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1.AbstractBackgroundType 2 diabetes (T2D) is a leading cause of both chronic kidney disease (CKD) and onward progression to end stage renal disease. Timely diagnosis coding of CKD in patients with T2D could lead to improvements in quality of care and patient outcomes.AimTo assess the consistency between estimated glomerular filtration rate (eGFR) based evidence of CKD and CKD diagnosis coding in UK primary care.Design and SettingA retrospective analysis of electronic health record data in a cohort of people with type 2 diabetes from 60 primary care centres within England between 2012 and 2022.MethodWe estimated the incidence rate of CKD per 100 person-years using eGFR-based CKD and diagnosis codes. Logistic regression was applied to establish which attributes were associated with diagnosis coding. Time from eGFR-based CKD to entry of a diagnosis code was summarised using the median and interquartile range.ResultsThe overall incidence of CKD was 2.32 (95% CI: 2.24, 2.41) and significantly different between eGFR-based criteria and diagnosis codes: 1.98 (95% CI: 1.90, 2.05) vs 1.06 (95% CI: 1.00, 1.11) respectively; pConclusionDiagnosis coding of patients with eGFR-based evidence of CKD in UK primary care is poor within patients with type 2 diabetes, despite CKD being a well-known complication of diabetes.2.How this fits inType 2 diabetes is a recognised cause of chronic kidney disease (CKD), and early identification and management of CKD can reduce the risk of progression and related complications. Diagnosis coding of CKD is associated with better patient outcomes, yet we have observed that less than half of patients with type 2 diabetes who meet eGFR-based criteria for stage 3-5 CKD have a CKD diagnosis code in their primary care record. There is a need to understand why CKD diagnosis coding practices are subpar in primary care and this research acts as a call-to-action to improve.

IntroductionWe performed a systematic review of comorbidities and symptoms of adult patients with coronavirus disease 2019 (COVID-19) to evaluate comorbidities, symptoms, and severity.Material and methodsWe searched databases and extracted comorbidities and symptoms from the included studies. We stratified the similar signs and symptoms in groups and on the basis of severity and compared them with stratified analysis. Individual case reports and case series with < 5 patients were excluded.ResultsA total of 163 studies with 43,187 patients were included. Mean age was 54.6 years. There were significantly fewer women in the study (43.9% vs. 56.1%, p < 0.0001). Prevalent cardiovascular comorbidities were hypertension (31.9%), obesity (27.9%), hyperlipidemia (26.4%), smoking (18.9%), diabetes mellitus (17.2%), atherosclerotic disease (9.2%) and arrhythmia (5.0%). The most frequently reported constitutional symptoms of COVID-19 were fever (73.9%), fatigue (33.4%), malaise (29.9%), myalgia and/or arthralgia (19.2%), generalized weakness (19.0%), and chills (11.3%). For the cardiovascular system, chest pain and/or tightness were most often reported (19.6%), followed by palpitations (5.2%). Hypertension and diabetes were common in severe disease. Obesity and congestive heart failure were not observed in any non-severe cases. Severe cases compared to non-severe cases more frequently had fever (87.8% vs. 58.5%, p < 0.001), shortness of breath (47.4% vs. 20.6%, p < 0.001), cough (66.8% vs. 62.9%, p < 0.001), sputum production (35.4% vs. 26.5%, p < 0.001) and rhinorrhea (32.2% vs. 7.3%, p < 0.001).ConclusionsHypertension, diabetes, and atherosclerotic diseases are common comorbidities across the world, with obesity as the second most common in the US and more common in men.

