Performance of Standardized Relative CBV for Quantifying Regional Histologic Tumor Burden in Recurrent High-Grade Glioma: Comparison against Normalized Relative CBV Using Image-Localized Stereotactic Biopsies.

BACKGROUND AND PURPOSE: Perfusion MR imaging measures of relative CBV can distinguish recurrent tumor from posttreatment radiation effects in high-grade gliomas. Currently, relative CBV measurement requires normalization based on user-defined reference tissues. A recently proposed method of relative CBV standardization eliminates the need for user input. This study compares the predictive performance of relative CBV standardization against relative CBV normalization for quantifying recurrent tumor burden in high-grade gliomas relative to posttreatment radiation effects. MATERIALS AND METHODS: We recruited 38 previously treated patients with high-grade gliomas (World Health Organization grades III or IV) undergoing surgical re-resection for new contrast-enhancing lesions concerning for recurrent tumor versus posttreatment radiation effects. We recovered 112 image-localized biopsies and quantified the percentage of histologic tumor content versus posttreatment radiation effects for each sample. We measured spatially matched normalized and standardized relative CBV metrics (mean, median) and fractional tumor burden for each biopsy. We compared relative CBV performance to predict tumor content, including the Pearson correlation (r), against histologic tumor content (0%-100%) and the receiver operating characteristic area under the curve for predicting high-versus-low tumor content using binary histologic cutoffs (≥50%; ≥80% tumor). RESULTS: Across relative CBV metrics, fractional tumor burden showed the highest correlations with tumor content (0%-100%) for normalized (r = 0.63, P < .001) and standardized (r = 0.66, P < .001) values. With binary cutoffs (ie, ≥50%; ≥80% tumor), predictive accuracies were similar for both standardized and normalized metrics and across relative CBV metrics. Median relative CBV achieved the highest area under the curve (normalized = 0.87, standardized = 0.86) for predicting ≥50% tumor, while fractional tumor burden achieved the highest area under the curve (normalized = 0.77, standardized = 0.80) for predicting ≥80% tumor. CONCLUSIONS: Standardization of relative CBV achieves similar performance compared with normalized relative CBV and offers an important step toward workflow optimization and consensus methodology.

Intensification patterns and the probability of HbA1c goal attainment in Type 2 diabetes mellitus: real-world evidence for the concept of 'intensification inertia'.

AIMS: To assess the effects of 'clinical' and 'intensification inertia' by evaluating the impact of different intensification interventions on the probability of HbA1c goal attainment using real-world data. METHODS: Electronic health records (Cleveland Clinic, 2005-2016) were used to identify 7389 people with Type 2 diabetes mellitus and HbA1c ≥53 mmol/mol (≥7.0%), despite a stable regimen of two oral antihyperglycaemic drugs for ≥6 months. The participants were stratified by index HbA1c and analysed over a 6-month period for pharmacological intensification, and then for 12 additional months for HbA1c goal attainment (<53 mmol/mol). RESULTS: The probability of HbA1c goal attainment (Kaplan-Meier analysis) in the group with index HbA1c 53-63 mmol/mol (7.0-7.9%) was highest with the addition of oral antidiabetic drugs [57.3% (95% CI 52.1, 62.0)] or glucagon-like peptide-1 receptor agonists [56.7% (95% CI 40.4, 68.6)], in the 64-74 mmol/mol (8.0-8.9%) group with the addition of oral antidiabetic drugs [31.9% (95% CI 25.1, 38.1)] or insulin [30.6% (95% CI 18.3, 41.0)], and in the ≥75 mmol/mol (≥9.0%) group with the addition of glucagon-like peptide-1 receptor agonists [53.0% (95% CI 31.8, 67.6)] or insulin [43.5% (95% CI 36.4, 49.8)]. CONCLUSIONS: Numerical, but not statistically significant, differences in HbA1c goal attainment probability by type of intensification were most marked in people with the highest index HbA1c [≥75 mmol/mol (≥9.0%)]; in this group, injectable therapy showed trends toward greater glycaemic control benefits. Additional research into the phenomenon of intensification inertia is warranted.

