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Background: Current guidelines recommend a seven-day course of antibiotic therapy for patients with ventilator-associated pneumonia (VAP). However, clinical and microbiologic resolution of infection may occur much sooner than seven days, particularly in patients with early VAP. Shortening the course of antibiotic therapy for early VAP likely results in lower antibiotic-associated complications, but it is unclear whether VAP recurrence rates will be higher in patients receiving fewer days of therapy. We propose to compare four days versus seven days of antibiotic therapy for early VAP in surgical patients in a multicenter, pragmatic, randomized clinical trial. Patients and Methods: Eligible patients admitted to a surgical intensive care unit with early VAP, defined as VAP occurring within two to seven days of intubation, will be randomized to receive four or seven days of antibiotic therapy. The two primary outcomes are: VAP recurrence, defined as VAP occurring two to 14 days after completion of initial therapy and antibiotic-free days, defined as the number of days without receiving any antibiotic agents within 30 days from completion of initial therapy. Data will be analyzed using both intention-to-treat and per-protocol strategies. Power analysis was performed assuming non-inferiority of four days vs. seven days for VAP recurrence and superiority of four days versus seven days for antibiotic-free days. The total sample size to detect a 10% difference between groups with 80% power and assuming a 10% dropout rate is 458 patients. Three separate data analyses are planned throughout the trial and sample size will be re-calculated at each interim analysis. Conclusions: The Duration of Antibiotic Therapy for Early VAP (DATE) Trial will enroll surgical patients with early VAP to analyze whether a shorter duration of antibiotic therapy results in similar clinical outcomes while decreasing antibiotic exposure.

MYD88 mutations are present in 95% of Waldenstrom Macroglobulinaemia (WM) patients, and support diagnostic discrimination from other IgM-secreting B-cell malignancies. Diagnostic discrimination can be difficult among suspected wild-type MYD88 (MYD88 WT ) WM cases. We systematically reviewed the clinical, pathological and laboratory studies for 64 suspected MYD88 WT WM patients. World Health Organization and WM consensus guidelines were used to establish clinicopathological diagnosis. Up to 30% of suspected MYD88 WT WM cases had an alternative clinicopathological diagnosis, including IgM multiple myeloma. The estimated 10-year survival was 73% (95% confidence interval [CI] 52-86%) for MYD88 WT versus 90% (95% CI 82-95%) for mutated (MYD88 MUT ) WM patients (Log-rank P < 0·001). Multivariate analysis only showed MYD88 mutation status (P < 0·001) as a significant determinant for overall survival. Diffuse large B-cell lymphoma (DLBCL) was diagnosed in 7 (15·2%) and 2 (0·76%) of MYD88 WT and MYD88 MUT patients, respectively (Odds ratio 23·3; 95% CI 4·2-233·8; P < 0·001). Overall survival was shorter among MYD88 WT patients with an associated DLBCL event (Log-rank P = 0·08). The findings show that among suspected MYD88 WT WM cases, an alternative clinicopathological diagnosis is common and can impact clinical care. WM patients with MYD88 WT disease have a high incidence of associated DLBCL events and significantly shorter survival versus those with MYD88 MUT disease., (© 2017 John Wiley & Sons Ltd.)

We propose a novel self-homodyne optical-electrical-optical clock recovery technique for binary phase-shift keying (BPSK) signals using commercial optical and electrical components. We present the principle of operation as well as a proof-of-concept experiment for a 10.7 Gb/s BPSK signal clock recovery transmitted over a dispersion-compensated link of 20 km of single-mode fiber. Suppression of pattern-related frequency noise at the output of the recovered clock is shown. The timing jitter of the recovered clock at 10.7 GHz was measured to be ∼450  fs (integration range: 100 Hz-10 MHz).

Ostensibly hydrophilic alginates are known to foul hydrophobic membranes, under various conditions. Here, controlled experiments have been conducted at high and low pH on the fouling of a polypropylene membrane by alginate and the results suggest that the observed fouling is due to an intrinsic property of the alginate. Thus quantum chemical calculations on the M and G monomers of alginate reveal that M adopts an equilibrium geometry that is hydrophilic on one face and hydrophobic on the other, i.e. is potentially amphiphilic. Molecular dynamics simulations on short alginate chains of different sequences interacting with a modelled polypropylene surface, show that this characteristic is carried over to the polymer and results in hydrophobic patches along the chain that facilitate attractive interactions with the polypropylene surface. This concept is buttressed by an analysis of the binding characteristics of a previously reported X-ray structure of the mannuronan C-5 epimerase AlgE4 enzyme., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The incidence and prognostic impact of nephropathy related to Waldenström macroglobulinaemia (WM) is currently unknown. We performed a retrospective study to assess biopsy-confirmed WM-related nephropathy in a cohort of 1391 WM patients seen at a single academic institution. A total of 44 cases were identified, the estimated cumulative incidence was 5·1% at 15 years. There was a wide variation in kidney pathology, some directly related to the WM: amyloidosis (n = 11, 25%), monoclonal-IgM deposition disease/cryoglobulinaemia (n = 10, 23%), lymphoplasmacytic lymphoma infiltration (n = 8, 18%), light-chain deposition disease (n = 4, 9%) and light-chain cast nephropathy (n = 4, 9%), and some probably related to the WM: thrombotic microangiopathy (TMA) (n = 3, 7%), minimal change disease (n = 2, 5%), membranous nephropathy (n = 1, 2%) and crystal-storing tubulopathy (n = 1, 2%). The median overall survival in patients with biopsy-confirmed WM-related nephropathy was 11·5 years, shorter than for the rest of the cohort (16 years, P = 0·03). Survival was better in patients with stable or improved renal function after treatment (P = 0·05). Based on these findings, monitoring for renal disease in WM patients should be considered and a kidney biopsy pursued in those presenting with otherwise unexplained renal failure and/or nephrotic syndrome., (© 2016 John Wiley & Sons Ltd.)

