Effectiveness of telemedicine diabetic retinopathy screening in the USA: a protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic retinopathy (DR) is the leading cause of vision loss among adults in the USA. Vision loss associated with diabetic retinopathy can be prevented with timely ophthalmologic care, and therefore, it is recommended that individuals with diabetes have annual retinal examinations. There is limited evidence on whether using telemedicine to screen for DR in primary care clinics in the USA effectively leads to increased DR screening rates. The objective of this systematic review is to collate evidence from existing studies to investigate the effectiveness of telemedicine DR screening (TDRS) in primary care clinics on DR screening rates. METHODS: Relevant studies will be identified through searching MEDLINE/PubMed interface, Scopus, and Web of Science from their inception until November 2021, as well as searching reference lists of included studies and previous related review articles or systematic reviews. There will be no restrictions on study design. Eligible studies will include subjects with either type 1 or type 2 diabetes, will evaluate telemedicine technology for screening of DR, will have been conducted in the USA, and will report DR screening rates or data necessary for calculating such rates. Two reviewers will screen search results independently. Risk-of-bias assessment and data extraction will be carried out by two reviewers. The version 2 of the Cochrane risk-of-bias tool (RoB 2) and the Newcastle-Ottawa scale (NOS) tool will be used to assess the quality and validity of individual studies. If feasible, we will conduct random-effects meta-analysis where appropriate. If possible, we will conduct subgroup analyses to explore potential heterogeneity sources (setting, socio-economic status, age, ethnicity, study design, outcomes). We will disseminate the findings through publications and relevant networks. DISCUSSION: This protocol outlines the methods for systematic review and synthesis of evidence of TDRS and its effect on DR screening rates. The results will be of interest to policy makers and program managers tasked with designing and implementing evidence-based services to prevent and manage diabetes and its complications in similar settings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021231067.

Gas diffusion through variably-water-saturated zeolitic tuff: Implications for transport following a subsurface nuclear event.

Noble gas transport through geologic media has important applications in the characterization of underground nuclear explosions (UNEs). Without accurate transport models, it is nearly impossible to distinguish between xenon signatures originating from civilian nuclear facilities and UNEs. Understanding xenon transport time through the earth is a key parameter for interpreting measured xenon isotopic ratios. One of the most challenging aspects of modeling gas transport time is accounting for the effect of variable water saturation of geological media. In this study, we utilize bench-scale laboratory experiments to characterize the diffusion of krypton, xenon, and sulfur hexafluoride (SF6) through intact zeolitic tuff under different saturations. We demonstrate that the water in rock cores with low partial saturation dramatically affects xenon transport time compared to that of krypton and SF6 by blocking sites in zeolitic tuff that preferentially adsorb xenon. This leads to breakthrough trends that are strongly influenced by the degree of the rock saturation. Xenon is especially susceptible to this phenomenon, a finding that is crucial to incorporate in subsurface gas transport models used for nuclear event identification. We also find that the breakthrough of SF6 diverges significantly from that of noble gases within our system. When developing field scale models, it is important to understand how the behavior of xenon deviates from chemical tracers used in the field, such as SF6 (Carrigan et al., 1996). These new insights demonstrate the critical need to consider the interplay between rock saturation and fission product sorption during transport modeling, and the importance of evaluating specific interactions between geomedia and gases of interest, which may differ from geomedia interactions with chemical tracers.

Ranked determinants of telemedicine diabetic retinopathy screening performance in the United States primary care safety-net setting: an exploratory CART analysis.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of blindness worldwide, despite easy detection and effective treatment. Annual screening rates in the USA remain low, especially for the disadvantaged, which telemedicine-based DR screening (TDRS) during routine primary care has been shown to improve. Screening rates from such programs have varied, however, pointing to inconsistent implementation and unaddressed barriers. This work seeks to identify and prioritize modifiable barriers for targeted intervention. METHODS: In this final phase of an exploratory mixed-methods study, we developed, validated, and administered a 62-item survey to multilevel stakeholders involved with TDRS in primary care safety-net clinics. Survey items were aligned with previously identified determinants of clinic-level screening and mapped to the Consolidated Framework for Implementation Research (CFIR). Classification and Regression Tree (CART) analyses were used to identify and rank independent variables predictive of individual-level TDRS screening performance. RESULTS: Overall, 133 of the 341 invited professionals responded (39%), representing 20 safety-net clinics across 6 clinical systems. Respondents were predominately non-Hispanic White (77%), female (94%), and between 31 and 65 years of age (79%). Satisfaction with TDRS was high despite low self-reported screening rates. The most important screening determinants were: provider reinforcement of TDRS importance; explicit instructions by providers to staff; effective reminders; standing orders; high relative priority among routine diabetic measures; established TDRS workflows; performance feedback; effective TDRS champions; and leadership support. CONCLUSIONS: In this survey of stakeholders involved with TDRS in safety-net clinics, screening was low despite high satisfaction with the intervention. The best predictors of screening performance mapped to the CFIR constructs Leadership Engagement, Compatibility, Goals & Feedback, Relative Priority, Champions, and Available Resources. These findings facilitate the prioritization of implementation strategies targeting determinants of TDRS performance, potentially increasing its public health impact.

