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To determine the frequency of a common luteinizing hormone variant in a Japanese population and to evaluate its significance in infertility, serum samples were collected from 169 healthy non-pregnant Japanese women, 105 healthy adult Japanese men and 97 female Japanese infertility patients. The luteinizing hormone variant includes two point mutations in the β-subunit gene (Trp8 to Arg8 and Ile15 to Thr15. DNA from blood cells was studied in 10 healthy women, 10 men and five patients using polymerase chain reaction and direct sequencing. In immunoassays, results with a monoclonal antibody recognizing only the wild-type hormone and a polyclonal antibody recognizing the variant as well were compared as a ratio; ratios in heterozygotes and in individuals with only wild-type alleles ranged from 0.19 to 0.50 and from 0.56 to 1.21, respectively, and 0.50 was considered a 'cut-off' value for identifying individuals with the variant. For the larger subject groups, the frequency of the variant was 9.5% in normals. The mean ratio (0.80 ± 0.35) in infertility patients was significantly lower (P < 0.01) than in healthy women (1.09 ± 0.56), and the variant occurred more frequently in infertility patients (16.5%) than in healthy women (8.3%; P < 0.05). The variant was more frequent in patients with ovulatory disorders (43.8%) than other patients (16.0%; P < 0.05). [ABSTRACT FROM PUBLISHER]

An abstract of the article "Phenotypic Plasticity in the Number of Central Strutted Processes in Cyclotella Meneghiniana (Bacillariophyceae)," by Y. Shirokawa, K. Karino, S. Mayama, Y. Wakamoto and M. Shimada is presented.

Both sexes of the damselfish Stegastes nigricans hold individual territories in which they feed on filamentous algae. At dawn, females visit males' territories to spawn, and the males guard the eggs until hatching. We examined how females' spawning behavior varied according to the distances to their mates. Females usually mated with a single male per morning. The distance to the territory of a mate (0.7-12.8 m) did not affect a female's total spawning time per morning, but affected the number of her spawning visits with that male. Females made many repeated spawning visits when spawning with males at short distances, while they spawned the entire clutch in one visit when spawning with males at long distances. This plasticity in female behavior appears to be related to two costs during the spawning visits: (1) intrusions by other fish to feed on algae in the female's territory during her absence, which may cause the female to return repeatedly to her territory for defense, and (2) attacks on the female by other territorial fish, which increased with the distance to their mates' territories. To minimize the sum of both costs, females should change the number of spawning visits depending on the distance to the males' territories. [ABSTRACT FROM AUTHOR]

Objective: Enhanced expression of transforming growth factor (TGF) β in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end-organ damage. ADAM9 activates TGFβ1 by cleaving the latency-associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGFβ1., Methods: We assessed the expression of ADAM9 in the kidneys of mice and humans who were lupus prone. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the up-regulation of ADAM9 and the subsequent activation of TGFβ1. To assess the role of ADAM9 in the development of tubular-intestinal fibrosis in individuals with LN, we generated MRL/lpr mice who were Adam9 deficient., Results: ADAM9 was highly expressed in tubules from MRL/lpr mice. The transcription factor hypoxia-inducible factor-1α was found to promote the transcription of ADAM9 in TECs. TECs from mice who were Adam9 deficient and exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGFβ1 from latent TGFβ1. Coculture of TECs from mice who were Adam9 deficient with fibroblasts in the presence of dimethyloxalylglycine and latent TGFβ1 produced decreased amounts of type I collagen and α-smooth muscle actin (SMA) by fibroblasts. MRL/lpr mice who were Adam9 deficient showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found to increase., Conclusion: Hypoxia promotes the expression of ADAM9 by TECs, which is responsible for the development of interstitial fibrosis in patients with LN by enhancing the TGFβ1 activation, which promotes fibroblasts to produce collagen and α-SMA., (© 2024 American College of Rheumatology.)