Whole-genome sequencing has identified highly prevalent somatic mutations including MYD88, CXCR4, and ARID1A in Waldenström macroglobulinemia (WM). The impact of these and other somatic mutations on transcriptional regulation in WM remains to be clarified. We performed next-generation transcriptional profiling in 57 WM patients and compared findings to healthy donor B cells. Compared with healthy donors, WM patient samples showed greatly enhanced expression of the VDJ recombination genes DNTT, RAG1, and RAG2, but not AICDA Genes related to CXCR4 signaling were also upregulated and included CXCR4, CXCL12, and VCAM1 regardless of CXCR4 mutation status, indicating a potential role for CXCR4 signaling in all WM patients. The WM transcriptional profile was equally dissimilar to healthy memory B cells and circulating B cells likely due increased differentiation rather than cellular origin. The profile for CXCR4 mutations corresponded to diminished B-cell differentiation and suppression of tumor suppressors upregulated by MYD88 mutations in a manner associated with the suppression of TLR4 signaling relative to those mutated for MYD88 alone. Promoter methylation studies of top findings failed to explain this suppressive effect but identified aberrant methylation patterns in MYD88 wild-type patients. CXCR4 and MYD88 transcription were negatively correlated, demonstrated allele-specific transcription bias, and, along with CXCL13, were associated with bone marrow disease involvement. Distinct gene expression profiles for patients with wild-type MYD88, mutated ARID1A, familial predisposition to WM, chr6q deletions, chr3q amplifications, and trisomy 4 are also described. The findings provide novel insights into the molecular pathogenesis and opportunities for targeted therapeutic strategies for WM.

U.S. Army Forward Surgical Teams (FSTs) are elite, multidisciplinary units that are highly mobile, and rapidly deployable. The mission of the FST is to provide resuscitative and damage control surgery for stabilization of life-threatening injuries in austere environments. The Army Trauma Training Center began in 2001 at the University of Miami Ryder Trauma Center under the direction of COL T. E. Knuth, MC USA (Ret.), as a multimodality combination of lectures, laboratory exercises, and clinical experiences that provided the only predeployment mass casualty and clinical trauma training center for all FSTs. Each of the subsequent five directors has restructured the training based on dynamic feedback from trainees, current military needs, and on the rapid advances in combat casualty care. We have highlighted these evolutionary changes at the Army Trauma Training Center in previous reviews. Under the current director, LTC J. M. Seery, MC USA, there are new team-building exercises, mobile learning modules and simulators, and other alternative methods in the mass casualty exercise. This report summarizes the latest updates to the state of the art training since the last review., (Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.)

We report a unidirectional frequency dissemination scheme for high-fidelity optical carriers deployable over telecommunication networks. For the first time, a 10 Gb/s Binary Phase Shift Keying (BPSK) signal from an ultra-narrow linewidth laser was transmitted through a field-installed optical fibre with round-trip length of 124 km between Cork City and town of Clonakilty, without inline optical amplification. At the receiver, using coherent communication techniques and optical injection-locking the carrier was recovered with noise suppression. The beat signal between the original carrier at the transmitter and recovered carrier at the receiver shows a linewidth of 2.8 kHz. Long term stability measurements revealed fractional instabilities (True Allan deviation) of 3.3 × 10(-14) for 1 s averaging time, prior to phase noise cancellation.

We hypothesize there are coagulation profile changes associated both with initiation of thromboporphylaxis (TPX) and with change in platelet levels in trauma patients at high-risk for venous thromboembolism (VTE). A total of 1203 trauma intensive care unit patients were screened with a VTE risk assessment profile. In all, 302 high-risk patients (risk assessment profile score ≥ 10) were consented for weekly thromboelastography. TPX was initiated between initial and follow-up thromboelastography. Seventy-four patients were analyzed. Upon admission, 87 per cent were hypercoagulable, and 81 per cent remained hypercoagulable by Day 7 (P = 0.504). TPX was initiated 3.4 ± 1.4 days after admission; 68 per cent received unfractionated heparin and 32 per cent received low-molecular-weight heparin. The VTE rate was 18 per cent, length of stay 38 (25-37) days, and mortality of 17.6 per cent. In all, 76 per cent had a rapid clotting time at admission versus 39 per cent at Day 7 (P < 0.001); correcting from 7.75 (6.45-8.90) minutes to 10.45 (7.90-15.25) minutes (P < 0.001). At admission, 41 per cent had an elevated maximum clot formation (MCF) and 85 per cent had at Day 7 (P < 0.001); increasing from 61(55-65) mm to 75(69-80) mm (P < 0.001). Platelets positively correlated with MCF at admission (r = 0.308, R(2) = 0.095, P = 0.008) and at Day 7 (r = 0.516, R(2) = 0.266, P < 0.001). Change in platelet levels correlated with change in MCF (r = 0.332, R(2) = 0.110, P = 0.005). In conclusion, hypercoagulability persists despite the use of TPX. Although clotting time normalizes, MCF increases in correlation with platelet levels. As platelet function is a dominant contributor to sustained trauma-evoked hypercoagulability, antiplatelet therapy may be indicated in the management of severely injured trauma patients.

We simulate and experimentally demonstrate a novel all-optical clock recovery technique for a BPSK OFDM superchannel. Four-wave mixing in SOAs is used to strip the modulation from the superchannel sub-carriers, two of which are filtered and beat together in a photodiode to recover the clock.

The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutations occurring in >10% of patients included MYD88, CXCR4, and ARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome-like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM.

