Minimal Reductions Research Articles

Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group.

Although chemotherapy has improved outcome of osteosarcoma, 30-40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline-induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m(2)) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data. Children and adolescents with nonmetastatic osteosarcoma were treated with MAP (methotrexate, doxorubicin, cisplatin) or MAPI (MAP/ifosfamide). Dexrazoxane was administered with all doxorubicin doses. Cardioprotection was assessed by measuring left ventricular fractional shortening. Interference with chemotherapy-induced cytotoxicity was determined by measuring tumor necrosis after induction chemotherapy. Feasibility of intensifying therapy with either high cumulative-dose doxorubicin or high-dose ifosfamide/etoposide was evaluated for "standard responders" (SR, <98% tumor necrosis at definitive surgery). Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450-600 mg/m(2)) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in five patients; 4/5 had transient effects. Left ventricular fractional shortening z-scores (FSZ) showed minimal reductions (0.0170 ± 0.009/week) over 78 weeks. Two patients (<1%) had secondary leukemia, one as a first event, a similar rate to what has been observed in prior trials. Intensification with high-dose ifosfamide/etoposide was also feasible. Dexrazoxane cardioprotection was safely administered. It did not impair tumor response or increase the risk of secondary malignancy. Dexrazoxane allowed for therapeutic intensification increasing the cumulative doxorubicin dose in SR to induction chemotherapy. These findings support the use of dexrazoxane in children and adolescents with osteosarcoma.

Large-scale expansion of no-take closures within the Great Barrier Reef has not enhanced fishery production.

A rare opportunity to test hypotheses about potential fishery benefits of large-scale closures was initiated in July 2004 when an additional 28.4% of the 348 000 km2 Great Barrier Reef (GBR) region of Queensland, Australia was closed to all fishing. Advice to the Australian and Queensland governments that supported this initiative predicted these additional closures would generate minimal (10%) initial reductions in both catch and landed value within the GBR area, with recovery of catches becoming apparent after three years. To test these predictions, commercial fisheries data from the GBR area and from the two adjacent (non-GBR) areas of Queensland were compared for the periods immediately before and after the closures were implemented. The observed means for total annual catch and value within the GBR declined from preclosure (2000-2003) levels of 12780 Mg and Australian $160 million, to initial post-closure (2005-2008) levels of 8143 Mg and $102 million; decreases of 35% and 36% respectively. Because the reference areas in the non-GBR had minimal changes in catch and value, the beyond-BACI (before, after, control, impact) analyses estimated initial net reductions within the GBR of 35% for both total catch and value. There was no evidence of recovery in total catch levels or any comparative improvement in catch rates within the GBR nine years after implementation. These results are not consistent with the advice to governments that the closures would have minimal initial impacts and rapidly generate benefits to fisheries in the GBR through increased juvenile recruitment and adult spillovers. Instead, the absence of evidence of recovery in catches to date currently supports an alternative hypothesis that where there is already effective fisheries management, the closing of areas to all fishing will generate reductions in overall catches similar to the percentage of the fished area that is closed.

Survival of Salmonella spp. in low water activity chicken base paste and powder formulated at different salt levels

Dry flavor ingredients such as black pepper and hydrolyzed vegetable protein (HVP) have been frequently recalled from the supply chain due to contamination with Salmonella. These spices are commonly used in preparation of savory meat flavor bases. This study evaluated the effect of various salt levels on the survival of Salmonella spp. in chicken bases formulated with pepper and HVP, in either paste or powder form. The salt content (% w/w), aw and pH for regular-salt, 45% reduced-salt and 90% reduced-salt paste formulations were 33.0, 0.686, 5.75; 18.2, 0.691, 5.85; and 3.5, 0.751, 5.96, respectively, and powder formulations were 34.0, 0.254, 6.15; 18.5, 0.290, 6.28; and 3.1, 0.301, 6.50, respectively. To mimic natural contamination, a dry sand inoculation technique was used to prepare the samples. A five serovar cocktail of Salmonella was used and the final inoculation level in the samples was 7.5 ± 0.2 log CFU/g. Inoculated paste samples were stored at 21 °C for up to 12 weeks, and up to 42 weeks for powder formulations. Salmonella counts did not increase in either treatment during storage. The effect of salt levels on Salmonella survival was insignificant. There was a 5.2 ± 0.4 log reduction in paste formulations by 3 week. However, low Salmonella counts (<1.0 log CFU/g) were detected in samples from 6 to 12 weeks. In powder formulations, minimal log reductions of 1.3 ± 0.1 were observed over 42 weeks. When preparing a food product that does not undergo a kill step, it is necessary to ensure the absence of Salmonella in the ingredients, as well as practicing strict adherence to good manufacturing practices including proper environmental monitoring and sanitation in food processing. Furthermore, adequate consumer cooking instructions are important to ensure proper Salmonella lethality during preparation of reconstituted dry products.

