Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 2: Detecting Hips at Risk: Early Biomechanical and Structural Mechanisms.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation (AF), in partnership with the Hospital for Special Surgery (HSS), convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations gleaned from 5 presentations given in the "early hip osteoarthritis" session of the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City. It also summarizes the workgroup recommendations from a small-group discussion on clinical research gaps.

Effect of the Mode of Fermentation on the Behavior of Penicillium bilaiae in Conditions of Abiotic Stress.

The ability of a Penicillium bilaiae strain to support acid production and simultaneously solubilize inorganic sources of phosphate in conditions of submerged, solid-state fermentation (SSF) and immobilized cell system was examined in this study. Abiotic stress factors such as NaCl and different values of pH were introduced into the different fermentation process schemes to measure the fungal response. The results showed a higher tolerance of P. bilaiae when the fermentation process was carried out in solid-state and immobilized-cell conditions, which mimics the natural state of the soil microorganisms. The acidic culture conditions were not found to be suitable for fungal growth, which increased at a higher pH, with values of 4.0 and 6.0 being optimal for all types of fermentation. The presence of increasing amounts of NaCl provoked low biomass growth, titratable acidity, and simultaneous phosphate (P) solubilization. These results were, however, less pronounced at pH 4.0 and 6.0, particularly in conditions of SSF. Studying stress-tolerant microbial characteristics, particularly in different conditions and combinations of stress factors, is of great importance for further managing the overall microbial inoculants' production and formulation process as well as their applications in specific soil-plant systems.

Fungi, P-Solubilization, and Plant Nutrition.

The application of plant beneficial microorganisms is widely accepted as an efficient alternative to chemical fertilizers and pesticides. It was shown that annually, mycorrhizal fungi and nitrogen-fixing bacteria are responsible for 5 to 80% of all nitrogen, and up to 75% of P plant acquisition. However, while bacteria are the most studied soil microorganisms and most frequently reported in the scientific literature, the role of fungi is relatively understudied, although they are the primary organic matter decomposers and govern soil carbon and other elements, including P-cycling. Many fungi can solubilize insoluble phosphates or facilitate P-acquisition by plants and, therefore, form an important part of the commercial microbial products, with Aspergillus, Penicillium and Trichoderma being the most efficient. In this paper, the role of fungi in P-solubilization and plant nutrition will be presented with a special emphasis on their production and application. Although this topic has been repeatedly reviewed, some recent views questioned the efficacy of the microbial P-solubilizers in soil. Here, we will try to summarize the proven facts but also discuss further lines of research that may clarify our doubts in this field or open new perspectives on using the microbial and particularly fungal P-solubilizing potential in accordance with the principles of the sustainability and circular economy.

Safety Level of Microorganism-Bearing Products Applied in Soil-Plant Systems.

The indiscriminate use of chemical fertilizers adversely affects ecological health and soil microbiota provoking loss of soil fertility and greater pathogen and pest presence in soil-plant systems, which further reduce the quality of food and human health. Therefore, the sustainability, circular economy, environmental safety of agricultural production, and health concerns made possible the practical realization of eco-friendly biotechnological approaches like organic matter amendments, biofertilizers, biopesticides, and reuse of agro-industrial wastes by applying novel and traditional methods and processes. However, the advancement in the field of Biotechnology/Agriculture is related to the safety of these microorganism-bearing products. While the existing regulations in this field are well-known and are applied in the preparation and application of waste organic matter and microbial inoculants, more attention should be paid to gene transfer, antibiotic resistance, contamination of the workers and environment in farms and biotech-plants, and microbiome changes. These risks should be carefully assessed, and new analytical tools and regulations should be applied to ensure safe and high-quality food and a healthy environment for people working in the field of bio-based soil amendments.

Fermentation Strategies to Improve Soil Bio-Inoculant Production and Quality.

The application of plant beneficial microorganisms has been widely accepted as an efficient alternative to chemical fertilizers and pesticides. Isolation and selection of efficient microorganisms, their characterization and testing in soil-plant systems are well studied. However, the production stage and formulation of the final products are not in the focus of the research, which affects the achievement of stable and consistent results in the field. Recent analysis of the field of plant beneficial microorganisms suggests a more integrated view on soil inoculants with a special emphasis on the inoculant production process, including fermentation, formulation, processes, and additives. This mini-review describes the different groups of fermentation processes and their characteristics, bearing in mind different factors, both nutritional and operational, which affect the biomass/spores yield and microbial metabolite activity. The characteristics of the final products of fermentation process optimization strategies determine further steps of development of the microbial inoculants. Submerged liquid and solid-state fermentation processes, fed-batch operations, immobilized cell systems, and production of arbuscular mycorrhiza are presented and their advantages and disadvantages are discussed. Recommendations for further development of the fermentation strategies for biofertilizer production are also considered.

