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The circumstances surrounding SUDEP suggest autonomic or respiratory collapse, implying central failure of regulation or recovery. Characterisation of the communication among brain areas mediating such processes may shed light on mechanisms and noninvasively indicate risk.We used rs-fMRI to examine network properties among brain structures in people with epilepsy who suffered SUDEP (n = 8) over an 8-year follow-up period, compared with matched high- and low-risk subjects (n = 16/group) who did not suffer SUDEP during that period, and a group of healthy controls (n = 16). Network analysis was employed to explore connectivity within a ‘regulatory-subnetwork’ of brain regions involved in autonomic and respiratory regulation, and over the whole-brain.Modularity, the extent of network organization into separate modules, was significantly reduced in the regulatory-subnetwork, and the whole-brain, in SUDEP and high-risk. Increased participation, a local measure of inter-modular belonging, was evident in SUDEP and high-risk groups, particularly among thalamic structures. The medial prefrontal thalamus was increased in SUDEP compared with all other control groups, including high-risk. Patterns of hub topology were similar in SUDEP and high-risk, but were more extensive in low-risk patients, who displayed greater hub prevalence and a radical reorganization of hubs in the subnetwork.SUDEP is associated with reduced functional organization among cortical and sub-cortical brain regions mediating autonomic and respiratory regulation. Living high-risk subjects demonstrated similar patterns, suggesting such network measures may provide prospective risk-indicating value, though a crucial difference between SUDEP and high-risk was altered connectivity of the medial thalamus in SUDEP, which was also elevated compared with all sub-groups. Disturbed thalamic connectivity may reflect a potential non-invasive marker of elevated SUDEP risk. Keywords: SUDEP, Rs-fmri, Graph theory, Amygdala, Thalamus

Abstract Background Hispanic/Latino populations have the second highest prevalence of diabetes (12.5%) among ethnic minority groups in the USA. They also have higher rates of uncontrolled diabetes and diabetes-related complications. Approximately 29% of diabetes care costs are attributed to inpatient hospital care. To reduce hospital length of stay and re-admission rates for diabetes, the American Diabetes Association (ADA) recommends a “structured discharge plan tailored to the individual patient with diabetes.” However, limited research exists on the feasibility and applicability of a transition of care model specifically tailored for the Hispanic/Latino population. Methods We conducted a 2-year pilot study to develop a practical, patient-centered, and culturally competent transition of care (TOC) model for Hispanic/Latino adults with diabetes discharged from the hospital to the community. Feasibility outcomes included recruitment rates, questionnaire completion rates, adherence to a 30-day post-discharge phone call, and resource needs and utilization for study implementation. Participant-centered outcomes included 30-day post-discharge emergency department (ED) visits, 30-day post-discharge unplanned re-admissions, follow-up visits within 2 weeks of discharge, and patient satisfaction with the TOC model. Results Twelve participants were enrolled over the study period, with weekly enrollment ranging from 0 to 4 participants. Participants’ average age in years was 47 (± 11.6); the majority were male (85%), and 75% had type 2 diabetes. Recruitment involved the support of 4 bilingual staff. The estimated time to review the chart, approach participants, obtain informed consent, complete questionnaires, and provide discharge instructions was approximately 2.5 h. Of the 10 participants who completed the 30-day post-discharge phone call, none had ED visits or unplanned hospital re-admissions within 30 days post-discharge, and all had a follow-up with a medical provider within 2 weeks. Conclusions Implementing a patient-centered and culturally competent TOC model for Hispanic/Latino adults with diabetes discharged from the hospital to the community is feasible when considering key resources for success. These include a bilingual team with dedicated and funded time, alignment with existing discharge process and integration into the Electronic Medical Record (EMR) systems.

Abstract This study examines factors associated with symptoms of loneliness among a sample (n = 213) of mostly Mexican-origin adults at risk of chronic diseases in Southern Arizona’s Pima, Yuma, and Santa Cruz counties. It uses baseline data from a community-based participatory research partnership and multinominal logistic regression models. Controlling for chronic diseases and sociodemographic characteristics, perceived social support and hope exhibit negative main effects on loneliness when comparing individuals who experienced loneliness for 5–7 days in the preceding week with those who did not encounter such feelings during the same period (adjusted odds ratio, AOR = 0.49 and 0.47; 95% confidence interval, CI = 0.34–0.73 and 0.29–0.75, respectively). However, when considered together, perceived social support and hope display a positive and statistically significant combined effect on loneliness (AOR = 1.03; 95% CI = 1.01–1.06). Holding all covariates constant, individuals reporting loneliness for 5–7 days exhibit a relative risk ratio of 1.24 (95% CI = 1.06–1.46) for a one-unit increase in physical problem severity compared to those who do not experience loneliness. Moreover, being 65 years old or older (AOR = 0.16, 95% CI = 0.03–0.84), and having been born in Mexico and lived in the US for less than 30 years (AOR = 0.12, 95% CI = 0.02–0.74) are associated with negative main effects on loneliness when comparing individuals who experienced loneliness 1–2, and 5–7 days in the preceding week with those who did not feel loneliness during the same timeframe, respectively. Recognizing the crucial role of loneliness in shaping health outcomes for Mexican-origin adults, our findings underscore the significance of fostering supportive environments that not only enhance well-being but also cultivate robust community bonds within the US-Mexico border region.

Background. Recurrent glomerulonephritis (GN) is an important cause of allograft loss after transplantation when GN is the primary cause of kidney failure. Retransplantation after allograft loss from recurrent disease requires careful consideration. We aimed to determine the probability of relisting and the risk of allograft loss after retransplantation in recipients with prior allograft loss from recurrent GN. Methods. Using data from the Australia and New Zealand Dialysis and Transplant Registry and multivariable Cox modeling, we compared the probability of waitlisting and allograft loss after second transplantation between those with and without prior allograft loss from recurrent disease. Results. Of 3276 patients who received a second kidney transplant, 179 (5%) lost their first allograft from recurrent GN. Between 2006 and 2021, 1524 patients with failed first allografts (6% with recurrent GN, 45% with primary GN but no disease recurrence) were relisted for transplantation. Compared with patients without primary GN, the adjusted hazard ratios (95% confidence intervals) for relisting in patients with primary GN, with and without disease recurrence, were 1.09 (0.88-1.34) and 1.16 (1.05-1.29), respectively. The respective adjusted hazard ratios for allograft loss after repeat transplantation were 0.77 (0.59-1) and 1.02 (0.9-1.16). Of the 81 patients who received a second allograft after losing their first allograft to GN recurrence, 18 patients (22%) also lost their second allograft because of recurrent GN. Conclusions. Patients with prior allograft loss from GN recurrence were not disadvantaged, with comparable waitlist potential and allograft outcome after repeat transplantation. However, >20% of those with prior allograft loss from disease recurrence also lost their second allografts from recurrent disease.