Macroporous flexible polyvinyl alcohol lithium adsorbent foam composite prepared via surfactant blending and cryo-desiccation

Macroporous polyvinyl alcohol (PVA) foam composites with high loading of uniformly distributed lithium ion sieves (LIS) were successfully fabricated and evaluated for Li+ recovery. Surfactant blending combined with cryo-desiccation effectively produced LIS/PVA foams with hierarchical porosity composed of macro- and mesopores. Glutaraldehyde cross-linking rendered the LIS/PVA foams insoluble in water but exhibited high water absorbency and flexibility. Relative to the LIS powder, the foams exhibited minimal reductions in adsorption capacity (qe) and kinetic properties due to: (1) high total porosity and surface area, (2) hydrophilicity of PVA matrix, and (3) high LIS loading, which promoted particle exposure on the foam surface. These features facilitated easy convective flow of water through the matrix and allowed intimate contact between the Li+ feed source and the LIS surface. Thus, LIS/PVA foams with high loadings (200–300wt%) exhibited meager reductions in qe (7–13%) and kinetic properties compared to the LIS powder. With LIS loading increase, Li+ selectivity of LIS/PVA foams against other cations (i.e. Na+, K+, Mg2+, Ca2+) likewise approached that of the LIS powder. While 300wt% LIS/PVA had low mechanical property, lower LIS loadings of 200- and 250wt% were highly durable and exhibited no deterioration in adsorption performance and reusability. Among the prepared LIS/PVA, 250wt% demonstrated the highest adsorption performance and can be repeatedly used for long-term application. The developed LIS/PVA foams are promising Li+ adsorbents for secondary Li+ sources; application of these foams via a simple “absorb and squeeze” mechanism could be more practical than the energy-intensive processes like packed bed and membrane systems.

Glucocorticoid-induced microRNA-511 protects against TNF by down-regulating TNFR1.

TNF is a central actor during inflammation and a well-recognized drug target for inflammatory diseases. We found that the mouse strain SPRET/Ei, known for extreme and dominant resistance against TNF-induced shock, displays weak expression of TNF receptor 1 protein (TNFR1) but normal mRNA expression, a trait genetically linked to the major TNFR1 coding gene Tnfrsf1a and to a locus harbouring the predicted TNFR1-regulating miR-511. This miRNA is a genuine TNFR1 regulator in cells. In mice, overexpression of miR-511 down-regulates TNFR1 and protects against TNF, while anti-miR-511 up-regulates TNFR1 and sensitizes for TNF, breaking the resistance of SPRET/Ei. We found that miR-511 inhibits endotoxemia and experimental hepatitis and that this miR is strongly induced by glucocorticoids and is a true TNFR1 modulator and thus an anti-inflammatory miR. Since minimal reductions of TNFR1 have considerable effects on TNF sensitivity, we believe that at least part of the anti-inflammatory effects of glucocorti-coids are mediated by induction of this miR, resulting in reduced TNFR1 expression.

The impact of pneumoperitoneum and Trendelenburg positioning on respiratory system mechanics during laparoscopic pelvic surgery in children: a prospective observational study.

