Impact of Professional Student Mentored Research Fellowship on Medical Education and Academic Medicine Career Path

CONTEXT: This study explores the long-term impact of the Professional Student Mentored Research Fellowship (PSMRF) program at the University of Kentucky College of Medicine (UKCOM) on medical students\u27 research productivity and career paths. METHODS: Demographic characteristics, academic profiles, number of publications and residency placements from 2007 to 2012 were used to assess 119 PSMRF graduates against a comparison cohort of 898 UKCOM (non-PSMRF) students. RESULTS: PSMRF students had higher MCAT scores at admission (31.5 ± 0.6 vs. 30.6 ± 0.2, p = 0.007) and achieved higher USMLE Step 1 scores (228 ± 4.2 vs. 223 ± 1.5, p = 0.03) than comparison group. PSMRF students were more likely to publish PubMed-indexed papers (36.7% vs. 17.9%, p \u3c 0.0001), achieve AOA status (19.3% vs. 8.5%, p = 0.0002) and match to top 25 US News and World Report residency programs (23.4% vs. 12.1%, p = 0.008). A greater proportion of PSMRF fellows matched to top tier competitive specialties (23% vs. 14.2%, p = 0.07), however this difference was not statistically significant. CONCLUSIONS: The PSMRF program shows a significant increase in enrollment, as well as positive associations with indicators of success in medical school and subsequent quality of residency program

Outcome of Patients With Small Vessel Vasculitis After Renal Transplantation: National Database Analysis

Background. Small vessel vasculitis commonly affects the kidney and can progress to end-stage renal disease. The goal of this study is to compare outcomes of patients who received a renal transplant as a result of small vessel vasculitis (group A) with those who received kidney transplants because of other causes (group B). Methods. This is a retrospective analysis of United Network for Organ Sharing registry data for adult primary kidney transplants from January 2000 to December 2014. Group A patients (N = 2196) were compared with a group B (N = 6588); groups were case matched for age, race, sex, donor type, and year of transplant in a 1:3 ratio. Results. Renal and patient survivals were better in the group A (P \u3c 0.001). New-onset diabetes after transplant developed in 8.3% of the group A and 11.3% of group B (P \u3c 0.001). Seventeen (0.8%) patients in group A developed recurrent disease. Of these, 7 patients had graft failure, 3 of which were due to disease recurrence. Group A patients had significantly higher risk of developing posttransplant solid organ malignancies (11.3% vs 9.3%, P = 0.006) and lymphoproliferative disorder (1.3% vs 0.8%, P = 0.026). Independent predictors of graft failure and patient mortality were recipients\u27 morbid obesity, diabetes, age, and dialysis duration (hazard ratio of 1.7, 1.4, 1.1/10 years, and 1.1/year for graft failure, and 1.7, 1.7, 1.6/10 years and 1.1/year for patient mortality, respectively). Conclusions. Renal transplantation in patients with has favorable long-term graft and patient outcomes with a low disease recurrence rate. However, they may have a higher risk of developing posttransplant malignancies

Kidney Recovery in Patients with Acute Kidney Injury Treated in Outpatient Hemodialysis or Rehabilitation Facilities

Rationale & Objective: Since January 2017, patients with acute kidney injury requiring dialysis (AKI-D) can be discharged to outpatient dialysis centers for continued hemodialysis (HD) support. We aimed to examine the rate of kidney recovery, time to recovery, and hospitalization-related clinical parameters associated with kidney recovery in patients with AKI-D. Study Design: Single-center prospective cohort study. Setting & Participants: 111 adult patients who were admitted to the University of Kentucky Hospital, experienced AKI-D, and were discharged with need of outpatient HD. Exposure: Hospitalization-related clinical parameters were evaluated. Outcome: Kidney recovery as a composite of being alive and no longer requiring HD or other form of kidney replacement therapy. Analytical Approach: Discrete-time survival analysis and logistic regression were used to determine adjusted probabilities of kidney recovery at prespecified time points and to evaluate clinical parameters associated with recovery. Results: 45 (41%) patients recovered kidney function, 25 (55.5%) within the first 30 days following discharge, 16 (35.5%) within 30 to 60 days, and 4 (9%) within 60 to 90 days. Adjusted probabilities of recovery were 36.7%, 27.4%, and 6.3%, respectively. Of the remaining patients, 49 (44%) developed kidney failure requiring chronic kidney replacement therapy and 17 (15%) died or went to hospice. Patients who did not recover kidney function were older, had more comorbid conditions, had lower estimated glomerular filtration rates at baseline, and received more blood transfusions during hospitalization when compared with those who recovered kidney function. Limitations: Selection bias given that patients included in the study were all eligible for AKI management with outpatient HD as part of Medicare/Medicaid services. Conclusions: At least one-third of AKI-D survivors discharged from an acute care hospital dependent on HD recovered kidney function within the first 90 days of discharge, more commonly in the first 30 days postdischarge. Future studies should elucidate clinical parameters that can inform risk classification and interventions to promote kidney recovery in this vulnerable and growing population