We describe the first experimental demonstration of a novel all-optical phase discrimination technique, which can separate the two orthogonal phase components of a signal onto different frequencies. This method exploits nonlinear mixing in a semiconductor optical amplifier (SOA) to separate a 10.65 Gbaud QPSK signal into two 10.65 Gb/s BPSK signals which are then demodulated using a delay interferometer (DI). Eye diagrams and spectral measurements verify correct operation and a conversion efficiency greater than 9 dB is observed on both output BPSK channels when compared with the input QPSK signal.

Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor κB (NF-κB). The signaling cascade(s) by which MYD88 L265P promotes NF-κB activation in WM remain unclear. By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-κB gatekeeper IκBα and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival. Coimmunoprecipitation studies identified Bruton tyrosine kinase (BTK) complexed to MYD88 in L265P-expressing WM cells, with preferential binding of MYD88 to phosphorylated BTK (pBTK). Increased pBTK was also observed in WM cells transduced to overexpress L265P vs wild-type MYD88. Importantly, MYD88 binding to BTK was abrogated following treatment of MYD88 L265P-expressing cells with a BTK kinase inhibitor. Inhibition of BTK or interleukin-1 receptor-associated kinase 1 and 4 (IRAK-1 and -4) kinase activity induced apoptosis of WM cells, and their combination resulted in more robust inhibition of NF-κB signaling and synergistic WM cell killing. The results establish BTK as a downstream target of MYD88 L265P signaling, and provide a framework for the study of BTK inhibitors alone, and in combination with IRAK inhibitors for the treatment of WM.

Two mechanisms that can make frequency conversion based on nonlinear mixing dependent on the phase of the input signal are identified. A novel phase-to-polarization converter that converts the orthogonal phase components of an input signal to two orthogonally polarized outputs is proposed. The operation of this scheme and a previously reported scheme at an increased symbol rate are simulated with semiconductor optical amplifiers (SOAs) as the nonlinear devices. Experimental results demonstrate the effectiveness of SOAs for nonlinear mixing over a wide range of wavelengths and difference frequencies and confirm the accuracy of the numerical model.

Anemia often prompts therapy in Waldenström macroglobulinemia (WM), although is not fully explained by bone marrow disease involvement in many patients. Hepcidin regulates gut absorption and distribution of iron and is elevated and associated with anemia in WM. Since hepcidin evaluation remains experimental, we initiated an American Board of Internal Medicine (ABIM) practice improvement project to determine baseline transferrin saturation (TSAT) levels in untreated anemic patients with WM. Among 108 patients with WM evaluated, 56 (52%) had a TSAT level ≤ 20%, which included 25 (23%) patients with severely depressed TSAT levels (≤ 10%). Sixteen patients with TSAT levels ≤ 10% received parenteral iron, and 14 of these patients showed improved hematocrit values (28.75% to 32.75%; P < .0001), mean corpuscular volume (MCV) (84.7 to 89.9; P = .006), and TSAT levels (8.1% to 21.2%; P < .0001). Anemia in 8 of these patients was previously refractory to oral iron therapy. Routine screening of iron saturation levels may therefore identify patients with WM and severe iron deficiency who may be candidates for parenteral iron therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

By whole-genome and/or Sanger sequencing, we recently identified a somatic mutation (MYD88 L265P) that stimulates nuclear factor κB activity and is present in >90% of Waldenström macroglobulinemia (WM) patients. MYD88 L265P was absent in 90% of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) patients. We therefore developed conventional and real-time allele-specific polymerase chain reaction (AS-PCR) assays for more sensitive detection and quantification of MYD88 L265P. Using either assay, MYD88 L265P was detected in 97 of 104 (93%) WM and 13 of 24 (54%) IgM MGUS patients and was either absent or rarely expressed in samples from splenic marginal zone lymphoma (2/20; 10%), CLL (1/26; 4%), multiple myeloma (including IgM cases, 0/14), and immunoglobulin G MGUS (0/9) patients as well as healthy donors (0/40; P < 1.5 × 10(-5) for WM vs other cohorts). Real-time AS-PCR identified IgM MGUS patients progressing to WM and showed a high rate of concordance between MYD88 L265P ΔCT and BM disease involvement (r = 0.89, P = .008) in WM patients undergoing treatment. These studies identify MYD88 L265P as a widely present mutation in WM and IgM MGUS patients using highly sensitive and specific AS-PCR assays with potential use in diagnostic discrimination and/or response assessment. The finding of this mutation in many IgM MGUS patients suggests that MYD88 L265P may be an early oncogenic event in WM pathogenesis.

Unlabelled: Familial disease is common in Waldenström macroglobulinemia (WM). We examined the impact of familial disease status on treatment outcome in WM and observed that familial disease was associated with inferior outcomes. However patients with familial WM receiving a bortezomib-containing regimen showed improved treatment outcomes vs. those receiving non–bortezomib-containing regimens. Bortezomib-containing regimens may therefore represent a more optimal treatment approach for patients with familial WM., Background: We examined the impact of familial predisposition on treatment outcome in 135 patients with Waldenström macroglobulinemia (WM), 26.7% of whom had first- or second-degree relatives with a B-cell lymphoproliferative disorder., Patients and Methods: All patients were rituximab naive and received a rituximab-containing regimen. There were no significant differences in baseline characteristics between cohorts., Results: Overall response (93.9% vs. 75.0%; P = .029) and complete response/very good partial response (CR/VGPR) (23.2% vs. 16.7%; P < .0001), time to progression (TTP) (45.5 vs. 21 months; P = .015) and time to next therapy (TTNT) (50.0 vs. 33.0 months; P = .024) favored patients with sporadic WM. By multivariate analysis, familial predisposition was an independent marker for disease progression (hazard ratio, 0.554). Patients with familial but not sporadic disease exhibited better responses, including CR/VGPR attainment (P = .0006) and a trend for longer progression-free survival (> 33 vs. 20.6 months; P = .08), with bortezomib-containing therapy., Conclusion: The findings convey that familial predisposition is an important determinant of treatment outcome in WM. Prospective studies to confirm these observations are needed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Waldenström's macroglobulinemia is an incurable, IgM-secreting lymphoplasmacytic lymphoma (LPL). The underlying mutation in this disorder has not been delineated., Methods: We performed whole-genome sequencing of bone marrow LPL cells in 30 patients with Waldenström's macroglobulinemia, with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings in samples from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors., Results: Among the patients with Waldenström's macroglobulinemia, a somatic variant (T→C) in LPL cells was identified at position 38182641 at 3p22.2 in the samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This variant predicted an amino acid change (L265P) in MYD88, a mutation that triggers IRAK-mediated NF-κB signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenström's macroglobulinemia and in 3 of 3 patients with non-IgM-secreting LPL (91% of all patients with LPL). MYD88 L265P was absent in paired normal tissue samples from patients with Waldenström's macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced IκBα and NF-κB p65 phosphorylation, as well as NF-κB nuclear staining, in Waldenström's macroglobulinemia cells expressing MYD88 L265P. Somatic variants in ARID1A in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenström's macroglobulinemia who had wild-type MYD88 had somatic variants in MLL2., Conclusions: MYD88 L265P is a commonly recurring mutation in patients with Waldenström's macroglobulinemia that can be useful in differentiating Waldenström's macroglobulinemia and non-IgM LPL from B-cell disorders that have some of the same features. (Funded by the Peter and Helen Bing Foundation and others.).