Background: The level of representation of women in cardiology remains low compared to that of men, particularly in leadership positions. We evaluated gender disparity in the authorship of Canadian Cardiovascular Society (CCS) guidelines. Methods: All CCS guidelines from 2001-2020 were identified. Gender was assessed based on pronoun use in the biographies and social media of the authors. Only primary panel authors were included in our analysis. Stratified analyses were performed based on subspecialties. Results: A total of 76 guidelines were identified, with 1172 authors (26% women, 74% men, P < 0.0001), with no significant change in percentage of women authors over 2 decades, (37.1% in 2001, 36.3% in 2020, P = 0.34). Inclusion of women as authors occurred less frequently than inclusion of men in general cardiology guidelines (20.1% vs 79.9%, P < 0.0001) and all subspecialties—heart failure (36.4% vs 63.6%, P < 0.0001), interventional cardiology (12.6% vs 87.4%, P < 0.0001), electrophysiology (20.2% vs 79.8%, P < 0.0001), and pediatric cardiology (41.7% vs 58.3%, P = 0.02). It was less likely for women to be a chair or cochair of a guideline writing committee, compared with men (20.1% vs 79.8%, P < 0.0001). There were 609 unique authors (25.6% women, 74.4% men, P < 0.0001), 542 unique medical doctorate (MD) authors (20.7% women, 79.3% men, P < 0.0001), and 67 unique non-MD authors (65.7% women, 34.3% men, P = 0.0003). Conclusions: There is a persistent shortfall in the inclusion of women authors for CCS guidelines, which has not changed over time. Further efforts are required to promote women's inclusion in leadership roles, which may lead to authorship of the guidelines. Résumé: Introduction: La représentation des femmes en cardiologie demeure faible par rapport à celle des hommes, particulièrement dans les positions de leadership. Nous avons évalué la disparité entre les sexes de la paternité des lignes directrices de la Société canadienne de cardiologie (SCC). Méthodes: Nous avons relevé toutes les lignes directrices de la SCC de 2001 à 2020. Nous avons déterminé le sexe en fonction de l'utilisation du pronom dans les biographies et les médias sociaux des auteurs. Seuls les auteurs du panel principal ont été ajoutés à notre analyse. Nous avons réalisé les analyses stratifiées en fonction des sous-spécialités. Résultats: Nous avons relevé un total de 76 lignes directrices, qui regroupaient 1 172 auteurs (26 % de femmes, 74 % d'hommes, P

Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform (PrPSc). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being the most common form. Currently, no treatment is available for prion diseases. Cellular cholesterol is known to impact prion conversion, which in turn results in an accumulation of cholesterol in prion-infected neurons. The major elimination of brain cholesterol is achieved by the brain specific enzyme, cholesterol 24-hydroxylase (CYP46A1). Cyp46A1 converts cholesterol into 24(S)-hydroxycholesterol, a membrane-permeable molecule that exits the brain. We have demonstrated for the first time that Cyp46A1 levels are reduced in the brains of prion-infected mice at advanced disease stage, in prion-infected neuronal cells and in post-mortem brains of sCJD patients. We have employed the Cyp46A1 activator efavirenz (EFV) for treatment of prion-infected neuronal cells and mice. EFV is an FDA approved anti-HIV medication effectively crossing the blood brain barrier and has been used for decades to chronically treat HIV patients. EFV significantly mitigated PrPSc propagation in prion-infected cells while preserving physiological PrPC and lipid raft integrity. Notably, oral administration of EFV treatment chronically at very low dosage starting weeks to months after intracerebral prion inoculation of mice significantly prolonged the lifespan of animals. In summary, our results suggest that Cyp46A1 as a novel therapeutic target and that its activation through repurposing the anti-retroviral medication EFV might be valuable treatment approach for prion diseases.

Cavitation in ball valve was numerically investigated using Computational Fluid Dynamics (CFD) modeling and then validated against results gained through experiments. The experiment was carried out in an assembly unit of the automotive industry to analyze flow patterns. The effect of bubbles on other thermophysical properties of the fluid was also examined using the multiphase k-ϵ viscous model in ANSYS FLUENT. The impact of changes in inlet pressure on vapor fraction was visualized through simulations and validated against experimental data, cavitation was calculated via cavitation index equation. It was observed that cavitation values ranged from 0.51 to 0.84 through computational fluid dynamics and from 0.46 to 0.80 in the experiment. Moreover, fluctuations in Turbulence Kinetic Energy (TKE) in the fluid through the boundary layers in the valve region, deformation in fluid particles in the form of Strain Rate (SR), and variations in the value of Wall Shear Stress (WSS) of the valve's internal walls were also studied through numerical simulations. The results show the pressure just before the valve drops and result in cavitation. Besides, turbulence kinetic energy, shear stress on the walls of a valve, strain rate, and fluid velocity were gradually increased at inlet pressure resulting erosion in the ball valve.