The aim of this study was to describe the changes in respiratory system compliance and other measures of respiratory mechanics associated with peritoneal insufflation (12mmHg pressure) with carbon dioxide (PNP12) and 20° Trendelenburg positioning (TDG20) in pediatric patients undergoing laparoscopic surgery for abdominal cryptorchidism. Twelve subjects with abdominal cryptorchidism undergoing orchiopexy were enrolled in the study. General anesthesia was conducted with sevoflurane/O2/air, fentanyl, and rocuronium. Pressure-controlled ventilation with a peak inspiratory pressure (PIP) of 10-15cm H2O and a positive end-expiratory pressure of 5cm H2O was titrated to achieve a tidal volume (VT/kg) of 6-10mL·kg(-1) and end-tidal carbon dioxide (EtCO2) of 35-40mmHg. Adjustments of PIP and respiratory rate (RR) were made to maintain the initial VT/kg and EtCO2<50mmHg. Measurements of weight-corrected dynamic compliance (Cdyn/kg), VT/kg, and EtCO2 were recorded at baseline, after PNP12, at TDG20, and again after deflation and return to the level position. Adjustments in PIP were required in all subjects to maintain the target VT/kg. The Cdyn/kg decreased 42% (95% confidence interval [CI]: 30 to 51; P<0.001) after PNP12, and it remained below baseline until deflation. The TDG20 caused only minimal additional reductions in Cdyn/kg (10% decrease; 95% CI: 0 to 19; P=0.048). The VT/kg decreased 42% (95% CI: 31 to 52; P=0.048) with PNP12, and after TDG20, it decreased a further 10% (95% CI: 4 to 19; P=0.038). After deflation, the VT/kg increased by 56% (95% CI: 28 to 90; P=0.001) and was then adjusted back to the initial values. The PNP12 significantly decreases Cdyn/kg and VT/kg in pediatric patients. The use of TDG20 produces a relatively minor additional impact in respiratory mechanics. This study emphasizes the need to adjust ventilator settings to maintain normal gas exchange during this procedure.

Activation of Retrotrapezoid Nucleus (RTN) Maintains Normal Breathing in Hyperoxia Despite the Loss of Carotid Body (CB) Input

Rationale and objectives: the CBs contribute greatly to resting ventilation in conscious mammals. For example, their excision produces large and long‐lasting breathing reductions. Yet sustained hyperoxia, which silences the CBs, produces minimal breathing reductions in conscious rats and mildly activates breathing in man. RTN is a major cluster of central respiratory chemoreceptors (CRCs). Here we tested whether, under hyperoxia, breathing might be maintained by a compensatory increase in RTN activity.Methods: RTN and nearby C1 neurons were bilaterally transduced with archaerhodopsin (PRSx8‐ArchT‐EYFP‐LVV). We first showed that RTN neurons were instantly silenced by green light in anesthetized rats. We then measured the effect of RTN inhibition (10s) on breathing (fR, VT) and BP in conscious rats exposed to normoxia (21% FiO2) or hyperoxia (65% FiO2). Arterial blood gases (PO2, PCO2), pHa and HCO3 were measured under both conditions.Results: hyperoxia produced a very mild respiratory acidosis. RTN inhibition elicited a much larger fR and VT reduction in rats exposed to hyperoxia than to normoxia. BP was unaffected under hypoxia or hyperoxia suggesting that the C1 neurons were minimally impacted by the light.Interpretation: in conscious rats hyperoxia activates RTN, which maintains ventilation at control level (normoxia) despite the presumed loss of CB activity. RTN activation by hyperoxia probably results from several mechanisms including mild respiratory acidosis, Haldane effect and CNS vasoconstriction, the latter causing reduced CO2 wash‐out and brain parenchymal acidification. Funding: HL074011 (PGG), 5T32HL007284‐38 (TMB).

