Towards an Epistemological Framework for Measuring the Fit of Information Systems Under Perpetual Change

The research reported in this paper is based on the argument that organizational information systems as we currently build them tend in most cases to disappoint. This happens because they are inflexible artifacts whose purpose is to model dynamic organizations. Our objectives are to find better ways of thinking about change and adaptation of information systems within organizations by exploring the concept of \u27fit\u27. The degree of fit between a given organization and a given information system can be judged subjectively, but currently there exists no measure which is general useful and objective. There is also no research that identifies what criteria people use when they make these subjective judgements. Our endeavours focus to determine what the barriers to such knowledge are, and to develop a generic framework for acquiring and maintaining such knowledge in any desired context

Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury

Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury.BackgroundVascular endothelial growth factor (VEGF) mRNA and protein expression are increased by hypoxia in a variety of cell types and organs. In the kidney, however, chronic hypoxia does not up-regulate VEGF mRNA. This suggests that VEGF may be regulated by unique mechanisms in the kidney.MethodsUnilateral ischemia was induced in rats by vascular cross-clamping (40 min) followed by reperfusion (0, 20, 40, and 80 min). The distribution of VEGF protein was determined by immunohistochemical staining and Western blotting. mRNA was detected by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining for VEGF was verified using two VEGF antibodies. To further substantiate the immunohistochemical findings, laser scanning confocal fluorescence microscopy was used to demonstrate the distribution of VEGF protein in rat renal tubular epithelial cells (NRK52-E) subjected to hypoxia (40 min) and re-oxygenation (0, 5, 20, 40 and 80 min).ResultsNormal kidneys showed diffuse immunohistochemical staining for VEGF in all tubules of the renal cortex and medulla. Following ischemia, staining demonstrated a prominent shift of cytoplasmic VEGF to the basolateral aspect of tubular cells with both VEGF antibodies. The distribution of cytoplasmic VEGF returned to normal following 40 and 80 minutes of reperfusion. Western blots of cytoplasmic samples from ischemic kidneys reperfused for 0 and 20 minutes showed decreased levels of VEGF164 compared with normal (P < 0.01). VEGF164 and VEGF188 levels in the membrane fraction showed no change. Northern blots and semiquantitative RT-PCR showed no significant up-regulation of VEGF mRNA or change in the splice pattern. NRK52-E cells subjected to hypoxia and re-oxygenation for 0 and 5 minutes showed increased staining for VEGF compared with normal, with prominent VEGF staining at the periphery of the cell, similar to the appearance in ischemic kidneys. VEGF staining became more diffuse with further re-oxygenation.ConclusionAlthough synthesis of VEGF mRNA and protein is not increased during ischemia reperfusion injury, pre-existing VEGF in the tubular cell cytoplasm redistributes to the basolateral aspect of the cells. These data suggest that the kidney may have evolved unique patterns of VEGF regulation to cope with acute hypoxia

Teaching Atraumatic Restorative Treatment in U.S. Dental Schools: A Survey of Predoctoral Pediatric Dentistry Program Directors

The International Dental Federation and World Health Organization have promoted the use of Atraumatic Restorative Treatment (ART) in modern clinical settings worldwide. In the United States, the practice of ART is not believed to be widely used, which may be a result of little attention given to ART training in predoctoral pediatric dentistry curricula in U.S. dental schools. This study investigated the extent of clinical and didactic instruction on ART provided in U.S. dental schools by surveying the predoctoral pediatric dentistry programs in 2010. Of the fifty-seven directors asked to complete the survey, forty-four responded for a response rate of 77 percent. Of these forty-four programs, 66 percent reported providing clinical training on ART, though only 14 percent provide this training often or very often. The types of ART training provided often or very often included interim treatment (18 percent) and single-surface cavities (14 percent) in primary teeth. However, ART was said to be rarely taught as a definitive treatment in permanent teeth (2 percent). Attitude was a major predictor, for clinical training provided and using professional guidelines in treatment decisions were associated with a positive attitude towards ART. These predoctoral pediatric dentistry programs used ART mainly in primary, anterior, and single-surface cavities and as interim treatment. As ART increases access of children to dental care, the incorporation of the ART approach into the curricula of U.S. dental schools should be facilitated by professional organizations.This project was funded by NIH/NIDC R T32 Grant DEO 14678-06