Accurate Patient-Specific Machine Learning Models of Glioblastoma Invasion Using Transfer Learning.

BACKGROUND AND PURPOSE: MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data. MATERIALS AND METHODS: We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models. RESULTS: Tumor cell density significantly correlated with relative CBV (r = 0.33, P < .001), and T1-weighted postcontrast (r = 0.36, P < .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (r = 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (r = 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (r = 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (r = 0.39, mean absolute error = 16.55%). CONCLUSIONS: Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.

Preclinical validation of a targeted next generation sequencing-based comprehensive chromosome screening methodology in human blastocysts.

STUDY QUESTION: Can a novel targeted next generation sequencing (tNGS) platform accurately detect whole chromosome aneuploidy in a trophectoderm biopsy and provide additional information to improve testing? SUMMARY ANSWER: Karyotypes obtained by tNGS were concordant with other validated platforms and single nucleotide polymorphism genotyping information obtained can be used for improved detection and quality control. WHAT IS KNOWN ALREADY: qPCR-based whole chromosome aneuploidy screening is highly accurate in comparison to other common methods and has been shown to improve IVF success in two randomized clinical trials. With aneuploidy screening becoming standard of care in many IVF centres, there is a need to develop platforms with high throughput, low cost capabilities. STUDY DESIGN SIZE, DURATION: Twelve well-characterized cell lines were obtained from a commercial cell line repository and 31 discarded human blastocysts were obtained from 17 IVF patients who underwent comprehensive chromosome screening (CCS). PARTICIPANTS/MATERIAL, SETTING, METHODS: All samples were processed using a unique amplification strategy which directly incorporated sequencing library adapters and barcodes. Sequencing was performed on an Ion Torrent Proton. A custom bioinformatics pipeline was used to determine the karyotype for each sample. The consistency of tNGS diagnoses with either conventional karyotyping of cell lines or quantitative real-time PCR based CCS of blastocyst biopsies was evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Overall consistency per sample of tNGS based CCS in 5-cell samples from a variety of cell lines was 99.2%. In the blinded analysis of rebiopsies of aneuploid blastocysts, an overall targeted tNGS CCS consistency of 98.7% was observed per sample. These data demonstrate the ability of tNGS based CCS to provide an accurate and high throughput evaluation of aneuploidy in the human blastocyst. LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: This study is limited to whole chromosome aneuploidy, as mosaicism and segmental aneuploidy have not been investigated. WIDER IMPLICATIONS OF THE FINDINGS: These data show an accurate, high throughput method, and with the greater depth of each amplicon sequenced in comparison to commercial kits, there is greater application available for single nucleotide polymorphism based analysis for quality control. STUDY FUNDING/COMPETING INTERESTS: This study was funded through intramural research funds provided by the Foundation for Embryonic Competence. There are no competing interests.

Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis.

AIMS: It remains uncertain if differences in mortality risk exist among the sulfonylureas, especially in patients with documented coronary artery disease (CAD). The purpose of this study was to assess the overall mortality risk of the individual sulfonylureas versus metformin in a large cohort of patients with type 2 diabetes. METHODS: A retrospective cohort study was conducted using an academic health centre enterprise-wide electronic health record (EHR) system to identify 23 915 patients with type 2 diabetes who initiated monotherapy with metformin (N = 12774), glipizide (N = 4325), glyburide (N = 4279) or glimepiride (N = 2537), ≥ 18 years of age, with and without a history of CAD, and not on insulin or a non-insulin injectable at baseline. The patients were followed for mortality by documentation in the EHR and Social Security Death Index. Multivariable Cox models with propensity analysis were used to compare cohorts. RESULTS: An increase in overall mortality risk was observed in the entire cohort with glipizide (HR 1.64; 95% CI 1.39-1.94), glyburide (HR 1.59; 95% CI 1.35-1.88), and glimepiride (HR 1.68; 95% CI 1.37-2.06) versus metformin; however, in those patients with documented CAD, a statistically significant increase in overall mortality risk was only found with glipizide (HR 1.41; 95% CI 1.07-1.87) and glyburide (HR 1.38; 95% CI 1.04-1.83) versus metformin. CONCLUSIONS: Glipizide, glyburide and glimepiride are associated with an increased risk of overall mortality versus metformin. Our results suggest that if a sulfonylurea is required to obtain glycaemic control, glimepiride may be the preferred sulfonylurea in those with underlying CAD.

