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Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results.

Abstract Background Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known. Methods A typical von Hippel-Lindau tumor suppressor (VHL)—PROTAC 14C-A947 (BRM degrader)—was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing. Bile duct-cannulated (BDC) rats allowed the elucidation of in vivo clearance pathways. Distribution kinetics was evaluated in the tissues and tumors of mice to support PK-PD correlation. In vitro studies enabled the evaluation of cell uptake mechanisms and cell retention properties. Results Here, we show that A947 quickly distributes into rat tissues after IV dosing, where it accumulates and is retained in tissues such as the lung and liver although it undergoes fast clearance from circulation. Similar uptake/retention kinetics enable tumor growth inhibition over 2–3 weeks in a lung cancer model. A947 quickly excretes in the bile of rats. Solute carrier (SLC) transporters are involved in hepatocyte uptake of PROTACs. Sustained BRM protein degradation is seen after extensive washout that supports prolonged cell retention of A947 in NCI-H1944 cells. A947 tissue exposure and pharmacodynamics are inversely correlated in tumors. Conclusions Plasma sampling for VHL-PROTAC does not represent the tissue concentrations necessary for efficacy. Understanding of tissue uptake and retention could enable less frequent IV administration to be used for therapeutic dosing.

Restoration supports the recovery of ecological attributes such as cover, complexity, and diversity to slow the areal decline of natural ecosystems. Restoration activity is intensifying worldwide to combat persistent stressors that are driving global declines to the extent and resilience of coral reefs. However, restoration is disputed as a meaningful aid to reef ecological recovery, often as an expensive distraction to addressing the root causes of reef loss. We contend this dispute partly stems from inferences drawn from small-scale experimental restoration outcomes amplified by misconceptions around cost-based reasoning. Alongside aggressive emissions reductions, we advocate urgent investment in coral reef ecosystem restoration as part of the management toolbox to combat the destruction of reefs as we know them within decades.

Objective: The northeastern state of Rhode Island (RI) has a Vaccinate Before You Graduate (VBYG) program that supplements the traditional primary care infrastructure by providing vaccines to adolescents while they are in school, with no out-of-pocket expenses. We analyzed data from RI’s immunization registry to evaluate whether VBYG also reduces disparities in adolescent immunization rates. Methods: We identified adolescent and catch-up vaccines administered in RI to people who were aged 11–18 at any point during the 5-year study period of 2019–2023, and conducted bivariate and multivariate analyses of vaccine administration data by setting (VBYG clinics, community health centers [CHCs], all other primary care practices [oPCPs], other school-based clinics, and other sites) and adolescent demographics (racial and ethnic identity, insurance status, sex, and age at time of vaccine). Results: Of over 387,000 routine vaccines administered during the study period, 3.3 % were administered by a VBYG clinic despite significant declines during school closures associated with the early COVID-19 pandemic. VBYG-administered doses went to slightly older youth, and a higher proportion were catch-up doses (25.7 % versus 14.1 % for CHC doses and 6.5 % for oPCP). Youths received an average of 2.71 vaccines in VBYG clinics compared to 1.77 from oPCPs and 2.08 from CHCs. A higher proportion of vaccines administered by VBYG went to adolescents of color and those without private insurance than those administered by oPCPs. Conclusions: VBYG provides a model to other jurisdictions of a vaccine safety net for adolescents who may not otherwise receive recommended vaccines before exiting the school system.

Virtual environments are becoming ubiquitous, and used in a variety of contexts-from entertainment to training and rehabilitation. Recently, technology for making them more accessible to blind or visually impaired users has been developed, by using sound to represent visual information. The ability of older individuals to interpret these cues has not yet been studied. In this experiment, we studied the effects of age and sensory modality (visual or auditory) on navigation through a virtual maze. We added a layer of complexity by conducting the experiment in a rotating room, in order to test the effect of the spatial bias induced by the rotation on performance. Results from 29 participants showed that with the auditory cues, it took participants a longer time to complete the mazes, they took a longer path length through the maze, they paused more, and had more collisions with the walls, compared to navigation with the visual cues. The older group took a longer time to complete the mazes, they paused more, and had more collisions with the walls, compared to the younger group. There was no effect of room rotation on the performance, nor were there any significant interactions among age, feedback modality and room rotation. We conclude that there is a decline in performance with age, and that while navigation with auditory cues is possible even at an old age, it presents more challenges than visual navigation.

