Glyoxal Caging of Nucleoside Antivirals toward Self-Activating, Extended-Release Prodrugs.

Nucleoside antivirals are a leading class of compounds prescribed as a first-line treatment for viral infections. However, inherent limitations such as low solubility and circulation lifetime can necessitate multi-intraday dosing. Here, we deploy the 1,2-dialdehyde glyoxal to generate antiviral nucleoside prodrugs with enhanced pharmacokinetic properties and extended-release activity to combat poor patient adherence. The near-quantitative reaction of glyoxal with acyclovir (ACV) drastically improves ACV solubility and enables subsequent drug release with a half-life of 1.9 h under physiological conditions. Further, glyoxal caging thermoreversibly disrupts ACV activity against HIV-1 reverse transcription in vitro and HSV-1 pathology in cellulo. Finally, the amenability of a panel of nucleoside reverse transcriptase inhibitors to glyoxal caging showcases the potential of this highly versatile method for achieving timed-release activation of a clinically important class of antiviral therapeutics.

Working Interdependently: How Individuals Constitute Effective Systems.

A system's ability to function-its "systemness"-depends upon the mindsets and behaviors of its people, but what exactly is it that individuals do to constitute effective systems? Systemness requires three kinds of ongoing conversations devoted to (1) developing and maintaining a shared purpose or goal, (2) developing and maintaining a systems perspective-understanding how all the various parts fit together in service of the shared purpose and integrating many unique, diverse perspectives to gain a more complete understanding of the situation at hand-and (3) managing the myriad interdependencies of all the people involved in the work. These conversations are needed across all levels of scale, from one patient's care plan to the implementation of strategy for a whole organization. The three conversations of systemness will only be effective to the extent that people are willing to express their unique perspectives and to be responsive to and influenced by what they hear from others. The skills of personal reflection, self-differentiation, attunement, and multiple perspective-taking are particularly important. Understanding the conversations and individual skills on which systemness depends offers new directions for health professions education and quality improvement, and may be relevant to societal challenges beyond healthcare.

Dampened circadian amplitude of EEG power in women after menopause.

Postmenopausal women are at high risk of developing sleep-wake disturbances. We previously reported dampened circadian rhythms of melatonin, alertness and sleep in postmenopausal compared with young women. The present study aims to further explore electroencephalography power spectral changes in the sleep of postmenopausal women. Eight healthy postmenopausal women were compared with 12 healthy, naturally ovulating, young women in their mid-follicular phase. Participants followed a regular 8-hr sleep schedule for ≥ 2 weeks prior to laboratory entry. The laboratory visit included an 8-hr baseline sleep period followed by an ultradian sleep-wake cycle procedure, consisting of alternating 1-hr wake periods and nap opportunities. Electroencephalography power spectral analysis was performed on non-rapid eye movement sleep obtained over a 48-hr period. The baseline nocturnal sleep of postmenopausal women comprised lower power within delta and sigma, and higher power within alpha bands compared with that of younger women. During nighttime naps of the ultradian sleep-wake cycle procedure, lower power within delta and sigma, and higher power within beta bands were observed in postmenopausal women. During the ultradian sleep-wake cycle procedure, postmenopausal women presented lower power of delta, theta and sigma (14-15 Hz), undetectable rhythms of delta and theta, and a dampened or undetectable rhythm of sigma (12-15 Hz) power compared with younger women. Our results support the hypothesis of a dampened circadian variation of sleep microstructure in healthy-sleeping postmenopausal women. Circadian changes with aging are potential mechanisms for increased susceptibility to develop sleep disturbances; however, further research is needed to clarify their clinical implications and contribution to insomnia.

The Impact of Celebrity and Influencer Illness Disclosures.

