Apollo Next Generation Sample Analysis (ANGSA): an Apollo Participating Scientist Program to Prepare the Lunar Sample Community for Artemis.

As a first step in preparing for the return of samples from the Moon by the Artemis Program, NASA initiated the Apollo Next Generation Sample Analysis Program (ANGSA). ANGSA was designed to function as a low-cost sample return mission and involved the curation and analysis of samples previously returned by the Apollo 17 mission that remained unopened or stored under unique conditions for 50 years. These samples include the lower portion of a double drive tube previously sealed on the lunar surface, the upper portion of that drive tube that had remained unopened, and a variety of Apollo 17 samples that had remained stored at -27 °C for approximately 50 years. ANGSA constitutes the first preliminary examination phase of a lunar "sample return mission" in over 50 years. It also mimics that same phase of an Artemis surface exploration mission, its design included placing samples within the context of local and regional geology through new orbital observations collected since Apollo and additional new "boots-on-the-ground" observations, data synthesis, and interpretations provided by Apollo 17 astronaut Harrison Schmitt. ANGSA used new curation techniques to prepare, document, and allocate these new lunar samples, developed new tools to open and extract gases from their containers, and applied new analytical instrumentation previously unavailable during the Apollo Program to reveal new information about these samples. Most of the 90 scientists, engineers, and curators involved in this mission were not alive during the Apollo Program, and it had been 30 years since the last Apollo core sample was processed in the Apollo curation facility at NASA JSC. There are many firsts associated with ANGSA that have direct relevance to Artemis. ANGSA is the first to open a core sample previously sealed on the surface of the Moon, the first to extract and analyze lunar gases collected in situ, the first to examine a core that penetrated a lunar landslide deposit, and the first to process pristine Apollo samples in a glovebox at -20 °C. All the ANGSA activities have helped to prepare the Artemis generation for what is to come. The timing of this program, the composition of the team, and the preservation of unopened Apollo samples facilitated this generational handoff from Apollo to Artemis that sets up Artemis and the lunar sample science community for additional successes.

Mechanobiology of bone healing and regeneration: in vivo models.

Mechanical boundary conditions are well known to influence the regeneration of bone and mechanobiology is the study of how mechanical or physical stimuli regulate biological processes. In vivo models have been applied over many years to investigate the effects of mechanics on bone healing. Early models have focused on the influence of mechanical stability on healing outcome, with an interest in parameters such as the magnitude of interfragmentary movement, the rate and timing of application of micromotion and the number of loading cycles. As measurement techniques have been refined, there has been a shift in orders of magnitude from investigations targeted at the organ level to those targeted at the tissue level and beyond. An understanding of how mechanics influences tissue differentiation during repair and regeneration crucially requires spatial and temporal knowledge of both the local mechanical environment in the healing tissue and a characterization of the tissues formed over the course of regeneration. Owing to limitations in the techniques available to measure the local mechanical conditions during repair directly, simulation approaches, such as the finite element method, are an integral part of the mechanobiologist's toolkit, while histology remains the gold standard in the characterization of the tissue formed. However, with rapid advances occurring in imaging modalities and methods to characterize tissue properties, new opportunities exist to better understand the role of mechanics in the biology of bone regeneration. Combined with developments in molecular biology, mechanobiology has the potential to offer exciting, new regenerative treatments for bone healing.

In vitro models for bone mechanobiology: applications in bone regeneration and tissue engineering.

