Multiple resistance factors collectively promote inoculum-dependent dynamic survival during antimicrobial peptide exposure in Enterobacter cloacae.

Antimicrobial peptides (AMPs) are a promising tool with which to fight rising antibiotic resistance. However, pathogenic bacteria are equipped with several AMP defense mechanisms, whose contributions to AMP resistance are often poorly defined. Here, we evaluate the genetic determinants of resistance to an insect AMP, cecropin B, in the opportunistic pathogen Enterobacter cloacae. Single-cell analysis of E. cloacae's response to cecropin revealed marked heterogeneity in cell survival, phenotypically reminiscent of heteroresistance (the ability of a subpopulation to grow in the presence of supra-MIC concentration of antimicrobial). The magnitude of this response was highly dependent on initial E. cloacae inoculum. We identified 3 genetic factors which collectively contribute to E. cloacae resistance in response to the AMP cecropin: The PhoPQ-two-component system, OmpT-mediated proteolytic cleavage of cecropin, and Rcs-mediated membrane stress response. Altogether, this evidence suggests that multiple, independent mechanisms contribute to AMP resistance in E. cloacae.

Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke.

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

Use of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease, characterized by the presence of autoantibodies to protein and non-protein antigens. Here we report the identification of specific anti-carbohydrate antibodies (ACAs) that are associated with pathogenesis and progression to T1D. We compare circulatory levels of ACAs against 202 glycans in a cross-sectional cohort of T1D patients (n = 278) and healthy controls (n = 298), as well as in a longitudinal cohort (n = 112). We identify 11 clusters of ACAs associated with glycan function class. Clusters enriched for aminoglycosides, blood group A and B antigens, glycolipids, ganglio-series, and O-linked glycans are associated with progression to T1D. ACAs against gentamicin and its related structures, G418 and sisomicin, are also associated with islet autoimmunity. ACAs improve discrimination of T1D status of individuals over a model with only clinical variables and are potential biomarkers for T1D.

Spin in Randomized Controlled Trials in Obstetrics and Gynecology: A Systematic Review.

Objectives: The objective of this study was to evaluate the extent, type, and severity of spin in randomized controlled trials (RCTs) in obstetrics and gynecology. Data Sources: The top five highest impact journals in obstetrics and gynecology were systematically searched for RCTs with non-significant primary outcomes published between January 1, 2019, and December 31, 2020. Methods: Study selection and data extraction assessment were conducted independently and in duplicate. The extent, type, and severity of spin was identified and reported with previously established methodology, and risk of bias was assessed with the Cochrane Risk-of-Bias 2 Tool independently and in duplicate. Fisher's exact tests were used to evaluate the association between study characteristics, risk of bias, and spin. Results: We identified 1475 publications, of which 59 met our inclusion criteria. Articles evaluated interventions in obstetrics (n = 37, 63%) and gynecology (n = 22, 37%). Spin was not detected in 28 (47%) of the articles: Three (5%) had one, 10 (17%) had two, and 18 (31%) had greater than two occurrences of spin. Compared with articles where no spin was detected, spin was associated with the Cochrane Risk-of-Bias domain pertaining to missing data (p < 0.05). No association was observed with the journal, funding source, number of authors, types of interventions, and whether the study involved gynecology or obstetrics. Conclusions: Spin was detected in nearly half of 1:1 parallel two-arm RCTs in obstetrics and gynecology, highlighting the need for caution in the interpretation of RCT findings, particularly when the primary outcome is nonsignificant.

Development of a Telemedicine Screening Program During the COVID-19 Pandemic.