Reduced Sialylation Impacts Ventricular Repolarization by Modulating Specific K+ Channel Isoforms Distinctly

Voltage-gated K(+) channels (Kv) are responsible for repolarizing excitable cells and can be heavily glycosylated. Cardiac Kv activity is indispensable where even minimal reductions in function can extend action potential duration, prolong QT intervals, and ultimately contribute to life-threatening arrhythmias. Diseases such as congenital disorders of glycosylation often cause significant cardiac phenotypes that can include arrhythmias. Here we investigated the impact of reduced sialylation on ventricular repolarization through gene deletion of the sialyltransferase ST3Gal4. ST3Gal4-deficient mice (ST3Gal4(-/-)) had prolonged QT intervals with a concomitant increase in ventricular action potential duration. Ventricular apex myocytes isolated from ST3Gal4(-/-) mice demonstrated depolarizing shifts in activation gating of the transient outward (Ito) and delayed rectifier (IKslow) components of K(+) current with no change in maximum current densities. Consistently, similar protein expression levels of the three Kv isoforms responsible for Ito and IKslow were measured for ST3Gal4(-/-) versus controls. However, novel non-enzymatic sialic acid labeling indicated a reduction in sialylation of ST3Gal4(-/-) ventricular Kv4.2 and Kv1.5, which contribute to Ito and IKslow, respectively. Thus, we describe here a novel form of regulating cardiac function through the activities of a specific glycogene product. Namely, reduced ST3Gal4 activity leads to a loss of isoform-specific Kv sialylation and function, thereby limiting Kv activity during the action potential and decreasing repolarization rate, which likely contributes to prolonged ventricular repolarization. These studies elucidate a novel role for individual glycogene products in contributing to a complex network of cardiac regulation under normal and pathologic conditions.

Influence of fuels, weather and the built environment on the exposure of property to wildfire.

Wildfires can pose a significant risk to people and property. Billions of dollars are spent investing in fire management actions in an attempt to reduce the risk of loss. One of the key areas where money is spent is through fuel treatment – either fuel reduction (prescribed fire) or fuel removal (fuel breaks). Individual treatments can influence fire size and the maximum distance travelled from the ignition and presumably risk, but few studies have examined the landscape level effectiveness of these treatments. Here we use a Bayesian Network model to examine the relative influence of the built and natural environment, weather, fuel and fuel treatments in determining the risk posed from wildfire to the wildland-urban interface. Fire size and distance travelled was influenced most strongly by weather, with exposure to fires most sensitive to changes in the built environment and fire parameters. Natural environment variables and fuel load all had minor influences on fire size, distance travelled and exposure of assets. These results suggest that management of fuels provided minimal reductions in risk to assets and adequate planning of the changes in the built environment to cope with the expansion of human populations is going to be vital for managing risk from fire under future climates.

Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies.

Lenalidomide is an oral immunomodulatory agent approved in relapsed multiple myeloma with dexamethasone, for transfusion-dependent anemia in myelodysplastic syndrome associated with deletion 5q, and in relapsed/progressive mantle cell lymphoma following bortezomib. In recent clinical trials, lenalidomide has shown promising activity in hematologic malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Starting doses and dosing schedules vary by malignancy, with lenalidomide started at a lower dose for CLL than for NHL or multiple myeloma. Certain adverse events (AEs) are common across tumor types (e.g., neutropenia, thrombocytopenia, fatigue), whereas others are more often associated with CLL patients (e.g., tumor lysis syndrome and tumor flare reaction). Effective management requires awareness of these differences as well as appropriate prophylaxis, monitoring, and treatment of AEs. This article reviews the efficacy and safety of lenalidomide in CLL and NHL, focusing on approaches for the advanced practitioner to improve patient quality of life through optimal management of side effects. With these steps, lenalidomide can be administered safely, at the best starting doses and with minimal dose interruptions or reductions across hematologic malignancies.

