Citations

Abstract Background Glial fibrillary acidic protein (GFAP) is a promising candidate blood‐based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease‐associated changes, its clinical correlates, and biofluid‐type dependency will influence its clinical utility. Methods We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aβ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aβ‐positive from Aβ‐negative ADAD participants and showed a stronger relationship with Aβ load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion Our findings support a role for plasma GFAP as a clinical biomarker of Aβ‐related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.

Abstract Purpose: We previously demonstrated that high levels of circulating methylated DNA are associated with subsequent disease progression in women with metastatic breast cancer (MBC). In this study, we evaluated the clinical utility of a novel liquid biopsy-breast cancer methylation (LBx-BCM) prototype assay using the GeneXpert cartridge system for early assessment of disease progression in MBC. Experimental Design: The 9-marker LBx-BCM prototype assay was evaluated in TBCRC 005, a prospective biomarker study, using plasma collected at baseline, week 4, and week 8 from 144 patients with MBC. Results: At week 4, patients with MBC with high cumulative methylation (CM) had a significantly shorter median PFS (2.88 months vs. 6.60 months, P = 0.001) and OS (14.52 months vs. 22.44 months, P = 0.005) compared with those with low CM. In a multivariable model, high versus low CM was also associated with shorter PFS (HR, 1.90; 95% CI, 1.20–3.01; P = 0.006). Change in CM from baseline to week 4 (OR, 4.60; 95% CI, 1.77–11.93; P = 0.002) and high levels of CM at week 4 (OR, 2.78; 95% CI, 1.29–5.99; P = 0.009) were associated with progressive disease at the time of first restaging. A robust risk model based on week 4 circulating CM levels was developed to predict disease progression as early as 3 months after initiating a new treatment. Conclusions: The automated LBx-BCM prototype assay is a promising clinical tool for detecting disease progression a month after initiating treatment in women with MBC undergoing routine care. The next step is to validate its clinical utility for specific treatments.

Abstract Background Sexual assault survivors are at increased risk for sexually transmitted infections. Due to patient vulnerability, institutions have implemented Sexual Assault Nurse Examiner (SANE) protocols to care for these patients. These protocols guide evidence collection, testing, treatment, and medical follow-up to ensure optimization of sexually transmitted infections (STIs) treatment, monitoring and follow-up. Previous gap analyses have identified decreased prescribing of prophylactic STI medications and scheduling follow-up appointments compared to guideline recommendations. The purpose of this study was to assess adherence of medication prescribing and follow-up scheduling practices to Centers for Disease Control (CDC) guidelines. Methods This study was a single-center, retrospective, observational, descriptive assessment which evaluated adherence rates to CDC guidelines, to scheduling medical follow-up, and patient attendance at scheduled appointments. Pediatric and adult patients who presented to the emergency department at Mayo Clinic Health System in La Crosse, WI from January 2018 through December 2021 were included. Data collected through chart review included demographics and laboratory data necessary for prescribing prophylactic HIV medications, antibiotics for STIs, emergency contraception, and vaccine administration. Descriptive statistics were used to evaluate results. Results One hundred three patients were evaluated. Majority of patients were female and presented within 3 days of assault. Medication adherence to CDC guidelines was ≥ 80% for chlamydia and gonorrhea whereas < 80% was noted for trichomoniasis and HIV prophylaxis. Adherence to post-ED discharge follow-up was 40%. Conclusion Opportunities to improve adherence of ED-SANE protocols for medication prescribing and medical follow-up for trichomoniasis and HIV prophylaxis exist. Disclosures All Authors: No reported disclosures.

Abstract Background Pneumocystis jirovecii pneumonia (PCP) is a potentially deadly infection afflicting the immunocompromised population, including solid organ transplant recipients. Several risk factors have been described, including acute rejection, lymphopenia, and cytomegalovirus (CMV) infection. However, little is known regarding the risk imparted by posttransplant lymphoproliferative disorder (PTLD). Methods We performed a nested case-control study of solid organ transplant recipients diagnosed with PCP from 2000-2020. PCP was defined as positive smear or polymerase chain reaction testing with compatible clinical symptoms and radiographic findings. Two control were matched to each case by year of first transplant, first transplanted organ, and sex. Each control had at least as much follow-up from their transplant date to their matched case’s PCP diagnosis date. Multivariable conditional logistic regression was performed to analyze theorized risk factors. Results Sixty-seven cases met inclusion criteria and were matched to 134 controls (Table 1). Median age was 60.9 years, and the most common transplant type was kidney (52.2%). Fourteen patients had a history of PTLD, 12 of which developed PCP. All cases of PTLD were monomorphic, 6 were EBV-positive, 9 were receiving chemotherapy at the index date, and only 1 control patient was receiving PCP prophylaxis. The cases with PTLD developed PCP a median of 85 days after PTLD diagnosis, while the two controls were diagnosed more than 1 year earlier. After adjusting for age, acute rejection requiring treatment within the last 6 months, CMV infection within 6 months, current PCP prophylaxis, and lymphopenia (lymphocyte count < 0.5 x109/L) within 6 months, PTLD had a significant association with PCP (OR 14.0, 95% CI 1.7-114.5; p = .014). Lymphopenia was also associated with PCP (OR 8.2, 95% CI 3.2-20.7; p < .001), while the other factors were not. Table 1:Characteristics of 67 Solid Organ Transplant Recipients with Pneumocystis Pneumonia and 134 Matched Controls Conclusion Diagnosis of PTLD is independently associated with subsequent PCP after adjustment for recognized risk factors. This association is likely influenced by PTLD-directed chemotherapy, particularly regimens containing rituximab. PCP prophylaxis should be initiated in solid organ transplant recipients with PTLD, particularly those undergoing active therapy, and those with severe lymphopenia. Disclosures All Authors: No reported disclosures.

