Equitable Representation of Pregnant and Lactating Women in Clinical Research: A Historical Review and Critical Analysis of Proposed Legislation.

A long history of policymaking and regulation constructed for the purpose of ensuring adequate fetal and infant protections has inadvertently sanctioned the widespread exclusion of pregnant and lactating patients from biomedical research, leaving a paucity of high quality data necessary for clinical decision-making. Although well-intended, the regulatory classification of pregnant women as "vulnerable," in conjunction with burdensome enrollment criteria and other factors weighing against broad inclusion, have ultimately placed the health and safety of these women and their babies in jeopardy. Robust measures are urgently needed to overcome patient and physician reluctance, address substantial evidence gaps, and rectify long-standing disparities which precipitate disproportionately poor health outcomes among this population. In February 2023, the Advancing Safe Medications for Moms and Babies Act of 2023 (the Act) was introduced in the United States House of Representatives with the overarching goal of enabling pregnant and lactating women to achieve equitable participation in clinical research and contribute to developing important biomedical knowledge to guide and improve health care delivered to these patients. This review discusses the historical influence of federal human subject protection regulations on the health and clinical treatment of pregnant and lactating women, outlines and critically analyzes the provisions incorporated into the Act, and reflects on the potential long-term impact the Act would have should it be successful in becoming law. KEY POINTS: · Pregnant and lactating patients are widely excluded from clinical research.. · Evidence guiding the treatment of these patients is limited and of unacceptably low quality.. · Proposed legislation seeks to rectify disparities and empower these patients through improved representation in research..

Potential cerebrovascular accident signal for risankizumab: A disproportionality analysis of the FDA Adverse Event Reporting System (FAERS).

AIMS: The interleukin-23 (IL-23) inhibitor risankizumab was recently approved for the treatment of moderate-to-severe plaque psoriasis in the United States. Low rates of cerebrovascular accident (CVA) were observed in risankizumab-treated patients during clinical trials. The aim of this study was to determine whether risankizumab may be associated with CVA in a real-world setting. METHODS: A retrospective disproportionality analysis was conducted utilizing postmarketing adverse event reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) through the fourth quarter of 2021. A custom query consisting of 22 CVA-related Medical Dictionary for Regulatory Activities (MedDRA) preferred terms previously reported in clinical trials of plaque psoriasis medications was used to identify cases. Disproportionality was measured by calculating reporting odds ratios (ROR) and 95% confidence intervals (CI), whereby the lower limit of a 95% CI >1.0 and ≥ three cases was considered a signal. RESULTS: Risankizumab was associated with significantly disproportionate CVA reporting compared to all other drugs in FAERS (ROR 2.48; 95% CI 2.14-2.88) as well as 11 alternative plaque psoriasis therapeutics across five pharmacologic classes. The largest disproportionality signals for risankizumab were identified relative to apremilast (ROR 9.07; 95% CI 7.56-10.89), ixekizumab (ROR 6.75; 95% CI 5.14-8.86), guselkumab (ROR 6.74; 95% CI 4.68-9.71), certolizumab (ROR 5.70; 95% CI 4.74-6.85) and etanercept (ROR 4.91; 95% CI 4.21-5.73). CONCLUSION: This study detected a previously unreported signal of disproportionate CVA reporting with the real-world use of risankizumab. Further long-term observational data will be necessary to better characterize this unconfirmed potential safety signal.

Commentary: Demand Avoidance Phenomena, a manifold issue? Intolerance of uncertainty and anxiety as explanatory frameworks for extreme demand avoidance in children and adolescents - a commentary on Stuart et al. (2020).

Demand Avoidance Phenomena (DAP) is a neutral term for Pathological Demand Avoidance, which is sometimes conceptualised as an autism subtype. There is much ongoing controversy around the construct. In this commentary, I attempt to contextualise the recent article, Intolerance of Uncertainty and anxiety (Stuart et al., 2019) within wider discourses. This discussion provides tentative support for monotropism autism theory and the growing body of research indicating that DAP may not be developmentally persistent (a high rate of persons not meeting clinical threshold into adulthood). Going forward I would suggest that Stuart and colleagues' research should be replicated, in order to add to the DAP literature.