At the ASCO 2024 meeting, Anthony P Conley, coauthor on this editorial, presented promising data from the phase 1/2 clinical trial called BETA PRIME (ClinicalTrials.gov NCT04673942) with AdAPT-001 plus a checkpoint inhibitor (CI). All participants gave informed consent to participate in BETA PRIME before taking part. AdAPT-001 is an oncolytic adenovirus that expresses a transforming growth factor beta (TGF-β) trap to neutralize active TGF-β. This editorial proposes that the TGF-β trap of AdAPT-001 reverses the immunosuppressive environment of tumor cells, and thus makes these tumors susceptible to CIs like the anti-PD-1 agent, nivolumab, and potentially other therapies as well.

Abstract After large-magnitude earthquakes, a crucial task for impact assessment is to rapidly and accurately estimate the ground shaking in the affected region. To satisfy real-time constraints, intensity measures are traditionally evaluated with empirical Ground Motion Models that can drastically limit the accuracy of the estimated values. As an alternative, here we present Machine Learning strategies trained on physics-based simulations that require similar evaluation times. We trained and validated the proposed Machine Learning-based Estimator for ground shaking maps with one of the largest existing datasets (

Abstract Background Sarcoptic mange is a serious animal welfare concern in bare-nosed wombats (Vombatus ursinus). Fluralaner (Bravecto®) is a novel acaricide that has recently been utilised for treating mange in wombats. The topical ‘spot-on’ formulation of fluralaner can limit treatment delivery options in situ, but dilution to a volume for ‘pour-on’ delivery is one practicable solution. This study investigated the in vitro acaricidal activity of Bravecto, a proposed essential oil-based diluent (Orange Power®), and two of its active constituents, limonene and citral, against Sarcoptes scabiei. Methods Sarcoptes scabiei were sourced from experimentally infested pigs. In vitro assays were performed to determine the lethal concentration (LC50) and survival time of the mites when exposed to varying concentrations of the test solutions. Results All compounds were highly effective at killing mites in vitro. The LC50 values of Bravecto, Orange Power, limonene and citral at 1 h were 14.61 mg/ml, 4.50%, 26.53% and 0.76%, respectively. The median survival times of mites exposed to undiluted Bravecto, Orange Power and their combination were 15, 5 and 10 min, respectively. A pilot survival assay of mites collected from a mange-affected wombat showed survival times of

Outbreaks of sarcoptic mange are sporadically reported in koala populations across Australia, but disease characteristics (e.g., distribution across the body) remain poorly understood. In an area of Northern Victoria regular cases coming into care suggest mange may have become enzootic, and here we characterise those koala mange admission records. In 18% (n = 10) of mange affected koala reports that had a recorded outcome (n = 55), the animals died before the carers could locate them, and of the remaining 45 koalas that were alive upon carer arrival, 80% (n = 36) had to be euthanised due to severe mange. The number of admissions varied among years (highest observed in 2019), and over 60% of affected koala admissions were male. Male admissions peaked in austral spring and again in late austral summer-autumn (mating and birthing seasons), with female admissions only exhibiting the latter peak (birthing season). Fissures of the epidermis of the front paws occurred in 100% of admitted koalas, with 70% also showing these signs elsewhere on ventral surfaces or limbs. Only male koalas had signs of mange on the chest and face, and only female koalas had signs of mange on their back. Collectively, this study suggests sarcoptic mange can be a severe disease in koalas, and that male koalas may play an important role in seasonal transmission dynamics. We discuss how these findings may help inform intervention strategies.

Sarcoptic mange, caused by epidermal infection with Sarcoptes scabiei, negatively impacts the health, welfare, and local abundance of bare-nosed wombats (Vombatus ursinus) in Australia. Improved understanding of the host immune response to disease and its contribution to pathophysiology could be used to inform management actions for this species in and ex situ. To evaluate the immune response of bare-nosed wombats to sarcoptic mange, we validated three assays (haptoglobin, agarose gel electrophoresis, and micro-erythrocyte sedimentation rate) measuring non-specific markers of inflammation using serum samples from free-living wombats from Tasmania (n = 33). We then analysed correlations between the assay results for each non-specific marker of inflammation and wombat’s sarcoptic mange scores, and performed histopathological examinations to investigate association of the acute phase response with systemic amyloidosis. We present evidence that haptoglobin and erythrocyte sedimentation rate increased, and albumin decreased, in association with sarcoptic mange scores. This research demonstrates links between the acute phase response and sarcoptic mange severity in bare-nosed wombats, highlighting the utility of non-specific markers of inflammation for aiding assessment of the systemic effects of mange. Showing the value of agarose gel electrophoresis, we also identified specific acute phase proteins warranting future evaluation and found evidence of an immunoglobulin response in mange-affected wombats, revealed by increasing γ-globulins in association with apparent disease severity. Meanwhile, owing to its relatively low resource requirements and rapidity, the erythrocyte sedimentation rate assay may be useful as a point-of-care test to support therapeutic decisions in the field. Our methods and findings are likely to be applicable to a range of other clinical and population health scenarios in captive and free-living wombats, and species impacted by sarcoptic mange globally.

The purpose of this commentary is to highlight the high occurrence of clinical pseudoprogression and delayed responses that have been observed to date with the locally injected oncolytic adenovirus, AdAPT-001, currently in a Phase 1/2 clinical trial (NCT04673942) for the treatment of treatment-refractory tumors. Not surprisingly, these have led to confusion about response assessment and whether to continue patients on treatment. AdAPT-001 carries a transforming growth factor (TGF)-beta trap (TGF-β), which sequesters TGF-β, a cytokine that potently regulates inflammation, fibrosis, and immunosuppression in cancer. Pseudoprogression (PsP) or progression prior to response or stabilization, has been widely recognized with radiotherapy for primary brain tumors and immune checkpoint inhibitors (ICIs). PsP has also been described and documented in the context of oncolytic virotherapy but perhaps to a lesser extent. However, repeated intratumoral injections with these immunostimulatory agents may induce a more intense immune response and release more antigenic epitopes than with ICIs, for example, which are strictly T-cell directed rather than also tumor-directed like AdAPT-001.