Background: Telemedicine use increased during the COVID-19 pandemic due to concerns for patient and provider safety. Given the lack of testing resources initially and the large geographical range served by Augusta University (AU), a telemedicine platform with up-to-date screening guidelines was implemented for COVID-19 testing in March 2020. Our objective was to understand the level of adherence to telemedicine screening guidelines for COVID-19. Methods: The study population included health care providers and population who participated in an encounter in the AU Health Express Care virtual care program from March 22 to May 21, 2020. All encounters were intended to be for COVID-19 screening, free, and available 24 h per day, 7 days per week. Screening guidelines were developed by AU based on information from the Centers for Disease Control and Prevention and the Georgia Department of Public Health. Results: Among 17,801 total encounters, 13,600 were included in the final analysis. Overall adherence to screening guidelines was 71% in the adult population and 57% in the pediatric population. When providers did not follow guidelines, 72% determined that the patient should have a positive screen. Guidelines themselves determined that only 52% of encounters should have a positive screen. Providers' specialty significantly correlated with guideline adherence (p = 0.002). Departments with the highest adherence were psychiatry, neurology, and ophthalmology. No significant correlation was found between guideline adherence and provider degree/position. Conclusions: This study provides proof of concept of a free telehealth screening platform during an ongoing pandemic. Our screening experience was effective and different specialties participated. Our patient population lived in lower than average income zip codes, suggesting that our free telemedicine screening program successfully reached populations with higher financial barriers to health care. Early training and a posteriori knowledge of telemedicine was likely key to screening guideline adherence.

T1DMicro: A Clinical Risk Calculator for Type 1 Diabetes Related Microvascular Complications.

Development of complications in type 1 diabetes patients can be reduced by modifying risk factors. We used a cross-sectional cohort of 1646 patients diagnosed with type 1 diabetes (T1D) to develop a clinical risk score for diabetic peripheral neuropathy (DPN), autonomic neuropathy (AN), retinopathy (DR), and nephropathy (DN). Of these patients, 199 (12.1%) had DPN, 63 (3.8%) had AN, 244 (14.9%) had DR, and 88 (5.4%) had DN. We selected five variables to include in each of the four microvascular complications risk models: age, age of T1D diagnosis, duration of T1D, and average systolic blood pressure and HbA1C over the last three clinic visits. These variables were selected for their strong evidence of association with diabetic complications in the literature and because they are modifiable risk factors. We found the optimism-corrected R2 and Harrell's C statistic were 0.39 and 0.87 for DPN, 0.24 and 0.86 for AN, 0.49 and 0.91 for DR, and 0.22 and 0.83 for DN, respectively. This tool was built to help inform patients of their current risk of microvascular complications and to motivate patients to control their HbA1c and systolic blood pressure in order to reduce their risk of these complications.

Bridging the Gap Between the Intensive Care Unit and the Acute Medical Care Unit.

BACKGROUND: Despite a growing cohort of intensive care unit (ICU) survivors, little is known about the early ICU aftercare period. OBJECTIVE: To identify gaps in early ICU aftercare and factors associated with poor hospital outcomes. METHODS: A multisite, retrospective study (January 1 to December 31, 2017) was conducted among randomly selected patients admitted to the medical ICU and subsequently transferred to acute medical care units. Records were reviewed for patient characteristics, ICU course, and early ICU aftercare practices and syndromes. Associations between practices and hospital outcomes were calculated with χ2 and Wilcoxon rank sum tests, followed by logistic regression. RESULTS: One hundred fifty-one patients met inclusion criteria (mean [SD] age, 64.2 [19.1] years; 51.7% male; 44.4% White). The most frequent diagnoses were sepsis (35.8%) and respiratory failure (33.8%). During early ICU aftercare, 46.4% had dietary restrictions, 25.8% had bed rest orders, 25.0% had a bladder catheter, 26.5% had advance directive documentation, 33.8% had dysphagia, 34.3% had functional decline, and 23.2% had delirium. Higher Charlson Comorbidity Index (odds ratio, 1.6) and midodrine use on medical units (odds ratio, 7.5) were associated with in-hospital mortality; mechanical ventilation in the ICU was associated with rapid response on medical unit (odds ratio, 12.9); and bladder catheters were associated with ICU readmission (odds ratio, 5.2). CONCLUSIONS: Delirium, debility, and dysphagia are frequently encountered in early ICU aftercare, yet bed rest, dietary restriction, and lack of advance directive documentation are common. Future studies are urgently needed to characterize and address early ICU aftercare.

The 3p21.31 genetic locus promotes progression to type 1 diabetes through the CCR2/CCL2 pathway.