A bispecific antibody that targets IL-6 receptor and IL-17A for the potential therapy of patients with autoimmune and inflammatory diseases.

Despite the success of current biological therapeutics for rheumatoid arthritis, these therapies, targeting individual cytokines or pathways, produce beneficial responses in only about half of patients. Therefore, better therapeutics are needed. IL-6 and IL-17A are proinflammatory cytokines in many autoimmune and inflammatory diseases, and several therapeutics have been developed to specifically inhibit them. However, targeting both of these cytokines with a bispecific therapeutic agent could account for their nonoverlapping proinflammatory functions and for the fact that IL-6 and IL-17A act in a positive feedback loop. Here, we present the development of MT-6194, a bispecific antibody targeting both IL-6R and IL-17A that was developed with the FynomAb technology. We also present data from mouse inflammatory disease experiments, indicating that simultaneous inhibition of both IL-6 and IL-17A yields enhanced efficacy compared with inhibition of each cytokine alone.

Dental Disorders Reported to the FDA Adverse Event Reporting System in Association with Buprenorphine: An Analysis by Ingredient Composition and Route of Administration.

BACKGROUND: Prior research has suggested buprenorphine-containing medications may be associated with an increased risk of dental disorders. However, published data describing adverse dental reactions in buprenorphine users by active ingredient composition and route of administration are limited. OBJECTIVE: The purpose of this study was to evaluate the influence of formulation on spontaneous reporting of dental disorders among patients treated with buprenorphine. METHODS: Adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) between 2015 and 2022 were analyzed. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated to measure disproportionality of dental disorder reporting as classified by 39 Medical Dictionary for Regulatory Activities preferred terms. RESULTS: Compared to pooled reports for all other drugs across FAERS, both buprenorphine monotherapy (ROR 3.09; 95% CI 2.61-3.66) and combination buprenorphine/naloxone (ROR 14.61; 95% CI 13.34-16.01) were associated with positive disproportionality signals. Signals of disproportionate dental disorder reporting were also detected for buprenorphine medicines administered by sublingual (ROR 20.03; 95% CI 18.04-22.24), buccal (ROR 4.46; 95% CI 3.00-6.61) and oral (ROR 7.17; 95% CI 5.03-10.22) routes, but not for other modalities. In considering active ingredient and route together, sublingual buprenorphine monotherapies (ROR 23.55; 95% CI 17.84-31.11) and sublingual buprenorphine/naloxone (ROR 19.47; 95% CI 17.39-21.80) were each associated with disproportionate reporting of dental disorders. CONCLUSION: Subject to the limitations of spontaneous adverse event data, this study identified significantly disproportionate reporting of dental disorders to FAERS among patients treated with buprenorphine- containing medications, including formulations administered by sublingual, buccal and oral routes. These findings are consistent with prior data and suggest that regular oral care and proper dental hygiene be emphasized for patients undergoing therapy with orally dissolving buprenorphine.

Postmarketing Reports of Incomplete Dosing-Related Complications with Self-Injected PCSK9 Inhibitors: A Descriptive Study and Disproportionality Analysis.

