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The hallmarks of chromosome organization in multicellular eukaryotes are chromosome territories (CT), chromatin compartments, and insulated domains, including topologically associated domains (TADs). Yet, most of these elements of chromosome organization are derived from analyses of a limited set of model organisms, while large eukaryotic groups, including insects, remain mostly unexplored. Here we combine Hi-C, biophysical modeling, and microscopy to characterize the 3D genome architecture of the silkmoth, Bombyx mori . In contrast to other eukaryotes, B. mori chromosomes form highly separated territories. Similar to other eukaryotes, B. mori chromosomes segregate into active A and inactive B compartments, yet unlike in vertebrate systems, contacts between euchromatic A regions appear to be a strong driver of compartmentalization. Remarkably, we also identify a third compartment, called secluded "S," with a unique contact pattern. Each S region shows prominent short-range self-contacts and is remarkably devoid of contacts with the rest of the chromosome, including other S regions. Compartment S hosts a unique combination of genetic and epigenetic features, localizes towards the periphery of CTs, and shows developmental plasticity. Biophysical modeling reveals that the formation of such secluded domains requires highly localized loop extrusion within them, along with a low level of extrusion in A and B. Our Hi-C data supports predicted genome-wide and localized extrusion. Such a broad, non-uniform distribution of extruders has not been seen in other organisms. Overall, our analyses support loop extrusion in insects and highlight the evolutionary plasticity of 3D genome organization, driven by a new combination of known processes.

Purpose: Many patients treated for ulcerative colitis (UC) do not achieve clinical remission. This real-world study assessed clinical remission and inadequate response rates among patients with UC in Germany treated with advanced therapies., Methods: This retrospective chart review included patients with UC newly initiating advanced (index) therapy (anti-TNFα agents, vedolizumab, tofacitinib) from January 2017-September 2019 (index date). Included patients had data for ≥ 12 months before (baseline period) and after the index date (follow-up period). Remission was defined as a partial Mayo score ≤ 1. Indicators of inadequate response were: index therapy discontinuation; therapy adjustments (index therapy dose escalation; augmentation with non-advanced therapies; corticosteroid [CS] use during maintenance therapy); CS dependency (use for ≥ 12 weeks); and UC-related hospitalisation, surgery or emergency department visit. Time to first remission and inadequate response were analyzed using Kaplan-Meier analyses., Results: Among 149 patients with UC (median age: 40 years), 96 (64.4%) were biologic-naïve and 42 (28.2%) received CS at the index date. Within 12 months, 52 patients (47.2%) were in remission; of these, 13 patients (25.0%) received ≥ 1 therapy adjustment. At 12 months, 55 patients (37.6%) had ≥ 1 indicator of an inadequate response. Median time to remission was longer among biologic-experienced vs biologic-naïve patients (24 vs 7 months; p = 0.012)., Conclusion: Over half of the patients were not in clinical remission after 12 months and more than one-third experienced inadequate response. One-quarter of patients in remission required therapy adjustments. Patients with UC require therapies that are more effective than those currently available to achieve better treatment outcomes., (© 2023. The Author(s).)