Objectives: This study aimed to understand the status quo of medical treatments of the primary disease and pregnancy outcomes in patients with Takayasu arteritis (TAK) and children's birth outcomes., Methods: This study retrospectively enrolled patients with TAK who conceived after the disease onset and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labor, and Welfare for Intractable Vasculitis., Results: This study enrolled 51 cases and 68 pregnancies 2019-2021. Of these, 48 cases and 65 pregnancies (95.6%) resulted in delivery and live-born babies. The median age of diagnosis and delivery was 22 and 31, respectively. Preconception therapy included prednisolone (PSL) in 51 (78.5%, median 7.5 mg/day), immunosuppressants in 18 (27.7%), and biologics in 12 (18.5%) pregnancies. Six cases underwent surgical treatment before pregnancy. Medications during pregnancy included PSL in 48 (73.8%, median: 9 mg/day), immunosuppressants in 13 (20.0%), and biologics in 9 (13.8%) pregnancies. Enlargement of an aneurysm was reported in one pregnancy, which might be associated with increased circulating plasma volume. TAK relapsed in 4 (6.2%) and 8 (12.3%) pregnancies during pregnancy and after delivery, respectively. Additionally, 13/62 (20.9%) preterm infants and 17/59 (28.8%) low birth weight infants were observed, and none had serious postnatal abnormalities. Of the 51 confirmed infants, 42 (82.4%) were exclusively breastfed or mixed with formula., Conclusion: Most pregnancies in TAK were manageable with PSL at ≤10 mg/day. Relapse during pregnancy and postpartum occurred in <20% of pregnancies., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (T fh ) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the T fh -specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human T fh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in T fh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity., (© 2024. The Author(s).)

Background: Prevention of unplanned pregnancies through modern contraceptives among HIV-positive women is one of the essential strategies for reducing mother-to-child transmission of HIV. Family planning and HIV services integration is a national strategy designed to scale-up modern contraceptives among HIV-positive women. This study aims to evaluate the success of a service integration strategy by comparing the prevalence of modern contraceptive use among HIV-positive women receiving ART within integrated services and those not on integrated services (HIV-negative women and HIV-positive women unaware of their status)., Methods: We used data from the Tanzania HIV impact survey (THIS) of 2016/17. THIS provided HIV counselling and testing with a return of results in over 30,000 adults over 15 years of age. Women tested positive self reported their enrollment into ARV with further confirmation through laboratory analysis for any detectible ARV in their blood. All non-pregnant women reported their contraceptive use. Univariate and multivariate logistic regression was used to assess the effect of accessing integrated services controlling for potential confounders., Results: A total of 14,986 women were included in the analysis; HIV-positive women were 1,066 and HIV-negative women were 13,830. Modern contraceptive use prevalence was 35% among HIV-positive women and 30% among HIV-negative women. Among HIV-positive women, those enrolled in integrated services (ART) had a higher prevalence of modern contraceptive (40%) compared to HIV-positive women unaware of their status (27%, p-value = 0.0014). The most common contraceptive methods in HIV-positive women were injectables (32%) and male condoms (31%), while in HIV-negative women, injectables (39%) and implants (30%, n = 1032) were the most preferred methods. Among HIV-positive women, enrolment into integrated services (currently on ART) demonstrated an increase in the odds of modern contraceptives by 85% (AOD = 1.85, 95%CI: 1.27-2.71)., Conclusion: This study found relatively low modern contraceptive use among HIV-positive women in the general population despite the existance of service integration program and guidelines to guide its implementation.Our study therefore calls for the evaluation on the implementation of the integration programme to identify factors that constrain or facilitate programme effectiveness., (© 2023. The Author(s).)

Males often perform mate choice with the aim of maximizing reproductive success. To identify profitable mates, the males of some animals are known to use visual and chemical cues derived from females. In this study, we aimed to examine mate discrimination by male guppies ( Poecilia reticulata ) using chemical cues received from females under different reproductive statuses, i.e., virgin females, pregnant females, females after copulation with another male, and post-partum females. We conducted a dichotomous choice experiment for each combination of chemical stimuli from females under different reproductive statuses. In experiment 1, in which females were removed from water that was subsequently used as a chemical stimulus, male preferences did not differ significantly in all combinations of chemical stimuli from females under different reproductive statuses. However, in experiment 2, in which females remained within bottles containing the water used as a chemical stimulus, with the exception of one combination of chemical stimuli, significant differences in male preferences were detected for chemical stimuli derived from females under different reproductive statuses. Overall, males generally showed a preference for chemical stimulus received from females after copulation with other males. The findings of this study indicate that male guppies can discriminate the reproductive status of females based solely on chemical cues that may disappear or degenerate within a short period of time, thereby facilitating profitable mate choice.

