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The Bacillus Calmette-Guérin (BCG) vaccine, which has been used for > 100 years to prevent tuberculosis, is well-established for bladder cancer treatment, and under study for neurological and autoimmune diseases. In patients with type 1 diabetes (T1D), BCG vaccinations have been shown in randomized clinical trials to gradually lower blood sugar to near normal levels. This effect appears to be driven by a BCG-induced shift in lymphoid cells' glucose metabolism from oxidative phosphorylation to aerobic glycolysis. The latter is a state of high glucose utilization that draws more glucose from the blood. Apart from blood, it is unknown whether BCG establishes residence in any organs and alters their glucose metabolism. In this two-year-long clinical trial in type 1 diabetics, we use positron emission tomography (PET) and x-ray computed tomography (CT) to map organs that increase their uptake of the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) before versus after BCG vaccinations. We also injected BALB/c mice with BCG to test for the presence of BCG in various organs. Results from both studies point to the spleen as the dominant site for glucose uptake and BCG residence. The human spleen is significant because its 47% increase in 18F-FDG uptake by a large population of lymphocytes and monocytes might help to explain BCG's systemic lowering of blood glucose to near normal levels. Findings suggest that the spleen, triggered by BCG, assumes a critical role in systemic glucose regulation in the absence of a functional pancreas.
Subject(s)
BCG Vaccine , Blood Glucose , Diabetes Mellitus, Type 1 , Fluorodeoxyglucose F18 , Positron-Emission Tomography , Spleen , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Spleen/metabolism , Spleen/diagnostic imaging , BCG Vaccine/therapeutic use , Humans , Animals , Blood Glucose/metabolism , Mice , Female , Male , Adult , Mice, Inbred BALB C , Middle Aged , Tomography, X-Ray Computed , Positron Emission Tomography Computed TomographyABSTRACT
INTRODUCTION: Hip fractures are a common traumatic injury that carry significant morbidity and mortality, and prognostication of functional outcome is becoming increasingly salient. Across multiple surgical specialties, the five-item and 11-item Modified Frailty Index (mFI-5 and mFI-11) have been found to be convenient, quick, and sensitive tools for identifying patients at risk for perioperative complications. A prior study described the superiority of an Age-Adjusted Modified Frailty Index (aamFI) for predicting perioperative complications compared to the mFI-5 in an elective hip surgery. We sought to externally validate the aamFI in a multicenter hip fracture cohort and hypothesize that these risk scores would not only predict functional dependence (FD) at discharge, but that the aamFI would outperform the mFI-5 and mFI-11. METHODS: The Pennsylvania Trauma Systems Foundation registry was queried from 2010 to 2020 for CPT codes, ICD-9 and ICD-10 codes pertaining to hip fracture patients. Patients with missing locomotion and transfer mobility data were excluded. FD status was determined by discharge locomotion and transfer mobility scores per existing methodology. Univariable and Multivariable analysis as well as receiver operator characteristic curves were used to evaluate and compare the three indices for prediction of functional status at discharge. P value < 0.05 was considered significant. RESULTS: Twelve thousand seven hundred and forty patients met inclusion criteria (FD: 8183; functional independent 4557). On univariable logistic regression analysis, the mFI-11 (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.47-1.58, P < 0.05), mFI-5 (OR 1.57, 95% CI 1.51-1.63), and aamFI (OR 1.57, 95% CI 1.52-1.62, P < 0.05) were associated with FD. On multivariable logistic regression analysis for predictors of FD, when controlling for age (for the mFI-11 and mFI-5), sex, injury severity score, and admission vitals (systolic blood pressure and respiratory rate), higher mFI-11 and mFI-5 scores independently predicted FD at discharge (OR 1.23, 95% CI 1.18-1.28, P < 0.05 and OR 1.23, 95% CI 1.18-1.29P < 0.05 respectively). Higher aaMFI scores had superior association with functional dependence (OR 1.59, 95% CI 1.54-1.64, P < 0.05). Receiver operator characteristic curves for the mFI-11, mFI-5, and aaMFI showed comparable diagnostic strength (area under curve [AUC] = 0.63 95% CI 0.62-0.64, P < 0.05; AUC = 0.63 95% CI 0.62-0.64, P < 0.05; and AUC = 0.67 95% CI 0.65-0.67, P < 0.05 respectively). CONCLUSIONS: The mFI-11, mFI-5, and aamFI are predictive of functional outcome following hip fracture. By including age, the aamFI retains the ease of use of the mFI-5 while improving its prognostic utility for functional outcome.