Abstract Background Russia’s invasion of Ukraine in February 2022 ignited the largest armed conflict in Europe since World War II. Ukrainian government agencies, civil society organizations, and international agencies have gathered an unprecedented amount of data about the impact of war on the environment, which is often the silent victim of war. We review these data and highlight the limitations of international governance for protection of the environment during time of war. Methods We performed an integrative review of academic, institutional, and media information resources using the search terms “Ukraine”, “Russia”, “war”, “environment”, “health”, “human rights”, “international humanitarian law”, “international human rights law”, “ecocide”, and “war crimes”. Main text Nearly 500,000 military personnel have been killed or wounded during the war, and more than 30,000 civilians have been killed or injured. Indirect health effects of the war have likely accounted for an even greater amount of civilian morbidity and mortality. The war has displaced more than 11 million people. Russia’s military forces have caused extensive damage to civilian infrastructure. The war has devastated Ukraine’s economy and reduced food and energy security in many countries. The war has caused more than $56.4 billion in damage to the environment. There has been widespread chemical contamination of air, water, and soil, and 30% of Ukraine has been contaminated with landmines and unexploded ordnance. Landscape destruction, shelling, wildfires, deforestation, and pollution have adversely affected 30% of Ukraine’s protected areas. Russia’s seizure of the Zaporizhzhia Nuclear Power Plant and destruction of the Nova Kakhovka Dam have posed risks of long-term environmental catastrophe. Most of these environmental impacts threaten human health. Conclusion In addition to enormous human costs, Russia’s war on Ukraine has had devastating impacts on the natural environment and the built environment. International law mandates that methods of warfare must be implemented with due regard to the protection and preservation of the natural environment. A just and lasting peace necessitates, among other requirements, rebuilding and restoration of Ukraine’s natural environment and built environment. The environmental consequences of all wars need to be investigated and more effective measures need to be implemented to protect the environment during war.

ObjectiveThe primary objective of this study was to evaluate patients’ knowledge regarding HPV vaccination and vaccine uptake in a diverse patient population. The secondary objective was to evaluate factors influencing the decision to vaccinate, potential barriers to vaccination, and to assess whether HPV vaccines were offered to or discussed with eligible patients in a safety net Obstetrics and Gynecology (Ob/Gyn) clinic.MethodsA 28-item survey was developed using Likert scale survey questions to assess patient agreement with statements regarding HPV and the vaccine. The surveys were administered to patients in the Ob/Gyn outpatient clinics from May 2021 through September 2022. Additionally, pharmacy data were reviewed and chart review was performed as a quality improvement initiative to assess the impact of expanded HPV vaccine eligibility to patients with private insurance on vaccine uptake. Descriptive statistics were performed.Results304 patients completed surveys from May 2021 through September 2022. The median age of respondents was 32 (range 18-80). 16 (5%) were Non-Hispanic White, 124 (41%) were Hispanic White, 58 (19%) were Non-Hispanic Black, 6 (2%) were Hispanic Black, 29 (9.5%) were Haitian, 44 (14%) were Hispanic Other, 7 (2%) were Non-Hispanic Other, 20 (6.6%) did not respond. 45 (14%) patients were uninsured. Many patients (62%) reported that a physician had never discussed HPV vaccination with them. Seventy nine percent of patients reported they had never received the HPV vaccine, and 69% of patients reported that lack of a medical provider recommendation was a major barrier. Among patients to whom HPV vaccination had been recommended, 57% reported that the vaccine was not available the same day in clinic.ConclusionOur study demonstrated that many patients never had a provider discuss HPV vaccination with them and never received the HPV vaccine. Additionally, amongst those who did initiate HPV vaccination, completion of the series remains a key barrier. Ensuring that providers discuss HPV vaccination and that patients receive HPV vaccines, along with expanding access to and convenience of HPV vaccination are critical aspects of preventing cervical cancer.

