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Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease whereby its main pathological drivers of disability and damage are vascular injury, inflammatory cell infiltration, and fibrosis. These mechanisms result in diffuse and diverse impairments arising from ischemic circulatory dysfunction leading to painful skin ulceration and calcinosis, neurovascular aberrations hindering gastrointestinal (GI) motility, progressive painful, incapacitating or immobilizing effects of inflammatory and fibrotic effects on the lungs, skin, articular and periarticular structures, and muscle. SSc-related impairments impede routine activities of daily living (ADLs) and disrupt three critical life areas: work, family, social/leisure, and also impact on psychological well-being. Physical activity and exercise are globally recommended; however, for connective tissue diseases, this guidance carries greater impact on inflammatory disease manifestations, recovery, and cardiovascular health. Exercise, through myogenic and vascular phenomena, naturally targets key pathogenic drivers by downregulating multiple inflammatory and fibrotic pathways in serum and tissue, while increasing circulation and vascular repair. G-FoRSS, The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis recognizes the scientific basis of and advocates for education and research of exercise as a systemic and targeted SSc disease-modifying treatment. An overview of biophysiological mechanisms of physical activity and exercise are herein imparted for patients, clinicians, and researchers, and applied to SSc disease mechanisms, manifestations, and impairment. A preliminary guidance on exercise in SSc, a research agenda, and the current state of research and outcome measures are set forth., Competing Interests: Declaration of competing interest None of the authors have conflicts to disclose in relation to this publication., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to report that are related to the reported content of this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In 2017, JECFA requested reproductive and developmental toxicity studies to finalize an acceptable daily intake for solvent rosemary extracts. Thus, an OECD 421 reproductive/developmental toxicity study was conducted using an acetone rosemary extract that complied with JECFA and EFSA food additive specifications. Rosemary extract was provided to rats at dietary concentrations of 0 (control), 2100, 3600, or 5000 mg/kg, for 14 days before mating, during mating, and thereafter (throughout gestation and up to Lactation Day 13 for females) until necropsy. General toxicity (clinical signs, body weight, food consumption) and reproductive/developmental outcomes (fertility and mating performance, estrous cycles, anogenital distance, thyroid hormones, reproductive organ weights, thyroid histopathology) were assessed. There were no signs of general toxicity and no effects on reproduction; thus, the highest concentration tested (equivalent to mean daily intakes of 316 or 401 mg/kg bw/day [149 or 189 mg/kg bw/day carnosol and carnosic acid] for males and females, respectively) was established as the no-observed-adverse-effect level for general and reproductive toxicity. Dose-related reductions in T4 were observed for Day 13 pups (not seen on Day 4) but were not accompanied by thyroid weight changes or histopathological findings; further investigations are required to determine the biological relevance of these T4 reductions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Toxicology studies conducted with oil-soluble rosemary extracts to support authorization as a food additive (antioxidant) in the EU include an Ames test using a supercritical carbon dioxide extract (D74), a full 90-day study using D74 and an acetone extract (F62), and an investigative 90-day study with a 28-day recovery period (using D74 only). D74 was non-mutagenic in the Ames test. In the full 90-day study, where rats (20/sex/group) were either provided control diet or diets containing D74 (300, 600, or 2400 mg/kg) or F62 (3800 mg/kg), liver enlargement and hepatocellular hypertrophy were observed. To determine a mode of action and assess the reversibility of the hepatic effects, an investigative 90-day study was conducted using female rats (10/group receiving control diet or diet containing 2400 mg/kg D74). Liver enlargement was fully reversible after 28 days and microsomal enzyme analysis revealed reversible induction of cytochrome P450 enzymes (CYP2A1, CYP2A2, CYP2C11, CYP2E1, and CYP4A), demonstrating that the hepatic effects were adaptive and of no toxicological concern. Therefore, the highest dietary concentrations were established as the NOAELs. The investigative 90-day study NOAEL (providing 64 mg/kg bw/day carnosol and carnosic acid [the primary antioxidant components]) was used to establish a temporary ADI for rosemary extracts., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Lacto-N-tetraose (LNT) is one of the most abundant oligosaccharides that are endogenously present in human breast milk. To simulate the composition of human breast milk more closely, commercial infant formula can be supplemented with human-identical milk oligosaccharides, which are manufactured structurally identical versions of their naturally occurring counterparts. As part of the safety evaluation of LNT, in vitro genotoxicity tests and a subchronic oral gavage toxicity study (in neonatal Sprague-Dawley rats) were conducted. In the subchronic study, LNT was administered at dose levels of 0, 1,000, 2500 or 4000 mg/kg body weight (bw)/day, once daily for at least 90 days, followed by a 4-week treatment-free period. An identically comprised reference control group received fructooligosaccharides powder (a non-digestible oligosaccharide used in infant formula) at 4000 mg/kg bw/day, to allow for direct comparison against the high-dose LNT group. LNT was non-genotoxic in the in vitro tests. There were no compound-related adverse effects in the 90-day study; therefore, 4000 mg/kg bw/day (the highest feasible dose) was established as the no-observed-adverse-effect-level. These results support