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Capture of a photon by an opsin visual pigment isomerizes its 11-cis-retinaldehyde (11cRAL) chromophore to all-trans-retinaldehyde (atRAL), which subsequently dissociates. To restore light sensitivity, the unliganded apo-opsin combines with another 11cRAL to make a new visual pigment. Two enzyme pathways supply chromophore to photoreceptors. The canonical visual cycle in retinal pigment epithelial cells supplies 11cRAL at low rates. The photic visual cycle in Müller cells supplies cones with 11-cis-retinol (11cROL) chromophore precursor at high rates. Although rods can only use 11cRAL to regenerate rhodopsin, cones can use 11cRAL or 11cROL to regenerate cone visual pigments. We performed a screen in zebrafish retinas and identified ZCRDH as a candidate for the enzyme that converts 11cROL to 11cRAL in cone inner segments. Retinoid analysis of eyes from Zcrdh-mutant zebrafish showed reduced 11cRAL and increased 11cROL levels, suggesting impaired conversion of 11cROL to 11cRAL. By microspectrophotometry, isolated Zcrdh-mutant cones lost the capacity to regenerate visual pigments from 11cROL. ZCRDH therefore possesses all predicted properties of the cone 11cROL dehydrogenase. The human protein most similar to ZCRDH is RDH12. By immunocytochemistry, ZCRDH was abundantly present in cone inner segments, similar to the reported distribution of RDH12. Finally, RDH12 was the only mammalian candidate protein to exhibit 11cROL-oxidase catalytic activity. These observations suggest that RDH12 in mammals is the functional ortholog of ZCRDH, which allows cones, but not rods, to regenerate visual pigments from 11cROL provided by Müller cells. This capacity permits cones to escape competition from rods for visual chromophore in daylight-exposed retinas.

This essay will review two books that describe and explain modern revolutions. First one is Handbook of Revolutions in the 21st Century. The New Waves of Revolutions, and the Causes and Effects of Disruptive Political Change edited by Jack A. Goldstone, Leonid Grinin and Andrey Korotayev. The book is a massive collection of 41 diverse chapters from numerous contributors. The book takes on almost every aspect of revolutionary theory and addresses quite a few of very recent revolutionary events, as well as many older ones. Second book is New Wave of Revolutions in the MENA Region. A Comparative Perspective edited by Leonid Issaev and Andrey Korotayev. The book contains 12 chapters from various contributors, each dedicated to a revolutionary episode in a country from the Middle East and Northern Africa region. The book provides an overview of the revolutionary processes in the region that shook the world several years ago with its rapid and unexpected domino-like revolutions. The book demonstrates that revolutions are ongoing in this part of the world.

Though rod and cone photoreceptors use similar phototransduction mechanisms, previous model calculations have indicated that the most important differences in their light responses are likely to be differences in amplification of the G-protein cascade, different decay rates of phosphodiesterase (PDE) and pigment phosphorylation, and different rates of turnover of cGMP in darkness. To test this hypothesis, we constructed TrUx;GapOx rods by crossing mice with decreased transduction gain from decreased transducin expression, with mice displaying an increased rate of PDE decay from increased expression of GTPase-activating proteins (GAPs). These two manipulations brought the sensitivity of TrUx;GapOx rods to within a factor of 2 of WT cone sensitivity, after correcting for outer-segment dimensions. These alterations did not, however, change photoreceptor adaptation: rods continued to show increment saturation though at a higher background intensity. These experiments confirm model calculations that rod responses can mimic some (though not all) of the features of cone responses after only a few changes in the properties of transduction proteins.