Background: Central venous catheters (CVCs) increase the risk of venous thromboembolism. We have previously demonstrated that pulmonary artery catheters are associated with a hypercoagulable state in an animal model and in patients. The purpose of this study is to determine whether the insertion of a CVC is associated with a similar response., Animal: 7F femoral artery catheters were placed in healthy anesthetized swine (N = 16). Serial arterial blood samples were drawn immediately before and after an 8.5F jugular vein CVC and then for 3 hours after CVC removal. Samples were analyzed using kaolin-activated thromboelastography (TEG) at precisely 2 minutes. Human: An institutional review board-approved prospective observational trial was conducted, with informed consent, in patients with critical illness (N = 8) at a Level I trauma center. Blood was drawn from indwelling arterial catheters immediately before and 60 minutes after CVC insertion. Samples were stored in sodium citrate for 15 minutes before TEG. Routine and special coagulation tests were performed on stored samples in the hospital pathology laboratory., Results: Insertion of a CVC decreased TEG clotting time (R) by 55% in swine and by 29% in humans (p < 0.001 and 0.019, respectively). Initial clot formation time (K) was reduced by 41% in swine and by 36% in humans (p = 0.003 and 0.019). Fibrin cross-linking (α) was accelerated by 28% in swine and by 17% in humans (p = 0.007 and 0.896), but overall clot strength (maximum amplitude) was not affected. There was no change in routine or special coagulation factors, including von Willebrand factor, antithrombin III, prothrombin time, international normalized ratio, or activated partial thromboplastin time. In animals, the hypercoagulable TEG response was persistent for 3 hours after CVC removal and was prevented by pretreatment with enoxaparin (n = 4) but not heparin (n = 2)., Conclusion: In healthy swine and patients with critical illness, a systemic hypercoagulable state occurred after CVC insertion, and this may partially account for an increased risk of venous thromboembolism. However, because the sample size was small and not powered to detect changes in coagulation proteins, no inferences can be made about the mechanism for the hypercoagulable response.

We observe a near-ideal high speed amplitude impulse response in an SOA-EAM-SOA configuration under optimum conditions. Full amplitude recovery times as low as 10 ps with modulation depths of 70% were observed in pump-probe measurements. System behavior could be controlled by the choice of signal wavelength, SOA current biases and EAM reverse bias voltages. Experimental data and impulse response modelling indicated that the slow tail in the gain response of first SOA was negated by a combination of cross-absorption modulation between pump and modulated CW probe, and self-gain modulation of the modulated CW probe in both the EAM and second SOA.

We report on the novel all-optical generation of duobinary (DB) and alternate-mark-inversion (AMI) modulation formats at 42.6 Gb/s from an input on-off keyed signal. The modulation converter consists of two semiconductor optical amplifier (SOA)-based Mach-Zehnder interferometer gates. A detailed SOA model numerically confirms the operational principles and experimental data shows successful AMI and DB conversion at 42.6 Gb/s. We also predict that the operational bandwidth can be extended beyond 40 Gb/s by utilizing a new pattern-effect suppression scheme, and demonstrate dramatic reductions in patterning up to 160 Gb/s. We show an increasing trade-off between pattern-effect reduction and mean output power with increasing bitrate.

We describe a novel SOA-based all-optical pure-phase modulator, and show how deleterious cross-gain modulation from the SOAs can be suppressed by utilizing an integrated interferometer structure. We experimentally demonstrate the use of the optical gate as a π/4 phase modulator producing 21.3 Gbaud 8PSK from 21.3 Gbit/s OOK and 21.3 Gbaud QPSK inputs. The modulator produces 3 dB of gain and coherent detection-based bit error rate measurements indicate a 2.4 dB excess penalty., (© 2011 Optical Society of America)

Simultaneous conversion of the two orthogonal phase components of an optical input to different output frequencies has been demonstrated by simulation and experiment. A single stage of four-wave mixing between the input signal and four pumps derived from a frequency comb was employed. The nonlinear device was a semiconductor optical amplifier, which provided overall signal gain and sufficient contrast for phase sensitive signal processing. The decomposition of a quadrature phase-shift keyed signal into a pair of binary phase-shift keyed outputs at different frequencies was also demonstrated by simulation.

