Impact of supplemental home enteral feeding postesophagectomy on nutrition, body composition, quality of life, and patient satisfaction.

The aim of this prospective cohort study is to analyze the impact of supplemental home enteral nutrition (HEN) post-esophageal cancer surgery on nutritional parameters, quality of life (QL), and patient satisfaction. A systematic review reported that over 60% of patients lose >10% of both body weight and BMI by 6 months after esophagectomy. Enteral feeding (EF) is increasingly a modern standard postoperatively; however, the impact of extended HEN postdischarge has not been systematically studied. One hundred forty-nine consecutive patients [mean age 62 ± 9, 80% male,76% adenocarcinoma, 66% on multimodal protocols, and 69% with BMI ≥ 25 kg/m2] were studied. Jejunal EF commenced day 1 postoperatively, and supplemental overnight HEN (764 kcal; 32g protein) continued on discharge for a planned further 4 weeks. Weight, BMI, and body composition analysis (bioimpedance analysis) were measured at baseline, preoperatively and at 1, 3, and 6 months, along with the EORTC QLQ-C30/OES18 QL measures. A patient satisfaction questionnaire addressed eight key items in relation to HEN (max score 100/item). Median (range) total duration of EF was 49 days (28-96). Overall compliance was 96%. At 6 months, compared with preoperatively, 58 (39%) patients lost >10% weight, with median (IQR) loss of 6.8 (4-9) kg, and 62 (41%) patients lost >10% BMI. Lean body mass and body fat were significantly (p < 0.001) decreased. Mean global QL decreased (p < 0.01) from 82 to 72. A high mean satisfaction score (>70 ± 11/100) was reported, >80 for practical training, activities of daily living, pain, anxiety, recovery and impact on caregivers, with lower scores for appetite (33 ± 24) and sleep (63 ± 30). Supplemental HEN for a minimum of one month postdischarge is associated with high compliance and patient satisfaction. Weight and BMI loss may still be substantial, however this may be less than published literature, in addition the impact on HR-QL may be attenuated. HEN has both subjective and objective rationale and merits further validation toward optimizing nutritional recovery and overall wellbeing.

Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS). Results: A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06). Conclusions: In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Biophysically inspired rational design of structured chimeric substrates for DNAzyme cascade engineering.

The development of large-scale molecular computational networks is a promising approach to implementing logical decision making at the nanoscale, analogous to cellular signaling and regulatory cascades. DNA strands with catalytic activity (DNAzymes) are one means of systematically constructing molecular computation networks with inherent signal amplification. Linking multiple DNAzymes into a computational circuit requires the design of substrate molecules that allow a signal to be passed from one DNAzyme to another through programmed biochemical interactions. In this paper, we chronicle an iterative design process guided by biophysical and kinetic constraints on the desired reaction pathways and use the resulting substrate design to implement heterogeneous DNAzyme signaling cascades. A key aspect of our design process is the use of secondary structure in the substrate molecule to sequester a downstream effector sequence prior to cleavage by an upstream DNAzyme. Our goal was to develop a concrete substrate molecule design to achieve efficient signal propagation with maximal activation and minimal leakage. We have previously employed the resulting design to develop high-performance DNAzyme-based signaling systems with applications in pathogen detection and autonomous theranostics.

Visual displays that directly interface and provide read-outs of molecular states via molecular graphics processing units.

The monitoring of molecular systems usually requires sophisticated technologies to interpret nanoscale events into electronic-decipherable signals. We demonstrate a new method for obtaining read-outs of molecular states that uses graphics processing units made from molecular circuits. Because they are made from molecules, the units are able to directly interact with molecular systems. We developed deoxyribozyme-based graphics processing units able to monitor nucleic acids and output alphanumerical read-outs via a fluorescent display. Using this design we created a molecular 7-segment display, a molecular calculator able to add and multiply small numbers, and a molecular automaton able to diagnose Ebola and Marburg virus sequences. These molecular graphics processing units provide insight for the construction of autonomous biosensing devices, and are essential components for the development of molecular computing platforms devoid of electronics.

Signal propagation in multi-layer DNAzyme cascades using structured chimeric substrates.

Signal propagation through enzyme cascades is a critical component of information processing in cellular systems. Although such systems have potential as biomolecular computing tools, rational design of synthetic protein networks remains infeasible. DNA strands with catalytic activity (DNAzymes) are an attractive alternative, enabling rational cascade design through predictable base-pair hybridization principles. Multi-layered DNAzyme signaling and logic cascades are now reported. Signaling between DNAzymes was achieved using a structured chimeric substrate (SCS) that releases a downstream activator after cleavage by an upstream DNAzyme. The SCS can be activated by various upstream DNAzymes, can be coupled to DNA strand-displacement devices, and is highly resistant to interference from background DNA. This work enables the rational design of synthetic DNAzyme regulatory networks, with potential applications in biomolecular computing, biodetection, and autonomous theranostics.

