SORD-deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights.

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, cerebrospinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding - enlarged "ballooned" myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.

Comparison of Attainment and Protective Effects of Lupus Low Disease Activity State In Patients With Newly Diagnosed Versus Established Systemic Lupus Erythematosus.

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

SMART-SLE: serology monitoring and repeat testing in systemic lupus erythematosus-an analysis of anti-double-stranded DNA monitoring.

OBJECTIVE: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive. METHODS: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare. RESULTS: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009). CONCLUSION: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.

Exploration for Asian longhorned beetle parasitoids in Korea using an improved sentinel log trap.

The Asian longhorned beetle (ALB), Anoplophora glabripennis (Motschulsky) (Coleoptera: Cerambycidae), is a destructive invasive woodboring insect pest, and efforts are being made to find parasitoids for ALB biological control. Through a four-year survey in Korea using a sentinel log trap associated with host chemical cues potentially important for host finding by parasitoids, two parasitoid species were discovered attacking ALB. One species is Spathius ibarakius Belokobylskij & Maetô, which is known to also parasitize citrus longhorned beetle, Anoplophora chinensis (Forster). The other parasitoid species, whose offspring were dead before imago, could not be morphologically identified at the adult stage. We attempted molecular and morphological identification of the larvae/pupae of the unidentified parasitoid; however, only superfamily-level identification was possible. The parasitism rate recovered in the logs was 0.3% by the unidentified parasitoid in Gapyeong-gun in 2019, while it reached 29.2% by S. ibarakius in Busan city in 2022. Future efforts for exploring ALB natural enemies in the pest's native range may focus on parasitoids with high parasitism rates.

Title: Exploration des parasitoïdes du longicorne asiatique en Corée à l'aide d'un piège à bûche sentinelle amélioré. Abstract: Le longicorne asiatique (LA), Anoplophora glabripennis (Motschulsky) (Coleoptera : Cerambycidae), est un insecte ravageur envahissant et destructeur du bois, et des efforts sont déployés pour trouver des parasitoïdes pour la lutte biologique contre lui. Au cours d'une étude de quatre ans en Corée utilisant un piège à bûche sentinelle associé à des signaux chimiques de l'hôte potentiellement importants pour la détection de l'hôte par les parasitoïdes, deux espèces de parasitoïdes ont été découvertes attaquant le longicorne. Une espèce est Spathius ibarakius Belokobylskij & Maetô, qui est connue pour parasiter également le longicorne des agrumes, Anoplophora chinensis (Forster). Les autres espèces de parasitoïdes, dont les descendants sont morts avant l'imago, n'ont pu être identifiées morphologiquement au stade adulte. Nous avons tenté une identification moléculaire et morphologique des larves/pupes du parasitoïde non identifié, mais seule une identification au niveau de la superfamille a été possible. Le taux de parasitisme observé dans les bûches était de 0,3 % par le parasitoïde non identifié à Gapyeong-gun en 2019, tandis qu'il atteignait 29,2 % par S. ibarakius dans la ville de Busan en 2022. Les efforts futurs pour explorer les ennemis naturels du capricorne dans l'aire de répartition naturelle du ravageur pourraient se concentrer sur les parasitoïdes à taux de parasitisme élevés.

Sord deficient rats develop a motor-predominant peripheral neuropathy unveiling novel pathophysiological insights.

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord -/- , Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord -/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord -/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord -/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding - enlarged "ballooned" myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord -/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.

Parasitoid-induced changes in metabolic rate and feeding activity of the emerald ash borer (Coleoptera: Buprestidae): implications for biological control.

Parasitoid-host interactions form the foundation of biological control strategies against many agriculture and forest insect pests. The emerald ash borer (EAB), Agrilus planipennis (Coleoptera: Buprestidae), is a serious invasive pest of ash (Fraxinus spp.) trees in North America. Tetrastichus planipennisi (Hymenoptera: Eulophidae) is a gregarious, koinobiont endoparasitoid, attacking late (3rd to 4th) instars of EAB larvae, which feed in the live phloem of ash trunks or branches, making serpentine-like galleries filled with larval frass. In the present study, we tested the hypothesis that T. planipennisi regulates the host metabolism and feeding activity to optimize its offspring development and fitness. We first compared the respiration rate of parasitized and unparasitized host larvae at different times after parasitism, and then measured feeding activity of both parasitized and unparasitized host larvae inside their feeding galleries. Although parasitized host larvae increased metabolic rate and feeding activity in the first few days of parasitism, T. planipennisi parasitism induced an overall reduction of the metabolic rate and decrease in feeding activity of parasitized host larvae over their development period. In addition, there was a negative relationship between feeding activity of parasitized hosts and brood sizes of the parasitoid progeny-i.e., the more parasitoid progeny a host larva received, the less feeding activity the host had. These findings suggest that T. planipennisi has limited ability to optimize its offspring development and fitness through regulations of the host metabolism and feeding activity and its parasitism reduces feeding damage of parasitized EAB larvae to infested ash trees.