Aspegillus terreus: From Soil to Industry and Back.

Aspergillus terreus is an important saprophytic filamentous fungus that can be found in soils. Like many other soil microorganisms, A. terreus demonstrates multiple functions and offers various important metabolites, which can be used in different fields of human activity. The first application of A. terreus on an industrial level is the production of itaconic acid, which is now considered as one of the most important bioproducts in the Green Chemistry field. The general schemes for itaconic acid production have been studied, but in this mini-review some lines of future research are presented based on analysis of the published results. A. terreus is also intensively studied for its biocontrol activity and plant growth-promoting effect. However, this microorganism is also known to infect important crops such as, amongst others, rice, wheat, potato, sugar cane, maize, and soybean. It was suggested, however, that the balance between positive vs. negative effects is dependent on the soil-plant-inoculant dose system. A. terreus has frequently been described as an important human pathogen. Therefore, its safety manipulation in biotechnological processes for the production of itaconic acid and some drugs and its use in soil-plant systems should be carefully assessed. Some suggestions in this direction are discussed, particularly concerning the uses in crop production.

Formulation of Microbial Inoculants by Encapsulation in Natural Polysaccharides: Focus on Beneficial Properties of Carrier Additives and Derivatives.

In the last 10-15 years, the wide application of bioformulated plant beneficial microorganisms is accepted as an effective alternative of chemical agro-products. Two main problems can be distinguished in their production and application: (a) economical competiveness based on the overall up-stream and down-stream operational costs, and (b) development of commercial products with a high soil-plant colonization potential in controlled conditions but not able to effectively mobilize soil nutrients and/or combat plant pathogens in the field. To solve the above problems, microbe-based formulations produced by immobilization methods are gaining attention as they demonstrate a large number of advantages compared to other solid and liquid formulations. This mini-review summarizes the knowledge of additional compounds that form part of the bioformulations. The additives can exert economical, price-decreasing effects as bulking agents or direct effects improving microbial survival during storage and after introduction into soil with simultaneous beneficial effects on soil and plants. In some studies, combinations of additives are used with a complex impact, which improves the overall characteristics of the final products. Special attention is paid to polysaccharide carriers and their derivates, which play stimulatory role on plants but are less studied. The mini-review also focuses on the potential difficulty in evaluating the effects of complex bio-formulations.

Historical overview of regulatory framework development on pricing and reimbursement of medicines in Bulgaria.

Objectives: The current study aims to analyze, from a historical perspective, the regulatory framework of prices and reimbursement in Bulgaria with emphasis on the introduction of economic evaluation.Methods: The study explores all regulatory changes during the period 1995-2016 combining the macroeconomic and regulatory analysis on medicines pricing and reimbursement. A roadmap summarizing the current regulatory requirements for the medicinal product entrance on national market and access to public funding was elaborated.Results: Demographic processes in the country have been negative for the past decade. On the other hand, health care and pharmaceutical expenditures experienced a growth up to 8.6% and 3% of total GDP, respectively. The total pharmaceutical market permanently grew from 309 to 1409 million of Euro. During the last 20 years, the pricing and reimbursement legislation of medicines in Bulgaria was changed extensively.Conclusion: Pricing policy remains oriented toward the lowest European prices and reimbursement policy impose cost containment measures. Appraisal of the obligatory Health Technology Assessment Dossiers and pharmacoeconomic analysis is in accordance with world recommendations. Main regulatory issues that still remain to be tackled are the slower entrance of medicines on the national market and lower national prices that often lead to parallel import.

Production of a potential liquid plant bio-stimulant by immobilized Piriformospora indica in repeated-batch fermentation process.

Piriformospora indica, a mycorrhizal-like fungus able to establish associations with roots of a wide range of plants, supporting plant nutrition and increasing plant resistance and tolerance to stress, was shown to solubilise phosphate applied in the form of animal bone char (HABO) in fermentation systems. The process of P solubilisation was caused most likely by proton extrusion and medium pH lowering. The fungal mycelium was successfully immobilized/retained in a polyurethane foam carrier. Further employment of the immobilized mycelium in repeated-batch fermentation process resulted in at least 5 cycles of P solubilization. The concentration of soluble P increased during the experiment with 1.0 and 3.0 g HABO l-1 and at the end of the 5th batch cycle reached 40.8 and 120 mg l-1, respectively. The resulting final liquid product, without or with solubilized phosphate, was found to significantly increase plant growth and P plant uptake. It can be used as a biostimulant containing microbial plant growth-promoting substances and soluble P derived from renewable sources (HABO) thus supporting the development of sustainable agro-ecosystems.