the safe use of LNT in infant formula and as a food ingredient, at levels not exceeding those found naturally in human breast milk., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Due to the alarming rise in opioid-related overdose deaths, a public health emergency was declared in British Columbia (BC). In this study, we examined the relationship between illicit fentanyl and heroin found in seized drugs and illicit overdose deaths in BC., Methods: An observational cross-sectional survey was conducted using BC data from Health Canada's Drug Analysis Service, which analyzes drug samples seized by law enforcement agencies, and non-intentional illicit overdoses from the BC Coroner's Service, from 2000 to 2016. Initial scatter plots and subsequent multivariate regression analysis were performed to describe the potential relationship between seized illicit fentanyl samples and overdose deaths and to determine if this differed from seized heroin and overdose deaths. Fentanyl samples were analyzed for other drug content., Results: Fentanyl is increasingly being found combined with other opioid and non-opioid illicit drugs. Strong positive relationships were found between the number of seized fentanyl samples and total overdose deaths (R2 = 0.97) as well as between seized fentanyl and fentanyl-detected overdose deaths (R2 = 0.99). A positive association was found between the number of seized heroin samples and total overdose deaths (R2 = 0.78)., Conclusion: This research contributes to the expanding body of evidence implicating illicit fentanyl use (often combined with heroin or other substances) in overdose deaths in BC. Policy makers and healthcare providers are urged to implement drug treatment and harm reduction strategies for people at risk of overdose associated with current trends in illicit opioid use., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The potential toxicity of two savory food ingredients produced by fermentation of enzymatically hydrolyzed corn starch (Savory Base 100 and Savory Base 200) was evaluated individually in a bacterial reverse mutation assay, an in vitro mammalian cell gene mutation assay, an acute oral study and as a mixture in a 90-day dietary study. In the bacterial reverse mutation and in vitro mammalian cell gene mutation assays, neither ingredient was mutagenic at concentrations up to 5000 μg/plate and 5000 μg/mL, respectively in the presence and absence of metabolic activation. In the acute study, the no-observed-adverse-effect level (NOAEL) for each Savory Base 100 and Savory Base 200 in male and female rats was 2000 mg/kg body weight. In the 90-day study, the hematology and clinical chemistry findings and histopathological changes noted in the liver, heart and kidneys were deemed to be of no toxicological significance, as the mean values were within the historical control range, were not dose-dependent, occurred at a similar frequency in control groups, or only occurred in the control group. Considering these findings, the NOAEL for Savory Base 100 and Savory Base 200 was 2333 and 1167 mg/kg body weight, respectively, the highest dose tested in each case., (Copyright © 2017 Elsevier Inc. All rights reserved.)

l-Fucose is a natural monosaccharide present in mammals where it is found predominantly as an O-glycosidically linked component of glycoproteins, glycolipids, and oligosaccharides. It is also present in its free form in human breast milk (human milk monosaccharide). l-Fucose plays important roles in the development of the immune and nervous systems and is involved in cognitive function and memory formation. The human-identical milk monosaccharide l-fucose is therefore proposed for use in infant formulas to better simulate the free saccharides present in human breast milk. As part of the safety evaluation of l-fucose, a subchronic dietary toxicity study preceded by an in utero phase was conducted in Sprague-Dawley rats. l-Fucose was without maternal toxicity or compound-related adverse effects on female reproduction and general growth and development of offspring at a maternal dietary level up to 1%, equivalent to a dose of 1655 mg/kg body weight (bw)/day. During the subchronic phase, no compound-related adverse effects were observed in first generation rats at dietary levels of up to 1% (highest level tested), corresponding to doses of 516 and 665 mg/kg bw/day in males and females, respectively. l-Fucose was non-genotoxic in a series of in vitro genotoxicity/mutagenicity tests. These results support the safe use of l-fucose in infant formula and as a food ingredient at levels equivalent to those present in human breast milk., (Copyright © 2015 Elsevier Inc. All rights reserved.)

N-Acetyl-d-neuraminic acid (Neu5Ac) is the predominant form of sialic acid (Sia) in humans, while other mammals express Sia as a mixture with N-glycolyl-d-neuraminic acid (Neu5Gc). Neu5Ac occurs in highest levels in the brain and in breast milk, and is therefore, coined a human-specific milk monosaccharide, and is thought to play an important nutritional role in the developing infant. Synthesized human-identical milk monosaccharide (HiMM) Neu5Ac is proposed for use in infant formulas to better simulate the free saccharides present in human breast milk. As part of the safety evaluation of HiMM Neu5Ac, a subchronic dietary toxicity study preceded by an in utero phase was conducted in Sprague-Dawley rats. Neu5Ac was without maternal toxicity or compound-related adverse effects on female reproduction and on the general growth and development of offspring at a maternal dietary level of up to 2%, equivalent to a dose of 1895mg/kg body weight (bw)/day. During the subchronic phase, no compound-related adverse effects were observed in first generation rats at dietary levels of up to 2% (highest level tested), corresponding to doses of 974 and 1246mg/kgbw/day in males and females, respectively. Neu5Ac also was non-genotoxic in a series of in vitro genotoxicity/mutagenicity tests. These results support the safe use of Neu5Ac both in infant formula and as a food ingredient at levels equivalent to those found naturally in human breast milk., (Copyright © 2014 Elsevier Inc. All rights reserved.)