This study examined the outcome of 248 Waldenstrom macroglobulinaemia (WM) rituximab-naïve patients who responded to a rituximab-containing regimen. Eighty-six patients (35%) subsequently received maintenance rituximab (M-Rituximab). No differences in baseline characteristics, and post-induction categorical responses between cohorts were observed. The median rituximab infusions during induction was 6 for both cohorts; and 8 over a 2-year period for patients receiving M-Rituximab. Categorical responses improved in 16/162 (10%) of observed, and 36/86 (41·8%) of M-Rituximab patients respectively, following induction therapy (P < 0·0001). Both progression-free (56·3 vs. 28·6 months; P = 0·0001) and overall survival (Not reached versus 116 months; P = 0·0095) were longer in patients who received M-Rituximab. Improved progression-free survival was evident despite previous treatment status, induction with rituximab alone or in combination therapy (P ≤ 0·0001). Best serum IgM response was lower (P < 0·0001), and haematocrit higher (P = 0·001) for patients receiving M-Rituximab. Among patients receiving M-Rituximab, an increased number of infectious events were observed, but were mainly ≤ grade 2 (P = 0·008). The findings of this observational study suggest improved clinical outcomes following M-Rituximab in WM patients who respond to induction with a rituximab-containing regimen. Prospective studies aimed at clarifying the role of M-Rituximab therapy in WM patients are needed to confirm these findings., (© 2011 Blackwell Publishing Ltd.)

The incorporation of rituximab into various regimens has improved depth of response in Waldenstrom macroglobulinaemia (WM), though the impact of achieving better responses remains to be determined. We examined response depth on progression-free survival (PFS) in 159 rituximab-naïve WM patients who received rituximab-based therapy. The median follow-up was 33·5 months, and categorical responses were as follows: complete response (CR, 8·8%); very good partial response (VGPR, 13·2%); partial response (50%); minor response (18·9%); Non-Responders (8·8%). Sequencing for polymorphic variants of FCGR2A, FCGR2B, and FCGR3A was performed, and impact on response depth determined. Achievement of better categorical responses was incrementally associated with improved PFS (P < 0·0001). No separation was observed between CR and VGPR, and attainment of at least a VGPR was associated with improved time-to-progression. Neither age, serum IgM, haematocrit, platelet count, serum β(2) microglobulin, WM International Prognostic Scoring System score, and treatment group predicted for CR/VGPR. Polymorphisms at FCGR3A-48 and -158 were associated with improved categorical responses, particularly attainment of CR/VGPR (P ≤ 0·03). The attainment of CR/VGPR was associated with significantly longer PFS in rituximab-naïve WM patients undergoing rituximab-based therapy, and was predicted by polymorphisms in FCGR3A., (© 2011 Blackwell Publishing Ltd.)

Background: Reduced heart rate variability (HRV) reflects autonomic dysfunction and can triage patients better than routine trauma criteria or vital signs. However, there is questionable specificity and no consensus measurement technique. The purpose of this study was to analyze whether factors that alter autonomic function affect the specificity of HRV for assessing traumatic injury., Methods: We evaluated 216 hemodynamically stable adults (3:1 M:F; 97:3 blunt:penetrating; age 49 years ± 1 year, mean ± standard error) undergoing computed axial tomography (CT) scan to rule out traumatic brain injury (TBI). All were prospectively instrumented with a Mars Holter system (GE Healthcare, Milwaukee, WI). HRV was determined offline using time domain (standard deviation of normal-normal intervals, root-mean-square successive difference) and frequency domain (very low frequency [VLF], LF, wideband frequency, high frequency [HF], low to HF index ratio) calculations from 15-minute electrocardiogram and correlated with routine vital signs, mortality, TBI, morbidity, length of stay (LOS), and comorbidities. Significance (p ≤ 0.05) was determined using nonparametric analysis, Student's t test, analysis of variance, or multiple logistic regression., Results: VLF alone predicted survival, severity of TBI, intensive care unit LOS, and hospital LOS (all p < 0.05). Beta-blockers or diabetes had no effect, whereas age, sedation, mechanical ventilation, spinal cord injury, and intoxication influenced one or more of the variables with age being the most powerful confounder (all p < 0.05). Except for the Glasgow Coma Scale, no other routine trauma or hemodynamic criteria correlated with any of these outcomes., Conclusions: Decreased VLF is an independent predictor of mortality and morbidity in hemodynamically stable trauma patients. Other time and other frequency domain variables correlated with some, but not all, outcomes. All were heavily influenced by factors that alter autonomic function, especially patient age.

We report the treatment outcome for 30 relapsed/refractory Waldenström's macroglobulinemia (WM) patients following bendamustine-containing therapy. Treatment consisted of bendamustine (90 mg/m2 I.V. on days 1, 2) and rituximab (375 mg/m2 I.V. on either day 1 or 2) for 24 patients. Six rituximab-intolerant patients received bendamustine alone (n=4) or with ofatumumab (1000 mg I.V. on day 1; n=2). Each cycle was 4 weeks, and median number of treatment cycles was 5. At best response, median serum IgM declined from 3980 to 698 mg/dL (P<.0001), and hematocrit rose from 31.9% to 36.6% (P=.0002). Overall response rate was 83.3%, with 5 VGPR and 20 PR. The median estimated progression-free survival for all patients was 13.2 months. Overall therapy was well tolerated. Prolonged myelosuppression was more common in patients who received prior nucleoside analogues. Bendamustine is active and produces durable responses in previously treated WM, both as monotherapy and with CD20-directed monoclonal antibodies.

We report remarkably fast and strongly wavelength-dependent gain recovery in a single SOA without the aid of an offset filter. Full gain recovery times as short as 9 ps were observed in pump-probe measurements when pumping to the blue wavelength side of a continuous wave probe, in contrast to times of 25 to 30 ps when pumping to the red wavelength side. Experimental and numerical analysis indicate that the long effective length and high gain led to deep saturation of the second half of the SOA by the probe. The consequent absorption of blue-shifted pump pulses in this region resulted in device dynamics analogous to those of the Turbo-Switch.

