Reduced fire severity offers near-term buffer to climate-driven declines in conifer resilience across the western United States.

Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration.

Adult Offspring of Deer Mouse Breeding Pairs Selected for Normal and Compulsive-Like Large Nesting Expression Invariably Show the Same Behavior Without Prior In-Breeding.

Obsessive-compulsive disorder is a neuropsychiatric condition with notable genetic involvement. Against this background, laboratory-housed deer mice of both sexes varyingly present with excessive and persistent large nesting behavior (LNB), which has been validated for its resemblance of clinical compulsivity. Although LNB differs from normal nesting behavior (NNB) on both a biological and cognitive level, it is unknown to what extent the expression of LNB and NNB is related to familial background. Here, we randomly selected 14 NNB- and 14 LNB-expressing mice (equally distributed between sexes) to constitute 7 breeding pairs of each phenotype. Pairs were allowed to breed two successive generations of offspring, which were raised until adulthood (12 weeks) and assessed for nesting expression. Remarkably, our findings show that offspring from LNB-expressing pairs build significantly larger nests compared to offspring from NNB-expressing pairs and the nesting expression of the offspring of each breeding pair, irrespective of parental phenotype or litter, is family specific. Collectively, the results of this investigation indicate that LNB can be explored for its potential to shed light on heritable neurocognitive mechanisms that may underlie the expression of specific persistent behavioral phenotypes.

Echocardiographic findings in non-hospitalised children and adolescents following acute COVID-19.

BACKGROUND: Although COVID-19 is known to have cardiac effects in children, seen primarily in severe disease, more information is needed about the cardiac effects following COVID-19 in non-hospitalised children and adolescents during recovery. This study aims to compare echocardiographic markers of cardiac size and function of children following acute COVID-19 with those of healthy controls. METHODS: This single-centre retrospective case-control study compared 71 cases seen in cardiology clinic following acute COVID-19 with 33 healthy controls. Apical left ventricle, apical right ventricle, and parasternal short axis at the level of the papillary muscles were analysed to measure ventricular size and systolic function. Strain was analysed on vendor-independent software. Statistical analysis was performed using t-test, chi-square, Wilcoxon rank sum, and regression modelling as appropriate (p < 0.05 significant). RESULTS: Compared to controls, COVID-19 cases had slightly higher left ventricular volumes and lower left ventricular ejection fraction and right ventricular fractional area change that remained within normal range. There were no differences in right or left ventricular longitudinal strain between the two groups. Neither initial severity nor persistence of symptoms after diagnosis predicted these differences. CONCLUSIONS: Echocardiographic findings in children and adolescents 6 weeks to 3 months following acute COVID-19 not requiring hospitalisation were overall reassuring. Compared to healthy controls, the COVID-19 group demonstrated mildly larger left ventricular size and lower conventional measures of biventricular systolic function that remained within the normal range, with no differences in biventricular longitudinal strain. Future studies focusing on longitudinal echocardiographic assessment of patients following acute COVID-19 are needed to better understand these subtle differences in ventricular size and function.

Building a Resilient Patient Safety Culture: A Large Healthcare Organization's Approach to Systematically Reviewing Serious Harm Events.

Across Canada, pressures related to staffing, burnout and funding continue to affect healthcare organizations and systems. These pressures impact the quality of care Canadians receive, most notably access to care. Evidence indicates that patients are more likely to suffer from preventable harm during periods of hospital overcrowding and, indeed, very recent data from the Canadian Institute for Health Information suggest that rates of preventable harm have increased modestly in Canadian hospitals. A key lever that can have a positive impact on patient safety culture and contribute to fewer preventable adverse events at an institutional level is systematic formal case reviews. This article describes a large healthcare organization's approach to systematically reviewing serious harm events. An evaluation of both quantitative and qualitative metrics suggests that Unity Health Toronto's critical incident review process has been effective at building a resilient patient safety culture that stood up to the challenges of the COVID-19 pandemic and continues to have a positive impact on patient safety at Unity Health Toronto.

Consistent spatial scaling of high-severity wildfire can inform expected future patterns of burn severity.

Increasing wildfire activity in forests worldwide has driven urgency in understanding current and future fire regimes. Spatial patterns of area burned at high severity strongly shape forest resilience and constitute a key dimension of fire regimes, yet remain difficult to predict. To characterize the range of burn severity patterns expected within contemporary fire regimes, we quantified scaling relationships relating fire size to patterns of burn severity. Using 1615 fires occurring across the Northwest United States between 1985 and 2020, we evaluated scaling relationships within fire regimes and tested whether relationships vary across space and time. Patterns of high-severity fire demonstrate consistent scaling behaviour; as fire size increases, high-severity patches consistently increase in size and homogeneity. Scaling relationships did not differ substantially across space or time at the scales considered here, suggesting that as fire-size distributions potentially shift, stationarity in patch-size scaling can be used to infer future patterns of burn severity.