BACKGROUNDInformation about the size, airway location, and longitudinal behavior of mucus plugs in asthma is needed to understand their role in mechanisms of airflow obstruction and to rationally design muco-active treatments.METHODSCT lung scans from 57 patients with asthma were analyzed to quantify mucus plug size and airway location, and paired CT scans obtained 3 years apart were analyzed to determine plug behavior over time. Radiologist annotations of mucus plugs were incorporated in an image-processing pipeline to generate size and location information that was related to measures of airflow.RESULTSThe length distribution of 778 annotated mucus plugs was multimodal, and a 12 mm length defined short ("stubby", ≤12 mm) and long ("stringy", >12 mm) plug phenotypes. High mucus plug burden was disproportionately attributable to stringy mucus plugs. Mucus plugs localized predominantly to airway generations 6-9, and 47% of plugs in baseline scans persisted in the same airway for 3 years and fluctuated in length and volume. Mucus plugs in larger proximal generations had greater effects on spirometry measures than plugs in smaller distal generations, and a model of airflow that estimates the increased airway resistance attributable to plugs predicted a greater effect for proximal generations and more numerous mucus plugs.CONCLUSIONPersistent mucus plugs in proximal airway generations occur in asthma and demonstrate a stochastic process of formation and resolution over time. Proximal airway mucus plugs are consequential for airflow and are in locations amenable to treatment by inhaled muco-active drugs or bronchoscopy.TRIAL REGISTRATIONClinicaltrials.gov; NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01716494, and NCT01760915.FUNDINGAstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and TEVA provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.

Many teachers tirelessly grapple with topics of text selection, evaluation, and comprehension--examining elements of diversity, quality, and kid appeal to empower teachers to select titles for classrooms through a critical lens--under a mandated scripted curriculum. The purpose of this column is to explore and draw upon teachers' knowledge around implementation of global texts with a focus on comprehension and "teaching within the cracks."

This article addresses the issue of neocolonialism and, in particular, the context in which this issue is addressed within the framework of Russian official foreign policy. The article gives an idea of the emergence and modern understanding of the concept of neocolonialism within the framework of political science. The authors use the method of content analysis of speeches, statements and articles by Russian officials that contain references to neo-colonialism and the fight against it on the African continent. It is shown that the narrative of neocolonialism occupies a fairly important place in the Russian Federation’s construction of its foreign policy identity as a form of building a discursive dialogue with Western countries. The peculiarities of the Russian discourse on neocolonialism are its focus on problems in the spheres of economics and security, as well as some abstractness in relation to specific forms and manifestations of neocolonialism in African countries.

Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of daylight vision and high-acuity perception, is the most debilitating feature of the disease. To understand better why cones degenerate and how cone vision might be restored, we have made the first single-cell recordings of light responses from degenerating cones and retinal interneurons after most rods have died and cones have lost their outer-segment disk membranes and synaptic pedicles. We show that degenerating cones have functional cyclic-nucleotide-gated channels and can continue to give light responses, apparently produced by opsin localized either to small areas of organized membrane near the ciliary axoneme or distributed throughout the inner segment. Light responses of second-order horizontal and bipolar cells are less sensitive but otherwise resemble those of normal retina. Furthermore, retinal output as reflected in responses of ganglion cells is less sensitive but maintains spatiotemporal receptive fields at cone-mediated light levels. Together, these findings show that cones and their retinal pathways can remain functional even as degeneration is progressing, an encouraging result for future research aimed at enhancing the light sensitivity of residual cones to restore vision in patients with genetically inherited retinal degeneration.

IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterised by thrombosis (arterial, venous or small vessel) or obstetrical events and persistent antiphospholipid antibodies (aPL), according to the Sydney classification criteria. Many studies have performed cluster analyses among patients with primary APS and associated autoimmune disease, but none has focused solely on primary APS. We aimed to perform a cluster analysis among patients with primary APS and asymptomatic aPL carriers without any autoimmune disease, to assess prognostic value.MethodsIn this multicentre French cohort study, we included all patients with persistent APS antibodies (Sydney criteria) measured between January 2012 and January 2019. We excluded all patients with systemic lupus erythematosus or other systemic autoimmune diseases. We performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with baseline patient characteristics to generate clusters.ResultsWe identified four clusters: cluster 1, comprising 'asymptomatic aPL carriers', with low risk of events during follow-up; cluster 2, the 'male thrombotic phenotype', with older patients and more venous thromboembolic events; cluster 3, the 'female obstetrical phenotype', with obstetrical and thrombotic events; and cluster 4, 'high-risk APS', which included younger patients with more frequent triple positivity, antinuclear antibodies, non-criteria manifestations and arterial events. Regarding survival analyses, asymptomatic aPL carriers relapsed less frequently than the others, but no other differences in terms of relapse rates or deaths were found between clusters.ConclusionsWe identified four clusters among patients with primary APS, one of which was 'high-risk APS'. Clustering-based treatment strategies should be explored in future prospective studies.

Tess EK Cersonsky,1 Audra C Fain,2 Adam K Lewkowitz,3,4 Erika F Werner,5 Emily S Miller,3,4 Melissa A Clark,4,6 Nina K Ayala3,4 1Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Department of Obstetrics & Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Warren Alpert Medical School of Brown University, Providence, RI, USA; 4Department of Obstetrics & Gynecology, Women & Infants Hospital of Rhode Island, Providence, RI, USA; 5Department of Obstetrics & Gynecology, Tufts University School of Medicine, Boston, MA, USA; 6Department of Health Services, Policy and Practice, Brown School of Public Health, Providence, RI, USACorrespondence: Tess EK Cersonsky, Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, 1176 5th Ave, 9th Floor, New York, NY, 10029, USA, Tel +1 203-828-7407, Email tess.cersonsky@gmail.comObjective: Outside of pregnancy, proactive coping has been associated with both mental and physical well-being and with improved quality of life in chronic disease, but its effects in pregnancy are understudied. Our objective was to evaluate whether early pregnancy proactive coping was associated with adverse perinatal outcomes.Study Design: This was a planned secondary analysis of nulliparous pregnant people recruited from a tertiary care center. Participants completed a validated assessment of proactive coping (Proactive Coping Scale) at 8– 20 weeks and were followed longitudinally through delivery. Detailed pregnancy and delivery data were collected by trained research personnel. The primary outcome was a composite of adverse perinatal outcomes including unplanned cesarean delivery, gestational diabetes, and hypertensive disorders of pregnancy. Secondary analyses included individual perinatal composite components and a neonatal morbidity composite measure. Multivariate regression compared adverse perinatal outcomes by Proactive Coping Scale quartile, controlling for a priori confounders.Results: Of the 281 parturients, the median Proactive Coping Scale score was 45.0 (range 25– 55), and 47% experienced an adverse perinatal outcome. After adjusting for confounders, those in the lowest Proactive Coping Scale quartile had 2.2 times higher odds of experiencing an adverse perinatal outcome compared to those in the highest Proactive Coping Scale quartile. There were no differences in odds of the individual composite components or the adverse neonatal outcome.Conclusion: Lower early pregnancy proactive coping scores are associated with significant increase in adverse perinatal outcomes. Interventions that target improving proactive coping may be a novel mechanism for reducing perinatal morbidity.Plain Language Summary: Proactive coping is the process of preparing for a stressor or goal, which has been studied in the context of chronic disease. We sought to understand how proactive coping relates to pregnancy outcomes. Our results indicated that higher proactive coping scores were associated with lower risk of adverse pregnancy outcomes. Therefore, interventions to increase proactive coping may have a role in reducing adverse pregnancy outcomes.Keywords: proactive coping, adverse pregnancy outcomes, cesarean delivery, gestational diabetes, hypertensive disorders of pregnancy