Successful establishment, spread, and impact of the introduced parasitoid Spathius galinae (Hymenoptera: Braconidae) on emerald ash borer (Coleoptera: Buprestidae) populations in postinvasion forests in Michigan.

Spathius galinae is a larval parasitoid native to the Russian Far East that was approved for release in the United States in 2015 for biological control of the emerald ash borer (EAB), Agrilus planipennis, an invasive beetle from Asia responsible for widespread mortality of ash trees (Fraxinus spp.) in North America. From 2015 to 2017, 1,340-1,445 females of S. galinae along with males were released into each release plot, paired with a nonrelease control plot (1-12.5 km apart), at 6 postinvasion forested sites containing abundant pole-sized ash trees in Michigan. By 2018, S. galinae had spread to all but one control plot. Based on the first year that S. galinae was found in trees in each control plot and the distances of those trees to the parasitoid release point within each site, we estimated that S. galinae spread at 3.7 (±1.9) km per year after its initial releases in 2015. The proportion of sampled trees with S. galinae broods, brood densities within sampled trees, and parasitism of EAB larvae increased sharply in both control and release plots after the last field releases in 2017, with the highest parasitism rates (42.8-60.3%) in 2020. Life table analysis showed that S. galinae alone reduced EAB's net population growth rate by 35-55% across sites from 2018 to 2020. These results demonstrate that S. galinae has established an increasing population in Michigan and now plays a significant role in reducing EAB populations in the area.

Postrelease assessment of Oobius agrili (Hymenoptera: Encyrtidae) establishment and persistence in Michigan and the Northeastern United States.

The emerald ash borer (EAB), Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), is an invasive woodboring pest of ash trees (Fraxinus sp.) in North America. Among the Asiatic parasitoids being released for the management of EAB in North America, Oobius agrili Zhang and Huang (Hymenoptera: Encyrtidae) is the only EAB egg parasitoid. To date, more than 2.5 million O. agrili have been released in North America; however, few studies have examined its success as a biological control agent of EAB. We conducted studies to assess O. agrili establishment, persistence, spread, and EAB egg parasitism rates in Michigan at the earliest release sites (2007-2010), as well as at more recent release sites (2015-2016) in 3 Northeastern United States (Connecticut, Massachusetts, New York). In both regions, we documented successful O. agrili establishment at all but one release site. In Michigan, O. agrili has persisted at release sites for over a decade and spread to all control sites located 0.6-3.8 km from release sites. Overall, EAB egg parasitism ranged from 1.5% to 51.2% (mean of 21.4%) during 2016-2020 in Michigan and from 2.6% to 29.2% (mean of 16.1%) during 2018-2020 in the Northeastern states. Future research efforts should focus on factors affecting the spatiotemporal variation in EAB egg parasitism rates by O. agrili, as well as its potential range in North America.

Effects of emamectin benzoate trunk injections on protection of neighboring ash trees against emerald ash borer (Coleoptera: Buprestidae) and on established biological control agents.

The emerald ash borer (EAB), Agrilus planipennis Fairmaire, is the most destructive invasive pest on ash (Fraxinus spp.) in the United States. We determined whether ash trees injected with emamectin benzoate (EB) could protect untreated neighboring ash trees. We also determined whether the selective treatment of ash trees with EB injections had adverse effects on the establishment of introduced larval parasitoids Tetrastichus planipennis Yang and Spathius galinae Belokobylskij & Strazenac. In experiment one, trees were treated with EB and then retreated 3 years later. Five years post initial treatment, we found that 90% of treated ash trees retained healthy crowns, significantly higher than those of untreated control ash trees (16%). For experiment two, trees only received one treatment of EB and after 2 years 100% of treated ash trees retained healthy crowns, significantly higher than those of untreated ash trees (50%). In both experiments, we found that distance from the central EB-treated tree was not a significant predictor for tree health or presence of EAB exit holes. Although distance from the EB-treated trees appeared to have a significant positive relationship with woodpecker feeding signs on neighboring trees, such relationships did not result in significant differences in the proportion of neighboring ash trees retaining healthy crowns between EB treatment and control plots. The introduced EAB parasitoids appeared to have established equally well between treatment and control plots. Findings are discussed in the context of integration of EB trunk injection with biological control for protection of North American ash against EAB.