Subject(s)
Frailty , Hip Fractures , Humans , Frailty/complications , Frailty/diagnosis , Functional Status , Patient Discharge , Postoperative Complications/etiology , Retrospective Studies , Hip Fractures/complications , Hip Fractures/epidemiology , Hip Fractures/surgery , Risk Factors , Risk Assessment/methodsABSTRACT
STUDY DESIGN: Retrospective Cohort Study. INTRODUCTION: The 11-item modified Frailty index (mFI-11) by the ACS-NSQIP database was used to predict which patients are high risk for complications and inpatient mortality. ACS-NSQIP now has switched to the 5-item MFI. However, there are no studies on how these frailty indices fare against each other and their prognostic value of functional independence in patients with spinal cord injury (SCI). OBJECTIVE: To compare the mFI-5 and mFI-11 in order to standardize frailty assessment in the SCI population. METHODS: Retrospective analysis of 272,174 patients with SCI from 2010 to 2020 from the Pennsylvania Trauma Systems Foundation (PTSF) registry. Multivariable logistic regression was used to determine the predictive value of mFI for functional independence as determined by locomotion and transfer mobility. RESULTS: A total of 1907 patients were included with a mean age of 46.9 ± 15.1 years. The 3 most common MFI factors were hypertension (32.2%), diabetes mellitus (13.7%) and chronic obstructive pulmonary disease (8.5%). Multivariable logistic regression analyses using MFI-5 and MFI-11 showed that a higher frailty score in MFI-5 (OR 1.375, P < .001) and in MFI-11 (OR 1.366, P < .001) were each predictive of poor functional status at discharge. ROC curves for the MFI-5 (AUC = .818, P < .001) and MFI-11 (AUC = .819, P < .001) demonstrated excellent diagnostic accuracy. CONCLUSION: The new MFI-5 is equivalent to its predecessor, the MFI-11, and predictive of functional outcomes in patients with SCI. MFI-5 can serve as the preferred frailty index at the point of care and in research contexts.
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Introduction Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Though there are many pharmacological therapeutics approved today for PD, surgical interventions such as deep brain stimulation (DBS) have shown convincing symptom mitigation and minimal complication rates in aggregate. Recently, the concept of frailty - defined as reduced physiologic reserve and function affecting multiple systems throughout the patient - has gained traction as a predictor of short-term postoperative morbidity and mortality. As such, the Modified Frailty Index-5 (mFI-5) is a postoperative morbidity predictor based on five factors and has been used in neurosurgical subspecialties such as tumor, vascular, and spine. Yet, there is minimal literature assessing frailty in the field of functional neurosurgery. With the prevalence of DBS in PD, this study evaluated the mFI-5 as a predictor of postoperative complications in a selected patient population. Methods The American College of Surgeons National Surgical Quality Improvement Program 2010-2019 Database was queried for Current Procedural Terminology (CPT) codes, as well as the International Classification of Diseases (ICD)-9 and ICD-10 codes pertaining to DBS procedures in PD patients. Each patient was scored by the mFI-5 protocol and stratified into groups of No Frailty (mFI-5=0), Moderate Frailty (mFI-5=1), and Significant Frailty (mFI-5≥2). The No Frailty group was used as a reference in multivariate and univariate analyses of the groups. Results A total of 1,645 subjects were included in the study and were subcategorized into groups of No Frailty (N=877), Moderate Frailty (N=561), and Significant Frailty (N=207) based on their frailty scores. The subjects' mean age was 65.8±9.4 years. Overall, 1,161 (70.6%) were male, while 484 (29.4%) were female. With reference to the No Frailty group in multivariate analysis, patients with moderate frailty experienced greater unplanned readmission (OR 2.613, 95% CI 1.143-5.973, p=0.023), while those with significant frailty experienced greater unplanned readmission (OR 3.723, 95% CI 1.376-10.073, p=0.010), any readmission (OR 2.396, 95% CI 1.098-5.230, p=0.028), non-home discharge (OR 4.317, 95% CI 1.765-10.562, p<0.001), and complications in aggregate (OR 2.211, 95% CI 1.285-3.806, p=0.004). Conclusions Until now, the available clinical tools were limited in providing accurate predictions with minimal information for postoperative outcomes in DBS for PD patients. Our data give clinicians insight into the relationship between frailty and surgical outcomes and will assist physicians in preparing for postoperative care by predicting outcomes of significantly frail PD patients receiving DBS therapy.