Multiple cross-sectional and longitudinal studies have shown that serum levels of the chemokine ligand 2 (CCL-2) are associated with type 1 diabetes (T1D), although the direction of effect differs. We assessed CCL-2 serum levels in a longitudinal cohort to clarify this association, combined with genetic data to elucidate the regulatory role of CCL-2 in T1D pathogenesis. The Diabetes Autoimmunity Study in the Young (DAISY) followed 310 subjects with high risk of developing T1D. Of these, 42 became persistently seropositive for islet autoantibodies but did not develop T1D (non-progressors); 48 did develop T1D (progressors). CCL-2 serum levels among the three study groups were compared using linear mixed models adjusting for age, sex, HLA genotype, and family history of T1D. Summary statistics were obtained from the CCL-2 protein quantitative trait loci (pQTL) and CCR2 expression QTL (eQTL) studies. The T1D fine mapping association data were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). Serum CCL-2 levels were significantly lower in both progressors (p = 0.004) and non-progressors (p = 0.005), compared to controls. Two SNPs (rs1799988 and rs746492) in the 3p21.31 genetic locus, which includes the CCL-2 receptor, CCR2, were associated with increased CCR2 expression (p = 8.2e-5 and 5.2e-5, respectively), decreased CCL-2 serum level (p = 2.41e-9 and 6.21e-9, respectively), and increased risk of T1D (p = 7.9e-5 and 7.9e-5, respectively). The 3p21.31 genetic region is associated with developing T1D through regulatory control of the CCR2/CCL2 immune pathway.

Evaluating the Impact of Mobile Phone Technology on Health Outcomes for Latinos with Type 2 Diabetes.

OBJECTIVES: To assess whether a Spanish-language text messaging program helps Latinos with diabetes better manage their disease. METHODS: Spanish-speaking Latinos with type 2 diabetes and HbA1c ≥ 8% (N = 38) were recruited January 1, 2016-May 31, 2016, at a large integrated healthcare delivery system. Participants received 1-3 Spanish-language text messages about diabetes self-care per day for 3 months with an optional 3-month extension. The Wilcoxon signed-rank test for paired data was used to compare pre-post intervention HbA1c. The Wilcoxon-Mann-Whitney nonparametric test was used to compare changes in HbA1c across groups. RESULTS: After 3 months, the median HbA1c reduction overall was 1.4 percentage points (IQR: 0.5-3.3, p < 0.01). Latinos having pre-intervention HbA1c > 10.0% had a greater reduction in median HbA1c (3.8, IQR: 0.5-5.3) compared with those having pre-intervention HbA1c ≤ 10.0% (0.9, IQR: 0.1-1.9, p < 0.05). This reduction in median HbA1c persisted after 6 months (1.3, IQR: 0.2-2.9, p < 0.01). CONCLUSION: A Spanish-language text messaging program was an effective way to improve glycemic control for Latinos with type 2 diabetes. POLICY IMPLICATIONS: Culturally and linguistically tailored text messaging programs for managing diabetes should be considered.

Patient Characteristics Associated With Choosing a Telemedicine Visit vs Office Visit With the Same Primary Care Clinicians.