BACKGROUND: Evolocumab and alirocumab are self-injected proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors indicated for low-density lipoprotein cholesterol reduction. Complications in the use or functionality of self-injection devices may precipitate incomplete dosing. OBJECTIVE: This study sought to characterize postmarketing dosing failure reports involving self-injected PCSK9 inhibitors. METHODS: US Food and Drug Administration Adverse Event Reporting System (FAERS) [2016-second quarter of 2023] data were utilized for a disproportionality analysis. Eight self-injected comparator medications served as referents. Medical Dictionary for Regulatory Activities preferred terms indicating explicit or probable failure to administer a complete dose classified cases. Proportional reporting ratios (PRRs) > 2.0 and lower 95% confidence intervals (CIs) > 1.0 indicated disproportionality signals. US FDA Manufacturer and User Facility Device Experience (MAUDE) [2013-2023] data underwent a narrative review. RESULTS: During the study period, 194,781 (evolocumab, n = 152,831; alirocumab, n = 41,950) drug-event pairs and 43,725 (evolocumab, n = 38,489; alirocumab, n = 5236) cases reported to FAERS identified PCSK9 inhibitors. MAUDE contained six evolocumab reports, half describing dose omission, and no alirocumab reports. A potential dosing failure signal was detected for evolocumab (PRR 2.01; 95% CI 1.98-2.03), but not alirocumab (PRR 0.99; 95% CI 0.97-1.02), relative to pooled comparator reports. Across three case term subcategories, incomplete dosing disproportionality signals were further identified for evolocumab patient usage complication terms (PRR 3.44; 95% CI 3.38-3.50) and alirocumab device malfunction terms (PRR 2.09; 95% CI 1.98-2.22). CONCLUSIONS: Proprotein convertase subtilisin kexin type 9 inhibitor incomplete dosing-related complications are frequently reported in the postmarketing setting. Systematic efforts to understand the incidence and mechanisms of dosing failure and associated patient burdens are needed.

IOS-1002, a Stabilized HLA-B57 Open Format, Exerts Potent Anti-Tumor Activity.

HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation.

Alopecia signals associated with calcitonin gene-related peptide inhibitors in the treatment or prophylaxis of migraine: A pharmacovigilance study.

STUDY OBJECTIVE: Although rarely observed in clinical trials, alopecia has been reported in migraine patients treated with calcitonin gene-related peptide (CGRP) inhibitors during the postmarketing period. This study sought to assess whether CGRP inhibitors are associated with disproportionate alopecia reporting relative to other drugs including those indicated for migraine treatment or prophylaxis in a real-world setting. DESIGN: Retrospective disproportionality analysis. DATA SOURCE: Spontaneous adverse events reported to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) through the fourth quarter of 2021. MEASUREMENTS AND MAIN RESULTS: Thirteen Medical Dictionary for Regulatory Activities preferred terms were used to define alopecia cases in FAERS. Disproportionality was measured by calculating proportional reporting ratios (PRR) and 95% confidence intervals (CI). A PRR >2.0 with a lower 95% CI >1.0 and ≥3 cases was considered a positive signal. During the study period, CGRP inhibitors were reported as suspect products in 55,994 adverse events including 1827 (3.26%) alopecia cases. Compared with all other drugs across FAERS, alopecia signals were detected for the collective CGRP inhibitor class (PRR 4.06; 95% CI 3.88-4.25) and fremanezumab (PRR 5.42; 95% CI 4.66-6.29), erenumab (PRR 4.29; 95% CI 4.05-4.54), galcanezumab (PRR 4.11; 95% CI 3.78-4.48), and eptinezumab (PRR 2.06; 95% CI 1.25-3.40) individually. CGRP inhibitors were consistently associated with alopecia signals relative to triptans (PRR 12.46; 95% CI 10.22-15.18) and celecoxib (PRR 3.50; 95% CI 3.19-3.83), but not in comparison with anticonvulsants, onabotulinumtoxinA, or beta-blockers across analyses. Within the CGRP inhibitor class, an alopecia signal was observed for biologics relative to drugs (PRR 6.11; 95% CI 3.79-9.87). CONCLUSION: Significant alopecia signals were identified for CGRP inhibitors relative to all other drugs and certain comparator migraine therapies based on adverse events reported to FAERS, with CGRP-targeting biologics primarily driving disproportionate reporting. Future observational data will be necessary to better characterize the potential association between real-world use of CGRP inhibitors and incident alopecia in patients with migraine.