The risk of overall mortality in patients with Type 2 diabetes receiving different combinations of sulfonylureas and metformin: a retrospective analysis.

AIMS: Sulfonylureas have been shown to increase mortality when used in combination with metformin. This may not be a class effect of sulfonylureas, but rather secondary to differences in properties inherent to the individual sulfonylureas (hypoglycaemic risk, sulfonylurea receptor selectivity and effects on myocardial ischemic preconditioning). The purpose of this study was to assess the risk of overall mortality in patients with Type 2 diabetes treated with different combinations of sulfonylureas and metformin. METHODS: A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record system to identify 7320 patients with Type 2 diabetes (3768 initiators of glyburide (glibenclamide) and metformin, 2277 initiators of glipizide and metformin and 1275 initiators of glimepiride and metformin), ≥ 18 years of age and not on insulin or a non-insulin injectable at baseline. The patients were followed for mortality by documentation in the electronic health record and Social Security Death Index. Multivariable Cox models with propensity analysis were used to compare cohorts. RESULTS: No statistically significant difference in overall mortality risk was observed among the different combinations of sulfonylureas and metformin: glimepiride and metformin vs. glipizide and metformin (HR 1.03; 95% CI 0.89-1.20), glimepiride and metformin vs. glyburide (glibenclamide) and metformin (HR 1.08; 95% CI 0.90-1.30), or with glipizide and metformin vs. glyburide (glibenclamide) and metformin (HR 1.05; 95% CI 0.95-1.15). CONCLUSIONS: Our results did not identify an increased mortality risk among the different combinations of sulfonylureas and metformin, suggesting that overall mortality is not substantially influenced by the choice of sulfonylurea.

Effects of a televised two-city safer sex mass media campaign targeting high-sensation-seeking and impulsive-decision-making young adults

This study evaluates the ability of a safer sex televised public service announcement (PSA) campaign to increase safer sexual behavior among at-risk young adults. Independent, monthly random samples of 100 individuals were surveyed in each city for 21 months as part of an interrupted-time-series design with a control community. The 3-month high-audience-saturation campaign took place in Lexington, KY, with Knoxville, TN, as a comparison city. Messages were especially designed and selected for the target audience (those above the median on a composite sensation-seeking/impulsive-decision-making scale). Data indicate high campaign exposure among the target audience, with 85 per cent-96 per cent reporting viewing one or more PSAs. Analyses indicate significant 5-month increases in condom use, condom-use self-efficacy, and behavioral intentions among the target group in the campaign city with no changes in the comparison city. The results suggest that a carefully targeted, intensive mass media campaign using televised PSAs can change safer sexual behaviors. (AU)

Response to occipital nerve block is not useful in predicting efficacy of occipital nerve stimulation.

Occipital nerve stimulation (ONS) may be effective for the treatment of headaches that are recalcitrant to medical therapy. The objective of this study was to determine if response to occipital nerve block (ONB) predicts response to ONS in patients with chronic, medically intractable headaches. We evaluated 15 patients who underwent placement of occipital nerve stimulators for the treatment of chronic headaches. Data were collected regarding analgesic response to ONB and to ONS. Nine of 15 patients were ONS responders (> or =50% reduction in headache frequency or severity). Thirteen patients had ONB prior to stimulator implantation. Ten of 13 who had ONB had significant relief of head pain lasting at least 24 h, and three were ONB non-responders. Of the three ONB non-responders, two were ONS responders. Of the two patients who did not have ONB prior to ONS, one was an ONS responder and one was an ONS non-responder. In conclusion, analgesic response to ONB may not be predictive of the therapeutic effect from ONS in patients with medically refractory chronic headaches.