Healthy bone healing is a remarkable, mechanically sensitive, scar-free process that leads rapidly to repair tissue of high mechanical quality and functionality, and knowledge of this process is essential for driving advances in bone tissue engineering and regeneration. Gaining this knowledge requires the use of models to probe and understand the detailed mechanisms of healing, and the tight coupling of biology and mechanics make it essential that both of these aspects are controlled and analysed together, using a mechanobiological approach. This article reviews the literature on in vitro models used for this purpose, beginning with two-dimensional (2D) cell culture models used for applying controlled mechanical stimuli to relevant cells, and detailing the analysis techniques required for understanding both substrate strain and fluid flow stimuli in sufficient detail to relate them to biological response. The additional complexity of three-dimensional (3D) models, enabling more faithful representation of the healing situation, can require correspondingly more sophisticated tools for mechanical and biological analysis, but has recently uncovered exciting evidence for the mechanical sensitivity of angiogenesis, essential for successful healing. Studies using explanted tissue continue to be vital in informing these approaches, providing additional evidence for the relevance of effects in biological and mechanical environments close to those in the living organism. Mechanobiology is essential for the proper analysis of models for bone regeneration, and has an exciting integrative role to play not only in advancing knowledge in this area, but also in ensuring successful translation of new tissue engineering and regenerative therapies to the clinic.

Immunopathogenesis of ovarian cancer.

Immune cells in the ovarian stromal microenvironment play an important role in ovarian tumorigenesis. Up-regulation of immune cell-derived mediators during ovulation may generate a proinflammatory niche, which may subsequently induce transformation of normal ovarian epithelial cells or endometriotic cells in the ovary. Once transformed ovarian epithelial cells develop, an immunoediting process occurs in which immune cells and their mediators dictate the development and progression of ovarian tumors. Tumor cells also develop several mechanisms to evade anti-tumor immunity by developing an immunosuppressive microenvironment. The differences in the population of immune cells infiltrating into ovarian tumor tissues are associated with differences in clinical outcomes. The underlying molecular mechanisms of the association begin to unravel with the development of microdissection techniques, high throughput technologies, in vitro functional assays, and in vivo mouse modeling. A better understanding of the complex relationship between ovarian tumor cells and the associated immune cells will allow us to develop novel immunologic strategies for ovarian cancer prevention and treatment.

Heterobifunctional poly(ethylene oxide) oligomers containing carboxylic acids.

Syntheses of vinylsilyl alcohols having one to three vinyl moieties and their use as initiators for ethylene oxide polymerizations are discussed. Poly(ethylene oxide) oligomers with vinylsilanes at one end and a hydroxyl group at the other were prepared in base-catalyzed reactions. Molecular weights determined from 1H NMR and gel permeation chromatography were close to the targeted values. Carboxylic acid functional poly(ethylene oxide) oligomers were prepared from ene-thiol addition reactions of mercaptoacetic acid across the vinylsilane terminus. It is anticipated that these carboxylic acid functional oligomers will complex to magnetite nanoparticles to afford complexes that can be dispersed in aqueous media.

Digital image correlation: a technique for determining local mechanical conditions within early bone callus.

Local mechanical conditions are known to play a role during the regeneration of musculoskeletal tissues, and histomorphometrical investigations of the time course of healing have enabled specific conclusions regarding the mechanosensitivity of tissue differentiation. However, the mechanism for this influence is not clearly understood. In order to extend this analysis, it is essential to link local histological understanding with direct characterisation of the local mechanical environment. Digital image correlation (DIC) is a computer-based image analysis technique that enables the non-contact measurement of strains on material surfaces and is finding application in many areas of biomechanics. Here we report a DIC technique to investigate the local distribution of mechanical strain within regenerating soft tissue sections. We provide exemplary data from analysis of a section of sheep bone callus. An assessment of displacement measurement accuracy gave an RMS error of 4.2 microm, corresponding to an estimated strain error of 1.4%. The sections showed concentrations of up to four times the applied strain and comparison of the strain patterns with histological analysis confirmed that these concentrations reflected boundaries between hard and soft callus.

Bilateral correction of metatarsal rotation in a dog using circular external skeletal fixation.

An 8-month-old castrated male Saint Bernard was evaluated for bilateral hind limb lameness. Lameness was ascribed to bilateral metatarsal rotational abnormalities on the basis of the physical examination and radiographic evaluations. Staged, bilateral deformity correction and tarsometatarsal arthrodeses were performed using circular external skeletal fixators. The dog's gait improved following surgery and the fixators were removed 3 (left hind paw) and 4 (right hind paw) months following surgery. Twenty months after the initial surgery, the owner reported that the dog was walking well without apparent lameness. Previous reports suggest that metatarsal rotation is untreatable; however, our results suggest that surgical correction of this deformity can substantially improve limb function in dogs affected with metatarsal rotation.