Background Women continue to be underrepresented in cardiology and even more so in leadership positions. We evaluated the trends and gender differences in the guideline writing groups of the American College of Cardiology/American Heart Association (ACC/AHA), Canadian Cardiovascular Society (CCS), and European Society of Cardiology (ESC) guidelines from 2006 to 2020. Methods and Results We extracted all guidelines authors from 2006 to 2020, assessed their gender from publicly available profiles, and compared differences based on subspecialties and specific societies. Stratified and trend analyses were performed using χ 2 and average annual percentage change/average 5 year percentage change. A total of 80 ACC/AHA (1288 authors [28% women]), 64 CCS (988 authors [26% women]), and 59 ESC (1157 authors [16% women]) guidelines were analyzed. A significant increase in inclusion of women was seen in ACC/AHA (12.6% [2006] to 42.6% [2020]; average annual percentage change, 6.6% [2.3% to 11.1%]; P =0.005) and ESC (7.1% [2006] to 25.8% [2020]; average annual percentage change, 6.6% [0.2% to 13.5%]; P =0.04), but the trend remained similar in CCS (20.6% [2006] to 36.3% [2020]; average annual percentage change, −0.1% (−3.7% to 3.5%); P =0.94), guideline authors. More women were coauthors in the ACC/AHA and ESC guidelines when women were chairs of guidelines. There was a persistent disparity of women among guideline authors for general cardiology and all subspecialties, except for pediatric cardiology and heart failure guidelines. The appointment of women authors as a chair was significantly low in all societies (22.4% [ACC/AHA], 16.9% [CCS], and 7.2% [ESC]; P =0.008). Conclusions There is a significant disparity in the inclusion of women on all national guideline committees, in addition to serving as a chair of cardiology guidelines. Further advocacy is required to promote equity, diversity, and inclusion in our cardiology guidelines globally.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the pathological isoform PrPSc. Elucidating the molecular and cellular mechanisms underlying prion propagation may help to develop disease interventions. Cell culture systems for prion propagation have greatly advanced molecular insights into prion biology, but translation of in vitro to in vivo findings is often disappointing. A wider range of cell culture systems might help overcome these shortcomings. Here, we describe an immortalized mouse neuronal astrocyte cell line (C8D1A) that can be infected with murine prions. Both PrPC protein and mRNA levels in astrocytes were comparable with those in neuronal and non-neuronal cell lines permitting persistent prion infection. We challenged astrocytes with three mouse-adapted prion strains (22L, RML, and ME7) and cultured them for six passages. Immunoblotting results revealed that the astrocytes propagated 22L prions well over all six passages, whereas ME7 prions did not replicate, and RML prions replicated only very weakly after five passages. Immunofluorescence analysis indicated similar results for PrPSc. Interestingly, when we used prion conversion activity as a readout in real-time quaking-induced conversion assays with RML-infected cell lysates, we observed a strong signal over all six passages, comparable with that for 22L-infected cells. These data indicate that the C8D1A cell line is permissive to prion infection. Moreover, the propagated prions differed in conversion and proteinase K–resistance levels in these astrocytes. We propose that the C8D1A cell line could be used to decipher prion strain biology.

