amyloid plaques in old animals, and overall cerebrospinal fluid amyloid-β. Lonafarnib reduces tau neuropathology and cerebrospinal fluid tau biomarkers in young and old animals. Co-infusion of both drugs was more effective in reducing intracellular amyloid-β than either drug alone, and appeared to improve contextual memory performance. However, an unexpected finding was that Lonafarnib treatment increased amyloid plaque size, suggesting that activating the endosomal-lysosomal system may inadvertently increase amyloid-β pathology if administered too late in the AD continuum. Taken together, these findings lend support to the application of repurposed drugs to attenuate AD neuropathology at various therapeutic time windows.

Audiobook routines: identifying everyday reading by listening practices amongst young adults

Purpose This article explores, identifies and conceptualises everyday audiobook reading practices amongst young adults.Design/methodology/approach Semi-structured interviews were conducted with ten Swedish audiobook users aged 18–19. The material was analysed using qualitative content analysis and focused on their audiobook use during an average weekday, as this was the time that they listened the most. The theoretical framework consists of theories on practice, time and everyday routine.Findings Five timespaces emerged when audiobook practices were most prevalent: morning routines, commuting routines, school routines, after school routines and bedtime routines. Within these timespaces, several practices could be identified and conceptualised. Three mobile practices were commute listening, exercise listening and chore listening while more stationary practices were homework listening, schoolwork listening and leisure listening. An unexpected finding was how audiobooks routinely were used to aid respondents’ wellbeing. This wellbeing listening was used to alleviate stress, loneliness and help listeners relax or fall asleep. Furthermore, respondents switch between Music, Audiobooks and Podcasts, which is conceptualised as MAP-switching.Originality/value There is a scarcity of research on audiobook use, and this paper contributes with new knowledge on audiobook reading practices, how audiobooks fit into everyday routine and provides concepts to aid further research on audiobook practices.

Age of exposure and subject/object asymmetries when wh-movement goes rightward

We report an experiment addressing the comprehension of LIS interrogatives in three adult populations with different times of exposure to sign language: native signers, early signers, and late signers. We investigate whether delayed exposure to language affects comprehension of interrogatives and whether there is an advantage for subject dependencies over object dependencies, as systematically reported for spoken languages. The answer to the first question is positive: there is evidence that natives outperform non-native signers, confirming permanent effects of delayed exposure to sign language even decades after childhood. However, the performance in subject interrogatives was lower than in object interrogatives in all groups of participants. We discuss several possible reasons for this unexpected finding.

Transjugular venous approach for Piccolo patent ductus arteriosus closure in a 1.4 kg infant

Transfemoral venous approach is the standard method for transcatheter patent ductus arteriosus closure using the Amplatzer Piccolo patent ductus arteriosus occluder in small infants. We report a 1.4 kg infant who underwent transcatheter Piccolo patent ductus arteriosus closure. Transjugular venous approach was taken due to the unexpected finding of interrupted inferior vena cava.

740 A case of acute Campylobacter COLI myocarditis post-mRNA anti-SARS-CoV-2 vaccine. Was vaccination an innocent bystander or a determining factor?

A 24-year-old healthy man, smoker (2 pack-years), was admitted to the Cardiology Unit for chest pain and fever occurred 2 days after anti-SARS-CoV-2 vaccination. There were no pathological findings at physical examination. The electrocardiogram showed diffuse ST elevation. Laboratory tests showed a significant increment of Troponin I levels (4697 ng/l → 6236 ng/l after 3 h), White Blood Cells (17 610/mmc) and C-Reactive Protein (8.36 mg/dl). Echocardiography showed normal left ventricular systolic function with no evidence of pericarditis. These findings were consistent with a probable case of acute myocarditis. Cardiac magnetic imaging demonstrated myocardial oedema of the posterior wall of the left ventricle at T2-weighted images, with patchy areas of subepicardial late gadolinium enhancement. Based on Centers for Disease Control and Prevention myocarditis diagnostic criteria, a diagnosis of acute myocarditis was made and treatment with Non-Steroidal Anti-Inflammatory Drugs was started. Regarding etiology agent determination, in the COVID19 era, the first suspect was anti-SARS-CoV-2 mRNA-vaccine-induced myocarditis. Several case series and analyses of a large national health care organization database helped to identify features linked to these types of myocarditis. The highest incidence was observed among male juvenile subjects, usually 48–72 h after the second dose of vaccination, with elevated levels of spike antibody for SARS-CoV-2. Nevertheless, in the presented clinical case, the patient had received the first dose of BNT162b2 vaccination two days before hospital admission and showed negative serology tests for SARS-CoV-2. In recent medical history, two days before the onset of fever and chest pain, the patient had episodes of diarrhea which persisted during the first week of hospitalization. All immunological and microbiological tests result negative, except for a stool culture positive for Campylobacter coli. Interestingly a revision of literature showed several cases of myocarditis linked to Campylobacter species. In particular, of 13 reported cases, 12 (92%) were male with a mean age of 26 ± 8.8 years, and cardiac symptoms present generally 2–4 days after diarrhea. In this particular setting, the first and more obvious hypothesis was strongly questioned because of an unexpected finding in the stool culture. In fact, Campylobacter spp. related myocarditis is an extremely rare condition, even if this pathogen is associated with important immunological interferences, as shown by its relationship with the Guillain-Barre syndrome. Further, myocarditis related to mRNA anti-SARS-CoV-2 vaccine is considered a rare complication. We hypothesized that the association of the two components could have acted synergistically to produce an immune system activation against cardiac muscle. Additional investigations are required to clarify the link between vaccination and possible improper immune response. In conclusion, this case represents a typical example in which the cause of the disease should be well investigated because the initial etiological theory is not definitive, especially in the SARS-CoV-2 era.

Effects of blood loss on organ attenuation on postmortem CT and organ weight at autopsy

Background Cases of external hemorrhage are difficult to recognize on postmortem computed tomography (PMCT). Purpose To investigate the effects of blood loss on CT attenuation of the spleen, liver, kidneys, and lungs on PMCT and to assess the relationship between blood loss and organ weight. Methods A total of 125 cases with blood loss were sex- and age-matched to 125 control cases without blood loss. Individual organ attenuation was measured on transverse CT images. Organ weights of the liver, spleen, kidneys, and lung were extracted from the autopsy protocols. Results Organ weight was significantly lower in cases with blood loss (lung 30%, spleen 28%, kidneys 14%, liver 18%) than in controls. CT attenuation of the lungs was significantly lower (30%) in cases with blood loss than in controls. CT attenuation of the spleen and kidneys did not significantly differ between cases and controls. CT attenuation of the liver was significantly higher (25%) in cases with blood loss than in controls. Conclusion Blood loss decreases organ weight and CT attenuation of the lungs but appears to have no significant effect on CT attenuation of the spleen and kidneys. The increased liver attenuation in cases with blood loss compared to controls was an unexpected finding and remains challenging to explain. One probable interpretation refers to different levels of hepatic glycogen; however, further work is warranted to substantiate this hypothesis.

Chapman: To be or not to be

<p>Declining core business in the conventional beverage categories of beer and carbonated sodas has compelled companies to turn to innovation to grow their sales and profitability. The research focus of this project was to determine, through adjacent category innovation whether my new branded premium craft carbonated soda product range was a consumer relevant innovation, scalable and therefore able to sustainably enhance market growth and profitability for my project partner, DB Breweries. A mixed methods research approach using qualitative and quantitative surveys revealed strong consumer preferences for the product to be authentic, artisanal, premium, health focussed and particularly targeted to females, older consumers and as an alternative to alcohol. These findings represented market opportunities, however, the clear-cut preference for a homespun, handcrafted, local and small batched produced product as opposed to mass machine manufactured, was an unexpected finding with significant implications for the project. This core finding created a tension between the preference for authenticity and the original concept of leveraging my project partner’s scale machine based manufacturing capacity. These findings and my advisory board’s guidance reshaped the business model canvas, proposing a joint venture between Chapman (my company) and my project partner, which as an established beverage company would bring know-how and distribution with my company being the entrepreneurial, authentic, artisanal, small batch producer. The reshaped strategy and business model shifted the adjacent category innovation from a product to a geographical perspective, with export potential to China and possibly the Muslim market. The online sales channel in China has significant export appeal with its deep retail market penetration and rapid growth, but very low current penetration in the beverage category which is forecast for significant growth. Successful export entry into China would establish a potential platform to enter segments of the global Muslim market, a commercially attractive market for premium non-alcoholic beverages. A deeper understanding of the rapidly growing negative consumer perception of artificial sweeteners led to a further innovative opportunity emerging from this project. As a consequence of this intersectional thinking a sub-project to develop a New Zealand natural sweetener based on indigenous plants, fruits or trees commenced. This research project has revealed the new branded premium carbonated soda product range to be a consumer relevant innovation, scalable but not as a straight forward product adjacent category innovation and with export success has the potential to significantly enhance market growth and profitability for DB Breweries. This project is now on a trajectory to be commercialised.</p>

Chapman: To be or not to be

<p>Declining core business in the conventional beverage categories of beer and carbonated sodas has compelled companies to turn to innovation to grow their sales and profitability. The research focus of this project was to determine, through adjacent category innovation whether my new branded premium craft carbonated soda product range was a consumer relevant innovation, scalable and therefore able to sustainably enhance market growth and profitability for my project partner, DB Breweries. A mixed methods research approach using qualitative and quantitative surveys revealed strong consumer preferences for the product to be authentic, artisanal, premium, health focussed and particularly targeted to females, older consumers and as an alternative to alcohol. These findings represented market opportunities, however, the clear-cut preference for a homespun, handcrafted, local and small batched produced product as opposed to mass machine manufactured, was an unexpected finding with significant implications for the project. This core finding created a tension between the preference for authenticity and the original concept of leveraging my project partner’s scale machine based manufacturing capacity. These findings and my advisory board’s guidance reshaped the business model canvas, proposing a joint venture between Chapman (my company) and my project partner, which as an established beverage company would bring know-how and distribution with my company being the entrepreneurial, authentic, artisanal, small batch producer. The reshaped strategy and business model shifted the adjacent category innovation from a product to a geographical perspective, with export potential to China and possibly the Muslim market. The online sales channel in China has significant export appeal with its deep retail market penetration and rapid growth, but very low current penetration in the beverage category which is forecast for significant growth. Successful export entry into China would establish a potential platform to enter segments of the global Muslim market, a commercially attractive market for premium non-alcoholic beverages. A deeper understanding of the rapidly growing negative consumer perception of artificial sweeteners led to a further innovative opportunity emerging from this project. As a consequence of this intersectional thinking a sub-project to develop a New Zealand natural sweetener based on indigenous plants, fruits or trees commenced. This research project has revealed the new branded premium carbonated soda product range to be a consumer relevant innovation, scalable but not as a straight forward product adjacent category innovation and with export success has the potential to significantly enhance market growth and profitability for DB Breweries. This project is now on a trajectory to be commercialised.</p>