Pericardial lipoma in a geriatric dog with an incidentally discovered thoracic mass.

An intrathoracic mass was discovered as an incidental finding in a 14-year-old, spayed, female Rottweiler cross during evaluation of urinary incontinence. Computed tomography suggested a pericardial or pleural location and high adipose content of the mass. The mass was removed via lateral thoracotomy with partial pericardectomy and was diagnosed as a pericardial lipoma. The dog recovered well, and there was no evidence of recurrence approximately one year later. Adipose tumours of the heart and its associated structures are rare in dogs and have been associated with both successful and fatal outcomes.

Efficacy of Low-dose (2 millicurie) versus Standard-dose (4 millicurie) Radioiodine Treatment for Cats with Mild-to-Moderate Hyperthyroidism.

BACKGROUND: Radioiodine (131 I) is effective treatment for hyperthyroidism in cats, but optimal dose to restore euthyroidism without inducing hypothyroidism is unclear. Treatment-induced hypothyroidism can lead to azotemia and reduced duration of survival. OBJECTIVE: To compare efficacy and short-term outcomes of low-dose 131 I versus higher, standard-dose 131 I as treatment for hyperthyroidism. ANIMALS: A total of 189 client-owned cats undergoing 131 I treatment for mild-to-moderate hyperthyroidism (serum T4 ≥ 4.0 µg/dL and <13.0 µg/dL). METHODS: Prospective, nonrandomized, cohort study comparing treatment with either low-dose (2 mCi, n = 150) or standard-dose (4 mCi, n = 39) 131 I. Serum T4 , thyroid-stimulating hormone (TSH), and creatinine concentrations were measured after 1, 3, and 6 months to determine persistent hyperthyroidism, overt hypothyroidism (low T4 , high TSH), subclinical hypothyroidism (normal T4 , high TSH), and azotemia. RESULTS: There was no significant difference in prevalence of cats with persistent hyperthyroidism between standard- and low-dose treatment groups at 3 (0% versus 5.3%; P = .34) and 6 (0% versus 3.3%; P = .51) months. Overt (18% versus 1%; P = .0005) or subclinical (46% versus 21%; P = .004) hypothyroidism was more common in cats at 6 months after standard-dose 131 I. No difference in incidence of azotemia existed between groups, but cats treated with standard-dose 131 I had higher creatinine concentrations (P < .05) and higher percent rises in creatinine (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Low-dose 131 I is safe and effective for cats with mild-to-moderate hyperthyroidism, as evidenced by a cure rate of >95% with reduced frequency of iatrogenic hypothyroidism and azotemia.

Angle stable locking reduces interfragmentary movements and promotes healing after unreamed nailing. Study of a displaced osteotomy model in sheep tibiae.

BACKGROUND: Large interfragmentary movements may delay bone-healing. The hypothesis of the present study was that a reduction of interfragmentary movements, especially of torsional rotation and bending angles, would support the healing process and lead to improved healing following unreamed tibial nailing. The objective of this study was to investigate healing of an unstable tibial osteotomy site following stabilization with unreamed nailing with a modified tibial device that had angle stable holes for the locking bolts. We compared those findings with healing after stabilization of such sites with standard unreamed tibial nailing. The duration of the study period was nine weeks. METHODS: The site of a standardized displaced osteotomy (3-mm gap) in twelve ovine tibiae was stabilized with unreamed tibial nailing: six animals were treated with a modified nail that had angle stable holes for the locking bolts, and six were treated with standard unreamed tibial nailing. In vivo gait analysis with optical measurements of interfragmentary movements and simultaneous measurements of ground reaction parameters were performed three days after the operation and once weekly afterward. After the animals were killed at nine weeks, the treated and contralateral tibiae were explanted, the implants were removed, and radiographs were made and evaluated for bridged cortices. Each pair of tibiae was also mechanically tested until torsional failure, after which the whole callus region was subjected to histological and histomorphometric analysis. RESULTS: Throughout the examination period, the interfragmentary movements in all directions were significantly smaller in the group treated with the angle stable tibial nail than they were in the group treated with standard unreamed tibial nailing. The limbs treated with the angle stable tibial nails returned to almost full weight-bearing during the period of the investigation, whereas those treated with standard nailing did not. Histomorphometric analysis, radiographic data, and mechanical testing showed superior bone-healing following treatment with the angle stable tibial nail. CONCLUSIONS: Use of an angle stable tibial nail may help to reduce interfragmentary movements in vivo and thus lead to superior bone-healing compared with that following standard unreamed tibial nailing.

