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1.AbstractSpotted fever rickettsiosis plagues countries around the world. One of the deadliest of this group, Rickettsiarickettsii, responsible for Rocky Mountain spotted fever, is an emerging tickborne illness in North America. The predominant clinical diagnostic is PCR based but does not work until disease has progressed to a severe phase of infection, at which point the outcome of a full recovery is significantly decreased. An alternative, loop mediated isothermal amplification through one-step strand displacement (LAMP-OSD) assay, was developed to improve diagnostic speed and sensitivity. Synthetic dsDNA genes from the 17 kDa surface antigen precursor (AY281069.1) amplified between fifteen minutes to an hour and were detected to concentrations as low as 102copies/μL. This RMSF LAMP-OSD assay shows promise to deliver results in just a few hours and the detection limit is potentially 100 times more sensitive than qPCR based assays.

PURPOSE Comprehensive genomic profiling to inform targeted therapy selection is a central part of oncology care. However, the volume and complexity of alterations uncovered through genomic profiling make it difficult for oncologists to choose the most appropriate therapy for their patients. Here, we present a solution to this problem, The Molecular Registry of Tumors (MRT) and our Molecular Tumor Board (MTB). PATIENTS AND METHODS MRT is an internally developed system that aggregates and normalizes genomic profiling results from multiple sources. MRT serves as the foundation for our MTB, a team that reviews genomic results for all Duke University Health System cancer patients, provides notifications for targeted therapies, matches patients to biomarker-driven trials, and monitors the molecular landscape of tumors at our institution. RESULTS Among 215 patients reviewed by our MTB over a 6-month period, we identified 176 alterations associated with therapeutic sensitivity, 15 resistance alterations, and 51 alterations with potential germline implications. Of reviewed patients, 17% were subsequently treated with a targeted therapy. For 12 molecular therapies approved during the course of this work, we identified between two and 71 patients who could qualify for treatment based on retrospective MRT data. An analysis of 14 biomarker-driven clinical trials found that MRT successfully identified 42% of patients who ultimately enrolled. Finally, an analysis of 4,130 comprehensive genomic profiles from 3,771 patients revealed that the frequency of clinically significant therapeutic alterations varied from approximately 20% to 70% depending on the tumor type and sequencing test used. CONCLUSION With robust informatics tools, such as MRT, and the right MTB structure, a precision cancer medicine program can be developed, which provides great benefit to providers and patients with cancer.

Approximately 1.6 million people in the United States are struggling with Inflammatory bowel disease. Even though there are a number of diagnostic tools present, including MRI, CT scan, and laboratory tests, the public still lacks access to diagnostic tools due to their expensive costs and needs for the labor of trained phlebotomists. In response, this study focused on modification from blood based enzyme-linked immunoassay (ELISA) to salivary based ELISA in order to expand its accessibility. A 1mL saliva sample was spiked with 1 ± 0.01 μg/mL lyophilized IgG TNFα proteins, and the unspiked saliva was used as a control to test the modified diagnostic. Saliva samples were processed through centrifugation and syringe filtration steps. The change in color between a serum and salivary ELISA kit using either centrifugation or syringe filtration steps was measured by a Color Analysis app that compared red, green and blue values and a microtiter plate reader. The new protocol of salivary-based ELISA lost sensitivity from 31.5pg/mL to 15.6pg/mL of TNFα protein concentration. The best centrifugation method was when a combination of stock saliva and buffer was used before spiking the sample. This means that we can modify the current serum based diagnostic tool to a salivary diagnostic using centrifugation to filter the sample and implement it in developing countries due to its lower cost.