Evaluation of multi-level barriers and facilitators in a large diabetic retinopathy screening program in federally qualified health centers: a qualitative study.

BACKGROUND: Recommended annual diabetic retinopathy (DR) screening for people with diabetes has low rates in the USA, especially in underserved populations. Telemedicine DR screening (TDRS) in primary care clinics could expand access and increase adherence. Despite this potential, studies have observed high variability in TDRS rates among clinics and over time, highlighting the need for implementation supports. Previous studies of determinants of TDRS focus on patients' perspectives, with few studies targeting upstream multi-level barriers and facilitators. Addressing this gap, this qualitative study aimed to identify and evaluate multi-level perceived determinants of TDRS in Federally Qualified Health Centers (FQHCs), to inform the development of targeted implementation strategies. METHODS: We developed a theory-based semi-structured interview tool based on the Consolidated Framework for Implementation Research (CFIR). We conducted 22 key informant interviews with professionals involved in TDRS (administrators, clinicians, staff). The interviews were audio-recorded and transcribed verbatim. Reported barriers and facilitators were organized into emergent themes and classified according to CFIR constructs. Constructs influencing TDRS implementation were rated for each study site and compared across sites by the investigators. RESULTS: Professionals identified 21 main barriers and facilitators under twelve constructs of the five CFIR domains. Several identified themes were novel, whereas others corroborated previous findings in the literature (e.g., lack of time and human resources, presence of a champion). Of the 21 identified themes, 13 were classified under the CFIR's Inner Setting domain, specifically under the constructs Compatibility and Available Resources. Themes under the Outer Setting domain (constructs External Incentives and Cost) were primarily perceived by administrators, whereas themes in other domains were perceived across all professional categories. Two Inner Setting (Leadership Engagement, Goals and Feedback) and two Process (Champion, Engaging) constructs were found to strongly distinguish sites with high versus low TDRS performance. CONCLUSIONS: This study classified barriers and facilitators to TDRS as perceived by administrators, clinicians, and staff in FQHCs, then identified CFIR constructs that distinguished high- and low-performance clinics. Implementation strategies such as academic detailing and collection and communication of program data and successes to leadership; engaging of stakeholders through involvement in implementation planning; and appointment of intervention champions may therefore improve TDRS implementation and sustainment in resource-constrained settings.

Implementation and sustainment of a statewide telemedicine diabetic retinopathy screening network for federally designated safety-net clinics.

CONTEXT: Diabetic retinopathy (DR) is the leading cause of incident blindness among working-age adults in the United States. Federally designated safety-net clinics (FDSC) often serve as point-of-contact for patients least likely to receive recommended DR screenings, creating opportunity for targeted interventions to increase screening access and compliance. STUDY DESIGN AND METHODS: With such a goal, we implemented and assessed the longitudinal performance of an FDSC-based telemedicine DR screening (TDRS) network of 22 clinical sites providing nonmydriatic fundus photography with remote interpretation and reporting. Retrospective analysis of patient encounters between February 2014 and January 2019 was performed to assess rates of pathology and referral. A generalized estimating equation logistic regression model was used for subset analysis from audits of pre- and post-implementation screening rates. Finally, patient surveys were conducted and assessed as a measure of intervention acceptability. RESULTS: Of the 13,923 individual telescreening encounters (4327 female, 4220 male, and 5376 unspecified; mean [SD] age, 54.9 [12.5] years) studied, 10,540 were of adequate quality to identify 3532 (33.5%) patients with ocular pathology: 2319 (22.0%) patients had some level of DR with 1604 (15.2%) requiring specialist referral, and 808 (7.7%) patients required referral for other ocular pathologies. The mean screening rate for audited clinics in the year prior to program implementation was 29.9% (641/2147), which increased to 47.7% (1012/2124) in the program's first year, doubling patients' odds of being screened (OR 2.2; 95% CI: 1.3-3.7; P = .003). These gains were sustained over four years following implementation (OR 1.9; 95% CI: 1.1-3.1; P = .018) despite varied clinic screening performance (4-year averaged range, 22.9-55.1%). Odds of early detection likewise doubled for patients with consecutive screenings (OR 2.2, 95% CI: 2.0-2.4; P < .001). Finally, surveyed patients preferred TDRS to specialist exams (82.5%; 776/941) and would recommend the service to friends (92.7%; 868/936). CONCLUSION AND RELEVANCE: A statewide, FDSC-centered TDRS network was successfully established and sustained in a medically underserved region of the United States. Our results suggest that large TDRS networks in FDSCs can increase screening access and compliance for otherwise unscreened populations, but outcomes can vary greatly among clinics. Further work to optimize program implementation is needed to maximize this model's impact.

