A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer.

In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes the high degree of heterogeneity associated with this disease. Specifically, we focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as a potential therapeutic vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment and scanning via unscheduled and non-productive RNA clamping by the eukaryotic translation initiation factor (eIF) 4A RNA helicase. We demonstrate that MG-002 potently inhibits mRNA translation and primary TNBC tumor growth without causing overt toxicity in mice. Importantly, given that metastatic spread is a major cause of mortality in TNBC, we show that MG-002 attenuates metastasis in pre-clinical models. We report on MG-002, a rocaglate that shows superior properties relative to existing eIF4A inhibitors in pre-clinical models. Our study also paves the way for future clinical trials exploring the potential of MG-002 in TNBC and other oncological indications.

Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine.

BACKGROUND: Although Zika virus (ZIKV) infection is typically self-limiting, other associated complications such as congenital birth defects and the Guillain-Barré syndrome are well described. There are no approved vaccines against ZIKV infection. METHODS: In this phase 1, open-label clinical trial, we evaluated the safety and immunogenicity of a synthetic, consensus DNA vaccine (GLS-5700) encoding the ZIKV premembrane and envelope proteins in two groups of 20 participants each. The participants received either 1 mg or 2 mg of vaccine intradermally, with each injection followed by electroporation (the use of a pulsed electric field to introduce the DNA sequence into cells) at baseline, 4 weeks, and 12 weeks. RESULTS: The median age of the participants was 38 years, and 60% were women; 78% were White and 22% Black; in addition, 30% were Hispanic. At the interim analysis at 14 weeks (i.e., after the third dose of vaccine), no serious adverse events were reported. Local reactions at the vaccination site (e.g., injection-site pain, redness, swelling, and itching) occurred in approximately 50% of the participants. After the third dose of vaccine, binding antibodies (as measured on enzyme-linked immunosorbent assay) were detected in all the participants, with geometric mean titers of 1642 and 2871 in recipients of 1 mg and 2 mg of vaccine, respectively. Neutralizing antibodies developed in 62% of the samples on Vero-cell assay. On neuronal-cell assay, there was 90% inhibition of ZIKV infection in 70% of the serum samples and 50% inhibition in 95% of the samples. The intraperitoneal injection of postvaccination serum protected 103 of 112 IFNAR knockout mice (bred with deletion of genes encoding interferon-α and interferon-ß receptors) (92%) that were challenged with a lethal dose of ZIKV-PR209 strain; none of the mice receiving baseline serum survived the challenge. Survival was independent of the neutralization titer. CONCLUSIONS: In this phase 1, open-label clinical trial, a DNA vaccine elicited anti-ZIKV immune responses. Further studies are needed to better evaluate the safety and efficacy of the vaccine. (Funded by GeneOne Life Science and others; ZIKA-001 ClinicalTrials.gov number, NCT02809443.).

Low-Efficacy Mu Opioid Agonists as Candidate Analgesics: Effects of Novel C-9 Substituted Phenylmorphans on Pain-Depressed Behavior in Mice.

Low efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO2 were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1hr. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics. Significance Statement This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics.

Estimating migration timing and abundance in partial migratory systems by integrating continuous antenna detections with physical captures.