PURPOSE The Oncology Care Model (OCM) is an episode-based alternative payment model for cancer care that seeks to reduce Medicare spending while maintaining care quality. We evaluated the impact of OCM on appropriate use of supportive care medications during cancer treatment. METHODS We evaluated chemotherapy episodes assigned to OCM (n = 201) and comparison practices (n = 534) using Medicare claims (2013-2019). We assessed denosumab use for beneficiaries with bone metastases from breast, lung, or prostate cancer; prophylactic WBC growth factor use for beneficiaries receiving chemotherapy for breast, lung, or colorectal cancer; and prophylactic use of neurokinin-1 (NK1) antagonists and long-acting serotonin antagonists for beneficiaries receiving chemotherapy for any cancer type. Analyses used a difference-in-difference approach. RESULTS After its launch in 2016, OCM led to a relative reduction in the use of denosumab for beneficiaries with bone metastases receiving bone-modifying medications (eg, 5.0 percentage point relative reduction in breast cancer episodes [90% CI, –7.1 to –2.8]). There was no OCM impact on use of prophylactic WBC growth factors during chemotherapy with high or low risk for febrile neutropenia. Among beneficiaries receiving chemotherapy with intermediate febrile neutropenia risk, OCM led to a 7.6 percentage point reduction in the use of prophylactic WBC growth factors during breast cancer episodes (90% CI, –12.6 to –2.7); there was no OCM impact in lung or colorectal cancer episodes. Among beneficiaries receiving chemotherapy with high or moderate emetic risk, OCM led to reductions in the prophylactic use of NK1 antagonists and long-acting serotonin antagonists (eg, 6.0 percentage point reduction in the use of NK1 antagonists during high emetic risk chemotherapy [90% CI, –9.0 to –3.1]). CONCLUSION OCM led to the reduced use of some high-cost supportive care medications, suggesting more value-conscious care.

We report a new determination of the orbits of the irregular Saturnian satellites. We fit their numerically integrated orbits to a data set containing Earth-based observations and imaging data from the Cassini spacecraft. We include the statistics of the observation residuals, the satellites’ orbital elements, and projected accuracies of the satellites’ positions. We also provide astrometric positions derived from the Cassini imaging. Two of the satellites are considered lost because they have not been observed for more than one epoch and have indeterminate uncertainties in their positions. Three of the satellites appear to be in a Kozai resonance, with one being the first irregular satellite of any planet found to be in a 270° rather than 90° resonance.

Purpose To assess the safety and efficacy of an intravitreal fluocinolone acetonide (FA) insert to manage inflammation associated with chronic noninfectious posterior uveitis. Design Multicenter, randomized, prospective, doubled-masked, sham-controlled, 3-year phase 3 clinical trial. Participants One hundred twenty-nine participants with recurrent noninfectious posterior uveitis were assigned randomly to FA insert (n = 87) or sham injection (n = 42). The more severely affected eye in participants with bilateral disease was designated as the study eye. Methods The insert (FA, 0.18 mg) was injected into the vitreous cavity; sham injection mimicked the insert delivery procedure. Ophthalmic examinations, OCT, and ocular tolerability and discomfort assessments were conducted; study visits were on days 7 and 28 and months 2, 3, 6, 9, and 12. Uveitis recurrence was treated as needed. The 6-month recurrence rate was the primary outcome measure. Results The 6-month (28% and 91%) and 12-month (38% and 98%) uveitis recurrence rates were significantly lower (P Conclusions Chronic noninfectious posterior uveitis was managed successfully in this study population; FA insert eyes experienced fewer uveitis recurrence episodes, required fewer adjunctive treatments, and demonstrated less visual acuity loss compared with sham eyes. The FA insert treatment group showed higher rates of cataract; delivery by injection was not associated with an increase in ocular adverse events or any other safety measures not typically associated with local steroid use, suggesting the procedure is appropriate for an office setting.