Iodine effective diffusion coefficients through volcanic rock: Influence of iodine speciation and rock geochemistry.

Accurate prediction of the subsurface transport of iodine species is important for the assessment of long-term nuclear waste repository performance, as well as monitoring compliance with the Comprehensive Nuclear-Test-Ban Treaty, given that radioiodine decays into radioxenon. However, the transport of iodine through intact geologic media is not well understood, compromising our ability to assess risk associated with radioiodine migration. The current study's goal is to quantify the matrix diffusion of iodine species through saturated volcanic rock, with particular attention paid to the redox environment and potential speciation changes. Diffusion experiments were run for iodide through lithophysae-rich lava, lithophysae-poor lava, and welded tuff, whereas iodate diffusion was studied through welded tuff. Iodine transport was compared with a conservative tracer, HDO, and effective diffusion coefficients were calculated. Likely due to a combination of size and anion exclusion effects, iodine species diffused more slowly than the conservative tracer through all rock types tested. Furthermore, oxidation of iodide to iodate was observed in the lithophysae-poor lava, affecting transport. Results provide much needed data for subsurface transport models that predict radioiodine migration from underground sources, and indicate the pressing need for geochemical and redox interactions to be incorporated into these models.

Aging effects on Cesium-137 (137Cs) sorption and transport in association with clay colloids.

Migration of radionuclides via colloid-facilitated transport is an important component of nuclear repository performance models. 137Cs sorption to bentonite colloids follows multi-site behavior, with sorption to weak sites being a rapid process and sorption to strong sites having slow kinetics. Experiments in this study targeted desorption of 137Cs from strong sites on the colloids by placing the 137Cs-bearing colloids in contact with a strongly-sorbing zeolite material that competes with the colloids for 137Cs sorption. Batch and column experiments were conducted to examine the effects of aging (i.e., increased contact time between 137Cs and colloids) on colloid-facilitated transport of 137Cs through crushed analcime columns. A larger proportion of 137Cs-bearing colloids eluted through a series of columns when the colloids were aged for 1200 days prior to injection in comparison to unaged colloids. Aging the colloids increased the partitioning of 137Cs to the colloids by nearly 20% after 1200 h. Slow desorption (0.27 hr-1) from the strong sites resulted in an increase of the Cs fraction bound to the strong sites from 0.365 to 0.87 by the second column injection, resulting in increased colloid-facilitated transport of Cs through strongly-sorbing zeolites from 0 in the second unaged column to 10% in the second aged column.

Comparison of experimental methods for estimating matrix diffusion coefficients for contaminant transport modeling.

Diffusion cell and diffusion wafer experiments were conducted to compare methods for estimating effective matrix diffusion coefficients in rock core samples from Pahute Mesa at the Nevada Nuclear Security Site (NNSS). A diffusion wafer method, in which a solute diffuses out of a rock matrix that is pre-saturated with water containing the solute, is presented as a simpler alternative to the traditional through-diffusion (diffusion cell) method. Both methods yielded estimates of effective matrix diffusion coefficients that were within the range of values previously reported for NNSS volcanic rocks. The difference between the estimates of the two methods ranged from 14 to 30%, and there was no systematic high or low bias of one method relative to the other. From a transport modeling perspective, these differences are relatively minor when one considers that other variables (e.g., fracture apertures, fracture spacings) influence matrix diffusion to a greater degree and tend to have greater uncertainty than effective matrix diffusion coefficients. For the same relative random errors in concentration measurements, the diffusion cell method yields effective matrix diffusion coefficient estimates that have less uncertainty than the wafer method. However, the wafer method is easier and less costly to implement and yields estimates more quickly, thus allowing a greater number of samples to be analyzed for the same cost and time. Given the relatively good agreement between the methods, and the lack of any apparent bias between the methods, the diffusion wafer method appears to offer advantages over the diffusion cell method if better statistical representation of a given set of rock samples is desired.