When celebrities, political figures, influencers, or anyone with a large following publicly disclose an illness or die, the news becomes a de facto public health campaign. Until health communicators began studying such disclosures and the effects of the following waves of media coverage, however, it was not known to what extent these events impacted the public. A growing body of research has empirically documented these events and examined the factors that predict which types of audiences are most affected and why. Beyond motivating research opportunities, celebrity and influencer health disclosures or deaths can impact calls to hotlines, views on health-related websites, discussions of related topics on social media, behavioral changes relevant to the disclosure, increased news coverage of celebrity health research, integration of celebrity health narratives into strategic health campaigns, and even policy changes. We provide an overview of research conducted in this area and detail examples of the impact that celebrity health disclosures and studies about those disclosures have had on public discourse and public health.

Powerful medical education improves health care quality and return on investment.

INTRODUCTION: Powerful medical education (PME) involves the use of new technologies informed by the science of expertise that are embedded in laboratories and organizations that value evidence-based education and support innovation. This contrasts with traditional medical education that relies on a dated apprenticeship model that yields uneven results. PME involves an amalgam of features, conditions and assumptions, and contextual variables that comprise an approach to developing clinical competence grounded in education impact metrics including efficiency and cost-effectiveness. METHODS: This article is a narrative review based on SANRA criteria and informed by realist review principles. The review addresses the PME model with an emphasis on mastery learning and deliberate practice principles drawn from the new science of expertise. Pub Med, Scopus, and Web of Science search terms include medical education, the science of expertise, mastery learning, translational outcomes, cost effectiveness, and return on investment. Literature coverage is comprehensive with selective citations. RESULTS: PME is described as an integrated set of twelve features embedded in a group of seven conditions and assumptions and four context variables. PME is illustrated via case examples that demonstrate improved ventilator patient management learning outcomes compared to traditional clinical education and mastery learning of breaking bad news communication skills. Evidence also shows that PME of physicians and other health care providers can have translational, downstream effects on patient care practices, patient outcomes, and return on investment. Several translational health care quality improvements that derive from PME include reduced infections; better communication among physicians, patients, and families; exceptional birth outcomes; more effective patient education; and return on investment. CONCLUSIONS: The article concludes with challenges to hospitals, health systems, and medical education organizations that are responsible for producing physicians who are expected to deliver safe, effective, and cost-conscious health care.

Derivative Method to Detect Sleep and Awake States through Heart Rate Variability Analysis Using Machine Learning Algorithms.

Sleep disorders can have harmful consequences in both the short and long term. They can lead to attention deficits, as well as cardiac, neurological and behavioral repercussions. One of the most widely used methods for assessing sleep disorders is polysomnography (PSG). A major challenge associated with this method is all the cables needed to connect the recording devices, making the examination more intrusive and usually requiring a clinical environment. This can have potential consequences on the test results and their accuracy. One simple way to assess the state of the central nervous system (CNS), a well-known indicator of sleep disorder, could be the use of a portable medical device. With this in mind, we implemented a simple model using both the RR interval (RRI) and its second derivative to accurately predict the awake and napping states of a subject using a feature classification model. For training and validation, we used a database providing measurements from nine healthy young adults (six men and three women), in which heart rate variability (HRV) associated with light-on, light-off, sleep onset and sleep offset events. Results show that using a 30 min RRI time series window suffices for this lightweight model to accurately predict whether the patient was awake or napping.

Exploring Relevant Time Windows in the Association Between PM2.5 Exposure and Amyotrophic Lateral Sclerosis: A Case-Control Study in Denmark.

Studies suggest a link between particulate matter less than or equal to 2.5 µm in diameter (PM2.5) and amyotrophic lateral sclerosis (ALS), but to our knowledge critical exposure windows have not been examined. We performed a case-control study in the Danish population spanning the years 1989-2013. Cases were selected from the Danish National Patient Registry based on International Classification of Diseases codes. Five controls were randomly selected from the Danish Civil Registry and matched to a case on vital status, age, and sex. PM2.5 concentration at residential addresses was assigned using monthly predictions from a dispersion model. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for confounding. We evaluated exposure to averaged PM2.5 concentrations 12-24 months, 2-6 years, and 2-11 years pre-ALS diagnosis; annual lagged exposures up to 11 years prediagnosis; and cumulative associations for exposure in lags 1-5 years and 1-10 years prediagnosis, allowing for varying association estimates by year. We identified 3,983 cases and 19,915 controls. Cumulative exposure to PM2.5 in the period 2-6 years prediagnosis was associated with ALS (OR = 1.06, 95% CI: 0.99, 1.13). Exposures in the second, third, and fourth years prediagnosis were individually associated with higher odds of ALS (e.g., for lag 1, OR = 1.04, 95% CI: 1.00, 1.08). Exposure to PM2.5 within 6 years before diagnosis may represent a critical exposure window for ALS.