This paper proposes the category of real-time artificial intelligence (AI) systems as applications of computerized control systems in dynamic, time-constrained contexts normally managed by human intelligence. Noting the accountability challenges which these systems introduce, the paper posits the need for robust documentation and records capacities within these systems. The paper surveys four real-time AI systems with significant records needs: autonomous vehicles, online content targeting systems, mixed-reality tools for surgical contexts, and digital twin systems in airport facilities management. The paper identifies paradata, or the data leading up to an output in a system's operation, as a key data category necessitating preservation for full transparency in the records generated by these systems. Paradata is defined as “information about the procedure(s) and tools used to create and process information resources, along with information about the persons carrying out those procedures.” Paradata uncovers opaque technological processes underlying the production of other datasets and at a granular level must be identified and preserved to delineate the boundaries between human and system agency in semi-autonomous systems. With a basis in control theory, the paper finally offers a framework for assessing the functions of real-time AI systems' operations and their documentation and records needs.

Abstract Roads have often been identified as barriers to the movement of free-ranging animals. However, whether restoration of landscape connectivity across roadways can mitigate barriers to movement is insufficiently understood in light of indirect effects of roads on wildlife movement. We GPS-tagged free-ranging Mojave desert tortoises (Gopherus agassizii) to quantify movement behavioral states using hidden Markov models in relation to a major highway and to document use of existing, permeable culverts. We then used the observed movement behaviors to parameterize simulations of tortoise movement to evaluate alternative culvert designs and placements for enhancing connectivity across the roadway. Tortoises were most active during mid-day, in warm temperatures, and when close to the highway. The highway affected transition probabilities between movement states, as females were more likely than males to switch to an energy-demanding traveling movement state, remain in that state, and move farther than usual within that state. In contrast, males were more likely than females to continue in the low-energy resting state when close to the highway, but if traveling, to travel farther than usual. We observed two highway crossings by a tagged tortoise, which was a higher rate of crossing than in simulated tortoises. Simulated crossing rates increased with culvert size and culvert density, and size and density appeared more important for crossing than if culverts were placed singly or in pairs. Existing culvert densities across the region appeared potentially sufficient for long-term genetic connectivity, but only if retrofitted to allow for tortoise access and passing. We concluded that existing highway traffic may indirectly depress tortoise populations adjacent to the highway, particularly via negative impacts to female movements, and that existing culverts in washes should be retrofitted to allow for periodic tortoise crossings to improve structural connectivity for occasional passage.

Abstract Introduction Annual influenza vaccinations are recommended for adolescents and adults with moderate to severe asthma. This study investigated the effect of tezepelumab, a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, on the humoral immune response to the quadrivalent seasonal influenza vaccine in patients with moderate to severe asthma. Methods VECTOR was a phase 3b, randomized, multicenter, double-blind, parallel-group, placebo-controlled study. Adolescents (aged 12–17 years) and young adults (aged 18–21 years) with moderate to severe asthma were enrolled across 15 centers in the USA. Patients received tezepelumab 210 mg or placebo subcutaneously at weeks 0, 4, 8, and 12, and a single dose of inactivated quadrivalent seasonal influenza vaccine at week 12 before receiving study treatment. Immediately before vaccination and at 4 weeks postvaccination (week 16), strain-specific antibody responses were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays. Safety was assessed. Results Seventy patients were randomized to tezepelumab (n = 35) or placebo (n = 35). There were no meaningful differences in HAI or MN antibody responses between treatment groups at week 16. HAI assay geometric mean fold rises (GMFRs) for influenza strains were 1.76–7.34 for tezepelumab and 1.46–4.75 for placebo. MN assay GMFRs were 4.00–14.56 for tezepelumab and 3.56–10.62 for placebo. In the HAI assay, a fourfold or larger rise in antibody titer from weeks 12 to 16 occurred in 15.2–78.8% and 15.2–51.5% of tezepelumab and placebo recipients, respectively, and 97.0–100% of patients in both treatment groups achieved an antibody titer of at least 40 at week 16. No unexpected safety findings occurred. Conclusion There was no observed suppression of the humoral immune response after influenza vaccination in adolescents and young adults with moderate to severe asthma treated with tezepelumab. Therefore, the influenza vaccine can be administered to this patient population during tezepelumab treatment. ClinicalTrials.gov identifier NCT05062759

The Statewide (formerly Southern) California Earthquake Center (SCEC) conducts multidisciplinary earthquake system science research that aims to develop predictive models of earthquake processes, and to produce accurate seismic hazard information that can improve societal preparedness and resiliency to earthquake hazards. As part of this program, SCEC has developed the CyberShake platform, which calculates physics-based probabilistic seismic hazard analysis (PSHA) models for regions with high-quality seismic velocity and fault models. The CyberShake platform implements a sophisticated computational workflow that includes over 15 individual codes written by 6 developers. These codes are heterogeneous, ranging from short-running high-throughput serial CPU codes to large, long-running, parallel GPU codes. Additionally, CyberShake simulation campaigns are computationally extensive, typically producing tens of terabytes of meaningful scientific data and metadata over several months of around-the-clock execution on leadership-class supercomputers. To meet the needs of the CyberShake platform, we have developed an extreme-scale workflow stack, including the Pegasus Workflow Management System, HTCondor, Globus, and custom tools. We present this workflow software stack and identify how the CyberShake platform and supporting tools enable us to meet a variety of challenges that come with large-scale simulations, such as automated remote job submission, data management, and verification and validation. This platform enabled us to perform our most recent simulation campaign, CyberShake Study 22.12, from December 2022 to April 2023. During this time, our workflow tools executed approximately 32,000 jobs, and used up to 73% of the Summit system at Oak Ridge Leadership Computing Facility. Our workflow tools managed about 2.5 PB of total temporary and output data, and automatically staged 19 million output files totaling 74 TB back to archival storage on the University of Southern California's Center for Advanced Research Computing systems, including file-based relational data and large binary files to efficiently store millions of simulated seismograms. CyberShake extreme-scale workflows have generated simulation-based probabilistic seismic hazard models that are being used by seismological, engineering, and governmental communities.

