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Objective: We tested whether long-term treatment with the angiotensin II receptor antagonist irbesartan reduces nucleic acid oxidation in patients with type 2 diabetes and microalbuminuria.Research Design and Methods: The Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA 2) study was a 2-year multicenter randomized double-blind trial comparing irbesartan (150 and 300 mg once daily) with placebo. We studied a subgroup of 50 patients where urine samples were available for analysis of albumin and the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo).Results: During the 2-year trial, no significant differences in 8-oxodG and 8-oxoGuo excretions between placebo and irbesartan treatment were seen. 8-oxodG and albumin excretion decreased with time (P = 0.0004 and P < 0.0001, respectively), whereas treatment-related differences were shown for albumin excretion (P = 0.0008) only, as previously reported. Important secondary findings were significant associations between changes in 8-oxodG excretion and changes in albumin excretion and glycated hemoglobin (HbA(1c)). During the study period, 8-oxodG excretion decreased by 3 and 26% in smokers and nonsmokers, respectively (P = 0.015), and urinary albumin excretion decreased 22% in smokers and 58% in nonsmokers (P = 0.011).Conclusions: Irbesartan treatment was not significantly more effective than placebo in reducing nucleic acid oxidation. The results indicate that DNA oxidation in diabetes patients is reduced by various components in the treatment of diabetes where glycemic control seems to be important and addition of angiotensin II receptor antagonists does not lead to any substantial additional reduction. Furthermore, the reductions in DNA oxidation and albumin excretion seem to be counteracted by smoking. [ABSTRACT FROM AUTHOR]

Objective: We analyzed data from a cohort of 1,381 newly diagnosed type 2 diabetic patients to test the hypothesis that urinary markers of nucleic acid oxidation are independent predictors of mortality.Research Design and Methods: We examined the relationship between urinary excretion of markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) and RNA oxidation (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and long-term mortality using Cox proportional hazards regression.Results: After multivariate adjustment, the hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.44 (1.12-1.85) and 1.54 (1.13-2.10), respectively. Conversely, no significant associations between 8-oxodG and mortality were found in the adjusted analyses.Conclusions: Urinary excretion of the RNA oxidation marker 8-oxoGuo measured shortly after diagnosis of type 2 diabetes predicts long-term mortality independently of conventional risk factors. This finding suggests that 8-oxoGuo could serve as a new clinical biomarker in diabetes. [ABSTRACT FROM AUTHOR]

Immunoglobulin G (IgG) antibodies that bind their cognate antigen in a pH-dependent manner (acid-switched antibodies) can release their bound antigen for degradation in the acidic environment of endosomes, while the IgGs are rescued by the neonatal Fc receptor (FcRn). Thus, such IgGs can neutralize multiple antigens over time and therefore be used at lower doses than their non-pH-responsive counterparts. Here, we show that light-chain shuffling combined with phage display technology can be used to discover IgG1 antibodies with increased pH-dependent antigen binding properties, using the snake venom toxins, myotoxin II and α-cobratoxin, as examples. We reveal differences in how the selected IgG1s engage their antigens and human FcRn and show how these differences translate into distinct cellular handling properties related to their pH-dependent antigen binding phenotypes and Fc-engineering for improved FcRn binding. Our study showcases the complexity of engineering pH-dependent antigen binding IgG1s and demonstrates the effects on cellular antibody-antigen recycling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Peripartum depression is common and treatment with mirtazapine may be indicated. However, evidence on its safety in pregnancy and lactation is fragmented. The objective of this systematic review was to evaluate the literature on the safety of mirtazapine in pregnancy and lactation., Methods: PubMed, Embase, Medline, PsycInfo, and clinicaltrials.gov were searched for 'antidepressants' or 'mirtazapine' in combination with 'pregnancy', 'lactation' or 'offspring'. No restrictions on type of study were applied and selection was performed by two independent reviewers using Covidence. Two reviewers extracted data and performed risk of bias assessment and evidence synthesis was performed for each outcome individually. The protocol was registered at PROSPERO (registration number CRD42021275127)., Results: The initial search yielded 15,380 articles after removal of duplicates. After screening based on title and abstract, 431 articles remained for full text review. Of these, 41 studies were included (15 cohort studies, one case-control study, 11 case series, and 14 case reports). In most studies, the outcomes in mirtazapine-exposed pregnancies were comparable to controls. However, results on congenital malformations and spontaneous abortion were conflicting. Neonatal adaptation syndrome was reported after mirtazapine exposure in late pregnancy. Data on mirtazapine exposure during lactation were scarce., Conclusions: We identified no substantial evidence indicating that mirtazapine exposure is associated with adverse outcomes in pregnancy or in offspring, other than neonatal adaptation syndrome. However, overall quality of evidence was low, and results on congenital malformations and spontaneous abortions were conflicting. Data on mirtazapine exposure through breastfeeding were limited and did not allow for conclusions., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Designing effective monoclonal antibody (mAb) therapeutics faces a multi-parameter optimization challenge known as "developability", which reflects an antibody's ability to progress through development stages based on its physicochemical properties. While natural antibodies may provide valuable guidance for mAb selection, we lack a comprehensive understanding of natural developability parameter (DP) plasticity (redundancy, predictability, sensitivity) and how the DP landscapes of human-engineered and natural antibodies relate to one another. These gaps hinder fundamental developability profile cartography. To chart natural and engineered DP landscapes, we computed 40 sequence- and 46 structure-based DPs of over two million native and human-engineered single-chain antibody sequences. We find lower redundancy among structure-based compared to sequence-based DPs. Sequence DP sensitivity to single amino acid substitutions varied by antibody region and DP, and structure DP values varied across the conformational ensemble of antibody structures. We show that sequence DPs are more predictable than structure-based ones across different machine-learning tasks and embeddings, indicating a constrained sequence-based design space. Human-engineered antibodies localize within the developability and sequence landscapes of natural antibodies, suggesting that human-engineered antibodies explore mere subspaces of the natural one. Our work quantifies the plasticity of antibody developability, providing a fundamental resource for multi-parameter therapeutic mAb design., (© 2024. The Author(s).)

