International Classification of Functioning, Disability and Health Core Set construction in systemic sclerosis and other rheumatic diseases: a EUSTAR initiative

Objectives. To outline rationale and potential strategies for rheumatology experts to be able to develop disease-specific Core Sets under the framework of the International Classification of Functioning, Disability and Health (ICF). ICF is a universal framework introduced by the World Health Organization (WHO) to describe and quantify the impact and burden on functioning of health conditions associated with impairment/disability. Methods. A combined effort of the EULAR Scleroderma Clinical Trial and Research and the ICF Research Branch was initiated to develop an ICF language for scleroderma. From our Medline literature review, using the abbreviation and spelled out version of ICF, we assembled approaches and methodological reasoning for steps of core set development. Results. The ICF can be used for patient care and policy-making, as well as the provision of resources, services and funding. The ICF is used on institutional, regional, national and global levels. Several diseases now have ICF Core Sets. Patients with complex rheumatologic diseases will benefit from a disease-specific ICF Core Set and should be included in all stages of development. ICF Core Set development for rheumatic diseases can be conducted from a number of feasible strategies. Conclusion. This overview should help to clarify useful processes leading to development of an ICF Core Set, and also provide a platform for expert groups considering such an endeavou

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

Asia; Colorectal cancer; PembrolizumabAsia; Cáncer colorrectal; PembrolizumabÀsia; Càncer colorectal; PembrolizumabThe phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002

Genetic Polymorphism of Geranylgeranyl Diphosphate Synthase (GGSP1) Predicts Bone Density Response to Bisphosphonate Therapy in Korean Women

Purpose: Genetic factor is an important predisposing element influencing the susceptibility to osteoporosis and related complications. The purpose of the present study is to investigate whether genetic polymorphisms of farnesyl diphosphate synthase (FDPS) or geranylgeranyl diphosphate synthase (GGPS) genes were associated with the response to bisphosphonate therapy. Materials and Methods: In the present study, 144 Korean women with osteoporosis were included. Among 13 genetic polymorphisms found within the FDPS and GGPS1 gene, 4 genetic polymorphisms with frequencies > 5% were selected for further study. Bone mineral density (BMD) response after 1 year treatment of bisphosphonate therapy was analyzed according to the genotypes. Results: Women with 2 deletion allele of GGPS1 -8188A ins/del (rs3840452) had significantly higher femoral neck BMD at baseline compared with those with one or no deletion allele (0.768 +/- 0.127 vs. 0.695 +/- 0.090 respectively; p = 0.041). The response rate of women with 2 deletion allele of GGPS1 -8188A ins/del (28.6%) was significantly lower than the rate of women with one (81.4%) or no deletion allele (75.0%) (p = 0.011). Women with 2 deletion allele of GGPS1 -8188A ins/del had 7-fold higher risk of non-response to bisphosphonate therapy compared with women with other genotypes in GGPS1 -8188 after adjusting for baseline BMD (OR = 7.48; 95% CI = 1.3242.30; p = 0.023). Other polymorphisms in FDPS or GGPS1 were not associated with lumbar spine BMD or femoral neck BMD. Conclusion: Our Study suggested that GGPS1 -8188A ins/del polymorphism may confer susceptibility to femoral heck BMD response to bisphosphonate therapy in Korean women. However, further study should be done to confirm the results in a larger population.This work was supported by a grant from Ministry of Health, Welfare and Family of Korea (03-PJ10-PG13- GD01-0002).Guo RT, 2007, P NATL ACAD SCI USA, V104, P10022, DOI 10.1073/pnas.0702254104Gallagher JC, 2006, BONE, V39, P1268, DOI 10.1016/j.bone.2006.06.007Bonnick S, 2006, J CLIN ENDOCR METAB, V91, P2631, DOI 10.1210/jc.2005-2602BONNICK SL, 2006, AM J MED S1, V119, pS25Kim SW, 2005, ENDOCR J, V52, P667Palomba S, 2005, OSTEOPOROSIS INT, V16, P943, DOI 10.1007/s00198-004-1800-5Lewiecki EM, 2003, J CLIN DENSITOM, V6, P307Palomba S, 2003, CLIN ENDOCRINOL, V58, P365Qureshi AM, 2002, CALCIFIED TISSUE INT, V70, P158Turner CH, 2002, OSTEOPOROSIS INT, V13, P97Mann V, 2001, J CLIN INVEST, V107, P899Keen RW, 2001, RHEUMATOLOGY, V40, P48Bergstrom JD, 2000, ARCH BIOCHEM BIOPHYS, V373, P231Crilly RG, 2000, OSTEOPOROSIS INT, V11, P607Eisman JA, 1999, ENDOCR REV, V20, P788Tsukamoto K, 1999, J HUM GENET, V44, P148Keen RW, 1998, BONE, V23, P367Masi L, 1998, BIOCHEM BIOPH RES CO, V248, P190Uitterlinden AG, 1998, NEW ENGL J MED, V338, P1016Mizunuma H, 1997, BONE, V21, P379Kurland ES, 1997, J CLIN ENDOCR METAB, V82, P2799Shiraki M, 1997, J BONE MINER RES, V12, P1438Sainz J, 1997, NEW ENGL J MED, V337, P77Johnson ML, 1997, AM J HUM GENET, V60, P1326Langdahl BL, 1997, BONE, V20, P289SILVERMAN SL, 1992, CALCIFIED TISSUE INT, V50, P101

