Period-dependent Associations between Hypotension during and for Four Days after Noncardiac Surgery and a Composite of Myocardial Infarction and Death: A Substudy of the POISE-2 Trial.

BACKGROUND: The relative contributions of intraoperative and postoperative hypotension to perioperative morbidity remain unclear. We determined the association between hypotension and a composite of 30-day myocardial infarction and death over three periods: (1) intraoperative, (2) remaining day of surgery, and (3) during the initial four postoperative days. METHODS: This was a substudy of POISE-2, a 10,010-patient factorial-randomized trial of aspirin and clonidine for prevention of myocardial infarction. Clinically important hypotension was defined as systolic blood pressure less than 90 mmHg requiring treatment. Minutes of hypotension was the exposure variable intraoperatively and for the remaining day of surgery, whereas hypotension status was treated as binary variable for postoperative days 1 to 4. We estimated the average relative effect of hypotension across components of the composite using a distinct effect generalized estimating model, adjusting for hypotension during earlier periods. RESULTS: Among 9,765 patients, 42% experienced hypotension, 590 (6.0%) had an infarction, and 116 (1.2%) died within 30 days of surgery. Intraoperatively, the estimated average relative effect across myocardial infarction and mortality was 1.08 (98.3% CI, 1.03, 1.12; P < 0.001) per 10-min increase in hypotension duration. For the remaining day of surgery, the odds ratio was 1.03 (98.3% CI, 1.01, 1.05; P < 0.001) per 10-min increase in hypotension duration. The average relative effect odds ratio was 2.83 (98.3% CI, 1.26, 6.35; P = 0.002) in patients with hypotension during the subsequent four days of hospitalization. CONCLUSIONS: Clinically important hypotension-a potentially modifiable exposure-was significantly associated with a composite of myocardial infarction and death during each of three perioperative periods, even after adjustment for previous hypotension.

The Clinical Utility of Next Generation Sequencing Results in a Community-Based Hereditary Cancer Risk Program.

Since the 2013 Supreme Court ruling on BRCA1/BRCA2 patenting, hereditary cancer gene panels now include BRCA1 and BRCA2, making these panels an option for first-tier testing. However, questions remain about the clinical utility and implications of these panels for medical management with inclusion of genes of unknown to moderate penetrance. To better understand how use of these panels affected our practice, we reviewed patients who underwent testing in our clinic from July 1, 2013 through May 23, 2014. Indications for testing included personal and/or family history of breast and/or ovarian cancer. A total of 136 patients underwent panel testing via a single commercial laboratory; 12 (8.8 %) patients were positive for a pathogenic or likely pathogenic mutation (four BRCA2 mutations, two TP53 mutations, one CDH1 mutation, two ATM mutations, and one patient each with a CHEK2, NBN, or PALB2 mutation). Of these positive patients, 100 % met the National Comprehensive Cancer Network (NCCN) guidelines for Hereditary Breast and Ovarian Cancer genetic testing (2.2014). Mutations in seven of twelve (58 %) patients led to changes in medical management; three of seven (43 %) had a non-BRCA1 or BRCA2 gene mutation. Our findings suggest that there is clinical utility of panels that include genes of unknown to moderate penetrance.

A critical role for IRF5 in regulating allergic airway inflammation.

Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of the expression of proinflammatory cytokine and responses to infection, but its role in regulating pulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviral vector-driven overexpression, and adoptive transfer approaches to interrogate the role of IRF5 in pulmonary immunity and during challenge with the aeroallergen, house dust mite. Global IRF5 deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5 was also essential for effective responses to inhaled allergen, controlling airway hyperresponsiveness, mucus secretion, and eosinophilic inflammation. Adoptive transfer of IRF5-deficient alveolar macrophages into the wild-type pulmonary milieu was sufficient to drive airway hyperreactivity, at baseline or following antigen challenge. These data identify IRF5-expressing macrophages as a key component of the immune defense of the airways. Manipulation of IRF5 activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune responses and, thus, the treatment of lung disorders.

Comparison of mortality between nosocomial and community-acquired febrile neutropenia patients treated initially with cefazolin plus tobramycin: retrospective chart review.