Many populations migrate between two different habitats (e.g. wintering/foraging to breeding area, mainstem-tributary, river-lake, river-ocean, river-side channel) as part of their life history. Detection technologies, such as passive integrated transponder (PIT) antennas or sonic receivers, can be placed at boundaries between habitats (e.g. near the confluence of rivers) to detect migratory movements of marked animals. Often, these detection systems have high detection probabilities and detect many individuals but are limited in their ability to make inferences about abundance because only marked individuals can be detected. Here, we introduce a mark-recapture modelling approach that uses detections from a double-array PIT antenna system to imply movement directionality from arrays and estimate migration timing. Additionally, when combined with physical captures, the model can be used to estimate abundances for both migratory and non-migratory groups and help quantify partial migration. We first test our approach using simulation, and results indicate our approach displayed negligible bias for total abundance (less than ±1%) and slight biases for state-specific abundance estimates (±1%-6%). We fit our model to array detections and physical captures of three native fishes (humpback chub [Gila cypha], flannelmouth sucker [Catostomus latipinnis] and bluehead sucker [Catostomus discobolus]) in the Little Colorado River (LCR) in Grand Canyon, AZ, a system that exhibits partial migration (i.e. includes residents and migrants). Abundance estimates from our model confirm that, for all three species, migratory individuals are much more numerous than residents. There was little difference in movement timing between 2021 (a year without preceding winter/spring floods) and 2022 (a year with a small flood occurring in early April). In both years, flannelmouth sucker arrived in mid-March whereas humpback chub and bluehead sucker arrivals occurred early- to mid-April. With humpback chub and flannelmouth sucker, movement timing was influenced by body size so that large individuals were more likely to arrive early compared to smaller individuals. With more years of data, this model framework could be used to evaluate ecological questions pertaining to flow cues and movement timing or intensity, relative trends in migrants versus residents and ecological drivers of skipped spawning.

Hepatocyte-specific loss of LAP2α protects against diet-induced hepatic steatosis, steatohepatitis, and fibrosis in male mice.

There is increasing evidence for the importance of the nuclear envelope in lipid metabolism, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Human mutations in LMNA, encoding A-type nuclear lamins, cause early-onset insulin resistance and NASH, while hepatocyte-specific deletion of Lmna predisposes to NASH with fibrosis in male mice. Given that variants in the gene encoding LAP2α, a nuclear protein that regulates lamin A/C, were previously identified in patients with NAFLD, we sought to determine the role of LAP2α in NAFLD using a mouse genetic model. Hepatocyte-specific Lap2α-knockout (Lap2α(ΔHep)) mice and littermate controls were fed normal chow or high-fat diet (HFD) for 8 wk or 6 mo. Unexpectedly, male Lap2α(ΔHep) mice showed no increase in hepatic steatosis or NASH compared with controls. Rather, Lap2α(ΔHep) mice demonstrated reduced hepatic steatosis, with decreased NASH and fibrosis after long-term HFD. Accordingly, pro-steatotic genes including Cidea, Mogat1, and Cd36 were downregulated in Lap2α(ΔHep) mice, along with concomitant decreases in expression of pro-inflammatory and pro-fibrotic genes. These data indicate that hepatocyte-specific Lap2α deletion protects against hepatic steatosis and NASH in mice and raise the possibility that LAP2α could become a potential therapeutic target in human NASH.NEW & NOTEWORTHY The nuclear envelope and lamina regulate lipid metabolism and susceptibility to nonalcoholic steatohepatitis (NASH), but the role of the nuclear lamin-binding protein LAP2α in NASH has not been explored. Our data demonstrate that hepatocyte-specific loss of LAP2α protects against diet-induced hepatic steatosis, NASH, and fibrosis in male mice, with downregulation of pro-steatotic, pro-inflammatory, and pro-fibrotic lamin-regulated genes. These findings suggest that targeting LAP2α could have future potential as a novel therapeutic avenue in NASH.

A Prospective Cohort Study of Novel Markers of Hepatitis B Virus Replication in Human Immunodeficiency Virus Coinfection.

