Relative Impact of Risk Factors, Thwarted Belongingness, and Perceived Burdensomeness on Suicidal Ideation in Veteran Service Members.

OBJECTIVE: We tested the associations between individualized risk factors, empirically validated constructs specific to suicide risk (i.e., thwarted belongingness and perceived burdensomeness, and two methods for conceptualizing suicidal ideation based on Suicide Index Score (SIS) and overall severity score of the Beck Scale for Suicide Ideation [BSS]). METHOD: The current study included a sample of 134 suicidal Veterans who were recruited from an inpatient psychiatry unit of a Veterans Affairs Medical Center. Participants completed the BSS, Interpersonal Needs Questionnaire, Outcome Questionnaire-45.2, Alcohol Use Disorder Identification Test, Drug Abuse Screening Test, and abbreviated versions of the Posttraumatic Stress Disorder Checklist-Military version (PCL-M) and Insomnia Severity Index. We used ordinary least squares regression with bootstrapping to conduct analyses due to the skewed distributions observed in the suicidal ideation outcomes. RESULTS: Thwarted belongingness was the only statistically significant correlate of the SIS, indicating a stronger desire to be dead than alive as Veterans perceived themselves as being increasingly disconnected and isolated from others (B = 0.36, standard error [SE] = 0.01, p = 0.005). In contrast, greater overall severity scores on the BSS were associated with higher ratings on the PCL-M (B = 0.21, SE = 0.07, p = 0.02) and for thwarted belongingness (B = 0.27, SE = 0.09, p = 0.04). Problematic alcohol use was significantly associated with lower overall severity scores (B = -.27, SE = 1.17, p < 0.001). CONCLUSION: Findings may inform clinical strategies for conceptualizing and targeting factors associated with suicidal risk.

Vitamin D therapy in individuals with prehypertension or hypertension: the DAYLIGHT trial.

BACKGROUND: A large body of epidemiological and experimental evidence suggests that vitamin D deficiency may promote hypertension. This raises the possibility that vitamin D supplementation could be a simple intervention to reduce blood pressure, but data from prospective, randomized trials are limited. METHODS AND RESULTS: A double-blind, randomized, controlled trial was conducted at 4 sites in the United States. We enrolled 534 individuals 18 to 50 years of age with low vitamin D status (25-hydroxyvitamin D levels ≤25 ng/mL) and systolic blood pressure of 120 to 159 mm Hg. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. The primary end point was change in mean 24-hour systolic blood pressure. Secondary end points included change in ambulatory diastolic blood pressure and clinic systolic and diastolic blood pressures. The median age was 38 years, and 62% of participants were men. Forty-six percent of participants were white, and 48% were black. The median 25-hydroxyvitamin D level at baseline was 15.3 ng/mL. Four-hundred fifty-five participants (85%) had at least 1 follow-up blood pressure measurement; 383 participants (72%) completed the full 6-month study. At the end of the study, there was no significant difference in the primary end point (change in mean 24-hour systolic blood pressure, -0.8 versus -1.6 mm Hg in the high-dose and low-dose arms; P=0.71) or in any of the secondary end points. Furthermore, there was no evidence of association between change in 25-hydroxyvitamin D and change in 24-hour systolic blood pressure at 6 months (Spearman correlation coefficient, -0.05, P=0.34). Results were consistent across prespecified subgroups. CONCLUSIONS: Vitamin D supplementation did not reduce blood pressure in individuals with prehypertension or stage I hypertension and vitamin D deficiency. Our findings suggest that the association between vitamin D status and elevated blood pressure noted in observational studies is not causal. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01240512.

Corticosteroid therapy in refractory shock following cardiac arrest: a randomized, double-blind, placebo-controlled, trial.