Context: The 250µg-cosyntropin stimulation test (CST) is used to diagnose non-classic congenital adrenal hyperplasia (NCCAH). The current recommendation is to perform CST when follicular 17-hydroxyprogesterone (17OHP) is 6-30 nmol/L, a cutoff derived from radioimmunoassay (RIA). Recently, enzyme-linked immunosorbent assay (ELISA) has replaced RIA., Objectives: We aimed to (1) determine the RIA and ELISA-based 17OHP cutoffs at which CST should be performed, (2) identify predictors of NCCAH., Methods: A retrospective study at an Israeli Health Maintenance Organization. Data were retrieved from women with suspected NCCAH, referred for CST during 2001-2020. NCCAH was defined as a stimulated 17OHP >30 nmol/L. Serum 17OHP levels were assayed by RIA from 1/2000-3/2015, and by ELISA from 4/2015-12/2020. ROC curves were generated and optimal 17OHP thresholds were determined. Multivariate analysis was performed., Results: CST was performed in 2409 women (1564 in RIA, 845 in ELISA). NCCAH was diagnosed in 4.7% of the RIA group and 7.5% of the ELISA group. The optimal basal 17OHP cutoff values predicting NCCAH were 6.1 nmol/L in RIA (sensitivity=93.2%, specificity=91.7%) and 8.2 nmol/L in ELISA (sensitivity=93.7%, specificity=92.3%). In multivariate analysis, higher basal 17OHP, lower LH: FSH ratio, and oligomenorrhea were predictors of NCCAH in RIA. Higher basal 17OHP, androstenedione, and total testosterone were predictors of NCCAH in ELISA. A lower LH: FSH ratio showed similar trend in ELISA., Conclusions: Optimal RIA-based basal 17OHP cutoff was comparable with that recommended in guidelines. The results suggest adopting a higher 17OHP cutoff when using ELISA. LH : FSH ratio improves the negative predictive value of basal 17OHP., Competing Interests: The 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 © 2023 Nakhleh, Saiegh, Shehadeh, Weintrob, Sheikh-Ahmad, Supino-Rosin, Alboim, Gendelman and Zloczower.)

Background: Real-world data regarding response rates in ulcerative colitis treatment are rare, particularly for later lines of therapy. This study aimed to assess continuity of and changes to advanced therapies, as well as costs and specific indicators defining suboptimal therapy., Methods: German claims data were retrospectively analyzed (January 2014 to June 2019). Patients with ulcerative colitis initiating an advanced therapy (adalimumab, golimumab, infliximab, tofacitinib, vedolizumab) were included. Inadequate response was indicated by therapy discontinuation, switch, escalation, augmentation, corticosteroid dependency, disease-related hospitalization, or surgery. Health care resource utilization (inpatient, outpatient, sick leaves, medication, aids, and remedies) and related costs were assessed from therapy initiation until discontinuation or loss to follow-up., Results: Among 574 patients (median age, 39 years; female sex, 53.5%) who initiated advanced therapies, 458 (79.8%) received an antitumor necrosis factor therapy, 113 (19.7%) vedolizumab, and 3 (0.5%) tofacitinib. After 12 months, 75% had ≥1 indicator for suboptimal therapy. The median time to first indicated inadequate response was 4.8 months. Therapy discontinuation (38%), switching (26%), and prolonged use of steroids (36%) were common within the first year of treatment. In an unadjusted comparison, all-cause total costs per person-year were significantly higher in those who switched vs patients remaining on their therapy (€44,570 vs €36,807; P < .001)., Conclusions: Our study indicates a high prevalence of inadequate response to advanced therapies. Only 25% of patients showed adequate response within 12 months after therapy initiation. Frequent dose and treatment changes were observed. The economic impact of suboptimal therapy in ulcerative colitis is substantial, highlighting the ongoing need for improved treatment strategies., (© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