Adherence to guideline-based antibiotic treatment for acute exacerbations of chronic obstructive pulmonary disease in an Australian tertiary hospital.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are an important cause of acute hospital admissions and incur significant costs, which include antibiotic costs. AIMS: This study aimed to (i) define antibiotic prescribing practice in patients admitted to a tertiary hospital with AECOPD and compare this with current locally and nationally recognised antibiotic prescribing guidelines and (ii) correlate variations in guideline-concordant antibiotic prescribing with mean length of stay (LOS) and rates of unplanned readmission to hospital. METHODS: Retrospective case series of 84 consecutive patients with uncomplicated AECOPD who met pre-specified selection criteria. RESULTS: Seventy-two of 84 participants (85.7%) received guideline-discordant antibiotics, of whom the majority (76%) received intravenous antibiotics. Mean LOS was significantly lower among patients receiving guideline-concordant therapy compared with those receiving guideline-discordant therapy (mean 1.6 days vs 3.7 days; P = 0.002). There was no significant difference between groups in rates of readmission. Estimated excess costs per patient associated with guideline-discordant therapy equalled $2642 which, if eliminated, would save approximately $300 000 per annum. CONCLUSION: In a tertiary hospital, Australian guidelines for treating patients with an AECOPD were rarely followed. The use of guideline-discordant therapy resulted in longer hospital stays and incurred greater costs. Studies are required to determine the reasons behind such discordant practice and to develop initiatives to improve antibiotic prescribing.

Effects of tetrahydropalmatine on post-traumatic stress disorder-induced changes in rat brain gene expression.

The aim of this research proposal was to investigate the effects of tetrahydropalmatine (THP) on gene expression in a post-traumatic stress disorder (PTSD) rodent model. Eighty male Sprague-Dawley rats were randomly assigned to the nonstressed groups or the 3-day restraint shock PTSD rodent model groups. There were four groups within the nonstressed rats (control, THP, midazolam, and midazolam with THP) and four groups within the stressed rats (control, THP, midazolam, and midazolam with THP). After injection the subjects were euthanized and the amygdala and hippocampus were sent for reverse transcriptase-polymerase chain reaction gene expression analysis. Of the genes interrogated, 17 genes in the amygdala and 18 genes in the hippocampus were found to have significant changes in gene expression and regulation. Significant transcriptional fold changes were found in important genes involved in dopamine, serotonin, acetylcholine, and gamma-aminobutyric acid neurotransmitter systems. The results provide quantifiable data demonstrating gene expression changes in PTSD-stressed and nonstressed rats receiving various treatments. These findings contribute important data to the limited molecular details pertaining to the neurobiology of PTSD.

Efficient RNAi-based gene family knockdown via set cover optimization.

OBJECTIVE: We address the problem of selecting an efficient set of initiator molecules (siRNAs) for RNA interference (RNAi)-based gene family knockdown experiments. Our goal is to select a minimal set of siRNAs that (a) cover a targeted gene family or a specified subset of it, (b) do not cover any untargeted genes, and (c) are individually highly effective at inducing knockdown. METHODS AND MATERIAL: We give two formalizations of the gene family knockdown problem. First, we show that the problem, minimizing the number of siRNAs required to knock down a family of genes, is NP-Hard via a reduction to the set cover problem. Second, we generalize the basic problem to incorporate additional biological constraints and optimality criteria. To solve the resulting set-cover variants, we modify the classical branch-and-bound algorithm to include some of these biological criteria. We find that in many typical cases these constraints reduce the search space enough that we are able to compute exact minimal siRNA covers within reasonable time. For larger cases, we propose a probabilistic greedy algorithm for finding minimal siRNA covers efficiently. We apply our methods to two different gene families, the FREP genes from Biomphalaria glabrata and the olfactory genes from Caenorhabditis elegans. RESULTS AND CONCLUSION: Our computational results on real biological data show that the probabilistic greedy algorithm produces siRNA covers as good as the branch-and-bound algorithm in most cases. Both algorithms return minimal siRNA covers with high predicted probability that the selected siRNAs will be effective at inducing knockdown. We also examine the role of "off-target" interactions: the constraint of avoiding covering untargeted genes can, in some cases, substantially increase the complexity of the resulting solution. Overall, we find that in many common cases our approach significantly reduces the number of siRNAs required in gene family knockdown experiments, as compared to knocking down genes independently.