BACKGROUND & AIMS: The contribution of the novel biomarkers, hepatitis B virus (HBV) RNA and HBV core-related antigen (HBcrAg), to characterization of HBV-human immunodeficiency virus (HIV) coinfection is unclear. We evaluated the longitudinal dynamics of HBV RNA and HBcrAg and their association with classical HBV serum biomarkers and liver histology and viral staining. METHODS: HBV-HIV co-infected adults from 8 North American centers entered a National Institutes of Health-funded prospective cohort study. Demographic, clinical, serological, and virological data were collected at entry and every 24 to 48 weeks for up to 192 weeks. Participants with HBV RNA and HBcrAg measured ≥2 times (N = 95) were evaluated; 56 had paired liver biopsies obtained at study entry and end of follow-up. RESULTS: Participants had a median age of 50 years; 97% were on combination anti-viral therapy. In hepatitis B e antigen (HBeAg)+ participants, there were significant declines in HBV RNA and HBcrAg over 192 weeks that tracked with declines in HBeAg, hepatitis B surface antigen, HBV DNA, and hepatitis B core antigen (HBcAg) hepatocyte staining grade (all P < .05). In HBeAg- participants, there were not significant declines in HBV RNA (P = .49) and HBcrAg (P = .63), despite modest reductions in hepatitis B surface antigen (P < .01) and HBV DNA (P = .03). HBV serum biomarkers were not significantly related to change in hepatic activity index, Ishak fibrosis score, or hepatocyte HBcAg loss (all P > .05). CONCLUSIONS: In HBV-HIV coinfected adults on suppressive dually active antiviral therapy, the use of novel HBV markers reveals continued improvement in suppression of HBV transcription and translation over time. The lack of further improvement in HBV serum biomarkers among HBeAg- patients suggests limits to the benefit of combination anti-viral therapy and provide rationale for additional agents with distinct mechanisms of action.

Adoptive Cellular Therapy for Metastatic Melanoma: The Road to Commercialization and Treatment Guidelines for Clinicians.

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has been gaining promise as a therapeutic option for metastatic melanoma. By harnessing the power of patients' tumor-resident lymphocytes, TIL therapy has shown promise in delivering durable, complete responses for patients who have progressed with other treatments, including checkpoint inhibition. This form of personalized medicine has traditionally been limited to select academic facilities with the infrastructure and resources to generate TIL cells and care for patients during the treatment phase. In this review, the authors discuss the role of TIL therapy for patients with metastatic melanoma, including the current state of therapeutic options, logistics of TIL harvest and infusion, management of infusion-specific toxicities, and foundational steps for surgeons and oncologists to establish cell-based therapies in individual hospitals and cancer centers.

Evidence for distinct genetic and environmental influences on fear acquisition and extinction.

BACKGROUND: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. METHODS: In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. RESULTS: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5). CONCLUSIONS: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

TACH101, a first-in-class pan-inhibitor of KDM4 histone demethylase.

Histone lysine demethylase 4 (KDM4) is an epigenetic regulator that facilitates the transition between transcriptionally silent and active chromatin states by catalyzing the removal of methyl groups on histones H3K9, H3K36, and H1.4K26. KDM4 overamplification or dysregulation has been reported in various cancers and has been shown to drive key processes linked to tumorigenesis, such as replicative immortality, evasion of apoptosis, metastasis, DNA repair deficiency, and genomic instability. KDM4 also plays a role in epigenetic regulation of cancer stem cell renewal and has been linked to more aggressive disease and poorer clinical outcomes. The KDM4 family is composed of four main isoforms (KDM4A-D) that demonstrate functional redundancy and cross-activity; thus, selective inhibition of one isoform appears to be ineffective and pan-inhibition targeting multiple KDM4 isoforms is required. Here, we describe TACH101, a novel, small-molecule pan-inhibitor of KDM4 that selectively targets KDM4A-D with no effect on other KDM families. TACH101 demonstrated potent antiproliferative activity in cancer cell lines and organoid models derived from various histologies, including colorectal, esophageal, gastric, breast, pancreatic, and hematological malignancies. In vivo , potent inhibition of KDM4 led to efficient tumor growth inhibition and regression in several xenograft models. A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.

Ascending Aortic Endograft and Thoracic Aortic Deformation After Ascending Thoracic Endovascular Aortic Repair.