Introduction: Drug trials in neonates are scarce, and the neonates may consequently be at risk of adverse drug reactions (ADRs). Spontaneous ADR reporting is an important tool for expanding the knowledge on drug safety in neonates. This study explores the quality of current neonatal ADR reports and the ADR reports of the most common drugs used in neonatal departments., Methods: An observational cross-sectional study focused on neonates was conducted using data on spontaneous reports extracted from the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) from the third quarter of 2014 up to December 2022. Only the primary suspect drugs given to neonates or subjects aged <30 days were included in the analysis., Results: Spontaneous reports from 13 million patients of all ages, totaling 50 million ADRs, were evaluated. Information regarding the age was missing in 40% of the reports, and data on 43,737 neonates with 948 different suspected drugs were identified and included in the analysis. We report the frequency of spontaneous ADR reports in the FAERS database for the ten most frequently administered drugs in neonatal intensive care units in the USA., Conclusion: Overall, neonatal ADRs are still underreported. The FAERS database in its current form discriminates insufficiently between prenatal and postnatal drug exposures. Hence, improved neonatal pharmacovigilance systems are urgently needed., 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. The author(s) declare that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Byskov, Baden, Andersen, Jimenez-Solem, Olsen, Gade and Lausten-Thomsen.)

In swimming, the underwater phase after the start and turn comprises gliding and dolphin kicking, with the latter also known as underwater undulatory swimming (UUS). Swimming performance is highly dependent on the underwater phase; therefore, understanding the training effects in UUS and underwater gliding can be critical for swimmers and coaches. Further, the development of technique in young swimmers can lead to exponential benefits in an athlete's career. This study aimed to evaluate the effects of a training protocol on UUS and underwater gliding performance and kinematics in young swimmers. Seventeen age group swimmers (boys = 10, girls = 7) performed maximal UUS and underwater gliding efforts before and after a seven-week training protocol. Time to reach 10 m; intra-cyclic mean, peak, and minimum velocities; and gliding performance improved significantly after the training protocol. The UUS performance improvement was mostly produced by an improvement of the upbeat execution, together with a likely reduction of swimmers' hydrodynamic drag. Despite the changes in UUS and gliding, performance was also likely influenced by growth. The findings from this study highlight kinematic variables that can be used to understand and quantify changes in UUS and gliding performance.

Competing Interests: Conflicts of interest Dr Dalhoff was a member of the Board of Anti-Doping Denmark from 2015 to 2020. Drs Heerfordt, Windfeld-Mathiasen, Mogensen, Andersen, and Horwitz have no conflicts of interest to declare.

Background: Antipsychotics are commonly administered to nursing home residents with dementia, despite the associated risk of severe adverse events., Objective: This study aimed to explore healthcare professionals' experiences in caring for nursing home residents with dementia, with a focus on rationales behind the use of antipsychotics., Method: Twelve semi-structured interviews with healthcare professionals' from Danish nursing homes were conducted and analyzed using the method Systematic Text Condensation., Results: Nonpharmacological interventions were reported as the primary approach to care and the first-choice treatment for behavioral and psychological symptoms of dementia (BPSD). Use of antipsychotics was considered to serve as a last resort, reserved for residents with severe symptoms. However, most informants preferred a more limited use. The study identified four main barriers to reduce the use of antipsychotics: "Scarcity of resources", "Perceiving antipsychotic use to provide relieve", "Reluctance towards deprescribing" and "Limited access to medical counseling", and three potential enablers: " Updating knowledge and nonpharmacological competencies ", " Management support and clear procedures " and " Regularity in interdisciplinary collaboration "., Conclusion: The treatment and care were reported as primarily following guidelines in BPSD. Several barriers were perceived to challenge the healthcare professionals' preference of limited use of antipsychotics. To further reduce the use, this study highlights the importance of understanding the adverse effects caused by limited resources, enhancing employee knowledge and competencies and ensuring regular interprofessional collaboration for assessing and reassessing the need to use antipsychotics., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Charlotte Vermehren received a grant by the Danish Health Authority (3165–0018) to fund the DECADE-project. The Danish Health Authority was not involved in study decisions. No other conflict of interest or funding relevant to the current study were declared., (© 2024 The Authors.)

Introduction: Meningiomas frequently occur within the field of neuro-oncology, but it is unclear whether exogenous or imbalanced endogenous hormones are involved in the pathophysiology. A previous case-control study found an almost 20-fold increase in the risk of developing meningioma among users of androgenic anabolic steroids. We, therefore, investigated this hypothesis., Methods: We compared the incidence rate of meningioma in a cohort of males sanctioned for the use of androgenic anabolic steroids with age- and sex-matched controls with an identical enrollment date., Results: We followed 1189 males sanctioned for using androgenic anabolic steroids for a total of 13,305 person-years and found 0 cases of meningioma. The control cohort of 59,450 males was followed for a total of 654,938 person-years, and 16 were diagnosed with meningioma. Thus, the incidence rate ratio was 0 (95% CI: 0-12.8)., Conclusion: We did not find any evidence supporting the hypothesis of an increased risk of meningioma development with the use of androgenic anabolic steroids. Due to the limited sample size, we cannot exclude androgenic anabolic steroids as a potential risk factor for meningioma development, despite the lack of apparent evidence in this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions., (© 2024. The Author(s).)

