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In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio - or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations., (© 2023. The Author(s).)

Background: Knee osteoarthritis (OA) is a common condition, associated with a high rate of disability and poor quality of life. Despite the importance of such evidence in public health, no umbrella review (i.e., a review of other systematic reviews and meta-analyses) has systematically assessed evidence on association between knee OA and adverse health outcomes., Aims: To map and grade all health outcomes associated with knee OA using an umbrella review approach., Methods: The search was made across several databases up to 22 April 2022. We used an umbrella review of systematic reviews with meta-analyses of observational studies assessing the effect sizes, based on random effect summary, 95% prediction intervals, heterogeneity, small study effects, and excess significance bias. The evidence was then graded from convincing (class I) to weak (class IV)., Results: Among 3,847 studies initially considered, five meta-analyses were included for a total of five different outcomes. Three adverse outcomes were significantly associated with knee OA (i.e., cardiovascular mortality, falls, and subclinical atherosclerosis). The presence of knee OA was associated with a significantly higher risk of cardiovascular mortality (odds ratio, OR = 1.17; 95%CI, confidence intervals: 1.02-1.34), falls (RR = 1.34; 95%CI: 1.10-1.64), and conditions associated with subclinical atherosclerosis (OR = 1.43; 95%CI: 1.003-2.05). The certainty of each of this evidence was weak., Conclusions: Our umbrella review suggests that knee OA can be considered as putative risk factor for some medical conditions, including cardiovascular diseases and falls, however, it is important to note that the evidence is affected by potential biases., (© 2022. The Author(s).)

Obesity and vitamin D deficiency are two major public health concerns. Evidence suggests that alteration in gut microbiota composition is a possible risk factor for obesity. Additionally, altered vitamin D status has a potential role in shaping the gut microbial community. Further, the prevalence of obesity has been rising in the Middle East, especially among women of reproductive age, which is of specific concern due to its adverse effects on the health of their offspring. To date, limited evidence is available on the association between gut microbiota composition and vitamin D levels in Arab women. This study aims to identify the associations between serum vitamin D, gut microbiota, and obesity among Saudi females. The current study is a case-control study including 92 women aged 18 to 25 years, ( n = 48) with normal weight and ( n = 44) with obesity. Anthropometric, biochemical, lifestyle data, and fecal samples were collected and analyzed. We used shotgun metagenomic sequencing to characterize microbial communities of stool samples. Vitamin D levels were significantly associated with alpha and beta diversities. Serum vitamin D levels were positively associated with bacteria known to regulate immunological responses; Bacteroides thetaiotaomicron in the normal weight group (r = 0.34, p = 0.03) and Bifidobacterium adolescentis in the obesity group (r = 0.33, p = 0.04). In conclusion, the findings suggest that vitamin D status may play a role in regulating the gut microbiota composition by inhibiting the growth of pathogenic bacteria while nourishing the beneficial strains.

Previous studies have suggested that dietary habits and dysbiosis of gut microbiota contributed to obesity development. Vitamin B12 is produced by microbes; however, the relationships between vitamin B12, gut microbiome, and obesity are understudied. We aimed to determine the association between vitamin B12 status and gut microbiota relative to obesity in 92 Saudi Arabian females aged 19-25 years who were obese (n = 44) or normal weight (n = 48). Anthropometric, biochemical data, and dietary data were collected. The microbial communities of stool samples were characterized using the shotgun metagenomic sequencing technique. The relationship between vitamin B12 status and gut microbiota composition was identified using Pearson correlation analysis. A statistically significant difference was found in bacterial α- and β-diversity between the groups relative to median serum vitamin B12 level (404.0 pg/mL) and body weight. In the total participants, dietary vitamin B12 intake was inversely correlated with Bifidobacterium kashiwanohense and Blautia wexlerae species. In obese participants, dietary vitamin B12 intake was inversely correlated with Akkermansia muciniphila species and species from the Verrucomicrobia phylum, whereas it was positively correlated with Bacteroides species. Our findings indicate that the abundance (frequency) and diversity (richness) of gut microbiota are associated with vitamin B12 levels and obesity in young females.

Oral bisphosphonates are a key intervention in the treatment of osteoporosis and in reducing the risk of fragility fractures. Their use is supported by over 3 decades of evidence; however, patient adherence to oral bisphosphonates remains poor in part due to complex dosing instructions and adverse events, including upper gastrointestinal symptoms. This problem has led to the development of novel oral bisphosphonate formulations. Buffered, effervescent alendronate is dissolved in water and so seeks to reduce upper gastro-intestinal adverse events, and gastro-resistant risedronate aims to reduce the complexity of dosing procedure (e.g. fasting prior to consumption) whilst still maintaining the efficacy of fracture risk reduction. Clinical trials and real-world data have been employed to demonstrate some benefits in terms of reduced upper gastro-intestinal adverse events, adherence, persistence and health economic outcomes. This report describes the result of an ESCEO (European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis) expert working group, which explores where oral bisphosphonates sit in current clinical practice guidelines, review their risk-benefit profile and the consequences of poor adherence before exploring novel oral bisphosphonate formulations and their potential clinical and health economic impact. Further research is required but there are signs that these novel, oral bisphosphonate formulations may lead to improved tolerance of oral bisphosphonates and thus, improved adherence and fracture outcomes., (© 2022. The Author(s).)

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration., (© 2022. The Author(s).)

X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease., (© 2022. Springer Nature Limited.)

Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon., (© 2022. The Author(s).)

Studies have explored how vitamin B12 status affects sleep among elders and children, but this remains to be investigated among young adults. We used the Pittsburgh Sleep Quality Index (PSQI) to assess the association between serum vitamin B12 and sleep among female college students in Saudi Arabia. In this cross-sectional study, we enrolled 355 participants (age (years), 20.7 ± 1.5; body mass index, 23.6 kg/m 2 ± 5.2) at King Saud University, Riyadh, Saudi Arabia. Fasting blood samples were analyzed regarding the serum vitamin B12 and blood lipids. Anthropometric, socio-demographic, clinical history, stress, physical activity, and dietary data were collected. We assessed the sleep statuses of the participants using the PSQI. Around 72% of the participants were "poor" sleepers (PSQI > 5). Subgroup analysis within the tertiles showed that participants with higher vitamin B12 in the second and third tertiles reported better scores for sleep quality (B ± SE = -12.7 ± 5.6, p = 0.03; B ± SE = -32.7 ± 16.4, p = 0.05, respectively) and also reported a lower use of sleep medication (B ± SE = -21.2 ± 9.9, p = 0.03, in the second tertile only), after adjusting for the waist-hip ratio and stress. However, sleep was not found to be directly associated with either serum vitamin B12 or dietary vitamin B12. In conclusion, the serum vitamin B12 results show that the participants with higher vitamin B12 in the second and third tertiles reported better scores on the sleep quality scale and a lower use of sleep medication. However, no such associations were observed with the overall PSQI. More studies with larger sample sizes are needed to establish a direct relationship between sleep and vitamin B12.

