GFR estimated with creatinine rather than cystatin C is more reflective of the true risk of adverse outcomes with low GFR in kidney transplant recipients.

BACKGROUND: Serum cystatin C-based estimated glomerular filtration rate (eGFRcys) generally associates with clinical outcomes better than serum creatinine-based eGFR (eGFRcr) despite similar precision in estimating measured GFR (mGFR). We sought to determine whether the risk of adverse outcomes with eGFRcr or eGFRcys was via GFR alone or also via non-GFR determinants among kidney transplant recipients. METHODS: Consecutive adult kidney transplant recipients underwent a standardized GFR assessment during a routine follow-up clinic visit between 2011 and 2013. Patients were followed for graft failure or the composite outcome of cardiovascular (CV) events or mortality through 2020. The risk of these events by baseline mGFR, eGFRcr and eGFRcys was assessed unadjusted, adjusted for mGFR and adjusted for CV risk factors. RESULTS: There were 1135 recipients with a mean baseline mGFR of 55.6, eGFRcr of 54.8 and eGFRcys of 46.8 ml/min/1.73 m2 and a median follow-up of 6 years. Each 10 ml/min/1.73 m2 decrease in mGFR, eGFRcr or eGFRcys associated with graft failure [hazard ratio (HR) 1.79, 1.68 and 2.07, respectively; P < .001 for all) and CV events or mortality outcome (HR 1.28, 1.19 and 1.43, respectively; P < .001 for all). After adjusting for mGFR, eGFRcys associated with graft failure (HR 1.57, P < .001) and CV events or mortality (HR 1.49, P < .001), but eGFRcr did not associate with either. After further adjusting for CV risk factors, risk of these outcomes with lower eGFRcys was attenuated. CONCLUSION: eGFRcr better represents the true relationship between GFR and outcomes after kidney transplantation because it has less non-GFR residual association. Cystatin C is better interpreted as a nonspecific prognostic biomarker than is eGFR in the kidney transplant setting.

Semi-supervised exercise training program more effective for individuals with postural orthostatic tachycardia syndrome in randomized controlled trial.

PURPOSE: Exercise like any medication requires the correct dose; to be effective the appropriate frequency, duration, and intensity are necessary. This study aimed to assess if a semi-supervised exercise training (ET) program would be more effective at improving aerobic fitness (VO2PEAK), exercise tolerance, and symptoms in individuals with postural orthostatic tachycardia syndrome (POTS) compared to the standard of care (SOC). METHODS: Subjects were randomized to either the ET or SOC groups (n 26 vs. 23; age 33 ± 11 vs. 37 ± 10 years; VO2PEAK 66 ± 15 vs. 62 ± 15% predicted, ET vs. SOC respectively, p > 0.05). Composite Autonomic Symptom Score (COMPASS 31), 10 min stand test, and cardiopulmonary exercise test were performed at baseline and following 12 weeks. The ET group received an exercise consultation and eight semi-supervised in-person or virtual exercise sessions. RESULTS: The ET group demonstrated a greater improvement in VO2PEAK, higher or longer tolerance for baseline peak workload, and more often had a delayed symptom onset with exercise than the SOC group (ΔVO2PEAK 3.4 vs. - 0.2 mL/min/kg, p < 0.0001, ΔWorkload 19 ± 17 vs. 0 ± 10 W; Workload time 63 ± 29 vs. 22 ± 30 s; onset-delay 80% vs. 30%, p < 0.05). Individuals in the ET group reported a significant improvement in orthostatic intolerance domain score (p = 0.02), but there was not a significant difference in the improvement in total COMPASS score (- 11.38 vs. - 6.49, p = 0.09). CONCLUSION: Exercise training was more effective with greater improvements in aerobic fitness, orthostatic symptoms, and exercise tolerance for individuals with POTS when intensity and progression were personalized and delivered with minimal supervision compared to the SOC.

Evaluation of a Novel Wellness Curriculum on Medical Student Wellbeing and Engagement Demonstrates a Need for Student-Driven Wellness Programming.