Occipital nerve stimulation for chronic headache--long-term safety and efficacy.

The aim of this study was to examine the safety and efficacy of occipital nerve stimulation for medically intractable headache. Electrical stimulation of large sensory afferents has an antinociceptive effect. Occipital nerve stimulation may be effective for the treatment of medically intractable headache. Retrospective analysis was performed of 15 patients with medically refractory headache who underwent implantation of an occipital nerve stimulator. Pre- and postimplant data regarding headache frequency, severity, disability, depression and poststimulator complications were collected. Twelve patients were female and three male. Ages ranged from 21 to 52 years (mean 39 years). Eight patients had chronic migraine, three chronic cluster, two hemicrania continua and two had post-traumatic headache. Eight patients underwent bilateral and seven had unilateral lead placement. Patients were measured after 5-42 months (mean 19). All six mean headache measures improved significantly from baseline (P < 0.03). Headache frequency per 90 days improved by 25 days from a baseline of 89 days; headache severity (0-10) improved 2.4 points from a baseline of 7.1 points; MIDAS disability improved 70 points from a baseline of 179 points; HIT-6 scores improved 11 points from a baseline of 71 points; BDI-II improved eight points from a baseline of 20 points; and the mean subjective percent change in pain was 52%. Most patients (60%) required lead revision within 1 year. One patient required generator revision. Occipital nerve stimulation may be effective in some patients with intractable headache. Surgical revisions may be commonly required. Safety and efficacy results from prospective, randomized, sham-controlled studies in patients with medically refractory headache are needed.

Peri-ictal SPECT and surgical treatment for intractable epilepsy related to schizencephaly.

The authors evaluated four patients with schizencephaly who underwent subtraction ictal SPECT coregistered to MRI (SISCOM) prior to epilepsy surgery. Three patients had a SISCOM alteration that was concordant with the epileptic brain tissue. Two of these patients were rendered seizure-free and one individual experienced a significant reduction in seizures. The patient with an indeterminate SISCOM had an unfavorable outcome. SISCOM is useful in evaluating patients with schizencephaly for epilepsy surgery.

The role of religion in predicting adolescent alcohol use and problem drinking.

OBJECTIVE: There are racial differences in adolescents' propensity to consume alcohol--with white adolescents tending to consume more alcohol than black adolescents--but there is no clear explanation for why such differences exist. The purpose of this study was to examine the relationship between religiosity, a cultural factor that is not well understood currently, and racial differences in adolescent alcohol use. METHOD: Participants were white and black ninth-grade adolescents (N = 899; 54% female, 57.5% white) involved in a 3-year longitudinal study of ways to reduce alcohol use and sexual risk-taking behavior among adolescents in Ohio and Kentucky. RESULTS: Findings indicate that religiosity is differentially associated with alcohol use and problem drinking for white and black adolescents. Religious service attendance was the most significant predictor of alcohol use for black adolescents, whereas religious fundamentalism was most important for white adolescents. In contrast, frequency of prayer was the significant predictor of problem drinking for black adolescents, whereas the level of importance placed on religion was the significant predictor for white adolescents. Important gender differences also emerged in both prediction models and are discussed. CONCLUSIONS: Since there is great heterogeneity among adolescents (in terms of race and gender) in their alcohol use and misuse, the "one-size-fits-all" approach to alcohol treatment and prevention is likely inappropriate. Moreover, conceptualizations of alcohol use and misuse, and its prevention and treatment, should include the consideration of such key cultural factors as religiosity.

Musical hallucinations associated with seizures originating from an intracranial aneurysm.