Early stage chemical development presents numerous challenges, and achieving a functional balance is a major hurdle, with many early compounds not meeting the clinical requirements for advancement benchmarks due to issues like poor oral bioavailability. There is a need to develop strategies for achieving the desired systemic concentration for these compounds. This will enable further evaluation of the biological response upon a compound–target interaction, providing deeper insight into the postulated biological pathways. Our study elucidates alternative drug delivery paradigms by comparing formulation strategies across oral (PO), intraperitoneal (IP), subcutaneous (SC), and intravenous (IV) routes. While each modality boasts its own set of merits and constraints, it is the drug’s formulation that crucially influences its pharmacokinetic (PK) trajectory and the maintenance of its therapeutic levels. Our examination of model compounds G7883 and G6893 highlighted their distinct physio-chemical attributes. By harnessing varied formulation methods, we sought to fine-tune their PK profiles. PK studies showcased G7883′s extended half-life using an SC oil formulation, resulting in a 4.5-fold and 2.5-fold enhancement compared with the IP and PO routes, respectively. In contrast, with G6893, we achieved a prolonged systemic coverage time above the desired target concentration through a different approach using an IV infusion pump. These outcomes underscore the need for tailored formulation strategies, which are dictated by the compound’s innate properties, to reach the optimal in vivo systemic concentrations. Prioritizing formulation and delivery optimization early on is pivotal for effective systemic uptake, thereby facilitating a deeper understanding of biological pathways and expediting the overall clinical drug development timeline.

Las acusaciones contra los judíos del Antiguo Testamento emanadas del De fide Catholica probablemente procuraron resquebrajar de manera indirecta cualquier atisbo de acercamiento hacia el otro religioso que pudiera surgir de alguien de la esfera eclesiástica, de los próximos a convertir, o, como sucediera en Chronica Maiora, de los recientemente convertidos. Tal brújula conceptual no estuvo exenta de exhibir toda clase de contradicciones.

Intro: In mid-May 2022,a monkeypox virus(MPXV) outbreak was identified in the UK,reporting new cases later in Portugal and Spain,and recently being declared a public health emergency by the WHO. The aim of this study was to describe the microbiological characteristics of MPXV infection in Barcelona. Methods: Clinical samples from patients with MPXV infection suspicion attended at Hospital Universitari Vall d'Hebron (HUVH) and Barcelona's primary healthcare centres were collected from May to July 2022. Laboratory-confirmation was initially performed by an in-house Orthopoxvirus RT-PCR assay until June,when commercial LightMix Modular Orthopoxvirus or MPXV-specific RT-PCR assays(RocheApplied Science,Germany)were available. Findings: A total of 802 samples from 511 patients were included. MPXV was laboratory-confirmed in 77.3%(395/511)of cases, 20.4%(104/511) were negative, while the remaining 2.3%(12/511) were unconclusive probably due to inhibitions or low-quality samples. Most confirmed cases were male patients(97.7%;n=386/395) and the median age was 37 years(IQR:31-44). Weekly MPXV incidence constantly increased. Discussion: The MPXV incidence trends reveal a high burden. Secondary related cases are expected when wide circulation occurs into the community. Samples from skin lesions had the best diagnostic performance;genital-chancre,throat and rectal samples also revealed higher viral loads, suggesting active viral replication and source of infection.Urine samples were positive but showing lower viral loads. Conclusion: The 2022 MPXV outbreak has had a high burden in Barcelona.Skin specimens seem to be the sample of choice for diagnosis.Even though MPX pathogenesis in humans is not still well-defined,viral replication seems to occur in oral,genital and rectal mucosa,suggesting a source of infection and playing a role in transmission,in contrast with other fluids like urine.These results are key information for prevention measures.