[Application of short-course radiotherapy with total neoadjuvant therapy in the treatment of middle and low rectal cancer].

Objective: To compare the efficacy and safety of short-course radiotherapy with total neoadjuvant therapy (SCRT-TNT) and neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced middle and low rectal cancer. Methods: A retrospective cohort study was carried out. A of 126 patients with locally advanced middle and low rectal cancer who were treated in the Department of Gastrointestinal Cancer Surgery of Fujian Cancer Hospital from September 2016 to March 2020 were enrolled, including 73 males and 53 females, with a mean age of (56.5±9.8) (23-77) years. Based on neoadjuvant regimen (nCRT treatment was performed before December 2018 and SCRT-TNT treatment was carried out after January 2019), patients were divided into nCRT group (n=68) and SCRT-TNT group (n=58). There were no statistically significant differences in age, sex, distance from tumor to anal verge, Eastern Cooperative Oncology Group (ECOG) performance status and clinical TNM stage between the two groups (all P>0.05). Patients in both groups received pelvic intensity-modulated radiotherapy (IMRT). The radiotherapy dose of nCRT group was 50Gy/25 times/5 weeks. Patients in nCRT group received oral capecitabine chemotherapy during radiotherapy and underwent surgery 6-8 weeks after chemoradiation. However, patients in SCRT-TNT group received CapeOX regimen (oxaliplatin+capecitabine) for 2 cycles of induction chemotherapy, followed by short-course radiotherapy (25Gy/5 times/5 days), then underwent a radical surgery two weeks after completion of consolidation chemotherapy (4 cycles). The adverse reactions, perioperative safety and efficacy of neoadjuvant therapy were compared and analyzed between the two groups. Results: Both groups completed neoadjuvant therapy as planned. Patients in nCRT group and SCRT-TNT group had similar incidence of adverse reactions to radiotherapy and chemotherapy, however, there were no statistically significant differences in the incidence of surgical complications, operation time, intraoperative blood loss and postoperative length of hospital stay (all P>0.05). A total of 119 patients underwent total mesenterectomy (TME), including 64 patients in the nCRT group and 55 patients in the SCRT-TNT group, all with R0 resection. The pathological complete response (pCR) rate was 10.9% (7/64) in the nCRT group and 25.5% (14/55) in the SCRT-TNT group, respectively, with a statistically significant difference (P=0.038). Two years after surgery, there was no statistically significant difference in local recurrence rate and overall survival rate between the two groups (both P>0.05). However, the clinical metastasis rate of SCRT-TNT group was significantly lower than that of nCRT group (20.3% vs 9.1%), with a statistically significant difference (P<0. 05). Conclusion: SCRT-TNT do not increase the adverse reactions of radio chemotherapy and perioperative risks in the treatment of locally advanced middle and low rectal cancer, and the tumor regression effect is good, which is worthy of clinical promotion.

Potential effects of RNA interference of Asian longhorned beetle on its parasitoid.

BACKGROUND: It is important to understand how non-target insects such as parasitoids may be impacted directly or indirectly by RNA interference with double-stranded RNA (dsRNA) that has emerged as a novel pest control tool. We examined the potential effects of a dsRNA targeting an inhibitor of apoptosis (IAP) of the Asian longhorned beetle Anoplophora glabripennis on its gregarious larval ectoparasitoid Ontsira mellipes, directly on adult wasp's survival via injection of 4 µg of dsIAP per wasp, and indirectly on the detectability and suitability of host larvae injected with 2, 4 or 8 µg of dsIAP per larva. RESULTS: Compared with no injection or injection with a control dsGFP targeting a region of gene coding for a green fluorescence protein (GFP), dsIAP did not affect adult wasp's survival. Ontsira mellipes locates hosts in the wood by sensing their movement. Host larvae did not completely cease movement after the injection of dsIAP and were still detected and parasitized. Clutch size was reduced and only 3.8% of the parasitoid offspring developed into adults on host larvae treated at the highest dose. However, clutch size was not affected and 25.5% of the parasitoid offspring developed into adults on host larvae treated at the lowest dose. The fitness of developed wasps (development time, sex ratio, body size, and fecundity) was not affected when compared to the control treatments. No dsIAP was detected in parasitoid larvae. CONCLUSION: The results show no direct effect of the dsRNA on its parasitoid, but the potential indirect effect of dsRNA-affected host on the parasitoid, which may be minimized through optimizing dsRNA dosage to promote compatible applications of both management options for this invasive forest pest. © 2022 Society of Chemical Industry. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Knock-in mouse models for CMTX1 show a loss of function phenotype in the peripheral nervous system.