Image accuracy improvements in microwave tomographic thermometry: phantom experience.

Evaluation of a laboratory-scale microwave imaging system for non-invasive temperature monitoring has previously been reported with good results in terms of both spatial and temperature resolution. However, a new formulation of the reconstruction algorithm in terms of the log-magnitude and phase of the electric fields has dramatically improved the ability of the system to track the temperature-dependent electrical conductivity distribution. This algorithmic enhancement was originally implemented as a way of improving overall imaging capability in cases of large, high contrast permittivity scatterers, but has also proved to be sensitive to subtle conductivity changes as required in thermal imaging. Additional refinements in the regularization procedure have strengthened the reliability and robustness of image convergence. Imaging experiments were performed for a single heated target consisting of a 5.1 cm diameter PVC tube located within 15 and 25 cm diameter monopole antenna arrays, respectively. The performance of both log-magnitude/phase and complex-valued reconstructions when subjected to four different regularization schemes has been compared based on this experimental data. The results demonstrate a significant accuracy improvement (to 0.2 degrees C as compared with 1.6 degrees C for the previously published approach) in tracking thermal changes in phantoms where electrical properties vary linearly with temperature over a range relevant to hyperthermia cancer therapy.

Evaluation of dosage adjustment in patients with renal impairment.

AIMS: To determine whether appropriate dosage adjustments are made in patients with significant renal impairment for drugs with a high fractional renal clearance. METHODS: Evaluation of dosage adjustment was performed in patients who were admitted to a 480-bed metropolitan hospital (Princess Alexandra Hospital, Brisbane, Australia) with an estimated creatinine clearance of < or =40 mL/min. All drugs had a high fractional renal excretion. A prescribed dose within 30% of the calculated dose was considered appropriate. RESULTS: Doses were found to be inappropriately high in 111 (44.8%) of 248 admission prescriptions of the targeted drugs. Doses were appropriately reduced in hospital in 26 patients (23.4%). Seventy-three (29.3%) prescriptions were continued with excessive doses. Only 34 prescriptions for the target drugs were initiated in hospital, of which 88.2% were appropriately dosed. CONCLUSIONS: A significant percentage of patients with renal impairment are admitted to hospital on inappropriately high doses of drugs, with a high fractional renal excretion and low therapeutic index. Doses are appropriately reduced in hospital in some patients but there is still room for improvement [corrected].

Microwave thermal imaging: initial in vivo experience with a single heating zone.

The deployment of hyperthermia as a routine adjuvant to radiation or chemotherapy is limited largely by the inability to devise treatment plans which can be monitored through temperature distribution feedback during therapy. A non-invasive microwave tomographic thermal imaging system is currently being developed which has previously exhibited excellent correlation between the recovered electrical conductivity of a heated zone and its actual temperature change during phantom studies. To extend the validation of this approach in vivo, the imaging system has been re-configured for small animal experiments to operate within the bore of a CT scanner for anatomical and thermometry registration. A series of 5-7 day old pigs have been imaged during hyperthermia with a monopole antenna array submerged in a saline tank where a small plastic tube surgically inserted the length of the abdomen has been used to create a zone of heated saline at pre-selected temperatures. Tomographic microwave data over the frequency range of 300-1000 MHz of the pig abdomen in the plane perpendicular to the torso is collected at regular intervals after the tube saline temperatures have settled to the desired settings. Images are reconstructed over a range of operating frequencies. The tube location is clearly visible and the recovered saline conductivity varies linearly with the controlled temperature values. Difference images utilizing the baseline state prior to heating reinforces the linear relationship between temperature and imaged saline conductivity. Demonstration of in vivo temperature recovery and correlation with an independent monitoring device is an important milestone prior to clinical integration of this non-invasive imaging system with a thermal therapy device.

Effect of ammonium sulfate fertilization on bahiagrass quality and copper metabolism in grazing beef cattle.