Background. The reoperation rate reported in the literature in cases of flexor tendon injuries within the fingers and thumb is about 20%, but the functional results of these reoperations are barely discussed. The aim of the study was to evaluate the results of flexor tendon grafting performed as a redo procedure in patients who had previously underwent unsuccessful flexor tendon surgery. Methods. This study reports the outcomes of deep flexor tendon and flexor pollicis longus tendon grafting in 122 fingers of 109 patients depending on two factors — the type of the first failed surgery (tendon suture in 51 fingers vs grafting in 71 fingers) and the type of the medical unit where the failed procedure had been performed (hand surgery department in 76 cases vs general trauma unit in 46 cases). Results. Our reoperative grafting procedures led to excellent results in 13 fingers of 51 (25.5% [95% CI: 14–40]) after failed tendon suture and in 32 fingers of 71 (45.1% [95% CI: 33–57]) after failed previous grafting, difference is statistically significant (÷2 = 4.888; p = 0.027). Failed surgeries performed at the hand surgery departments were redone with 48.7% [95% CI: 37–60] of excellent results (in 37 fingers of 76) and 14.5% [95% CI: 7–24] of fair results (in 11 fingers of 76). Failed surgeries performed at the general trauma units were redone with 17.4% [95% CI: 8–31] of excellent results (in 8 fingers of 46). This value statistically significantly differed from the hand surgery departments group: ÷2 = 12.054; p = 0.001. For a total, excellent results were obtained in 36.9% [95% CI: 28–46] (in 45 fingers of 122) of reoperative grafting procedures and good results in 34.5% [95% CI: 26–43] (in 42 fingers of 122). Conclusions. Analysis of the functional results of deep flexor tendon and flexor pollicis longus tendon grafting performed as a reoperative procedure showed that the excellent results with full finger function were achievable in patients who had previously undergone unsuccessful flexor tendon surgery in zone 2. But in general, the rates of motion recovery were significantly lower than in uncomplicated cases, even with a long history of injury. The worst functional results of reoperations were in patients who had previously been unsuccessfully operated in non-specialized medical units.

Rationale: Extrapulmonary manifestations of asthma, including fatty infiltration in tissues, may reflect systemic inflammation and influence lung function and disease severity. Objectives: To determine if skeletal muscle adiposity predicts lung function trajectory in asthma. Methods: Adult SARP III (Severe Asthma Research Program III) participants with baseline computed tomography imaging and longitudinal postbronchodilator FEV1% predicted (median follow-up 5 years [1,132 person-years]) were evaluated. The mean of left and right paraspinous muscle density (PSMD) at the 12th thoracic vertebral body was calculated (Hounsfield units [HU]). Lower PSMD reflects higher muscle adiposity. We derived PSMD reference ranges from healthy control subjects without asthma. A linear multivariable mixed-effects model was constructed to evaluate associations of baseline PSMD and lung function trajectory stratified by sex. Measurements and Main Results: Participants included 219 with asthma (67% women; mean [SD] body mass index, 32.3 [8.8] kg/m2) and 37 control subjects (51% women; mean [SD] body mass index, 26.3 [4.7] kg/m2). Participants with asthma had lower adjusted PSMD than control subjects (42.2 vs. 55.8 HU; P

Multiple thoracic imaging modalities have been developed to link structure to function in the diagnosis and monitoring of lung disease. Volumetric computed tomography (CT) renders three-dimensional maps of lung structures and may be combined with positron emission tomography (PET) to obtain dynamic physiological data. Magnetic resonance imaging (MRI) using ultrashort-echo time (UTE) sequences has improved signal detection from lung parenchyma; contrast agents are used to deduce airway function, ventilation-perfusion-diffusion, and mechanics. Proton MRI can measure regional ventilation-perfusion ratio. Quantitative imaging (QI)-derived endpoints have been developed to identify structure-function phenotypes, including air-blood-tissue volume partition, bronchovascular remodeling, emphysema, fibrosis, and textural patterns indicating architectural alteration. Coregistered landmarks on paired images obtained at different lung volumes are used to infer airway caliber, air trapping, gas and blood transport, compliance, and deformation. This document summarizes fundamental good practice stereological principles in QI study design and analysis; evaluates technical capabilities and limitations of common imaging modalities; and assesses major QI endpoints regarding underlying assumptions and limitations, ability to detect and stratify heterogeneous, overlapping pathophysiology, and monitor disease progression and therapeutic response, correlated with and complementary to, functional indices. The goal is to promote unbiased quantification and interpretation of in vivo imaging data, compare metrics obtained using different QI modalities to ensure accurate and reproducible metric derivation, and avoid misrepresentation of inferred physiological processes. The role of imaging-based computational modeling in advancing these goals is emphasized. Fundamental principles outlined herein are critical for all forms of QI irrespective of acquisition modality or disease entity.