Aberrant functional connectivity (FC) of the brain regions, evaluated by functional magnetic resonance imaging (fMRI), affects clinical courses in inflammatory arthritis (IA). The static analysis methods would be simplistic to estimate the whole picture of resting-state brain function because blood oxygen level-dependent (BOLD) signals fluctuate over time. The effects of FC dynamics on clinical course are unknown in IA. Therefore, we aimed to evaluate dynamic FC for therapeutic responsiveness to biologics in IA patients. We analyzed resting-state fMRI data of 64 IA patients in 2 cohorts. Dynamic FC was derived as a correlation coefficient of the windowed BOLD signal time series. We determined representative whole-brain dynamic FC patterns by k-means++ cluster analysis, leading to 4 distinct clusters. In the first cohort, occurrence probability of the distinct cluster was associated with favorable therapeutic response in disease activity and patients' global assessment, which was validated by the second cohort. The whole-brain FC of the distinct cluster indicated significantly increased corticocortical connectivity, and probabilistically decreased after therapy in treatment-effective patients compared with -ineffective patients. Taken together, frequent emergence of corticocortical connections was associated with clinical outcomes in IA. The coherence of corticocortical interactions might affect pain modulation, possibly relevant to therapeutic satisfaction., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiorgan dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30-40% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue-resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. This study was undertaken to explore new therapeutic targets for NPSLE focusing on microglia., Methods: RNA sequencing of microglia in MRL/lpr, lupus-prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified, and its role in microglial activation and phagocytosis was investigated using specific inhibitors and small interfering RNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL/lpr was also evaluated., Results: Transcriptome analysis revealed the up-regulation of Ikbke, which encodes the inhibitor of NF-κB kinase subunit ɛ (IKBKε) in both microglia from MRL/lpr mice and cytokine-stimulated microglia in vitro. Intracerebroventricular administration of an IKBKε inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lpr mice. Mechanistically, IKBKε inhibition reduced glycolysis, which dampened microglial activation and phagocytosis., Conclusion: These findings suggest that IKBKε plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE., (© 2022 American College of Rheumatology.)

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases., (© 2023. The Author(s).)

Background Vascular compression is important for deep vein thrombosis screening. However, pressure analysis of ultrasound vessel models has not been performed. Therefore, we compared the human popliteal vein and several ultrasound vessel models at 50% compression. Methodology Four major ultrasound vascular models used in Japan and the popliteal vein of one subject constituted our measurement targets. Using a pressure-sensitive measuring device, the compressive force required to shorten the vessel diameter by 50% was determined. Results The compression force that shortened the popliteal vein by 50% was measured to be 191 ± 65 g. The blue phantom, ultrasound CV Pad II, ultrasound training block, and UGP-GEL required compression force of 701 ± 8 g, 265 ± 12 g, 697 ± 20 g, and 745 ± 15 g, respectively. The compression force for the ultrasound training block was 2.6 times higher than that for the ultrasound CV Pad II. The gel material around the vessels was the same; however, different vascular tubes required 2.6 times higher compression force. Conclusions This study showed that the objective numerical values of the compressive force were required to compress an ultrasound vascular model. Reproduction of the compressibility of veins required either removing the vascular structure or using thin tubing material., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sato et al.)