Quantitative analysis of woodpecker habitat using high-resolution airborne LiDAR estimates of forest structure and composition

Light detection and ranging (LiDAR) technology has the potential to radically alter the way researchers and managers collect data on wildlife–habitat relationships. To date, the technology has fostered several novel approaches to characterizing avian habitat, but has been limited by the lack of detailed LiDAR-habitat attributes relevant to species across a continuum of spatial grain sizes and habitat requirements. We demonstrate a novel three-step approach for using LiDAR data to evaluate habitat based on multiple habitat attributes and accounting for their influence at multiple grain sizes using federally endangered red-cockaded woodpecker (RCW; Picoides borealis) foraging habitat data from the Savannah River Site (SRS) in South Carolina, USA. First, we used high density LiDAR data (10returns/m2) to predict detailed forest attributes at 20-m resolution across the entire SRS using a complementary application of nonlinear seemingly unrelated regression and multiple linear regression models. Next, we expanded on previous applications of LiDAR by constructing 95% joint prediction confidence intervals to quantify prediction error at various spatial aggregations and habitat thresholds to determine a biologically and statistically meaningful grain size. Finally, we used aggregations of 20-m cells and associated confidence interval boundaries to demonstrate a new approach to produce maps of RCW foraging habitat conditions based on the guidelines described in the species' recovery plan. Predictive power (R2) of regression models developed to populate raster layers ranged from 0.34 to 0.81, and prediction error decreased as aggregate size increased, but minimal reductions in prediction error were observed beyond 0.64-ha (4×4 20-m cells) aggregates. Mapping habitat quality while accounting for prediction error provided a robust method to determine the potential range of habitat conditions and specific attributes that were limiting in terms of the amount of suitable habitat. The sequential steps of our analytical approach provide a useful framework to extract detailed and reliable habitat attributes for a forest-dwelling habitat specialist, broadening the potential to apply LiDAR in conservation and management of wildlife populations.

Dose calibration optimization and error propagation in polymer gel dosimetry

This study reports on the relative precision, relative error, and dose differences observed when using a new full-image calibration technique in NIPAM-based x-ray CT polymer gel dosimetry. The effects of calibration parameters (e.g. gradient thresholding, dose bin size, calibration fit function, and spatial remeshing) on subsequent errors in calibrated gel images are reported. It is found that gradient thresholding, dose bin size, and fit function all play a primary role in affecting errors in calibrated images. Spatial remeshing induces minimal reductions or increases in errors in calibrated images. This study also reports on a full error propagation throughout the CT gel image pre-processing and calibration procedure thus giving, for the first time, a realistic view of the errors incurred in calibrated CT polymer gel dosimetry. While the work is based on CT polymer gel dosimetry, the formalism is valid for and easily extended to MRI or optical CT dosimetry protocols. Hence, the procedures developed within the work are generally applicable to calibration of polymer gel dosimeters.

A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension

A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH.

A fuzzy-rough approach for finding various minimal data reductions using ant colony optimization

Finding out information about features is one of the main goals of feature selection. In that case there is not particularly care about the resulting classification accuracy, but we are interested in maximizing dependency degree. A data set can have several minimal data reductions; however, most of the methods are able to find only one minimal data reduction which is not beneficial. In this paper, we propose a feature selection method based on modified Ant Colony Optimization algorithm ACO. The main contribution of this paper includes using fuzzy-rough gain ratio as heuristic information and new rules for pheromone updating in ACO. Unlike most of the methods which find only one minimal reduction, this method is able to find various minimal data reductions. The proposed method is compared with three other meta-heuristic methods. The results show that our approach is very successful in finding various minimal data reductions.

Chronic pain in children and adolescents: 24-42 month outcomes of an inpatient/day hospital interdisciplinary pain rehabilitation program.

The purpose of this research was to describe 24-42 month outcomes of a combined inpatient/day hospital interdisciplinary pain rehabilitation program for children and adolescents with chronic pain and functional disability. One-hundred-seventy-three children and adolescents (mean age=15.1 years, SD=2.5) were treated in the three-week program. Mixed effects regression models (MERM) examined changes over time in pain ratings (0-10), school days missed by children and work days missed by parents in the preceding week, and the number of days hospitalized in the preceding month. Participants reported a significant decline in pain from admission to 24-42 month follow-up. The largest declines in pain occurred from discharge to 1-month follow-up (6.20 vs. 4.81 on a 0-10 numerical rating scale) and from 12 months to 24-42 month follow-up (4.90 vs. 3.56). Two distinct trajectories of treatment response were identified using growth mixture modeling: children with initially high pain ratings exhibited large reductions in pain ratings, while those with lower pain ratings at admission showed minimal reductions. Treatment resulted in significant reductions in school and work days missed and the number of days hospitalized (all p's < 0.001), with reductions evident at 1-month follow-up and maintained through 24-42 month follow-up. These results suggest that interdisciplinary pain rehabilitation is a promising approach to chronic pain and associated disability in children, with enduring improvements found 24-42 months following program completion. Distinct trajectories of treatment response were identified.