Background: In 2016, an expert working group was convened under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and formulated consensus recommendations for the conduct of clinical trials for drugs to prevent or treat sarcopenia., Aims: The objective of the current paper is to provide a 2020 update of the previous recommendations in accordance with the evidence that has become available since our original recommendations., Methods: This paper is based on literature reviews performed by members of the ESCEO working group and followed up with face to face meetings organized for the whole group to make amendments and discuss further recommendations., Results: The randomized placebo-controlled double-blind parallel-arm drug clinical trials should be the design of choice for both phase II and III trials. Treatment and follow-up should run at least 6 months for phase II and 12 months for phase III trials. Overall physical activity, nutrition, co-prescriptions and comorbidity should be recorded. Participants in these trials should be at least 70-years-old and present with a combination of low muscle strength and low physical performance. Severely malnourished individuals, as well as bedridden patients, patients with extremely limited mobility or individuals with physical limitations clearly attributable to the direct effect of a specific disease, should be excluded. Multiple outcomes are proposed for phase II trials, including, as example, physical performance, muscle strength and mass, muscle metabolism and muscle-bone interaction. For phase III trials, we recommend a co-primary endpoint of a measure of functional performance and a Patient Reported Outcome Measure., Conclusion: The working group has formulated consensus recommendations on specific aspects of trial design, and in doing so hopes to contribute to an improvement of the methodological robustness and comparability of clinical trials. Standardization of designs and outcomes would advance the field by allowing better comparison across studies, including performing individual patient-data meta-analyses, and different pro-myogenic therapies.

Vitamin B12 insufficiency is a global health issue among women of childbearing age, yet few studies have investigated its prevalence and risk factors among healthy Middle Eastern populations. This cross-sectional study included 346 Saudi women aged 19-30 years and enrolled at King Saud University, Riyadh, Saudi Arabia. A series of questionnaires were administered to record the study participants' sociodemographic status, medical history, dietary intake, and physical activity. Participants' anthropometric data were also recorded and their fasting blood samples were analyzed. The rate of vitamin B12 insufficiency (≤220 pmol/L) was approximately 6% among the study participants. After adjusting for confounding factors, it was observed that the risk factors for vitamin B12 insufficiency included daily sitting time ≥ 7 h, low income (<10,000 Saudi riyal) and increasing age. The recommended dietary allowance of vitamin B12 (>2.4 mcg/day) has been shown to confer reasonable protection against vitamin B12 insufficiency. These study findings highlight that a combination of increased physical activity and dietary vitamin B12 intake above the current recommended dietary allowance may help improve the serum vitamin B12 levels of young women of childbearing age, especially those with a low socioeconomic status. Timely detection and protection against vitamin B12 insufficiency in this subpopulation are important to prevent maternal and fetal health risks.

Vitamin B12 deficiency leads to adverse effects on human health, but limited information is available as to whether abnormal vitamin B12 levels are associated between parents and offspring. The present study aimed to assess the association between circulating levels of vitamin B12 in Saudi parents and their children as well as its association with pro-inflammatory markers. A total of 104 Saudi families: 49 fathers, 63 mothers, 94 sons and 79 daughters were selected for the study. Fasting blood samples and anthropometrics were collected. Biochemical parameters, various pro-inflammatory markers and vitamin B12 were measured. Results showed a significant positive correlation between B12 levels in most parent-offspring pairs: mother-daughter (N = 46 pairs, r = 0.72, p < 0.0001); father-daughter (N = 39, r = 0.62, p < 0.0001) and mother-son (N = 51, r = 0.42, p < 0.01). This association was absent in father-son pairs (N = 48, r = 0.26, p = 0.09). Also, B12 was inversely associated with tumor necrosis factor-α and plasminogen activator inhibitor-1 in parents (r = -0.32; p < 0.01 and r = -0.31; p < 0.01 respectively) and children (r = -0.14; p < 0.01 and r = -0.19; p < 0.01 respectively). A significant inverse correlation was found between vitamin B12 and leptin in mothers (r = -0.31, p < 0.05). Our study suggests a strong familial component between B12 levels indicating a possible genetic influence on individual B12 status. Our study also suggests an inverse correlation between circulating levels of vitamin B12 and pro-inflammatory markers. The present study highlights the importance of extending screening in families of patients with abnormal B12 levels and expanding treatment, if necessary, to maximize clinical benefits.

Objective: To evaluate the preferences of patients with osteoarthritis for treatment., Methods: A discrete-choice experiment was conducted among adult OA patients who were presented with 12 choice sets of two treatment options and asked in each to select the treatment they would prefer. Based on literature reviews, expert consultation, patient survey and expert meeting, treatment options were characterized by seven attributes: improvement in pain, improvement in walking, ability to manage domestic activities, ability to manage social activities, improvement in overall energy and well-being, risk of moderate/severe side effects and impact on disease progression. Random parameters logit model was used to estimate patients' preferences and a latent class model was conducted to explore preferences classes., Results: 253 OA patients from seven European countries were included (74% women; mean age 71.3 years). For all seven treatment attributes, significant differences were observed between levels. Given the range of levels of each attribute, the most important treatment attribute in this group was impact on disease progression (29.5%) followed by walking improvement (17.1%) and pain improvement (16.3%). The latent class model identified two preference classes. In the first class (probability of 56%), patients valued impact of disease progression the most (39%). In the second class, walking improvement and improvement in overall energy and well-being were the most important (23%)., Conclusion: This study suggests that all seven treatment attributes were important for OA patients. Overall, given the range of levels, the most important outcomes were impact on disease progression and improvement in pain and walking., Competing Interests: Declaration of Competing Interest Professor Bruyère reports grants from Biophytis, IBSA, MEDA, Servier, SMB, Theramex, outside the submitted work. Professor Cooper reports personal fees from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. Professor Conaghan has received consulting fees or done speakers bureaus for AbbVie, EMD Serono, Flexion Therapeutics, Galapagos, Novartis, Pfizer, Samumed and Stryker. Professor Dennison has received consulting fees from UCB and Pfizer. Dr. Herrero-Beaumont reports grants from Novartis, grants from Sandoz, grants from Pfizer, grants from Amgen, grants from Mylan, grants from Servier, outside the submitted work; In addition, Dr. Herrero-Beaumont has a patent Patent for the use of 6-shogaol on osteoporosis treatment. Spanish patent issued, and a patent Patent on the use of osteostatin in osteoarthritis treatment issued. Professor Reginster reports grants and personal fees from IBSA-GENEVRIER, grants and personal fees from MYLAN, grants and personal fees from RADIUS HEALTH, personal fees from PIERRE FABRE, grants from CNIEL, personal fees from DAIRY RESEARCH COUNCIL, outside the submitted work. Professor Thomas reports personal fees from Abbvie, grants and personal fees from Amgen, personal fees from Arrow, personal fees from Biogen, personal fees from BMS, grants and personal fees from Chugai, personal fees from Expanscience, personal fees from Gilead, personal fees from Grunenthal, grants and personal fees from HAC-Pharma, personal fees from LCA, personal fees from Lilly, personal fees from Medac, grants and personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Theramex, personal fees from Thuasne, personal fees from TEVA, grants and personal fees from UCB, grants from Bone therapeutics, personal fees from Nordic, outside the submitted work. Professor Rizzoli reports personal fees from Amgen, CNiEL, Danone, Mylan, Nestle, Radius health, Sandoz, TEVA/Theramex, outside the submitted work. The other authors have no conflict of interest relevant to the content of this study., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

An abnormal lipid profile is an independent risk factor for cardiovascular diseases. The relationship between vitamin B12 deficiency and lipid profile is inconclusive, with most studies conducted in unhealthy populations. In this study, we aimed to assess the relationship between serum vitamin B12 levels and lipid profiles in a cross-sectional study that included 341 apparently healthy Saudi women, aged 19-30 years, from different colleges at King Saud University, Saudi Arabia. Sociodemographic, anthropometric, biochemical, and lifestyle data were collected, including diet and physical activity. Serum vitamin B12 deficiency was defined as serum B12 level of <148 pmol/L. The prevalence of vitamin B12 deficiency was approximately 0.6%. Using multivariable linear regression models, serum vitamin B12 levels were found to be inversely associated with total cholesterol (B = -0.26; p < 0.001), low-density lipoprotein cholesterol levels (B = -0.30; p < 0.001), and triglyceride (B = -0.16; p < 0.01) after adjusting for potential confounders, while obesity indices of body mass index, central obesity, and fat percentage showed no association. Therefore, we conclude that low serum vitamin B12 levels are independently associated with abnormal lipid profiles in healthy young Saudi women. Further interventional studies are needed to determine whether improving serum vitamin B12 levels in a healthy population can improve lipid profiles.