Influence of Cocoa Flavanols and Procyanidins on Free Radical-induced Human Erythrocyte Hemolysis

Cocoa can be a rich source of antioxidants including the flavan-3-ols, epicatechin and catechin, and their oligomers (procyanidins). While these flavonoids have been reported to reduce the rate of free radical-induced erythrocyte hemolysis in experimental animal models, little is known about their effect on human erythrocyte hemolysis. The major objective of this work was to study the effect of a flavonoid-rich cocoa beverage on the resistance of human erythrocytes to oxidative stress. A second objective was to assess the effects of select purified cocoa flavonoids, epicatechin, catechin, the procyanidin Dimer B2 and one of its major metabolites, 3ʹ-O-methyl epicatechin, on free radical-induced erythrocyte hemolysis in vitro. Peripheral blood was obtained from 8 healthy subjects before and 1, 2, 4 and 8 h after consuming a flavonoid-rich cocoa beverage that provided 0.25 g/kg body weight (BW), 0.375 or 0.50 g/kg BW of cocoa. Plasma flavanol and dimer concentrations were determined for each subject. Erythrocyte hemolysis was evaluated using a controlled peroxidation reaction. Epicatechin, catechin, 3ʹ-O-methyl epicatechin and (-)-epicatechin-(4β > 8)epicatechin (Dimer B2) were detected in the plasma within 1 h after the consumption of the beverage. The susceptibility of erythrocytes to hemolysis was reduced significantly following the consumption of the beverages. The duration of the lag time, which reflects the capacity of cells to buffer free radicals, was increased. Consistent with the above, the purified flavonoids, epicatechin, catechin, Dimer B2 and the metabolite 3ʹ-O-methyl epicatechin, exhibited dose-dependent protection against AAPH-induced erythrocyte hemolysis at concentrations ranging from 2.5 to 20 μM. Erythrocytes from subjects consuming flavonoid-rich cocoa show reduced susceptibility to free radical-induced hemolysis (p < 0.05)

Molecular dissection of the domain architecture and catalytic activities of human PrimPol

PrimPol is a primase–polymerase involved in nuclear and mitochondrial DNA replication in eukaryotic cells. Although PrimPol is predicted to possess an archaeo-eukaryotic primase and a UL52-like zinc finger domain, the role of these domains has not been established. Here, we report that the proposed zinc finger domain of human PrimPol binds zinc ions and is essential for maintaining primase activity. Although apparently dispensable for its polymerase activity, the zinc finger also regulates the processivity and fidelity of PrimPol's extension activities. When the zinc finger is disrupted, PrimPol becomes more promutagenic, has an altered translesion synthesis spectrum and is capable of faithfully bypassing cyclobutane pyrimidine dimer photolesions. PrimPol's polymerase domain binds to both single- and double-stranded DNA, whilst the zinc finger domain binds only to single-stranded DNA. We additionally report that although PrimPol's primase activity is required to restore wild-type replication fork rates in irradiated PrimPol−/− cells, polymerase activity is sufficient to maintain regular replisome progression in unperturbed cells. Together, these findings provide the first analysis of the molecular architecture of PrimPol, describing the activities associated with, and interplay between, its functional domains and defining the requirement for its primase and polymerase activities during nuclear DNA replication

Group Music Intervention Reduces Aggression and Improves Self-esteem in Children with Highly Aggressive Behavior: A Pilot Controlled Trial