Objectives Long-term benzodiazepine use is common despite known risks. In the original Eliminating Medications Through Patient Ownership of End Results (EMPOWER) Study set in Canada, patient education led to increased rates of benzodiazepine cessation. We aimed to determine the effectiveness of implementing an adapted EMPOWER quality improvement (QI) initiative in a US-based healthcare system.Design We used a pre–post design with a non-randomised control group.Setting A network of primary care clinics.Participants Patients with ≥60 days’ supply of benzodiazepines in 6 months and ≥1 risk factor (≥65 years of age, a concurrent high-risk medication prescribed or a diazepam equivalent daily dose ≥10) were eligible.Intervention In March 2022, we engaged 22 primary care physicians (PCPs), and 308 of their patients were mailed an educational brochure, physician letter and flyer detailing benzodiazepine risks; the control group included 4 PCPs and 291 of their patients.Primary and secondary measures The primary measure was benzodiazepine cessation by 9 months. We used logistic regression and a generalised estimating equations approach to control for clustering by PCP, adjusting for demographics, frailty, number of risk factors, and diagnoses of arthritis, depression, diabetes, falls, and pain.Results Patients in the intervention and control groups were comparable across most covariates; however, a greater proportion of intervention patients had pain-related diagnoses and depression. By 9 months, 26% of intervention patients (81 of 308) had discontinued benzodiazepines, compared with 17% (49 of 291) of control patients. Intervention patients had 1.73 greater odds of benzodiazepine discontinuation compared with controls (95% CI: 1.09, 2.75, p=0.02). The unadjusted number needed to treat was 10.5 (95% CI: 6.30, 34.92) and the absolute risk reduction was 0.095 (95% CI: 0.03 to 0.16).Conclusions Results from this non-randomised QI initiative indicate that patient education programmes using the EMPOWER brochures have the potential to promote cessation of benzodiazepines in primary care.

BackgroundChikungunya virus (CHIKV) has spread across Brazil with varying incidence rates depending on the affected areas. Due to cocirculation of arboviruses and overlapping disease symptoms, CHIKV infection may be underdiagnosed. To understand the lack of CHIKV epidemics in São José do Rio Preto (SJdRP), São Paulo (SP), Brazil, we evaluated viral circulation by investigating anti-CHIKV IgG seroconversion in a prospective study of asymptomatic individuals and detecting anti-CHIKV IgM in individuals suspected of dengue infection, as well as CHIKV presence in Aedes mosquitoes. The opportunity to assess two different groups (symptomatic and asymptomatic) exposed at the same geographic region aimed to broaden the possibility of identifying the viral circulation, which had been previously considered absent.Methodology/principal findingsBased on a prospective population study model and demographic characteristics (sex and age), we analyzed the anti-CHIKV IgG seroconversion rate in 341 subjects by ELISA over four years. The seroprevalence increased from 0.35% in the first year to 2.3% after 3 years of follow-up. Additionally, we investigated 497 samples from a blood panel collected from dengue-suspected individuals during the 2019 dengue outbreak in SJdRP. In total, 4.4% were positive for anti-CHIKV IgM, and 8.6% were positive for IgG. To exclude alphavirus cross-reactivity, we evaluated the presence of anti-Mayaro virus (MAYV) IgG by ELISA, and the positivity rate was 0.3% in the population study and 0.8% in the blood panel samples. In CHIKV and MAYV plaque reduction neutralization tests (PRNTs), the positivity rate for CHIKV-neutralizing antibodies in these ELISA-positive samples was 46.7%, while no MAYV-neutralizing antibodies were detected. Genomic sequencing and phylogenetic analysis revealed CHIKV genotype ECSA in São José do Rio Preto, SP. Finally, mosquitoes collected to complement human surveillance revealed CHIKV positivity of 2.76% of A. aegypti and 9.09% of A. albopictus (although it was far less abundant than A. aegypti) by RT-qPCR.Conclusions/significanceOur data suggest cryptic CHIKV circulation in SJdRP detected by continual active surveillance. These low levels, but increasing, of viral circulation highlight the possibility of CHIKV outbreaks, as there is a large naïve population. Improved knowledge of the epidemiological situation might aid in outbreaks prevention.

Abstract Background Food ladders are tools designed to facilitate home-based dietary advancement in children with food allergies through stepwise exposures to increasingly allergenic forms of milk and egg. Several studies have now documented safety and efficacy of food ladders. In 2021, we published a Canadian adaptation of the previously existing milk and egg ladders originating in Europe using foods more readily available/consumed in Canada. Our study adds to the growing body of evidence supporting food ladder use and provides safety and effectiveness data for our Canadian adaptation of the milk and egg ladders. Methods Surveys were distributed to families of children using the Canadian Milk Ladder and/or the Canadian Egg Ladder at baseline, with follow up surveys at 3 months, 6 months, and 12 months. Data were analyzed using REDCap and descriptive and inferential statistics are presented. Results One hundred and nine participants were started on milk/egg ladders between September 2020 and June 2022. 53 participants responded to follow up surveys. Only 2 of 53 (3.8%) participants reported receiving epinephrine during the study. Severe grade 4 reactions (defined according to the modified World Allergy Organization grading system) were not reported by any participants. Minor cutaneous adverse reactions were common, with about 71% (n = 10/14) of respondents reporting cutaneous adverse reactions by 1 year of food ladder use. An increasing proportion of participants could tolerate most foods from steps 2–4 foods after 3, 6, and 12 months of the food ladder compared to baseline. Conclusion The Canadian food ladders are safe tools for children with cow’s milk and/or egg allergies, and participants tolerated a larger range of foods with food ladder use compared to baseline.

Abstract In drug development a frequently used phrase is “data‐driven”. Just as high‐test gas fuels a car, so drug development “runs on” high‐quality data; hence, good data management practices, which involve case report form design, data entry, data capture, data validation, medical coding, database closure, and database locking, are critically important. This review covers the essentials of clinical data management (CDM) for the United States. It is intended to demystify CDM, which means nothing more esoteric than the collection, organization, maintenance, and analysis of data for clinical trials. The review is written with those who are new to drug development in mind and assumes only a passing familiarity with the terms and concepts that are introduced. However, its relevance may also extend to experienced professionals that feel the need to brush up on the basics. For added color and context, the review includes real‐world examples with RRx‐001, a new molecular entity in phase III and with fast‐track status in head and neck cancer, and AdAPT‐001, an oncolytic adenovirus armed with a transforming growth factor‐beta (TGF‐β) trap in a phase I/II clinical trial with which the authors, as employees of the biopharmaceutical company, EpicentRx, are closely involved. An alphabetized glossary of key terms and acronyms used throughout this review is also included for easy reference.