Vitamin D is endowed with a number of biological properties, including down-regulation of inflammation, and might contribute to the pathogenesis of autism spectrum disorders (ASD). Vitamin D binds to the vitamin D Receptor (VDR); the biological activity of the ensuing complex depends on VDR FokI, BsmI, ApaI, and TaqI gene polymorphisms. We evaluated such Single Nucletoide Polymorphismsm (SNPs) in a cohort of 100 Italian families with ASD children. FokI genotype distribution was skewed in ASD children compared with their healthy sibs (P c = 0.03 2 df) and to a group of 170 Italian healthy women (HC) (P c = 0.04 2 df). FokI genotype and allelic distribution skewing were also observed in mothers of ASD children compared to HC (P c = 0.04 2 df). Both Transmission Disequilibrium Test for single loci and haplotype analysis distribution revealed a major FokI (C) allele-mediated protective effect, which was more frequently transmitted (73%) than not transmitted to healthy sibs (P = 0.02). A protective FokI-, BsmI-, ApaI-, and TaqI (CCAG) haplotype was more frequently carried by healthy sibs than by ASD children (P = 1 × 10 -4 ; OR: 0.1, 95% CI: 0.03-0.4) too. Finally, a strong gene-dose association of FokI (T) allele with both higher Childhood Autism Rating Scale score (P c = 0.01) and, particularly, with hyperactivity behavior (P c = 0.006) emerged in ASD children. Because the protein produced by the FokI (T) allele is transcriptionally less active than that produced by the FokI (C) allele, the reduced biological activity of the vitamin D/VDR complex prevalent in ASD could favor ASD- and maternal immune activation- associated inflammation. Vitamin D supplementation might be useful in preventative and rehabilitation protocols for ASD. Autism Res 2020, 13: 680-690. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D deficiency and Vitamin D receptor (VDR) polymorphisms are associated with structural and functional brain abnormalities and behavioral disorders. We analyzed the association of VDR gene polymorphisms in a cohort of 100 Italian families with ASD children. A strong correlation between one of the VDR polymorphisms and hyperactivity behavior was evidenced in ASD children. In healthy mothers, the same VDR polymorphism was also correlated with an increased risk of giving birth to children with ASD., (© 2020 International Society for Autism Research, Wiley Periodicals, Inc.)

Objective: A summary of recommendations is given within the Gulf Cooperation Council (GCC) setting on the assessment and management of vitamin D deficiency in the region., Methods: An assembly of 11 regional experts gathered to formulate an all-inclusive approach to vitamin D deficiency within GCC., Results and Conclusion: Several gaps were identified before regional guidelines could be developed. These include adequacy and standardization of vitamin D testing, frequency of repeated testing and reference ranges, distinguishing prevention from the treatment of vitamin D deficiency, quality assurance of vitamin D products sold within GCC including contents and origins of products, and cut-points for vitamin D levels in local populations. A platform is created that can be further developed for overall regional implementation.

Objectives: Mediterranean diet has several beneficial effects on health, but data regarding the association between Mediterranean diet and knee osteoarthritis (OA) are limited mainly to cross-sectional studies. We investigated whether higher Mediterranean diet adherence is prospectively associated with lower risk of radiographic OA (ROA), radiographic symptomatic knee OA (SxOA) and pain worsening in North American people at high risk or having knee OA., Methods: Adherence to the Mediterranean diet was evaluated using a validated Mediterranean diet score (aMED), categorized in five categories (Q1 to Q5, higher values reflecting higher adherence to Mediterranean diet). Knee OA outcomes included incident (1) ROA, (2) SxOA, as the new onset of a combination of a painful knee and ROA, (3) knee pain worsening, i.e. a Western Ontario and McMaster Universities Osteoarthritis Index difference between baseline and each annual exam of ≥14%., Results: 4330 subjects (mean age: 61.1 years; 58.0% females) were included. Based on a multivariable Poisson regression analysis, during a mean follow-up period of 4 years, participants who were more highly adherent to a Mediterranean diet (Q5) reported lower risk of pain worsening (relative risk, RR = 0.96; 95% CI: 0.91-0.999) compared to those in Q1. In 2994 people free from SxOA at baseline, higher adherence to a Mediterranean diet was associated with a lower risk for SxOA during follow-up by 9% (Q5 vs. Q1; RR = 0.91; 95% CI: 0.82-0.998). No significant associations emerged between aMED and incident ROA., Conclusion: Higher adherence to Mediterranean diet is associated with a lower risk of pain worsening and symptomatic forms of knee OA., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: The purpose of this paper was to review the available approaches for bone strength assessment, osteoporosis diagnosis and fracture risk prediction, and to provide insights into radiofrequency echographic multi spectrometry (REMS), a non-ionizing axial skeleton technique., Methods: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review the current image-based methods for bone strength assessment and fracture risk estimation, and to discuss the clinical perspectives of REMS., Results: Areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is the consolidated indicator for osteoporosis diagnosis and fracture risk assessment. A more reliable fracture risk estimation would actually require an improved assessment of bone strength, integrating also bone quality information. Several different approaches have been proposed, including additional DXA-based parameters, quantitative computed tomography, and quantitative ultrasound. Although each of them showed a somewhat improved clinical performance, none satisfied all the requirements for a widespread routine employment, which was typically hindered by unclear clinical usefulness, radiation doses, limited accessibility, or inapplicability to spine and hip, therefore leaving several clinical needs still unmet. REMS is a clinically available technology for osteoporosis diagnosis and fracture risk assessment through the estimation of BMD on the axial skeleton reference sites. Its automatic processing of unfiltered ultrasound signals provides accurate BMD values in view of fracture risk assessment., Conclusions: New approaches for improved bone strength and fracture risk estimations are needed for a better management of osteoporotic patients. In this context, REMS represents a valuable approach for osteoporosis diagnosis and fracture risk prediction.

The co-existence of impaired bone health (osteopenia/osteoporosis), reduced muscle mass and strength (sarcopenia), and increased adiposity (obesity) in middle-aged and older people has been identified in recent studies, leading to a proposal for the existence of "osteosarcopenic obesity" as a distinct entity. Evidence for the pathophysiological overlap of these conditions is mounting, although a causal relationship is yet to be established. Each component condition occurs frequently with increasing age, and with shared risk factors in many instances, thus, an overlap of these three conditions is not surprising. However, whether the concurrent existence of sarcopenia, osteoporosis and obesity leads to an increased risk of adverse musculoskeletal outcomes and mortality above and beyond the risks associated with the sum of the component parts remains to be proven and is a question of research interest. In this article, we review evidence for the existence of osteosarcopenic obesity including the current operational definition of osteosarcopenic obesity, prevalence, pathophysiology, outcomes and exploratory approaches to the management of components. We conclude that, there is insufficient evidence to support a discrete clinical entity of osteosarcopenic obesity at this time. To expand knowledge and understanding in this area, there is a need for consensus on a definition of osteosarcopenic obesity which will allow for identification, further epidemiological studies and comparisons between studies. Additionally, studies should assess whether the clinical outcomes associated with osteosarcopenic obesity are worse than the mere addition of those linked with its components. This will help to determine whether defining a person as having this triad will eventually result in a more effective treatment than addressing each of the three conditions separately.