BackgroundFrom this retrospective study, we aimed to (1) describe the prevalence and characteristics of non-criteria features in primary antiphospholipid syndrome (p-APS) and (2) determine their prognostic value.MethodsThis retrospective French multicenter cohort study included all patients diagnosed with p-APS (Sydney criteria) between January 2012 and January 2019. We used Kaplan-Meier and adjusted Cox proportional hazards models to compare the incidence of relapse in p-APS with and without non-criteria manifestations.ResultsOne hundred and seventy-nine patients with p-APS were included during the study time, with a median age of 52.50 years [39.0; 65.25] and mainly women (n = 112; 62.6%). Among them, forty-three patients (24.0%) presented at least one non-criteria manifestation during the follow-up: autoimmune cytopenias (n = 17; 39.5%), Libman Sachs endocarditis (n = 5; 11.6%), APS nephropathy (n = 4; 9.3%), livedo reticularis (n = 8; 18.6%), and neurological manifestations (n = 12; 27.9%). In comparison to p-APS without any non-criteria manifestations (n = 136), p-APS with non-criteria features had more arterial thrombosis (n = 24; 55.8% vs n = 48; 35.3%; p = 0.027) and more frequent pre-eclampsia (n = 6; 14.3% vs n = 4; 3.1%; p = 0.02). The prevalence of triple positivity was significantly increased in patients with non-criteria features (n = 20; 47.6% vs n = 25; 19.8%; p = 0.001). Patients with p-APS and non-criteria manifestations (n = 43) received significantly more additional therapies combined with vitamin K antagonists and/or antiaggregants. Catastrophic APS (CAPS) tended to be more frequent in p-APS with non-criteria features (n = 2; 5.1% vs none; p = 0.074). The p-APS with non-criteria manifestations had significantly increased rates of relapse (n = 20; 58.8% vs 33; 33.7%; p = 0.018) in bivariate analysis, but in survival analyses, the hazard ratio (HR) of relapse was not significantly different between the two groups (HR at 1.34 [0.67; 2.68]; p = 0.40).ConclusionsThe presence of non-criteria features is important to consider, as they are associated with particular clinical and laboratory profiles, increased risk of relapse, and need for additional therapies. Prospective studies are necessary to better stratify the prognosis and the management of p-APS.

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Background Adverse medical events affect 10% of American households annually, inducing a variety of harms and attitudinal changes. The impact of adverse events on perceived abandonment by patients and their care partners has not been methodically assessed.Objective To identify ways in which providers, patients and families responded to medical mishaps, linking these qualitatively and statistically to reported feelings of abandonment and sequelae induced by perceived abandonment.Methods Mixed-methods analysis of responses to the Massachusetts Medical Errors Recontact survey with participants reporting a medical error within the past 5 years. The survey consisted of forty closed and open-ended questions examining adverse medical events and their consequences. Respondents were asked whether they felt ‘that the doctors abandoned or betrayed you or your family’. Open-ended responses were analysed with a coding schema by two clinician coders.Results Of the 253 respondents, 34.5% initially and 20% persistently experienced abandonment. Perceived abandonment could be traced to interactions before (18%), during (34%) and after (45%) the medical mishap. Comprehensive post-incident communication reduced abandonment for patients staying with the provider associated with the mishap. However, 68.4% of patients perceiving abandonment left their original provider; for them, post-error communication did not increase the probability of resolution. Abandonment accounted for half the post-event loss of trust in clinicians.Limitations Survey-based data may under-report the impact of perceived errors on vulnerable populations. Moreover, patients may not be cognizant of all forms of adverse events or all sequelae to those events. Our data were drawn from a single state and time period.Conclusion Addressing the deleterious impact of persisting abandonment merits attention in programmes responding to patient safety concerns. Enhancing patient engagement in the aftermath of an adverse medical event has the potential to reinforce therapeutic alliances between patients and their subsequent clinicians.

