Kaiser Permanente Sacramento Medical Center

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.

Abstract Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor–associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells. Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018–29. ©2017 AACR. See related commentary by Lakshmanan and Byrd, p. 940. This article is highlighted in the In This Issue feature, p. 920

UNLABELLED: This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. CONCLUSION: PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

BACKGROUND: Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS: To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS: We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION: Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING: This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Prehospital resuscitation and stabilization of major trauma victims is increasingly employed. To evaluate the benefits of one such maneuver, fluid administration, we reviewed 52 consecutive trauma cases in which patients had a blood pressure of less than 100 mm Hg either at the scene or on arrival to hospital. In all cases, transport time to hospital was less than IV establishment time. Fluid volume infused had little influence on final outcomes. A percentage of patients with correctable surgical lesions might have been salvaged had prompt transport been instituted. Field maneuvers in critically injured patients should be minimized to decrease ultimate mortality.

CONTEXT.—: Controversies and uncertainty persist in prostate cancer grading. OBJECTIVE.—: To update grading recommendations. DATA SOURCES.—: Critical review of the literature along with pathology and clinician surveys. CONCLUSIONS.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

To gain control over your schedule, you must do the unthinkable: Offer every patient an appointment for today.

Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.

OBJECTIVE: To assess the potential role of matrix metalloproteinases (MMPs) in the pathogenesis of pterygia by comparing the immunolocalization patterns of MMPs in altered limbal basal stem cells, activated fibroblasts, and areas of elastotic degeneration adjacent to the pterygia. METHODS: Nine primary and 1 recurrent pterygia along with normal superior limbal-conjunctival tissue and cornea were immunostained with mouse monoclonal antibodies specific for MMP-1, MMP-2, MMP-3, MMP-9, membrane type 1 (MT1)-MMP (MMP-14), and membrane type 2-MMP (MMP-15). RESULTS: Normal conjunctival, limbal, and corneal cells lacked significant immunostaining except for cell surface MT1-MMP. In contrast, altered limbal basal epithelial cells of the 9 primary and 1 recurrent pterygia immunostained for all 6 MMPs. Activated and altered fibroblasts associated with the pterygia immunostained primarily for MMP-1. In contrast, stromal areas of elastotic degeneration (pingueculae) showed variable immunostaining of MMPs. CONCLUSIONS: Altered limbal basal epithelial cells (pterygium cells) immunostained for multiple types of MMPs in contrast to normal conjunctival, limbal, and corneal cells. The pterygium cells invading over Bowman's layer produce elevated MMP-1, MMP-2, and MMP-9 expression, which probably are the main MMPs responsible for the dissolution of Bowman's layer. Pterygium cells may also cause activation of fibroblasts at the head of the pterygium, leading to the initial cleavage of fibrillar collagen in Bowman's layer by the production of MMP-1. Altered fibroblasts in areas of elastotic degeneration (pingueculae) trailing behind the pterygium constitute a second type of tumor, which is noninvasive. CLINICAL RELEVANCE: These data of altered MMP expression support the concept that altered basal limbal epithelial cells play a key role in the formation and migration of a pterygium.

BACKGROUND: Patients' expectations and the role they play in medical care are increasingly considered to be important, but the factors that influence these expectations have not been well studied. OBJECTIVE: To examine the factors that influence patients' expectations for care in office practice. DESIGN: Qualitative inquiry nested within a large clinical survey. SETTING: Three general internal medicine practices in one mid-sized city in northern California. PATIENTS: 688 patients visiting their internists' offices were surveyed (response rate, 86%); 88 patients who reported one or more omissions of care on a post-visit questionnaire and were available for a telephone interview 1 to 7 days after the visit were included in the qualitative inquiry. MEASUREMENTS: Proportion of surveyed patients who reported one or more omissions of care, and qualitative analysis of the sources of patients' expectations, as determined from the telephone interviews. Interviews focused on the sources of expectations and perceptions of omission. Using an iterative process and working by consensus, investigators developed coding categories on a randomly selected 50% of the transcripts. The other 50% of the sample was used for validation. RESULTS: The 125 patients who had unmet expectations perceived omissions that were related to physician preparation for the visit (23%), history taking (26%), physical examination (30%), diagnostic testing (28%), prescription of medication (19%), referral to specialists (26%), and physician-patient communication (15%). Unmet expectations were shaped by patients' current somatic symptoms (intensity of symptoms, functional impairment, duration of symptoms, and perceived seriousness of symptoms) (74%); perceived vulnerability to illness (related to age, family history, personal lifestyle, or previously diagnosed conditions) (50%); past experiences (personal or familial) with similar illnesses (42%); and knowledge acquired from physicians, friends, family, or the media (54%). CONCLUSIONS: Patients' expectations for care are derived from multiple sources; their complexity should discourage simple schemes for "demand management." Nevertheless, the results of this study may help physicians to take a more empathetic stance toward their patients' requests and to devise more successful strategies for clinical negotiation.