Objectives: Type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) are common diseases that frequently co-exist, along with overweight/obesity. While the mechanical impact of excess body weight on joints may explain lower limb OA, we sought to explore whether T2DM is linked to OA outside of excess weight and whether T2DM may play a role in OA pathophysiology. The consequence of T2DM on OA outcomes is a question of research interest., Methods: We conducted a critical review of the literature to explore the association between T2DM and OA, whether any association is site-specific for OA, and whether the presence of T2DM impacts on OA outcomes. We also reviewed the literature to assess the safety of anti-OA treatments in patients with T2DM., Results: T2DM has a pathogenic effect on OA through 2 major pathways involving oxidative stress and low-grade chronic inflammation resulting from chronic hyperglycemia and insulin resistance. T2DM is a risk factor for OA progression and has a negative impact on arthroplasty outcomes. Evidence is mounting for safety concerns with some of the most frequently prescribed anti-OA medications, including paracetamol, non-steroidal anti-inflammatory drugs, and corticosteroid injections, while other anti-OA medications may be safely prescribed in OA patients with T2DM, such as glucosamine and intra-articular hyaluronic acid., Conclusions: Future research is needed to better understand whether diabetes control and prevention can modulate OA occurrence and progression. The selection of therapy to treat OA symptoms in patients with T2DM may require careful consideration of the evidence based to avoid untoward safety issues., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Statins have several pleiotropic effects, but the literature regarding the possible relationship between use of statins and outcomes in knee osteoarthritis (OA) is limited. The aim of this study was to investigate whether statin use is associated with a lower risk of radiographic OA (ROA), radiographic symptomatic knee OA, and pain in North American individuals., Methods: A total of 4,448 community-dwelling adults from the Osteoarthritis Initiative were followed for 4 years. Statin use (including the time from baseline and the type of statin) was defined through self-report information and confirmed by a trained interviewer. Knee OA outcomes included incident ROA, symptomatic knee OA (new onset of a combination of a painful knee and ROA), and knee pain worsening (i.e., a Western Ontario and McMaster Universities Osteoarthritis Index difference between baseline and each annual examination ≥14%)., Results: At baseline, 1,127 participants (25.3% of the total population) used statins. Based on a multivariable Poisson regression analysis with robust variance estimators, any use of statins was not associated with a lower risk of pain worsening (relative risk [RR] 0.97, 95% confidence interval [95% CI] 0.93-1.02), incident ROA, or symptomatic knee OA. However, statin use for more than 5 years (RR 0.91, 95% CI 0.83-0.997) and use of atorvastatin (RR 0.95, 95% CI 0.91-0.996) were associated with a reduced risk of developing pain, while rosuvastatin use was associated with a higher risk (RR 1.18, 95% CI 1.12-1.24). Analysis with adjustment for the propensity score confirmed these findings., Conclusion: The effect of statin use on knee OA outcomes remains unclear, although in our study, a significantly lower risk of developing knee pain was observed in individuals using statins for >5 years and those using atorvastatin., (© 2018, American College of Rheumatology.)

It is well recognized that poor muscle function and poor physical performance are strong predictors of clinically relevant adverse events in older people. Given the large number of approaches to measure muscle function and physical performance, clinicians often struggle to choose a tool that is appropriate and validated for the population of older people they deal with. In this paper, an overview of different methods available and applicable in clinical settings is proposed. This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were organized afterwards where the whole group could amend and discuss the recommendations further. Several characteristics should be considered when choosing a tool: (1) purpose of the assessment (intervention, screening, diagnosis); (2) patient characteristics (population, settings, functional ability, etc.); (3) psychometric properties of the tool (test-retest reliability, inter-rater reliability, responsiveness, floor and ceiling effects, etc.); (4) applicability of the tool in clinical settings (overall cost, time required for the examination, level of training, equipment, patient acceptance, etc.); (5) prognostic reliability for relevant clinical outcomes. Based on these criteria and the available evidence, the expert group advises the use of grip strength to measure muscle strength and the use of 4-m gait speed or the Short Physical Performance Battery test to measure physical performance in daily practice. The tools proposed are relevant for the assessment of muscle weakness and physical performance. Subjects with low values should receive additional diagnostic workups to achieve a full diagnosis of the underlying condition responsible (sarcopenia, frailty or other).

There is increasing emphasis on patient-centred research to support the development, approval and reimbursement of health interventions that best meet patients' needs. However, there is currently little guidance on how meaningful patient engagement may be achieved. An expert working group, representing a wide range of stakeholders and disciplines, was convened by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the World Health Organization (WHO). Through a structured, collaborative process the group generated practical guidance to facilitate optimal patient engagement in clinical development and regulatory decisions. Patient engagement is a relational process. The principles outlined in this report were based on lessons learned through applied experience and on an extensive dialogue among the expert participants. This practice guidance forms a starting point from which tailoring of the approach to suit different chronic diseases may be undertaken.

The study aimed to determine whether neck circumference is associated with bone metabolism markers among adult Arab women and found modest but significant associations with bone resorption markers, suggesting that neck circumference, a surrogate measure of upper subcutaneous fat, influences bone turnover expression among adult females., Introduction: Body fat distribution is associated with decreased bone resorption and neck circumference (NC), a surrogate measure for upper body fat, has never been tested as a marker that can reflect bone turnover. This is the first study aimed to analyze the associations between NC and several bone biomarkers among adult Saudi women., Methods: This cross-sectional study included a total of 265 middle-aged Saudi women [86 non-obese (mean age 52.7 ± 8.1; mean BMI 26.9 ± 2.3) and 179 obese (mean age 50.6 ± 7.5; mean BMI 35.7 ± 4.5)] recruited from primary care centers in Riyadh, Saudi Arabia. Anthropometrics included BMI, NC, waist and hip circumferences, total body fat percentage (%), and blood pressure. Biochemical parameters included glucose and lipid profile which were measured routinely. Serum levels of 25(OH) D, parathyroid hormone, RANKl, sclerostin, C-terminal telopeptide of collagen I (CTX-I), Dkk1, IL1β, osteoprotegerin, osteopontin, and osteocalcin were measured using commercially available assays., Results: In all groups, NC was inversely associated with PTH (R = - 0.22; p < 0.05) and positively associated with osteoprotegerin (R = 0.20; p < 0.05) even after adjustments for age and BMI. Using all anthropometric indices as independent variables showed that only NC explained the variance perceived in CTX-I (p = 0.049). In the non-obese, waist-hip ratio (WHR) was significantly associated with sclerostin (R = 0.40; p < 0.05) and body fat was significantly associated with osteopontin (R = 0.42; p < 0.05)., Conclusion: NC is modestly but significantly associated with bone biomarkers, particularly the bone resorption markers, among adult Arab women. The present findings highlight the importance of NC as measure of upper body subcutaneous fat in influencing bone biomarker expression in adult females.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely recommended and prescribed to treat pain in osteoarthritis. While measured to have a moderate effect on pain in osteoarthritis, NSAIDs have been associated with wide-ranging adverse events affecting the gastrointestinal, cardiovascular, and renal systems. Gastrointestinal toxicity is found with all NSAIDs, which may be of particular concern when treating older patients with osteoarthritis, and gastric adverse events may be reduced by taking a concomitant gastroprotective agent, although intestinal adverse events are not ameliorated. Cardiovascular toxicity is associated with all NSAIDs to some extent and the degree of risk appears to be pharmacotherapy specific. An increased risk of acute myocardial infarction and heart failure is observed with all NSAIDs, while an elevated risk of hemorrhagic stroke appears to be restricted to the use of diclofenac and meloxicam. All NSAIDs have the potential to induce acute kidney injury, and patients with osteoarthritis with co-morbid conditions including hypertension, heart failure, and diabetes mellitus are at increased risk. Osteoarthritis is associated with excess mortality, which may be explained by reduced levels of physical activity owing to lower limb pain, presence of comorbid conditions, and the adverse effects of anti-osteoarthritis medications especially NSAIDs. This narrative review of recent literature identifies data on the safety of non-selective NSAIDs to better understand the risk:benefit of using NSAIDs to manage pain in osteoarthritis.