Abstract Background One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network’s objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. Methods We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. Results Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55–9.60]; z = 4.728; P-value

The mechanisms driving dynamics of many epidemiologically important mosquito-borne pathogens are complex, involving combinations of vector and host factors (e.g., species composition and life-history traits), and factors associated with transmission and reporting. Understanding which intrinsic mechanisms contribute most to observed disease dynamics is important, yet often poorly understood. Ross River virus (RRV) is Australia's most important mosquito-borne disease, with variable transmission dynamics across geographic regions. We used deterministic ordinary differential equation models to test mechanisms driving RRV dynamics across major epidemic centers in Brisbane, Darwin, Mandurah, Mildura, Gippsland, Renmark, Murray Bridge, and Coorong. We considered models with up to two vector species (Aedes vigilax, Culex annulirostris, Aedes camptorhynchus, Culex globocoxitus), two reservoir hosts (macropods, possums), seasonal transmission effects, and transmission parameters. We fit models against long-term RRV surveillance data (1991-2017) and used Akaike Information Criterion to select important mechanisms. The combination of two vector species, two reservoir hosts, and seasonal transmission effects explained RRV dynamics best across sites. Estimated vector-human transmission rate (average β = 8.04x10-4per vector per day) was similar despite different dynamics. Models estimate 43% underreporting of RRV infections. Findings enhance understanding of RRV transmission mechanisms, provide disease parameter estimates which can be used to guide future research into public health improvements and offer a basis to evaluate mitigation practices.

Application of cardiac patches to the heart surface can be undertaken to provide support and facilitate regeneration of the damaged cardiac tissue following ischemic injury. Biomaterial composition is an important consideration in the design of cardiac patch materials as it governs host response to ultimately prevent the undesirable fibrotic response. Here, we investigate a novel patch material, poly (itaconate-co-citrate-co-octanediol) (PICO), in the context of cardiac implantation. Citric acid (CA) and itaconic acid (ITA), the molecular components of PICO, provided a level of protection for cardiac cells during ischemic reperfusion injury in vitro. Biofabricated PICO patches were shown to degrade in accelerated and hydrolytic conditions, with CA and ITA being released upon degradation. Furthermore, the host response to PICO patches after implantation on rat epicardium in vivo was explored and compared to two biocompatible cardiac patch materials, poly (octamethylene (anhydride) citrate) (POMaC) and poly (ethylene glycol) diacrylate (PEGDA). PICO patches resulted in less macrophage infiltration and lower foreign body giant cell reaction compared to the other materials, with corresponding reduction in smooth muscle actin-positive vessel infiltration into the implant region. Overall, this work demonstrates that PICO patches release CA and ITA upon degradation, both of which demonstrate cardioprotective effects on cardiac cells after ischemic injury, and that PICO patches generate a reduced inflammatory response upon implantation to the heart compared to other materials, signifying promise for use in cardiac patch applications.

Patterns of extinction risk can vary across taxa, with species of some groups being particularly vulnerable to extinction. Rails (Aves: Rallidae) represent one of the most extreme yet well-documented cases of mass extinction within a modern vertebrate group. Between 54 and 92% of rail species became extinct following waves of human contact during both the Holocene and the Anthropocene eras, and a third of the extant species are currently threatened or near-threatened. Here, we (1) examine extinction filters through consecutive human contacts with rails, investigating the role of intrinsic life-history traits and (2) investigate the drivers of contemporary vulnerability. During the most recent wave of extinction, we found that body size was an important correlate of rail extinctions, with both smaller and larger bodied species more likely to become extinct. Island endemism and small clutch size were the strongest predictors of contemporary vulnerability. Overall, island endemic rails tend to follow the same trajectory as extinct species, suffering mostly from invasive predators and overhunting, but with different traits targeted contemporarily compared to past extinctions. Moreover, modern anthropogenic threats have created the potential for new intricate pathways – or a contemporary ‘field of bullets’ – making future vulnerability potentially less predictable.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

BackgroundOne in every 200 US jobs is in a beauty salon or auto repair shop, where workers are regularly exposed to volatile organic compounds (VOCs) that may cause a range of short- and long-term health issues. In these shops, Latino workers are overrepresented and lack culturally and linguistically appropriate industrial hygiene resources. This leaves a gap in knowledge on inhalation exposures to VOCs in this hard-to-reach and ubiquitous worker population.ObjectiveOur goal was to recruit hard-to-reach, predominantly Spanish-speaking workers in beauty salons and auto repair shops and monitor total VOC inhalation exposures for over entire work shifts, with minimal impact on workers, clients, and business.MethodsWe developed and refined measurement and exposure assessment methods for personal and area full-shift VOC inhalation exposures.ResultsWith minimal participant loss, we measured over 500 h of real-time, personal VOC exposures and recorded activities and other exposure factors for 47 participants, while also documenting chemical inventories and quantifying indoor area concentrations of specific VOCs among 10 auto repair shops and 10 beauty salons.ConclusionLessons learned from our study can assist future studies of inhalation exposures in other hard-to-reach occupational populations.

Abstract As genotyping by sequencing (GBS) becomes more prevalent and cost‐effective, there is a benefit in being able to apply the data to solve a variety of problems. However, high degrees of missing data and overreliance on single nucleotide polymorphisms (SNPs), while ignoring other forms of genetic variation, frequently plague attempts to make full use of GBS sequence data. Here we have developed two R scripts to serve as a tool in haplotype determination at loci of interest within biparental populations. One of these scripts, Sparse Tag Allele Caller (STAC), provides both automated calling and visual representations of the data around a locus of interest to assist in rapid data compilation decision‐making. The other script, STAC Integrate, allows automated quality control and logic‐based integration of presence/absence data with SNP data, while also rendering global overviews of recombination and coverage across the genome. These scripts are designed to be used together to maximize the utility of the available data. These tools were validated on a biparental population of wheat that was genotyped through GBS. They successfully enabled haplotype determination of a locus that was difficult to directly genotype, and their systemic accuracy was demonstrated in multiple populations and species. These scripts may serve as a tool for researchers attempting to make better use of GBS and other genetic marker data for both research and crop breeding decisions.