To assess the impact of S fertilization on bahiagrass (Paspalum notatum) quality and Cu metabolism in cattle, two studies were conducted during the summer grazing season (1999 and 2000). Pasture replicates (16.2 ha; n = 2/treatment) received the same fertilizer treatment in each growing season, consisting of 1) 67 kg N/ha from ammonium sulfate (AS), 2) 67 kg N/ha from ammonium nitrate (AN), and 3) control (no fertilizer; C). Forage sampling was conducted at 28-d intervals following fertilization by the collection of whole plants (four samples/pasture) in randomly distributed 1-m2 grazing exclusion cages and analyzed for CP, in vitro organic matter digestibility, S, P, Ca, K, Mg, Na, Fe, Al, Mn, Cu, and Zn. To determine the effect of fertilizer treatment on liver trace mineral concentrations in grazing cattle, random liver tissue samples were collected (n = 12; four/treatment) at the start and end of the study period in 2000. Ammonium sulfate fertilization increased (P < 0.001) forage S concentration in both years. Plant tissue N concentrations were increased by N fertilization, regardless of source, in 2000, but not in 1999. Cows grazing AS pastures had lower (P < 0.05) liver Cu concentrations at the end of the study period in 2000 compared to AN and C. In Exp. 2, 37 Cu-deficient heifers grazing AS fertilized pastures were obtained from the same location and allocated to one of two treatments, consisting of supplements providing 123 mg/d of either inorganic (Cu sulfate; n = 12) or organic (Availa-Cu; n = 15) Cu. Treatments were delivered for 83 d. Liver Cu increased over time in all heifers regardless of treatment; however, heifers supplemented with Availa-Cu tended (P = 0.09) to have higher mean liver Cu concentrations than those receiving Cu sulfate. The results of these studies indicate that AS fertilization of bahiagrass increases forage S concentrations. When provided free-choice access to a complete salt-based trace mineral supplement, cows grazing AS-fertilized pastures had lower liver Cu concentrations than cows grazing pastures fertilized with AN; upon removal from high-S pastures, cattle were able to respond to Cu supplementation.

Effectiveness of GnRH plus prostaglandin F2alpha for estrus synchronization in cattle of Bos indicus breeding.

Postpartum and lactating crossbred cows containing a percentage of Bos indicus breeding at three locations were studied to determine the efficacy of GnRH + PGF2alpha combinations for synchronization of estrus and(or) ovulation. Cows were equally distributed to each of three treatments by body condition score at the start of the experiment (d 0). All cows received 100 microg of GnRH on d 0 and 25 mg of PGF2alpha 7 d later. The three insemination protocols included 1) AI 12 h after exhibiting estrus during d 7 to 12 of the experiment (Select-Synch; n = 197); 2) timed-AI + 100 microg of GnRH on d 9 of the experiment (CO-Synch; n = 193); 3) AI 12 h after exhibiting estrus during d 7 to 10 of the experiment. Cows not exhibiting estrus by d 10 were timed-AI and injected with 100 microg of GnRH on d 10 of the experiment (Hybrid-Synch; n = 200). The percentage of cows exhibiting estrus during d 7 to 12 of the experiment was lower (P < 0.05) for CO-Synch (17.6%) cows than for Select-Synch or Hybrid-Synch (45.2 and 33.0%, respectively) cows, which did not differ (P > 0.05). For the Select-Synch and Hybrid-Synch cows that exhibited estrus during d 7 to 10 of the experiment and were artificially inseminated, conception rates were similar across treatments (50.5%). Pregnancy rates were greater (P < 0.01) for CO-Synch and Hybrid-Synch (31.0 and 35.5%, respectively) cows than for Select-Synch (20.8%) cows. A greater (P < 0.01) percentage of cycling cows became pregnant (34.5%) than noncycling cows (25.9%) across all treatments. The CO-Synch and Hybrid-Synch synchronization protocols resulted in greater pregnancy rates compared with the Select-Synch protocol in postpartum and lactating crossbred cows containing a percentage of Bos indicus breeding.

A two-stage microwave image reconstruction procedure for improved internal feature extraction.

We have developed a two-stage Gauss-Newton reconstruction process with an automatic procedure for determining the regularization parameter. The combination is utilized by our microwave imaging system and has facilitated recovery of quantitatively improved images. The first stage employs a Levenberg-Marquardt regularization along with a spatial filtering technique for a few iterations to produce an intermediate image. In effect, the first set of iterative image reconstruction steps synthesizes a priori information from the measurement data versus actually requiring physical prior information on the interrogated object. Because of the interaction of the Levenberg-Marquardt regularization and spatial filtering at each iteration, the intermediate image produced from the first reconstruction stage represents an improvement in terms of the least squared error over the initial uniform guess; however, it has not completely converged in a least squared sense. The second stage involves using this distribution as a priori information in an iteratively regularized Gauss-Newton reconstruction with a weighted Euclidean distance penalty term. The penalized term restricts the final image to a vicinity (determined by the scale of the weighting parameter) about the intermediate image while allowing more flexibility in extracting internal object structures. The second stage makes use of an empirical Bayesian/random effects model that enables an optimal determination of the weighting parameter of the penalized term. The new approach demonstrates quantifiably improved images in simulation, phantom and in vivo experiments with particularly striking improvements with respect to the recovery of heterogeneities internal to large, high contrast scatterers such as encountered when imaging the human breast in a water-coupled configuration.