Monoclonal antibodies (mAbs) as therapeutics necessitate favorable pharmacokinetic properties, including extended serum half-life, achieved through pH-dependent binding to the neonatal Fc receptor (FcRn). While prior research has mainly investigated IgG-FcRn binding kinetics with a focus on single affinity values, it has been shown that each IgG molecule can engage two FcRn molecules throughout an endosomal pH gradient. As such, we present here a more comprehensive analysis of these interactions with an emphasis on both affinity and avidity by taking advantage of switchSENSE technology, a surface-based biosensor where recombinant FcRn was immobilized via short DNA nanolevers, mimicking the membranous orientation of the receptor. The results revealed insight into the avidity-to-affinity relationship, where assessing binding through a pH gradient ranging from pH 5.8 to 7.4 showed that the half-life extended IgG1-YTE has an affinity inflection point at pH 7.2, reflecting its engineering for improved FcRn binding compared with the wild-type counterpart. Furthermore, IgG1-YTE displayed a pH switch for the avidity enhancement factor at pH 6.2, reflecting strong receptor binding to both sides of the YTE-containing Fc, while avidity was abolished at pH 7.4. When compared with classical surface plasmon resonance (SPR) technology and complementary methods, the use of switchSENSE demonstrated superior capabilities in differentiating affinity from avidity within a single measurement. Thus, the methodology provides reliable kinetic rate parameters for both binding modes and their direct relationship as a function of pH. Also, it deciphers the potential effect of the variable Fab arms on FcRn binding, in which SPR has limitations. Our study offers guidance for how FcRn binding properties can be studied for IgG engineering strategies.

Recycling IgG antibodies bind to their target antigen at physiological pH in the blood stream and release them upon endocytosis when pH levels drop, allowing the IgG antibodies to be recycled into circulation via FcRn-mediated cellular pathways, while the antigens undergo lysosomal degradation. This enables recycling antibodies to achieve comparable therapeutic effect at lower doses than their non-recycling counterparts. The development of such antibodies is typically achieved by histidine doping of their variable regions or by performing in vitro antibody selection campaigns utilizing histidine doped libraries. Both are strategies that may introduce sequence liabilities. Here, we present a methodology that employs a naïve antibody phage display library, consisting of natural variable domains, to discover antibodies that bind α-cobratoxin from the venom of Naja kaouthia in a pH-dependent manner. As a result, an antibody was discovered that exhibits a 7-fold higher off-rate at pH 5.5 than pH 7.4 in bio-layer interferometry experiments. Interestingly, no histidine residues were found in its variable domains, and in addition, the antibody showed pH-dependent binding to a histidine-devoid antigen mutant. As such, the results demonstrate that pH-dependent antigen-antibody binding may not always be driven by histidine residues. By employing molecular dynamics simulations, different protonation states of titratable residues were found, which potentially could be responsible for the observed pH-dependent antigen binding properties of the antibody. Finally, given the typically high diversity of naïve antibody libraries, the methodology presented here can likely be applied to discover recycling antibodies against different targets ab initio without the need for histidine doping., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Introduction: Behavioural and psychological symptoms of dementia (BPSD) should only rarely and briefly be treated with antipsychotics. Despite recommendations to the contrary, the use of antipsychotics in nursing home residents with dementia is widespread and followed by serious adverse effects. Intervention studies on methods to reduce the use of antipsychotics in persons with dementia are few and needed. The aim of this protocol is to describe the rationale and content of the intervention DEprescribing and Care to reduce Antipsychotics in DEmentia (DECADE)-a hybrid effectiveness-implementation pilot study., Materials and Methods: This is a protocol of a prospective hybrid effectiveness-implementation pilot study. The primary aim of DECADE is to reduce the use of antipsychotic drugs by 50% in 50% of nursing home residents with dementia while maintaining or improving BPSD. The intervention is implemented in six nursing homes including approximately 190 residents with dementia and consists of Academic Detailing, medication review, education of nursing home staff, and care plans. The evaluation of feasibility and potential effectiveness is an overall assessment of all clinical and process outcomes. Logistic regression analyses will be used to investigate factors characterizing situations with prescription of antipsychotics. BPSD is analysed with a before- and after design using self-controlled case series methods and the use of antipsychotics is analysed as interrupted time series., Discussion: This protocol describes a study that will provide an indication of DECADE effectiveness and a model for upscaling and further evaluation in a controlled design., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Benthien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Intravitreal injection (IVI) of antibody biologics is a key treatment approach in ophthalmology. Pharmaceutical compounding and storage of prefilled syringes for IVI must take place without impairing the structure and function of the biologics. This study investigated the effect of withdrawing and storing the therapeutic antibody faricimab (Vabysmo, Roche, Basel, Switzerland) in the Zero Residual silicone oil-free, 0.2-mL syringe (SJJ Solutions, The Hague, the Netherlands)., Methods: To assess the effect of syringe withdrawal on faricimab, we compared samples from syringes prepared at day 0 with samples taken directly from faricimab vials. To assess the effect of syringe storage on faricimab, we kept prefilled syringes in the dark at 4  o C for 7, 14, or 37 days and compared samples from these syringes with day 0. We measured protein concentration (with spectrophotometry), stability and integrity (with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size-exclusion chromatography (SEC), and melting temperature (Tm)), as well as binding of faricimab to its cognate antigens: vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2) (with enzyme-linked immunosorbent assay (ELISA))., Results: Faricimab migrated in line with its expected molecular mass under both reducing and non-reducing conditions for all time points when analyzed with SDS-PAGE, without any sign of degradation products or aggregation. The SEC elution profiles were identical for all time points. There were slight variations in Tm for different time points compared to day 0 but without consistent relationship with storage time. ELISA did not detect differences in VEGF-A or Ang-2 binding between time points, and faricimab did not bind the neonatal Fc receptor., Conclusions: Withdrawal and storage of faricimab in syringes for up to day 37 did not impair the structure and bi-specific binding properties of the therapeutic antibody., (© 2023. The Author(s).)