We propose and numerically investigate for the first time a novel all-optical on-off-keying to alternate-mark-inversion modulation format converter operating at 40 Gbps employing a semiconductor optical amplifier (SOA)-based Mach-Zehnder interferometer (MZI). We demonstrate that this SOA-MZI operates as a pulse subtractor, and in the absence of patterning will produce perfectly phase inverted pulses regardless of the individual SOA phase excursions. We use a comprehensive computer model to illustrate the impact of patterning on the output phase modulation, which is quantified through the definition of the phase compression factor.

We propose a novel scheme employing complementary data inputs to overcome the patterning normally associated with semiconductor optical amplifier based gates and demonstrate the scheme experimentally at 42.6Gb/s. The scheme not only avoids introducing patterning during switching, but also compensates for much of the patterning present on the input data. A novel gate was developed for the experiment to provide the complementary signals required for the scheme.

Background: For logistics, the US Army recommends Hextend (Hospira; 6% hetastarch in buffered electrolyte, HET) for battlefield resuscitation. To support this practice, there are laboratory data, but none in humans. To test the hypothesis that HET is safe and effective in trauma, we reviewed our first 6 months of use at a civilian level 1 trauma center., Study Design: From June 2008 to December 2008, trauma patients received standard of care (SOC) +/- 500 to 1,000 mL of HET within 2 hours of admission at surgeon discretion. Each case was reviewed, with waiver of consent., Results: There were 1,714 admissions; 805 received HET and 909 did not. With HET versus SOC, overall mortality was 5.2% versus 8.9% (p = 0.0035) by univariate analysis. Results were similar after penetrating injury only (p = 0.0016) and in those with severe injury, defined by Glasgow Coma Scale <9 (p = 0.0013) or Injury Severity Score >26 (p = 0.0142). After HET, more patients required ICU admission (40.9% vs. 34.5%; p = 0.0334) and transfusions of blood (34.4% vs. 20.2%; p = 0.0014) or plasma (20.7% vs. 12.2%; p = 0.0251), but there were no treatment-related differences in prothrombin time or partial thromboplastin time. The 24-hour urine outputs and requirements for blood, plasma, and other fluids were similar. However, increased early deaths with SOC implicate possible selection bias. If that factor was controlled for with multivariate analysis, the same trends were present, but the apparent treatment effects of HET were no longer statistically significant., Conclusions: In the first trial to date in hemodynamically unstable trauma patients, and the largest trial to date in any population of surgical patients, initial resuscitation with HET was associated with reduced mortality and no obvious coagulopathy. A randomized blinded trial is necessary before these results can be accepted with confidence., (Copyright 2010 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Hypogammaglobulinemia is common in Waldenström's macroglobulinemia. The etiology of this finding remains unclear, but it has been speculated to be based on tumor-induced suppression of the 'uninvolved' immunoglobulin production, Design and Methods: We evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated patients with Waldenström's macroglobulinemia and investigated the associated clinicopathological findings and impact of therapy. We also sequenced eight genes (AICDA, BTK, CD40, CD154, NEMO, TACI, SH2D1A, UNG) implicated in immunoglobulin deficiency in 19 Waldenström's macroglobulinemia patients with IgA and/or IgG hypogammaglobulinemia., Results: At baseline 63.3%, 58.0% and 49.3% of the 207 patients had abnormally low serum levels of IgA, IgG, or both. No association between IgA and IgG hypogammaglobulinemia and disease burden, serum IgM levels, beta(2)-microglobulin, International Prognostic Scoring System score, or incidence of recurrent infections was observed, although the presence of adenopathy and/or splenomegaly was associated with a lower incidence of hypogammaglobulinemia. Lower IgA and IgG levels were associated with disease progression in patients managed with a 'watch and wait' strategy. IgA and/or IgG levels remained abnormally low despite response to treatment, including complete remissions. A missense mutation in the highly conserved catalytic site of UNG was observed in a patient with hypogammaglobulinemia, warranting further study of this pathway in Waldenström's macroglobulinemia., Conclusions: IgA and IgG hypogammaglobulinemia is common in Waldenström's macroglobulinemia and persists despite therapeutic intervention and response. IgA and IgG hypogammaglobulinemia does not predict the risk of recurrent infections in patients with Waldenström's macroglobulinemia, although lower levels of serum IgA and IgG are associated with disease progression in Waldenström's macroglobulinemia patients being managed with a 'watch and wait' strategy.

Waldenstrom Macroglobulinemia (WM) is a B-cell malignancy characterized by excess bone marrow (BM) lymphoplasmacytic cells (LPC). The accumulation of LPC in WM may represent a failure of B-cells to properly differentiate into plasma cells. The present study investigated transcriptional expression of genes involved in late B-cell differentiation, including PRDM1, PAX5, XBP1 transcripts and ERN1, in BM B-cells from 31 patients with WM and six healthy donors. Real time reverse transcription polymerase chain reaction (RT-PCR) determined that approximately 80% of the patients had high XBP1 spliced mRNA expression, 80% of whom had high mRNA ERN1alpha expression. XBP1, PRDM1 and PAX5 mRNA was present in all patients studied. Using relative quantitative RT-PCR we isolated two groups with low and high expression of XBP1, XBP1 spliced and ERN1alpha. Sequence analysis showed germline polymorphisms in all genes studied. These data depict for the first time a heterogeneous expression pattern of the genes involved in late differentiation process of plasma cells in patients with WM and propose a role of XBP1-ERN1alpha in WM pathogenesis.

Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoma characterized by bone marrow (BM) involvement of IgM secreting lymphoplasmacytic cells. The induction of unfolded protein response (UPR) genes ("physiologic" UPR) enables cells to differentiate into professional secretory cells capable of production of high amounts of endoplasmic reticulum (ER)-processed proteins, such as immunoglobulins. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected, called proapoptotic/terminal UPR. We show that WM cells inherently express the physiologic UPR machinery compared with normal BM cells, and that increased ER stress leads to proapoptotic/terminal UPR in WM cells. We therefore examined tunicamycin, ER stress inducer, for potential antitumor effects in WM. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited DNA synthesis in WM cell lines and primary BM CD19(+) cells from patients with WM with an inhibitory concentration (IC(50)) of 0.5 microg/mL to 1 microg/mL, but not in healthy donor cells. Importantly, coculture of WM cells in the context of the BM microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrate that ER stress inducer synergizes with other agents used in the treatment of WM. These preclinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.

Waldenström macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPCs). Excess mast cells (MCs) are commonly present in WM, and provide growth and survival signals to LPCs through several TNF family ligands (CD40L, a proliferation-inducing ligand [APRIL], and B-lymphocyte stimulator factor [BLYS]). As part of these studies, we demonstrated that WM LPCs secrete soluble CD27 (sCD27), which is elevated in patients with WM (P < .001 vs healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs. Moreover, the SGN-70 humanized monoclonal antibody, which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated up-regulation of CD40L and APRIL on WM MCs. Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM.

This study of the putative saprotrophs of Conidiobolus and Basidiobolus aids the understanding of their ecological roles in litter, and their relationship with the entomogenous fungi of the Entomophthorales. A total of 47 isolates (ten spp.) were screened for their ability to utilise pure compounds, arthropod cadavers, and plant leaf fragments as substrates. Isolates co-occurred in a larch plantation (Larix sp.) or were from adjacent habitats. Of the 21 isolates (nine spp.) tested on potential prime carbon sources, none could utilise common plant structural polymers. Conidiobolus adiaeretus, C. iuxtagenitus, and B. ranarum from litter and some soil isolates of C. heterosporus, C. pumilus, and C. firmipilleus could use starches and glycogen. In marked contrast, all could utilise animal chitin, gelatine, casein, N-acetyl glucosamine, and trehalose. The lipids tributyrin and sunflower oil also supported growth. Conidia on cadavers usually led to high levels of colonisation as was the case for 30 isolates (ten species). Collembola were more frequently and rapidly colonised than mites. Cadavers of many other arthropods were also internally colonised. The ability to utilise cadavers of diverse arthropods indicates that trophic competition between co-occurring test species may be minimal. Niche differentiation may depend more on non-trophic features of their life history. Negative correlation of performance with the presence of naturally occurring, non-test fungi suggests competition with (or antibiosis from) at least some of the other fungi. In washed or unwashed plant fragments of larch litter (F-layer) only occasional local growth and resting spore formation occurred. Extra nutrients did not facilitate colonisation. Alternative forms of repetitional conidia showed a strong association with plant fragments but not with cadavers.

The presence of valine (V) at position 158 of FcgammaRllla (CD16) is known to improve clinical response to rituximab in indolent non-Hodgkin lymphoma (NHL). Little is known about the basic mechanisms for this observation. We examined natural killer (NK) cells from healthy donors representing the FcgammaRIIIa-158 polymorphic subgroups (V/V, V/F, and F/F) for gene transcript and cell surface CD16 expression, rituximab binding, and rituximab-dependent NK cell-mediated cytotoxicity. We observed higher levels of FcgammaRIIIa transcripts among individuals with the FcgammaRIIIa-158 V/V versus V/F or F/F genotype (P < .001); increased cell surface CD16 expression by quantitative flow cytometry on NK cells from individuals expressing at least one valine at FcgammaRIIIa-158 versus F/F (P = .029); as well as augmented rituximab binding and rituximab-mediated, antibody-dependent cellular cytotoxicity (ADCC). These results suggest that individuals expressing at least one valine at FcgammaRIIIa-158 might, in part, have better clinical outcomes due to increased CD16 expression, rituximab binding, and rituximab-mediated ADCC.

A significant impairment in understanding the biology and advancing therapeutics for Waldenstrom's macroglobulinemia (WM) has been the lack of a representative cell line and animal model. We, therefore, report on the establishment of the BCWM.1 cell line, which was derived from the long-term culture of CD19(+) selected bone marrow lymphoplasmacytic cells isolated from an untreated patient with WM. BCWM.1 cells morphologically resemble lymphoplasmacytic cells (LPC) and propagate in RPMI-1640 medium supplemented with 10% fetal bovine serum. Phenotypic characterization by flow cytometric analysis demonstrated typical WM LPC characteristics: CD5(-), CD10(-), CD19(+), CD20(+), CD23(+), CD27(-), CD38(+), CD138(+), CD40(+), CD52(+), CD70(+), CD117(+), cIgM(+), cIgG(-), cIgA(-), ckappa(-), clambda(+), as well as the survival proteins APRIL and BLYS, and their receptors TACI, BCMA and BAFF-R. Enzyme-linked immunosorbent assay studies demonstrated secretion of IgMlambda and soluble CD27. Karyotypic and multicolor fluorescence in situ hybridization studies did not demonstrate cytogenetic abnormalities. Molecular analysis of BCWM.1 cells confirmed clonality by determination of IgH rearrangements. Inoculation of BCWM.1 cells in human bone marrow chips implanted in severe combined immunodeficient-hu mice led to rapid engraftment of tumor cells and serum detection of human IgM, lambda, and soluble CD27. These studies support the use of BCWM.1 cells as an appropriate model for the study of WM, which in conjunction with the severe combined immunodeficient-hu mouse model may be used as a convenient model for studies focused on both WM pathogenesis and development of targeted therapies for WM.