Nonactive antenna compensation for fixed-array microwave imaging: Part II--Imaging results.

Model-based imaging techniques utilizing microwave signal illumination rely heavily on the ability to accurately represent the wave propagation with a suitable numerical model. To date, the highest quality images from our prototype system have been achieved utilizing a single transmitter/single receiver measurement system where both antennas are manually repositioned to facilitate multiple illuminations of the imaging region, thus requiring long data acquisition times. In an effort to develop a system that can acquire data in a real time manner, a 32-channel network has been fabricated with all ports capable of being electronically selected for either transmit or receive mode. The presence of a complete array of antenna elements at data collection time perturbs the field distributions being measured, which can subsequently degrade the image reconstruction due to increased data-model mismatch. Incorporating the nonactive antenna-compensation model from Part I of this paper into our hybrid element near field image reconstruction algorithm is shown to restore image quality when fixed antenna-array data acquisition is used. Improvements are most dramatic for inclusions located in near proximity to the antenna array itself, although cases of improvement in the recovery of centered heterogeneities are also illustrated. Increases in the frequency of illumination are found to warrant an increased need for nonactive antenna compensation. Quantitative measures of recovered inclusion shape and position reveal a systematic improvement in image reconstruction quality when the nonactive antenna-compensation model is employed. Improvements in electrical property value recovery of localized heterogeneities are also observed. Image reconstructions in freshly excised breast tissue illustrate the applicability of the approach when used with our two-dimensional microwave imaging system.

Non-invasive thermal assessment of tissue phantoms using an active near field microwave imaging technique.

An active microwave imaging system for non-invasive temperature sensing has been developed and evaluated. The system is designed to assess biological tissues undergoing thermal therapy. This paper presents results that demonstrate the imaging capabilities of the microwave method using simulated and experimental phantom materials. Results from both numerical studies and laboratory experiments have been analysed and are presented. The imaging system uses a 16 channel fixed monopole array transceiver unit operating over a bandwidth of 300-900 MHz. The annular array diameter is 14.75 cm and is immersed in a 0.9% saline solution. Standard heterodyning principles are used for signal detection leading to a dynamic range of the system of better than 115dB. Image formation is accomplished with a 2-D finite element based, near-field iterative technique. This allows the simultaneous reconstruction of both the real and imaginary components of the dielectric property distribution in tissue equivalent phantoms. Data acquisition currently captures 144 complex field measurements per image. Image reconstruction requires approximately 2 min per iteration with a typical convergence in less than 10 steps. Experiments performed to evaluate the temperature dependence of biological phantoms (saline with variable salt concentrations) are described. The numerical accuracy and precision of the reconstruction algorithm based upon these phantom studies are presented. Simple laboratory models of localized hyperthermia have been used to evaluate the experimental accuracy and precision of the imaging system. A numerical precision of 0.02 degrees C and an accuracy of 0.37 degrees C have been observed with the current algorithm. In laboratory experiments, images have been reconstructed at different target temperatures and target saline concentrations. The effect of placing high contrast biological phantoms (i.e. bone/fat simulants) along with the heated objects have also been studied. Localized heating of the biological phantom is achieved by pumping a saline solution of pre-selected concentration through enclosed ends of hollow dielectric cylinders having approximately 5cm inner diameter and 4 mm wall thickness. The temperature of the heated zone is preset and maintained to +/-0.2 degrees C by an external heater and circulator. The results currently show that a maximum temperature precision of 0.98 degrees C and maximum relative accuracy of 0.56 degrees C has been achieved in the laboratory using the current generation of the prototype system.

A circular organization chart promotes a hospital-wide focus on teams.

Our Lady of the Way Hospital, like most hospitals in the late 1980s and early 1990s, exemplified the bureaucratic organization represented by the traditional "line and box organization chart." Additionally, as in most small hospitals, the CEO of Our Lady of the Way Hospital--a 39-bed, JCAHO accredited, general, acute care hospital in Martin, Kentucky--had direct management responsibility for several functional departments. In 1992, administration replaced the traditional, hierarchical organization chart with a circular structure that reflected its increased reliance on team processes throughout the organization. The new structure also significantly reduced the number of reporting assignments to the CEO. This article describes the hospital's transition to a team-based organization, illustrates the application of a circular organization chart, and assesses its value and limitations.