BackgroundData regarding the long-term protection afforded by vaccination for the SARS-CoV-2 infection are essential for allocation of scarce vaccination resources worldwide.MethodsWe conducted a retrospective cohort study aimed at studying the kinetics of IgG antibodies against SARS-CoV-2 in COVID-19-naïve patients fully vaccinated with two doses of Comirnaty mRNA COVID-19 vaccine. Geometric mean concentrations (GMCs) of antibody levels were reported. Linear models were used to assess antibody levels after full vaccination and their decline over time.ResultsThe study included 4,740 patients and 5,719 serological tests. Unadjusted GMCs peaked 28-41 days after the first dose at 10,174 AU/mL (95% CI: 9,211-11,237) and gradually decreased but remained well above the positivity cut-off. After adjusting for baseline characteristics and repeated measurements, the antibodies half-life time was 34.1 days (95% CI: 33.1-35.2), and females aged 16-39 years with no comorbidities had antibody levels of 20,613 AU/mL (95% CI: 18,526-22,934) on day 28 post-first-dose. Antibody levels were lower among males (0.736 of the level measured in females; 95% CI: 0.672-0.806), people aged 40-59 (0.729; 95% CI: 0.649-0.818) and ≥ 60 years (0.452; 95% CI: 0.398-0.513), and patients having haematological (0.241; 95% CI: 0.190-0.306) or solid malignancies (0.757; 95% CI: 0.650-0.881), chronic kidney disease with glomerular filtration rate (GFR) ≥ 30 (0.434; 95% CI: 0.354-0.532) or with GFR < 30 mL/min (0.176; 95% CI: 0.109-0.287), and immunosuppression (0.273; 95% CI: 0.235-0.317). Body mass index, cardiovascular disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes and inflammatory bowel diseases were not associated with antibody levels.ConclusionsVaccination with two doses resulted in persistently high levels of antibodies (≥ cut-off of 50 AU/mL) up to 137 days post-first-dose. Risk factors for lower antibody levels were identified.

Purpose: As protection from COVID-19 following two doses of the BNT162b2 vaccine showed a time dependent waning, a third (booster) dose was administrated. This study aims to compare the antibody response following the third dose versus the second and to evaluate post-booster seroconversion., Methods: A prospective observational study conducted in Maccabi Healthcare Services. Serial SARS-CoV-2 Spike IgG tests, 1,2,3 and 6 months following the second vaccine dose and one month following the third were obtained. Neutralizing antibody levels were measured in a subset of participants. Per individual SARS-CoV-2 Spike IgG titer ratios were calculated one month after the booster administration compared to titers one month following the second dose and prior to booster., Results: Among 110 participants,56 (51%) were women. Mean age was 61.7 ± 1.9 years and 66 (60%) were immunocompromised. One month after third dose, IgG titers were induced 7.83 (95 %CI 5.25-11.67) folds and 2.40 (95 %CI 1.90-3.03) folds compared to one month after the second, in the immunocompromised and immunocompetent groups, respectively. Of the 17 immunocompromised participants who were seronegative after the second dose, 4 (24%) became seropositive following the third. Comparing the titers prior to the third dose, an increase of 50.7 (95 %CI 32.5-79.1) fold in the immunocompromised group and 25.7 (95 %CI 19.1-34.7) fold in and immunocompetent group, was observed., Conclusion: A third BNT162b2 vaccine elicited robust humoral response, superior to the response observed following the second, among immunocompetent and immunocompromised individuals., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To compare 2 CoV-SARS-2 ('anti-s') antibody levels after vaccination between residents in long-term geriatric care (LTGC) and residents in assisted-living facilities who had received two doses of the BNT162b2 vaccine. SARS-CoV-2 serology was tested with Quant II IgG CoV-SARS-2. Blood samples were collected 3-4 months after administration of the second vaccine dose., Results: Anti-s ≥ 50 AU/ml was found in 85.4% of 90 residents in LTGC (median 498 AU/ml) and 94.9% of 214 residents in assisted living (median 728 AU/ml). p = .006. Factors associated with anti-s < 300 AU/ml were multi-morbidity, diabetes mellitus and cancer.

Israel experienced a new wave of coronavirus disease during June 2021, six months after implementing a national vaccination campaign. We conducted 3 discrete analyses using data from a large health maintenance organization in Israel to determine whether IgG levels of fully vaccinated persons decrease over time, describe the relationship between IgG titer and subsequent PCR-confirmed infection, and compare PCR-confirmed infection rates by period of vaccination. Mean IgG levels steadily decreased over the 6-month period in the total tested population and in all age groups. An inverse relationship was found between IgG titer and subsequent PCR-positive infection. Persons vaccinated during the first 2 months of the campaign were more likely to become infected than those subsequently vaccinated. The vaccinated group >60 years of age had lower initial IgG levels and were at greater risk for infection. The findings support the decision to add a booster vaccine for persons >60 years of age.