ABSTRACT: Purpose: Since the Consensus Statement diffused by the Amsterdam Placental Workshop Group, knowledge of the meaning of placental vascular malperfusion has become essential in the unavoidable analysis of obstetrical history in a patient followed for autoimmune disease or any other maternal comorbidity. We aimed to analyse the prevalence of various placental lesions from a 6-months prospective observational study and to correlate the various placental profiles to obstetrical outcome, maternal diseases and pregnancy treatments. The frequency of foetal vascular malperfusion lesion could be estimated at 8.7%, in our population and to understand its neonatal associations. Methods: The study groups consisted of 208 consecutive women which ended the pregnancy and have placental analysis during the period of the study. Results: From December 2015 to October 2017, from overall 4398 delivered pregnancies in university obstetrical department, 208 (4.7%) placental analysis have been done and included in the study. The placental analysis have been done for vascular obstetrical complications during the pregnancy (n = 106; 51%), unexplained abnormal foetal heart rate tracings (n = 59; 28,3%), suspicion of intra-amniotic infection (n = 12; 5,7%%), term new-borns Apgar score

Introduction: Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can be associated with autoimmune and inflammatory diseases. This study aimed to describe kidney involvement in patients with CMML, their treatments, and outcomes. Methods: We conducted a French and American multicenter retrospective study in 15 centers, identifying patients with CMML with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities. Results: Sixteen patients (males, n = 14; median age 76.5 years [71.9–83]) developed a kidney disease 6 months [1.6–25.6] after the diagnosis of CMML. At the time of kidney disease diagnosis, median urinary protein-to-creatinine ratio was 2 g/g [1.25–3.4], and median serum creatinine was 2.26 mg/dl [1.46–2.68]. Fourteen patients (87.5%) underwent a kidney biopsy, and the 2 main pathological findings were lysozyme nephropathy (56%) and renal infiltration by the CMML (37.5%). Ten patients received a new treatment following the CMML-associated kidney injury. Among patients with monitored kidney function, and after a median follow-up of 15 months [9.9–34.9], 4 patients had CKD stage 3, 4 had CKD stage 4, 1 had an end-stage kidney disease. In our patient series, 2 patients evolved to an acute myeloid leukemia (AML), and 5 died. Compared with 116 CMML controls, patients who had a kidney involvement had a higher monocyte count (P < 0.001), had more CMML-1 (P = 0.005), were more susceptible to develop an AML (P = 0.02), and were more eligible to receive a specific hematologic treatment, with hydroxyurea, or hypomethylating agents (P < 0.001), but no survival difference was seen between the 2 groups (P = 0.6978). Conclusion: In this cohort of patients with CMML with a kidney injury, the 2 most frequent renal complications were lysozyme-induced nephropathy and renal infiltration by the CMML. Kidney involvement should be closely monitored in patients with CMML.