Life-threatening, high-intensity trauma- and context-dependent anxiety in zebrafish and its modulation by epinephrine.

Trauma-related psychopathology transpires in some individuals after exposure to a life-threatening event. While aberrant adrenergic processes may contribute to this, a clear understanding of how said processes influence trauma-related conditions, remain inadequate. Here, we aimed to develop and describe a novel zebrafish (Danio rerio) model of life-threatening trauma-induced anxiety that may be representative of trauma related anxiety, and to evaluate the impact of stress-paired epinephrine (EPI) exposure in the model system. Four groups of zebrafish were each exposed to different and unique stress-related paradigms, i.e., i) a sham (trauma free), ii) high-intensity trauma (triple hit; THIT), iii) high-intensity trauma in the presence of EPI exposure (EHIT), and iv) EPI exposure on its own, all applied in the presence of a color context. Novel tank anxiety was subsequently assessed at 1, 4, 7 and 14 days after the traumatic event. The present results demonstrate that 1) through day 14, THIT or EPI exposure alone induced persistent anxiety-like behavior, 2) EHIT blunted the delayed anxiety-like sequalae associated with severe trauma, 3) exposure to a trauma-paired color context prior to anxiety testing bolstered the subsequent anxiety-like behavior of THIT, but not EHIT -exposed fish, and 4) despite this, THIT- and EPI-exposed fish showed a lesser degree of contextual avoidance behavior compared to sham- or EHIT-exposed fish. These results indicate that the stressors induced long-lasting anxiety-like behavior reminiscent of post trauma anxiety, while EPI displays complex interactions with the stressor, including a buffering effect to subsequent exposure of a trauma-paired cue.

Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.

OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Iron and n-3 fatty acid depletion, alone and in combination, during early development provoke neurochemical changes, anhedonia, anxiety and social dysfunction in rats.

Objectives: Both iron and omega-3 (n-3) fatty acids (FA) play important roles in the development and functioning of the brain. We investigated the effects of n-3 FA and iron deficiencies, alone and in combination, during early development on behaviour and brain monoamines in rats. Methods: Using a 2-factorial design, female Wistar rats were randomly allocated to one of four diet groups: Control, n-3 FA deficient (n-3 FAD), iron deficient (ID), or n-3 FAD + ID. Females received these diets throughout mating, pregnancy and lactation. Offspring (n = 24/group; male:female = 1:1) continued on the same diet until post-natal day 42-45, and underwent a sucrose preference test (SPT), novel object recognition test, elevated plus maze (EPM) and social interaction test (SIT). Results: ID offspring consumed less sucrose in the SPT and spent more time in closed arms and less time in open arms of the EPM than non-ID offspring. In female offspring only, ID and n-3 FAD reduced time approaching and together in the SIT, with an additive effect of ID and n-3 FAD for even less time approaching and spent together in the n-3 FAD + ID group compared to controls. ID offspring had higher striatal dopamine and norepinephrine and lower frontal cortex dopamine concentrations. N-3 FAD and ID affected frontal cortex serotonin concentrations in a sex-specific manner. Conclusions: Our results suggest that ID and n-3 FAD during early development provoke anhedonia, anxiety and social dysfunction in rats, with potential additive and attenuating effects when combined. These effects may in part be attributed to disturbances in brain neurochemistry and may be sex-specific.

The Psychopharmacology of Obsessive-Compulsive Disorder: A Preclinical Roadmap.

This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies for OCD are then reviewed, including monotherapy with serotonin reuptake inhibitors and augmentation with antipsychotic medication and with psychologic treatment. Neuromodulatory therapies for OCD are also described, including psychosurgery, deep brain stimulation, and noninvasive brain stimulation. Psychotherapies for OCD are then reviewed, focusing on behavior therapy, including exposure and response prevention and cognitive therapy, and the efficacy of these interventions is discussed, touching on issues such as the timing of sessions, the adjunctive role of pharmacotherapy, and the underlying mechanisms. Next, current research on the neurobiology of OCD is examined, including work probing the role of various neurotransmitters and other endogenous processes and etiology as clues to the neurobiological fault that may underlie OCD. A new perspective on preclinical research is advanced, using the Research Domain Criteria to propose an adaptationist viewpoint that regards OCD as the dysfunction of a normal motivational system. A systems-design approach introduces the security motivation system (SMS) theory of OCD as a framework for research. Finally, a new perspective on psychopharmacological research for OCD is advanced, exploring three approaches: boosting infrastructure facilities of the brain, facilitating psychotherapeutic relearning, and targeting specific pathways of the SMS network to fix deficient SMS shut-down processes. SIGNIFICANCE STATEMENT: A significant proportion of patients with obsessive-compulsive disorder (OCD) do not achieve remission with current treatments, indicating the need for innovations in psychopharmacology for the disorder. OCD may be conceptualized as the dysfunction of a normal, special motivation system that evolved to manage the prospect of potential danger. This perspective, together with a wide-ranging review of the literature, suggests novel directions for psychopharmacological research, including boosting support systems of the brain, facilitating relearning that occurs in psychotherapy, and targeting specific pathways in the brain that provide deficient stopping processes in OCD.