Abstract We present JBrowse 2, a general-purpose genome annotation browser offering enhanced visualization of complex structural variation and evolutionary relationships. It retains core features of JBrowse while adding new views for synteny, dotplots, breakpoints, gene fusions, and whole-genome overviews. It allows users to share sessions, open multiple genomes, and navigate between views. It can be embedded in a web page, used as a standalone application, or run from Jupyter notebooks or R sessions. These improvements are enabled by a ground-up redesign using modern web technology. We describe application functionality, use cases, performance benchmarks, and implementation notes for web administrators and developers.

Sarcoptes scabiei is the microscopic burrowing mite responsible for sarcoptic mange, which is reported in approximately 150 mammalian species. In Australia, sarcoptic mange affects a number of native and introduced wildlife species, is particularly severe in bare-nosed wombats (Vombatus ursinus) and an emerging issue in koala and quenda. There are a variety of acaricides available for the treatment of sarcoptic mange which are generally effective in eliminating mites from humans and animals in captivity. In wild populations, effective treatment is challenging, and concerns exist regarding safety, efficacy and the potential emergence of acaricide resistance. There are risks where acaricides are used intensively or inadequately, which could adversely affect treatment success rates as well as animal welfare. While reviews on epidemiology, treatment strategies, and pathogenesis of sarcoptic mange in wildlife are available, there is currently no review evaluating the use of specific acaricides in the context of their pharmacokinetic and pharmacodynamic properties, and subsequent likelihood of emerging drug resistance, particularly for Australian wildlife. This review critically evaluates acaricides that have been utilised to treat sarcoptic mange in wildlife, including dosage forms and routes, pharmacokinetics, mode of action and efficacy. We also highlight the reports of resistance of S. scabiei to acaricides, including clinical and in vitro observations.

Chordoma is a rare, but aggressive bone tumor with a high recurrence rate that primarily arises at the cranial and caudal ends of the axial skeleton. Systemic chemotherapies are not effective against the tumor, and outside of surgical resection and radiation, no approved options are available. Prognosis depends on the extent of surgical resection, with the more the better, and adjuvant radiotherapy. Herein is presented the first-ever case of a recurrent chordoma patient that responded to the combination of one dose of an experimental TGF-beta trap carrying oncolytic adenovirus, known as AdAPT-001, followed by immune checkpoint inhibitor therapy, despite prior progression on an anti-PD-1. This case report highlights the potential of AdAPT-001 as a treatment modality in combination with checkpoint inhibition for recurrent chordoma.

Systemic autoimmune and autoinflammatory diseases are characterized by genetic and cellular heterogeneity. While current single-cell genomics methods provide insights into known disease subtypes, these analysis methods do not readily reveal novel cell-type perturbation programs shared among distinct patient subsets. Here, we performed single-cell RNA-Seq of PBMCs of patients with systemic juvenile idiopathic arthritis (SJIA) with diverse clinical manifestations, including macrophage activation syndrome (MAS) and lung disease (LD). We introduced two new computational frameworks called UDON and SATAY-UDON, which define patient subtypes based on their underlying disrupted cellular programs as well as associated biomarkers or clinical features. Among twelve independently identified subtypes, this analysis uncovered what we believe to be a novel complement and interferon activation program identified in SJIA-LD monocytes. Extending these analyses to adult and pediatric lupus patients found new but also shared disease programs with SJIA, including interferon and complement activation. Finally, supervised comparison of these programs in a compiled single-cell pan-immune atlas of over 1,000 healthy donors found a handful of normal healthy donors with evidence of early inflammatory activation in subsets of monocytes and platelets, nominating possible biomarkers for early disease detection. Thus, integrative pan-immune single-cell analysis resolved what we believe to be new conserved gene programs underlying inflammatory disease pathogenesis and associated complications.

Abstract Wildlife managers often rely on population estimates, but estimates can be challenging to obtain for geographically widespread species. Spotlight surveys provide abundance data for many species and, when conducted over wide spatial scales, have potential to provide population estimates of geographically widespread species. The bare‐nosed wombat (Vombatus ursinus) has a broad geographical range and is subject to spotlight surveys. We used 19 years (2002–2020) of annual spotlight surveys to provide the first estimates of population abundance for two of the three extant bare‐nosed wombat subspecies: V. u. ursinus on Flinders Island; and V. u. tasmaniensis on the Tasmanian mainland. Using distance sampling methods, we estimated annual rates of change and 2020 population sizes for both subspecies. Tasmanian mainland surveys included habitat data, which allowed us to also look for evidence of habitat associations for V. u. tasmaniensis. The average wombat density estimate was higher on Flinders Island (0.42 ha−1, 95% CI = 0.25–0.79) than on the Tasmanian mainland (0.11 ha−1, CI = 0.07–0.19) and both wombat subspecies increased over the 19‐year survey period with an estimated annual growth rate of 2.90% (CI = −1.7 to 7.3) on Flinders Island and 1.20% (CI = −1.1 to 2.9) on mainland Tasmania. Habitat associations for V. u. tasmaniensis were weak, possibly owing to survey design; however, we detected regional variation in density for this subspecies. We estimated the population size of V. u. ursinus to be 71,826 (CI = 43,913–136,761) on Flinders Island, which when combined with a previously published estimate of 2599 (CI = 2254–2858) from Maria Island, where the subspecies was introduced, provides a total population estimate. We also estimated 840,665 (CI = 531,104–1,201,547) V. u. tasmaniensis on mainland Tasmania. These estimates may be conservative, owing to individual heterogeneity in when wombats emerge from burrows. Although these two subspecies are not currently threatened, our population estimates provide an important reference when assessing their population status in the future, and demonstrate how spotlight surveys can be valuable to inform management of geographically widespread species.

Background Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus.Methods In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in “regressor” models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure.Results Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood.Conclusions Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.

Understanding the spread of pathogens through the environment is critical to a fuller comprehension of disease dynamics. However, many mathematical models of disease dynamics ignore spatial effects. We seek to expand knowledge around the interaction between the bare-nosed wombat (Vombatus ursinus) and sarcoptic mange (etiologic agent Sarcoptes scabiei), by extending an aspatial mathematical model to include spatial variation. S. scabiei was found to move through our modelled region as a spatio-temporal travelling wave, leaving behind pockets of localized host extinction, consistent with field observations. The speed of infection spread was also comparable with field research. Our model predicts that the inclusion of spatial dynamics leads to the survival and recovery of affected wombat populations when an aspatial model predicts extinction. Collectively, this research demonstrates how environmentally transmitted S. scabiei can result in travelling wave dynamics, and that inclusion of spatial variation reveals a more resilient host population than aspatial modelling approaches.