Importance: Video or telephone telemedicine can offer patients access to a clinician without arranging for transportation or spending time in a waiting room, but little is known about patient characteristics associated with choosing between telemedicine or office visits. Objective: To examine patient characteristics associated with choosing a telemedicine visit vs office visit with the same primary care clinicians. Design, Setting, and Participants: This cross-sectional study included data from 1 131 722 patients who scheduled a primary care appointment through the Kaiser Permanente Northern California patient portal between January 1, 2016, and May 31, 2018. All completed primary care appointments booked via the patient portal were identified. Only index visits without any other clinical visits within 7 days were included to define a relatively distinct patient-initiated care-seeking episode. Visits for routine physical, which are not telemedicine-eligible, were excluded. Data were analyzed from July 1, 2018, to December 31, 2019. Main Outcomes and Measures: Patient choice between an office, video, or telephone visit. Relative risk ratios (RRRs) for patient sociodemographic characteristics (age, sex, race/ethnicity, neighborhood socioeconomic status, language preference), technology access (neighborhood residential internet, mobile portal use), visiting the patient's own personal primary care clinician, and in-person visit barriers (travel-time, parking, cost-sharing), associated with choice of video or telephone telemedicine (vs office visit). Results: Of 2 178 440 patient-scheduled primary care visits scheduled by 1 131 722 patients, 86% were scheduled as office visits and 14% as telemedicine visits, with 7% of the telemedicine visits by video. Choosing telemedicine was statistically significantly associated with patient sociodemographic characteristics. For example, patients aged 65 years and over were less likely than patients aged 18 to 44 years to choose telemedicine (RRR, 0.24; 95% CI, 0.22-0.26 for video visit; RRR 0.55; 95% CI, 0.54-0.57 for telephone visit). Choosing telemedicine was also statistically significantly associated with technology access (patients living in a neighborhood with high rates of residential internet access were more likely to choose a video visit than patients whose neighborhoods had low internet access: RRR, 1.10; 95% CI, 1.06-1.14); as well as in-person visit barriers (patients whose clinic had a paid parking structure were more likely to choose a telemedicine visit than patients whose facility had free parking: RRR, 1.70; 95% CI, 1.41-2.05 for video visit; and RRR, 1.73, 95% CI, 1.61-1.86 for telephone visit). Conclusions and Relevance: In this cross-sectional study, patients usually chose an in-person visit when scheduling an appointment online through the portal. Telemedicine may offer the potential to reach vulnerable patient groups and improve access for patients with transportation, parking, or cost barriers to clinic visits.

Study protocol: Using peer support to aid in prevention and treatment in prediabetes (UPSTART).

BACKGROUND: There is an urgent need to develop and evaluate effective and scalable interventions to prevent or delay the onset of type 2 diabetes mellitus (T2DM). METHODS: In this randomized controlled pragmatic trial, 296 adults with prediabetes will be randomized to either a peer support arm or enhanced usual care. Participants in the peer support arm meet face-to-face initially with a trained peer coach who also is a patient at the same health center to receive information on locally available wellness and diabetes prevention programs, discuss behavioral goals related to diabetes prevention, and develop an action plan for the next week to meet their goals. Over six months, peer coaches call their assigned participants weekly to provide support for weekly action steps. In the final 6 months, coaches call participants at least once monthly. Participants in the enhanced usual care arm receive information on local resources and periodic updates on available diabetes prevention programs and resources. Changes in A1c, weight, waist circumference and other patient-centered outcomes and mediators and moderators of intervention effects will be assessed. RESULTS: At least 296 participants and approximately 75 peer supporters will be enrolled. DISCUSSION: Despite evidence that healthy lifestyle interventions can improve health behaviors and reduce risk for T2DM, engagement in recommended behavior change is low. This is especially true among racial and ethnic minority and low-income adults. Regular outreach and ongoing support from a peer coach may help participants to initiate and sustain healthy behavior changes to reduce their risk of diabetes. TRIAL REGISTRATION: The ClinicalTrials.gov registration number is NCT03689530.

Initial Glycemic Control and Care Among Younger Adults Diagnosed With Type 2 Diabetes.