Hallucinations are defined as sensory phenomena in the absence of external sensory stimuli. Auditory hallucinations have been shown to arise from many different intracranial lesions, but seizures manifesting as musical hallucinations triggered by unruptured intracranial aneurysms are rare. We present a case of persistent, episodic musical hallucinations associated with seizures that led to the discovery of 2 small intracranial aneurysms. Typical electroencephalographic findings for seizure activity were observed but resolved after surgical clipping of the aneurysms. Concomitantly, the patient's hallucinations resolved. The literature on musical hallucinations is reviewed.

Test-retest reproducibility of the exercise treadmill examination in lumbar spinal stenosis.

OBJECTIVE: To provide further validation of the treadmill test by assessing its "test-retest" reproducibility. PATIENTS AND METHODS: In this prospective study, 28 patients with severe lumbar spinal stenosis underwent exercise treadmill testing, first at a walking speed of 1.2 mph and then at the patient's preferred walking speed. All patients had a second treadmill examination or "retest." No treatment intervention was performed between the initial test and the retest. Time to first symptoms (TFS) and total ambulation time (TAT) were measured. Differences between the baseline examination and the retest examination were assessed by using the concordance correlation coefficient (CCC) as well as graphically. RESULTS: There was good reproducibility between baseline test and retest results for all 4 end points: 1.2 mph, TFS (CCC = 0.90); 1.2 mph, TAT (CCC = 0.89); preferred walking speed, TFS (CCC = 0.98); and preferred walking speed, TAT (CCC = 0.96). The median difference between trials was not significantly different from zero for any of the 4 outcomes. CONCLUSIONS: Exercise treadmill testing has good test-retest reproducibility. There was no learning phenomenon associated with the test procedure. The study further validates the clinical utility of exercise treadmill testing in patients with lumbar spinal stenosis and neurogenic claudication.

Surgical evaluation and management of lumbar synovial cysts: the Mayo Clinic experience.

OBJECT: The authors report a retrospective analysis of 194 patients surgically treated at their institutions for symptomatic lumbar synovial cysts from January 1974 to January 1996. METHODS: Patient characteristics including age, sex, symptoms, signs, and preoperative neuroimaging studies were reviewed. Surgical procedures, complications, results, and pathological findings were correlated with preoperative assessment. One hundred ninety-four patients were surgically treated for symptomatic lumbar synovial cysts. Eighty percent were diagnosed and treated between 1987 and 1996. There were 100 men and 94 women with an average age of 66 years (range 28-94 years). The most common symptoms were painful radiculopathy (85%) and neurogenic single or multiroot claudication (44%). However, sensory loss (43%) and motor weakness (27%) were also presenting symptoms. Eleven percent of patients had undergone previous lumbar surgery prior to being referred to the Mayo Clinic. Preoperative neurological examination demonstrated motor weakness (40%), sensory loss (45%), reflex changes (57%), and variants of cauda equina syndrome (13%). In 19% of patients, normal neurological status was demonstrated. There was equal left/right-sided laterality, and eight patients presented with bilateral synovial cysts. The most commonly affected level was L4-5 (64%). All patients underwent laminectomy and resection of the cyst. Concomitant fusion was performed in 18 patients in whom clinical evidence of instability had been observed. However, subsequent fusion was required in only four patients who developed symptomatic spondylolisthesis. Surgery-related complications included cerebrospinal fluid leak (three patients), discitis (one patient), epidural hematoma (one patient), seroma (one patient), and deep vein thrombosis (one patient). One patient died 3 days after surgery of cardiac dysrhythmia. Follow-up data obtained for at least 6 months postoperatively were available in 147 patients. Of these, 134 (91%) reported good relief of their pain and 82% experienced improvement in their motor deficits. CONCLUSIONS: Lumbar synovial cysts are a more common cause of lumbar radicular pain than previously thought. Surgical removal of the cyst is a safe and effective treatment for symptomatic relief in patients with lumbar synovial cysts. A concomitant fusion procedure may be performed in select cases. In this study, only a few patients developed symptomatic spinal instability requiring a second operation.