Abstract Background Sarcoptes scabiei is globally distributed and one of the most impactful mammalian ectoparasites. Sarcoptic mange, caused by infection with S. scabiei, causes disruption of the epidermis and its bacterial microbiota, but its effects on host fungal microbiota and on the microbiota of marsupials in general have not been studied. Here, we (i) examine bacterial and fungal microbiota changes associated with mange in wild bare-nosed wombats (BNWs) and (ii) evaluate whether opportunistic pathogens are potentiated by S. scabiei infection in this species. Methods Using Amplicon Sequencing of the 16S rRNA and ITS2 rDNA genes, we detected skin microbiota changes of the bare-nosed wombat (Vombatus ursinus). We compared the alpha and beta diversity among healthy, moderate, and severe disease states using ANOVA and PERMANOVA with nesting. Lastly, we identified taxa that differed between disease states using analysis of composition of microbes (ANCOM) testing. Results We detected significant changes in the microbial communities and diversity with mange in BNWs. Severely affected BNWs had lower amplicon sequence variant (ASV) richness compared to that of healthy individuals, and the microbial communities were significantly different between disease states with higher relative abundance of potentially pathogenic microbial taxa in mange-affected BNWs including Staphylococcus sciuri, Corynebacterium spp., Brevibacterium spp., Brachybacterium spp., and Pseudogymnascus spp. and Debaryomyces spp. Conclusion This study represents the first investigation of microbial changes in association with sarcoptic mange in a marsupial host, as well as the first investigation of fungal microbial changes on the skin of any host suffering from sarcoptic mange. Our results are broadly consistent with bacterial microbiota changes observed in humans, pigs, canids, and Iberian ibex, suggesting the epidermal microbial impacts of mange may be generalisable across host species. We recommend that future studies investigating skin microbiota changes include both bacterial and fungal data to gain a more complete picture of the effects of sarcoptic mange. Graphical Abstract

Background. Kidney transplants from small pediatric donors are considered marginal and often transplanted as dual grafts. This study aimed to compare long-term outcomes between recipients of single kidney transplants (SKTs) and dual en bloc kidney transplants (EBKTs) from small pediatric donors. Methods. Data were obtained from the Australia and New Zealand Dialysis and Transplant Registry. All adult recipients of kidney transplants from donors aged ≤5 y were identified. The primary outcome of interest was death-censored graft survival by donor type. The secondary outcomes were early graft loss, delayed graft function, serum creatinine posttransplantation, acute rejection, and patient survival. Results. There were 183 adult recipients of kidney transplants from donors aged ≤5 y old. Of these, 60 patients had EBKT grafts, 79 patients had SKT grafts, and 44 patients had grafts of unknown type. Compared with SKT donors, EBKT donors had lower mean age (P < 0.001) and body weight (P < 0.001). There was no significant difference in death-censored graft survival between the groups, with median survival of 23.8 y (interquartile range 21.2–25) in the EBKT cohort and 21.8 y (11.6–26.8) in the SKT cohort (hazard ratio 1.3; 95% confidence interval, 0.59-2.64; P = 0.56). EBKT grafts had lower acute rejection rates than SKT grafts (P = 0.014). There was no significant difference observed between groups with respect to early graft loss, delayed graft function, posttransplantation serum creatinine posttransplantation, or patient survival. Conclusions. EBKT and SKTs from small pediatric donors are associated with excellent long-term graft survival rates.

Identifying environmental characteristics that limit species' distributions is important for contemporary conservation and inferring responses to future environmental change. The Tasmanian native hen is an island endemic flightless rail and a survivor of a prehistoric extirpation event. Little is known about the regional-scale environmental characteristics influencing the distribution of native hens, or how their future distribution might be impacted by environmental shifts (e.g. climate change). Using a combination of local fieldwork and species distribution modelling, we assess environmental factors shaping the contemporary distribution of the native hen, and project future distribution changes under predicted climate change. We find 37% of Tasmania is currently suitable for the native hens, owing to low summer precipitation, low elevation, human-modified vegetation and urban areas. Moreover, in unsuitable regions, urban areas can create ‘oases’ of habitat, able to support populations with high breeding activity by providing resources and buffering against environmental constraints. Under climate change predictions, native hens were predicted to lose only 5% of their occupied range by 2055. We conclude that the species is resilient to climate change and benefits overall from anthropogenic landscape modifications. As such, this constitutes a rare example of a flightless rail to have adapted to human activity.

IntroductionThe current standard of care for newly diagnosed glioblastoma (GBM) is maximum surgical resection followed by concurrent treatment with temozolomide (TMZ) and radiotherapy (RT) and then six to twelve cycles of maintenance TMZ. RRx-001, an NLRP3 inhibitor and nitric oxide (NO) donor with chemoradiosensitizing, vascular normalizing and macrophage repolarizing properties, is currently in a Phase III trial for small cell lung cancer (SCLC). The purpose of this non-randomized trial was to establish the safety and look for a signal of clinical activity of RRx-001 as an add-on to RT and TMZ in patients with newly diagnosed glioblastoma.MethodsIn this non-randomized, open-label, two part trial called G-FORCE-1 (NCT02871843), the first four cohorts of adult patients with histologically confirmed high grade gliomas received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and escalating doses of once weekly RRx-001 from 0.5 mg to 4 mg according to a 3+3 design followed by a 6 week no treatment interval and then standard maintenance TMZ (150 mg/m2 Cycle 1 and 200 mg/m2 in subsequent cycles) until disease progression. The second two cohorts of patients received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and once weekly RRx-001 4 mg followed by a 6 week no treatment interval and then two different maintenance schedules until disease progression according to the same 3+ 3 design: 1. 0.5 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapy; 2. 4 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapyThe primary endpoint was the recommended dose/maximally tolerated dose of the combination of RRx-001, TMZ and RT. Secondary endpoints were overall survival, progression free survival, objective response rate, duration of response and clinical benefit response.ResultsA total of 16 newly diagnosed glioblastoma patients were enrolled. No dose limiting toxicities were observed and no MTD was reached. The recommended dose is 4 mg. After 24 months of follow up the median OS was 21.9 months (95% CI: 11.7 – NA). PFS median was 8 months (95% CI: 5 – NA). The overall response rate was 18.8% (3 PR out of 16) and the disease control rate was 68.8% (3 PR, 8 SD out of 16).ConclusionsThe addition of RRx-001 to TMZ and RT and to TMZ during maintenance was safe and well-tolerated and deserves further study.