The goal of this study was to determine the cell origin of human pterygia. In order to determine the origin of these cells, longitudinal cryostat sections through five primary and two recurrent pterygia were studied immunohistochemically by finding limbal basal stem cell staining patterns as defined by monoclonal antibodies AE1 (staining positive) and AE5 (staining negative). In addition, sections were stained with antivimentin antibody. Altered limbal basal cells invading normal cornea along the basement membrane were identified in seven human pterygia with these specific monoclonal antibodies. A group of limbal basal cells (vimentin and AE1 positive) was always present between the dissolved edge of Bowman's layer and vascularized conjunctiva which contained goblet cells. Scattered patches of cells staining positive with both vimentin and AE5 (in addition to their AE1 staining) were also found in conjunctival epithelium growing on corneal basement membrane adjacent to the migrating limbal cells, indicating local infiltration by the altered limbal basal cells. This same pattern was also found in recurrent pterygia. Based on this data we propose that the pathogenesis of pterygia is due to a normal stationary parental limbal epithelial basal cell becoming altered and giving rise to a zone of motile daughter cells, the pterygium cells, which leave the limbal region and migrate as a group centripetally along the corneal basement membrane dissolving Bowman's layer. Since these altered limbal basal cells are found at the microscopic advancing edge over Bowman's layer with no fibroblast mass under them, the pterygium cell apparently precedes the rapid growth of the fibroblasts from the stroma.(ABSTRACT TRUNCATED AT 250 WORDS)

PURPOSE To assess whether reirradiation (re-RT) and concurrent bevacizumab (BEV) improve overall survival (OS) and/or progression-free survival (PFS), compared with BEV alone in recurrent glioblastoma (GBM). The primary objective was OS, and secondary objectives included PFS, response rate, and treatment adverse events (AEs) including delayed CNS toxicities. METHODS NRG Oncology/RTOG1205 is a prospective, phase II, randomized trial of re-RT and BEV versus BEV alone. Stratification factors included age, resection, and Karnofsky performance status (KPS). Patients with recurrent GBM with imaging evidence of tumor progression ≥ 6 months from completion of prior chemo-RT were eligible. Patients were randomly assigned 1:1 to re-RT, 35 Gy in 10 fractions, with concurrent BEV IV 10 mg/kg once in every 2 weeks or BEV alone until progression. RESULTS From December 2012 to April 2016, 182 patients were randomly assigned, of whom 170 were eligible. Patient characteristics were well balanced between arms. The median follow-up for censored patients was 12.8 months. There was no improvement in OS for BEV + RT, hazard ratio, 0.98; 80% CI, 0.79 to 1.23; P = .46; the median survival time was 10.1 versus 9.7 months for BEV + RT versus BEV alone. The median PFS for BEV + RT was 7.1 versus 3.8 months for BEV, hazard ratio, 0.73; 95% CI, 0.53 to 1.0; P = .05. The 6-month PFS rate improved from 29.1% (95% CI, 19.1 to 39.1) for BEV to 54.3% (95% CI, 43.5 to 65.1) for BEV + RT, P = .001. Treatment was well tolerated. There were a 5% rate of acute grade 3+ treatment-related AEs and no delayed high-grade AEs. Most patients died of recurrent GBM. CONCLUSION To our knowledge, NRG Oncology/RTOG1205 is the first prospective, randomized multi-institutional study to evaluate the safety and efficacy of re-RT in recurrent GBM using modern RT techniques. Overall, re-RT was shown to be safe and well tolerated. BEV + RT demonstrated a clinically meaningful improvement in PFS, specifically the 6-month PFS rate but no difference in OS.