The X-linked form of Charcot-Marie-Tooth disease (CMTX1) is the second most common form of CMT. In this study we used CRISPR/Cas9 to develop new "knock-in" models of CMTX1 that are more representative of the spectrum of mutations seen with CMTX1 than the Cx32 knockout (KO) mouse model used previously. We compared mice of four genotypes - wild-type, Cx32KO, p.T55I, and p.R75W. Sciatic motor conduction velocity slowing was the most robust electrophysiologic indicator of neuropathy, showing reductions in the Cx32KO by 3 months and in the p.T55I and p.R75W mice by 6 months. At both 6 and 12 months, all three mutant genotypes showed reduced four limb and hind limb grip strength compared to WT mice. Performance on 6 and 12 mm width balance beams revealed deficits that were most pronounced at on the 6 mm balance beam at 6 months of age. There were pathological changes of myelinated axons in the femoral motor nerve in all three mutant lines by 3 months of age, and these became more pronounced at 6 and 12 months of age; sensory nerves (femoral sensory and the caudal nerve of the tail) appeared normal at all ages examined. Our results demonstrate that mice can be used to show the pathogenicity of human GJB1 mutations, and these new models for CMTX1 should facilitate the preclinical work for developing treatments for CMTX1.

An integrative phenology and climatic suitability model for emerald ash borer.

Introduction: Decision support models that predict both when and where to expect emerald ash borer (EAB), Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), are needed for the development and implementation of effective management strategies against this major invasive pest of ash (Fraxinus species) in North America and other regions such as Europe. We present a spatialized model of phenology and climatic suitability for EAB for use in the Degree-Days, Risk, and Phenological event mapping (DDRP) platform, which is an open-source decision support tool to help detect, monitor, and manage invasive threats. Methods: We evaluated the model using presence records from three geographic regions (China, North America, and Europe) and a phenological dataset consisting primarily of observations from the northeastern and midwestern United States. To demonstrate the model, we produced phenological event maps for a recent year and tested for trends in EAB's phenology and potential distribution over a recent 20-year period. Results: Overall, the model exhibited strong performance. Presence was correctly estimated for over 99% of presence records and predicted dates of adult phenological events corresponded closely with observed dates, with a mean absolute error of ca. 7 days and low estimates of bias. Climate stresses were insufficient to exclude EAB from areas with native Fraxinus species in North America and Europe; however, extreme weather events, climate warming, and an inability for EAB to complete its life cycle may reduce suitability for some areas. Significant trends toward earlier adult emergence over 20 years occurred in only some areas. Discussion: Near real-time model forecasts for the conterminous United States are available at two websites to provide end-users with decision-support for surveillance and management of this invasive pest. Forecasts of adult emergence and egg hatch are particularly relevant for surveillance and for managing existing populations with pesticide treatments and parasitoid introductions.

Impact of low disease activity, remission, and complete remission on flares following tapering of corticosteroids and immunosuppressive therapy in patients with systemic lupus erythematous: a multinational cohort study.

BACKGROUND: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission. METHODS: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission. FINDINGS: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare. INTERPRETATION: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months. FUNDING: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB.

Ovarian steroid cell tumor associated with von Hippel-Lindau syndrome: a report of two cases and literature review.