Cefazolin plus tobramycin have been determined to be effective for community-acquired FN, but have not been evaluated in the treatment of nosocomial FN. This study compared the incidence of mortality from 2002 to 2004 with 2008 to 2009 in patients with nosocomial FN treated with cefazolin plus tobramycin and compared characteristics of patients with nosocomially acquired FN to community acquired FN. A retrospective chart review of 45 nosocomial FN episodes from 2008 to 2009, and 54 episodes from 2002 to 2004 treated with cefazolin plus tobramycin was conducted. Data on the community acquired FN episodes was obtained from our previous research. Nosocomial FN mortality increased from 4% in 2002-2004 to 13% in 2008-2009 (p = 0.08). The nosocomial cohort was at higher risk of medical complications and mortality than the community-acquired cohort based on several variables (neutrophil nadir, duration of neutropenia and fever, hematological malignancy, MASCC and Talcott score; p < 0.05). As a result, the nosocomial cohort was treated with longer courses of antibiotic therapy (14 days vs 7 days; p < 0.0001) and were more likely to require broader spectrum antibiotics (64 out of 99 vs 34 out of 96; p < 0.0001). There was an observed increased risk of mortality from 2002 to 2004 compared with 2008 to 2009 in patients treated with cefazolin plus tobramycin for nosocomial FN, this was notable despite not attaining statistical significance. Therefore, this regimen is not appropriate for nosocomial FN.

Validation of the HZETRN code for laboratory exposures with 1A GeV iron ions in several targets.

A new version of the HZETRN code capable of validation with HZE ions in either the laboratory or the space environment is under development. The computational model consists of the lowest order asymptotic approximation followed by a Neumann series expansion with non-perturbative corrections. The physical description includes energy loss with straggling, nuclear attenuation, nuclear fragmentation with energy dispersion and downshift. Measurements to test the model were performed at the Alternating Gradient Synchrotron and the NASA Space Radiation Laboratory at Brookhaven National Laboratory with iron ions. Surviving beam particles and produced fragments were measured with solid-state detectors. Beam analysis software has been written to relate the computational results to the measured energy loss spectra of the incident ions for rapid validation of modeled target transmission functions.

Femoral condylar lift-off in vivo in total knee arthroplasty.

We carried out weight-bearing video radiological studies on 40 patients with a total knee arthroplasty (TKA), to determine the presence and magnitude of femoral condylar lift-off. Half (20) had posterior-cruciate-retaining (PCR) and half (20) posterior-cruciate-substituting (PS) prostheses. The selected patients had successful arthroplasties with no pain or instability. Each carried out successive weight-bearing knee bends to maximum flexion, and the radiological video tapes were analysed using an interactive model-fitting technique. Femoral lift-off was seen at some increment of knee flexion in 75% of patients (PCR TKA 70%; PS TKA 80%). The mean values for lift-off were 1.2 mm with a PCR TKA and 1.4 mm with a PS TKA. Lift-off occurred mostly laterally with the PCR TKA, and both medially and laterally with the PS TKA. Separation between the femoral condyles and the articular surface of the tibia was recorded at 0 degrees, 30 degrees, 60 degrees and 90 degrees of flexion. Femoral condylar lift-off may contribute to eccentric polyethylene wear, particularly in designs of TKA which have flatter condyles. Coronal conformity is an important consideration in the design of a TKA.

AbiQ, an abortive infection mechanism from Lactococcus lactis.

Lactococcus lactis W-37 is highly resistant to phage infection. The cryptic plasmids from this strain were coelectroporated, along with the shuttle vector pSA3, into the plasmid-free host L. lactis LM0230. In addition to pSA3, erythromycin- and phage-resistant isolates carried pSRQ900, an 11-kb plasmid from L. lactis W-37. This plasmid made the host bacteria highly resistant (efficiency of plaquing <10(-8)) to c2- and 936-like phages. pSRQ900 did not confer any resistance to phages of the P335 species. Adsorption, cell survival, and endonucleolytic activity assays showed that pSRQ900 encodes an abortive infection mechanism. The phage resistance mechanism is limited to a 2.2-kb EcoRV/BclI fragment. Sequence analysis of this fragment revealed a complete open reading frame (abiQ), which encodes a putative protein of 183 amino acids. A frameshift mutation within abiQ completely abolished the resistant phenotype. The predicted peptide has a high content of positively charged residues (pI = 10.5) and is, in all likelihood, a cytosolic protein. AbiQ has no homology to known or deduced proteins in the databases. DNA replication assays showed that phage c21 (c2-like) and phage p2 (936-like) can still replicate in cells harboring AbiQ. However, phage DNA accumulated in its concatenated form in the infected AbiQ+ cells, whereas the AbiQ- cells contained processed (mature) phage DNA in addition to the concatenated form. The production of the major capsid protein of phage c21 was not hindered in the cells harboring AbiQ.

Pulmonary function correlates in the prediction of long-term weight gain in cystic fibrosis patients with gastrostomy tube feedings.