Emollient product design: objective measurements of formulation structure, texture and performance, and subjective assessments of user acceptability.

BACKGROUND: The choice of prescribed emollients is usually based on cost and patient preference. Differences in formulations can affect user acceptability. AIM: To compare the physical performance, user acceptability and various product design features of two emollient gels that are prescribed in the UK and alleged to be therapeutically interchangeable because their formulations are described as having the same contents of oily ingredients. RESULTS: We found that here are in fact significant measurable differences between the structure and performance of the two formulations, which materially affect their user acceptability. These differences are attributed to the use of different types of gelling agents and other ingredients of differing grades/quality and concentrations, and probably due to the formulations being made by different manufacturing processes. We also identified other product design features that are important to user appeal, including the type of container in which the formulations are presented, the type of dispensing devices provided, and the nature and form of the supplied user instructions. CONCLUSION: Patients and prescribers should be aware that there can be important differences in performance and user appeal between emollients, even between products that, superficially, may appear to be very similar. These important performance aspects should be characterized for new emollient introductions to encourage better informed product selection.

Human Papillomavirus Prevalence Is Associated With Socioeconomic Gradients Within a Medically Underserved Appalachian Region.

OBJECTIVES: To assess type-specific prevalence of human papillomavirus (HPV) infection in a medically underserved Appalachian area and to determine whether gradients in poverty are associated with prevalence. METHODS: Among 398 women, a validated assay tested self-collected cervicovaginal samples for 37 HPV types. Three economic strata were created based on household income: below the federal poverty level for 1 person, between the FPLs for families of 1 to 4 persons, and above the FPL for a family of 4. RESULTS: Prevalence was 55.6%, with 33% having at least 1 high-risk infection. Prevalence was 27.8% for 9-valent HPV vaccine-preventable types and 39.2% for multiple types. Compared with FPL for a family of 4, women with federal poverty level for 1 person had 3 times greater prevalence, 2.3 times greater prevalence of high-risk types, and 2.5 times greater prevalence of multiple types. CONCLUSION: Human papillomavirus prevalence was high, with one-third of the sample having at least 1 high-risk type and those in the lowest-income category being disproportionately infected.

A prospective observational study of the association between cabin and outside air temperature, and patient temperature gradient during helicopter transport in New South Wales.

The prevalence of hypothermia in patients following helicopter transport varies widely. Low outside air temperature has been identified as a risk factor. Modern helicopters are insulated and have heating; therefore outside temperature may be unimportant if cabin heat is maintained. We sought to describe the association between outside air, cabin and patient temperature, and having the cabin temperature in the thermoneutral zone (18-36°C) in our helicopter-transported patients. We conducted a prospective observational study over one year. Patient temperature was measured on loading and engines off. Cabin and outside air temperature were recorded for the same time periods for each patient, as well as in-flight. Previously identified risk factors were recorded. Complete data was obtained for 133 patients. Patients' temperature increased by a median of 0.15°C (P=0.013). There was no association between outside air temperature or cabin temperature and patient temperature gradient. The best predictor of patient temperature on landing was patient temperature on loading (R2=0.86) and was not improved significantly when other risk factors were added (P=0.63). Thirty-five percent of patients were hypothermic on loading, including those transferred from district hospitals. No patient loaded normothermic became hypothermic when the cabin temperature was in the thermoneutral zone (P=0.04). A large proportion of patients in our sample were hypothermic at the referring hospital. The best predictor of patient temperature on landing is patient temperature on loading. This has implications for studies that fail to account for pre-flight temperature.

Body composition and behaviour in adult rats are influenced by maternal diet, maternal age and high-fat feeding.