Drug nanosuspensions offer a promising approach to improve bioavailability for poorly soluble drug candidates. Such formulations often necessitate the inclusion of an excipient to stabilize the drug nanoparticles. However, the rationale for the choice of the correct excipient for a given drug candidate remains unclear. To gain molecular insight into formulation design, this work first utilizes a molecular dynamics simulation to computationally investigate drug–excipient interactions for a number of combinations that have been previously studied experimentally. We find that hydrophobic interactions drive excipient adsorption to drug nanoparticles and that the fraction of polar surface area serves as a predictor for experimental measurements of nanosuspension stability. To test these ideas prospectively, we applied our model to an uncharacterized drug compound, GDC-0810. Our simulations predicted that a salt form of GDC-0810 would lead to more stable nanosuspensions than the neutral form; therefore, we tested the stability of salt GDC-0810 nanosuspensions and found that the salt form readily formed nanosuspensions even without the excipient. To avoid computationally expensive simulations in the future, we extended our model by showing that simple, two-dimensional properties of single drug molecules can be used to rationalize nanosuspension designs without simulations. In all, our work demonstrates how computational tools can provide molecular insight into drug–excipient interactions and aid in rational formulation design.

Background: Specialized pro-resolving lipid mediators (SPM) such as resolvin D1 (RvD1) attenuate inflammation and exhibit vasculo-protective properties. Methods: We investigated poly-lactic-co-glycolic acid (PLGA)-based nanoparticles (NP), containing a peptide targeted to tissue factor (TF) for delivery of 17R-RvD1 and a synthetic analog 17-R/S-benzo-RvD1 (benzo-RvD1) using in vitro and in vivo models of acute vascular injury. NPs were characterized in vitro by size, drug loading, drug release, TF binding, and vascular smooth muscle cell migration assays. NPs were also characterized in a rat model of carotid angioplasty. Results: PLGA NPs based on a 75/25 lactic to glycolic acid ratio demonstrated optimal loading (507.3 pg 17R-RvD1/mg NP; P = ns) and release of RvD1 (153.1 pg 17R-RvD1/mg NP; P < .05). NPs incorporating the targeting peptide adhered to immobilized TF with greater avidity than NPs with scrambled peptide (50 nM: 41.6 ± 0.52 vs 32.66 ± 0.34; 100 nM: 35.67 ± 0.95 vs 23.5 ± 0.39; P < .05). NPs loaded with 17R-RvD1 resulted in a trend toward blunted vascular smooth muscle cell migration in a scratch assay. In a rat model of carotid angioplasty, 16-fold more NPs were present after treatment with TF-targeted NPs compared with scrambled NPs (P < .01), with a corresponding trend toward higher tissue levels of 17R-RvD1 (P = .06). Benzo-RvD1 was also detectable in arteries treated with targeted NP delivery and accumulated at 10 times higher levels than NP loaded with 17R-RvD1. There was a trend toward decreased CD45 immunostaining in vessels treated with NP containing benzo-RvD1 (0.76 ± 0.38 cells/mm2 vs 122.1 ± 22.26 cells/mm2; P = .06). There were no significant differences in early arterial inflammatory and cytokine gene expression by reverse transcription-polymerase chain reaction. Conclusions: TF-targeting peptides enhanced NP-mediated delivery of SPM to injured artery. TF-targeted delivery of SPMs may be a promising therapeutic approach to attenuate the vascular injury response.

Academic medical centers (AMCs) rely on engaged and motivated faculty for their success. Significant burnout among clinical and research faculty has resulted in career disengagement and turnover. As such, AMCs must be vested in cultivating faculty engagement and well-being through novel initiatives that support faculty. The Well-Being Education Grants program was established by the Office for Well-Being within the Center for Faculty Development at Massachusetts General Hospital to provide the impetus many faculty needed to dedicate time to their well-being, demonstrating that investments in multi-component interventions around faculty well-being require resources and funding.