We present a high-resolution global shape model of Ceres determined using the stereophotoclinometry technique developed at the Jet Propulsion Laboratory by processing Dawn's Framing Camera data acquired during Approach to post-Low Altitude Mapping Orbit (LAMO) phases of the mission. A total of about 38,000 images were processed with pixel resolutions ranging from 35.6 km/pixel to 35 m/pixel and the final global shape model was produced with 100-m grid spacing. The final SPC-derived topography was computed relative to the (482 km, 482 km, 446 km) mean ellipsoid, which ranges from −7.3 km to 9.5 km. For the purpose of validation, we performed various error analyses to assess and quantify realistic uncertainties in the derived topography, such as dividing the data into different subsets and re-computing the entire topography. Based on these studies, we show that the average total height error of the final global topography model is 10.2 m and 88.9% of the surface has the total height error below 20 m. We also provide improved estimates of several physical parameters of Ceres. The resulting GM estimate is (62.62905 ± 0.00035) km3/s2, or the mass value of (938.392 ± 0.005) × 1018 kg. The volume estimate is (434.13 ± 0.50) × 106 km3 with a volumetric mean radius of 469.72 km. Combined with the mass estimate, the resulting bulk density is (2161.6 ± 2.5) kg/m3. Other improved parameters include the pole right ascension, α0 = (291.42763 ± 0.0002)°, pole declination, δ0 = (66.76033 ± 0.0002)°, and prime meridian and rotation rate of (W0 = 170.309 ± 0.011)° and (dW/dt = 952.1532635 ± 0.000002) deg/day, respectively. Also, for geophysical and geological studies, we provide spherical harmonic coefficients and a gravitational slope map derived from the global shape model.

Isothermal nucleic acid amplification tests (iNAT), such as loop-mediated isothermal amplification (LAMP), are good alternatives to polymerase chain reaction (PCR)-based amplification assays, especially for point-of-care and low resource use, in part because they can be carried out with relatively simple instrumentation. However, iNATs can generate spurious amplicons, especially in the absence of target sequences, resulting in false positive results. This is especially true if signals are based on non-sequence-specific probes, such as intercalating dyes or pH changes. In addition, pathogens often prove to be moving, evolving targets, and can accumulate mutations that will lead to inefficient primer binding and thus false negative results. Internally redundant assays targeting different regions of the target sequence can help to reduce such false negatives. Here we describe rapid conversion of three previously described SARS-CoV-2 LAMP assays that relied on non-sequence-specific readout into assays that can be visually read using sequence-specific fluorogenic oligonucleotide strand exchange (OSD) probes. We evaluate one-pot operation of both individual and multiplex LAMP-OSD assays and demonstrate detection of SARS-CoV-2 virions in crude human saliva.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

The Kuiper Belt is a distant region of the Solar System. On 1 January 2019, the New Horizons spacecraft flew close to (486958) 2014 MU69, a Cold Classical Kuiper Belt Object, a class of objects that have never been heated by the Sun and are therefore well preserved since their formation. Here we describe initial results from these encounter observations. MU69 is a bi-lobed contact binary with a flattened shape, discrete geological units, and noticeable albedo heterogeneity. However, there is little surface color and compositional heterogeneity. No evidence for satellites, ring or dust structures, gas coma, or solar wind interactions was detected. By origin MU69 appears consistent with pebble cloud collapse followed by a low velocity merger of its two lobes., 43 pages, 8 figure

The Advanced Pointing Imaging Camera (APIC) is designed to obtain high-resolution imaging data to measure a target’s geophysical and geodetic properties. The development of APIC originates from NASA’s Homesteader program of technology development for candidate New Frontiers missions. The unique science enabled by APIC derives from its ability to simultaneously take images of the target and star field, allowing high-precision camera pointing knowledge with each high-resolution target image. APIC is small (28 ​cm ​× ​18 ​cm ​× ​24 ​cm encompassing volume), light-weight (6 ​kg total), and moderate in power (13 ​W maximum) while being high performance and robust to long missions in deep space. APIC incorporates two imagers, one narrow-angle camera (NAC) and one wide-angle camera (WAC) that can operate simultaneously. Both cameras utilize the CMOS-based Mars 2020 Engineering Camera technology with an option of either clear or Red-Green-Blue colors and have wide apertures to enable short exposures and thus perform at a wide range of targets. The NAC has a pixel resolution of 18 ​μrad and 4° field of view and the WAC has a pixel resolution of 82 ​μrad and 18° field of view. APIC also has two gimbals, allowing rapid camera pointing updates without the need to change the spacecraft attitude; thus, not interfering with other onboard sensors or spacecraft operations. Both gimbals are capable of compensating for relative spacecraft-target motion (i.e., image motion compensation) with an angular speed of up to 30°/s (i.e., 0.5 ​rad/s). Many of APIC components are commercial-off-the-shelf (COTS), or adapted from other NASA flight programs, which makes APIC very competitive in cost and gives it a high technical maturity. APIC’s high-resolution images enable the determination of high-accuracy topography for geologic studies. This paper presents details of APIC’s characteristics and functionalities as well as specific science objectives that APIC data can address, such as measuring a geometric tidal flexing through estimating the tidal Love number, h2 and l2, and small rotational effects, such as libration and precession, of natural satellites and small bodies (i.e., asteroids and comets) that are key to exploring a planetary body’s interior. Improved knowledge of spacecraft orbit via landmark tracking using the APIC data would also improve the recovery of low-degree gravitational parameters such as k2. In this paper, the performance of APIC is presented by showing how well the tidal deformation and libration measurements can be recovered with realistic mission scenarios and configurations.