BACKGROUND: The purpose of this study was to determine whether the provision of corticosteroids improves time to shock reversal and outcomes in patients with post-cardiac arrest shock. METHODS: We conducted a randomized, double-blind trial of post-cardiac arrest patients in shock, defined as vasopressor support for a minimum of 1 hour. Patients were randomized to intravenous hydrocortisone 100 mg or placebo every 8 hours for 7 days or until shock reversal. The primary endpoint was time to shock reversal. RESULTS: Fifty patients were included with 25 in each group. There was no difference in time to shock reversal between groups (hazard ratio: 0.83 [95% CI: 0.40-1.75], p = 0.63). We found no difference in secondary outcomes including shock reversal (52% vs. 60%, p = 0.57), good neurological outcome (24% vs. 32%, p = 0.53) or survival to discharge (28% vs. 36%, p = 0.54) between the hydrocortisone and placebo groups. Of the patients with a baseline cortisol < 15 ug/dL, 100% (6/6) in the hydrocortisone group achieved shock reversal compared to 33% (1/3) in the placebo group (p = 0.08). All patients in the placebo group died (100%; 3/3) whereas 50% (3/6) died in the hydrocortisone group (p = 0.43). CONCLUSIONS: In a population of cardiac arrest patients with vasopressor-dependent shock, treatment with hydrocortisone did not improve time to shock reversal, rate of shock reversal, or clinical outcomes when compared to placebo. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT00676585, registration date: May 9, 2008.

Whole exome sequence analysis of Peters anomaly.

Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the first study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.

ED patients with vertigo: can we identify clinical factors associated with acute stroke?

BACKGROUND: Vertigo is a common emergency department (ED) complaint with benign and serious etiologies with overlapping features. Misdiagnosis of acute stroke may result in significant morbidity and mortality. Magnetic resonance imaging (MRI) is superior to computer tomography (CT) for diagnosis of acute stroke but is costly with limited availability. OBJECTIVE: The aim of this study was to identify clinical characteristics associated with a cerebrovascular cause for vertigo. METHODS: We performed a retrospective chart review on patients with an MRI for vertigo, with or without additional historical or physical examination findings, over 18 months. Study patients were seen in the ED for vertigo within 2 weeks of MRI. Data collected included medical history, physical findings, and imaging results. Fisher's exact test was used to identify factors associated with the primary outcome, an acute stroke. RESULTS: There were 325 eligible patients; 131 were ED patients. Patients were 57 (± 18) years, and 53% were women. There were 12 ED patients with a new stroke (9.2%). Two variables were associated with acute stroke: a presenting complaint of gait instability (odds ratio, 9.3; 95% confidence interval, 2.6-33.9) or a subtle neurologic finding (odds ratio, 8.7; 95% confidence interval, 2.3-33.1). One patient with a new stroke had a prior stroke, 3 were age >65 years, and none had coronary artery disease or dysrhythmia. Among patients with acute stroke, 5 also had head CT, and none detected the stroke. CONCLUSIONS: This study identified 2 variables associated with acute stroke that should be considered in the evaluation of ED patients with vertigo. Head CT was inadequate for diagnosing acute stroke in this patient population.

A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer.

PURPOSE: Histologic tumor grade is a well-established prognostic factor for breast cancer, and tumor grade-associated genes are the common denominator of many prognostic gene signatures. The objectives of this study are as follows: (a) to develop a simple gene expression index for tumor grade (molecular grade index or MGI), and (b) to determine whether MGI and our previously described HOXB13:IL17BR index together provide improved prognostic information. EXPERIMENTAL DESIGN: From our previously published list of genes whose expression correlates with both tumor grade and tumor stage progression, we selected five cell cycle-related genes to build MGI and evaluated MGI in two publicly available microarray data sets totaling 410 patients. Using two additional cohorts (n = 323), we developed a real-time reverse transcription PCR assay for MGI, validated its prognostic utility, and examined its interaction with HOXB13:IL17BR. RESULTS: MGI performed consistently as a strong prognostic factor and was comparable with a more complex 97-gene genomic grade index in multiple data sets. In patients treated with endocrine therapy, MGI and HOXB13:IL17BR modified each other's prognostic performance. High MGI was associated with significantly worse outcome only in combination with high HOXB13:IL17BR, and likewise, high HOXB13:IL17BR was significantly associated with poor outcome only in combination with high MGI. CONCLUSIONS: We developed and validated a five-gene reverse transcription PCR assay for MGI suitable for analyzing routine formalin-fixed paraffin-embedded clinical samples. The combination of MGI and HOXB13:IL17BR outperforms either alone and identifies a subgroup ( approximately 30%) of early stage estrogen receptor-positive breast cancer patients with very poor outcome despite endocrine therapy.

Evaluation of Structured Assessment and Mediating Factors of Suicide-Focused Group Therapy for Veterans Recently Discharged from Inpatient Psychiatry.