Molecular and Physiological Functions of PACAP in Sweat Secretion.

Sweat plays a critical role in human body, including thermoregulation and the maintenance of the skin environment and health. Hyperhidrosis and anhidrosis are caused by abnormalities in sweat secretion, resulting in severe skin conditions (pruritus and erythema). Bioactive peptide and pituitary adenylate cyclase-activating polypeptide (PACAP) was isolated and identified to activate adenylate cyclase in pituitary cells. Recently, it was reported that PACAP increases sweat secretion via PAC1R in mice and promotes the translocation of AQP5 to the cell membrane through increasing intracellular [Ca2+] via PAC1R in NCL-SG3 cells. However, intracellular signaling mechanisms by PACAP are poorly clarified. Here, we used PAC1R knockout (KO) mice and wild-type (WT) mice to observe changes in AQP5 localization and gene expression in sweat glands by PACAP treatment. Immunohistochemistry revealed that PACAP promoted the translocation of AQP5 to the lumen side in the eccrine gland via PAC1R. Furthermore, PACAP up-regulated the expression of genes (Ptgs2, Kcnn2, Cacna1s) involved in sweat secretion in WT mice. Moreover, PACAP treatment was found to down-regulate the Chrna1 gene expression in PAC1R KO mice. These genes were found to be involved in multiple pathways related to sweating. Our data provide a solid basis for future research initiatives in order to develop new therapies to treat sweating disorders.

Genomic answers for children: Dynamic analyses of >1000 pediatric rare disease genomes.

PURPOSE: This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program. METHODS: Extensive analyses of 960 families with suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes. RESULTS: Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases). CONCLUSION: Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.

Does the legacy of historical thinning treatments foster resilience to bark beetle outbreaks in subalpine forests?

Promoting ecological resilience to increasing disturbance activity is a key management priority under warming climate. Across the Northern Hemisphere, tree mortality from widespread bark beetle outbreaks raises concerns for how forest management can foster resilience to future outbreaks. Density reduction (i.e., thinning) treatments can increase vigor of remaining trees, but the longevity of treatment efficacy for reducing susceptibility to future disturbance remains a key knowledge gap. Using one of the longest-running replicated experiments in old-growth subalpine forests, we measured stand structure following a recent (early 2000s) severe mountain pine beetle (MPB; Dendroctonus ponderosae) outbreak to examine the legacy of historical (1940s) thinning treatments on two components of resilience. We asked: 'How did historical thinning intensity affect (1) tree-scale survival probability and stand-scale survival proportion (collectively "resistance" to outbreak) for susceptible trees (lodgepole pine [Pinus contorta] ≥ 12 cm diameter) and (2) post-outbreak stand successional trajectories?' Overall outbreak severity was high (MPB killed 59% of susceptible individuals and 78% of susceptible basal area), and historical thinning had little effect on tree-scale and stand-scale resistance. Tree-scale survival probability decreased sharply with increasing tree diameter and did not differ from the control (uncut stands) in the historical thinning treatments. Stand-scale proportion of surviving susceptible trees and basal area did not differ from the control in historically thinned stands, except for treatments that removed nearly all susceptible trees, in which survival proportion approximately doubled. Despite limited effects on resistance to MPB outbreak, the legacy of historical treatments shifted dominance from large-diameter to small-diameter lodgepole pine by the time of outbreak, resulting in historically thinned stands with ~2× greater post-outbreak live basal area than control stands. MPB-driven mortality of large-diameter lodgepole pine in control stands and density-dependent mortality of small-diameter trees in historically thinned stands led to convergence in post-outbreak live tree stand structure. One exception was the heaviest historical thinning treatments (59-77% basal area removed), for which sapling dominance of shade-tolerant, unsusceptible conifers was lower than control stands. After six decades, thinning treatments have had minimal effect on resistance to bark beetle outbreaks, but leave persistent legacies in shaping post-outbreak successional trajectories.

NASH: regulatory considerations for clinical drug development and U.S. FDA approval.