Impacts of implementation of Colombian environmental flow methodologies on the flow regime and hydropower production of the Chinchiná River, Colombia

We investigated the potential impacts on hydropower generation of applying six Colombian and two international best practice environmental flow methodologies within a small Andean river catchment, the Chinchiná River basin. Post-impact flow and hydropower production levels under the eight methodologies and a “no environmental flow scenario” were determined using a Microsoft Excel® flow diversion and hydropower production spreadsheet model. A flow regime alteration index (FRAI) was developed based on the degree of variation between the pre- and post-impact flow conditions of the 33 characteristic Indicators of Hydrologic Alteration flow regime parameters, facilitating a simplified comparison of the overall degree of alteration among the nine different environmental flow scenarios. Hydropower production decreased with increasing levels of environmental flow releases, with decreases of 16.9–76.4% relative to production levels in the absence of an environmental flow. None of the eight investigated methodologies maintained “sustainable” (<20%) levels of flow regime alteration while facilitating minimal reductions in hydropower generation. Methodologies which maintained sustainable flow regime alteration levels resulted in >50% decrease in hydropower production and >40% decrease in flow diversion capacity. We recommend a dual approach of hydropower re-operation and fine-tuning of existing national standards to consider the characteristic inter- and intra-annual seasonality and ecologically relevant flow events, maximizing benefits between power generation and environmental sustainability. Our findings are relevant to the Chinchiná River basin and regions of similar hydro-geographical conditions utilized for small scale hydropower production, and underscore the need for further development of existing environmental flow methodologies.

Rapid biochemical response to denosumab in fibrous dysplasia of bone: report of two cases

We report on the clinical and biochemical outcomes in two adult patients with active polyostotic fibrous dysplasia (FD) treated with the RANK-L inhibitor, denosumab, following unsatisfactory responses to prior long-term bisphosphonate therapy. A 44-year-old female (case 1) who had received a cumulative dose of 20 mg zoledronic acid over 2.5 years and a 48-year-old male (case 2) who had received a cumulative dose of 45 mg zoledronic acid over 8 years both experienced minimal reductions in pain scores and markers of bone turnover. Following initiation of denosumab 60 mg sc, changes in bone pain, bone turnover [assessed by serum amino-terminal propeptide of type I collagen (PINP) and urinary deoxypyridinoline] were monitored over a period of 20 and 8 months, respectively. Following administration of denosumab, both patients demonstrated a rapid and pronounced biochemical response: Within 4-7 weeks, bone turnover markers fell to levels within the respective reference range, and one patient reported a reduction in pain. Treatment with denosumab was well tolerated. However, transient asymptomatic hypocalcaemia and/or hypophosphatemia associated with a transient two to threefold increase in serum PTH levels was observed in both patients. Dosing intervals for denosumab varied significantly between the two patients, depending on disease activity at baseline. Denosumab appears to be effective in reducing bone turnover in adult patients with active FD. However, caution should be exercised, and patients should be monitored carefully as significant fluctuations in biochemical and hormonal indices can occur.