Evaluation of a Neck Cream Developed to Enhance Nitric Oxide Availability in Aging Skin.

BACKGROUND: To meet the unique needs of aging skin of the neck, a new neck cream that enhances nitric oxide availability has been developed to visibly improve signs of aging and overall quality of skin. METHODS: The primary objective of this dual center, open label clinical trial was to assess the efficacy and tolerability of the new neck cream applied twice daily over 12 weeks in aging women with mild-to-moderate lines and wrinkles of the neck (Group 1, N=26). A second group with mild-to-moderate lines and wrinkles and photodamage of the neck and décolleté (Group 2, N=10) applied the neck cream (AM/PM) in combination with a double-conjugated retinoid/alpha hydroxy acid (AHA-Ret; PM) to both the neck and décolleté over 12 weeks. RESULTS: Group 1 demonstrated significant improvements from baseline in the neck of 21% (P=.007) for wrinkles and lines, 27% (P=.004) for skin texture, and 26% (P=.003) for skin tone at 12 weeks. Significant improvements were also observed at 4 and 8 weeks. In Group 2, significant improvements were observed from baseline in the neck and décolleté areas with a 34% (P=.01) improvement in photodamaged skin in the décolleté area. The neck cream was well tolerated with few mild and transient adverse events. CONCLUSION: A new neck cream formulated to enhance nitric oxide availability to the skin when applied alone or in combination with AHA-Ret provided statistically significant improvements from baseline in skin appearance of the neck and décolleté, most notably in lines and wrinkles, skin texture, and skin tone. CITATION: Robinson DM, Kaufman J, Giannini A, et al. Evaluation of a neck cream developed to enhance nitric oxide availability in aging skin. J Drugs Dermatol. 2023;22(9):881-886. doi:10.36849/JDD.7210.

Understanding COVID-19 Vaccine Knowledge, Beliefs, and Trusted Information Sources Among Black Women in Kentucky: Implications for Vaccine Uptake.

To optimize COVID-19 vaccination rates among Black women in the United States, it is crucial to understand their vaccine beliefs and determine the most effective communication sources and messages to encourage vaccination. Consequently, we conducted seven focus groups with 20 Black women from Kentucky (aged 18-37 years) between October and November 2020. We identified five themes reflecting the participants' level of awareness, knowledge of the vaccine and vaccine development process; their uncertainty about vaccine safety and clinical trials; their willingness to get vaccinated, and their preferences for trusted sources and persuasive messages to motivate vaccine uptake. Despite the participants' high level of awareness about the vaccine's development, significant concerns were identified regarding the speed of the vaccine's development and clinical trials, known medical injustices against Black people, political influence, vaccine efficacy, and potential side effects that fed their unwillingness to vaccinate. Based on our findings, we recommend vaccination campaigns targeting Black women should prioritize messaging highlighting the benefits and limitations of the vaccine while emphasizing its protective benefits for self, family, and community. Campaigns should also include Black healthcare providers as sources of messages. The findings have additional implications for encouraging continued confidence in the vaccine and improving uptake.

Improving African Americans' Intentions to Enroll in a Health Registry: Message Development and Evaluation.

African Americans' enrollment in health registries is low, negatively affecting their representation in clinical research. Young African Americans are particularly underrepresented. Because medical discoveries are typically based on findings from research that lacks minority representation, new treatments may not be equally effective with members of the African American community. This may further exacerbate health disparities. In this two-phase study, we first collected data from five focus groups to (a) investigate young African Americans' knowledge about and attitudes toward health registries and (b) explore their perceptions about current messages used to recruit participants into health registries. The findings from the first phase of our research showed that participants had limited awareness and understanding of health registries' functions and held negative attitudes toward research participation. In Phase 2, we conducted an experiment to compare the effects of a current message, a new message designed based on the findings from our Phase 1 study, and a control. Results showed mixed findings on the impact of the new targeted message. Based on the findings from both phases of this study, we present and discuss future strategies.