PURPOSE: We previously discovered that the pathogenesis of pterygia was due to a vimentin-expressing, altered limbal epithelial basal cell, the pterygium cell. Since UV radiation epidemiologically correlates as the etiologic agent for pterygia and limbal tumors and is mutagenic for the p53 gene, our goal was to search for p53 gene mutations immunohistochemically in the altered limbal basal cells of these growths and of pingueculae from which they seem to originate. METHODS: Longitudinal serial sections through six pingueculae, 14 primary and five recurrent pterygia, and five limbal tumors were studied immunohistochemically with p53 monoclonal antibody DO-1 and, in some specimens, with antivimentin antibody. RESULTS: P53 expression was found in the limbal cells of all pterygia, limbal tumors, and Stage II pingueculae, but not in normal limbal-corneal epithelial cells. However, when the same specimens were examined with a TUNEL assay, few if any apoptotic cells were found. A finding of increased nuclear p53 gene product with little or no apoptosis is consistent with an activating mutation of the p53 gene, resulting in increased steady-state levels of the protein. CONCLUSIONS: The finding of increased nuclear p53 in the limbal epithelium of pterygia, limbal tumors, and most pingueculae indicates the probable existence of p53 mutations in these cells as an early event in their development, which is consistent with their causation by UV radiation causation. In addition, due to a damaged p53-dependent programmed cell death mechanism, mutations in other genes are progressively acquired which allows the multi-step development of pterygia and limbal tumor cells from p53 positive cells overlying a Stage II pinguecula. Similarly, a pterygium dysplasia could arise from a pterygium cell. A classification for limbal basal cell tumors is proposed, and the different stromal changes in pingueculae, pterygia, and limbal tumors are identified. Two cell types were also identified: a p53-positive pinguecula limbal epithelial cell (a pinguecula II cell) and a p53-positive pterygium dysplasia cell (pterygium dysplasia cell).

BACKGROUND: The tumor suppressor gene p53 is expressed without apoptosis in the limbal basal stem cells of all pterygia and limbal tumors and most pingueculae from which these growths seem to originate. Oncogenic human papillomaviruses (HPVs) have been found in pterygia and limbal tumors, and HPV and p53 overexpression commonly coexist in oropharyngeal and penile carcinomas. OBJECTIVE: To search for HPV DNA as a cofactor in the development of pingueculae, pterygia, and limbal tumors. METHODS: We examined specimens--1 of pinguecula, 13 of pterygia (7 primary, 1 recurrent, 1 with dysplasia, and 4 primary not tested for p53), and 10 of limbal tumors (2 with actinic keratosis dysplasia, 1 with conjunctival intraepithelial neoplasia, 3 with carcinoma in situ, and 4 with squamous cell carcinoma)-expressing p53. Specimens were tested for the presence of HPV DNA by the polymerase chain reaction using degenerate consensus primers for the highly conserved portion of the L1 region that encodes a capsid protein of the virus. This assay has a wide spectrum with capability of detecting essentially all known HPV types. Nested polymerase chain reaction was performed on all specimens. Primers of the cystic fibrosis gene were used to confirm the presence of genomic DNA and to rule out inhibitors. Purified HPV DNA type 11 was the positive control, and HPV-negative genomic DNA was the negative control. RESULTS: Using consensus primers for the highly conserved portion of the L1 region, all specimens of pingueculae, pterygia, and limbal tumors studied were negative for HPV DNA by nested polymerase chain reaction. CONCLUSIONS: Human papillomavirus DNA is not required as a cofactor in the development of pterygia and limbal tumors. These data support the theory that increased p53 expression in the limbal epithelia of pingueculae, pterygia, and limbal tumors indicates the probable existence of p53 mutations in these cells as an early event in their development, which is consistent with UV irradiation causation. Thus, due to a damaged p53-dependent programmed cell death mechanism, mutations in other genes may be progressively acquired. This would allow for the multistep development of pterygia and limbal tumor cells from p53-mutated limbal epithelial basal stem cells overlying pingueculae.