Prion Protein Amino Acid Determinants of Differential Susceptibility and Molecular Feature of Prion Strains in Mice and Voles

The bank vole is a rodent susceptible to different prion strains from humans and various animal species. We analyzed the transmission features of different prions in a panel of seven rodent species which showed various degrees of phylogenetic affinity and specific prion protein (PrP) sequence divergences in order to investigate the basis of vole susceptibility in comparison to other rodent models. At first, we found a differential susceptibility of bank and field voles compared to C57Bl/6 and wood mice. Voles showed high susceptibility to sheep scrapie but were resistant to bovine spongiform encephalopathy, whereas C57Bl/6 and wood mice displayed opposite features. Infection with mouse-adapted scrapie 139A was faster in voles than in C57Bl/6 and wood mice. Moreover, a glycoprofile change was observed in voles, which was reverted upon back passage to mice. All strains replicated much faster in voles than in mice after adapting to the new species. PrP sequence comparison indicated a correlation between the transmission patterns and amino acids at positions 154 and 169 (Y and S in mice, N and N in voles). This correlation was confirmed when inoculating three additional rodent species: gerbils, spiny mice and oldfield mice with sheep scrapie and 139A. These rodents were chosen because oldfield mice do have the 154N and 169N substitutions, whereas gerbil and spiny mice do not have them. Our results suggest that PrP residues 154 and 169 drive the susceptibility, molecular phenotype and replication rate of prion strains in rodents. This might have implications for the assessment of host range and molecular traceability of prion strains, as well as for the development of improved animal models for prion diseases

Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions

Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion

Unraveling infectious structures, strain variants and species barriers for the yeast prion [PSI+]

Prions are proteins that can access multiple conformations, at least one of which is beta-sheet rich, infectious and self-perpetuating in nature. These infectious proteins show several remarkable biological activities, including the ability to form multiple infectious prion conformations, also known as strains or variants, encoding unique biological phenotypes, and to establish and overcome prion species (transmission) barriers. In this Perspective, we highlight recent studies of the yeast prion [PSI+], using various biochemical and structural methods, that have begun to illuminate the molecular mechanisms by which self-perpetuating prions encipher such biological activities. We also discuss several aspects of prion conformational change and structure that remain either unknown or controversial, and we propose approaches to accelerate the understanding of these enigmatic, infectious conformers

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care

Tolerability of Intermittent Hemodialysis in a Cohort of Patients with Left Ventricular Assist Device

Background: The use of left ventricular assist device (LVAD) has emerged as a popular treatment for patients with advanced heart failure. It is not uncommon for these patients to suffer from renal failure requiring renal replacement therapy. The purpose of this study is to assess hemodynamic parameters and ability to complete the prescribed hemodialysis session in a series of patients who underwent numerous dialysis treatments. Methods: Nine patients with Heart Mate II LVAD received 170 intermittent inpatient hemodialysis treatments between January 1, 2010 and December 31, 2012. Assessment included vital signs, ultrafiltrate removed, hemodialysis duration, symptoms, early terminations (ET), and adverse events during each hemodialysis session. Results: The mean age was 53 ± 18 with a range of 26-83 years, with a male predominance (7/9). Indication for LVAD was as destination therapy (DT) in the majority of patients (6/9). Nine patients who received a total of 170 hemodialysis sessions with a mean prescribed and achieved: ultrafiltration (liters) 1.98 ± 1.5 and 1.90 ± 1.6; hemodialysis duration (hours) 3.12 ± 0.3 and 2.86 ± 0.9, respectively. Early termination was experienced in 11 sessions (6.5%). Causes of ET were hypotension in 72.7%, other causes were equally distributed between clotted extra-corporeal circuits, nausea & vomiting and LVAD alarm (9.1% in each). Serious arrhythmias were not observed in any of the hemodialysis treatments. Six out of nine patients (66.7%) recovered kidney function and became dialysis independent. Conclusion: In a hospital setting, patients with LVAD can often tolerate and complete the prescribed hemodialysis treatment