Background/Objectives: Despite the role of metabolism in breast cancer metastasis, we still cannot predict which breast tumors will progress to distal metastatic lesions or remain dormant. This work uses metabolic imaging to study breast cancer cell lines (4T1, 4T07, and 67NR) with differing metastatic potential in a 3D collagen gel bioreactor system. Methods: Within the bioreactor, hyperpolarized magnetic resonance spectroscopy (HP-MRS) is used to image lactate/pyruvate ratios, while fluorescence lifetime imaging microscopy (FLIM) of endogenous metabolites measures metabolism at the cellular scale. Results: HP-MRS results showed no lactate peak for 67NR and a comparatively large lactate/pyruvate ratio for both 4T1 and 4T07 cell lines, suggestive of greater pyruvate utilization with greater metastatic potential. Similar patterns were observed using FLIM with significant increases in FAD intensity, redox ratio, and NAD(P)H lifetime. The lactate/pyruvate ratio was strongly correlated to NAD(P)H lifetime, consistent with the role of NADH as an electron donor for the glycolytic pathway, suggestive of an overall upregulation of metabolism (both glycolytic and oxidative), for the 4T07 and 4T1 cell lines compared to the non-metastatic 67NR cell line. Conclusions: These findings support a complementary role for HP-MRS and FLIM enabled by a novel collagen gel bioreactor system to investigate metastatic potential and cancer metabolism.

Background Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc.Objective We aimed to assess the safety and biological efficacy of IL-2LD in patients with SSc.Methods As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6.Results At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+ T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period.Conclusion IL-2LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LD therapeutic efficacy in SSc.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Introduction: Neuromuscular blockers (NMB) are used in surgical procedures to facilitate muscle relaxation and intubation. NMBs are then reversed at the end of the surgery with either an acetylcholinesterase inhibitor, such as neostigmine, or a modified cyclodextrin compound, such as sugammadex. Neostigmine and glycopyrrolate elicit counteracting cholinergic effects, potentially impairing postoperative gastrointestinal motility. This may have higher significance in colorectal surgery procedures given the baseline risk of delayed postoperative motility associated with some operations. Methods: This is a retrospective, single-center, cohort review of open colorectal procedures that received either sugammadex alone, or neostigmine with glycopyrrolate. The primary outcome was time from end of colorectal procedure to time of first bowel movement. Secondary outcomes included incidence of postoperatively placed nasogastric tubes, nausea and vomiting, need for motility agents or TPN, hospital length of stay, 30-day hospital readmission or return to emergency department (ED). Results: A total of 99 patients were included in the sugammadex group and 350 in the neostigmine + glycopyrrolate group. Time to first bowel movement was significantly faster in the sugammadex group (61.7 h) compared to the neostigmine group (71.9 h) (p = 0.03). Secondary outcomes were similar between the two groups, except for a higher incidence of postoperative nausea and vomiting in the sugammadex group (p = 0.04). Discussion: These findings support that sugammadex may be utilized for open colorectal procedures to aid in earlier discharge which could lead to differences in length of stay. Using sugammadex did not result in patients requiring additional interventions or experiencing symptoms of post-operative ileus. Conclusion: Compared to neostigmine and glycopyrrolate, patients receiving sugammadex for neuromuscular blockade reversal in open colorectal procedures experienced a shorter time to return of bowel function. The results from this study confirm the findings from previous retrospective studies that were conducted.

Rationale: Cross-sectional analysis of mucus plugs in computed tomography (CT) lung scans in the Severe Asthma Research Program (SARP)-3 showed a high mucus plug phenotype. Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function. Methods: In a longitudinal analysis of baseline and Year 3 CT lung scans in SARP-3 participants, radiologists generated mucus plug scores to assess mucus plug persistence over time. Changes in mucus plug score were analyzed in relation to changes in lung function and CT air trapping measures. Measurements and Main Results: In 164 participants, the mean (range) mucus plug score was similar at baseline and Year 3 (3.4 [0-20] vs. 3.8 [0-20]). Participants and bronchopulmonary segments with a baseline plug were more likely to have plugs at Year 3 than those without baseline plugs (risk ratio, 2.8; 95% confidence interval [CI], 2.0-4.1; P