BACKGROUND: Vascular stents are small tubular scaffolds used in the treatment of arterial stenosis (narrowing of the vessel). Most vascular stents are metallic and are deployed either by balloon expansion or by self-expansion. A shape memory polymer (SMP) stent may enhance flexibility, compliance, and drug elution compared to its current metallic counterparts. The purpose of this study was to describe the fabrication of a laser-activated SMP stent and demonstrate photothermal expansion of the stent in an in vitro artery model. METHODS: A novel SMP stent was fabricated from thermoplastic polyurethane. A solid SMP tube formed by dip coating a stainless steel pin was laser-etched to create the mesh pattern of the finished stent. The stent was crimped over a fiber-optic cylindrical light diffuser coupled to an infrared diode laser. Photothermal actuation of the stent was performed in a water-filled mock artery. RESULTS: At a physiological flow rate, the stent did not fully expand at the maximum laser power (8.6 W) due to convective cooling. However, under zero flow, simulating the technique of endovascular flow occlusion, complete laser actuation was achieved in the mock artery at a laser power of ~8 W. CONCLUSION: We have shown the design and fabrication of an SMP stent and a means of light delivery for photothermal actuation. Though further studies are required to optimize the device and assess thermal tissue damage, photothermal actuation of the SMP stent was demonstrated.

BACKGROUND: The association of serum lipids with coronary heart disease has been studied extensively in middle-aged men and, to a lesser extent, in similar women. Less well defined are lipid variables predictive of CHD in individuals of age > or = 60 years. METHODS AND RESULTS: The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years; 14% were black; and 43% were men). Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. Baseline mean total cholesterol was 6.11 mmol/L (236 mg/dL); HDL cholesterol, 1.39 mmol/L (54 mg/dL); and non-HDL cholesterol, 4.72 mmol/L (182 mg/dL). Triglyceride levels were 1.62 mmol/L (144 mg/dL) for fasting participants and 1.78 mmol/L for the total group. LDL cholesterol, estimated in fasting samples with triglycerides of < 4.52 mmol/L, averaged 3.98 mmol/L (154 mg/dL). Mean follow-up was 4.5 years. In multivariate Cox regression analyses, baseline total, non-HDL, and LDL cholesterol levels and the ratios of total, non-HDL, and LDL to HDL cholesterol were significantly related to CHD incidence. HDL cholesterol and triglycerides were not significant in these analyses. In fasting participants with triglyceride levels of < 4.52 mmol/L, a 1.03 mmol/L (40 mg/dL) higher baseline total, non-HDL, or LDL cholesterol was associated with a 30% to 35% higher CHD event rate. CONCLUSIONS: The results of this study support the concept that serum lipids are CHD risk factors in older Americans.

OBJECTIVES: To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of the first protease inhibitor-based single-tablet regimen (STR) for initial treatment of HIV-1 infection. METHODS: Antiretroviral therapy (ART)-naive adults with estimated glomerular filtration rate ≥ 70 mL/min were randomized 2:1 to receive the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) STR (TAF: N = 103) or darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (TDF: N = 50) once daily with matched placebos for 48 weeks. RESULTS: At week 24, viral suppression (HIV-1 RNA <50 copies/mL) rates were similar (TAF 74.8% vs. TDF 74.0%). At week 48, rates were TAF 76.7% vs. TDF 84.0%; the difference was driven by higher rate of discontinuations in TAF (6.8%) vs. TDF (2%). Among those with virologic failure, none developed resistance. Most adverse events were of mild/moderate severity. The mean change in serum creatinine from baseline at week 48 was 0.06 mg/dL (95% confidence interval: 0.04 to 0.08) for TAF vs. 0.09 mg/dL (95% confidence interval: 0.05 to 0.14) for TDF (P = 0.053). The % change in retinol binding protein/Cr ratio was +9 (TAF) vs. +54 (TDF), P = 0.003; the % change in urine β-2 microglobulin/Cr ratio was -42.0 (TAF) vs. +2.3 (TDF), P = 0.002. The % change in hip bone mineral density (BMD) was -0.84 (TAF) vs. -3.82 (TDF), P < 0.001 and in spine BMD was -1.57 (TAF) vs. -3.62 (TDF), P = 0.003. There were no fractures in either group. CONCLUSIONS: The TAF arm had significantly improved renal and bone safety parameters: less proteinuria and less change in hip and spine BMD, consistent with results from a similarly designed study of the elvitegravir/C/F/TAF STR. This D/C/F/TAF STR offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved long-term renal and bone safety with TAF.