Background: Knowledge within the field of multiple sclerosis treatment during pregnancy is vital to ensure the most optimal clinical practice. Immunomodulatory treatment in pregnancy could in theory affect the normal development and maturation of the immune system of the fetus with a potential increased risk of infections, consequently. We therefore set out to investigate whether exposure to interferon-beta in utero affected the risk of acquiring infections in early childhood., Methods: This retrospective matched cohort study utilized data from the Danish Multiple Sclerosis Registry linked with national Danish registries to identify all children born of mothers with MS in Denmark from 1998 to 2018. The study included 510 children exposed to interferon-beta in utero. The children were matched 1:1 on various of demographic characteristics with children born to mothers with untreated MS and 1:3 with children born to mothers without MS. Each child was followed for up to five years. Using individual-level data, we investigated all-cause mortality, rate of hospital admissions due to infections, and redeemed prescriptions of antibiotics. The primary statistical model applied was a negative binomial regression analysis., Results: We found no differences in childhood mortality, for hospital admissions the rate ratio compared to healthy controls was 0.79 (0.62-1.00). Regarding antibiotic prescriptions, the results were similar (RR 1.00 (0.90-1.11). Furthermore, we found no certain dose-response relationship between interferon-beta exposure duration and hospital admission rate (P = 0.47) or redeemed antibiotic prescription (P = 0.71)., Conclusion: Exposure to interferon-beta during gestation has little to no impact on the risk of acquiring significant infections during the first five years of childhood., Competing Interests: Declaration of Competing Interest Melinda Magyari has served on scientific advisory board, as consultant for, received support for congress participation or speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Alexion, Bristol Myers Squibb. The Danish MS Registry received research support from Biogen, Genzyme, Roche, Merck, Novartis. The rest of the authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies in vitro was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. In vivo a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy., Competing Interests: MB and PS are employed by Tacalyx GmbH. JHWL is scientific founder and shareholder of TigaTx. All other 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 Lustig, Chan, Jansen, Bräutigam, Kölling, Gehlert, Baumann, Mester, Foss, Andersen, Bastian, Sondermann, Peipp, Burger, Leusen and Valerius.)

Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases., (© 2023. The Author(s).)

Markerless motion capture has improved physical screening efficiency in sport and occupational settings; however, reliability of kinematic measurements from commercial systems must be established. Further, the impact of torso-borne equipment on these measurements is unclear. The purpose of this study was to evaluate the reliability of HumanTrak, a markerless motion capture system, for estimating peak trunk flexion in squat movements with and without a weighted vest. Eighteen participants completed body weight squats (BWSQ) and overhead squats (OHSQ) to their maximum depth (unrestricted-range) and to a plyometric box (fixed-range) while wearing no body armour (NBA) or 9 kg body armour (BA9). Peak trunk flexion was measured using HumanTrak. Testing was performed in two sessions on one day (intra-day) and one session on a separate day (inter-day) to assess reliability. HumanTrak had a standard error of measurement < 3.74° across all movements and conditions. Reliability was good to excellent (ICC = 0.82-0.96) with very large to nearly perfect Pearson correlations (r > 0.80) for all comparisons except unrestricted-range BWSQ with BA9 (ICC = 0.60-0.71, r = 0.71). HumanTrak was more reliable for intra- than inter-day, but reliability was still excellent for almost all inter-day comparisons (ICC > 0.82). HumanTrak is reliable for detecting differences in peak trunk flexion > 8.5° when body armour is not worn and > 10.5° when body armour is worn. Practitioners can assess meaningful changes in sagittal plane trunk motion when screening squat movements regardless of whether body armour is worn., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: One of the co-authors was an employee of VALD Performance at the time this study was conducted. There was no influence from VALD Performance on the findings or interpretation of the results. This research was partially supported by the Macquarie University Research Excellence Stipend Scholarship and the VALD Performance Stipend Scholarship., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aggregates of the protein tau are proposed to drive pathogenesis in neurodegenerative diseases. Tau can be targeted by using passively transferred antibodies (Abs), but the mechanisms of Ab protection are incompletely understood. In this work, we used a variety of cell and animal model systems and showed that the cytosolic Ab receptor and E3 ligase TRIM21 (T21) could play a role in Ab protection against tau pathology. Tau-Ab complexes were internalized to the cytosol of neurons, which enabled T21 engagement and protection against seeded aggregation. Ab-mediated protection against tau pathology was lost in mice that lacked T21. Thus, the cytosolic compartment provides a site of immunotherapeutic protection, which may help in the design of Ab-based therapies in neurodegenerative disease.

Background: Depression or depressive symptoms are common among pregnant women. The use of antidepressants during pregnancy has grown steadily. The risk of offspring being born small for gestational age or prematurely when exposed to duloxetine during pregnancy is not established., Objective: We aimed to investigate the association between duloxetine exposure during pregnancy and offspring being born small for gestational age or prematurely., Methods: We conducted an observational study including live births in Sweden and Denmark (2004-2016). Duloxetine exposure during early (0-140 days) or late (141 to delivery) pregnancy compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, venlafaxine-exposed, and duloxetine discontinuers., Results: In total, 2,083,467 pregnancies were identified, where 1589 and 450 were duloxetine exposed in early and late pregnancy, respectively. For small for gestational age, no increased risk was seen for duloxetine across comparators. In the early and late exposure windows, propensity score-matched odds ratios for small for gestational age ranged between 0.64 (95% confidence interval 0.44-0.95) and 1.48 (95% confidence interval 0.85-2.57). For preterm birth, the findings differed across comparators and exposure-time windows, but trended towards an increased risk for duloxetine-exposed when compared with duloxetine-non-exposed, selective serotonin reuptake inhibitor-exposed, and duloxetine discontinuers in both early exposure and late exposure. The odds ratios ranged between 1.17 and 2.04, of which some did not reach statistical significance. No clear association was observed when compared with venlafaxine exposed, 0.91 (95% confidence interval 0.73-1.14) for early exposure and 1.26 (95% confidence interval 0.86-1.86) for late exposure. Most preterm births (79.2%) occurred in weeks 33-36 of gestation., Conclusions: Duloxetine exposure during pregnancy is unlikely to increase the risk of small for gestational age. Although not consequently statistically significant across comparisons, a trend towards an increased risk of preterm birth was observed for duloxetine exposed. Therefore, an increased risk of preterm birth cannot be excluded, especially for women exposed to duloxetine throughout pregnancy., (© 2022. The Author(s).)