Gait evaluation: a tool to monitor bone healing?

BACKGROUND: Current clinical methods for monitoring fracture healing are often invasive and inaccurate. This paper evaluates the use of a pressure sensitive platform to improve monitoring. METHODS: Standardised 3 mm diaphyseal bone defects were created in the right tibia of 64 female sheep and stabilised with either a rigid monolateral external fixator or a more flexible variant. Over a nine week healing period gait parameters were measured using a pressure sensitive platform and interfragmentary movements at the fracture site were monitored. Frequency spectra were calculated for the ground reaction forces. The tibiae were tested biomechanically after sacrifice and callus sections were analysed histomorphometrically. FINDINGS: All animals unloaded the operated and overloaded the contralateral hindlimb. Callus mineralisation and stiffness, as well as limb loading increased during healing whilst interfragmentary movements were reduced. Larger interfragmentary movements resulted in a slower fracture healing rate as documented histologically and biomechanically. Frequency analysis showed upto 14 dB loss of power at frequencies associated with bone mechanotransduction at four weeks postoperatively, reducing to a 3 dB loss at nine weeks. INTERPRETATION: Gait analysis is a valuable tool for monitoring the course of fracture healing. Different fixation stiffnesses caused different initial interfragmentary movements leading to different healing rates. Ground reaction forces were strongly related to the course of callus mineralisation and thus directly reflected the recovery of stiffness at the fracture site. Reduced levels of loading frequencies that may affect bone healing persist to nine weeks postoperatively.

Three-dimensional conformal radiation therapy alone or in combination with surgery for treatment of canine intracranial meningiomas.

Treatment protocols, treatment planning methods and tumour types in studies evaluating radiotherapy for canine brain tumours have been varied. This case series retrospectively evaluated the outcome of definitive, three-dimensional conformal radiation therapy (3D-CRT) as either a sole modality or as an adjuvant to surgery in 31 dogs diagnosed with meningioma by histopathology (n = 10) or cross-sectional imaging of the head (n = 21, assessed independently by two board certified radiologists). Prescribed dose ranged from 45 to 54 Gy in 2.5 to 3 Gy fractions. Median overall survival was 577 days (interquartile range = 272-829 days; range = 30-1942 days) when all deaths were considered and 906 days (interquartile range = 336-912 days; range = 10 -1942 days) when only dogs dying due to meningioma were considered. No significant difference in survival time was detected for the defined clinical or imaging findings or between treatment with radiotherapy alone versus adjuvant radiotherapy, suggesting that 3D-CRT may be a viable alternative to surgery.

Adverse reactions in horses that underwent general anesthesia and cervical myelography.