PURPOSE: We aim to quantify multiaxial cardiac pulsatility-induced deformation of the thoracic aorta after ascending thoracic endovascular aortic repair (TEVAR) as a part of the GORE ARISE Early Feasibility Study. MATERIALS AND METHODS: Fifteen patients (7 females and 8 males, age 73±9 years) with ascending TEVAR underwent computed tomography angiography with retrospective cardiac gating. Geometric modeling of the thoracic aorta was performed; geometric features including axial length, effective diameter, and centerline, inner surface, and outer surface curvatures were quantified for systole and diastole; and pulsatile deformations were calculated for the ascending aorta, arch, and descending aorta. RESULTS: From diastole to systole, the ascending endograft exhibited straightening of the centerline (0.224±0.039 to 0.217±0.039 cm-1, p<0.05) and outer surface (0.181±0.028 to 0.177±0.029 cm-1, p<0.05) curvatures. No significant changes were observed for inner surface curvature, diameter, or axial length in the ascending endograft. The aortic arch did not exhibit any significant deformation in axial length, diameter, or curvature. The descending aorta exhibited small but significant expansion of effective diameter from 2.59±0.46 to 2.63±0.44 cm (p<0.05). CONCLUSION: Compared with the native ascending aorta (from prior literature), ascending TEVAR damps axial and bending pulsatile deformations of the ascending aorta similar to how descending TEVAR damps descending aortic deformations, while diametric deformations are damped to a greater extent. Downstream diametric and bending pulsatility of the native descending aorta was muted compared with that in patients without ascending TEVAR (from prior literature). Deformation data from this study can be used to evaluate the mechanical durability of ascending aortic devices and inform physicians about the downstream effects of ascending TEVAR to help predict remodeling and guide future interventional strategies. CLINICAL IMPACT: This study quantified local deformations of both stented ascending and native descending aortas to reveal the biomechanical impact of ascending TEVAR on the entire thoracic aorta, and reported that the ascending TEVAR muted cardiac-induced deformation of the stented ascending aorta and native descending aorta. Understanding of in vivo deformations of the stented ascending aorta, aortic arch and descending aorta can inform physicians about the downstream effects of ascending TEVAR. Notable reduction of compliance may lead to cardiac remodeling and long-term systemic complications. This is the first report which included dedicated deformation data regarding ascending aortic endograft from clinical trial.

Immunostaining for hepatitis B viral antigens in liver: Association with clinical, biochemical, and virologic features of disease.

BACKGROUND AND AIM: Staining for hepatitis B viral antigens is often done in liver biopsies from patients with chronic hepatitis B, but its correlates with clinical phenotypes are not well described. METHODS: Biopsies were collected from a large cohort of adults and children with chronic hepatitis B viral infection through the Hepatitis B Research Network. Immunohistochemical staining of sections was done for hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) and then centrally read by the pathology committee. The degree of liver injury and pattern of staining were then correlated with clinical characteristics, including the clinical phenotype of hepatitis B. RESULTS: Biopsies from 467 subjects were studied, including 46 from children. Immunostaining for HBsAg was positive in 417 (90%) with scattered hepatocyte staining being the most common pattern. HBsAg staining correlated best with serum levels of HBsAg and hepatitis B viral DNA; the absence of HBsAg staining was often a prelude to loss of HBsAg from serum. HBcAg staining was positive in 225 (49%), and, while cytoplasmic staining was more frequent than nuclear staining, both nuclear and cytoplasmic positivity were often seen in the same specimen. Staining for HBcAg correlated with both level of viremia and liver injury. No biopsies from inactive carriers had stainable HBcAg, while 91% of the biopsies from those with hepatitis B e antigen-positive chronic hepatitis B stained positively for HBcAg. CONCLUSION: Immunostaining for hepatitis B viral antigens may yield helpful insights into liver disease pathogenesis but appears to add little to commonly used serological and biochemical blood tests.

Clinician preferences for single-unit implant restoration designs and materials: A survey of the membership of the Pacific Coast Society for Prosthodontics.