Background Due to the current Coronavirus Disease 2019 (COVID-19) pandemic, there is a realization for innovation in procedures and protocols to minimize hospital stay and at the same time ensure continued evidence-based treatment delivered to the patients. We present a same-day discharge protocol for transcatheter mitral valve repair (TMVR) using MitraClip under general anaesthesia in a six-patient case series. This protocol aims to reduce the length of hospital stay, thereby minimizing potential for nosocomial COVID-19 infections and to promote safe discharge with cautious follow-up. Case summary Six patients with severe symptomatic mitral valve (MV) regurgitation underwent successful transfemoral MV repair using standard procedures. Following repair, patients were monitored on telemetry in the recovery area for 3 h, ambulated to assess vascular access stability and underwent post-procedural transthoracic echocardiogram to assess for any pericardial effusion or post-procedural prosthetic mitral stenosis. Conclusion Same-day discharge after TMVR is possible when done cautiously with close follow-up, can minimize hospital stay, improve resource utilization, and reduce risk of nosocomial COVID-19 infection.

Currently there is no recognized curative treatment for diabetic polyneuropathy (DPN). Strict glucose control and symptomatic pain relief are the first line management routes. DPN is a common complication of diabetes and has a major detrimental influence on the quality of life (QOL) for many patients. Due to the scope of the problem, it is imperative that treatment options which impede DPN's progression and restore sensorineural function should be researched comprehensively and made available to the masses at an economical cost. We reviewed a multitude of atypical treatment options for DPN including capsaicin, lidocaine, acupuncture, electrical nerve stimulation, alpha lipoic acid, benfotiamine, and acetyl-l-carnitine and explored the evidence to date regarding their safety and efficacy. Most of these options have been around for a long time and have promising pilot studies or small-scale trials focused on DPN treatment.

Recurrent gastrointestinal bleeding (GIB) is a common complication following left ventricular assist device (LVAD) implantation. Our study aimed to estimate the comparative efficacy of different pharmacologic interventions for the prevention of GIB, through a network meta-analysis (NMA). A total of 13 observational studies comparing six strategies. Among those, 4 were for primary, and 9 were for secondary prevention of GIB. On NMA, thalidomide (Hazard ratio [HR]: 0.016, Credible interval [CrI]I: 0.00053-0.12), omega-3-fatty acid (HR:0.088, CrI: 0.026-0.77), octreotide (HR: 0.17, CrI: 0.0589-0.41) and danazol (HR:0.17, CrI: 0.059-0.41) reduced the risk of GIB. The use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker (ACEi/ARB) and digoxin were not associated with any significant reduction. Based on NMA, combining indirect treatment comparisons, thalidomide, danazol, and octreotide treatments were associated with decreased risk of recurrent GIB. Additionally, Omega 3 fatty acids were associated with a lower risk of the primary episode of GIB in the LVAD patient population.

Background: Prevention of recurrent Clostridioides difficile infection (CDI) is a challenge in clinical practice, particularly in patients who need systemic antimicrobial therapy. We aimed to evaluate the role of oral vancomycin prophylaxis (OVP) in prevention of primary or future CDI in patients on systemic antimicrobial therapy. Methods: A systematic search of MEDLINE, Embase, and Web of Science was performed from 2000 to January 2020. We included case-control or cohort studies that included patients on systemic antimicrobial therapy who did or did not receive oral vancomycin prophylaxis (OVP) and were evaluated for development of CDI. Odds ratio (OR) estimates with 95% confidence intervals (CI) were calculated. Results: Four studies including 1352 patients evaluated OVP for primary CDI prevention, with CDI occurring in 29/402 patients on OVP (7.4%) compared with 10.4% (99/950) without OVP. Meta-analysis revealed no significant decrease in risk of CDI in patients who received OVP (OR, 0.18; 95% CI, 0.03–1.03; p = 0.06). There was significant heterogeneity with I 2 = 76%. Ten studies including 9258 patients evaluated OVP for secondary CDI prevention. Future CDI occurred in 91/713 patients on OVP (13.3%) compared with 21.9% (1875/8545) who did not receive OVP. Meta-analysis revealed a statistically significant decreased risk of future CDI (OR, 0.34; 95% CI, 0.20–0.59; p