BACKGROUND: The study was prompted by a perceived high prevalence of myelographic complications varying in severity and type, and attributed to the contrast material or the procedure. HYPOTHESES: 1. Any adverse reaction (AAR) is associated with a change in CSF volume induced either by removal of CSF or addition of contrast material. 2. AAR occurs more frequently in horses with higher premyelography neurologic grade. 3. Nonspecific hyperthermia is attenuated by anti-inflammatory and osmotic agents. ANIMALS: Horses (n = 278) that underwent myelography between 2000 and 2012 at 5 institutions: A (87), B (68), C (65), D (46), and E (12). METHODS: Multi-institutional, retrospective, observational cross-sectional study. RESULTS: AAR were observed in 95/278 (34%) horses, were associated with longer general anesthesia time (P = .04) and higher contrast-medium volume (P = .04); euthanasia because of AAR was performed in 5/278 (2%) horses. Adverse neurologic reactions were the most common type of complication observed occurring in 15/278 (5%) and 42/235 (18%) of horses in the intra- and postmyelography periods. A relationship between AAR and premyelography neurologic grade was not identified (P = .31). Nonspecific hyperthermia was observed in 25/235 (11%) horses; no relationship was observed with administration of anti-inflammatory drugs and osmotic agents (P = .30). CONCLUSIONS AND CLINICAL IMPORTANCE: The category of AAR occurred in one-third of the horses generally was mild and self-limiting. These reactions were associated with increased contrast-medium volume and longer anesthesia time; but, no specific procedural recommendations could be made because of small odds ratios (OR) of <2 for each 1 mL increase in contrast material and for each 1 minute of additional anesthesia time.

A method for evaluating performance of ambulatory pediatric tasks.

Four evaluations of ambulatory pediatric tasks were used for quality assurance in eight pediatric group practices situated in two teaching hospitals and six related health centers. The evaluations used criteria incorporating branching logic to judge the quality of care revealed in data abstracted from medical records. Performance was evaluated for follow-up of positive urine cultures, assessment and follow-up of otitis media, initial assessment for gastroenteritis, and "well child" care for infants. A computerized data system was developed to process evaluation data and produce easily read reports. This work is part of a controlled trial of the feasibility, cost, and effectiveness of quality assurance as a means to improve patient care, but this preliminary report concerns only the principles for design of the evaluations and their use in quality assurance. Acceptance of evaluations by site providers was high: of 203 provider responses to a survey, only four reported disagreement with the criteria. Rates of cases "variant" from criteria and found on peer review to represent deficiencies in care, when averaged across sites, ranged by task from 1% to 47% of cases evaluated. In most sites, providers planned and implemented actions to correct these deficiencies. It is noted that improvements in care may increase costs of care.

Decision-analytic determination of study size. The case of electronic fetal monitoring.

There is uncertainty about the efficacy of electronic fetal monitoring (EFM) in lowering perinatal mortality among births at low prospective risk. A randomized controlled trial offers the greatest promise of reducing this uncertainty. Haphazard methods of evaluating decision making have prevailed in the past and have led to study sizes too small to estimate effects on perinatal mortality. Statistical methods can determine the study size necessary to meet statistical parameters. Choice of these parameters is, however, somewhat arbitrary. Decision-analytic methods calculate the expected value of information (EVI) as the likely worth of future decision guidance. The optimal size, cost, and focus for an evaluation study can then be taken as those maximizing the net EVI after consideration of study cost. This methodology indicates that, in evaluating EFM, two randomly-assigned groups of roughly 180,000 births each should be studied. This would achieve net expected societal benefits estimated at $118 million at a cost of roughly $22 million. The optimal study size is somewhat sensitive to analytic parameters. If feasible, a superior dynamic strategy is to allow study findings to determine the ultimate study size.

Health versus money. Value judgments in the perspective of decision analysis.

An important, but largely uninvestigated, value trade-off balances marginal nonhealth consumption against marginal medical care. Benefit-cost analysts have traditionally, if not fully satisfactorily, dealt with this issue by valuing health gains by their effects on productivity. Cost-effectiveness analysts compare monetary and health effects and leave their relative valuations to decision makers. A decision-analytic model using the satisfaction or utility gained from nonhealth consumption and the level of health enables one to calculate willingness to pay--a theoretically superior way of assigning monetary values to effects for benefit-cost analysis-and to determine minimally acceptable cost-effectiveness ratios. Examples show how a decision-analytic model of utility can differentiate medical actions so essential that failure to take them would be considered negligent from actions so expensive as to be unjustifiable, and can help to determine optimal legal arrangements for compensation for medical malpractice.

Electronic fetal monitoring and clinical practice. A survey of obstetric opinion.