Large-vessel vasculitis (LVV) is subclassified into two phenotypes; Takayasu arteritis and giant cell arteritis. Although the pathogenesis of LVV is not fully established, IL-6-IL-17 axis and IL-12-IFN-γ axis play critical roles in the disease development. We aimed to clarify the association between the disease state and cytokine/chemokine levels, to assess disease course as prognosis and to predict regulators in patients with LVV using the blood profiles of multiple cytokines/chemokines. This retrospective analysis comprised 35 LVV patients whose blood were collected, and multiplex cytokine/chemokine analysis with 28 analytes was performed. The differences of cytokines/chemokines corresponding disease status, upstream regulator analysis, pathway analysis and cluster analysis were conducted using the cytokines/chemokines profile. Relapse-free survival rate was calculated with Kaplan-Meier analysis in the classified clusters. In the robust analysis, IL-4, CCL2/MCP-1, TNFSF13/APRIL, TNFSF13B/BAFF, CHI3L1 and VEGF-A levels were significantly changed after treatment. Untreated LVV patients demonstrated activation of NFκB-related molecules and these patients are potentially treated with JAK/STAT inhibitors, anti-TNF-α inhibitors and IL-6 inhibitors. Cluster analysis in active LVV patients revealed two clusters including one with high blood levels of IL-1β, IL-6, IL-17, IL-23 and CCL20/MIP-3. A subgroup of the LVV patients showed activated IL-17 signature with high relapse frequency, and JAK/TyK2 inhibitors and IFN-γ inhibitors were detected as potentially upstream inhibitors. Blood cytokine/chemokine profiles would be useful for prediction of relapse and potentially contributes to establish therapeutic strategy as precision medicine in LVV patients., Competing Interests: MK (3rd author) reports grants from GlaxoSmithKline plc, Mitsubishi Tanabe, Astellas, Sanofi, Taisho Pharmaceutical, NIPPON SHINYAKU CO., LTD., Taiju Life Social Welfare Foundation, Kowa CO. Ltd., Terumo Corporation, KYOCERA Corporation, CHUGAI PHARMACEUTICAL CO., LTD., MOCHIDA PHARMACEUTICAL CO., LTD., LOTTE CO., LTD., Hitachi, Ltd., Takeda Pharmaceutical CO. Ltd., and YAMAZAKI BAKING CO., LTD., outside the submitted work. MaK has received research grants from AbbVie, Actelion, and GlaxoSmithKline, and speaking fees from Eli Lilly. TA reports grants from Astellas, Takeda Pharmaceutical, Mitsubishi Tanabe, Chugai Pharmaceutical, Daiichi Sankyo, Otsuka Pharmaceutical, Pfizer, and Alexion, and personal fees from Mitsubishi Tanabe, Chugai Pharmaceutical, Astellas, Takeda Pharmaceutical, Pfizer, AbbVie, Eisai, Daiichi Sankyo, Bristol-Myers Squibb, UCB Japan, Eli Lilly Japan, AstraZeneca, MEDICAL & BIOLOGICAL LABORATORIES, ONO PHARMACEUTICAL, Novartis, and Nippon Boehringer Ingelheim, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abe, Kono, Kono, Katsuyama, Ohmura, Sato, Karino, Fujieda, Kato, Hasebe, Murakami and Atsumi.)

Objectives: The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients' data., Methods: Sleep disturbance stress (SDS) for 2 weeks was placed on 6-8-week-old female MRL/ lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE., Results: SDS-subjected MRL/ lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/ lpr . A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b . We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/ lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/ lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE., Conclusions: The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis., Methods: We built gene expression predictive models in blood B cells, CD4 + and CD8 + T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches., Results: TWAS identified 171 genes for SLE (p<1.0×10 -5 ); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10 -8 ). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10 -9 ) around CD83 . For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1 , and that presence of the SLE risk allele decreased ACAP1 expression., Conclusions: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI)., Patients and Methods: Structural and resting-state functional MRI data were acquired from patients with IA, patients with osteoarthritis (OA) and heathy controls (HCs). Two datasets were adopted to derive (51 IA, 56 OA, and 17 HCs) and validate (31 IA) the observations. 33 IA patients in the derivation dataset and all the patients in validation dataset required biological treatment and were clinically evaluated before and after therapy. Via whole-brain pair-wise FC analyses, we analyzed IA-specific FC measures relevant to therapeutic response to biologics., Results: The value of FC between left insular cortex (IC) and anterior cingulate cortex (ACC) was significantly low in IA patients compared with OA patients and HCs. We demonstrated that the FC between left anterior long insular gyrus as a subdivision of IC and ACC was significantly associated with therapeutic response to biologics regarding the improvement of patients' global assessment (PGA) in both derivation and validation datasets., Conclusion: Disease-specific resting-state FC provides a means to assess the therapeutic improvement of PGA and would be a clinical decision-making tool with predictability for treatment response in both RA and SpA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Multicentric Castleman disease-thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly (MCD-TAFRO)-is an emergent phenotype characterized by lymphoproliferation, fluid collection, hemocytopenia and multiple organopathy. Although studies have demonstrated an aberrant blood cytokine/chemokine profile referred to as "chemokine storm", the pathogenesis remains unclear. We aimed to identify pathogenic key molecules, potential diagnostic targets and therapeutic markers in MCD-TAFRO using serum cytokine/chemokine profiles. We performed the targeted cytokine/chemokine multiplex analysis in six cases of MCD-TAFRO with remission or non-remission status. We observed significant changes in serum concentrations of CCL2, CCL5, and Chitinase-3-like-1 in the MCD-TAFRO patients with active state compared to inactive state. Ingenuity pathway analysis revealed that glycogen synthase kinase 3 (GSK3) and CCR6, which is expressed in megakaryocytes, were detected as upstream positive regulators for activating MCD-TAFRO status. More GSK3β + CCR6 + cells like megakaryocytes were detected in the bone marrow of patients with MCD-TAFRO than in those with systemic lupus erythematosus, MCD-not otherwise specified or autoimmune haemophagocytic lymphohistiocytosis. The cellularity of GSK3β + CCR6 + cells was correlated with disease activity, including thrombocytopenia and anaemia. In conclusion, GSK3β and CCR6 of bone marrow cells were potentially involved in the pathogenesis of MCD-TAFRO and may act as diagnostic targets and therapeutic markers., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