Beyond potency, a good developability profile is a key attribute of a biological drug. Selecting and screening for such attributes early in the drug development process can save resources and avoid costly late-stage failures. Here, we review some of the most important developability properties that can be assessed early on for biologics. These include the influence of the source of the biologic, its biophysical and pharmacokinetic properties, and how well it can be expressed recombinantly. We furthermore present in silico, in vitro , and in vivo methods and techniques that can be exploited at different stages of the discovery process to identify molecules with liabilities and thereby facilitate the selection of the most optimal drug leads. Finally, we reflect on the most relevant developability parameters for injectable versus orally delivered biologics and provide an outlook toward what general trends are expected to rise in the development of biologics.

Introduction: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic., Objective: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS)., Methods: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects., Results: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response., Conclusions: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations., Competing Interests: Competing interests: ARL research fundings from Sanofi. SW has received speaker honoraria from and served on scientific advisory boards for Biogen, Janssen-Cilag, Sanofi and Novartis. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, BMS, Jansen, Sanofi, Merck and Novartis. TH has received speaker honoraria and/or unrestricted research grants from Biogen, Merck, Roche, Novartis, Sanofi and Bristol-Myers Squibb, and participated in clinical trials organised by Merck, Sanofi and Roche. TB has received unrestricted research grants from Biogen Idec and Sanofi Genzyme. MK-M has received unrestricted research grants to his institution; scientific advisory board and speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi, and has participated in clinical trials organised by Biogen, Merck, Novartis, Roche and Sanofi. HFH has received honoraria for lecturing or advice from Biogen, Merck, Roche, Novartis and Sanofi. AS is shareholder of Age Labs, a molecular diagnostics company that discovers, develops and commercialises diagnostic tests for the early detection of age-related diseases. EGC has received honoraria for lecturing and advice from Biogen, BMS, Janssen, Merck, Novartis, Roche and Sanofi., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 serum samples. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring., (© 2022. The Author(s).)

Objective: The purpose of this study was to investigate the psychiatric morbidity among men with abuse of anabolic steroids., Methods: The design is a retrospectively matched cohort study. Five hundred and fourty-five males, who tested positive for anabolic steroids in Danish fitness centers during the period January 3, 2006 to March 1, 2018, were matched with 5450 randomly chosen male controls. Data was cross-referenced with seven national registers pertaining to information about education, employment status, and psychiatric comorbidity. Main outcomes and measures were prescription of psychopharmacological treatment., Results: The incidence of treatment with anxiolytics (HR: 2.34, 95% CI: 1.62-3.38) and antipsychotics (HR: 2.69, 95% CI: 1.99-3.63) displayed a remarkable increase in the years following doping sanction, compared to the control group. The prevalence of antidepressant use was already markedly elevated several years before doping sanction, but also displayed a higher incidence in the years following sanction (HR: 1.65, 95% CI: 1.28-2.13). The associations remained highly significant after controlling for socioeconomic factors., Conclusion: Anabolic steroids use is strongly associated with psychiatric morbidity., (© 2022 The Authors. Depression and Anxiety published by Wiley Periodicals LLC.)

Background: Similar muscle performance adaptations have been shown following volume-equated resistance training using cluster (CLUS) versus traditional (TRAD) set structures. This study aimed to examine the effects of higher-volume CLUS compared to lower-volume TRAD set structures on muscle performance., Methods: Twenty resistance-trained males (age 20.9±4.3 years) were randomized into one of two bench press training routines performed for 6 weeks. Subjects in CLUS (N.=10), performed six sets of five repetitions at 85% one-repetition maximum (1RM) with 30 seconds inter-repetition rest and three minutes of inter-set rest. In contrast, subjects in TRAD (N.=10) performed three sets of five repetitions at 85% 1RM with five minutes of inter-set rest. Muscular strength (1RM), concentric velocity, power, local muscular endurance and maintenance of muscle performance (in training sessions) were assessed., Results: For 1RM there was a significant time effect (P<0.001) with moderate effect sizes (ES) within each group (CLUS: ES=0.48; TRAD: ES=0.67). A trend towards significant time effect was found for concentric velocity (P=0.05; CLUS: ES=-0.36; TRAD ES=-0.96). There were no other significant time or group effects nor group × time interactions. Greater maintenance of concentric velocity and power (sets 1-3) was found for CLUS compared to TRAD at week one (P<0.05) but not at week 6., Conclusions: High load resistance training in the bench press exercise, utilizing intra-set rest periods to increase the training volume, does not yield any muscular performance benefits compared to traditional set structures.