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Introduction Lumbar spine interbody fusions have been performed to relieve back pain and improve stability due to various underlying pathologies. Anterior interbody fusion and posterior interbody fusion approaches are two main approaches that are classically compared. In an attempt to compare these two approaches to the spine, large retrospective national database reviews have been performed to compare and predict 30-day postoperative outcomes; however, they have conflicting findings. Obesity, defined as having a body mass index (BMI) over 30 kg/m2, may also contribute to the extent of spine pathology and is associated with increased rates of postoperative complications. Complication rates in patients who are obese have yet to be thoroughly investigated using a large national database. Our present investigation aims to make this comparison using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. The goal of the present study is to utilize a nationwide prospective database to determine short-term differences in postoperative outcomes between posterior and anterior lumbar fusion in patients with obesity and relate these findings to previous studies in the general population. Methods A retrospective cohort analysis was conducted on 9,021 patient data from the ACS-NSQIP database from 2015 to 2019 who underwent an elective, single-level fusion via anterior or posterior surgical approach. This database captures over 150 clinical variables on individual patient cases, including demographic data, preoperative risk factors and laboratory values, intraoperative data, and significant events up to postoperative day 30. All outcome measures were included in this analysis with special attention to rates of deep venous thrombosis (DVT) and pulmonary embolism (PE), prolonged length of stay (LOS), reoperation, and operation time. Results Multivariable analysis controlling for age, BMI, sex, race, functional status, American Society of Anesthesiologists (ASA) class, and selected comorbidities with P < 0.05 demonstrated that the anterior approach was an independent predictor for all significant outcomes except prolonged length of stay. Compared to the posterior approach, the anterior approach had a shorter total operation time (B = -13.257, 95% confidence interval (CI) [-17.522, -8.992], P < 0.001), higher odds of deep vein thrombosis (odds ratio (OR) = 2.210, 95% CI [1.211, 4.033], P= 0.010), and higher odds of pulmonary embolism (OR = 2.679, 95% CI [1.311, 5.477], P = 0.007) and was protective against unplanned reoperation (OR = 0.702, 95% CI [0.548, 0.898], P = 0.005). Conclusions The obese population makes up a large and growing demographic of those undergoing spine surgery, and as such, it is pertinent to investigate the differences, advantages, and disadvantages of lumbar fusion approaches in this group. While anterior approaches may be protective of longer operation time and unplanned reoperation, this benefit may not be clinically significant when considering an increased risk of DVT and PE. Given the short-term nature of this dataset and the limitations inherent in large de-identified retrospective database studies, these findings are interpreted with caution. Longer-term follow-up studies accounting for confounding variables with spine-centered outcomes will be necessary to further elucidate these nuances.