We investigated the effects of group music intervention on aggression and self-esteem in children with highly aggressive behavior. Forty-eight children were allocated to either a music intervention group or an untreated control group. The music intervention group received 50 min of music intervention twice weekly for 15 consecutive weeks. The outcome measures were Child Behavior Checklist Aggression Problems Scale (Parents), Child Aggression Assessment Inventory (Teachers) and Rosenberg Self-esteem Scale. After 15 weeks, the music intervention group showed significant reduction of aggression and improvement of self-esteem compared with the control group. All outcome measures were significantly lower in the music intervention group than prior to treatment, while there was no change in the control group. These findings suggest that music can reduce aggressive behavior and improve self-esteem in children with highly aggressive behavior. Music intervention is an easily accessible therapy for children and as such may be an effective intervention for aggressive behavior. Further more, objective and replicable measures are required from a randomized controlled trial with a larger sample size and active comparable control

Estimation of manganese daily intake among adults in Korea

The purpose of this study was to estimate daily intake of manganese in Korean adults. Manganese intake was estimated through the use of the database of manganese content in frequently consumed Korean foods after first conducting anthropometric measurement and a survey on dietary intake with 354 Korean adults. Average age, height, weight and body mass index were 54.6 years, 165.7 cm, 67.2 kg and 24.5 kg/m2 in males and 53.8 years, 153.7 cm, 59.1 kg and 24.9 kg/m2 in females. The daily energy intakes of subjects were 1740.1 kcal in males and 1432.6 kcal in females. Male and female subjects recorded, respectively, 5.2 mg and 4.1 mg in manganese intake indicating that the male subjects consume more manganese (p<0.001). And they posted, respectively, 3.0 mg and 2.9 mg in manganese intake per 1000 kcal of energy consumption; it turned out that there was no significant difference. Daily manganese intake of both males and females posted, respectively, 148.8% and 135.2% of the adequate intake, and 8 males and 3 females surpassed the tolerable upper intake level. It is suggested that the study for accurate determination of manganese consumption needs to be more diversified based on the database of manganese content in Korean foods

Fin whales of the Great Bear Rainforest : Balaenoptera physalus velifera in a Canadian Pacific fjord system

Funding: This research was supported by a Mitacs Accelerate Internship (IT21479); the Save Our Seas Foundation; Willow Grove Foundation; Donner Canadian Foundation; Tides Canada; LUSH Charity Pot; private donations to North Coast Cetacean Society; Fisheries and Oceans Canada; and the Canada Nature Fund for Aquatic Species at Risk (CANAFSAR 2019-2021).Fin whales (Balaenoptera physalus) are widely considered an offshore and oceanic species, but certain populations also use coastal areas and semi-enclosed seas. Based upon fifteen years of study, we report that Canadian Pacific fin whales (B. p. velifera) have returned to the Kitimat Fjord System (KFS) in the Great Bear Rainforest, and have established a seasonally resident population in its intracoastal waters. This is the only fjord system along this coast or elsewhere in which fin whales are known to occur regularly with strong site fidelity. The KFS was also the only Canadian Pacific fjord system in which fin whales were commonly found and killed during commercial whaling, pointing to its long-term importance. Traditional knowledge, whaling records, and citizen science databases suggest that fin whales were extirpated from this area prior to their return in 2005-2006. Visual surveys and mark-recapture analysis documented their repopulation of the area, with 100-120 whales using the fjord system in recent years, as well as the establishment of a seasonally resident population with annual return rates higher than 70%. Line transect surveys identified the central and outer channels of the KFS as the primary fin whale habitat, with the greatest densities occurring in Squally Channel and Caamano Sound. Fin whales were observed in the KFS in most months of the year. Vessel- and shore-based surveys (27,311 km and 6,572 hours of effort, respectively) indicated regular fin whale presence (2,542 detections), including mother-calf pairs, from June to October and peak abundance in late August-early September. Seasonal patterns were variable year-to-year, and several lines of evidence indicated that fin whales arrived and departed from the KFS repeatedly throughout the summer and fall. Additionally, we report on the population's social network and morphometrics. These findings offer insights into the dynamics of population recovery in an area where several marine shipping projects are proposed. The fin whales of the Great Bear Rainforest represent a rare exception to general patterns in this species' natural history, and we highlight the importance of their conservation.Publisher PDFPeer reviewe