Abstract Background Sarcoptes scabiei is one of the most impactful mammalian parasites. There has been much research on immunological and clinical pathological changes associated with S. scabiei parasitism across a range of host species. This rich body of literature is complex, and we seek to bring that complexity together in this study. We first (1) synthesise narrative reviews of immunopathological relationships to S. scabiei infection to construct overarching hypotheses; then (2) undertake a systematic meta-analysis of primary literature on immunological and clinical pathological changes; and lastly (3) contrast our findings from the meta-analysis to our synthesis from narrative reviews. Methods We synthesised 55 narrative reviews into two overarching hypotheses representing type I and type IV immune responses to S. scabiei infection. We then systematically extracted all literature reporting immunological variables, acute phase proteins, oxidant/antioxidant status, and erythrocytic, hepatological and nephrological changes, calculating 565 effect sizes between controls and sarcoptic mange affected groupings, refining (simplifying) hypotheses from narrative reviews. Results Immunological and clinical pathological parameters were most often studied in dogs (n = 12) and humans (n = 14). Combining immunological and clinical pathological information across mammalian species (n = 19) helped yield general insights into observed disease responses. This is evidenced by interspecific consensus in 27 immunological and clinical pathology variables (6/26 type I hypersensitivity, 3/20 type IV hypersensitivity, 6/10 oxidant/antioxidant status, 3/6 acute phase protein, 4/7 erythrocytic, and 5/10 hepatological/nephrological). Conclusions Elevated IgE, eosinophils and mast cells in type I hypersensitivity response corresponded to what was described in narrative reviews. Results from type IV hypersensitivity response suggested typical antibody response, however cell-mediated response was less evident. Some consensus of acute phase protein response and shifted oxidant/antioxidant balance and slight evidence of anemia. We highlight the need for mange/scabies studies to more routinely compare immunological and clinical pathological changes against controls, and include collection of a more standardised suite of variables among studies.

RRx-001 is a shape shifting small molecule with Fast Track designation for the prevention/amelioration of chemoradiation-induced severe oral mucositis (SOM) in newly diagnosed Head and Neck cancer. It has been intentionally developed or “engineered” as a chimeric single molecular entity that targets multiple redox-based mechanisms. Like an antibody drug conjugate (ADC), RRx-001 contains, at one end a “targeting” moiety, which binds to the NLRP3 inflammasome and inhibits it as well as Kelch-like ECH-associated protein 1 (KEAP1), the negative regulator of Nrf2, and, at the other end, a conformationally constrained, dinitro containing 4 membered ring, which fragments under conditions of hypoxia and reduction to release therapeutically active metabolites i.e., the payload. This “payload”, which is delivered specifically to hypoperfused and inflamed areas, includes nitric oxide, nitric oxide related species and carbon-centered radicals. As observed with ADCs, RRx-001 contains a backbone amide “linker” attached to a binding site, which correlates with the Fab region of an antibody, and to the dinitroazetidine payload, which is microenvironmentally activated. However, unlike ADCs, whose large size impacts their pharmacokinetic properties, RRx-001 is a nonpolar small molecule that easily crosses cell membranes and the blood brain barrier (BBB) and distributes systemically. This short review is organized around the de novo design and in vivo pro-oxidant/pro-inflammatory and antioxidant/anti-inflammatory activity of RRx-001, which, in turn, depends on the reduced to oxidized glutathione ratio and the oxygenation status of tissues.

BackgroundBromonitrozidine (RRx-001) is a minimally toxic, NLRP3 inhibitor that has been observed, in experimental systems, to also downregulate CD47, repolarize tumor associated macrophages (TAMs) and normalize aberrant tumor perfusion. This phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced cancer and no standard options.MethodsThis single arm, single site, open-label pilot study (NCT02518958) called PRIMETIME was designed to evaluate the safety profile of RRx-001 and nivolumab in patients with advanced malignancies and no other standard therapeutic options. A 3 + 3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. The RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, twelve patients received treatment for only 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 16 weeks of the first dose of RRx-001 and nivolumab were characterized according to CTCAE v4.03.ResultsTwelve patients received ≥1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no DLTs. The main adverse event related to RRx-001 was infusion reaction (33.3%). The main adverse event related to the combination was pseudoprogression manifested by larger tumors in patients that were symptomatically improved (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). The objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of ≥SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination.ConclusionsThe combination of RRx-001 and nivolumab was safe and well-tolerated with preliminary evidence of anti-cancer activity. Further clinical trials with RRx-001 and nivolumab are warranted.Clinical trial registrationClinicalTrials.gov identifier, NCT02518958.

Bacteria produce a variety of polysaccharides with functional roles in cell surface coating, surface and host interactions, and biofilms. We have identified an 'Orphan' bacterial cellulose synthase catalytic subunit (BcsA)-like protein found in four model pseudomonads, P. aeruginosa PA01, P. fluorescens SBW25, P. putida KT2440 and P. syringae pv. tomato DC3000. Pairwise alignments indicated that the Orphan and BcsA proteins shared less than 41% sequence identity suggesting they may not have the same structural folds or function. We identified 112 Orphans among soil and plant-associated pseudomonads as well as in phytopathogenic and human opportunistic pathogenic strains. The wide distribution of these highly conserved proteins suggest they form a novel family of synthases producing a different polysaccharide. In silico analysis, including sequence comparisons, secondary structure and topology predictions, and protein structural modelling, revealed a two-domain transmembrane ovoid-like structure for the Orphan protein with a periplasmic glycosyl hydrolase family GH17 domain linked via a transmembrane region to a cytoplasmic glycosyltransferase family GT2 domain. We suggest the GT2 domain synthesises β-(1,3)-glucan that is transferred to the GH17 domain where it is cleaved and cyclised to produce cyclic-β-(1,3)-glucan (CβG). Our structural models are consistent with enzymatic characterisation and recent molecular simulations of the PaPA01 and PpKT2440 GH17 domains. It also provides a functional explanation linking PaPAK and PaPA14 Orphan (also known as NdvB) transposon mutants with CβG production and biofilm-associated antibiotic resistance. Importantly, cyclic glucans are also involved in osmoregulation, plant infection and induced systemic suppression, and our findings suggest this novel family of CβG synthases may provide similar range of adaptive responses for pseudomonads.