Ablation of Multiwavelet Re-entry Guided by Circuit-Density and Distribution

Background— A key mechanism responsible for atrial fibrillation is multiwavelet re-entry (MWR). We have previously demonstrated improved efficiency of ablation when lesions were placed in regions of high circuit-density. In this study, we undertook a quantitative assessment of the relative effect of ablation on the probability of MWR termination and the inducibility of MWR, as a function of lesion length and circuit-density overlap. Methods and Results— We used a computational model to simulate MWR in tissues with (and without) localized regions of decreased action potential duration and increased intercellular resistance. We measured baseline circuit-density and distribution. We then assessed the effect of various ablation lesion sets on the inducibility and duration of MWR as a function of ablation lesion length and overlap with circuit-density. Higher circuit-density reproducibly localized to regions of shorter wavelength. Ablation lines with high circuit-density overlap showed maximum decreases in duration of MWR at lengths equal to the distance from the tissue boundary to the far side of the high circuit-density region (high-overlap, −43.5% [confidence interval, −22.0% to −65.1%] versus low-overlap, −4.4% [confidence interval, 7.3% to −16.0%]). Further ablation (beyond the length required to cross the high circuit-density region) provided minimal further reductions in duration and increased inducibility. Conclusions— Ablation at sites of high circuit-density most efficiently decreased re-entrant duration while minimally increasing inducibility. Ablation lines delivered at sites of low circuit-density minimally decreased duration yet increased inducibility of MWR.

Decontamination Treatments for Psychrotrophic Microorganisms on Chicken Meat during Storage at Different Temperatures

The antimicrobial effectiveness of five chemical decontaminants (12 % trisodium phosphate [TSP], 1,200 ppm acidified sodium chlorite [ASC], 2 % citric acid [CA], 220 ppm of peroxyacids [PA], or 50 ppm of chlorine dioxide [CD]) against psychrotrophic populations on skinned chicken legs was assessed throughout 120 h of storage under various temperature abuse scenarios. Three different simulated cold chain disruptions were used: T1 (12 h at 1 ± 1 °C, 6 h at 15 ± 1 °C, and 102 h at 4 ± 1 °C), T2 (18 h at 1 ± 1 °C, 6 h at 15 ± 1 °C, and 96 h at 10 ± 1 °C), or T3 (18 h at 4 ± 1 °C, 6 h at 20 ± 1 °C, and 96 h at 7 ± 1 °C). Microbiological analyses were carried out at 0, 24, 72, and 120 h of storage. Substantial microbial reductions, with respect to control (untreated) samples, were obtained in legs treated with TSP, ASC, and CA, with average values ranging from 1.54 ± 1.52 to 2.02 ± 2.19 log CFU/cm(2). TSP was the most effective compound under mild abuse temperature conditions (T1), with mean reductions of 2.01 ± 1.67 log CFU/cm(2), whereas ASC, followed by CA, proved to be particularly useful under moderate abuse conditions (T3; average reductions of 2.99 ± 2.27 and 1.98 ± 1.65 log CFU/cm(2), respectively). Treatment with PA or CD resulted in minimal microbial reductions.

Cost-Effectiveness of a Package of Interventions for Expedited Antiretroviral Therapy Initiation During Pregnancy in Cape Town, South Africa

Initiating antiretroviral therapy (ART) early in pregnancy is an important component of effective interventions to prevent the mother-to-child transmission of HIV (PMTCT). The rapid initiation of ART in pregnancy(RAP) program was a package of interventions to expedite ART initiation in pregnant women in Cape Town, South Africa. Retrospective cost-effectiveness, sensitivity and threshold analyses were conducted of the RAP program to determine the cost-utility thresholds for rapid initiation of ART in pregnancy. Costs were drawn from a detailed micro-costing of the program. The overall programmatic cost was US$880 per woman and the base case cost-effectiveness ratio was US$1,160 per quality-adjusted lifeyear (QALY) saved. In threshold analyses, the RAP program remained cost-effective if mother-to-child transmission was reduced by C0.33 %; if C1.76 QALY were saved with each averted perinatal infection; or if RAP-related costs were under US$4,020 per woman. The package of rapid initiation services was very cost-effective, as compared to standard services in this setting. Threshold analyses demonstrated that the intervention required minimal reductions in perinatal infections in order to be cost-effective. Interventions for the rapid initiation of ART in pregnancy hold considerable potential as a cost-effective use of limited resources for PMTCT in sub-Saharan Africa.