OBJECTIVE: The prevalence of type 2 diabetes is increasing among adults under age 45. Onset of type 2 diabetes at a younger age increases an individual's risk for diabetes-related complications. Given the lasting benefits conferred by early glycemic control, we compared glycemic control and initial care between adults with younger onset (21-44 years) and mid-age onset (45-64 years) of type 2 diabetes. RESEARCH DESIGN AND METHODS: Using data from a large, integrated health care system, we identified 32,137 adults (aged 21-64 years) with incident diabetes (first HbA1c ≥6.5% [≥48 mmol/mol]). We excluded anyone with evidence of prior type 2 diabetes, gestational diabetes mellitus, or type 1 diabetes. We used generalized linear mixed models, adjusting for demographic and clinical variables, to examine differences in glycemic control and care at 1 year. RESULTS: Of identified individuals, 26.4% had younger-onset and 73.6% had mid-age-onset type 2 diabetes. Adults with younger onset had higher initial mean HbA1c values (8.9% [74 mmol/mol]) than adults with onset in mid-age (8.4% [68 mmol/mol]) (P < 0.0001) and lower odds of achieving an HbA1c <7% (<53 mmol/mol) 1 year after the diagnosis (adjusted odds ratio [aOR] 0.70 [95% CI 0.66-0.74]), even after accounting for HbA1c at diagnosis. Adults with younger onset had lower odds of in-person primary care contact (aOR 0.82 [95% CI 0.76-0.89]) than those with onset during mid-age, but they did not differ in telephone contact (1.05 [0.99-1.10]). Adults with younger onset had higher odds of starting metformin (aOR 1.20 [95% CI 1.12-1.29]) but lower odds of adhering to that medication (0.74 [0.69-0.80]). CONCLUSIONS: Adults with onset of type 2 diabetes at a younger age were less likely to achieve glycemic control at 1 year following diagnosis, suggesting the need for tailored care approaches to improve outcomes for this high-risk patient population.

Absence of Ischemic Injury after Sacrificing the Superior Petrosal Vein during Microvascular Decompression.

BACKGROUND: Sacrificing the superior petrosal vein (SPV) is controversial during a microvascular decompression (MVD). There have been multiple reports of complications including life-threatening brainstem infarction and cerebellar edema. OBJECTIVE: To analyze the potential for vascular complications when the SPV is sacrificed during an MVD. METHODS: Retrospective chart review was performed to identify all MVDs for trigeminal neuralgia and hemifacial spasm from 2007 to 2018 at 1 institution. Cases with ≥1 mo of follow-up were included and SPV sacrifice was noted. The primary outcome was complications related to SPV sacrifice including sinus thrombosis, cerebellar edema, and midbrain or pontine infarction. Imaging was used to confirm all potential vascular complications noted in medical records. Fisher's exact test and unpaired t-tests were used to compare between groups. RESULTS: A total of 732 MVD cases were identified and 592 met inclusion criteria with an average follow-up of 11.8 ± 16.4 mo and a male-to-female ratio of 1:2.2. The SPV was sacrificed in 217 cases and retained in 375 cases. No SPV-related vascular complications were found in this study. Two unrelated cases of vascular complications were identified and both were in the nonsacrificed group. One case involved cerebellar bleeding while the other was an ipsilateral transverse sinus thrombosis that was present preoperatively. CONCLUSION: In MVDs, there is no difference in the rate of vascular complications when the SPV is sacrificed compared to preserved. To best visualize a cranial nerve and optimize safe decompression, surgeons should feel free to sacrifice the SPV.

In Vivo Bioluminescence Tomography Center of Mass-Guided Conformal Irradiation.

PURPOSE: The cone-beam computed tomography (CBCT)-guided small animal radiation research platform (SARRP) has provided unique opportunities to test radiobiologic hypotheses. However, CBCT is less adept to localize soft tissue targets growing in a low imaging contrast environment. Three-dimensional bioluminescence tomography (BLT) provides strong image contrast and thus offers an attractive solution. We introduced a novel and efficient BLT-guided conformal radiation therapy and demonstrated it in an orthotopic glioblastoma (GBM) model. METHODS AND MATERIALS: A multispectral BLT system was integrated with SARRP for radiation therapy (RT) guidance. GBM growth curve was first established by contrast CBCT/magnetic resonance imaging (MRI) to derive equivalent sphere as approximated gross target volume (aGTV). For BLT, mice were subject to multispectral bioluminescence imaging, followed by SARRP CBCT imaging and optical reconstruction. The CBCT image was acquired to generate anatomic mesh for the reconstruction and RT planning. To ensure high accuracy of the BLT-reconstructed center of mass (CoM) for target localization, we optimized the optical absorption coefficients µa by minimizing the distance between the CoMs of BLT reconstruction and contrast CBCT/MRI-delineated GBM volume. The aGTV combined with the uncertainties of BLT CoM localization and target volume determination was used to generate estimated target volume (ETV). For conformal irradiation procedure, the GBM was first localized by the predetermined ETV centered at BLT-reconstructed CoM, followed by SARRP radiation. The irradiation accuracy was qualitatively confirmed by pathologic staining. RESULTS: Deviation between CoMs of BLT reconstruction and contrast CBCT/MRI-imaged GBM is approximately 1 mm. Our derived ETV centered at BLT-reconstructed CoM covers >95% of the tumor volume. Using the second-week GBM as an example, the ETV-based BLT-guided irradiation can cover 95.4% ± 4.7% tumor volume at prescribed dose. The pathologic staining demonstrated the BLT-guided irradiated area overlapped well with the GBM location. CONCLUSIONS: The BLT-guided RT enables 3-dimensional conformal radiation for important orthotopic tumor models, which provides investigators a new preclinical research capability.