Background: Results showing that sera from double vaccinated individuals have minimal neutralizing activity against Omicron have been interpreted as indicating the need for a third vaccine dose for protection. However, there is little information about early immune responses to Omicron infection in double vaccinated individuals., Methods: We measured inflammatory mediators, antibodies to the SARS-CoV-2 spike and nucleocapsid proteins, and spike peptide-induced release of interferon gamma in whole blood in 51 double-vaccinated individuals infected with Omicron, in 14 infected with Delta, and in 18 healthy controls. The median time points for the first and second samples were 7 and 14 days after symptom onset, respectively., Findings: Infection with Omicron or Delta led to a rapid and similar increase in antibodies to the receptor-binding domain (RBD) of Omicron protein and spike peptide-induced interferon gamma in whole blood. Both the Omicron- and the Delta-infected patients had a mild and transient increase in inflammatory parameters., Interpretation: The results suggest that two vaccine doses are sufficient to mount a rapid and potent immune response upon infection in healthy individuals of with the Omicron variant., Funding: The study was funded by the Oslo University Hospital, and by grants from The Coalition for Epidemic Preparedness Innovations, Research Council of Norway (no 312780, 324272), South-Eastern Norway Regional Health Authority (no 2019067, 2021071, 10357, 2021047, 33612, 2021087, 2017092), EU Horizon 2020 grant no 848099, a philantropic donation from Vivaldi Invest A/S, and The European Virus Archive Global., Competing Interests: Author AS reports being an employee and shareholder at Age Labs outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial and financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Søraas, Grødeland, Granerud, Ueland, Lind, Fevang, Murphy, Huse, Nygaard, Steffensen, al-Baldawi, Holberg-Petersen, Andresen, Ågnes, Ranheim, Schanke, Istre, Dahl, Chopra, Dudman, Kaarbø, Andersen, Vaage, Tran, Vaage, Michelsen, Müller, Aukrust, Halvorsen, Dahl, Holter and Lund-Johansen.)

Introduction: The acquisition of humoral immunity in utero is essential for the fetus. The crucial protein, which is responsible for this part of immunity, is immunoglobulin-G (IgG). Immune functions of IgGs are mediated via the interaction of the crystallizable fragment (Fc) region of IgG with specific Fc γ receptors (FcγRs). However, an atypical FcγR, the neonatal Fc receptor (FcRn), is a key regulator of IgG transfer across the human placenta. During the last four decades ex vivo placental perfusion studies have contributed significantly to the study of mechanisms of IgG transfer across the multicellular placental barrier., Method: A PubMed search was conducted by using specific keywords: placenta, perfusion and IgG to review manuscripts using human placental perfusion to study the transplacental transfer of IgG. Relevant studies found in reference lists of these manuscripts were also added to the review, and references were included that supported or gave nuance to the discussion of the mechanisms of IgG kinetics in the placenta., Results and Discussion: We found twenty publications on the study of transplacental transfer of IgG using human ex vivo placental perfusion, by research groups with partly different settings. This review summarizes knowledge about placental IgG transfer, with a strong focus on the contributions from ex vivo placental perfusion studies., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antibody-based therapeutics (ABTs) are used to treat a range of diseases. Most ABTs are either full-length IgG1 antibodies or fusions between for instance antigen (Ag)-binding receptor domains and the IgG1 Fc fragment. Interestingly, their plasma half-life varies considerably, which may relate to how they engage the neonatal Fc receptor (FcRn). As such, there is a need for an in-depth understanding of how different features of ABTs affect FcRn-binding and transport behavior. Here, we report on how FcRn-engagement of the IgG1 Fc fragment compare to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-α. The results reveal FcRn-dependent intracellular accumulation of the Fc, which is in line with shorter plasma half-life than that of full-length IgG1 in human FcRn-expressing mice. Receptor domain fusion to the Fc increases its half-life, but not to the extent of IgG1. This is mirrored by a reduced cellular recycling capacity of the Fc-fusions. In addition, binding of cognate Ag to ABTs show that complexes of similar size undergo cellular transport at different rates, which could be explained by the biophysical properties of each ABT. Thus, the study provides knowledge that should guide tailoring of ABTs regarding optimal cellular sorting and plasma half-life., (© 2022. The Author(s).)

Recombinantly produced biotherapeutics hold promise for improving the current standard of care for snakebite envenoming over conventional serotherapy. Nanobodies have performed well in the clinic, and in the context of antivenom, they have shown the ability to neutralize long α-neurotoxins in vivo . Here, we showcase a protein engineering approach to increase the valence and hydrodynamic size of neutralizing nanobodies raised against a long α-neurotoxin (α-cobratoxin) from the venom of the monocled cobra Naja kaouthia . Based on the p53 tetramerization domain, a panel of anti-α-cobratoxin nanobody-p53 fusion proteins, termed Quads, were produced with different valences, inclusion or exclusion of Fc regions for endosomal recycling purposes, hydrodynamic sizes, and spatial arrangements, comprising up to 16 binding sites. Measurements of binding affinity and stoichiometry showed that the nanobody binding affinity was retained when incorporated into the Quad scaffold, and all nanobody domains were accessible for toxin binding, subsequently displaying increased blocking potency in vitro compared to the monomeric format. Moreover, functional assessment using automated patch-clamp assays demonstrated that the nanobody and Quads displayed neutralizing effects against long α-neurotoxins from both N. kaouthia and the forest cobra N. melanoleuca . This engineering approach offers a means of altering the valence, endosomal recyclability, and hydrodynamic size of existing nanobody-based therapeutics in a simple plug-and-play fashion and can thus serve as a technology for researchers tailoring therapeutic properties for improved neutralization of soluble targets such as snake toxins.