Background The coronavirus disease 2019 (COVID-19) pandemic has resulted in drastic changes to the practice of medicine, requiring healthcare systems to find solutions to reduce the risk of infection. Using a case series, we propose a protocol for same-day discharge (SDD) for selected patients undergoing transcatheter aortic valve replacement (TAVR) using real-time remote cardiac monitoring. Six patients with severe symptomatic aortic stenosis underwent TAVR and were discharged on the same day. Case summary Six patients with symptomatic severe native or bioprosthetic aortic valve stenosis underwent a successful transfemoral TAVR using standard procedures, including the use of rapid atrial pacing to assess the need for permanent pacemaker implantation. Following TAVR, patients were monitored on telemetry in the recovery area for 3 h, ambulated to assess vascular access stability, and discharged with real-time remote cardiac monitoring if no new conduction abnormality was observed. The patients were seen by tele-visits within 2 days and 2 weeks after discharge. Discussion Amidst the COVID-19 pandemic, SDD following successful transfemoral TAVR may be feasible for selected patients and reduce potential COVID-19 exposure.

Background: Cardiac sarcoidosis (CS) affects 35% of patients with pulmonary sarcoidosis (PS). CS presentation varies from asymptomatic patients to sudden cardiac death. The current screening modalities like EKG and conventional echocardiography lack sensitivity for early detection of CS. Speckle tracking echocardiography (STE) has shown potential for early detection of subclinical myocardial damage in patients with PS. We aimed to investigate the role of STE in early detection of CS. Methods: We queried Medline, EmCare, CINAHL, Cochrane Database and Google Scholar for articles investigating the role of left ventricle global longitudinal strain (LVGLS) in asymptomatic patients with PS versus (vs) controls. Studies that included patients with suspected or proven CS, patients with cardiac symptoms, arrhythmias, coronary artery disease or valvular abnormalities were excluded. The standard mean difference (SMD) in GLS for both groups was pooled using random effects model. Results: Our search yielded a total of 9 studies with a total of 967 patients with PS undergoing screening for CS. In individual studies, the baseline characteristics were not significantly different between both groups. Overall, the studies had more females than males. All patients in our cohort had preserved ejection fraction (EF) and no cardiac symptoms. The LVGLS was significantly decreased in the PS group as compared to controls, SMD: -3.98, (95% CI: -5.32 to -2.64; p-value 2 = 94.70%, Figure 1. Conclusion: As compared to controls, patients with PS with no clinically suspected or proven CS, and normal EF, have impaired LVGLS. More studies are warranted to investigate the role of LVGLS in CS screening.

Background: Octogenarians and nonagenarians are under-represented in major clinical trials studying the role of anticoagulation (AC) in atrial fibrillation (AF). These patients are at an increased risk of bleeding owing to their frailty, their propensity for falls, and frequently impaired kidney function. We performed a meta-analysis of studies that investigated the role of AC in these patients. Methods: We queried Medline, EmCare, CINHAL, Cochrane Database, and Google Scholar for studies investigating the role of AC for AF in octogenarians and nonagenarians. Our primary efficacy outcome was major thromboembolism (TE), and secondary safety outcome was major bleeding (MB). We used the PM method with HKSJ adjustment to estimate risk ratio (RR) with a 95% confidence interval (CI). Heterogeneity was assessed using Higgin’s I 2 . R version 3.6.2 was used for statistical analysis. Heterogeneity was addressed using outlier analysis. dmetar() package in R was used, and the pooled estimate was re-calculated, excluding the outliers. Results: Ten observational studies, including a total of 34,697 patients were included. There was no difference in the risk of TE [RR: 0.82, 95% CI: 0.49-1.38, I 2 =74%] or MB [RR: 1.00, 95% CI: 0.55-1.83, I 2 =88%] between the AC and Non-AC group. However, the pooled estimates were associated with considerable heterogeneity. Outlier analysis identified two studies "Perera et al., 2009" and "Yamashita et al., 2016" as an outlier for pooled estimation of TE, while [1] "Siu et al., 2014", "Bertozzo et al., 2016", "Ekerstad et al., 2018" and "Alnsasra et al., 2018" were outliers in the pooled estimate of MB. Following exclusion of outliers for each endpoint, the reanalyzed RR for TE and MB were [RR: 0.94, 95% CI: 0.82- 1.09, I 2 =0%] and [RR: 1.57, 95% CI: 1.41- 1.74, I 2 =0%]. Conclusion: There was no difference in the risk of TE, while the risk of MB increased with the use of AC for AF in octogenarians and nonagenarians.