BACKGROUND: Gastrostomy tube feedings have a positive effect on nutritional status and are currently recommended for cystic fibrosis patients who fall below 85% ideal weight for height. However, the impact of pulmonary function at the time of gastrostomy tube placement on long-term nutritional status has not been ascertained. METHODS: We retrospectively evaluated whether nutrition status and/or pulmonary function at gastrostomy tube placement surgery were predictive of subsequent long-term (> or =2 yrs) weight velocity. We identified 21 cystic fibrosis patients (12 male), ages 5-18 years at gastrostomy tube insertion. Patients were divided into two groups according to their weight gain response after 2 years on gastrostomy tube feeding. Responders were defined as having a positive change in weight/age z-score (deltaWAZpost) at 2 years follow-up compared to the 2 year period preceding gastrostomy tube insertion (deltaWAZpre). Nonresponders were defined as having a negative WAZpost. RESULTS: Responders had significantly better FEV1 at surgery (61 +/- 26 [SE] vs. 24 +/- 3 %pred.; p < 0.05). In responders, epsilonWAZpre was -0.37 +/- 0.08 and was -0.46 +/- 0.07 in nonresponders (p-NS). In contrast, AWAZpost was 0.92 +/- 0.11 in responders and -0.40 +/- 0.07 in nonresponders (p < 0.001). Furthermore, a significant correlation between weight/age z-score change and pulmonary function was found when FEV1 <40% predicted (r = 0.88; p < 0.004) whereas no significant correlation was present when FEV1 > or =40% predicted. CONCLUSIONS: We conclude that the long-term nutritional benefit of gastrostomy tube placement is critically dependent on pre-surgical pulmonary function. Our findings suggest that gastrostomy tube insertion in malnourished cystic fibrosis patients should be considered an early intervention rather than one of last resort.

Assessment of the size, position, and optical properties of breast tumors in vivo by noninvasive optical methods.

We present a method for the noninvasive determination of the size, position, and optical properties (absorption and reduced scattering coefficients) of tumors in the human breast. The tumor is first detected by frequency-domain optical mammography. It is then sized, located, and optically characterized by use of diffusion theory as amodel for the propagation of near-infrared light in breast tissue. Our method assumes that the tumor is a spherical inhomogeneity embedded in an otherwise homogeneous tissue. We report the results obtained on a 55-year-old patient with a papillary cancer in the right breast. We found that the tumor absorbs and scatters near-infrared light more strongly than the surrounding healthytissue. Our method has yielded a tumor diameter of 2.1 ? 0.2cm, which is comparable with the actual size of 1.6 cm, determined after surgery. From the tumor absorption coefficients at two wavelengths (690 and 825 nm), we calculated the total hemoglobin concentration (40 ? 10 muM) and saturation (71 ? 9%) of the tumor. These results can provide the clinical examiner with more detailed information about breast lesions detected by frequency-domain optical mammography, thereby enhancing its potential for specificity.

Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy.

PURPOSE: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. METHODS: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-microg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200, and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. RESULTS: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100-400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC(0-24)) values for ethinyl estradiol were 18-30% lower in cycles 2 through 4 compared with cycle 1 (p < or = 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7-33.0% higher (p < or = 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T(max)) values determined during topiramate therapy were not significantly different from those at baseline. CONCLUSIONS: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing > or = 35 microg of ethinyl estradiol.

PIP: The efficacy of combined oral contraceptives (OCs) is diminished in women taking enzyme-inducing anti-epileptic drugs such as phenytoin, phenobarbital, and carbamazepine. In preliminary in vitro studies, a new anti-epileptic drug derived from D-fructose, topiramate, produced no clinically relevant inhibitory effects on the metabolism of such drugs as barbiturates, classic neuroleptics, and tricyclic antidepressants. To assess this new drug, 12 women with documented histories of epilepsy took an OC containing 1 mg norethindrone and 35 mcg ethinyl estradiol as well as topiramate (100-400 mg every 12 hours) for 4 menstrual cycles. Serial blood samples were obtained on day 20 of the 4 cycles. None of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate. Ethinyl estradiol serum levels were reduced by an average of 30% from baseline. The mean area under the concentration-versus-time curve over the 24-hour period values for ethinyl estradiol were 18-30% lower in cycles 2-4 than the baseline cycle and mean oral serum clearance values were 14.7-33.0% higher. This compares favorably with the 40-72% reductions in progestin and estrogen levels recorded in women taking a levonorgestrel-containing OC and enzyme-inducing anti-epileptics. Although topiramate's modest interaction with OCs is not likely to interfere with contraceptive efficacy, the reduction in serum estrogen concentrations has the potential to increase the incidence of breakthrough bleeding, indicating the OC should contain at least 35 mcg of estrogen.

Monocyte activation by an oral immunomodulator (bestatin) in lymphoma patients following autologous bone marrow transplantation.