Objective: To examine the association between maternal exposure to ciprofloxacin and the risk of miscarriage and major malformations., Design: A nationwide register-based cohort study., Setting: Data were obtained from the Medical Birth Registry, the National Hospital Registry, the Danish National Prescription Registry and Statistics Denmark., Population: Data were collected in the period between 1997 and 2016 and included all registered pregnancies that ended in an elective termination, miscarriage, stillbirth or a live birth. Exposure was defined as redeeming one or more prescriptions of ciprofloxacin., Methods: Miscarriage was defined as a diagnosis given before 22 weeks without any medical intervention. Major malformations were classified according to EUROCAT 1.4. We matched ciprofloxacin-exposed pregnancies to unexposed pregnancies on the propensity score in a ratio 1:4. To estimate the hazard ratio (HR) of miscarriage a Cox proportional hazard regression model was used. A log binomial model was used to estimate the relative risk ratio (RR) of major malformations., Main Outcome Measures: HR of miscarriage and the RR of major malformations., Results: A total of 1 650 649 pregnancies were identified. Of these, 10 250 (2050 ciprofloxacin-exposed) and 6100 (1220 ciprofloxacin-exposed) were included in the miscarriage and major malformation analysis, respectively. The HR of miscarriage was 0.99 (95% confidence interval [CI] 0.84-1.17). For major malformation, the RR was 1.01 (95% CI 0.72-1.40). For the organ-specific major malformations and the sensitivity analyses, no significant increased risks were identified., Conclusion: We demonstrated no association between miscarriage and maternal ciprofloxacin exposure within the first 22 weeks of pregnancy, or between major malformations and maternal exposure during the first trimester., Tweetable Abstract: No association between maternal ciprofloxacin exposure and adverse pregnancy outcomes., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess the 30-day mortality following morphine, oxycodone, and mixed poisonings compared to tramadol poisonings; and (3) assess the development in tramadol poisonings during a 12-year period. Poisonings were identified from 2006 to 2017. A Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) along with 95% confidence intervals (CIs) for 30-day mortality following morphine, oxycodone or mixed poisonings compared to tramadol poisonings. We identified 7718 opioid poisonings among 6365 patients. The patients with a tramadol poisoning were younger and had less comorbidities than the patients with a morphine, oxycodone or mixed poisoning. Within 30 days, a total of 205 patients died. The 30-day mortality risk was higher following morphine (aHR 3.2, 95% CI 2.0-5.1), oxycodone (aHR 2.1, 95% CI 1.2-3.6) and mixed poisonings (aHR 1.6, 95% CI 1.0-2.7) compared to tramadol poisonings. The annual number of tramadol poisonings increased from 233 in 2006 to 501 in 2013 and declined to 348 in 2017. In conclusion, despite a lower mortality risk compared to other opioid poisonings, physicians should consider the poisoning and abuse risks when prescribing tramadol., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

This study aimed 1) to examine variables that may quantify the ability to apply force in the water and 2) to test their relationship with free swimming performance. Sixteen regional-level swimmers participated in this study. Average (F avg ) and maximum (F max ) forces were measured for 30 s arm stroke tethered swimming in a flume at zero and 1.389 m/s water flow speeds. The maximum and average force's relative changes (ΔF max and ΔF avg , respectively) were calculated between tethered swimming at zero and 1.389 m/s water flow speeds. Free swimming speeds were obtained from 25, 50, and 100 m front crawl trials, and were correlated with ΔF max and ΔF avg . A negative correlation was found between ΔF max and 25, 50 and 100 m speeds ( r  =  -0.84, r  = -0.74, r  = -0.55; p  < 0.05, respectively) and ΔF avg correlated negatively with 25 and 50 m speeds ( r  = -0.63, r  = -0.54; p  < 0.05, respectively), but it did not correlate with 100 m swimming speed. The relative change in force could be used to quantify the ability to apply force in the water. This could aid coaches to understand if changes in swimmers' ability to apply force in the water contribute to improvements in performance.

Objective: To investigate the association between mirtazapine exposure in pregnancy and risk of specific adverse pregnancy outcomes., Methods: A register-based nationwide cohort study was conducted including all registered pregnancies in Denmark from 1997 to 2016. Mirtazapine-exposed pregnancies were compared with mirtazapine unexposed pregnancies in a 1:4 ratio matched according to propensity scores. Outcomes were major congenital malformations analyzed using log binomial models, and spontaneous abortion, stillbirth and neonatal death analyzed using Cox proportional hazard regression., Results: From a source population of 1,650,649 pregnancies, the propensity score-matched cohort included 4475 pregnancies (895 mirtazapine exposed) in the analysis of major congenital malformations. The analyses of spontaneous abortion included 9 500 pregnancies (1900 mirtazapine exposed), and for the analyses of stillbirths and neonatal deaths 9725 (1 945 mirtazapine-exposed) and 4485 pregnancies (897 mirtazapine-exposed) were included, respectively. Thirty-one (3.5%) children were diagnosed with major congenital malformation among the mirtazapine exposed compared with 152 (4.3%) among the unexposed pregnancies (OR=0.81, 95% CI 0.55-1.20). Spontaneous abortion occurred in 237 (12.5%) of the mirtazapine exposed compared with 931 (12.3%) of the unexposed pregnancies (HR = 1.04%, 95% CI 0.91-1.20). The analyses revealed no increased risk of stillbirth (HR = 0.88%, 95% CI 0.34-2.29) or neonatal death (HR = 0.60%, 95% CI 0.18-2.02)., Conclusions: In this nationwide Danish register study, mirtazapine exposure in pregnancy was not associated with major congenital malformations, spontaneous abortion, stillbirth, or neonatal death. Clinicians and patients can be reassured that mirtazapine is safe in pregnancy., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Serum albumin (SA), the most abundant soluble protein in the body, maintains plasma oncotic pressure and regulates the distribution of vascular fluid and has a range of other important functions. The goals of this review are to expand clinical knowledge regarding the functions of SA, elucidate effects of dysregulated SA concentration, and discuss the clinical relevance of hypoalbuminemia resulting from various diseases. We discuss potential repercussions of SA dysregulation on cholesterol levels, liver function, and other processes that rely on its homeostasis, as decreased SA concentration has been shown to be associated with increased risk for cardiovascular disease, hyperlipidemia, and mortality. We describe the anti-inflammatory and antioxidant properties of SA, as well as its ability to bind and transport a plethora of endogenous and exogenous molecules. SA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. Of current relevance are antibody-based inhibitors of the neonatal Fc receptor (FcRn), several of which are under clinical development to treat immunoglobulin G (IgG)-mediated autoimmune disorders; some have been shown to decrease SA concentration. FcRn acts as a homeostatic regulator of SA by rescuing it, as well as IgG, from intracellular degradation via a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of SA and the potential clinical impact of decreased SA are needed; in particular, the potential for certain treatments to reduce SA concentration, which may affect efficacy and toxicity of medications and disease progression., Competing Interests: DG, EL, and JVS are employees of argenx, the manufacturer of efgartigimod (FDA approved in gMG and under investigation in primary immune thrombocytopenia, pemphigus vulgaris and foliaceus, chronic inflammatory demyelinating polyneuropathy, bullous pemphigoid, and idiopathic inflammatory myopathy [myositis]). JTA has received funding from Syntimmune and argenx as part of fee-for-service agreements. ED is a postdoctoral research fellow of the Research Foundation – Flanders (grant number 12X9420N). JEK has participated on the Medical Advisory Committee of Sanofi Genzyme and Plasma Advisory Committee of Haemonetics. DR is the founder of Staten Biotechnology. NS is a member of the scientific advisory board and a speaker for argenx. IS, is supported by the Clinical Research Fund of the University Hospitals Leuven. ESW may receive royalties from patents owned by the UK Medical Research Council, UT Southwestern Medical Center, and Texas A&M University, and has financial interests in argenx, Astero BioPharma LLC, Astero Erado Inc., and Astero Technologies LLC. GV is a paid consultant for argenx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The development (medical writing and editorial support) of this manuscript received funding from argenx. Authors who are not affiliated with argenx were not paid for their contributions to this work. The funder was involved in conception of design, interpretation of data, writing of this article, and decision to submit it for publication., (Copyright © 2022 Ward, Gelinas, Dreesen, Van Santbergen, Andersen, Silvestri, Kiss, Sleep, Rader, Kastelein, Louagie, Vidarsson and Spriet.)