STATEMENT OF PROBLEM: Clinical research has difficulty keeping pace with the rapid evolution of materials, protocols, and designs of single-unit implant restorations. The clinical design preferences of prosthodontics for different clinical scenarios are lacking. PURPOSE: The purpose of this cross-sectional survey was to determine the current prevalence of usage of various treatment options and materials for single-unit implant-supported restorations. MATERIAL AND METHODS: From August to September of 2022, a survey invitation was sent to members of the Pacific Coast Society for Prosthodontics (PCSP). The survey was hosted online and asked 37 questions related to the materials, protocols, and design preferences for single-unit implant-supported restorations in various clinical scenarios. The prompts included the suggestion that answers should be based on preferences for the "ideal" treatment of a hypothetical patient seeking implant treatment for the replacement of a single missing tooth. RESULTS: Of 133 questionnaires sent via email, 35 were returned. The results are presented with histograms that use color coding as an experience proxy metric. A total of 87% of respondents was in private practice, and 60% reported having restored more than 1000 single-unit implant restorations. For the replacement of a single maxillary central incisor under ideal conditions and angulation through the palatal surface, respondents preferred bone level implants (93%) and screw-retained restorations (80%), with 50% of those being zirconia with a titanium abutment and 21% being cast metal-ceramic. For an identical scenario, except that the angulation would be through the facial surface, respondents preferred the angled screw system (55%) and cemented (41%) restorations. For the replacement of a single missing mandibular molar under ideal conditions, respondents preferred bone level implants (79%) and screw-retained restorations (79%), with 70% of those being zirconia with a titanium abutment and 17% being cast metal-ceramic. CONCLUSIONS: While a wide range of protocols, designs, and materials exist for the replacement of a single missing tooth, these results provide a snapshot of current single-unit implant prosthodontic preferences in the Western United States and Canada.

Posterior restoration rotational torque associated with cuspal incline angulation: A proof of concept.

STATEMENT OF PROBLEM: Off-axis, external forces with a moment arm on posterior restorations have not been investigated in experimental studies. PURPOSE: The purpose of this proof-of-concept study was to determine the interaction between occlusal force directed toward cuspal incline angulations with variations in base width and preparation vertical heights. Torque forces on a single crown restoration in simulated premolar and molar tooth forms were calculated for 3 different rotational axes. MATERIAL AND METHODS: Trigonometric calculations were made to determine the amount of torque generated in a simulated-crown restoration in premolar and molar tooth forms. Restorations with different cuspal incline angulations were loaded with an off-axis force of 200 N. This force was applied to 5 different cuspal incline angulations in both tooth forms at varying preparation heights. Right triangles were used to enable trigonometric computations of the resulting moment arms that accompanied the 3 rotational axes. RESULTS: The total torque values were calculated with a range from 7.5 to 372.8 Ncm. The highest levels of torque were generated in the 5-mm-high molar tooth form with a rotational axis located within the root form, perpendicular to the 45-degree cuspal incline. In general, large moment arms were generated with steep cuspal incline angulations and mid-root axis locations; the lowest torque values in all cuspal incline angulations were found in the rotational axis locations at the crown finish line. The torque values at the rotational axis finish line location were found to be greatest in the largest vertical tooth form height category (5 mm) in both tooth model sizes. CONCLUSIONS: The crown restoration cuspal incline angulations, vertical preparation heights, base widths, and rotational axis locations all played a role in the torque force levels generated, probably influencing restoration stability.

Introducing the Fear Learning and Anxiety Response (FLARe) app and web portal for the remote delivery of fear conditioning experiments.

Experimental paradigms measuring key psychological constructs can enhance our understanding of mechanisms underlying human psychological well-being and mental health. Delivering such paradigms remotely affords opportunities to reach larger, more representative samples than is typically possible with in-person research. The efficiency gained from remote delivery makes it easier to test replication of previously established effects in well-powered samples. There are several challenges to the successful development and delivery of remote experimental paradigms, including use of an appropriate delivery platform, identifying feasible outcome measures, and metrics of participant compliance. In this paper, we present FLARe (Fear Learning and Anxiety Response), open-source software in the form of a smartphone app and web portal for the creation and delivery of remote fear conditioning experiments. We describe the benefits and challenges associated with the creation of a remote delivery platform for fear conditioning, before presenting in detail the resultant software suite, and one instance of deploying this using the FLARe Research infrastructure. We provide examples of the application of FLARe to several research questions which illustrate the benefits of the remote approach to experiment delivery. The FLARe smartphone app and web portal are available for use by other researchers and have been designed to be user-friendly and intuitive. We hope that FLARe will be a useful tool for those interested in conducting well-powered fear conditioning studies to inform our understanding of the development and treatment of anxiety disorders.