Bestatin (ubenimex), an inhibitor of aminopeptidase, is an oral immunomodulator that binds to CD13 (aminopeptidase N) on macrophages/monocytes. To examine its immunomodulatory effect after high-dose therapy and autologous bone marrow transplantation (BMT), a dose-finding phase Ib trial was conducted with 30 Hodgkin's disease and non-Hodgkin's lymphoma patients who received no drug (control), 10 and 30 mg (low dose), or 90 and 180 mg (high dose) of bestatin daily for 60 days following autologous BMT. Bestatin administration was initiated when the absolute neutrophil count was greater than 250/mm3 on 2 consecutive days. The serum neopterin levels, an indicator of monocyte/macrophage activation, increased in the high-dose group compared to the control group (not significantly) and the low-dose group (significantly). Similarly, the colony-stimulating activity in the sera was significantly increased in the high-dose group compared to the control and low-dose groups. We also examined the expression of cell-surface markers on monocytes in these patients by fluorescent cytometry analysis. There was no significant difference either in the frequency or absolute number of monocytes (CD14+) among the three groups at any time. However, a significant increase in the frequency of CD16(FcgRIII)-positive monocytes (a marker of activation) was observed in the high-dose group compared to controls from day 14 to day 60 after the start of bestatin administration. Further, the frequency of HLA-DR+ monocytes (another marker of activation) was significantly increased in the high-dose group. These results indicate that bestatin at higher doses (90 and 180 mg daily), but not lower doses, activates macrophages/monocytes, as demonstrated by phenotypic marker (HLA-DR and CD16) up-regulation, and this provides augmentation of neopterin and colony-stimulating activity in the serum of patients following autologous BMT.

Total and allergen-specific IgE in relation to allergic response pattern following bone marrow transplantation.

Total and allergen-specific serum IgE were measured in relation to allergic response pattern before and after bone marrow transplant (BMT) in seven sibling donor/recipient pairs. Two non-atopic recipients developed persistently raised total serum IgE levels but no apparent allergic response after BMT from non-atopic donors; three non-atopic recipients showed raised total serum IgE after BMT, with allergen-specific IgE to the same allergens as their respective atopic donors. A penicillin-tolerant recipient showed clinical sensitivity and specific IgE to penicillin after BMT from a penicillin-sensitive donor, but with this case both donor and recipient showed raised serum IgE levels. One atopic recipient showed decreased total IgE after BMT from a mildly atopic donor. These allergic response patterns could occur as a result of repopulation in the recipient with IgE-specific T lymphocytes having similar regulatory influences as in the donor. The pattern of acquired responses would also be consistent with reconstitution by primed B lymphocytes of donor origin.

The action spectrum for benzanthrone photosensitization of mouse macrophages.

An in vitro method for determination of the phototoxic action spectrum of benzanthrone was established using a cover slip-test tube culture system with mouse peritoneal macrophages. The action spectrum peaked between 380 and 400 nm with abrupt fall-off to either side. These findings correlate closely with both the absorption spectrum of benzanthrone and the clinical action spectrum of phototoxicity in humans.

Value of serum C-reactive protein measurement in the management of bone marrow transplant recipients. Part I: Early transplant period.

Serum C-reactive protein concentrations were measured serially during the early transplant period in 68 bone marrow recipients transplanted for leukaemia (34), chronic granulocytic leukaemia (2), severe aplastic anaemia (6), and various inborn errors of metabolism (26). There were 116 clearly documented episodes of infection or acute graft versus host disease or both. Serum C-reactive protein concentrations in patients with viral (11) or fungal infection (6) were normal or only slightly raised. In 32 patients with isolated acute graft versus host disease, only three (10%) showed serum C-reactive protein concentrations above 40 mg/l. Values greater than 40 mg/l were strongly suggestive of bacterial infections and values above 100 mg/l were seen only in patients (43) with bacterial infections with or without acute graft versus host disease. These findings suggest that serum C-reactive protein concentrations are valuable both for diagnosis and monitoring of such infections.

Value of serum C-reactive protein measurement in the management of bone marrow transplant recipients. Part II: Late post-transplant period.

Seventeen bone marrow recipients transplanted for acute leukaemia (8), chronic leukaemia (1), severe aplastic anaemia (3), and various inborn errors of metabolism (5) had 22 episodes of documented infection in the late (greater than 3 months) post-transplant period. Serum C-reactive protein concentrations were considerably increased in patients with bacterial infections, but not in those with viral or fungal infections. Serum C-reactive protein values were normal in 20 patients transplanted for acute leukaemia (12), chronic leukaemia (1), severe aplastic anaemia (2), and various inborn errors of metabolism (5) who had active chronic graft versus host disease but no evidence of infection. These findings indicate that serum C-reactive protein concentrations are useful in the diagnosis and monitoring of bacterial infections even in the presence of chronic graft versus host disease.

Increased serum IgE concentrations during infection and graft versus host disease after bone marrow transplantation.

Serum IgE concentrations estimated in 25 bone marrow transplant recipients during episodes of infection or graft versus host disease, or both, were raised not only in some patients with acute graft versus host disease but also in many patients with infection. Raised values were not seen in chronic graft versus host disease. The routine estimation of serum IgE in bone marrow transplant recipients had minimal value because of the lack of specificity of the IgE response.