IntroductionLesbian, Gay, Bi-sexual, Transgender, Questioning, Intersex, and Asexual (LGBTQIA+) patients report experiences of discrimination within healthcare settings due to a lack of provider knowledge and biases of healthcare workers. There is an identified need among all health professions to provide more culturally competent healthcare for this community. Early interventions during healthcare profession training programs may be effective to address this need. The overall goal of this study was to assess the educational impact of an active learning session that was specifically designed to enhance LGBTQIA+ cultural competency awareness using an interprofessional setting.MethodsThis 2-year study involved students from 16 healthcare professional programs joining virtually to form interprofessional teams. A small group case-based learning approach was used and included pre/post-activity surveys to measure the change in student attitude and confidence, as well as the change in perception of the importance of the activity.ResultsResults indicate an increase in perception of importance (p < 0.005) and in overall level of confidence (p < 0.001) with respect to LGBTQIA+ issues post-session. Key themes established through the session represent an overall recognition of the importance of interprofessional education and awareness of LGBTQIA+ healthcare needs.DiscussionThe results demonstrate the effectiveness of a case-based approach for enhancing cultural competency awareness across different healthcare professions programs. This session also provided an interprofessional learning environment to allow multiple healthcare professions program students to interact and share perspectives. The positive impact of this intervention in a highly collaborative virtual learning environment also highlights that this immersive active learning approach that can be adopted across different programs and institutions.

The availability of remote sensing imagery at high spatiotemporal resolutions presents the opportunity to monitor the surface motion of rock glaciers, a key constraint for characterizing the dynamics of their evolution. In this paper, we investigate four North American rock glaciers by automatically measuring their horizontal surface displacement using photogrammetric data acquired with crewed and uncrewed aircraft along with orbital spacecraft over monitoring periods of up to eight years. We estimate vertical surface changes on these rock glaciers with photogrammetrically generated digital elevation models (DEM) and digitized topographic maps. Uncertainty analysis shows that the imagery with the highest resolution and most precise positioning have the best performance when used with the automated change detection algorithm. This investigation produces gridded velocity fields over the entire surface area of each study site, from which we estimate the age of rock glacier formation using along-flow velocity integration. Though the age estimates vary, the ice within the modern extent of these landforms began flowing between 3000 and 7000 years before present, postdating the last glacial maximum. Surface elevation change maps indicate present-day thinning at the lower latitude/higher elevation sites in Wyoming, while the higher latitude/lower elevation sites in Alaska exhibit relatively stable surface elevations.

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited. One of the reasons is the complex physicochemical properties of the heterobifunctional PROTACs. A promising strategy to improve pharmacokinetics of highly lipophilic compounds, such as PROTACs, is encapsulation in liposome systems. Here we describe liposome systems for intravenous administration to enhance the PK properties of two bivalent PROTAC molecules, by reducing clearance and increasing systemic coverage. We developed and characterized a PROTAC-in-cyclodextrin liposome system where the drug was retained in the liposome core. In PK studies at 1 mg/kg for GNE-01 the PROTAC-in-cyclodextrin liposome, compared to the solution formulation, showed a 80- and a 380-fold enhancement in AUC for mouse and rat studies, respectively. We further investigated the same PROTAC-in-cyclodextrin liposome system with the second PROTAC (GNE-02), where we monitored both lipid and drug concentrations in vivo. Similarly, in a mouse PK study of GEN-02, the PROTAC-in-cyclodextrin liposome system exhibited enhancement in plasma concentration of a 23× increase over the conventional solution formulation. Importantly, the lipid CL correlated with the drug CL. Additionally, we investigated a conventional liposome approach for GNE-02, where the PROTAC resides in the lipid bilayer. Here, a 5× increase in AUC was observed, compared to the conventional solution formulation, and the drug CL was faster than the lipid CL. These results indicate that the different liposome systems can be tailored to translate across multiple PROTAC systems to modulate and improve plasma concentrations. Optimization of the liposomes could further improve tumor concentration and improve the overall therapeutic index (TI). This delivery technology may be well suited to bring novel protein targeted PROTACs into clinics.