Background: Long term outcomes of culprit multi-vessel and left main patients who presented with Non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) and underwent either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) are not well defined. Randomized trials comparing the two modalities constituted mainly of patients with stable coronary artery disease (SCAD). We performed a meta-analysis of studies that compared the long term outcomes of CABG vs. PCI in NSTE-ACS. Methods: Medline, EmCare, CINAHL, Cochrane databases were queried for relevant articles. Studies that included patients with SCAD and ST-elevation myocardial infarction were excluded. Our primary outcome was major adverse cardiac events (MACE) at 3-5 years, defined as a composite of all-cause mortality, stroke, re-infarction and repeat revascularization. The secondary outcome was re-infarction at 3 to 5 years. We used the Paule-Mandel method with Hartung-Knapp-Sidik-Jonkman adjustment to estimate risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed using Higgin’s I 2 statistics. All statistical analysis was carried out using R version 3.6.2 Results: Four observational studies met our inclusion criteria with a total number of 6695 patients. At 3 to 5 years, the PCI group was associated with a higher risk of MACE as compared to CABG, (RR): 1.52, 95% CI: 1.28 to 1.81, I 2 =0% (PANEL A). The PCI group also had a higher risk of re-infarctions during the period of follow up, RR: 1.88, 95% CI 1.49 to 2.38, I 2 =0% (PANEL B). Conclusion: In this meta-analysis, CABG was associated with a lower risk of MACE and re-infarctions as compared to PCI during 3 to 5 years follow up period.

Background: The optimum revascularization modality in multi-vessel and left main disease patients presenting with non-ST elevation acute coronary syndrome (non-STE-ACS) is not well studied. The current recommendations are based on studies that primarily included patients with stable angina. Patients with non-STE-ACS were under-represented in clinical trials. We performed a meta-analysis of studies comparing coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) in non-STE-ACS, and reporting 30 days major adverse cardiac events (MACE). Methods: We searched Medline, EmCare, CINAHL, Cochrane database, and Google Scholar for relevant articles. We excluded studies that included patients with stable coronary artery disease and ST elevation myocardial infarction. Our primary outcome was 30 days MACE defined as all-cause death, stroke, repeat revascularization and re-infarction. We used the Paule-Mandel method with the Hartung-Knapp-Sidik-Jonkman adjustment to estimate risk ratio (RR) with a 95% confidence interval (CI). Heterogeneity was assessed using Higgin’s I 2 statistics. To account for heterogeneity, a meta-regression analysis was performed. Results: Five observational studies met our inclusion criteria summing to a total number of 7161 patients. At 30 days, there was no difference between CABG vs. PCI in terms of MACE, RR: 0.96, 95% CI 0.38 to 2.39, I 2 = 81% (Panel A). A meta-regression analysis reported that a history of PCI was associated with a lower risk of MACE with CABG compared to PCI (Panel B). Conclusion: At 30 days, there was no difference in MACE between the CABG and PCI groups. However, a history of PCI was associated with a lower risk of MACE in patients who underwent CABG.