Beliefs Underlying Colorectal Cancer Information Seeking Among Young Black Adults: a Reasoned Action Approach Elicitation Study.

Colorectal cancer in younger adults is more likely to be diagnosed at an advanced stage. Furthermore, younger Black adults are more likely to be diagnosed with and die from colorectal cancer than younger White adults. Given these persistent racial disparities, urgent attention is needed to increase colorectal cancer awareness and information seeking among young Black adults. Guided by the reasoned action approach, the purpose of this study was to identify behavioral, normative, and control beliefs that influence general colorectal cancer information seeking, talking to a healthcare provider about colorectal cancer, and talking to family about cancer history. The sample included N = 194 participants; Mage = 28.00 (SD = 5.48). Thirty-one percent had ever searched for colorectal cancer information. We identified salient educational advantages to seeking information about colorectal cancer and talking to healthcare providers and family members about cancer history. Barriers included fear, misinformation, low priority, inaccessibility of information, and lack of interest or willingness. This is one of the few studies to investigate cancer communication behaviors among young Black adults. The findings can inform interventions to motivate engagement in cancer communication behaviors.

Engagement With a Youth Community Advisory Board to Develop and Refine a Facebook HPV Vaccination Promotion Intervention (#HPVvaxtalks) for Young Black Adults (18-26 years old).

Human papillomavirus (HPV) vaccination rates remain suboptimal among young Black adults (18-26 years). Research focused on HPV vaccination among young Black adults is limited. Guided by the Theory of Planned Behavior, we developed #HPVvaxtalks, a theoretically grounded and culturally appropriate Facebook intervention in collaboration with a youth community advisory board (YCAB) to increase awareness of HPV risk factors, risk perception, HPV vaccine-related knowledge, vaccination intention, and uptake for Black individuals. Engagement with YCAB members fostered opportunity to discuss priorities reflecting the community's interest and make #HPVvaxtalks more relevant. This article describes the YCAB engagement and collaborative process in the development and refinement of posts/messages for #HPVvaxtalks. Five young Black adults (18-26 years of age) were invited to become members of a YCAB. YCAB reviewed the preliminary version of #HPVvaxtalks intervention materials and provided critiques and suggestions for refinement. Following the completion of the collaborative process, YCAB members completed individual interviews to reflect on the process. Feedback from YCAB participants focused on the relevance, engagement, clarity, and organization of the content and the media utilized. Participants suggested using "memes" to improve cultural relevance and engagement for young Black individuals. All YCAB members expressed satisfaction with the development process. Collaboration with a YCAB was crucial in developing a culturally relevant and acceptable #HPVvaxtalks intervention, which includes 40 messages/posts for young Black adults. Undergoing the iterative process of intervention development and refinement with the priority population can be an essential component in the design and implementation of health promotion activities.