Fetal exposure to maternal undernutrition has lifelong consequences for physiological and metabolic function. Maternal low-protein diet is associated with an age-related phenotype in rats, characterised by a period of resistance to development of obesity in early adulthood, giving way to an obesity-prone, insulin-resistant state in later adulthood. Offspring of rats fed a control (18 % casein) or low-protein (9 % casein; LP) diet in pregnancy were challenged with a high-fat diet at 9 months of age. To assess whether other maternal factors modulated the programming effects of nutrition, offspring were studied from young (2-4 months old) and older (6-9 months old) mothers. Weight gain with a high-fat diet was attenuated in male offspring of older mothers fed LP (interaction of maternal age and diet; P = 0·011) and adipose tissue deposition was lower with LP feeding in both males and females (P < 0·05). Although the resistance to weight gain and adiposity was partially explained by lower energy intake in offspring of LP mothers (P < 0·001 males only), it was apparent that energy expenditure must be influenced by maternal diet and age. Assessment of locomotor activity indicated that energy expenditure associated with physical activity was unlikely to explain resistance to weight gain, but showed that offspring of older mothers were more anxious than those of younger mothers, with more rearing observed in a novel environment and on the elevated plus-maze. The data showed that in addition to maternal undernutrition, greater maternal age may influence development and long-term body composition in the rat.

De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations.

BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHODS: To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children's Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3. RESULTS: We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb-1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age. CONCLUSION: The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3.

Dispersion stability and electrokinetic properties of intrinsic plutonium colloids: implications for subsurface transport.

Subsurface transport of plutonium (Pu) may be facilitated by the formation of intrinsic Pu colloids. While this colloid-facilitated transport is largely governed by the electrokinetic properties and dispersion stability (resistance to aggregation) of the colloids, reported experimental data is scarce. Here, we quantify the dependence of ζ-potential of intrinsic Pu(IV) colloids on pH and their aggregation rate on ionic strength. Results indicate an isoelectric point of pH 8.6 and a critical coagulation concentration of 0.1 M of 1:1 electrolyte at pH 11.4. The ζ-potential/pH dependence of the Pu(IV) colloids is similar to that of goethite and hematite colloids. Colloid interaction energy calculations using these values reveal an effective Hamaker constant of the intrinsic Pu(IV) colloids in water of 1.85 × 10(-19) J, corresponding to a relative permittivity of 6.21 and refractive index of 2.33, in agreement with first principles calculations. This relatively high Hamaker constant combined with the positive charge of Pu(IV) colloids under typical groundwater aquifer conditions led to two contradicting hypotheses: (a) the Pu(IV) colloids will exhibit significant aggregation and deposition, leading to a negligible subsurface transport or (b) the Pu(IV) colloids will associate with the relatively stable native groundwater colloids, leading to a considerable subsurface transport. Packed column transport experiments supported the second hypothesis.

Infantile cardiomyopathy caused by a mutation in the overlapping region of mitochondrial ATPase 6 and 8 genes.

BACKGROUND: Infantile cardiomyopathy is a genetically heterogeneous disorder with significant morbidity and mortality. METHODS: This study aimed to identify the mutation present in four unrelated patients who presented as infants with isolated hypertrophic cardiomyopathy. RESULTS: In all four, a novel mitochondrial m.8528T-->C mutation was identified. This results in a change of the initiation codon in ATPase 6 to threonine and a concurrent change from a highly conserved hydrophobic amino acid, tryptophan, at position 55 of ATPase 8 to a highly basic arginine. To our knowledge, this is the first report of a mutation affecting both mitochondrial genome-encoded complex V subunit proteins. Testing of the relatives of one patient indicated that the mutation is heteroplasmic and correlated with disease. CONCLUSION: Mitochondrial genome sequencing should be considered in patients with infantile hypertrophic cardiomyopathy.

Pediatric restrictive cardiomyopathy associated with a mutation in beta-myosin heavy chain.

Most children do not have a known cause of cardiomyopathy which limits the potential for disease-specific therapies. Of the different phenotypic presentations of cardiomyopathy, the restrictive form carries the poorest prognosis and has the lowest rate of identification of etiology. We present the first description of a beta-myosin heavy chain gene mutation in an infant with restrictive cardiomyopathy requiring cardiac transplantation. As demonstrated by three-dimensional protein structure modeling, the missense mutation is in a highly conserved amino acid at the critical binding region for the essential light chain. This case emphasizes that mutations in sarcomeric proteins, which are known to cause hypertrophic cardiomyopathy in adults, may be associated with the development of restrictive physiology in childhood. Identification of the genetic basis of pediatric cardiomyopathy has important implications for management and genetic counseling.