Steroid cell tumor (SCT) is a rare sex cord-stromal tumor accounting for only 0.1% of ovarian tumors. Steroid cell tumor, not otherwise specified (SCT, NOS) is of uncertain lineage and is the most common among the three subtypes of SCT. Patients often present with endocrine abnormalities. Von Hippel-Lindau (VHL) syndrome is an autosomal dominant disorder resulting from inactivating gene deletions, frameshifts, and missense mutations of the VHL gene. VHL syndrome can involve multiple organs and clinically is subclassified into type 1 and type 2 based on the risk of pheochromocytoma (PCC). The association of VHL syndrome with genital tract tumors is rare, and here we report two cases of SCT, NOS in patients with VHL disease. The first case is a 19-year old female with VHL and prior resection of bilateral cerebellar hemangioblastomas. During the radiological surveillance, she was found to have multiple small enhancing foci in the cerebellar hemispheres and a stable small enhancing focus in the T6 cord with associated edema, likely reflecting a small hemangioblastoma. She had long history of irregular menses and ultrasound of pelvis found a large right ovarian mass. Cystectomy specimen showed a 6.4 cm well-circumscribed lesion with yellow cut surface. Histologic examination and immunohistochemical staining confirmed the diagnosis of SCT, NOS. The second patient is a 39-year-old female with VHL, previous surgery for retinal hemangioblastomatosis and cerebellar hemangioblastoma, history of abnormal uterine bleeding and elevated testosterone. CT of abdomen and pelvis revealed bilateral multiple cystic and solid renal lesions and a large left ovarian complex cyst. Bilateral partial nephrectomy showed multiple renal cysts and clear cell renal cell carcinomas (RCCs). Left salpingo-oophorectomy showed a 7 cm lesion with yellow-orange cut surface and features consistent with SCT, NOS. Review of the previously reported VHL SCT cases (not including the current two cases) indicated a probable link between VHL syndrome and SCT.

Face image-sketch synthesis via generative adversarial fusion.

Face image-sketch synthesis is widely applied in law enforcement and digital entertainment fields. Despite the extensive progression in face image-sketch synthesis, there are few methods focusing on generating a color face image from a sketch. The existing methods pay less attention to learning the illumination or highlight distribution on the face region. However, the illumination is the key factor that makes the generated color face image looks vivid and realistic. Moreover, existing methods tend to employ some image preprocessing technologies and facial region patching approaches to generate high-quality face images, which results in the high complexity and memory consumption in practice. In this paper, we propose a novel end-to-end generative adversarial fusion model, called GAF, which fuses two U-Net generators and a discriminator by jointly learning the content and adversarial loss functions. In particular, we propose a parametric tanh activation function to learn and control illumination highlight distribution over faces, which is integrated between the two U-Net generators by an illumination distribution layer. Additionally, we fuse the attention mechanism into the second U-Net generator of GAF to keep the identity consistency and refine the generated facial details. The qualitative and quantitative experiments on the public benchmark datasets show that the proposed GAF has better performance than existing image-sketch synthesis methods in synthesized face image quality (FSIM) and face recognition accuracy (NLDA). Meanwhile, the good generalization ability of GAF has also been verified. To further demonstrate the reliability and authenticity of face images generated using GAF, we use the generated face image to attack the well-known face recognition system. The result shows that the face images generated by GAF can maintain identity consistency and well maintain everyone's unique facial characteristics, which can be further used in the benchmark of facial spoofing. Moreover, the experiments are implemented to verify the effectiveness and rationality of the proposed parametric tanh activation function and attention mechanism in GAF.

'Not at target': prevalence and consequences of inadequate disease control in systemic lupus erythematosus-a multinational observational cohort study.

BACKGROUND: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes. METHODS: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI). RESULTS: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients. CONCLUSION: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.

Patterns of Medication Use in Systemic Lupus Erythematosus: A Multicenter Cohort Study.

OBJECTIVE: Evidence for the utility of medications in settings lacking randomized trial data can come from studies of treatment persistence. The present study was undertaken to examine patterns of medication use in systemic lupus erythematosus (SLE) using data from a large multicenter longitudinal cohort. METHODS: Prospectively collected data from the Asia Pacific Lupus Collaboration cohort including disease activity (SLE Disease Activity Index 2000 [SLEDAI-2K]) and medication details, captured at every visit from 2013-2018, were used. Medications were categorized as glucocorticoids (GCs), antimalarials (AM), and immunosuppressants (IS). Cox regression analyses were performed to determine the time-to-discontinuation of medications, stratified by SLE disease activity. RESULTS: Data from 19,804 visits of 2,860 patients were analyzed. Eight medication categories were observed: no treatment; GC, AM, or IS only; GC plus AM; GC plus IS; AM plus IS; and GC plus AM plus IS (triple therapy). Triple therapy was the most frequent pattern (31.4% of visits); single agents were used in 21% of visits, and biologics in only 3%. Time-to-discontinuation analysis indicated that medication persistence varied widely, with the highest treatment persistence for AM and lowest for IS. Patients with a time-adjusted mean SLEDAI-2K score of ≥10 had lower discontinuation of GCs and higher discontinuation of IS. CONCLUSION: Most patients received combination treatment. GC persistence was high, while IS persistence was low. Patients with high disease activity received more medication combinations but had reduced IS persistence, consistent with limited utility. These data confirm unmet need for improved SLE treatments.