Prosthesis-Implant Arch Area Ratio (PIAAR) - A New Geometric Paradigm, Replacing the Current 'A-P Spread' of a Cantilever in Full-Arch Implant Prosthesis: A Proof-of-Concept Experiment.

PURPOSE: The anterior-posterior spread concept is relied upon to understand the bioengineering aspects of cantilevers in fixed complete denture prostheses. This concept is not evidence-based. With no other category existing in contemporary implant dentistry, this conventional anterior-posterior spread concept may have limited more precise and accurate biomechanical analysis. This paper aims to validate a scientific rationale for utilizing this new prosthesis-implant arch area ratio instead of the preexisting anterior-posterior spread concept. MATERIALS AND METHODS: Utilizing the preexisting mathematical principle of "Heron's formula," enabling the calculation of the area of a triangle with three known lengths and no angular information, a new prosthesis-implant arch area ratio is introduced through algebraic derivation. Geometrically, three different sections of prosthetic cantilevers are defined as: (1) anterior cantilever; (2) lateral cantilever; (3) posterior cantilever. The prosthesis-implant arch area ratio is defined as the prosthesis arch area (anterior, lateral, or posterior cantilever) divided by the sum of the platform arch area and the selected prosthesis arch area. As a proof-of-concept experiment, fifteen different laboratory cast arches (n = 15) were chosen; theorized four implant platforms were referenced from the conventional anterior-posterior spread ration of 1:1.5, followed by calculating platform arch area and prosthesis arch area using Heron's formula. Then, three different horizontal arch width ratios (1:1, 1.25:1, and 1.5:1) under the constant linear height ratio of anterior-posterior spread (1:1.5) were drawn to assign different experimental groups of prosthesis arch area on each patient scenario, followed by cantilever comparison combining all ratio values (n = 45). One-way ANOVA and Tukey's post hoc multiple comparison tests were used for statistical analysis. RESULTS: One-way ANOVA revealed statistical differences of all prosthesis-implant arch area ratios on each cantilever group; anterior cantilever, F(2, 42) = 8.326, p = 0.0009; lateral cantilever F(2, 42) = 43.92, p < 0.0001; posterior cantilever, F(2, 42) = 26.66, p < 0.0001, as well as cantilever's comparison, F(2, 132) = 240.8, p < 0.0001. Tukey's post hoc test showed a statistically significant ascending trend of prosthesis-implant arch area ratio as the horizontal width ratio increases. Interestingly, the posterior cantilever had the greatest prosthesis-implant arch area ratio. CONCLUSIONS: Compared to the preexisting anterior-posterior spread concept, a new prosthesis-implant arch area ratio seemed to be a more categorized, geometric, and perceptive modality of assessing the prosthetic cantilever in a full-arch implant-supported prosthesis, allowing a more systematic indexing of different full-arch implant clinical scenarios with greater specificity and consistency.

What to do When Decompressive Gastrostomies and Jejunostomies are not Options? A Scoping Review of Transesophageal Gastrostomy Tubes for Advanced Malignancies.

BACKGROUND: In advanced malignant bowel obstruction, decompressive gastrostomy tubes (GTs) may not be feasible due to ascites, peritoneal carcinomatosis, and altered gastric anatomy. Whereas nasogastric tubes (NGTs) allow temporary decompression, percutaneous transesophageal gastrostomy tubes (PTEGs) are an alternative method for long-term palliative decompression. This study performed a scoping review to determine outcomes with PTEG in advanced malignancies. METHODS: A systematic literature search was performed to include all studies that reported the clinical results of PTEGs for malignancy. No language, national, or publication status restrictions were used. RESULTS: The analysis included 14 relevant studies with a total of 340 patients. In 11 studies, standard PTEGs were inserted with a rupture-free balloon's placement into the mouth or nose and esophageal puncture under fluoroscopy or ultrasound, followed by a guidewire into the stomach with placement of a single-lumen tube. Of 340 patients, 65 (19.1%) had minor complications, and 5 (2.1%) had significant complications, including bleeding and severe aspiration pneumonia. Of 171 patients, 169 with PTEGs (98.8%) reported relief of nasal discomfort from NGT and alleviation of obstructive symptoms. The one randomized controlled trial reported a significantly higher quality of life with PTEGs than with NGTs. CONCLUSIONS: When decompression for advanced malignancy is technically not feasible with a gastrostomy tube, the PTEG is a viable, safe option for palliation. The PTEG is associated with lower significant complication rates than the gastrostomy tube and significantly higher patient-derived outcomes than the NGT.