Long-term Traffic-related Air Pollutant Exposure and Amyotrophic Lateral Sclerosis Diagnosis in Denmark: A Bayesian Hierarchical Analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Limited evidence suggests ALS diagnosis may be associated with air pollution exposure and specifically traffic-related pollutants. METHODS: In this population-based case-control study, we used 3,937 ALS cases from the Danish National Patient Register diagnosed during 1989-2013 and matched on age, sex, year of birth, and vital status to 19,333 population-based controls free of ALS at index date. We used validated predictions of elemental carbon (EC), nitrogen oxides (NO x ), carbon monoxide (CO), and fine particles (PM 2.5 ) to assign 1-, 5-, and 10-year average exposures pre-ALS diagnosis at study participants' present and historical residential addresses. We used an adjusted Bayesian hierarchical conditional logistic model to estimate individual pollutant associations and joint and average associations for traffic-related pollutants (EC, NO x , CO). RESULTS: For a standard deviation (SD) increase in 5-year average concentrations, EC (SD = 0.42 µg/m 3 ) had a high probability of individual association with increased odds of ALS (11.5%; 95% credible interval [CrI] = -1.0%, 25.6%; 96.3% posterior probability of positive association), with negative associations for NO x (SD = 20 µg/m 3 ) (-4.6%; 95% CrI = 18.1%, 8.9%; 27.8% posterior probability of positive association), CO (SD = 106 µg/m 3 ) (-3.2%; 95% CrI = 14.4%, 10.0%; 26.7% posterior probability of positive association), and a null association for nonelemental carbon fine particles (non-EC PM 2.5 ) (SD = 2.37 µg/m 3 ) (0.7%; 95% CrI = 9.2%, 12.4%). We found no association between ALS and joint or average traffic pollution concentrations. CONCLUSIONS: This study found high probability of a positive association between ALS diagnosis and EC concentration. Further work is needed to understand the role of traffic-related air pollution in ALS pathogenesis.

From Passive Gatekeeper to Quarterback: Evolving Perceptions of Primary Care Among Medical Students in Longitudinal Outpatient Clerkships.

BACKGROUND: Longitudinal clerkships provide students with meaningful clinical care roles that promote learning and professional development. It remains unclear how longitudinal primary care clerkships inform students' perceptions of primary care. OBJECTIVE: To explore perceptions of primary care among medical students enrolled in longitudinal primary care clerkships. DESIGN: Qualitative, semi-structured interviews with medical students over 4 years. PARTICIPANTS: Thirty-eight medical students participated at baseline; 35 participated in a 2-year follow-up interview; 24 participated at 4 years. Each student was enrolled in one of two longitudinal primary care clerkships: a team-based Education-Centered Medical Home (ECMH) or a one-on-one individual preceptorship (IP). APPROACH: De-identified interview transcripts were analyzed using a process of open and axial coding, followed by elaborative coding for longitudinal analysis. Codes were compiled into a set of themes and compared across time periods and between clerkships. KEY RESULTS: Students reported that primary care serves as a first point of contact, emphasizing longitudinal care with a wide scope of practice and approaching patient care with a biopsychosocial perspective. Student perceptions of primary care greatly expanded over the course of 4 years: for instance, initial perceptions of primary care physicians evolved from "passive gatekeeper" to a more nuanced "quarterback." Students in ECMH, whose clerkship provided more opportunity for patient continuity, further reflected on the relationships they themselves developed with patients. CONCLUSIONS: Regardless of their eventual specialty choice, longitudinal experiences may aid all students in fostering a sense of the broad scope and importance of primary care. However, without numerous opportunities to witness continuity of care, students may perceive primary care as having limited scope and importance. Longitudinal clerkships, emphasizing continuity with patients and preceptors, may foster in students a broad and nuanced perspective of the scope of primary care as a field.

Individual metabolomic signatures of circadian misalignment during simulated night shifts in humans.

Misalignment of the daily sleep-wake and fasting-feeding cycles with the endogenous circadian timing system is an inevitable consequence of night shift work and is associated with adverse metabolic health effects. However, a detailed characterisation of the effects of night shifts on 24-h rhythms in the metabolome is missing. We performed targeted metabolomic profiling on plasma samples collected every 2 h from healthy human subjects during two 24-h measurement periods at baseline and on the fourth day of a simulated night shift protocol, in which the habitual sleep-wake cycle was delayed by 10 h. Thirty-two out of the 130 detected metabolites showed a 24-h rhythm both at baseline and during the night shift condition. Among these, 75% were driven by sleep-wake and fasting-feeding cycles rather than by the endogenous circadian clock, showing an average phase delay of 8.8 h during the night shift condition. Hence, the majority of rhythmic metabolites were misaligned relative to the endogenous circadian system during the night shift condition. This could be a key mechanism involved in the increased prevalence of adverse metabolic health effects observed in shift workers. On the individual level, the response to the night shift protocol was highly diverse, with phase shifts of rhythmic metabolite profiles ranging from a 0.2-h advance in one subject to a 12-h delay in another subject, revealing an individual metabolomic signature of circadian misalignment. Our findings provide insight into the overall and individual responses of the metabolome to circadian misalignment associated with night schedules and may thereby contribute to the development of individually tailored strategies to minimise the metabolic impacts of shift work.