Manufacture of stable palladium and gold nanoparticles on native and genetically engineered flagella scaffolds.

The use of bacterial flagella as templates for the immobilization of Pd and Au nanoparticles is described. Complete coverage of D. desulfuricans flagellar filaments by Pd(0) nanoparticles was obtained via the H(2)-mediated reduction of Pd(NH3)4]Cl2 but similar results were not obtained using HAuCl4. The introduction of additional cysteine-derived thiol residues in the E. coli FliC protein increased Au(III) sorption and reduction onto the surface of the flagellar filament and resulted in the production of stabilized Au(0) nanoparticles of approximately 20-50 nm diameter. We demonstrate the application of molecular engineering techniques to manufacture biologically passivated Au(0) nanoparticles of a size suitable for catalytic applications.

Caller characteristics influence recruitment to collective anti-predator events in jackdaws.

Across the animal kingdom, examples abound of individuals coming together to repel external threats. When such collective actions are initiated by recruitment signals, individuals may benefit from being selective in whom they join, so the identity of the initiator may determine the magnitude of the group response. However, the role of signaller discrimination in coordinating group-level responses has yet to be tested. Here we show that in wild jackdaws, a colonial corvid species, collective responses to anti-predator recruitment calls are mediated by caller characteristics. In playbacks next to nestboxes, the calls of nestbox residents attracted most recruits, followed in turn by other colony members, non-colony members and rooks (a sympatric corvid). Playbacks in fields outside nestbox colonies, where the immediate threat to broods was lower, showed similar results, with highest recruitment to nearby colony members' calls. Responses were further influenced by caller sex: calls from non-colony member females were less likely to elicit responsive scolding by recruits than other calls, potentially reflecting social rank associated with sex and colony membership. These results show that vocal discrimination mediates jackdaws' collective responses and highlight the need for further research into the cognitive basis of collective actions in animal groups.

Toward the definition of specific protection goals for the environmental risk assessment of chemicals: A perspective on environmental regulation in Europe.

This critical review examines the definition and implementation of environmental protection goals for chemicals in current European Union (EU) legislation, guidelines, and international agreements to which EU countries are party. The European chemical industry is highly regulated, and prospective environmental risk assessments (ERAs) are tailored for different classes of chemical, according to their specific hazards, uses, and environmental exposure profiles. However, environmental protection goals are often highly generic, requiring the prevention of "unacceptable" or "adverse" impacts on "biodiversity" and "ecosystems" or the "environment as a whole." This review aims to highlight working examples, challenges, solutions, and best practices for defining specific protection goals (SPGs), which are seen to be essential for refining and improving ERA. Specific protection goals hinge on discerning acceptable versus unacceptable adverse effects on the key attributes of relevant, sensitive ecological entities (ranging from organisms to ecosystems). Some isolated examples of SPGs for terrestrial and aquatic biota can be found in prospective ERA guidance for plant protection products (PPPs). However, SPGs are generally limited to environmental or nature legislation that requires environmental monitoring and retrospective ERA. This limitation is due mainly to the availability of baselines, which define acceptable versus unacceptable environmental effects on the key attributes of sentinel species, populations and/or communities, such as reproductive status, abundance, or diversity. Nevertheless, very few regulatory case examples exist in which SPGs incorporate effect magnitude, spatial extent, and temporal duration. We conclude that more holistic approaches are needed for defining SPGs, particularly with respect to protecting population sustainability, ecosystem function, and integrity, which are implicit in generic protection goals and explicit in the International Programme for Chemical Safety (IPCS) definition of "adverse effect." A possible solution, which the chemical industry is currently assessing, is wider application of the ecosystem services approach proposed by the European Food Safety Authority (EFSA) for the risk assessment of PPPs. Integr Environ Assess Manag 2017;13:17-37. © 2016 SETAC.

Is an ecosystem services-based approach developed for setting specific protection goals for plant protection products applicable to other chemicals?