The current study investigated the impact of adding the Suicide Status Form (SSF) to a suicide-focused group therapy for veterans recently discharged from an inpatient psychiatry setting. A sample of 141 veterans was enrolled and randomized into a Usual Assessment Group Therapy or SSF-Assessment Group Therapy. Participants completed interviews at baseline, 1, and 3 months. No significant differences were observed between groups regarding group attendance (IRR = 1.01, Std. Err = 0.08, 95% CI = 0.87, 1.18) or client satisfaction (ß = 0.23, Std. Err = 0.66, p = 0.73, d = -.25). No main effects were observed across the study on secondary outcomes of interest for suicidal ideation and overall symptom distress, although participants in both treatment conditions reported significant improvements on these outcomes over the course of the study. Patients in the Usual Assessment Group Therapy demonstrated greater reductions in overall symptom distress across the 3-month follow-up window (ß = 6.08, Std. Err = 2.04, p = 0.003; f2 = 0.05). Follow-up path analyses revealed that more frequent session attendance was significantly related to less suicidal ideation at 1-month, higher working alliance between individual members and group facilitators was associated with greater suicidal ideation at 1-month, and higher group cohesion among group members at 1-month was significantly associated with less thwarted belongingness at 1-month. Although the SSF did not improve the impact of an existing suicide-focused group therapy, the study findings support future research on group treatments for suicidal veterans.

The prognostic biomarkers HOXB13, IL17BR, and CHDH are regulated by estrogen in breast cancer.

PURPOSE: We previously identified three genes, HOXB13, IL17BR, and CHDH, that strongly predict clinical outcome in estrogen receptor (ER)-positive breast cancer patients receiving tamoxifen monotherapy. The biological mechanisms linking these genes to estrogen signaling and tamoxifen response in breast cancer remain to be determined. EXPERIMENTAL DESIGN: In a consecutive series of 148 ER-positive and ER-negative breast cancers, HOXB13, IL17BR, and CHDH gene expression was measured by quantitative real-time PCR and correlated with ER, PR, and HER2 expression. The role of estrogen and ER in the regulation of these three genes was assessed in several ER-positive and ER-negative breast cancer cell lines. RESULTS: In primary breast tumors, HOXB13 expression correlated negatively, and IL17BR and CHDH expression correlated positively, with ER status, and all three genes exhibited an ER-dependent correlation pattern with HER2 status that differs from PR and PS2, two canonical estrogen-regulated genes. Results using breast cancer cell lines show that these genes are regulated by estradiol in an ER-dependent manner, and that this regulation is abrogated by tamoxifen. CONCLUSIONS: HOXB13, IL17BR, and CHDH are estrogen-regulated genes, but their pattern of correlation with known positive (ER, PR) and negative (HER2) predictors of tamoxifen response differs from canonical ER signature genes. These results provide a biological rationale for the prognostic utility of these three genes in early-stage ER-positive breast cancer and for their potential to predict anti-estrogen resistance.

Circulating microRNAs in patients with hormone receptor-positive, metastatic breast cancer treated with dovitinib.

BACKGROUND: Serial analysis of biomarkers in the circulation of patients undergoing treatment ("liquid biopsies") can provide new insights into drug effects. In particular the analysis of cell-free, circulating nucleic acids such as microRNAs (miRs) can reveal altered expression patterns indicative of mechanism of drug action, cancer growth, and tumor-stroma interactions. RESULTS: Here we analyzed plasma miRs in patients with hormone receptor positive, metastatic breast cancer with prior disease progression during aromatase inhibitor therapy (n = 8) in a phase I/II trial with the multiple tyrosine kinase inhibitor dovitinib (TKI258). Plasma miR levels were measured by quantitative RT-qPCR before and after treatment with dovitinib. A candidate miR signature of drug response was established from a 379 miR screen for detectable plasma miRs as well as from the published literature. Changes in miR expression patterns and tumor sizes were compared. In this analysis we identified miR-21-5p, miR-100-5p, miR-125b-5p, miR-126-3p, miR-375 and miR-424-5p as potential indicators of a response to dovitinib. The altered expression patterns observed for the six circulating miRs separated patients with resistant disease from those with drug responsive disease. There was no relationship between adverse effects of dovitinib treatment and identifiable changes in miR patterns. CONCLUSION: We conclude that changes in the expression patterns of circulating miRs can be indicators of drug responses that merit prospective studies for validation.

Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial: a protocol for the pragmatic randomised study of appendicitis treatment.

INTRODUCTION: Several European studies suggest that some patients with appendicitis can be treated safely with antibiotics. A portion of patients eventually undergo appendectomy within a year, with 10%-15% failing to respond in the initial period and a similar additional proportion with suspected recurrent episodes requiring appendectomy. Nearly all patients with appendicitis in the USA are still treated with surgery. A rigorous comparative effectiveness trial in the USA that is sufficiently large and pragmatic to incorporate usual variations in care and measures the patient experience is needed to determine whether antibiotics are as good as appendectomy. OBJECTIVES: The Comparing Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial for acute appendicitis aims to determine whether the antibiotic treatment strategy is non-inferior to appendectomy. METHODS/ANALYSIS: CODA is a randomised, pragmatic non-inferiority trial that aims to recruit 1552 English-speaking and Spanish-speaking adults with imaging-confirmed appendicitis. Participants are randomised to appendectomy or 10 days of antibiotics (including an option for complete outpatient therapy). A total of 500 patients who decline randomisation but consent to follow-up will be included in a parallel observational cohort. The primary analytic outcome is quality of life (measured by the EuroQol five dimension index) at 4 weeks. Clinical adverse events, rate of eventual appendectomy, decisional regret, return to work/school, work productivity and healthcare utilisation will be compared. Planned exploratory analyses will identify subpopulations that may have a differential risk of eventual appendectomy in the antibiotic treatment arm. ETHICS AND DISSEMINATION: This trial was approved by the University of Washington's Human Subjects Division. Results from this trial will be presented in international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02800785.

A Case of Beare-Stevenson Syndrome with Unusual Manifestations.

BACKGROUND: Beare-Stevenson syndrome (BSS) is an extremely rare genetic disorder, with fewer than 25 cases reported worldwide. This autosomal dominant syndrome has been linked to two mutations in the fibroblast growth factor receptor 2 gene (FGFR2), Tyr375Cys and Ser372Cys, both causing amino acid changes. CASE REPORT: BSS is characterized by a range of morphological features, some more classically associated than others, of which craniosynostosis has been almost uniformly present. Other common features include cutis gyrata, acanthosis nigricans, ear and eye defects, skin/mucosal tissue tags, prominent umbilical stump, and anogenital anomalies. This account reports what we believe to be the 25th case of BSS, and exhibits a constellation of the characteristic features similar to those previously described, including the presence of cutis gyrata, proptosis, a bifid scrotum, and hypospadias. However, craniosynostosis was not detected prenatally by ultrasound or at birth. Prenatal ultrasound may detect some dysmorphic features of BSS. Many of these features have also been associated with other genetic disorders with overlapping phenotypes. Our case presented with the unusual features of a natal tooth and absence of craniosynostosis at birth. At birth, a diagnosis of BSS was suspected based on clinical features despite the absence of craniosynostosis. This was later confirmed with the use of molecular analysis, revealing a Tyr375Cys mutation of exon 9 of the FGFR2 gene. CONCLUSIONS: We suggest that a normal antenatal ultrasound scan and the absence of craniosynostosis at birth should not preclude further workup for BSS if this possibility is clinically suspected.

A subset of nondescript axillary lymph node inclusions have the immunophenotype of endosalpingiosis.

We report 2 cases of bland, otherwise nondescript axillary lymph node inclusions that have the immunophenotype of endosalpingiosis in patients with concurrent invasive breast carcinomas. Neither inclusion demonstrated the classic morphology of endosalpingiosis with admixed ciliated and secretory cells. Rather, both cases were composed of nondescript cuboidal to columnar bland epithelial cells situated within the lymph node capsule. Whereas both inclusions labeled diffusely for estrogen receptor and lacked evidence of a myoepithelial component, both labeled diffusely for PAX8 and WT-1, which distinguished them from their corresponding concurrent primary mammary carcinomas. These findings suggest that a subset of otherwise nondescript axillary lymph node inclusions represent endosalpingiosis and highlight the utility of PAX8 and WT-1 immunohistochemistry in distinguishing these from metastatic well-differentiated ductal carcinoma.

Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker.

BACKGROUND: Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)-positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node-negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole. METHODS: A prospective-retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided. RESULTS: High H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03). CONCLUSIONS: In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence.

Prevalence and significance of lactic acidosis in diabetic ketoacidosis.

PURPOSE: The prevalence and clinical significance of lactic acidosis in diabetic ketoacidosis (DKA) are understudied. The objective of this study was to determine the prevalence of lactic acidosis in DKA and its association with intensive care unit (ICU) length of stay (LOS) and mortality. METHODS: Retrospective, observational study of patients with DKA presenting to the emergency department of an urban tertiary care hospital between January 2004 and June 2008. RESULTS: Sixty-eight patients with DKA who presented to the emergency department were included in the analysis. Of 68 patients, 46 (68%) had lactic acidosis (lactate, >2.5 mmol/L), and 27 (40%) of 68 had a high lactate (>4 mmol/L). The median lactate was 3.5 mmol/L (interquartile range, 3.32-4.12). There was no association between lactate and ICU LOS in a multivariable model controlling for Acute Physiology and Chronic Health Evaluation II, glucose, and creatinine. Lactate correlated negatively with blood pressure (r = -0.44; P < .001) and positively with glucose (r = 0.34; P = .004). CONCLUSIONS: Lactic acidosis is more common in DKA than traditionally appreciated and is not associated with increased ICU LOS or mortality. The positive correlation of lactate with glucose raises the possibility that lactic acidosis in DKA may be due not only to hypoperfusion but also to altered glucose metabolism.

Adrenal lymphangioma: clinicopathologic and immunohistochemical characteristics of a rare lesion.

Adrenal lymphangiomas, also known as cystic adrenal lymphangiomas, are rare, benign vascular lesions that usually remain asymptomatic throughout life. Although previously adrenal lymphangioma lesions were primarily found at autopsy, they are currently detected during imaging work-up for unrelated causes and are likely to imitate other adrenocortical or adrenal medullary neoplasms. We aimed to retrospectively review all adrenal lymphangioma cases at our hospital and further document their lymphatic origin by immunohistochemical staining. A search of surgical pathology records (1984-2008) was conducted. All hematoxylin and eosin sections were retrieved from archives and reviewed by 2 pathologists in the study. Clinical information was gathered from electronic medical records. Representative paraffin-embedded sections from each case were selected for immunohistochemical analysis using monoclonal antibodies D2-40 and AE1/AE3. A total of 9 adrenal lymphangioma cases were identified (6 women and 3 men). All 9 patients were adults at time of diagnosis with a mean age of 42 years (range, 28-56 years). There were 7 white patients, 1 African American patient, and 1 Asian patient. The average size of an adrenal lymphangioma lesion was 4.9 cm (range, 2.0-13.5 cm). Adrenal lymphangioma was twice more frequently located on the right side (6 right-sided and 3 left-sided). Clinically, 4 (44%) of the 9 lesions presented with abdominal, flank, or back pain. One lymphangioma was found during work-up for labile hypertension. The remaining 4 lesions (44%) were asymptomatic and incidentally found during imaging studies for unrelated causes. Surgical removal was achieved by total adrenalectomy in 8 of the 9 lesions and by partial adrenalectomy in the remaining case. No evidence of recurrence or development of a contralateral lesion was encountered in any of the patients. Histologically, our adrenal lymphangiomas showed a typical multicystic architecture with dilated spaces lined by flattened, bland, simple lining. The cystic channels/spaces occasionally contained proteinaceous material and lacked red blood cell content. On immunohistochemical stains, D2-40 cytoplasmic staining was positive in all 9 examined lesions, whereas AE1/AE3 was negative, thus, confirming their lymphatic nature. D2-40 staining was diffuse in 2 and focal in the 7 remaining lesions. Adrenal lymphangiomas are very rare, benign lymphatic neoplasms with a female, right-sided predominance in our current series. They may clinically present with abdominal pain or can be incidentally found during adulthood as a mass, necessitating surgical removal to rule out other types of adrenal neoplasms.

PAX2(-)/PAX8(-)/inhibin A(+) immunoprofile in hemangioblastoma: A helpful combination in the differential diagnosis with metastatic clear cell renal cell carcinoma to the central nervous system.