IntroductionVaccination against HPV is safe and effective in cancer prevention, yet vaccination uptake remains low. Strong recommendation of HPV vaccination by healthcare providers increases immunization rates, but gaps in knowledge persist surrounding HPV and HPV vaccination amongst health professional students (HPS). It is critical to educate HPS in all professions to maximize vaccination opportunities and increase vaccine uptake. The objective of this study is to evaluate evidence on HPV knowledge, vaccine uptake, and educational interventions in HPS to identify specific deficits to improve education.MethodsA systematic literature search for articles on HPV vaccine uptake, knowledge, and educational interventions in HPS was performed in PubMed, Embase, Web of Science, CINAHL, and Scopus from January 1, 2006 – July 21, 2021. Included studies assessed HPS for HPV vaccine uptake, knowledge, counseling comfort, or educational interventions to increase HPV vaccine knowledge. Studies were screened for inclusion by 2 independent reviewers and evaluated for risk of bias. PRISMA guidelines for reporting were followed.ResultsTwenty-one unique articles met inclusion criteria and were included in the analysis. Of the studies included, 20 included knowledge, 11 included vaccine uptake, 8 included interventions, and 12 included counseling comfort. The students in the studies included medical (n=14), dental (n=7), dental hygiene (n=6), nursing (n=3), physician assistant (n=2), public health (n=1), and pharmacy (n=1). Across studies, HPV vaccine series initiation ranged from 34.6-70.3%, with 28.3-58.3% up to date on vaccination. Most students knew that HPV causes cervical cancer (99%), but fewer knew that HPV causes head and neck cancer (40-47%) and oropharyngeal cancer (45%). Educational interventions included team-based approaches and lectures, and improved outcomes including vaccine knowledge, vaccination schedule, and cancer knowledge. Medical students with lower knowledge of HPV were more hesitant to recommend vaccination at baseline but were more likely to recommend vaccination after an education session.DiscussionAcross HPS, inadequacies persist in HPV vaccine uptake, knowledge, and counseling comfort. It is critical to target vaccine uptake in this population and improve existing educational efforts to reduce preventable cancers. Institutions must prioritize HPV vaccine education to impact HPV related death.

Available soil moisture is thought to be the limiting factor for most ecosystem processes in the cold polar desert of the McMurdo Dry Valleys (MDVs) of Antarctica. Previous studies have shown that microfauna throughout the MDVs are capable of biological activity when sufficient soil moisture is available (~2–10% gravimetric water content), but few studies have attempted to quantify the distribution, abundance, and frequency of soil moisture on scales beyond that of traditional field work or local field investigations. In this study, we present our work to quantify the soil moisture content of soils throughout the Fryxell basin using multispectral satellite remote sensing techniques. Our efforts demonstrate that ecologically relevant abundances of liquid water are common across the landscape throughout the austral summer. On average, the Fryxell basin of Taylor Valley is modeled as containing 1.5 ± 0.5% gravimetric water content (GWC) across its non-fluvial landscape with ~23% of the landscape experiencing an average GWC > 2% throughout the study period, which is the observed limit of soil nematode activity. These results indicate that liquid water in the soils of the MDVs may be more abundant than previously thought, and that the distribution and availability of liquid water is dependent on both soil properties and the distribution of water sources. These results can also help to identify ecological hotspots in the harsh polar Antarctic environment and serve as a baseline for detecting future changes in the soil hydrological regime.