Waldenström's macroglobulinemia is a B-cell disorder characterized by bone marrow infiltration with lymphoplasmacytic cells and demonstration of an immunoglobulin M monoclonal gammopathy. Despite advances in therapy, Waldenström's macroglobulinemia remains incurable. As such, novel therapeutic agents are needed for the treatment of Waldenström's macroglobulinemia. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of Waldenström's macroglobulinemia so as to better target therapeutics for this malignancy. Importantly, as part of these efforts, we have prioritized the development of stem cell-sparing drugs because autologous stem cell transplantation remains a viable salvage option in Waldenström's macroglobulinemia. These efforts have led to the development of several novel agents for treating Waldenström's macroglobulinemia, including bortezomib; monoclonal antibodies and/or blocking protein targeting CD40, CD52, or CD70, a proliferation-inducing ligand and B-lymphocyte stimulator; the immunomodulator thalidomide as an enhancer of rituximab activity, as well as agents interfering with stem cell factor, phosphatidylinositol 3-kinase/Akt, phosphodiesterase, cholesterol, and protein kinase C beta signaling. This report provides an update on biologic studies and clinical efforts for the development of these novel agents in the treatment of Waldenström's macroglobulinemia.

The UV photo-oxidation of oligo(ethylene glycol) (OEG)-terminated self-assembled monolayers (SAMs) has been studied using static secondary ion mass spectrometry, X-ray photoelectron spectroscopy, contact angle measurement, and friction force microscopy. OEG-terminated SAMs are oxidized to yield sulfonates, but photodegradation of the OEG chain also occurs on a more rapid time scale, yielding degradation products that remain bound to the surface via gold-sulfur bonds. The oxidation of these degradation products is the rate-limiting step in the process. Photopatterning of OEG-terminated SAMs may be accomplished by using a mask and suitable light source or by using scanning near-field photolithography (SNP) in which the mask is replaced by a scanning near-field optical microscope coupled to a UV laser. Using SNP, it is possible to fabricate patterns in SAMs with a full width at half-maximum height (fwhm) as small as 9 nm, which is approximately 15 times smaller than the conventional diffraction limit. SNP-patterned OEG-terminated SAMs may be used to fabricate protein nanopatterns. By adsorbing carboxylic acid-terminated thiols into oxidized regions and converting these to active ester intermediates, it has been possible to fabricate lines of protein molecules with widths of only a few tens of nanometers.

We investigate the dependence of the speed of recovery of optically excited semiconductor optical amplifiers (SOAs) on the active region dimensions. We use a picosecond pump-probe arrangement to experimentally measure and compare the gain and phase dynamics of four SOAs with varying active region dimensions. A sophisticated time domain SOA model incorporating amplified spontaneous emission (ASE) agrees well with the measurements and shows that, in the absence of a continuous wave (CW) beam, the ASE plays a similar role to such a holding beam. The experimental results are shown to be consistent with a recovery rate which is inversely proportional to the optical area. A significant speed increase is predicted for an appropriate choice of active region dimensions.

Objective: To evaluate the efficacy and safety of inhaled tobramycin (TOBI) in the treatment of ventilator-associated pneumonia (VAP) in a randomized, double-blind pilot study., Patients and Methods: Ten patients from a cohort of 108 mechanically ventilated patients with documented clinical and bacteriological evidence of VAP caused by Pseudomonas aeruginosa or Acinetobacter spp. in the surgical and trauma intensive care units of a university teaching hospital were randomized to receive either TOBI (n = 5) or intravenous tobramycin (TOBRA; n = 5). The two groups were similar in their Acute Physiology and Chronic Health Evaluation (APACHE) score, Clinical Pulmonary Infection Score (CPIS), and Multiple Organ Dysfunction Score (MODS) prior to randomization. The primary outcome measure was resolution of pneumonia. The CPIS and MODS were used as objective indicators of clinical progress., Results: All TOBI patients had clinical resolution of VAP. Two TOBRA patients were considered failures. One had deterioration in MODS, and the other had doubling of his serum creatinine concentration. The patients treated with TOBI may have had more ventilator-free days than those receiving TOBRA, but the difference was not statistically significant owing to the small sample size (24 +/- 3 vs. 14 +/- 13 days; p = 0.12)., Conclusion: Aerosolized tobramycin for the treatment of VAP appeared safe and effective in this pilot study. A larger study is warranted to determine if aerosolized tobramycin will lead to better outcomes than intravenous tobramycin when used for the treatment of VAP.

Background: Alemtuzumab is a monoclonal antibody used in the treatment of CD52-expressing B-cell malignancies, including Waldenstrom's macroglobulinemia (WM). Recent studies demonstrate high levels of alemtuzumab activity in relapsed/refractory disease. One potential target of alemtuzumab is bone marrow mast cells (BMMCs), which provide growth and survival signaling for WM lymphoplasmacytic cells., Patients and Methods: We therefore examined BMMCs (FceRI+, CD117+) from WM and other mast cell (MC) disorders for expression of CD52., Results: We identified cell surface antigen expression by multicolor flow cytometric analysis and found CD52 expressed on human mast-derived cell line-1 (HMC-1) and LAD2 MC lines, on BMMC from 13 of 15 patients with WM, and on BMMCs from 4 of 4 patients with systemic mastocytosis (SM). None of 4 healthy donors expressed CD52. Reverse-transcriptase polymerase chain reaction analysis confirmed CD52 expression in the HMC-1 and LAD2 MC lines, in BMMCs from 14 of 15 patients with WM, and 3 of 3 patients with SM. CD52 transcripts were also detected in BMMCs from 6 of 6 healthy donors, despite the absence of CD52 cell surface expression. Importantly, we observed high levels of alemtuzumab-mediated, antibody-dependent, cell-mediated cytotoxicity against LAD2 MCs and BMMCs from patients with WM and SM., Conclusion: These studies demonstrate that CD52 is widely expressed on human MCs and WM bone marrow lymphoplasmacytic cells and provide the preclinical rationale for the use of alemtuzumab in the treatment of WM and possibly other MC-related disorders.