Clearly defined protection goals specifying what to protect, where and when, are required for designing scientifically sound risk assessments and effective risk management of chemicals. Environmental protection goals specified in EU legislation are defined in general terms, resulting in uncertainty in how to achieve them. In 2010, the European Food Safety Authority (EFSA) published a framework to identify more specific protection goals based on ecosystem services potentially affected by plant protection products. But how applicable is this framework to chemicals with different emission scenarios and receptor ecosystems? Four case studies used to address this question were: (i) oil refinery waste water exposure in estuarine environments; (ii) oil dispersant exposure in aquatic environments; (iii) down the drain chemicals exposure in a wide range of ecosystems (terrestrial and aquatic); (iv) persistent organic pollutant exposure in remote (pristine) Arctic environments. A four-step process was followed to identify ecosystems and services potentially impacted by chemical emissions and to define specific protection goals. Case studies demonstrated that, in principle, the ecosystem services concept and the EFSA framework can be applied to derive specific protection goals for a broad range of chemical exposure scenarios. By identifying key habitats and ecosystem services of concern, the approach offers the potential for greater spatial and temporal resolution, together with increased environmental relevance, in chemical risk assessments. With modifications including improved clarity on terminology/definitions and further development/refinement of the key concepts, we believe the principles of the EFSA framework could provide a methodical approach to the identification and prioritization of ecosystems, ecosystem services and the service providing units that are most at risk from chemical exposure.

Transforming ecosystems: When, where, and how to restore contaminated sites.

Chemical contamination has impaired ecosystems, reducing biodiversity and the provisioning of functions and services. This has spurred a movement to restore contaminated ecosystems and develop and implement national and international regulations that require it. Nevertheless, ecological restoration remains a young and rapidly growing discipline and its intersection with toxicology is even more nascent and underdeveloped. Consequently, we provide guidance to scientists and practitioners on when, where, and how to restore contaminated ecosystems. Although restoration has many benefits, it also can be expensive, and in many cases systems can recover without human intervention. Hence, the first question we address is: "When should we restore contaminated ecosystems?" Second, we provide suggestions on what to restore-biodiversity, functions, services, all 3, or something else--and where to restore given expected changes to habitats driven by global climate change. Finally, we provide guidance on how to restore contaminated ecosystems. To do this, we analyze critical aspects of the literature dealing with the ecology of restoring contaminated ecosystems. Additionally, we review approaches for translating the science of restoration to on-the-ground actions, which includes discussions of market incentives and the finances of restoration, stakeholder outreach and governance models for ecosystem restoration, and working with contractors to implement restoration plans. By explicitly considering the mechanisms and strategies that maximize the success of the restoration of contaminated sites, we hope that our synthesis serves to increase and improve collaborations between restoration ecologists and ecotoxicologists and set a roadmap for the restoration of contaminated ecosystems.

Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases.

Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis ( ClinicalTrials.gov Identifier: NCT02243787).

Translational asymmetry as a sensitive indicator of cadmium stress in plants: a laboratory test with wild-type and mutant Arabidopsis thaliana.

• Translational and bilateral asymmetry have been proposed as sensitive measures of stress in plants, but few studies have addressed the asymmetry-stress association for individuals grown under strictly defined conditions. Here, we assess the impact of cadmium (Cd) stress on various asymmetry measures in a wild-type and mutant strain of Arabidopsis thaliana. • Fitness measures (fresh weight, pod count and shoot length) and developmental stability (DS) measures (bilateral asymmetry and translational asymmetry (TA)) were compared between plants grown under different cadmium concentrations. • Cadmium stress sharply increased TA in both strains but had inconsistent effects on bilateral asymmetry. The TA effects were detected at a Cd concentration when effects on growth and reproduction were not yet evident. • Translational asymmetry, but not bilateral asymmetry, may therefore act as a sensitive indicator of cadmium stress and could be used to assess soil contamination in transplanted A. thaliana.