Due to its eccentric orbit about Jupiter, Europa experiences periodic tidal deformation, which causes changes in its gravitational field and induces both radial and transverse displacements of the surface. The amplitude and phase of these tidal changes are diagnostic of internal structure, and can be measured with sufficient radiometric and optical tracking of a spacecraft during a series of flyby encounters with Europa. This paper presents results of the simulated accuracy for recovery of the tides of Europa through measuring the second-degree tidal Love numbers k 2 , h 2 , and l 2 . A reference trajectory, which consists of a total of 45 close flybys, was considered and a detailed covariance analysis was performed. The study was based on Earth-based Doppler tracking during ± 2 h of each periapsis passage and surface imaging data taken below 500 km altitude. The result shows that the formal uncertainty of the second-degree tidal Love numbers can be estimated to be σ k 2 = 0.01 , σ h 2 = 0.02 , and σ l 2 = 0.01 , which is sufficient to constrain the global ice thickness to about 10 km under reasonable assumptions. Moreover, the forced librations of Europa can be measured to 0.3″ accuracy, which can further constrain Europa's interior structure.

Elevated levels of fecal indicator bacteria (FIB) have been observed at Topanga Beach, CA, USA. To identify the FIB sources, a microbial source tracking study using a dog-, a gull- and two human-associated molecular markers was conducted at 10 sites over 21 months. Historical data suggest that episodic discharge from the lagoon at the mouth of Topanga Creek is the main source of bacteria to the beach. A decline in creek FIB/markers downstream from upper watershed development and a sharp increase in FIB/markers at the lagoon sites suggest sources are local to the lagoon. At the lagoon and beach, human markers are detected sporadically, dog marker peaks in abundance mid-winter, and gull marker is chronically elevated. Varied seasonal patterns of FIB and source markers were identified showing the importance of applying a suite of markers over long-term spatial and temporal sampling to identify a complex combination of sources of contamination.

Human fecal contamination of water is a public health risk. However, inadequate testing solutions frustrate timely, actionable monitoring. Bacterial culture-based methods are simple but typically cannot distinguish fecal host source. PCR assays can identify host sources but require expertise and infrastructure. To bridge this gap we have developed a field-ready nucleic acid diagnostic platform and rapid sample preparation methods that enable on-site identification of human fecal contamination within 80 min of sampling. Our platform relies on loop-mediated isothermal amplification (LAMP) of human-associated Bacteroides HF183 genetic markers from crude samples. Oligonucleotide strand exchange (OSD) probes reduce false positives by sequence specifically transducing LAMP amplicons into visible fluorescence that can be photographed by unmodified smartphones. Our assay can detect as few as 17 copies/ml of human-associated HF183 targets in sewage-contaminated water without cross-reaction with canine or feline feces. It performs robustly with a variety of environmental water sources and with raw sewage. We have also developed lyophilized assays and inexpensive 3D-printed devices to minimize cost and facilitate field application.