Recent insights into IQSEC2 disease are summarized in this review as follows: (1) Exome sequencing of IQSEC2 patient DNA has led to the identification of numerous missense mutations that delineate at least six and possibly seven essential functional domains present in the IQSEC2 gene. (2) Experiments using IQSEC2 transgenic and knockout (KO) mouse models have recapitulated the presence of autistic-like behavior and epileptic seizures in affected animals; however, seizure severity and etiology appear to vary considerably between models. (3) Studies in IQSEC2 KO mice reveal that IQSEC2 is involved in inhibitory as well as stimulatory neurotransmission. The overall picture appears to be that mutated or absent IQSEC2 arrests neuronal development, resulting in immature neuronal networks. Subsequent maturation is aberrant, leading to increased inhibition and reduced neuronal transmission. (4) The levels of Arf6-GTP remain constitutively high in IQSEC2 knockout mice despite the absence of IQSEC2 protein, indicating impaired regulation of the Arf6 guanine nucleotide exchange cycle. (5) A new therapy that has been shown to reduce the seizure burden for the IQSEC2 A350V mutation is heat treatment. Induction of the heat shock response may be responsible for this therapeutic effect.

Purposeful induction of fever for healing, including the treatment of epilepsy, was used over 2000 years ago by Hippocrates. More recently, fever has been demonstrated to rescue behavioral abnormalities in children with autism. However, the mechanism of fever benefit has remained elusive due in large part to the lack of appropriate human disease models recapitulating the fever effect. Pathological mutations in the IQSEC2 gene are frequently seen in children presenting with intellectual disability, autism and epilepsy. We recently described a murine A350V IQSEC2 disease model, which recapitulates important aspects of the human A350V IQSEC2 disease phenotype and the favorable response to a prolonged and sustained rise in body core temperature in a child with the mutation. Our goal has been to use this system to understand the mechanism of fever benefit and then develop drugs that can mimic this effect and reduce IQSEC2-associated morbidity. In this study, we first demonstrate a reduction in seizures in the mouse model following brief periods of heat therapy, similar to what was observed in a child with the mutation. We then show that brief heat therapy is associated with the correction of synaptic dysfunction in neuronal cultures of A350V mice, likely mediated by Arf6-GTP.

Background: Biliary atresia (BA) is a progressive pediatric inflammatory disease of the liver that leads to cirrhosis and necessitates liver transplantation. The rapid progression from liver injury to liver failure in children with BA suggests that factors specific to the perinatal hepatic environment are important for disease propagation. Hematopoietic stem and progenitor cells (HSPCs) reside in the fetal liver and are known to serve as central hubs of inflammation. We hypothesized that HSPCs are critical for the propagation of perinatal liver injury (PLI). Methods: Newborn BALB/c mice were injected with rhesus rotavirus (RRV) to induce PLI or with PBS as control. Livers were compared using histology and flow cytometry. To determine the effects of HSPCs on PLI, RRV-infected neonatal mice were administered anti-CD47 and anti-CD117 to deplete HSPCs. Results: PLI significantly increased the number of common myeloid progenitors and the number of CD34+ hematopoietic progenitors. Elimination of HSPCs through antibody-mediated myeloablation rescued animals from PLI and significantly increased survival (RRV+isotype control 36.4% vs. RRV+myeloablation 77.8%, Chi-test = 0.003). Conclusions: HSPCs expand as a result of RRV infection and propagate PLI. Targeting of HSPCs may be useful in preventing and treating neonatal inflammatory diseases of the liver such as BA.

The ice-cored Galena Creek Rock Glacier, Wyoming, USA, has been the subject of a number of studies that sought to determine the origin of its ice. We present new observations of the rock glacier's internal structure from ground-penetrating radar to constrain ice and debris distribution and accumulation. We imaged dipping reflectors in the center of the glacier that are weak and discontinuous, in contrast to strong reflectors toward the edge of the cirque beneath large debris-avalanche chutes. These reflectors form a network of concave-up, up-glacier dipping layers. We interpret these as englacial debris bands formed by large debris falls buried by subsequent ice and snow accumulation. They are discontinuous where ice outpaces debris accumulation, but with sufficient debris accumulation an interleaved pattern of ice and debris layers can form. We propose a model in which the ice in these interleaved layers is snowfall preserved by debris-facilitated accumulation. Large debris falls that occur in early spring bury sections of the snowpack, which are then preserved through summer and incorporated into the rock glacier body over time. This study highlights the importance of sequential accumulation of ice and debris for understanding the dynamics of rock glaciers and debris-covered glaciers.