Background: Alzheimer's disease (AD) is associated with the accumulation of amyloid-β (Aβ) within senile plaques in the brain and neuroinflammation, possibly driven by the activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the NLRP3 inflammasome assembly., Objective: We utilized an in vitro model reproducing the Aβ-driven inflammation seen in AD to analyze whether stavudine (D4T), a prototypical NRTI, modulates Aβ-mediated inflammasome activation and the ability of macrophages to eliminate Aβ via phagocytosis and autophagy., Methods: THP-1-derived macrophages were stimulated in vitro with Aβ42 or with Aβ42 after LPS-priming in the presence/absence of D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR; phagocytosis, as well as ASC-Speck formation, was analyzed by Amnis FlowSight Imaging; NLRP3-produced cytokines were quantified by ELISA and, finally, autophagy was analyzed by measuring p-ERK1/2, p-AKT, beclin, p70-S6Kinase, and Lamp by ELISA and western blot., Results: IL-1β, IL-18, and caspase-1 were increased whereas Aβ phagocytosis and TREM2 were reduced in LPS+Aβ42-stimulated cells. D4T reduced NLRP3 assembly as well as IL-18 and caspase-1 production, but did not affect IL-1β production and TREM2 expression. Notably, whereas D4T reduced Aβ phagocytosis, Aβ autophagy by macrophages was stimulated by D4T, as witnessed by the down-modulation of ERK1/2 and AKT phosphorylation and the upregulation of beclin, LAMP, and p70-S6K, their downstream targets., Conclusion: In this in vitro model of AD, D4T reduces NLRP3 inflammasome-associated inflammation and stimulates Aβ autophagy by macrophages. It will be interesting to verify the possibly beneficial effects of D4T in the clinical scenario.

Musculoskeletal disorders affect morbidity, quality of life and mortality, and represent an increasing economic and societal burden in the context of population aging and increased life expectancy. Improvement of quality of life should be one of the priorities of any interventions to prevent and treat musculoskeletal disorders in the ageing population. Two main approaches, namely generic and disease-specific instruments, can be applied to measure health-related quality of life. Among the generic tools available in scientific literature, the short form 36 questionnaire (SF-36) and the Euroqol five item questionnaire (EQ-5D) are two of the most popular questionnaires used to quantify the health related quality of life in people with musculoskeletal disorders. However, because generic tools may not always be able to detect subtle effects of a specific condition on quality of life, a specific tool is highly valuable. Specific tools improve the ability to clinically characterize quality of life in subjects with a specific musculoskeletal disorder, as well as the capacity to assess changes over time in the QoL of these subjects. The recent development of specific tools should help to validate preventive and therapeutic interventions in this field.

Aims/hypothesis: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulatory macrophage-derived factor that increases with obesity and leads to a higher risk of cardiovascular disease (CVD). Despite this, its role in adipose tissue and the adipocyte is unknown. Therefore, the aims of this study were to clarify the expression of Lp-PLA2 in relation to different adipose tissue depots and type 2 diabetes, and ascertain whether markers of obesity and type 2 diabetes correlate with circulating Lp-PLA2. A final aim was to evaluate the effect of cholesterol on cellular Lp-PLA2 in an in vitro adipocyte model., Methods: Analysis of anthropometric and biochemical variables from a cohort of lean (age 44.4 ± 6.2 years; BMI 22.15 ± 1.8 kg/m 2 , n = 23), overweight (age 45.4 ± 12.3 years; BMI 26.99 ± 1.5 kg/m 2 , n = 24), obese (age 49.0 ± 9.1 years; BMI 33.74 ± 3.3 kg/m 2 , n = 32) and type 2 diabetic women (age 53.0 ± 6.13 years; BMI 35.08 ± 8.6 kg/m 2 , n = 35), as part of an ethically approved study. Gene and protein expression of PLA2 and its isoforms were assessed in adipose tissue samples, with serum analysis undertaken to assess circulating Lp-PLA2 and its association with cardiometabolic risk markers. A human adipocyte cell model, Chub-S7, was used to address the intracellular change in Lp-PLA2 in adipocytes., Results: Lp-PLA2 and calcium-independent PLA2 (iPLA2) isoforms were altered by adiposity, as shown by microarray analysis (p < 0.05). Type 2 diabetes status was also observed to significantly alter gene and protein levels of Lp-PLA2 in abdominal subcutaneous (AbdSc) (p < 0.01), but not omental, adipose tissue. Furthermore, multivariate stepwise regression analysis of circulating Lp-PLA2 and metabolic markers revealed that the greatest predictor of Lp-PLA2 in non-diabetic individuals was LDL-cholesterol (p = 0.004). Additionally, in people with type 2 diabetes, oxidised LDL (oxLDL), triacylglycerols and HDL-cholesterol appeared important predictors, accounting for 59.7% of the variance (p < 0.001). Subsequent in vitro studies determined human adipocytes to be a source of Lp-PLA2, as confirmed by mRNA expression, protein levels and immunochemistry. Further in vitro experiments revealed that treatment with LDL-cholesterol or oxLDL resulted in significant upregulation of Lp-PLA2, while inhibition of Lp-PLA2 reduced oxLDL production by 19.8% (p < 0.05)., Conclusions/interpretation: Our study suggests adipose tissue and adipocytes are active sources of Lp-PLA2, with differential regulation by fat depot and metabolic state. Moreover, levels of circulating Lp-PLA2 appear to be influenced by unfavourable lipid profiles in type 2 diabetes, which may occur in part through regulation of LDL-cholesterol and oxLDL metabolism in adipocytes.

Data regarding the prevalence and predictors of vitamin D deficiency during early pregnancy are limited. This study aims to fill this gap. A total of 578 Saudi women in their 1 st trimester of pregnancy were recruited between January 2014 and December 2015 from three tertiary care antenatal clinics in Riyadh, Saudi Arabia. Information collected includes socio-economic, anthropometric, and biochemical data, including serum vitamin D (25(OH)D) levels, intake of calcium and vitamin D, physical activity, and sun exposure indices. Pregnant women with 25(OH)D levels <50 nmol/L were considered vitamin D deficient. The majority of participants ( n = 468 (81%)) were vitamin D deficient. High levels of indoor activity, whole body clothing, multiparity, total cholesterol/HDL ratio(>3.5), low HDL-cholesterol, and living in West Riyadh were significant independent predictors for vitamin D deficiency, with odds ratios (ORs) (95% confidence interval) of 25.4 (5.5&ndash;117.3), 17.8 (2.3&ndash;138.5), 4.0 (1.7&ndash;9.5), 3.3 (1.4&ndash;7.9), 2.8 (1.2&ndash;6.4), and 2.0 (1.1&ndash;3.5), respectively. Factors like increased physical activity, sun exposure at noon, sunrise or sunset, high educational status, and residence in North Riyadh were protective against vitamin D deficiency with ORs 0.2 (0.1&ndash;0.5); 0.2 (0.1&ndash;0.6); 0.3 (0.1&ndash;0.9); and 0.4 (0.2&ndash;0.8), respectively. All ORs were adjusted for age, BMI, sun exposure, parity, summer season, vitamin D intake, multivitamin intake, physical activity, education, employment, living in the north, and coverage with clothing. In conclusion, the prevalence of vitamin D deficiency among Saudi women during early pregnancy was high (81%). Timely detection and appropriate supplementation with adequate amounts of vitamin D should reduce the risks of vitamin D deficiency and its complications during pregnancy.