Matrix diffusion coefficients in volcanic rocks at the Nevada test site: influence of matrix porosity, matrix permeability, and fracture coating minerals.

Diffusion cell experiments were conducted to measure nonsorbing solute matrix diffusion coefficients in forty-seven different volcanic rock matrix samples from eight different locations (with multiple depth intervals represented at several locations) at the Nevada Test Site. The solutes used in the experiments included bromide, iodide, pentafluorobenzoate (PFBA), and tritiated water ((3)HHO). The porosity and saturated permeability of most of the diffusion cell samples were measured to evaluate the correlation of these two variables with tracer matrix diffusion coefficients divided by the free-water diffusion coefficient (D(m)/D*). To investigate the influence of fracture coating minerals on matrix diffusion, ten of the diffusion cells represented paired samples from the same depth interval in which one sample contained a fracture surface with mineral coatings and the other sample consisted of only pure matrix. The log of (D(m)/D*) was found to be positively correlated with both the matrix porosity and the log of matrix permeability. A multiple linear regression analysis indicated that both parameters contributed significantly to the regression at the 95% confidence level. However, the log of the matrix diffusion coefficient was more highly-correlated with the log of matrix permeability than with matrix porosity, which suggests that matrix diffusion coefficients, like matrix permeabilities, have a greater dependence on the interconnectedness of matrix porosity than on the matrix porosity itself. The regression equation for the volcanic rocks was found to provide satisfactory predictions of log(D(m)/D*) for other types of rocks with similar ranges of matrix porosity and permeability as the volcanic rocks, but it did a poorer job predicting log(D(m)/D*) for rocks with lower porosities and/or permeabilities. The presence of mineral coatings on fracture walls did not appear to have a significant effect on matrix diffusion in the ten paired diffusion cell experiments.

Serum leptin level is a regulator of bone mass.

Leptin is a powerful inhibitor of bone formation in vivo. This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system and beta-adrenergic receptors on osteoblasts. However, the mechanisms whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons remain unclear. In this study, we compared the ability of leptin to regulate body weight and bone mass and show that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Using a knock-in of LacZ in the leptin locus, we failed to detect any leptin synthesis in the central nervous system. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, we observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicate that adipocyte-derived circulating leptin is a determinant of bone formation and suggests that leptin antiosteogenic function is conserved in vertebrates.

Optimal asthma control, starting with high doses of inhaled budesonide.

The aim of this study was to determine whether outcomes in poorly controlled asthma can be further improved with a starting dose of inhaled budesonide higher than that recommended in international guidelines. The study had a parallel-group design and included 61 subjects with poorly controlled asthma, randomized to receive 3,200 microg or 1,600 microg budesonide daily by Turbuhaler for 8 weeks (double-blind), then 1,600 microg x day(-1) for 8 weeks (single-blind), followed by 14 months of open-label budesonide dose down-titration using a novel algorithm, with a written asthma crisis plan based on electronic peak expiratory flow monitoring. The primary outcome variable for weeks 1-16 was change in airway hyperresponsiveness (AHR), and, for the open-label phase, mean daily budesonide dose. By week 16, there were large changes from baseline in all outcomes, with no significant differences between the 3,200- and 1,600-microg x day(-1) starting dose groups (AHR increased by 3.2 versus 3.0 doubling doses, p=0.7; morning peak flow increased by 134 versus 127 L x min(-1), p=0.8). Subjects starting with 3,200 microg x day(-1) were 3.8 times more likely to achieve AHR within the normal range, as defined by a provocative dose of histamine causing a 20% fall in forced expiratory volume in one second (PD20) of > or = 3.92 micromol by week 16 (p=0.03) [corrected]. During dose titration, there was no significant difference in mean budesonide dose (1,327 versus 1,325 microg x day(-1), p>0.3). Optimal asthma control was achieved in the majority of subjects (at completion/withdrawal: median symptoms 0.0 days x week(-1), beta2-agonist use 0.2 occasions x day(-1), and PD20 2.4 micromol). In subjects with poorly controlled asthma, a starting dose of 1,600 microg x day(-1) budesonide was sufficient to lead to optimal control in most subjects. The high degree of control achieved, compared with previous studies, warrants further investigation.