Rapid Spread of an Introduced Parasitoid for Biological Control of Emerald Ash Borer (Coleoptera: Buprestidae) in Maryland.

Emerald ash borer (Agrilus planipennis Fairmaire (Coleoptera: Buprestidae)), an invasive phloem-feeding beetle native to Asia, has devastated North American ash forests since its detection in Michigan, United States in 2002. As the emerald ash borer has continued to spread, the potential for successful long-term management hinges upon the release, establishment, and spread of introduced larval and egg parasitoids for biological control. Here, we focus on the establishment and evidence for spatial spread of introduced larval parasitoid, Spathius agrili Yang and Spathius galinae Belokobylskij & Strazanac (Hymenoptera: Braconidae) in the state of Maryland. To assess each species, we analyzed historical release and recovery data and resampled previous release sites and nonrelease sites for establishment. We found little evidence of establishment or spread for S. agrili, despite a comparatively large number of release locations, events, and individuals. By contrast, despite much lower propagule pressure and shorter history of releases, we detected multiple established populations of S. galinae at release sites and at sites up to 90 km from the nearest release point approximately 3 yr after its most current release. Our findings show that S. galinae has established and spread rapidly following field releases whereas its congener, S. agrili has not. Although it may still be too early to evaluate the level of population control and ash protection afforded by S. galinae, these findings indicate the need for continued investment in S. galinae for emerald ash borer classical biological control efforts.

Lupus low disease activity state and remission and risk of mortality in patients with systemic lupus erythematosus: a prospective, multinational, longitudinal cohort study.

BACKGROUND: Treat-to-target goals for patients with systemic lupus erythematosus (SLE) have been validated to protect against organ damage and to improve quality of life. We aimed to investigate the association between lupus low disease activity state (LLDAS) and remission and risk of mortality in patients with SLE. We hypothesised that LLDAS has a protective association with mortality risk. METHODS: In this prospective, multinational, longitudinal cohort study, we used data from patients with SLE in the Asia Pacific Lupus Collaboration cohort collected between May 1, 2013, and Dec 31, 2020. Eligible patients were adults (aged ≥18 years) who met either the 1997 American College of Rheumatology modified classification criteria for SLE or the 2012 Systemic Lupus International Collaborating Clinics classification criteria. The primary outcome was all-cause mortality, and LLDAS, remission, and variations of remission with lower glucocorticoid thresholds were the primary exposure variables. Survival analyses were used to examine longitudinal associations between these endpoints and risk of mortality. This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: Among a total of 4106 patients in the cohort, 3811 (92·8%) patients were included in the final analysis (median follow-up 2·8 years [IQR 1·0-5·3]; 3509 [92·1%] women and 302 [7·9%] men), of whom 80 died during the observation period (crude mortality rate 6·4 deaths per 1000 person-years). LLDAS was attained at least once in 43 (53·8%) of 80 participants who died and in 3035 (81·3%) of 3731 participants who were alive at the end of the study (p<0·0001); 22 (27·5%) participants who died versus 1966 (52·7%) who were alive at the end of the study attained LLDAS for at least 50% of observed time (p<0·0001). Remission was attained by 32 (40·0%) of 80 who died and in 2403 (64·4%) of 3731 participants who were alive at the end of the study (p<0·0001); 14 (17·5%) participants who died versus 1389 (37·2%) who were alive at the end of the study attained remission for at least 50% of observed time (p<0·0001). LLDAS for at least 50% of observed time (adjusted hazard ratio 0·51 [95% CI 0·31-0·85]; p=0·010) and remission for at least 50% of observed time (0·52 [0·29-0·93]; p=0·027) were associated with reduced risk of mortality. Modifying the remission glucocorticoid threshold (<5·0 mg/day prednisolone) was more protective against mortality than current remission definitions (0·31 [0·12-0·77]; p=0·012), and glucocorticoid-free remission was the most protective (0·13 [0·02-0·96]; p=0·046). INTERPRETATION: LLDAS significantly reduced the risk of mortality in patients with SLE. Remission did not further reduce the risk of mortality compared with LLDAS, unless lower glucocorticoid thresholds were used. FUNDING: The Asia-Pacific Lupus Collaboration received funding from Janssen, Bristol Myers Squibb, Eli Lilly, and UCB for this study.