PROBLEM: Medical training is stressful and has well-established implications for student wellbeing. Despite widespread efforts to reduce student burnout through wellness programming in medical schools, there is a paucity of literature examining students' perception of wellness and engagement with these programs. As such, we sought to evaluate: 1) medical students' level of engagement with a multifaceted wellness curriculum, 2) factors students perceived as important to wellbeing, and 3) associations with longitudinal measures of wellbeing and perceived stress. Intervention: A multipronged wellness curriculum was instituted at Mayo Clinic Alix School of Medicine-AZ (MCASOM-AZ) in 2017. This includes mental health services, curriculum-embedded seminars, wellness committee (composed of students, faculty, and administration) driven programming, and student proposed wellness activities that are reviewed and funded by the committee. The authors invited students at our institution to complete questionnaires at three timepoints during the 2018-2019 academic year. Questionnaires asked participants to rank eight factors from least to most important to their overall wellbeing. Participants self-reported their participation in each prong of the wellness curriculum and ranked the impact of each on their overall wellbeing. Their wellbeing and perceived stress were measured at each timepoint using validated psychological instruments. Context: As MCASOM-AZ opened in 2017, the student body at the time of study consisted of first- and second-year medical students. All students had the opportunity to engage with all aspects of the wellness curriculum and participate in this study, however participation was elective and all responses were anonymous. Of the MCASOM-AZ student body comprised of 100 students, 58 consented to participate in the study, 41.4% of which were Year 1 and 58.6% of which were Year 2 students. Participant age and gender were collected and were representative of the larger student body. Impact: Students engaged most with student-initiated wellness. They perceived unscheduled time as most impactful to their overall wellbeing with student-initiated activities as second-most impactful. Students with higher perceived stress were more likely than others to use mental health resources, which otherwise ranked lower in importance. Ranking academic performance as important to wellbeing was associated with higher wellbeing. There was no difference in wellbeing between students who participated in the wellness curriculum and those who did not. However, overall student wellbeing increased over the course of the year while perceived stress decreased. Lessons Learned: Medical school programs may benefit from allowing students to direct or contribute to the design of their own wellness curriculum. Additionally, medical education should work toward creating a more supportive learning environment with improved flexibility in order to better meet students' individual needs without compromising their education. Despite having low utilization rates overall, mental health resources remain an important aspect of student support services as they are used by students under greater amounts of perceived stress than their peers.Supplemental data for this article is available online at https://doi.org/10.1080/10401334.2021.2004415 .

VO2peak prior to transplant differentiates survival post kidney transplant.

The OPTN/UNOS utilizes the calculated estimated posttransplant survival (EPTS) score as the measure of post-kidney transplant survival to guide allocation of deceased donor kidney transplantation. This score does not include any metric of functional capacity. Peak oxygen uptake (VO2peak ), is an established predictor of survival among both the general and diseased populations. We assessed the association and discriminative capacity of VO2peak and that of EPTS score and all-cause mortality post-kidney transplant. Additionally, we assessed the "mortality risk" lower VO2peak conferred on those patients with low EPTS score. Among a cohort of 293 transplant recipients with at least 3-years post-transplant follow-up, the median VO2peak was 15.0 ml/Kg/min. Lower pre-transplant VO2peak and higher EPTS score conferred higher risk of post-transplant mortality. Among the cohort of "low-risk" patients (patients with EPTS score < 50) those with lower VO2peak had significantly higher risk of mortality (log rank p = 0.045). In fact, the mortality risk among those with low-EPTS (< 50) and low VO2peak  < 12 ml/Kg/min was equivalent to those with high EPTS (> 80) score. We concluded functional capacity as defined by VO2peak is an important reflection of post-transplant survival. VO2peak is able to identify those with low EPTS who have similar survival to that of high EPTS phenotype.