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BACKGROUND: There is a lack of data on whether intracranial pressure (ICP)-guided therapy with an intraparenchymal fiberoptic monitor (IPM) or an external ventricular drain (EVD) leads to superior outcomes. Our goal is to determine the relationship between ICP-guided therapy with an EVD or IPM and mortality. METHODS: Retrospective analysis of severe traumatic brain injury cases that required IPM or EVD placement for ICP-guided therapy from January 1, 2010 to December 31, 2020. The data were obtained from the Pennsylvania Trauma Systems Foundation registry. RESULTS: A total of 2305 patients met the inclusion criteria, with 1048 (45.5%) IPM and 1257 (54.5%) EVD placed. Inpatient mortality occurred in 337 (32.2%) and 334 (26.6%) patients in the IPM and EVD cohorts, respectively (P = 0.003). Even among those treated medically only, inpatient mortality occurred in 171 (30.8%) of those with an IPM and in 100 (23.4%) of those with an EVD (P = 0.010). Multivariable logistic regression analysis showed that older age (odds ratio [OR] 1.03, P < 0.001), lower Glasgow Coma Scale (GCS) score (OR 1.16, P < 0.001), requiring surgery (OR 1.22, P = 0.049), and an IPM (OR 1.40, P = 0.001) were significant predictors of mortality. Propensity score-adjusted analysis using inverse probability of treatment weighted method revealed a 28% decrease in mortality and a 14% decrease in length of hospital stay with EVD use when adjusting for age, sex, GCS, Injury Severity Score, surgery, and Hispanic ethnicity. CONCLUSIONS: A significant mortality benefit was associated with the use of EVD compared to IPM. This mortality benefit was observed regardless of whether patients required surgery or not.
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Brain Injuries, Traumatic , Brain Injuries , Humans , Retrospective Studies , Ventriculostomy , Propensity Score , Brain Injuries, Traumatic/therapy , Brain Injuries/surgery , Intracranial Pressure , Monitoring, Physiologic/methodsABSTRACT
STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: To determine the ability of early vital sign abnormalities to predict functional independence in patients with SCI that required surgery. METHODS: A retrospective analysis of data extracted from the Pennsylvania Trauma Outcome Study database. Inclusion criteria were patients >18 years with a diagnosis of SCI who required urgent spine surgery in Pennsylvania from 1/1/2010-12/31/2020 and had complete records available. RESULTS: A total of 644 patients met the inclusion criteria. The mean age was 47.1 ± 14.9 years old and the mean injury severity score (ISS) was 22.3 ± 12.7 with the SCI occurring in the cervical, thoracic, and lumbar spine in 61.8%, 19.6% and 18.0%, respectively. Multivariable logistic regression analyses for predictors of functional independence at discharge showed that higher HR at the scene (OR 1.016, 95% CI 1.006-1.027, P = .002) and lower ISS score (OR .894, 95% CI .870-.920, P < .001) were significant predictors of functional independence. Similarly, higher admission HR (OR 1.015, 95% CI 1.004-1.027, P = .008) and lower ISS score (OR .880, 95% CI 0.864-.914, P < .001) were significant predictors of functional independence. Peak Youden indices showed that patients with HR at scene >70 and admission HR ≥83 were more likely to achieve functional independence. CONCLUSIONS: Early heart rate is a strong predictor of functional independence in patients with SCI. HR at scene >70 and admission HR ≥83 is associated with improved outcomes, suggesting lack of neurogenic shock.
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BACKGROUND: Hypoxic brain injury is the leading cause of death in comatose patients following resuscitation from cardiac arrest. Neurological outcome can be difficult to prognosticate following resuscitation, and goals of care discussions are often informed by multiple prognostic tools. One tool that has shown promise is the SLANT score, which encompasses five metrics including initial nonshockable rhythm, leukocyte count after targeted temperature management, total adrenaline dose during resuscitation, lack of bystander cardiopulmonary resuscitation, and time to return of spontaneous circulation. This cohort study aimed to provide an external validation of this score by using a database of comatose cardiac arrest survivors from our institution. METHODS: We retrospectively queried our database of cardiac arrest survivors, selecting for patients with coma, sustained return of spontaneous circulation, and use of targeted temperature management to have a comparable sample to the index study. We calculated SLANT scores for each patient and separated them into risk levels, both according to the original study and according to a Youden index analysis. The primary outcome was poor neurologic outcome (defined by a cerebral performance category score of 3 or greater at discharge), and the secondary outcome was in-hospital mortality. Univariable and multivariable analyses, as well as a receiver operator characteristic curve, were used to assess the SLANT score for independent predictability and diagnostic accuracy for poor outcomes. RESULTS: We demonstrate significant association between a SLANT group with increased risk and poor neurologic outcome on univariable (p = 0.005) and multivariable analysis (odds ratio 1.162, 95% confidence interval 1.003-1.346, p = 0.046). A receiver operating characteristic analysis indicates that SLANT scoring is a fair prognostic test for poor neurologic outcome (area under the curve 0.708, 95% confidence interval 0.536-0.879, p = 0.024). Among this cohort, the most frequent SLANT elements were initial nonshockable rhythm (84.5%) and total adrenaline dose ≥ 5 mg (63.9%). There was no significant association between SLANT score and in-hospital mortality (p = 0.064). CONCLUSIONS: The SLANT score may independently predict poor neurologic outcome but not in-hospital mortality. Including the SLANT score as part of a multimodal approach may improve our ability to accurately prognosticate comatose survivors of cardiac arrest.