Management of Frailty: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To analyze and determine the comparative effectiveness of interventions targeting frailty prevention or treatment on frailty as a primary outcome and quality of life, cognition, depression, and adverse events as secondary outcomes. DESIGN: Systematic review and network meta-analysis (NMA). METHODS: Data sources-Relevant randomized controlled trials (RCTs) were identified by a systematic search of several electronic databases including MEDLINE, EMBASE, CINAHL, and AMED. Duplicate title and abstract and full-text screening, data extraction, and risk of bias assessment were performed. Data extraction-All RCTs examining frailty interventions aimed to decrease frailty were included. Comparators were standard care, placebo, or another intervention. Data synthesis-We performed both standard pairwise meta-analysis and Bayesian NMA. Dichotomous outcome data were pooled using the odds ratio effect size, whereas continuous outcome data were pooled using the standardized mean difference (SMD) effect size. Interventions were ranked using the surface under the cumulative ranking curve (SUCRA) for each outcome. The quality of evidence was evaluated using the GRADE approach. RESULTS: A total of 66 RCTs were included after screening of 7090 citations and 749 full-text articles. NMA of frailty outcome (including 21 RCTs, 5262 participants, and 8 interventions) suggested that the physical activity intervention, when compared to placebo and standard care, was associated with reductions in frailty (SMD -0.92, 95% confidence interval -1.55, -0.29). According to SUCRA, physical activity intervention and physical activity plus nutritional supplementation were probably the most effective intervention (100% and 71% likelihood, respectively) to reduce frailty. Physical activity was probably the most effective or the second most effective interventions for all included outcomes. CONCLUSION AND IMPLICATIONS: Physical activity is one of the most effective frailty interventions. The quality of evidence of the current review is low and very low. More robust RCTs are needed to increase the confidence of our NMA results and the quality of evidence.

Clinical Response to Real-Time Patient-Reported Diabetic Peripheral Neuropathy Symptoms.

INTRODUCTION: To assess clinician response to real-time patient-reported data about diabetic peripheral neuropathy (DPN) symptoms, we analyzed DPN diagnosis and treatment patterns after administration of a 4-question symptom questionnaire in a large vertically integrated health care system. METHODS: Retrospective cohort study to analyze data from 160,852 patients screened for DPN symptoms from April 2012 to March 2014. Electronic medical record data were used to study changes in DPN diagnosis, treatment initiation, and treatment intensification. We used logistic regression to study the association of patient characteristics with the odds of clinical response. RESULTS: Of patients queried, 50,684 (31.5%) reported symptoms. Patients reporting DPN symptoms experienced a greater increase in new DPN diagnoses (16 percentage points; p < 0.0001) and medication use (4 percentage points; p < 0.0001) compared with those denying symptoms. Among patients reporting symptoms, women and nonwhite patients were less likely to receive a DPN diagnosis, whereas older patients were more likely to receive a DPN diagnosis. Overall, patients who were older, were Asian (hazard ratio = 0.67, 95% confidence interval = 0.63-0.77), and had lower socioeconomic status (hazard ratio = 0.89, 95% confidence interval = 0.80-0.99) were less likely to be treated. However, these racial and socioeconomic differences were not statistically significant for patients with preexisting DPN diagnoses. CONCLUSION: Patients' real-time reports of DPN symptoms were associated with increased clinical activity. Patient- and clinician-level factors associated with the likelihood of receiving a DPN diagnosis need further study because a formal diagnosis may be associated with more equitable treatment.