Potential application of glycerol in the production of plant beneficial microorganisms.

This review highlights the importance of research for development of biofertilizer and biocontrol products based on the use of glycerol for further process scale-up to industrial microbiology. Glycerol can be used successfully in all stages of production of plant beneficial microorganisms. It serves as an excellent substrate in both submerged and solid-state fermentation processes with free and immobilized microbial cells. Glycerol is also one of the most attractive formulation agents that ensures high cell density and viability including in harsh environmental conditions. Future research is discussed to make this inexpensive material a base for industrial production of plant beneficial microorganisms.

Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of ß-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

OBJECTIVE: Standardized, reproducible, and feasible quantification of ß-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

Comparison of Handgrip and Leg Extension Strength in Predicting Slow Gait Speed in Older Adults.

OBJECTIVES: To compare the relative predictive power of handgrip and leg extension strength in predicting slow walking. DESIGN: Report of correlative analysis from two epidemiological cohort studies. SETTING: Foundation of the National Institutes of Health Sarcopenia Project. PARTICIPANTS: Men and women aged 67 to 93 (N=6,766). MEASUREMENTS: Leg strength, handgrip strength, and gait speed were measured. Strength cutpoints associated with slow gait speed were developed using classification and regression tree analyses and compared using ordinary least squares regression models. RESULTS: The cutpoints of lower extremity strength associated with slow gait speed were 154.6 N-m in men and 89.9 N-m in women for isometric leg extension strength and 94.5 N-m in men and 62.3 N-m in women for isokinetic leg extension strength. Weakness defined according to handgrip strength (odds ratios (OR)=1.99 to 4.33, c-statistics=0.53 to 0.67) or leg strength (ORs=2.52 to 5.77; c-statistics=0.61 to 0.66) was strongly related to odds of slow gait speed. Lower extremity strength contributed 1% to 16% of the variance and handgrip strength contributed 3% to 17% of the variance in the prediction of gait speed depending on sex and mode of strength assessment. CONCLUSION: Muscle weakness of the leg extensors and forearm flexors is related to slow gait speed. Leg extension strength is only a slightly better predictor of slow gait speed. Thus, handgrip and leg extension strength appear to be suitable for screening for muscle weakness in older adults.

Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study.

This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 ± 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet. Images were reviewed centrally using a streamlined semiautomatic approach. Quantitative volumetric measurements on plaque morphology (lumen, wall, and outer wall) and plaque tissue composition [lipid-rich necrotic core (LRNC), calcification, and fibrous tissue] were obtained. Inter-scan reproducibility was summarized using the within-subject standard deviation, coefficient of variation (CV) and intraclass correlation coefficient (ICC). Good to excellent reproducibility was observed for both morphological (ICC range 0.98-0.99) and compositional (ICC range 0.88-0.96) measurements. Measurement precision was related to the size of structures (CV range 2.5-4.9 % for morphology, 36-44 % for LRNC and calcification). Comparable measurement variability was found between the two platforms on both plaque morphology and tissue composition. In conclusion, good to excellent inter-scan reproducibility of carotid MRI can be achieved in multicenter settings with comparable measurement precision between platforms, which may facilitate future multicenter endeavors that use serial MRI to monitor atherosclerotic plaque progression.

Strength and function response to clinical interventions of older women categorized by weakness and low lean mass using classifications from the Foundation for the National Institute of Health sarcopenia project.

BACKGROUND: The Foundation for the National Institutes of Health Sarcopenia Project developed data-driven cut-points for clinically meaningful weakness and low lean body mass. This analysis describes strength and function response to interventions based on these classifications. METHODS: In data from four intervention studies, 378 postmenopausal women with baseline and 6-month data were evaluated for change in grip strength, appendicular lean mass corrected for body mass index, leg strength and power, and short physical performance battery (SPPB). Clinical interventions included hormones, exercise, and nutritional supplementation. Differences in outcomes were evaluated between (i) those with and without weakness and (ii) those with weakness and low lean mass or with one but not the other. We stratified analyses by slowness (walking speed ≤ 0.8 m/s) and by treatment assignment. RESULTS: The women (72±7 years; body mass index of 26±5kg/m(2)) were weak (33%), had low lean mass (14%), or both (6%). Those with weakness increased grip strength, lost less leg power, and gained SPPB score (p < .05) compared with nonweak participants. Stratified analyses were similar for grip strength and SPPB. With lean mass in the analysis, individuals with weakness had larger gains in grip strength and SPPB scores regardless of low lean mass (p < .01). CONCLUSIONS: Older women with clinically meaningful muscle weakness increased grip strength and SPPB, regardless of the presence of low lean mass following treatment with interventions for frailty. Thus, results suggest that muscle weakness, as defined by the Foundation for the National Institutes of Health Sarcopenia Project, appears to be a treatable symptom.