Abstract Background Eculizumab, an inhibitor of terminal complement activation, has been utilized in pre-transplant desensitization, treatment of antibody-mediated rejection and thrombotic microangiopathy in solid organ transplant recipients (SOTR). Eculizumab is associated with meningococcal disease, leading to guidelines for vaccination against serogroups ACWY (menACWY) and B (menB) at least 2 weeks prior to eculizumab therapy. In persons requiring emergent use of eculizumab, prophylaxis for at least 2 weeks is recommended. SOTRs respond suboptimally to vaccination, raising consideration for pre-transplant vaccination and prolonged prophylaxis in those undergoing eculizumab therapy. We sought to describe meningococcal vaccination and prophylaxis practices among SOTRs receiving eculizumab. Methods We performed a retrospective chart review of meningococcal vaccination, including number and timing pre- or post-transplant, along with prophylaxis prescribing and duration in SOTRs receiving eculizumab across 3 distinct Mayo Clinic Enterprise sites (Rochester, Arizona, and Florida). Results 200 SOTRs receiving at least one dose of eculizumab between 1/1/2008 and 9/16/2021 were reviewed. Eculizumab indications included antibody mediated rejection (38%), desensitization (26%), and thrombotic microangiopathy (19%). 83% (166/200) of SOTRs received eculizumab for an unanticipated post-transplant complication. Vaccination rates were 82% (164/200) and 35.5% (71/200) for menACWY dose 1 and 2, respectively, and 54% (108/200) and 28.5% (57/200) for menB dose 1 and 2, respectively. The majority received their first vaccination post-transplant: menACWY 66.5% (133/200) and menB 2.5% (185/200). Among those without vaccination pre-eculizumab, 22.3% (41/184) were not prescribed prophylaxis. The median duration of prophylaxis was 62 (range 4-2651) days. Conclusion Most SOTRs underwent meningococcal vaccinations near the time of eculizumab administration post-transplant for an unanticipated complication. One-fifth of those meeting criteria were not provided meningococcal prophylaxis. These findings may support pre-transplant administration of meningococcal vaccinations and heightened awareness for meningococcal prophylaxis in SOTRs receiving eculizumab. Disclosures All Authors: No reported disclosures.

Abstract Purpose Medical school tuition has increased at alarming rates ahead of inflation over the past 20 years. The authors investigated whether state-funded medical schools have had an increased number of out-of-state matriculants, which may create a diaspora of displaced in-state medical students matriculating to out-of-state programs and incurring substantial debt. Method Publicly available data from the Association of American Medical Colleges (AAMC) were accessed from 2004 through 2019 for applicants and matriculants at U.S. state-funded schools. Schools listed as public that reported tuition charges in the AAMC Tuition and Student Fees reports were included in this study. The numbers and trends of medical school applications and trends in tuition costs and average indebtedness were summarized for in-state and out-of-state matriculants. Values were analyzed by group as median and interquartile range (IQR). Group differences were assessed via t tests. P values less than .05 were considered statistically significant. Results From 2004 through 2019, the annual number of out-of-state matriculants in state-funded schools increased 7% (16%–23% [7,195–11,144]). Among 74 schools with data in 2004, the median percentage of out-of-state applications increased from 60% (IQR, 31%–74%) to 80% (IQR, 57%–85%; P < .001), and the median percentage of out-of-state matriculants increased from 13% (IQR, 5%–23%) to 17% (IQR, 11%–33%; P < .001). In 2004, the mean (standard error) debt upon completion of medical school (inflation adjusted to 2018 dollars) was $144,100 ($10,950); by 2016, the mean debt had increased to $251,600 ($32,040), a 75% increase over 12 years. Conclusions Since 2004, substantial increases have occurred in out-of-state matriculants at state-funded medical schools. This may displace residents from attending their in-state schools, causing them to attend out-of-state or private medical schools, where tuition is typically much higher.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.