The antimalarial drug amodiaquine stabilizes p53 through ribosome biogenesis stress, independently of its autophagy-inhibitory activity

Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report a novel activity of the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, a rate-limiting step for ribosome biogenesis, in a dose-dependent manner. Amodiaquine triggers degradation of the catalytic subunit of RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization of p53. Pol I shutdown occurs in the absence of DNA damage and without the subsequent ATM-dependent inhibition of rRNA transcription. RNAseq analysis revealed mechanistic similarities of amodiaquine with BMH-21, the first-in-class Pol I inhibitor, and with chloroquine, the antimalarial analog of amodiaquine, with well-established autophagy-inhibitory activity. Interestingly, autophagy inhibition caused by amodiaquine is not involved in the inhibition of rRNA transcription, suggesting two independent anticancer mechanisms. In vitro, amodiaquine is more efficient than chloroquine in restraining the proliferation of human cell lines derived from colorectal carcinomas, a cancer type with predicted susceptibility to ribosome biogenesis stress. Taken together, our data reveal an unsuspected activity of a drug approved and used in the clinics for over 30 years, and provide rationale for repurposing amodiaquine in cancer therapy

The willingness of US pediatric dentists to use Atraumatic restorative treatment (ART) with their patients: a conjoint analysis

Objectives: The atraumatic restorative treatment (ART) was developed as an affordable, patient-friendly dental caries management procedure that does not need extensive operator training or special skills. The aim of this study was to determine factors that influence the decision to use ART using an innovative marketing research technique known as conjoint analysis. Methods: A conjoint survey was completed by 723 members of the American Academy of PediatricDentistry.Three factors (age of the child, level of cooperation, type of insurance) were varied across three levels to create nine patient scenarios. The weights that practitioners placed on these factors in decisions to use ART in treating carious lesions were determined by conjoint analysis. Factors such as lesion location, depth, and extension were fixed in the nine clinical scenarios. Results: Seven-hundred twenty-three pediatric dentists completed the survey (32 percent). Age of the child was the most important factor in pediatric dentists’ decisions to use ART (46 percent) compared with level of cooperation (41 percent) and type of insurance coverage (11 percent). For the age factor, the age of 2 years had the greatest utility (0.55) compared with age 4 (−0.09) and age 6 (−0.46). For types of insurance coverage, having no insurance (0.124) had the greatest utility compared with having public insurance (−0.119). Conclusions: Although insurance coverage was the least important among the factors, being without insurance, being very young, and being uncooperative was the scenario where pediatric dentists most favored ART when making trade offs between different factors using the conjoint design.This project was funded by NIH/NIDC R T32 grant DEO 14678-06

Outcomes and risk factors associated with SARS-CoV-2 infection in a North American registry of patients with multiple sclerosis

Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment

A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI- WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/ min/1.73 m2 vs. 67.1 ml/min/1.73 m2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR (31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients.Steven J. Chadban, Josette Marie Eris, John Kanellis, Helen Pilmore, Po Chang Lee, Soo Kun Lim, Chad Woodcock, Nicol Kurstjens, Graeme Rus

Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution

International audienc

Sex-Specific Association of the Putative Fructose Transporter SLC2A9 Variants With Uric Acid Levels Is Modified by BMI

OBJECTIVE—High serum uric acid levels lead to gout and have been reported to be associated with an increased risk of hypertension, obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Recently, the putative fructose transporter SLC2A9 was reported to influence uric acid levels. The aim of the present study was to examine the association of four single nucleotide polymorphisms within this gene with uric acid levels and to determine whether this association is modified by obesity