Intravitreal injections (IVI) of biologics targeting vascular endothelial growth factor (anti-VEGF) led to a paradigm shift in the management and prognosis of prevalent retinal conditions. Yet, IVI are typically performed with syringes that are neither developed nor approved for this purpose. Notably, syringes lubricated with silicone oil (SiO) are extensively used despite multiple reports showing that such syringes can cause deposition of SiO droplets in the vitreous body and patient discomfort. Thus, there is a need for SiO-free substitutes specifically tailored for IVI. Here, we report on the development and testing of such a syringe. This syringe has no dead volume, and its design allows for high-accuracy dosing. Also, it permits pharmaceutical compounding and storage of bevacizumab, ranibizumab, and aflibercept for up to 30 days without compromising their functional binding or transport properties. Finally, the new syringe demonstrated a favorable safety profile regarding release of SiO compared to SiO lubricated alternatives, including commercially prefilled syringes. Accordingly, the newly developed syringe is an appealing alternative for IVI., Competing Interests: GM, ØJ, MS, JA, and MM are part of collaborative agreements related to development of the syringes by SJJ Solutions. MM has been a member of advisory boards at Bayer, Roche, Novartis, and Allergan and has received lecture fees from Bayer and Roche. ØJ has been a member of advisory boards at Bayer, Roche, and Allergan and has received lecture fees from Bayer, Roche, and Allergan. Author CP was employed by Luminex Corporation. The authors declare that this study received funding from SJJ Solutions. The funder had the following involvement: SJJ Solutions designed the Zero Residual™ Silicone Free Syringe in collaboration with the researchers, and was responsible for producing the syringe., (Copyright © 2022 Gjølberg, Lode, Melo, Mester, Probst, Sivertsen, Jørstad, Andersen and Moe.)

Humans have four IgG antibody subclasses that selectively or differentially engage immune effector molecules to protect against infections. Although IgG1 has been studied in detail and is the subclass of most approved antibody therapeutics, increasing evidence indicates that IgG3 is associated with enhanced protection against pathogens. Here, we report that IgG3 has superior capacity to mediate intracellular antiviral immunity compared with the other subclasses due to its uniquely extended and flexible hinge region, which facilitates improved recruitment of the cytosolic Fc receptor TRIM21, independently of Fc binding affinity. TRIM21 may also synergize with complement C1/C4-mediated lysosomal degradation via capsid inactivation. We demonstrate that this process is potentiated by IgG3 in a hinge-dependent manner. Our findings reveal differences in how the four IgG subclasses mediate intracellular immunity, knowledge that may guide IgG subclass selection and engineering of antiviral antibodies for prophylaxis and therapy.

Objective: To investigate whether exposure to tramadol during early pregnancy is associated with an increased risk of spontaneous abortion or major congenital malformations., Methods: The study is a nationwide cohort study including all registered pregnancies in Denmark between January 1, 1997, and December 31, 2016. The Danish National Prescription Register was used to identify maternal exposure to tramadol. Pregnancies with maternal exposure to tramadol were matched with pregnancies without maternal exposure to tramadol in a ratio of up to 1:4 using propensity scoring. The primary outcomes were spontaneous abortion and major congenital malformations. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) of spontaneous abortion, and log binominal models were used to estimate the relative risk ratios (RRs) of major congenital malformations., Results: A total of 36,467 (tramadol exposure n=7,310) and 18,907 (tramadol exposure n=3,796) pregnancies were included in the analyses of spontaneous abortion and major congenital malformations, respectively. Spontaneous abortion occurred in 893 (12.2%) pregnancies with maternal exposure to tramadol and in 3,471 (11.9%) pregnancies without maternal exposure to tramadol (HR 1.06, 95% CI 0.99-1.14). A major congenital malformation occurred in the offspring of 151 (4.0%) pregnancies with maternal exposure to tramadol, compared with 579 (3.8%) in pregnancies without maternal exposure to tramadol (RR 1.04, 95% CI 0.87-1.24)., Conclusion: Exposure to tramadol during early pregnancy does not appear to be associated with an increased risk of spontaneous abortion or major congenital malformations., Competing Interests: Financial Disclosure Espen Jimenez-Solem has performed research sponsored by Eli Lilly, Johnson & Johnson, Gilead, and Vertex Pharmaceuticals. The other authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)