The coming decades of planetary science and deep space exploration will likely have a combination of more ambitious missions and ever more constrained budgets. The outer solar system, in particular, poses a challenge for lower mission cost as the principal need for a robotic craft — a source of energy — is difficult to supply through conventional means (solar energy). Even as far from the Sun as Saturn, the solar energy density is only 1% of that at Earth. Not viewed typically as a power source for low-cost missions, radioisotope power systems (RPS) may well fill that role by providing power to small spacecraft in the outer solar system. And the outer solar system beckons with extremely compelling science. The rich dynamics of the atmospheres of the gas giants are continuously operating laboratories of extreme weather processes, examples of which in miniaturized scale may become more familiar here on Earth. Enceladus, a small moon of Saturn, has been seen by the Cassini mission to be a site of continuous high geologic activity, with plumes of water vapor and particles pumped hundreds of kilometers above the surface, indeed into Saturn orbit. The internal heating mechanisms of this activity beg for explanation, and more importantly, initial measurements by the Cassini spacecraft give tantalizing clues that the geo-thermal source of the heating is, in fact, maintaining a global sub-surface ocean, which in combination could provide a habitat for life. This paper will explore how existing and currently available RPS elements may make mission concepts to explore the intriguing science of Enceladus economically tractable, and at the same time provide a generic platform for other small but highly capable spacecraft to explore the outer solar system.

Some molecular methods for tracking fecal pollution in environmental waters have both PCR and quantitative PCR (qPCR) assays available for use. To assist managers in deciding whether to implement newer qPCR techniques in routine monitoring programs, we compared detection limits (LODs) and costs of PCR and qPCR assays with identical targets that are relevant to beach water quality assessment. For human-associated assays targeting Bacteroidales HF183 genetic marker, qPCR LODs were 70 times lower and there was no effect of target matrix (artificial freshwater, environmental creek water, and environmental marine water) on PCR or qPCR LODs. The PCR startup and annual costs were the lowest, while the per reaction cost was 62% lower than the Taqman based qPCR and 180% higher than the SYBR based qPCR. For gull-associated assays, there was no significant difference between PCR and qPCR LODs, target matrix did not effect PCR or qPCR LODs, and PCR startup, annual, and per reaction costs were lower. Upgrading to qPCR involves greater startup and annual costs, but this increase may be justified in the case of the human-associated assays with lower detection limits and reduced cost per sample.

There is no equivalent of GPS in “deep space,” that is beyond the Earth Moon system (and use of GPS beyond LEO and MEO is already problematic.) NASA has been awarded a patent on the concept of the “Deep-space Positioning System” (DPS) which is a self-contained instrument concept that would use in-situ observations to provide an automated and autonomous means of determining its position in the Solar System, and at least as important, its position relative to a target, whether that target is a planet, asteroid, moon or comet. In addition, the DPS system computes trajectory change parameters, as necessary to keep a spacecraft on a planned trajectory. Implementation options include the use of a radio receiver to receive a frequency beacon from a non-in-situ source for additional navigation information over and above that which can be provided by the cameras that are the principal data source of DPS. This paper discusses the DPS instrument concept, and its potential use in deep space.

The Affordable Care Act has created an unprecedented opportunity to enroll criminal justice-involved individuals in Medicaid. Many jurisdictions within Medicaid expansion states are launching efforts to enroll this population in health insurance and provide connections to services in the community. This study examined one early initiative to enroll individuals in Medicaid during the intake process at the Cook County Jail in Illinois. Several elements were identified as critical to the program's success: key early planning decisions made within the context of a cross-agency group, a high level of dedication among partnering organization leaders, program buy-in among security personnel, and the unique way in which Cook County verifies inmate identity for Medicaid enrollment purposes. These features can potentially guide other jurisdictions attempting to implement similar initiatives.

The Altair lunar lander navigation system is driven by a set of requirements that not only specify a need to land within 100 m of a designated spot on the Moon, but also be capable of a safe return to an orbiting Orion capsule in the event of loss of Earth ground support. These requirements lead to the need for a robust and capable on-board navigation system that works in conjunction with an Earth ground navigation system that uses primarily ground-based radiometric tracking. The resulting system relies heavily on combining a multiplicity of data types including navigation state updates from the ground based navigation system, passive optical imaging from a gimbaled camera, a stable inertial measurement unit, and a capable radar altimeter and velocimeter. The focus of this paper is on navigation performance during the trans-lunar cruise, lunar orbit, and descent/landing mission phases with the goal of characterizing knowledge and delivery errors to key mission events, bound the statistical delta V costs for executing the mission, as well as the determine the landing dispersions due to navigation. This study examines the nominal performance that can be obtained using the current best estimate of the vehicle, sensor, and environment models. Performance of the system under a variety sensor outages and parametric trades is also examined.