Interviews with 12 obstetricians recognized for their scientific and clinical contributions in the use of electronic fetal monitoring (EFM) revealed notable areas of agreement and disagreement in the interpretation and use of these methods. In reviewing 14 abnormal fetal heart rate (FHR) patterns, the obstetricians displayed an average pairwise agreement of 68% in classifying the patterns as "innocuous," "nonreassuring," or "ominous." When these patterns persisted after corrective treatment, average pairwise agreement was 69% in deciding between continued monitoring and immediate delivery. With the additional option of scalp blood pH sampling, average agreement was 59%. For the set of FHR patterns studied, scalp blood pH sampling was recommended more often to confirm conservative management of labor than to verify the need to intervene. The obstetricians may be classified by their degrees of (1) alarm and (2) interventionism, and by their (3) frequency of and (4) motivation for scalp sampling. Associations among these four dimensions of behavior were limited.

Feasibility of willingness-to-pay measurement in chronic arthritis.

Quantification of nonmonetary aspects of disease is a major challenge for economic analysts. Using the amounts of money recipients are willing to pay for nonmonetary benefits has theoretical appeal, but it has proven difficult to implement. Difficulties encountered include noncomprehension by subjects, misrepresentation of preferences, extraneous determinants of answers, and ethical concerns. In a preliminary exploration of feasibility, 184 patients with osteoarthritis and rheumatoid arthritis were asked their willingness to pay (WTP) for hypothetical complete cure. With minimal pressure put on the patients to respond, 27 percent gave plausible answers. People with more schooling, with paid employment, or who were having more treatments for their arthritis were more likely to respond. Patients were willing on average to pay 17 percent of family income for arthritis cure. Methods for measuring WTP are being strengthened and may soon play an important role in health services research.

Cost-effectiveness of screening for hypo- and hyperthyroidism in India.

The development of relatively inexpensive radioimmunoassay techniques opens new possibilities for widespread screening for hypo- and hyperthyroidism in developing regions where iodine deficiency is great. From component cost analysis, it appears that radioimmunoassays of thyroid hormones can be performed in India for as little as 2.4 rupees (29 cents) per test. Cost-effectiveness analysis indicates that screening for hypothyroidism in iodine-deficient areas in India is, of alternative detection strategies, the most cost-effective: Cases are found at an average cost of 40 rupees ($4.80) per case. Cost breakdowns and considerations of convenience and acceptability indicate that filter paper methods may soon be preferred to whole-blood assays, especially for screening. Cost-effectiveness findings for these screening strategies and for reasonable modifications of them should be compared with the estimated cost-effectiveness of iodine supplementation in determining optimal health policy toward subclinical thyroid disease.

Acetabular morphology and resurfacing design.

The bony surfaces of 18 archaeological hemipelves were scanned using a 3D laser surface scanner and CyDir software on a Silicon Graphics workstation. The acetabular area was selected and point data from the approximately spherical bone surface saved. These data were input to a MATLAB routine that calculated the radius and centre of the best-fit sphere. The goodness of fit was estimated using the mean and standard deviation of the distance of the bone surface points from the sphere surface. Eight points, at approximately equal distances around the acetabular rim, were selected with reference to bony landmarks. A plane containing three of these points served as an orientation reference plane. The vectors joining the eight rim points to the centre of the best-fit sphere were found. The angles between these vectors and the normal to the reference plane were calculated. Paired angles were summed to give the angle subtended by the acetabular rim in four directions. The overall mean angle was 158 degrees (range of mean angles 145 degrees -173 degrees ). The largest individual angles, some exceeding 180 degrees, were in the superior-inferior direction, while the mean angle in the anterior-posterior direction, i.e. that controlling flexion-extension, was 152 degrees. Males had larger subtended angles than females, although the difference was not statistically significant. Simulated reaming increased all angles by approximately 10 degrees. The subtended angles are important parameters in the design of the acetabular component of a hip replacement and particularly important in resurfacing hip replacement when the volume available is tightly constrained.