Histopathologic features of necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is an uncommon granulomatous dermatosis that can occur in patients with or without associated diabetes mellitus (DM). Prior studies have attempted to determine distinctive histopathologic features of NL in patients with and without DM. METHODS: A retrospective review of 97 patients with NL was performed to determine the similar and distinctive histopathologic features in patients with DM and without DM. RESULTS: Of the 97 patients, 32% (n = 31) had DM. Epidermal acanthosis was seen more commonly in diabetics than nondiabetics (32.3% vs. 12.1%; p = 0.017). Naked (sarcoidal/tuberculoid) granulomas were more frequently observed in nondiabetics than diabetics (22.7% vs. 3.2%; p = 0.016). Eosinophils were more common in nondiabetics than diabetics (38.5% vs. 9.7%; p = 0.004), while neutrophilic infiltration was more common in diabetics than nondiabetics (45.2% vs. 17.5%; p = 0.004). CONCLUSIONS: This study corroborates well-documented histopathologic features of NL and shows distinctive histopathologic features of NL among patients with DM-I, DM-II, and without DM. These results support the hypothesis that there are different underlying drivers of NL between diabetics and nondiabetics.

Duration of delayed graft function and its impact on graft outcomes in deceased donor kidney transplantation.

BACKGROUND: There is controversy regarding the impact of delayed graft function (DGF) on kidney transplant outcomes. We hypothesize that the duration of DGF, rather than DGF itself, is associated with long-term kidney graft function. METHODS: We analyzed all deceased donor kidney transplants (DDKT) done at our center between 2008 to 2020. We determined factors associated with DGF duration. DGF duration was assessed at three 14-day intervals: < 14 DGF days, 14-27 DGF days, > 28 DGF days. We studied the impact of DGF duration on survival and graft function and resource utilization, including hospital length of stay and readmissions. RESULTS: 1714 DDKT recipients were included, 59.4% (n = 1018) had DGF. The median DGF duration was 10 days IQR (6,15). The majority of recipients (95%) had resolution of DGF within 28 days. Donor factors associated with DGF days were longer cold ischemia time, donor on inotropes, older age, donation after circulatory death, higher terminal creatinine, and hypertension. Recipient factors associated with increased DGF duration included male sex, length on dialysis before transplant, and higher body mass index. There were no differences in acute rejection events or interstitial fibrosis progression by 4 months when comparing DGF days. The median length of stay was 3 days. However, readmissions increased with increasing DGF duration. Death-censored graft survival was not associated with the length of DGF except when DGF lasted > 28 days. CONCLUSIONS: Inferior graft survival was observed only in recipients of DDKT with DGF lasting beyond 28 days. DGF lasting < 28 days had no impact on graft survival. Duration of DGF, rather than DGF itself, is associated with graft survival. TRIAL REGISTRATION: Retrospective study approved by Mayo Clinic IRB number ID: 20-011561.

A Framework for Revisiting Brain Death: Evaluating Awareness and Attitudes Toward the Neuroscientific and Ethical Debate Around the American Academy of Neurology Brain Death Criteria.

BACKGROUND: There remains a lack of awareness around the American Academy of Neurology (AAN) procedural criteria for brain death and the surrounding controversies, leading to significant practice variability. This survey study assessed for existing knowledge and attitude among healthcare professionals regarding procedural criteria and potential change after an educational intervention. METHODS: Healthcare professionals with increased exposure to brain injury at Mayo Clinic hospitals in Arizona and Florida were invited to complete an online survey consisting of 2 iterations of a 14-item questionnaire, taken before and after a 30-minute video educational intervention. The questionnaire gathered participants' opinion of (1) their knowledge of the AAN procedural criteria, (2) whether these criteria determine complete, irreversible cessation of brain function, and (3) on what concept of death they base the equivalence of brain death to biological death. RESULTS: Of the 928 people contacted, a total of 118 and 62 participants completed the pre-intervention and post-intervention questionnaire, respectively. The results show broad, unchanging support for the concept of brain death (86.8%) and that current criteria constitute best practice. While 64.9% agree further that the loss of consciousness and spontaneous breathing is sufficient for death, contradictorily, 37.6% believe the loss of additional integrated bodily functions such as fighting infection is necessary for death. A plurality trusts these criteria to demonstrate loss of brain function that is irreversible (67.6%) and complete (43.6%) at baseline, but there is significantly less agreement on both at post-intervention. CONCLUSION: Although there is consistent support that AAN procedural criteria are best for clinical practice, results show a tenuous belief that these criteria determine irreversible and complete loss of all brain function. Despite support for the concept of brain death first developed by the President's Council, participants demonstrate confusion over whether the loss of consciousness and spontaneous breath are truly sufficient for death.