Objective Growing evidence demonstrates a relationship between excess health risk and preventable productivity loss. There is a need to quantify how much lost productivity is avoidable through employer-sponsored health management interventions. This study introduced the Normal Impairment Factor (NIF) to recognize the amount of productivity loss that cannot be mitigated through health management interventions. Methods A health assessment questionnaire was administered to 772,750 employees, representing 106 employers within five industry sectors. Researchers used multivariate regression procedures to examine the association between preventable health risks and self-reported productivity loss. Results Back pain, mental well being, and stress risk were the strongest predictors of on-the-job productivity loss. A strong association was also detected between the number of health risks and productivity loss ranging from 3.4% for those at lowest risk (the NIF group) to 24.0% loss for those at risk for eight risks. Conclusions This study demonstrated the utility of the NIF in estimating the level of productivity loss that cannot be regained through health management interventions.

Storage technology has enjoyed considerable growth since the first disk drive was introduced. The stability of these interfaces has allowed for continual advances within both the storage devices and applications, without frequent changes to the standards. Ultimately, however, the interface determines the functionality supported by the devices, and current interfaces are now holding system designers back. Storage technology has progressed to the point that a change in the device interface is needed. Object-based storage is designed to address this problem. A storage object is a logical collection of bytes on a storage device, with well-known methods for access, attributes describing characteristics of the data, and security policies that prevent unauthorized access. We refer to a device that stores objects as an object-based storage device (OSD). The benefits of object-based storage are cross-platform data sharing and application level security.

The automation of biological laboratory assays may require lengthy incubations of reagents on the work surface of a pipetting robot. Commercial devices are readily available for keeping these reagents accessible and warm, but there are few existing technologies for storing accessible reagents below the freezing point of water. Here, we introduce a low cost, small footprint, robot accessible reagent cooler, based on compressor technology capable of acting as an enzyme freezer or extreme cold reagent storage device.

Objective: We sought to gather employer perspectives about value-focused activities (VFAs), intentions to make decisions based on value, and other factors affecting decisions. Methods: Health decision-makers (n = 174), both American College of Occupational and Environmental Medicine members and corporate HR/benefits directors, responded to an Internet-based questionnaire. Results: Of a total of 32 listed VFAs, companies reported, on average, performing 5.2 activities currently and considering 2.6. Twenty-five percent of companies reported doing eight or more. The most common VFAs were providing access to flu shots, centers of excellence, and wellness programs. Greater access to detailed outcome data was associated with doing more VFAs, as was greater accountability for absence, disability, and productivity outcomes. Conclusions: Employers vary widely in the number of VFAs in which they participate. Decision-makers with more information about, and accountability for, value outcomes reported doing more VFAs.

Background: The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas. Patients and methods: Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n = 282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n = 74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors. Results: NAC was associated with improved disease-specific survival for this cohort of patients (P = 0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53 ‐ 0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72 ‐ 0.95) for patients receiving NAC. Conclusion: NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients

The potential for non-reciprocal Robertsonian translocations of wheat (Triticum aestivum L.) to assist in the stacking of genes was assessed from a study of their cytological and genetic behaviour. To obtain translocations, a double monosomic (3B+5A; 2n=40=19ii+2i) was crossed reciprocally with a contrasting disomic. Individuals inheriting a broken monosome were identified from the loss of one arm-specific DNA marker coupled with retention of a marker for the opposite arm. No double breaks (potential translocations) were found in 180 cross progeny recovered from pollen of the double monosomic but two instances (loss of 5AL plus 3BS; loss of 5AL plus 3BL) were found in 251 progeny recovered from ovules. Meiotic pairing and multi-color genome-specific fluorescence in situ hybridization (mcGISH) showed that each plant with a double break contained one translocated chromosome between the A and B genomes that had rejoined at the centromere and that formed a trivalent (19ii + 1iii) in about 83% of PMC. Most trivalents (approximately 92%) aligned at metaphase in a ‘V’ configuration (alternate disjunction) while the rest aligned in linear ‘I’ (adjacent disjunction) or ambiguous ‘L’ configurations. Genetic analysis of a testcross of these ‘fusion monosomics’ showed that this preferential co-orientation of the trivalent influenced the assortment of the chromosome arms involved. Loci that were located in the hemizygous ends of the ‘V’ trivalent showed strong quasi-linkage in that most ovules from the female testcross carried relevant DNA markers either from both standard chromosomes or from neither. This shows that, in most cases, the two standard chromosomes assorted to the same pole while the fused monosome segregated to the opposite pole. For heterozygous loci (present both on the fusion monosome and the standard chromosomes) assortment was either independent or showed partial linkage to the hemizygous arm depending on the reported recombination distance from centromere. Marker assortment was further distorted in male testcrosses and in doubled haploids (made from the fusion monosomics by the maize method) by the strong selective advantage of pollen or haploids that inherited the standard chromosomes rather than the deficiencies. This genetic data shows that under the combined influence of alternate disjunction and natural selection, progeny of fusion monosomics will revert to the standard disomic arrangement, fixing the gene content of both hemizygous arms in the process. Thus, any pair of genes could be targeted for joint fixation by isolating the fusion monosome that will link them temporarily in a segregating population.

While the in vitro selection of nucleic acid binding species (aptamers) requires numerous liquid-handling steps, these steps are relatively straightforward and the overall process is therefore amenable to automation. Here we demonstrate that automated selection techniques are capable of generating aptamers against a number of diverse protein targets. Automated selection techniques can be integrated with automated analytical methods, including sequencing, determination of binding constants, and structural analysis. The methods that have so far been developed can be further multiplexed, and it should soon be possible to attempt the selection of aptamers against organismal proteomes or metabolomes.

Recombinant human bone morphogenetic protein-2 is an osteoinductive protein that plays a pivotal role in bone growth and regeneration. Several hundred studies were conducted in the past 7 years in numerous animal models to establish unequivocally the efficacy, safety, mechanism of action, pharmacokinetics, and surgical handling properties of recombinant human bone morphogenetic protein-2, building a solid foundation for clinical development programs. Pilot clinical trials have shown the feasibility and safety of recombinant human bone morphogenetic protein-2 treatment, and defined the effective dose for its use in open long bone fractures and for augmentation or preservation of the alveolar bone in the dental ridge. Prospective observational clinical studies helped define clinical efficacy end points, identify significant variables, and estimate appropriate population sample size for pivotal clinical trials. Pivotal clinical trials of recombinant human bone morphogenetic protein-2 are underway in patients with open tibial shaft fractures and in patients with a deficiency of the alveolar ridge.

The design of a bone morphogenetic protein (BMP) clinical study directly depends on the relationship of the proposed BMP treatment to the standard of care. One must consider whether the intended use of BMP will (a) replace or (b) augment the existing surgical standard of care. In (a), meaningful clinical studies can be designed to test whether the proposed BMP treatment is equivalent or superior to the standard of care. For example, recombinant human (rh) BMP-2 is being tested as a complete replacement for the use of autograft in several spine fusion procedures. These clinical studies compare the outcomes of patients who have been randomized to receive rhBMP-2 or autograft. All patients receive the same spine instrumentation. The control group (autograft) was chosen because it represents the current standard of care. The most conservative design for studies of this sort is one that will definitively establish the statistical equivalence of the two treatments. The size of each group should be sufficiently large to allow a conclusion that the outcome of the two treatments differs by no more than a small amount (e.g., ±10%) and should limit the probability of a type II error (not detecting a difference that actually exists) to less than 20%. In (b), the only meaningful design for a clinical study is one that tests whether the proposed BMP treatment …