A scoping review of the distribution and frequency of extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae in shrimp and salmon.

Antimicrobial-resistant (AMR) bacteria are a threat to public health as they can resist treatment and pass along genetic material that allows other bacteria to become drug-resistant. To assess foodborne AMR risk, the Codex Guidelines for Risk Analysis of Foodborne AMR provide a framework for risk profiles and risk assessments. Several elements of a risk profile may benefit from a scoping review (ScR). To contribute to a larger risk profile structured according to the Codex Guidelines, our objective was to conduct a ScR of the current state of knowledge on the distribution, frequency and concentrations of extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae in salmon and shrimp. Articles were identified via a comprehensive search of five bibliographic databases. Two reviewers screened titles and abstracts for relevance and characterised full-text articles with screening forms developed a priori. Sixteen relevant studies were identified. This review found that there is a lack of Canadian data regarding ESBL-producing Enterobacteriaceae in salmon and shrimp. However, ESBL- producing Escherichia coli, Klebsiella pneumoniae and other Enterobacteriaceae have been isolated in multiple regions with a history of exporting seafood to Canada. The literature described herein will support future decision-making on this issue as research/surveillance and subsequent assessments are currently lacking.

Characterisation of burden of illness measures associated with human (Fluoro)quinolone-resistant Campylobacter spp. infections - a scoping review.

Campylobacter spp. are one of the most common causes of bacterial gastroenteritis in Canada and worldwide. Fluoroquinolones are often used to treat complicated human campylobacteriosis and strains of Campylobacter spp. resistant to these drugs are emerging along the food chain. A scoping review was conducted to summarise how human (fluoro)quinolone-resistant (FQR; quinolones including fluoroquinolones) Campylobacter spp. infections are characterised in the literature by describing how burden of illness (BOI) associated with FQR is measured and reported, describing the variability in reporting of study characteristics, and providing a narrative review of literature that compare BOI measures of FQR Campylobacter spp. infections to those with susceptible infections. The review identified 26 studies that yielded many case reports, a lack of recent literature and a lack of Canadian data. Studies reported 26 different BOI measures and the most common were hospitalisation, diarrhoea, fever and duration of illness. There were mixed results as BOI measures reported in literature were inconsistently defined and there were limited comparisons between resistant and susceptible infections. This presents a challenge when attempting to assess the magnitude of the BOI due to FQR Campylobacter spp., highlighting the need for more research in this area.

Dentithecamides A-H, Diacylated Zoanthoxanthin Derivatives with PAX3-FOXO1 Inhibitory Activity from the Hydroid Dentitheca habereri.

Chemical investigation of the marine hydroid Dentitheca habereri led to the identification of eight new diacylated zoanthoxanthin alkaloids, named dentithecamides A-H (1-8), along with three previously reported analogues, zoamides B-D (9-11). The structures of compounds 1-11 were elucidated by spectroscopic and spectrometric analyses, including IR, HRESIMS, and NMR experiments, and by comparison with literature data. Compounds 1-11 are the first zoanthoxanthin alkaloids to be reported from a hydroid. Dentithecamides A (1) and B (2) along with zoamides B-D (9-11), which all share a conformationally mobile cycloheptadiene core, inhibited PAX3-FOXO1 regulated transcriptional activity and thus provided a structural framework for the potential development of more potent PAX3-FOXO1 inhibitors.