BACKGROUND: Hemangioblastomas account for up to 2.5% of all intracranial tumors. They may occur sporadically or as a part of the multisystem genetic syndrome of Von Hippel-Lindau syndrome (VHL). Patients with VHL are also at an increased risk of developing clear cell renal cell carcinoma (ccRCC). Distinguishing hemangioblastomas from metastatic ccRCC to the central nervous system (CNS) can be challenging at times when based solely on hematoxylin and eosin-stained sections. We propose an immunohistochemistry (IHC) panel of combination of PAX2, PAX8, and inhibin A as a helpful approach in distinguishing the 2 lesions. DESIGN: Archival tissues from 20 hemangioblastomas and 16 ccRCCs metastatic to the CNS were retrieved from our surgical pathology files (2001 to 2010). IHC for PAX2, PAX8, and inhibin A was performed on routine or tissue microarray sections using standard IHC protocol. The intensity of nuclear staining was evaluated for each marker and was assigned an incremental 0, 1+, 2+, and 3+ score. The extent of staining was categorized as focal (<25%), multifocal (25% to 75%), or diffuse (>75%). RESULT: (1) Hemangioblastoma: The Von Hippel-Lindau syndrome was diagnosed in 4 of 16 (25%) patients, 2 of whom developed multiple hemangioblastomas. All 20 (100%) hemangioblastomas were positive for inhibin A (cytoplasmic). The staining intensity was moderate or strong (2+ or 3+) in 19 cases (95%), all of which were multifocal or diffuse in extent. Nuclear PAX2 staining was present in 1 of 19 evaluable lesions (5%), whereas PAX8 staining was not present in any of the 20 examined lesions. (2) Metastatic ccRCC to the CNS: Fourteen of 16 (88%) examined ccRCCs were positive for PAX2, whereas 15 of 16 (94%) lesions showed PAX8 staining. None of 16 (0%) examined ccRCCs were positive for inhibin A. CONCLUSIONS: We propose the use of the combination of PAX2, PAX8, and inhibin A as a helpful ancillary IHC panel to resolve the differential diagnosis of hemangioblastoma versus metastatic ccRCC. The immunoprofile of PAX2(+) or PAX8(+) and inhibin A(-) supports the diagnosis of metastatic ccRCC with a sensitivity of 94%, specificity of 100%, and positive predictive value of 100%. The PAX2(-), PAX8(-), and inhibin A(+) profile supports the diagnosis of hemangioblastoma with a sensitivity of 95%, specificity of 100%, and positive predictive value of 100%.

Coronary artery bypass graft surgery depletes plasma thiamine levels.

OBJECTIVE: Thiamine is an essential component of cellular metabolism, and lack of this vitamin results in a potentially life-threatening biochemical lesion. The stress of surgery and critical disease depletes electrolytes, minerals, and essential biochemical substrates. We hypothesized that critical illness (represented by major surgery) would result in decreased thiamine levels over time. METHODS: We performed a prospective, observational study of serial thiamine levels of 15 patients who underwent non-emergent coronary artery bypass graft surgery. The primary endpoint was change in thiamine levels from before to immediately after surgery. Secondary endpoints included change in thiamine levels from presurgical to 6- and 24-h time points. RESULTS: Of the 15 study patients, 1 did not have a plasma thiamine measurement at time 0 because of laboratory error and could not be accounted for in paired comparisons over time. Plasma thiamine levels decreased significantly from before to after coronary artery bypass grafting (P=0.0004). In addition, there was a statistically significant decrease in thiamine levels from before surgery to 24h (P=0.003). CONCLUSION: Our data suggest that major surgery (as a surrogate for the stress of critical illness) depletes thiamine levels; further study is needed to determine whether routine replacement of thiamine in the critically ill is warranted.

Local delivery of tobramycin from injectable biodegradable polyurethane scaffolds.