The recently published results of the sequential treatment of postmenopausal osteoporotic women with subcutaneous abaloparatide (80 µg/day) (ABL) for 18 months followed by 6 months of oral alendronate (70 mg/week) (ALN) support the administration of an anti-resorptive agent after completion of a treatment course with an osteoanabolic agent. The ABL/ALN sequence resulted in greater bone mineral density gains at all skeletal sites and in a reduction of vertebral, non-vertebral, major and clinical fractures compared to what is observed after 18 months of placebo followed by 6 months of ALN. Whereas questions remained unanswered about the ideal anti-resorptive agent to be used after ABL, the optimal duration of the administration of the anti-resorptive drug or the potential interest of re-initiating a course of ABL after a limited administration of ALN, these results support the use of the ABL/ALN sequence in the management of postmenopausal osteoporosis.

Background: Several guidelines have been reported for bone-directed treatment in women with early breast cancer (EBC) for averting fractures, particularly during aromatase inhibitor (AI) therapy. Recently, a number of studies on additional fracture related risk factors, new treatment options as well as real world studies demonstrating a much higher fracture rate than suggested by randomized clinical controlled trials (RCTs). Therefore, this updated algorithm was developed to better assess fracture risk and direct treatment as a position statement of several interdisciplinary cancer and bone societies involved in the management of AI-associated bone loss (AIBL)., Patients and Methods: A systematic literature review identified recent advances in the management of AIBL. Results with individual agents were assessed based on trial design, size, follow-up, and safety., Results: Several fracture related risk factors in patients with EBC were identified. Although, the FRAX algorithm includes fracture risk factors (RF) in addition to BMD, it does not seem to adequately address the effects of AIBL. Several antiresorptive agents can prevent and treat AIBL. However, concerns regarding compliance and long-term safety remain. Overall, the evidence for fracture prevention is strongest for denosumab 60 mg s.c. every 6 months. Additionally, recent studies as well as an individual patient data meta-analysis of all available randomized trial data support additional anticancer benefits from adjuvant bisphosphonate treatment in postmenopausal women with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality that needs to be taken into account when advising on management of AIBL., Conclusions: In all patients initiating AI treatment, fracture risk should be assessed and recommendation with regard to exercise and calcium/vitamin D supplementation given. Bone-directed therapy should be given to all patients with a T-score<-2.0 or with a T-score of <-1.5 SD with one additional RF, or with ≥2 risk factors (without BMD) for the duration of AI treatment. Patients with T-score>-1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12 - 24 months. Furthermore, because of the decreased incidence of bone recurrence and breast cancer specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.

Background: We aimed to compare the prevalence of childhood obesity and other cardiometabolic risk factors from two independent cohorts (2008 and 2013) in Riyadh, Saudi Arabia., Methods: A total of 4549 adolescents aged 12-18 years [2454 boys, 2095 girls], taken from two independent cohorts, 5 years apart (2008 and 2013), were included. Anthropometrics were measured, and fasting blood samples were taken to ascertain glucose and lipid profile., Results: The overall prevalence of obesity was significantly higher in 2013 [15.3 (95% confidence interval 13.7-16.9)] than 2008 [12.6 (11.3-13.9)] (P = 0.012). Stratified by sex, the prevalence of obesity among boys was significantly higher in 2013 than 2008 [2008 = 12.0 (10.3-13.7) versus 2013 = 17.4 (15.1-19.7); P < 0.001]. The age groups 13 and 15 years had a significantly higher mean triglycerides in 2013 than 2008 (P-values 0.003 and <0.001, respectively) and lower mean HDL-cholesterol also in the 13 years old age group (P < 0.001)., Conclusions: The prevalence of childhood obesity in Saudi Arabia has increased in particular age groups (13-15 years) during a 5-year span. Special attention is warranted in these vulnerable age groups, particularly in boys, as cardiometabolic risk factors appear to worsen., (© 2016 John Wiley & Sons Ltd.)

Unlabelled: Middle East respiratory syndrome-related coronavirus (MERS-CoV) spreads to humans via zoonotic transmission from camels. MERS-CoV belongs to lineage C of betacoronaviruses (betaCoVs), which also includes viruses isolated from bats and hedgehogs. A large portion of the betaCoV genome consists of two open reading frames (ORF1a and ORF1b) that are translated into polyproteins. These are cleaved by viral proteases to generate 16 nonstructural proteins (nsp1 to nsp16) which compose the viral replication-transcription complex. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs. Results indicated widespread positive selection, acting mostly on ORF1a. The proportion of positively selected sites in ORF1a was much higher than that previously reported for the surface-exposed spike protein. Selected sites were unevenly distributed, with nsp3 representing the preferential target. Several pairs of coevolving sites were also detected, possibly indicating epistatic interactions; most of these were located in nsp3. Adaptive evolution at nsp3 is ongoing in MERS-CoV strains, and two selected sites (G720 and R911) were detected in the protease domain. While position 720 is variable in camel-derived viruses, suggesting that the selective event does not represent a specific adaptation to humans, the R911C substitution was observed only in human-derived MERS-CoV isolates, including the viral strain responsible for the recent South Korean outbreak. It will be extremely important to assess whether these changes affect host range or other viral phenotypes. More generally, data herein indicate that CoV nsp3 represents a major selection target and that nsp3 sequencing should be envisaged in monitoring programs and field surveys., Importance: Both severe acute respiratory syndrome coronavirus (SARS-CoV) and MERS-CoV originated in bats and spread to humans via an intermediate host. This clearly highlights the potential for coronavirus host shifting and the relevance of understanding the molecular events underlying the adaptation to new host species. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs and in 87 sequenced MERS-CoV isolates. Results indicated widespread positive selection, stronger in ORF1a than in ORF1b. Several selected sites were found to be located in functionally relevant protein regions, and some of them corresponded to functional mutations in other coronaviruses. The proportion of selected sites we identified in ORF1a is much higher than that for the surface-exposed spike protein. This observation suggests that adaptive evolution in ORF1a might contribute to host shifts or immune evasion. Data herein also indicate that genetic diversity at nonstructural proteins should be taken into account when antiviral compounds are developed., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Middle East respiratory syndrome coronavirus (MERS-CoV) originated in bats and spread to humans via zoonotic transmission from camels. We analyzed the evolution of the spike (S) gene in betacoronaviruses (betaCoVs) isolated from different mammals, in bat coronavirus populations, as well as in MERS-CoV strains from the current outbreak. Results indicated several positively selected sites located in the region comprising the two heptad repeats (HR1 and HR2) and their linker. Two sites (R652 and V1060) were positively selected in the betaCoVs phylogeny and correspond to mutations associated with expanded host range in other coronaviruses. During the most recent evolution of MERS-CoV, adaptive mutations in the HR1 (Q/R/H1020) arose in camels or in a previous host and spread to humans. We determined that different residues at position 1020 establish distinct inter- and intra-helical interactions and affect the stability of the six-helix bundle formed by the HRs. A similar effect on stability was observed for a nearby mutation (T1015N) that increases MERS-CoV infection efficiency in vitro. Data herein indicate that the heptad repeat region was a major target of adaptive evolution in MERS-CoV-related viruses; these results are relevant for the design of fusion inhibitor peptides with antiviral function.