Background: Prevention of recurrent Clostridioides difficile infection (CDI) is a challenge in clinical practice, particularly in patients who need systemic antimicrobial therapy. We aimed to evaluate the role of oral vancomycin prophylaxis (OVP) in prevention of primary or future CDI in patients on systemic antimicrobial therapy. Methods: A systematic search of MEDLINE, Embase, and Web of Science was performed from 2000 to January 2020. We included case-control or cohort studies that included patients on systemic antimicrobial therapy who did or did not receive oral vancomycin prophylaxis (OVP) and were evaluated for development of CDI. Odds ratio (OR) estimates with 95% confidence intervals (CI) were calculated. Results: Four studies including 1352 patients evaluated OVP for primary CDI prevention, with CDI occurring in 29/402 patients on OVP (7.4%) compared with 10.4% (99/950) without OVP. Meta-analysis revealed no significant decrease in risk of CDI in patients who received OVP (OR, 0.18; 95% CI, 0.03–1.03; p = 0.06). There was significant heterogeneity with I2 = 76%. Ten studies including 9258 patients evaluated OVP for secondary CDI prevention. Future CDI occurred in 91/713 patients on OVP (13.3%) compared with 21.9% (1875/8545) who did not receive OVP. Meta-analysis revealed a statistically significant decreased risk of future CDI (OR, 0.34; 95% CI, 0.20–0.59; p 2 = 59%. Discussion: Based on observational data, OVP appears to decrease the risk of future CDI in patients with prior CDI who require systemic antimicrobial therapy. However, OVP was not effective for primary prevention of CDI.

INTRODUCTION Inflammatory bowel disease (IBD) patients are off and on treated with steroids which is associated with increased risk of osteoporosis and fragility fractures. We conducted an analysis to study the burden of osteoporotic fractures compared to acute myocardial infarction (AMI) or stroke in hospitalized patients with IBD. METHODS We used the National Inpatient Sample database from 2007 through 2014, to identify patients admitted with primary or secondary diagnosis of IBD using the ICD-9 codes. We identified primary diagnosis of osteoporotic fractures (excluding traumatic injuries, open fracture, readmission indicators), acute myocardial infarction and stroke using respective diagnostic codes. We analyzed trends in nationwide estimates for annual admissions, age at admission, length of stay (LOS), in-patient mortality and total hospital charge (adjusted for inflation). RESULTS Over the eight-year study period, there were an estimated 2,296,145 admissions with IBD. Overall, hip fractures as primary diagnosis accounted for 0.5% of these hospitalizations, non-hip fractures for 0.6%, AMI for 0.8% and stroke for 0.6%. Among patients over 50 years old, the prevalence was 1.0% for hip fractures, 0.9% for non-hip fractures, 1.3% for AMI and 1.0% for stroke. Temporal trend was unchanged over the studied period. More females were admitted with fractures (70.5%) and strokes (55.7%) as compared to AMI (42.4%). Highest mortality was seen among patients admitted for stroke (7.1%), followed by AMI (4.1%) and fractures where mortality with hip fractures was significantly higher than non-hip fractures (2.7% vs 1.7%, p CONCLUSION Proportion of IBD patients admitted primarily for nontraumatic fractures is similar to stroke admission, particularly in patients older than 50. Hip fractures are more common than non-hip fractures. Mortality is higher with hip fractures than non-hip fractures. LOS among studied causes is highest for hip fractures and stroke. Cost of hospitalization although not as much with fractures than AMI, showed a rising trend during the study period.

INTRODUCTION Inflammatory bowel disease (IBD) patients with colonic involvement are known to have microbiome changes which may increase their risk of C. difficile infection (CDI). We conducted an analysis to describe the implications of CDI on hospitalized IBD patients. METHODS We used the National Inpatient Sample database from 2007 through 2018, to identify patients admitted with primary or secondary diagnosis of IBD using the ICD-9 or ICD-10 codes. We identified CDI as well as colectomy using diagnostic codes. We identified trends in nationwide estimates for annual admissions, age at admission, length of stay (LOS), in-patient mortality, Elixhauser comorbidity index and total hospital charge (adjusted for inflation). We used the Cochran-Armitage test for trend significance. RESULTS Between 2007 and 2018, there were an estimated total of 3,728,348 admissions with IBD, of which 161,744 patients had CDI (4.3%). Median age at admission was 52 years, with 56.7% females. There was a rising trend of CDI among IBD patients, from 2.9% in 2007 to a peak of 5.4% in 2015 with a decline towards the end of study period at 4.4% in 2018. Mean score for Elixhauser comorbidity index increased from 4.6 to 7.4 (p-trend The median LOS was 4 days for patients without CDI vs 6 days with CDI. Trend in LOS was stable for patients without CDI but decreased from 8 days to 5 days over the 12-year study period for patients with CDI (p-trend The overall mortality among IBD patients was 1.6% with no significant trend observed over time. All cause in-hospital mortality was significantly higher among patients with concomitant CDI (6.8%) vs without CDI (1.4%) (RR 4.99, 95% CI 4.89 - 5.10). Within CDI subgroup, there was a trend of decrease in mortality from 7-11% in the beginning of the study, to about 3-3.5% towards the end of the study period (p-trend After adjusting for inflation, there was a significant increase in charges among both subgroups: increased from $28,575 in 2007 to $68,614 in 2018 (p-trend CONCLUSION The incidence of CDI in IBD patients increased over the study period with stability towards the latter half. Hospitalized IBD patients with concomitant CDI have a higher comorbidity index, a longer length of stay, a higher risk of colectomy and an increased risk of mortality when compared to those without CDI. Total hospitalization charges are also significantly higher with CDI subgroup and have been increasing overtime.