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Cardiopulmonary Resuscitation , Hypothermia, Induced , Out-of-Hospital Cardiac Arrest , Humans , Retrospective Studies , Coma/etiology , Coma/therapy , Cohort Studies , Out-of-Hospital Cardiac Arrest/therapy , Cardiopulmonary Resuscitation/adverse effects , Hypothermia, Induced/adverse effects , Epinephrine , SurvivorsABSTRACT
Background: Prosthetic joint infection (PJI) is a well-described complication after total joint arthroplasty which imposes a substantial burden of morbidity and mortality on the individual, as well as cost to the health-care system. This study used a break-even analysis to investigate the cost-effectiveness of pulsed saline lavage (PSL) for PJI prophylaxis after a primary total knee arthroplasty (TKA) and total hip arthroplasty (THA). Methods: An established model was used to calculate the minimum cost-effective absolute risk reduction of PSL for infection prophylaxis after a total joint arthroplasty. Baseline infection rates of TKA and THA and the cost of a revision surgery for PJI were derived from the literature while the cost of PSL implementation was obtained from institutional data. Results: PSL is cost-effective at an initial infection rate of 1.10%, revision costs of $32,132 for TKA PJI, and a protocol cost of $38.28 if it reduces infection rates by 0.12% or prevents infection in 1 out of 839 patients. PSL is cost-effective at an initial infection rate of 1.63% and a revision cost of $39,713 for THA PJI if it reduces infection rates by 0.10% or prevents infection in 1 out of 1037 patients. The absolute risk reduction needed for economic viability did not change with varying baseline infection rates and did not exceed 0.38% for infection treatment costs as low as $10,000 and remained less than 0.47% even if PSL cost was as high as $150. Conclusions: The use of PSL is a cost-effective protocol for PJI prophylaxis after TKAs and THAs.
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While a headache can have a wide variety of clinical presentations, it may occasionally be a red flag for underlying pathology that should prompt further investigation. Here, we present a case report demonstrating headache as an uncommon symptom of deep brain stimulation (DBS) device failure and discuss its clinical significance in the rapidly expanding list of current indications of DBS treatment. A 61-year-old female underwent bilateral hypothalamic DBS implantation for refractory morbid obesity. After a successful course involving significant weight loss, the patient began to experience worsening of her chronic headaches, refractory to her existing regiment. On interrogation, her generator was found to be depleted and its subsequent replacement led to a near total resolution of her headaches. This represents one of the few reported instances of headache as a sign of device failure in DBS treatment, thus adding to the wide possibility of headache presentations and their underlying pathology.
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Myc has emerged as a pivotal transcription factor for four metabolic pathways: aerobic glycolysis, glutaminolysis, polyamine synthesis, and HIF-1α/mTOR. Each of these pathways accelerates the utilization of sugar. The BCG vaccine, a derivative of Mycobacteria-bovis, has been shown to trigger a long-term correction of blood sugar levels to near normal in type 1 diabetics (T1D). Here we reveal the underlying mechanisms behind this beneficial microbe-host interaction. We show that baseline glucose transport is deficient in T1D monocytes but is improved by BCG in vitro and in vivo. We then show, using RNAseq in monocytes and CD4 T cells, that BCG treatment over 56 weeks in humans is associated with upregulation of Myc and activation of nearly two dozen Myc-target genes underlying the four metabolic pathways. This is the first documentation of BCG induction of Myc and its association with systemic blood sugar control in a chronic disease like diabetes.