Cerebral aneurysms treated by traditional endovascular methods using platinum coils have a tendency to be unstable, either due to chronic inflammation, compaction of coils, or growth of the aneurysm. We propose to use alternate filling methods for the treatment of intracranial aneurysms using polyurethane-based shape memory polymer (SMP) foams. SMP polyurethane foams were surgically implanted in a porcine aneurysm model to determine biocompatibility, localized thrombogenicity, and their ability to serve as a stable filler material within an aneurysm. The degree of healing was evaluated via gross observation, histopathology, and low vacuum scanning electron microscopy imaging after 0, 30, and 90 days. Clotting was initiated within the SMP foam at time 0 (<1 h exposure to blood before euthanization), partial healing was observed at 30 days, and almost complete healing had occurred at 90 days in vivo, with minimal inflammatory response.

STUDY DESIGN: A retrospective review of instrumented spine registry from an integrated US healthcare system. OBJECTIVE: Investigate the 30-day readmission rate and risk factors after instrumented spine surgery. SUMMARY OF BACKGROUND DATA: Published readmission rates range from 2% to over 20%. We were interested in learning which patients were at greatest risk, when did readmissions occur, and why. METHOD: 30-day readmission rates were determined for 14,939 patients after an index spine procedure between 1/2009 and 3/2013. Data were analyzed with descriptive statistics, univariate, and multivariate logistic regression analysis. RESULT: The average age of the cohort was 59 (SD = 13.4) and 52% were female. The 30-day readmission rate was 5.5% (821/14,939). The temporal pattern for readmission was: 17% (140) at week 1, 48% (394) at week 2, 72% (591) at week 3, and 100% (821) at week 4. The leading causes were wound complications (infection, hematoma, dehiscence, seroma), sepsis, pain management, pneumonia, and pulmonary emboli/deep venous thrombosis. In a multivariate model, readmission risk factors were: malignancy (OR 2.99, 95% CI: 1.56, 5.73), operative time more than 400 minutes (OR 2.59, 95% CI: 1.66, 4.02), operative time 300-399 minutes (OR 2.33, 95% CI: 1.54-3.52), hospital stay 6-10 days (OR 2.03, 95% CI: 1.31-3.14), hospital stay more than 10 days (OR 1.85, 95% CI: 1.1, -3.08), surgical complications (OR 1.67, 95% CI: 1.18, 2.36), operative time 200-299 (OR 1.52, 95% CI: 1.04, 2.22), depression (OR 1.48, 95% CI: 1.14, 1.93), rheumatoid arthritis (OR 1.45, 95% CI: 1.05, 2.01), deficiency anemia (OR 1.30, 95% CI: 1.05, 1.61), and hypothyroidism (OR 1.29, 95% CI: 1.01, 1.64). CONCLUSION: Surgical complications (dural tear, deep infections, superficial infections, epidural hematoma), malignancy, lengthy operative times, and lengthy initial hospitalizations are all risk factors for 30-day readmission. These findings should be considered during preoperative assessment and surgical planning. LEVEL OF EVIDENCE: 3.

The prompt diagnosis and therapy of bacterial meningitis remain enduring clinical challenges, for no physician would knowingly delay appropriate therapy. However, whether a delay in the initiation of antimicrobials in fact causes a worse outcome is a separate and tangential question. In clinical medicine a treatment decision involves a bedside estimate of the risk and potential severity of illness balanced against the benefits and adverse effects of therapy. For severe infections, the inexorable damage of untreated disease is presumed, and antimicrobials properly are given without hesitation. In contrast the methodical weighing of evidence regarding the issue of causation is for the purpose of characterizing biologic phenomena. Although legal and medical implications may be contained in such an analysis, its relevance to any particular clinical case is only retrospective. To judge responsibly the strength of a causative link, all available scientific evidence must be analyzed by established criteria. Such as analysis suggests that any connection between a delay in the treatment of bacterial meningitis and outcome depends on the presenting clinical pattern. If the presentation is that of a nonspecific illness with general symptoms, then a short delay of < 3 to 5 days does not appear to alter the risk of sequelae or death. In the case of fulminant meningitis a delay in initiating therapy seems unconnected to outcome. Finally for patients with a history of clinically overt meningitis, an inappropriate delay in commencing therapy incrementally increases the risk of permanent injury.