Misfolding of the prion protein (PrP) and templating of its pathological conformation onto cognate proteins causes a number of lethal disorders of central nervous system in humans and animals, such as Creutzfeldt-Jacob disease, chronic wasting disease and bovine spongiform encephalopathy. Structural rearrangement of PrPC into PrPSc promotes aggregation of misfolded proteins into β-sheet-rich fibrils, which can be visualized by conformationally sensitive fluorescent probes. Early detection of prion misfolding and deposition might provide useful insights into its pathophysiology. Pentameric formyl thiophene acetic acid (pFTAA) is a novel amyloid probe that was shown to sensitively detect various misfolded proteins, including PrP. Here, we compared sensitivity of pFTAA staining and spectral microscopy with conventional methods of prion detection in mouse brains infected with mouse-adapted 22L prions. pFTAA bound to prion deposits in mouse brain sections exhibited a red-shifted fluorescence emission spectrum, which quantitatively increased with disease progression. Small prion deposits were detected as early as 50 days post-inoculation, well before appearance of clinical signs. Moreover, we detected significant spectral shifts in the greater brain parenchyma as early as 25 days post-inoculation, rivaling the most sensitive conventional method (real-time quaking-induced conversion). These results showcase the potential of pFTAA staining combined with spectral imaging for screening of prion-infected tissue. Not only does this method have comparable sensitivity to established techniques, it is faster and technically simpler. Finally, this readout provides valuable information about the spatial distribution of prion aggregates across tissue in the earliest stages of infection, potentially providing valuable pathophysiological insight into prion transmission.

Prion diseases are fatal transmissible neurodegenerative disorders that affect animals and humans. Prions are proteinaceous infectious particles consisting of a misfolded isoform of the cellular prion protein PrPC, termed PrPSc. PrPSc accumulates in infected neurons due to partial resistance to proteolytic digestion. Using compounds that interfere with the production of PrPSc or enhance its degradation cure prion infection in vitro, but most drugs failed when used to treat prion-infected rodents. In order to synergize the effect of anti-prion drugs, we combined drugs interfering with the generation of PrPSc with compounds inducing PrPSc degradation. Here, we tested autophagy stimulators (rapamycin or AR12) and cellulose ether compounds (TC-5RW or 60SH-50) either as single or combination treatment of mice infected with RML prions. Single drug treatments significantly extended the survival compared to the untreated group. As anticipated, also all the combination therapy groups showed extended survival compared to the untreated group, but no combination treatment showed superior effects to 60SH-50 or TC-5RW treatment alone. Unexpectedly, we later found that combining autophagy stimulator and cellulose ether treatment in cultured neuronal cells mitigated the pro-autophagic activity of AR12 and rapamycin, which can in part explain the in vivo results. Overall, we show that it is critical to exclude antagonizing drug effects when attempting combination therapy. In addition, we identified AR-12 as a pro-autophagic drug that significantly extends survival of prion-infected mice, has no adverse side effects on the animals used in this study, and can be useful in future studies.