Prognostic value of inositol polyphosphate-5-phosphatase expression in recurrent and metastatic cutaneous squamous cell carcinoma.

BACKGROUND: Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. OBJECTIVE: To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. METHODS: We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. RESULTS: Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). LIMITATIONS: This is a multicenter but single institution study of a white population. CONCLUSION: Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.

CSF Pressure, Volume, and Post-Dural Puncture Headache: A Case-Control Study and Systematic Review.

OBJECTIVES: (1) To perform a systematic literature review to evaluate associations between post-dural puncture headache (PDPH) and opening pressure (OP), closing pressure (CP), and volume of cerebrospinal fluid (V) removed. (2) To perform a case-control study to evaluate pressure-volume index (PVI) as a novel risk factor for PDPH. BACKGROUND: According to the International Classification of Headache Diagnoses, 3rd Edition (ICHD-3), the diagnosis of PDPH requires documentation of intracranial hypotension. However, this remains an unproven concept. METHODS: A systematic literature review was conducted, searching Cochrane Database of Systematic Reviews, Ovid EMBASE, OVID MEDLINE, Scopus, and Web of Science. Study inclusion required a comparison of headache incidence following a LP as a function of OP, CP, and/or V. A retrospective, case-control study with 1:1 matching was conducted utilizing ICHD-3 criteria. Patients with factors that could influence CSF pressure were excluded. RESULTS: In our case-control study, we did not identify a paired difference in either median (95% CI) elastance (0.05 [-0.09, 0.11], P = .503) or PVI (4.53 [-7.98, 19.97], P = .678). We identified 22 references, evaluating V (n = 14), OP (n = 11), and/or CP (n = 4). There was no convincing evidence for an association of PDPH with either OP or CP. A minority of studies documenting an association with V included patients with high-volume CSF removal, and/or stratified patients by the timing of the headache onset. CONCLUSIONS: The overall risk of PDPH does not appear to be influenced by OP, CP, V or PVI. PDPH may be related to V in instances of high-volume removal, and depend on the timing of outcome assessment. Future revision of criteria should consider the existence of immediate and delayed PDPH subtypes, and not presume intracranial hypotension as a mandatory feature.

Decline in the seroprevalence of syphilis markers among first-time blood donors in Libreville (Gabon) between 2004 and 2016.

BACKGROUND: Very few studies have been conducted on the seroprevalence of syphilis in Gabon. According to the World Health Organization, the average seroprevalence of syphilis has declined from 5.5 to 1.1% in Central Africa. The aim of this study was to test the hypothesis that syphilis decreased in Gabon between 2004 and 2016 and to identify factors involved in this pattern by testing a large sample of first-time blood donors in the capital Libreville. METHODS: The detection of Treponema pallidum was done using a Rapid Plasma Reagin test (RPR) and confirmed by an ELISA test using the Biorad Syphilis Total Antibody EIA II kit or BioMerieux Trepanostika TP recombinant. Assays were performed by dedicated technicians according to manufacturers' recommendations and following the laboratory standard operating procedures. Test results were manually transferred into the laboratory Excel files and hand-written in the laboratory logbook for syphilis testing. Logistic regression was used to assess the impact of sociodemographic characteristics on syphilis marker seroprevalence in both univariate and multivariable analysis. Odds ratios (OR) and 95% confidence intervals were calculated. RESULTS: The seroprevalence of syphilis markers was 8.4% (95% CI = 7.9-8.9) in 2004 and 2.4% (95% CI = 2.1-2.7) in 2016. The difference was significant [OR = 3.78; 95% CI (3.26-4.38); P < 0.001]. The decrease in syphilis seroprevalence was significant in both women and men and in each age group in univariate analysis. In multivariable analysis, controlling for all sociodemographic factors, the decrease in syphilis seroprevalence from 2004 to 2016 remained significant (OR = 3.29; 95% CI = 2.88-3.88, P < 0.001). The seroprevalence of syphilis decreased significantly in men compared to women and young donors compared to donors aged ≥36 years. CONCLUSIONS: This study shows a significant decline in syphilis seroprevalence in first-time blood donors in Libreville, Gabon. Government actions, including multiple HIV prevention activities, are a likely part of this decline.