Incense smoke exposure has recently been linked to cardiovascular disease risk, heart rate variability, and endothelial dysfunction. To test the possible underlying mechanisms, oxidative stress, and inflammatory markers, gene expressions of cardiac hypertrophic and xenobiotic-metabolizing enzymes and ultrastructural changes were measured, respectively, using standard, ELISA-based, real-time PCR, and transmission electron microscope procedures in heart tissues of Wistar rats after chronically exposing to Arabian incense. Malondialdehyde, tumor necrosis alpha (TNF)-α, and IL-4 levels were significantly increased, while catalase and glutathione levels were significantly declined in incense smoke-exposed rats. Incense smoke exposure also resulted in a significant increase in atrial natriuretic peptide, brain natriuretic peptide, β-myosin heavy chain, CYP1A1 and CYP1A2 messenger RNAs (mRNAs). Rats exposed to incense smoke displayed marked ultrastructural changes in heart muscle with distinct cardiac hypertrophy, which correlated with the augmented hypertrophic gene expression as well as markers of cardiac damage including creatine kinase-myocardial bound (CK-MB) and lactate dehydrogenase (LDH). Increased oxidative stress, inflammation, altered cardiac hypertrophic gene expression, tissue damage, and architectural changes in the heart may collectively contribute to increased cardiovascular disease risk in individuals exposed to incense smoke. Increased gene expressions of CYP1A1 and CYP1A2 may be instrumental in the incense smoke-induced oxidative stress and inflammation. Thus, incense smoke can be considered as a potential environmental pollutant and its long-term exposure may negatively impact human health.

We report trends in type 2 diabetes mellitus and obesity in adults residing in the Arabian Gulf States. Among the Saudi population, the prevalence of diabetes increased from 10.6% in 1989 to 32.1% in 2009. Prevalence of the disease increased faster among Saudi men than women, with growth rates of 0.8% and 0.6% per year, respectively., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Boswellia papyrifera and Boswellia carterii diffuses smoke polluting air that adversely affects indoor environment that certainly harm human health. Therefore, this study aims at ascertaining the effect of these plants on gonadal hormones and molecular changes in rat spermatozoa. The animals were exposed to 4 g/kg body weight of B. papyrifera and B. carterii daily for 120 days along with suitable controls. Significant decreases in FSH, LH and testosterone levels were evidenced, along with a reduction of protein, sialic acid, and carnitine levels. In sperm physiology, sperm count, motility, speed decrease, whereas sperm anomalies increase. TEM observation indicates morphological changes in plasma and acrosomal membranes, cytoplasmic droplet in the tail region, vacuolated, and disorganization of the mitochondrial sheath. These findings demonstrate that B. papyrifera and B. carterii smoke affects the process of sperm formation and maturation, which indicates the detrimental effects of these plants on the reproductive system., (Copyright © 2014 Académie des sciences. Published by Elsevier SAS. All rights reserved.)

Thiamine deficiency has been documented to be prevalent in patients with diabetes mellitus, and correction of thiamine deficiency in this population may provide beneficial effects in several cardiometabolic parameters, including prevention of impending complications secondary to chronic hyperglycemia. In this interventional study, we aim to determine whether thiamine supplementation is associated with cardiometabolic improvements in patients with diabetes mellitus type 2 (DMT2). A total of 86 subjects (60 DMT2 and 26 age- and BMI-matched controls) were included and were given thiamine supplements (100 mg/day) for six months. Anthropometrics and metabolic profiles were measured routinely. Serum thiamine and its derivatives were measured using high performance liquid chromatography. In all groups, there was a significant decrease in total cholesterol after three months (p = 0.03) as well as in HDL cholesterol after six months of thiamine supplementation (p = 0.009). Significant improvements were also observed in the mean serum levels of creatinine (p = 0.001), as well as thiamine and its derivatives in both serum and urinary levels across follow-up visits (p-values 0.002 and <0.001, respectively). In the DMT2 group, improvements were observed in lipid profile (mean serum LDL and total cholesterol with p-values 0.008 and 0.006, respectively), serum thiamine (p < 0.001), TMP (p < 0.001), TDP (p < 0.001), urinary thiamine (p < 0.001) and serum creatinine (p < 0.001). Thiamine supplementation is a promising adjuvant therapy for patients with DMT2. Longer clinical trials are needed to determine its protective effect in DMT2 complications.

Objective: Central obesity and sub-clinical inflammation increase metabolic risk, this study examined the intracellular inflammatory pathways in adipose tissue (AT) that contribute to this risk., Design and Methods: This study therefore addressed the influence of NFκB and JNK activation in human abdominal subcutaneous (AbdSc) and omental (Om) AT, the effect of adiposity, T2DM status and the role of TNFα in vitro, using molecular biology techniques., Results: Our data showed NFκB activity is increased in Om AT versus AbdSc AT (P<0.01), which was reversed with respect to depot specific activation of JNK (P<0.01). However, T2DM status appeared to preferentially activate NFκB (P<0.001) over JNK. Furthermore, in vitro studies showed recombinant human (rh) TNFα treated AbdSc adipocytes increased NFκB activity over time (2-48 h, P<0.05) whilst JNK activity reduced (2 h, 4 h, P<0.05); inhibitor studies supported a preferential role for NFκB as a modulator of TNFα secretion., Conclusions: These studies suggest distinct changes in NFκB and JNK activation, dependent upon AT depot, adiposity and T2DM status, with in vitro use of rh TNFα leading to activation of NFκB. Consequently NFκB appears to play a central role in inflammatory mediated metabolic disease over JNK, highlighting NFκB as a potential key target for therapeutic intervention., (Copyright © 2013 The Obesity Society.)

This review aims to search and summarise the available evidence on the association between dietary factors and type 2 diabetes mellitus (T2DM) in Middle Eastern populations, where diabetes prevalence is among the highest in the world. Electronic databases were searched; authors, libraries, and research centres in the Middle East were contacted for further studies and unpublished literature. Included studies assessed potential dietary factors for T2DM in Middle Eastern adults. Two reviewers assessed studies independently. Extensive searching yielded 17 studies which met the inclusion criteria for this review. The findings showed that whole-grain intake reduces the risk of T2DM, and potato consumption was positively correlated with T2DM. Vegetables and vegetable oil may play a protective role against T2DM. Dietary patterns that are associated with diabetes were identified, such as Fast Food and Refined Grains patterns. Two studies demonstrated that lifestyle interventions decreased the risk of T2DM. In summary, the identified studies support an association between some dietary factors and T2DM; however, many of the included studies were of poor methodological quality so the findings should be interpreted with caution. The review draws attention to major gaps in current evidence and the need for well-designed studies in this area.

Boswellia papyrifera and Boswellia carterii, known as Arabian incense, diffuses smoke, contaminating the air, which adversely affects human health. Therefore, this study was designed to ascertain the effect of these plants on histopathological and ultrastructure changes in cauda epididymis of Albino rats. Animals were exposed to 4 g/kg body weight of B. papyrifera and B. carterii daily for 120 days along with suitable controls. Our study indicates a significant reduction in epithelial heights. Cells showed signs of degeneration. The ultrastructural study revealed that the cauda epididymis was affected, including its cell types. Furthermore, a decrease in the size of mitochondria, Golgi complex, and both ERs was observed. In all treated groups, plasma fructose decreased considerably, indicating the sign of reduced energy, vital for motility and other sperm functions. The results of this study suggest that these plants systematically affect cauda epididymal cell types and its lumen through its potential toxicity., (Copyright © 2013. Published by Elsevier SAS.)