Utilization of the Nasoseptal Flap for Repair of Cerebrospinal Fluid Leak after Endoscopic Endonasal Approach for Resection of Pituitary Tumors.

BACKGROUND: One of the most frequent complications after endoscopic endonasal approach (EEA) for resection of pituitary tumors is cerebrospinal fluid (CSF) leaks. With the introduction of the pedicled nasoseptal flap, the reconstruction of the skull base has improved significantly resulting in a decrease in the occurrence of persistent CSF leaks. We present our experience utilizing the pedicled nasoseptal flap technique after EEA for reconstruction of the skull base in cases where CSF leak was detected. METHODS: Data for patients undergoing EEA for pituitary tumors was retrospectively reviewed. These included demographic, clinical, operative, radiographic, and pathological information. Incidence of post-operative complications and CSF leaks were recorded. Descriptive statistical analysis was performed. RESULTS: Between 2008 and 2015, 67 patients and 69 hospital admissions with pituitary tumors underwent a nasoseptal flap to reconstruct a skull base defect at Johns Hopkins Hospital. The mean age at surgery was 54.5±14.2 years. Fifty-two percent of patients were male. Forty-six percent of patients were white, 33% African-American, and 12% belonged to other racial groups. There was an intraoperative CSF leak in 39% of patients. Seventy percent of patients with an intraoperative CSF leak had a nasoseptal flap reconstruction of the skull base. There were zero postoperative CSF leaks. CONCLUSION: With the introduction of the pedicled nasoseptal flap for reconstruction of the skull base after EEA for resection of pituitary adenomas, the incidence of postoperative CSF leaks has decreased significantly. In this retrospective analysis, we demonstrate the effectiveness of the use of nasoseptal flap in repairing CSF leak after EEA.

Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment.

BACKGROUND: Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model. METHODS: C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry. RESULTS: Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines. CONCLUSIONS: Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

Retrosigmoid approach for glycerin rhizotomy in the treatment of trigeminal neuralgia without overt arterial compression: updated case series.

OBJECTIVE: Trigeminal neuralgia (TN) is a neuropathic pain disorder characterized by severe, lancinating facial pain that is commonly treated with neuropathic medication, percutaneous rhizotomy, and/or microvascular decompression (MVD). Patients who are not found to have distinct arterial compression during MVD present a management challenge. In 2013, the authors reported on a small case series of such patients in whom glycerin was injected intraoperatively into the cisternal segment of the trigeminal nerve. The objective of the authors' present study was to report their updated experience with this technique to further validate this novel approach. METHODS: The authors performed a retrospective analysis of data obtained in patients in whom glycerin was directly injected into the inferior third of the cisternal portion of the trigeminal nerve. Seventy-four patients, including 14 patients from the authors' prior study, were identified, and demographic information, intraoperative findings, postoperative course, and complications were recorded. Fisher's exact test, unpaired t-tests, and Kaplan-Meier survival curves using Mantel log-rank test were used to compare the 74 patients with a cohort of 476 patients who received standard MVD by the same surgeon. RESULTS: The 74 patients who underwent MVD and glycerin injection had an average follow-up of 19.1 ± 18.0 months, and the male/female ratio was 1:2.9. In 33 patients (44.6%), a previous intervention for TN had failed. On average, patients had an improvement in the Barrow Neurological Institute Pain Intensity score from 4.1 ± 0.4 before surgery to 2.1 ± 1.2 after surgery. Pain improvement after the surgery was documented in 95.9% of patients. Thirteen patients (17.6%) developed burning pain following surgery. Five patients developed complications (6.7%), including incisional infection, facial palsy, CSF leak, and hearing deficit, all of which were minor. CONCLUSIONS: Intraoperative injection of glycerin into the trigeminal nerve is a generally safe and potentially effective treatment for TN when no distinct site of arterial compression is identified during surgery or when decompression of the nerve is deemed to be inadequate.