Infections often compromise the healing of open fractures. While local antibiotic delivery from PMMA beads is an established clinical treatment of infected fractures, surgical removal of the beads is required before implanting a bone graft. A more ideal therapy would comprise a scaffold and antibiotic delivery system administered in one procedure. Biodegradable polyurethane (PUR) scaffolds have been shown in previous studies to promote new bone formation in vivo, but their potential to control infection through release of antibiotics has not been investigated. In this study, injectable PUR scaffolds incorporating tobramycin were prepared by reactive liquid molding. Scaffolds had compressive moduli of 15-115 kPa and porosities ranging from 85-93%. Tobramycin release was characterized by a 45-95% burst (tuned by the addition of PEG), followed by up to 2 weeks of sustained release, with total release 4-5-times greater than equivalent volumes of PMMA beads. Released tobramycin remained biologically active against Staphylococcus aureus, as verified by Kirby-Bauer assays. Similar results were observed for the antibiotics colistin and tigecycline. The versatility of the materials, as well as their potential for injection and controlled release, may present promising opportunities for new therapies for healing of infected wounds.

The role of cranial computed tomography in the immediate post-cardiac arrest period.

Patients who initially survive cardiac arrest are often admitted to an intensive care unit comatose and on mechanical ventilation. It is not clear whether or not a screening cranial computed tomography (CT scan) is necessary in the immediate post-arrest period. We hypothesized that there may be clinically relevant information gleaned from head CT scans obtained early in the post-arrest period that could affect immediate management of these patients, even when non-neurologic causes of cardiac arrest are suspected. A retrospective data analysis was conducted of all survivors (age >18 years) of non-traumatic out-of-hospital cardiac arrest (OHCA) who underwent non-contrast head CT (NCHCT) within the first 24 h of admission. A total of 84 patients were identified and 51 (60.7%) met the inclusion criteria. As much as 45 (88.2%) patients in the total cohort had an NCHCT negative for ICH or herniation; of this group, 39 (76.5%) had a normal NCHCT, while six (11.8%, 95% CI: 5.1-23.8%) demonstrated varying degrees of cerebral edema or loss of gray-white matter distinction consistent with anoxic brain injury, but without herniation. Six patients (11.8%, 95% CI: 5.1-23.8%) exhibited findings consistent with either an ICH (with or without herniation) or herniation without an ICH. Four (7.8%) of these patients had an ICH without herniation, one had an acute SAH with edema and herniation, and one had frank herniation due to massive cerebral edema. The overall incidence of any kind of intracranial hemorrhage in our cohort was 9.8% (95% CI: 3.8-21.4%). In this cohort of post-cardiac arrest patients who underwent cranial computed tomography, 11.8% of patients had clinically significant abnormalities identified. The exact role of neuroimaging in this population is still in evolution, and further prospective evaluation is warranted.

Thiamine deficiency in critically ill patients with sepsis.

OBJECTIVE: The objective of the study was to determine the prevalence of absolute thiamine deficiency (TD) in critically ill patients with sepsis and to examine the association between thiamine levels and lactic acidosis. DESIGN: This was a prospective, observational study. SETTING: The setting was an urban, tertiary care center with approximately 50,000 emergency department visits per year and intensive care units numbering approximately 50 total beds. PATIENTS: Thirty study patients admitted with clinical suspicion of infection and evidence of tissue hypoperfusion, as defined by a lactic acid level greater than 4 mmol/L or hypotension (systolic blood pressure <90 mm Hg) requiring vasopressor support, were enrolled. A control group of 30 patients presenting to the emergency department with minor emergencies was also enrolled. INTERVENTIONS: There were no interventions. MEASUREMENTS AND MAIN RESULTS: Plasma thiamine levels were measured at 0, 24, 48, 72, and 162 hours for patients in the study group. Absolute TD was defined as less than or equal to 9 nmol/L derived from established abnormal ranges per Quest laboratory. In the study group, 3 (10%) of 30 had absolute TD upon presentation; and an additional 3 patients (6/30, 20%) developed TD within 72 hours. None of the 30 controls (0/30, 0%) exhibited absolute TD. Of the vasopressor-dependent population, 7.7% (2/26) displayed TD on presentation. For the group overall, there was no correlation between thiamine and lactic acidosis. However, in patients without liver dysfunction, thiamine was statistically significantly negatively correlated with lactic acidosis (r = -.50; P = .02). The relationship between thiamine and lactic acidosis held after multivariable regression analysis controlling for age, sex, and comorbid disease (P < .02). CONCLUSIONS: These preliminary findings indicate that critically ill patients may present with TD or develop this deficiency during their acute illness. We also identified a potential association between thiamine levels and lactic acidosis in patients without significant liver injury.