The trade-up hypothesis is a female behavioral strategy related to mating with multiple males. In this hypothesis, females can produce high-quality offspring while avoiding the risk of losing reproductive opportunities by non-selective mating with males at first mating and then re-mating with more attractive males. As an internal mechanism to realize this behavioral strategy, we predicted that females would immediately fertilize their eggs when they mated with attractive males, whereas females would delay fertilization when they mated with unattractive males to trade-up sires of offspring. The guppy (Poecilia reticulata) is an ovoviviparous fish with internal fertilization, and females show a clear mate preference based on the area of orange coloration on the bodies of males. In addition, it is known that females show a re-mating strategy consistent with the trade-up hypothesis. We tested whether the attractiveness of mated males affected the gestation period and the timing of fertilization. Females were paired with either colorful males or drab males, and the gestation periods (the number of days from mating to parturition) were compared. In addition, we dissected the abdomens of the females at intervals of several days after mating and observed whether the eggs were fertilized. The gestation period in females that were paired with attractive colorful males was significantly shorter than that in females that were paired with drab males. We found that females that mated with colorful males also had their eggs fertilized earlier than those that mated with drab males. Our findings show that differences in the timing of fertilization according to attractiveness of the mate increase the opportunity for cryptic female choice and trading up., Competing Interests: The authors have declared that no competing interests exist.

Aim: Chest compression depth (CCD) in cardiopulmonary resuscitation is important. However, lightweight rescuers have difficulty achieving an appropriate depth. Chest compression force (CCFORCE) can be increased by placing the arms at 100° to the patient's frontal plane. In a simulation manikin study, we compared the CCD at 90° and 100° among lightweight Asian females and hypothesized that the CCD would be greater when the arms were placed at 100°., Methods: We included 35 lightweight female students from Shimane University who performed compressions 30 times each at 90° and 100°. The CCFORCE and CCD and the residual force on the chest wall during decompression for each chest compression were compared using CPRmeter-2., Results: Of the 35 participants, 3 were excluded because their angles deviated from the prescribed angle. Thirty-two participants were categorized according to CCD at 90°: ≤40 mm (group 1), 41-49 mm (group 2), and ≥ 50 mm (group 3). The overall mean CCD increased from 90° to 100° (44.3 ± 8.2 mm vs. 48.1 ± 7.2 mm; p < 0.05). The mean CCD changes between 90° and 100° were 34.4 ± 4.7 mm vs. 42.9 ± 4.8 mm (p < 0.05) in group 1, 44.9 ± 2.5 mm vs. 47.0 ± 4.2 mm (p = 0.17) in group 2, and 53.0 ± 2.7 mm vs. 55.4 ± 5.6 mm (p < 0.05) in group 3. The residual force was greater when the chest compression angle was 100°., Conclusion: CCD can be increased for lightweight rescuers when using a forward leaning position of 100° to the frontal plane of the patient. Further research is required to obtain more realistic situations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Objective: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations., Methods: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations., Results: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10 -8 ). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r g =-0.242) and non-albumin protein (r g =0.238)., Conclusion: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)