Arginine is preferred to glucagon for stimulation testing of ß-cell function.

A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess ß-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m²). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) µU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) µU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of ß-cell function.

The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates.

BACKGROUND: Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts. METHODS: The Foundation for the National Institutes of Health Sarcopenia Project used data from nine sources of community-dwelling older persons: Age, Gene/Environment Susceptibility-Reykjavik Study, Boston Puerto Rican Health Study, a series of six clinical trials, Framingham Heart Study, Health, Aging, and Body Composition, Invecchiare in Chianti, Osteoporotic Fractures in Men Study, Rancho Bernardo Study, and Study of Osteoporotic Fractures. Feedback from conference attendees was obtained via surveys and breakout groups. RESULTS: The pooled sample included 26,625 participants (57% women, mean age in men 75.2 [±6.1 SD] and in women 78.6 [±5.9] years). Conference attendees emphasized the importance of evaluating the influence of body mass on cutpoints. Based on the analyses presented in this series, the final recommended cutpoints for weakness are grip strength <26kg for men and <16kg for women, and for low lean mass, appendicular lean mass adjusted for body mass index <0.789 for men and <0.512 for women. CONCLUSIONS: These evidence-based cutpoints, based on a large and diverse population, may help identify participants for clinical trials and should be evaluated among populations with high rates of functional limitations.

Grip strength cutpoints for the identification of clinically relevant weakness.

BACKGROUND: Weakness is common and contributes to disability, but no consensus exists regarding a strength cutpoint to identify persons at high risk. This analysis, conducted as part of the Foundation for the National Institutes of Health Sarcopenia Project, sought to identify cutpoints that distinguish weakness associated with mobility impairment, defined as gait speed less than 0.8 m/s. METHODS: In pooled cross-sectional data (9,897 men and 10,950 women), Classification and Regression Tree analysis was used to derive cutpoints for grip strength associated with mobility impairment. RESULTS: In men, a grip strength of 26-32 kg was classified as "intermediate" and less than 26 kg as "weak"; 11% of men were intermediate and 5% were weak. Compared with men with normal strength, odds ratios for mobility impairment were 3.63 (95% CI: 3.01-4.38) and 7.62 (95% CI 6.13-9.49), respectively. In women, a grip strength of 16-20 kg was classified as "intermediate" and less than 16 kg as "weak"; 25% of women were intermediate and 18% were weak. Compared with women with normal strength, odds ratios for mobility impairment were 2.44 (95% CI 2.20-2.71) and 4.42 (95% CI 3.94-4.97), respectively. Weakness based on these cutpoints was associated with mobility impairment across subgroups based on age, body mass index, height, and disease status. Notably, in women, grip strength divided by body mass index provided better fit relative to grip strength alone, but fit was not sufficiently improved to merit different measures by gender and use of a more complex measure. CONCLUSIONS: Cutpoints for weakness derived from this large, diverse sample of older adults may be useful to identify populations who may benefit from interventions to improve muscle strength and function.

Cutpoints for low appendicular lean mass that identify older adults with clinically significant weakness.

BACKGROUND: Low lean mass is potentially clinically important in older persons, but criteria have not been empirically validated. As part of the FNIH (Foundation for the National Institutes of Health) Sarcopenia Project, this analysis sought to identify cutpoints in lean mass by dual-energy x-ray absorptiometry that discriminate the presence or absence of weakness (defined in a previous report in the series as grip strength <26kg in men and <16kg in women). METHODS: In pooled cross-sectional data stratified by sex (7,582 men and 3,688 women), classification and regression tree (CART) analysis was used to derive cutpoints for appendicular lean body mass (ALM) that best discriminated the presence or absence of weakness. Mixed-effects logistic regression was used to quantify the strength of the association between lean mass category and weakness. RESULTS: In primary analyses, CART models identified cutpoints for low lean mass (ALM <19.75kg in men and <15.02kg in women). Sensitivity analyses using ALM divided by body mass index (BMI: ALMBMI) identified a secondary definition (ALMBMI <0.789 in men and ALMBMI <0.512 in women). As expected, after accounting for study and age, low lean mass (compared with higher lean mass) was associated with weakness by both the primary (men, odds ratio [OR]: 6.9 [95% CI: 5.4, 8.9]; women, OR: 3.6 [95% CI: 2.9, 4.3]) and secondary definitions (men, OR: 4.3 [95% CI: 3.4, 5.5]; women, OR: 2.2 [95% CI: 1.8, 2.8]). CONCLUSIONS: ALM cutpoints derived from a large, diverse sample of older adults identified lean mass thresholds below which older adults had a higher likelihood of weakness.