Nonalcoholic fatty liver disease is a growing public health crisis, with phenotypes from nonalcoholic fatty liver to nonalcoholic steatohepatitis, currently known as NASH, which can progress to liver fibrosis and end stage cirrhosis. NASH is associated with an increased risk of cardiovascular disease and Type 2 diabetes mellitus. There are still no U.S. FDA approved drugs or biological treatments for NASH or related liver diseases. Despite official agency guidance, the regulatory pathway to ultimate product approval is unclear, due to both the extra-hepatic factors that contribute to NASH, as well as the organizational structure of FDA, with its traditional separation of therapeutic indications within discrete review divisions. There is hope that continued evolution of the regulatory process will lead to the ability for clinical trial endpoints supporting NASH treatment approval to include both liver-based and traditional metabolic measures, independent of specific FDA division review.

Short-interval severe fire erodes the resilience of subalpine lodgepole pine forests.

Subalpine forests in the northern Rocky Mountains have been resilient to stand-replacing fires that historically burned at 100- to 300-year intervals. Fire intervals are projected to decline drastically as climate warms, and forests that reburn before recovering from previous fire may lose their ability to rebound. We studied recent fires in Greater Yellowstone (Wyoming, United States) and asked whether short-interval (<30 years) stand-replacing fires can erode lodgepole pine (Pinus contorta var. latifolia) forest resilience via increased burn severity, reduced early postfire tree regeneration, reduced carbon stocks, and slower carbon recovery. During 2016, fires reburned young lodgepole pine forests that regenerated after wildfires in 1988 and 2000. During 2017, we sampled 0.25-ha plots in stand-replacing reburns (n = 18) and nearby young forests that did not reburn (n = 9). We also simulated stand development with and without reburns to assess carbon recovery trajectories. Nearly all prefire biomass was combusted ("crown fire plus") in some reburns in which prefire trees were dense and small (≤4-cm basal diameter). Postfire tree seedling density was reduced sixfold relative to the previous (long-interval) fire, and high-density stands (>40,000 stems ha-1) were converted to sparse stands (<1,000 stems ha-1). In reburns, coarse wood biomass and aboveground carbon stocks were reduced by 65 and 62%, respectively, relative to areas that did not reburn. Increased carbon loss plus sparse tree regeneration delayed simulated carbon recovery by >150 years. Forests did not transition to nonforest, but extreme burn severity and reduced tree recovery foreshadow an erosion of forest resilience.

Electrocardiographic changes in non-hospitalised children with COVID-19.

OBJECTIVES: Many children diagnosed with COVID-19 infections did not require hospitalisation. Our objective was to analyse electrocardiographic changes in children with asymptomatic, mild or moderate COVID-19 who did not require hospitalisation. METHODS: All children are seen in a paediatric cardiology clinic who had asymptomatic, mild or moderate COVID-19 that did not require hospitalisation and had at least one electrocardiogram after their diagnosis were included in this retrospective analysis. Records were reviewed to determine COVID-19 disease severity and presence of Long COVID. Rhythm assessment, atrial enlargement, ventricular hypertrophy, PR/QRS/QT interval duration and ST-T wave abnormalities were analysed by a paediatric electrophysiologist. Clinically ordered echocardiograms were reviewed for signs of myopericarditis (left ventricular ejection fraction and pericardial effusion) on any subject with an electrocardiographic abnormality. RESULTS: Of the 82 children meeting inclusion criteria (14.4 years, range 1-18 years, 57% male), 17 patients (21%) demonstrated electrocardiographic changes. Ten patients (12%) had electrocardiogram of borderline significance, which included isolated mild PR prolongation or mild repolarisation abnormalities. The other seven patients (9%) had concerning electrocardiographic findings consisting of more significant repolarisation abnormalities. None of the patients with an abnormal electrocardiogram revealed any echocardiographic abnormality. All abnormal electrocardiograms normalised over time except in two cases. Across the entire cohort, greater COVID-19 disease severity and long COVID were not associated with electrocardiographic abnormalities. CONCLUSIONS: Electrocardiographic abnormalities are present in a minority of children with an asymptomatic, mild or moderate COVID-19 infection. Many of these changes resolved over time and no evidence of myopericarditis was present on echocardiography.

Breastfeeding Among Pediatric Emergency Physicians: Rates, Barriers, and Support.

OBJECTIVES: Physician mothers are at risk for early cessation of breastfeeding, in part because of challenges associated with returning to work. Given the inherent unpredictability of emergency medicine practice, we hypothesized that pediatric emergency medicine (PEM) physicians would face unique challenges in continuing breastfeeding while working in their field. The aims of this study were to determine the 6-month breastfeeding rates of PEM physicians, gain insight into their experiences expressing breast milk while working in pediatric emergency departments, and determine factors that support or discourage successful breastfeeding. METHODS: This study was a cross-sectional survey of members of the American Academy of Pediatrics Section on Emergency Medicine via its quarterly membership survey program. Separate survey pathways were developed for respondents who had ever breastfed and those who had not. RESULTS: One hundred ninety-three responded; 91 had breastfed, and 102 had not. Of those who breastfed, 90% did so for 6 months or longer. