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Abstract Oncogenic KRAS plays a vital role in controlling tumor metabolism by enhancing aerobic glycolysis. Obesity driven by chronic consumption of high-fat diet (HFD) is a major risk factor for oncogenic KRAS-mediated pancreatic ductal adenocarcinoma (PDAC). However, the role of HFD in KRAS-mediated metabolic reprogramming has been obscure. Here, by using genetically engineered mouse models expressing an endogenous level of KRASG12D in pancreatic acinar cells, we demonstrate that hyperactivation of KRASG12D by obesogenic HFD, as compared to carbohydrate-rich diet, is responsible for enhanced aerobic glycolysis that associates with critical pathogenic responses in the path towards PDAC. Ablation of Cox-2 attenuates KRAS hyperactivation leading to the reversal of both aggravated aerobic glycolysis and high-grade dysplasia under HFD challenge. Our data highlight a pivotal role of the cooperative interaction between obesity-ensuing HFD and oncogenic KRAS in driving the heightened aerobic glycolysis during pancreatic tumorigenesis and suggest that in addition to directly targeting KRAS and aerobic glycolysis pathway, strategies to target the upstream of KRAS hyperactivation may bear important therapeutic value.

Abstract Background Dizziness and vertigo affect around 15% of adults annually and represent common reasons for contacting health services, accounting for around 3% of all emergency department visits worldwide. Vertigo is also associated with excessive use of diagnostic imaging and emergency care and decreased productivity, primarily because of work absenteeism. Vestibular rehabilitation is an evidence-based treatment for chronic dizziness and supervised group exercise therapy has recently been shown to be effective after vestibular neuritis, a common cause of acute onset vertigo. However, such interventions are not readily available and there is a need for more easily accessible tools. The purpose of this study is to investigate the effects on vestibular symptoms of a 6-week online vestibular rehabilitation tool after acute onset vertigo, with the aim of aiding vestibular rehabilitation by presenting a more accessible tool that can help to reduce recovery time. Methods Three hundred twenty individuals diagnosed with acute vestibular syndrome (AVS) will be recruited from multiple hospitals in Sweden and the effects of an online vestibular rehabilitation tool, YrselTräning, on vestibular symptoms after acute onset vertigo will be compared to standard care (written instructions leaflet) in a two-armed, evaluator-blinded, multicenter randomized controlled trial. The primary outcome will be the Vertigo Symptom Scale Short Form (VSS-SF) score at 6 weeks after symptom onset. Secondary outcomes include effects of the intervention on activities of daily living, mood and anxiety, vestibular function recovery, mobility measures, health economic effects, and the reliability of the Swedish VSS-SF translation. Discussion Participants using the online vestibular rehabilitation tool are expected to recover earlier and to a greater extent from their symptoms as compared to standard care. Since up to 50% of people with AVS without treatment develop persistent symptoms, effective treatment of AVS will likely lead to a higher quality of life and help reduce the societal costs associated with dizziness and vertigo. Trial registration Clinicaltrials.gov NCT05056324 . Registered on September 24, 2021.

Abstract Background Critically ill COVID-19 patients may develop acute respiratory distress syndrome and the need for respiratory support, including mechanical ventilation in the intensive care unit. Previous observational studies have suggested early tracheotomy to be advantageous. The aim of this parallel, multicentre, single-blinded, randomized controlled trial was to evaluate the optimal timing of tracheotomy. Methods SARS-CoV-2-infected patients within the Region Västra Götaland of Sweden who needed intubation and mechanical respiratory support were included and randomly assigned to early tracheotomy (≤ 7 days after intubation) or late tracheotomy (≥ 10 days after intubation). The primary objective was to compare the total number of mechanical ventilation days between the groups. Results One hundred fifty patients (mean age 65 years, 79% males) were included. Seventy-two patients were assigned to early tracheotomy, and 78 were assigned to late tracheotomy. One hundred two patients (68%) underwent tracheotomy of whom sixty-one underwent tracheotomy according to the protocol. The overall median number of days in mechanical ventilation was 18 (IQR 9; 28), but no significant difference was found between the two treatment regimens in the intention-to-treat analysis (between-group difference: − 1.5 days (95% CI − 5.7 to 2.8); p = 0.5). A significantly reduced number of mechanical ventilation days was found in the early tracheotomy group during the per-protocol analysis (between-group difference: − 8.0 days (95% CI − 13.8 to − 2.27); p = 0.0064). The overall correlation between the timing of tracheotomy and days of mechanical ventilation was significant (Spearman’s correlation: 0.39, p

Abstract Background The generation of human induced pluripotent stem cells (hiPSCs) has opened a world of opportunities for stem cell-based therapies in regenerative medicine. Currently, several human kidney organoid protocols are available that generate organoids containing kidney structures. However, these kidney organoids are relatively small ranging up to 0.13 cm2 and therefore contain a small number of nephrons compared to an adult kidney, thus defying the exploration of future use for therapy. Method We have developed a scalable, easily accessible, and reproducible protocol to increase the size of the organoid up to a nephron sheet of 2.5 cm2 up to a maximum of 12.6 cm2 containing a magnitude of nephrons. Results Confocal microscopy showed that the subunits of the nephrons remain evenly distributed throughout the entire sheet and that these tissue sheets can attain ~ 30,000–40,000 glomerular structures. Upon transplantation in immunodeficient mice, such nephron sheets became vascularized and matured. They also show reuptake of injected low-molecular mass dextran molecules in the tubular structures, indicative of glomerular filtration. Furthermore, we developed a protocol for the cryopreservation of intermediate mesoderm cells during the differentiation and demonstrate that these cells can be successfully thawed and recovered to create such tissue sheets. Conclusion The scalability of the procedures, and the ability to cryopreserve the cells during differentiation are important steps forward in the translation of these differentiation protocols to future clinical applications such as transplantable auxiliary kidney tissue.

Abstract Background Dizziness is a common complaint among older adults and may affect quality of life in a negative way. The aim of this study was to assess health-related quality of life (HRQL), sense of coherence (SOC), self-rated health (SRH) and comorbidity in relation to dizziness, among older persons from an urban population. Methods The study is part of the Gothenburg H70 Birth Cohort Studies (H70). A cross-sectional population-based sample including 662 79-years-olds (404 women, 258 men, 62% response rate) were surveyed with questions regarding dizziness, imbalance, comorbidities and general health. HRQL was assessed using the 36-item Short Form-36 Health Survey (SF-36) and SOC with the 13-items questionnaire Sense of Coherence (SOC-13). Results Half of the participants reported problems with dizziness (54%). Dizziness was negatively associated with HRQL, including after adjusting for comorbidities, especially in the physical domains of SF-36. Having dizziness was also associated with poorer SRH, tiredness and comorbidity among both men and women. SOC (mean total score), however, did not differ between dizzy and non-dizzy participants. Conclusions Dizziness was negatively associated with HRQL, also after adjusting for comorbidities. Identification and treatment of dizziness, when possible, are important because reduction of dizziness symptoms may potentially help to enhance overall well-being in this age group.

Abstract Background Patients with chronic kidney disease (CKD) and arterial calcification are considered at increased risk of adverse cardiovascular outcomes. However, the optimal site for measurement of arterial calcification has not been determined. The primary aim of this study was to examine the pattern of arterial calcification in different stages of CKD. Methods This was an observational, cross-sectional study that included 580 individuals with CKD stages 1–5 (no dialysis) from the Copenhagen CKD Cohort. Calcification of the carotid, coronary and iliac arteries, thoracic and abdominal aorta was assessed using non-contrast multidetector computed tomography scans and quantified according to the Agatston method. Based on the distribution of Agatston scores in the selected arterial region, the subjects were divided into calcium score categories of 0 (no calcification), 1–100, 101–400 and > 400. Results Participants with CKD stages 3–5 had the highest prevalence of calcification and the highest frequency of calcium scores > 400 in all arterial sites. Calcification in at least one arterial site was present in > 90% of patients with CKD stage 3. In all five CKD stages prevalence of calcification was greatest in both the thoracic and abdominal aorta, and in the iliac arteries. These arterial sites also showed the highest calcium scores. High calcium scores (> 400) in all five arterial regions were independently associated with prevalent cardiovascular disease. In multivariable analyses, after adjusting for cardiovascular risk factors, declining creatinine clearance was associated with increasing calcification of the coronary arteries (p = 0.012) and the thoracic aorta (p = 0.037) only. Conclusions Arterial calcification is highly prevalent throughout all five CKD stages and is most prominent in both the thoracic and abdominal aorta, and in the iliac arteries. Follow-up studies are needed to explore the potential of extracardiac calcification sites in prediction of cardiovascular events in the CKD population.