Guanidino quinazolines and pyrimidines promote readthrough of premature termination codons in cells with native nonsense mutations.

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.

A Theoretically Based Analysis of Twitter Conversations about Trauma and Mental Health: Examining Responses to Storylines on the Television Show Queen Sugar.

Entertainment programming in the United States has long addressed major public health issues. In the present study, we used a culture-centric approach to systematically investigate the role of television storylines in facilitating health-related conversations on social media. In particular, we examined Twitter conversations about sexual and police-involved trauma prompted by portrayals on the fictional television drama Queen Sugar. Guided by the culture-centric model of narratives in health promotion, we classified the tweets (N = 1,671) into four main thematic categories: identification, social proliferation, emotions, and intentions. The analysis also revealed several subthemes, including identification with characters and cultural elements, expressions of pain and joy, information seeking and sharing, and the need to address intergenerational trauma and promote intergenerational conversations. The data suggests that Twitter may provide a vehicle for engaging in difficult conversations. We discuss the theoretical and practical implications of the study for mental health communication with Black Americans.

Health Information Seeking as a Coping Strategy to Reduce Alzheimer's Caregivers' Stress.

Individuals with Alzheimer's disease and other forms of dementia (referred to as AD) deteriorate over time, and there will likely be a corresponding increase in levels of burden and stress for caregivers. Despite the significant contributions made by informal caregivers, there are no widely available mechanisms that meet the information needs of informal caregivers. Using a qualitative approach, the current study focuses on AD caregiver information seeking. The study involved conducting interviews to answer the following research questions: (1) What motivating factors lead informal caregivers of people with AD to seek out information?; (2) Is there a relationship between information seeking and resulting perceived stress levels?; and (3) Why do informal caregivers choose to utilize certain resources more than others during their information seeking process? Findings revealed that caregivers' largest motivation for seeking information is to learn how to better care for their loved one. Caregivers tend to rely on mediated resources that they find credible, and interpersonal resources such as people with similar experiences to their own. Many participants were satisfied with information available, but others felt that their interactions with healthcare professionals created more stress and emotional anguish than anticipated. This study offers an initial step in finding ways to meet the needs of those who seek to mitigate their stress through information seeking. By studying the information needs of the caregiving population, healthcare workers and communicators will be more knowledgeable about the relationship between information seeking and stress and coping.

Effect of Ventricular Assist Device Self-care Simulation-Based Mastery Learning on Driveline Exit Site Infections: A Pilot Study.

BACKGROUND: Ventricular assist device simulation-based mastery learning (SBML) results in better patient and caregiver self-care skills compared with usual training. OBJECTIVE: The aim of this study was to evaluate the effect of SBML on driveline exit site infections. METHODS: We compared the probability of remaining infection free at 3 and 12 months between patients randomized to SBML or usual training. RESULTS: The SBML-training group had no infections at 3 months and 2 infections at 12 months, yielding a Kaplan-Meier estimate of the probability of remaining infection free of 0.857 (95% confidence interval [CI], 0.692-1.00) at 12 months. The usual-training group had 6 infections at 3 months with no additional infections by 12 months. Kaplan-Meier estimates of remaining infection free at 3 and 12 months were 0.878 (95% CI, 0.758-1.00) and 0.748 (95% CI, 0.591-0.946), respectively. Time-to-infection distributions for SBML versus usual training showed a difference in 12-month infection rates of 0.109 (P = .07). CONCLUSIONS: Ventricular assist device self-care SBML resulted in fewer 12-month infections.

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome.

BACKGROUND: Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. OBJECTIVE: Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. METHODS: We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. RESULTS: We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. CONCLUSION: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.