In this study the effect of Boswellia papyrifera (B. papyrifera) and Boswellia carterii (B. carterii) smoke exposure on spermatogenesis and sperm parameters in male albino rats was investigated. Rats (n = 11) were exposed daily in smoking chambers to smoke emanated by burning 4 g each of either B. papyrifera or B. carterii for 48 days. At the end of exposure duration rats were killed, and the testes were excised and analysed for histopathological and ultrastructural changes. Sperm analysis including total sperm count, motility, velocity and relative percentage of abnormal sperms were recorded. Rats exposed to B. papyrifera and B. carterii showed significant disturbances in spermatogenetic patterns and changes in sperm kinetics compared to unexposed rats. Atrophied seminiferous tubules with dynamic changes were also noticed. The boundaries of intercellular and intracellular vacuoles were seen in the Sertoli cells. Furthermore, in spermatids acrosomal vesicles were not fully formed. Degenerating spermatids were devoid of their nuclear membrane with electron dense matrix and vacuolization. Structural changes in Leydig cells were observed. Sperm analysis in exposed rats exhibited significant decrease in the sperm count, motility, speed and an increase in sperm anomalies when compare to controls. These findings demonstrate that the B. papyrifera and B. carterii smoke affects the process of spermatogenesis and sperm parameters and indicate the detrimental effects of these incense materials on human reproductive system.

Background: Hypovitaminosis D has been associated with an increased prevalence of Type 2 diabetes mellitus (DMT2) and metabolic syndrome manifestations. The purpose of this study was to examine the association between 25-hydroxy-vitamin D (25-OH-VitD) levels and indices of insulin resistance (IR), including adipocytokines, in a Saudi population with or without DMT2., Subjects and Methods: A total of 266 subjects (153 DMT2 and 113 healthy controls) aged 26-80 yr were randomly selected from the existing Biomarkers Screening in Riyadh Program (RIYADH Cohort). Subjects were assessed clinically, anthropometry was performed, morning blood chemistries, including fasting glucose (FG), triglycerides, total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol were obtained. Homeostasis model assessment of IR (HOMA-IR) was calculated, and serum 25-OH-VitD, leptin, adiponectin, resistin, insulin, high sensitivity CRP (hsCRP), and tumor necrosis factor α concentrations were measured using specific assays., Results: In DMT2 subjects, negative correlations between 25-OH-vitD and body mass index (BMI), FG, insulin, HOMA-IR, cholesterol, LDL-C, and hsCRP were observed, while a positive correlation between 25-OH-VitD and adiponectin was detected. The later remained significant after controlling for BMI. Interestingly, only weak and nonsignificant associations between 25-OH-VitD and metabolic parameters were observed in the control group, whereas, when the entire population was examined, negative correlations were evident primarily between 25-OH-VitD and FG, HOMA-IR, total cholesterol, LDL-C. These associations remained significant after controlling for BMI., Conclusions: These results suggest that hypovitaminosis D associations with metabolic disturbances are accentuated in DMT2. The BMIindependent positive correlation between 25-OH-VitD and adiponectin suggests a potential role for this adipocytokine as a link between 25-OH-VitD and IR in patients with DMT2.

Background: Thiamine deficiency has been linked to microvascular complications in patients with diabetes mellitus (DM). In this study, we aim to assess blood and urine thiamine status by high performance liquid chromatography (HPLC) in patients with DM Type 1 and Type 2 (DMT1, DMT2) and to identify associations with markers of incipient nephropathy and kidney dysfunction., Subjects and Methods: A total of 205 subjects (43 DMT1 and 162 DMT2) with and without microalbuminuria and 26 non-diabetic controls were included. Fasting blood samples were collected and anthropometric parameters were measured. Fasting blood, lipid and renal profile were determined routinely. Blood thiamine concentration, its phosphate esters and urine thiamine were quantified using HPLC., Results: Blood thiamine concentrations (ng 1-1) were decreased by 75.7% and 49.6% in patients with DMT1 and DMT2, respectively [controls (54.8+/-11.4); DMT1 (41.5+/-17.9); DMT2 (27.2+/-12.7), p<0.001]. Among those with normo-albuminuria, urinary excretion of thiamine was significantly increased to 390.1 microg/ml and 1212.4 microg/ml in DMT1 and DMT2 respectively, as compared to controls (326.4 microg/ml). DMT1 and DMT2 patients with micro- albuminuria on the other hand had 2.5- and 3.4-fold increase in urinary excretion of thiamine compared to controls., Conclusion: Low levels of blood thiamine are present in patients with DMT1 and DMT2, and are associated with increased thiamine clearance.

Adipocytes secrete many proteins that regulate metabolic functions. The gene inter-α (globulin) inhibitor H5 (ITIH-5) encodes a secreted protein and is known to be expressed abundantly in the placenta. However, using gene expression profiles data we observed high expression of ITIH-5 in adipose tissue. The aim of this study was to test the hypothesis that ITIH-5 is strongly expressed in human adipocytes and adipose tissue, and is related to obesity and clinical metabolic variables. ITIH-5 adipose tissue mRNA expression was analyzed with DNA microarray and real-time PCR, and its association with clinical variables was examined. ITIH-5 protein expression was analyzed using western blot. ITIH-5 mRNA expression was abundant in human adipose tissue, adipocytes, and placenta, and higher in subcutaneous (sc) compared to omental adipose tissue (P < 0.0001). ITIH-5 mRNA and protein expression in sc adipose tissue were higher in obese compared to lean subjects (P < 0.0001 and P < 0.001, respectively). ITIH-5 mRNA expression was reduced after diet-induced weight loss (P < 0.0001). ITIH-5 mRNA expression was associated with anthropometry and clinical metabolic variables. In conclusion, ITIH-5 is highly expressed in sc adipose tissue, increased in obesity, down regulated after weight loss, and associated with measures of body size and metabolism. Together, this indicates that ITIH-5 merits further investigation as a regulator of human metabolism.

Background and Purpose: Hyperglycemia induced endoplasmic reticulum (ER) stress in diabetic vascular cells is considered an increasingly important factor for the genesis and development of atherosclerosis and cardiovascular complications. This study investigated firstly, the effect of hyperglycemia in ER stress induction in Human Umbilical Vein Endothelial Cells (HUVECs) and secondly, the impact of Glucagon like petide-1 (GLP-1) analogue, Liraglutide, in reducing ER stress in HUVECs exposed to high glucose (HG)., Experimental Approach: HUVECs were incubated for 12 hr in 5 mmol/L normal glucose (NG) or in 25 mmol/L (HG) glucose with or without different concentrations of Liraglutide (1 nM, 10 nM or 100 nM) and components of ER stress pathways studied, using western blotting, to assess their expression levels., Key Results: Our data confirmed that exposure of HUVECs to HG up-regulated both up- (Bip/Grp78, PERK and IRE1α) and downstream (Calnexin, PDI and Ero1-Lα) markers of ER stress compared with control. Furthermore, Liraglutide showed a dose dependent capacity in preventing the onset of ER stress in HUVECs, with a maximum activity at 100 nM. HG also upregulated proapoptotic PUMA protein levels compared to controls. Interestingly, Liraglutide also induced OPA1, a marker of mitochondrial fusion, in a dose dependent manner., Conclusions and Implications: Liraglutide prevented the onset of ER stress in human endothelial cells exposed to HG. Our data suggest that Liraglutide may exert its effects by inducing mitochondrial fusion processes, thus preventing HG induced mitochondrial fragmentation and apoptosis in human endothelial cells., (Copyright © 2011 Elsevier B.V. All rights reserved.)