Pulmonary Pathology Society Survey on Practice Approaches in the Histologic Diagnosis of Fibrotic Interstitial Lung Disease: Consensus and Opportunities.

CONTEXT.­: The pathologic diagnosis of usual interstitial pneumonia (UIP) remains a challenging area, and application of histologic UIP guidelines has proved difficult. OBJECTIVE.­: To understand current practice approaches by pulmonary pathologists for the histologic diagnosis of UIP and other fibrotic interstitial lung diseases (ILDs). DESIGN.­: The Pulmonary Pathology Society (PPS) ILD Working Group developed and sent a 5-part survey on fibrotic ILD electronically to the PPS membership. RESULTS.­: One hundred sixty-one completed surveys were analyzed. Of the respondents, 89% reported using published histologic features in clinical guidelines for idiopathic pulmonary fibrosis (IPF) in their pathologic diagnosis; however, there was variability in reporting terminology, quantity and quality of histologic features, and the use of guideline categorization. Respondents were very likely to have access to pulmonary pathology colleagues (79%), pulmonologists (98%), and radiologists (94%) to discuss cases. Half of respondents reported they may alter their pathologic diagnosis based on additional clinical and radiologic history if it is pertinent. Airway-centered fibrosis, granulomas, and types of inflammatory infiltrates were considered important, but there was poor agreement on how these features are defined. CONCLUSIONS.­: There is significant consensus among the PPS membership on the importance of histologic guidelines/features of UIP. There are unmet needs for (1) consensus and standardization of diagnostic terminology and incorporation of recommended histopathologic categories from the clinical IPF guidelines into pathology reports, (2) agreement on how to incorporate into the report relevant clinical and radiographic information, and (3) defining the quantity and quality of features needed to suggest alternative diagnoses.

Topical Ruxolitinib in the Treatment of Necrobiosis Lipoidica: A Prospective, Open-Label Study.

Necrobiosis lipoidica (NL) is a rare granulomatous disease. There are few effective treatments for NL. We sought to investigate the efficacy and safety of the Jak1/2 inhibitor, ruxolitnib, in the treatment of NL and identify the biomarkers associated with the disease and treatment response. We conducted an open-label, phase 2 study of ruxolitinib in 12 patients with NL. We performed transcriptomic analysis of tissue samples before and after treatment. At week 12, the mean NL lesion score decreased by 58.2% (SD = 28.7%, P = .003). Transcriptomic analysis demonstrated enrichment of type I and type II IFN pathways in baseline disease. Weighted gene coexpression network analysis demonstrated post-treatment changes in IFN pathways with key hub genes IFNG and signal transducer and activator of transcription 1 gene STAT1. Limitations include small sample size and a study group limited to patients with <10% body surface area. In conclusion, ruxolitinib is an effective treatment for NL and targets the key pathogenic mediators of the disease.

Association of Primary Care Risk Mitigation Visits and Nonelective Emergency Department Visits in Patients Using Long-term Opioid Therapy.

Objective: To determine risk factors for nonelective emergency department visits (NEDVs) and whether primary care visits incorporating risk mitigation tools prevented NEDVs among patients using long-term opioid therapy (LOT). Patients and Methods: We retrospectively searched the electronic health records at Mayo Clinic primary care outpatient practices in Arizona and Florida in all of 2018 and 2019 for the records of individual adult patients using LOT. Patient and clinician demographic characteristics and patient risk factors were compared between patients with and without risk mitigation visits. Univariate and multivariable logistic regression was used to determine risk factors for NEDVs. Results: Among 457 patients using LOT identified during the study period, most were women (n=266, 58.2%), and the median age was 69 years. Long-term opioid therapy risk mitigation visits were performed equally by family medicine and internal medicine clinicians and by a significantly higher proportion of Florida clinicians than Arizona clinicians (87.0% vs 70.5%; P<.001). Older age, falls, and mental health care utilization all increased the risk of NEDVs. Risk mitigation visits were protective against NEDVs (odds ratio, 0.56; 95% CI, 0.35-0.89; P=.01) after adjustment for older age, falls, and mental health care utilization. Conclusion: Risk mitigation visits are effective in preventing NEDVs, and all patients using LOT should have such visits when possible.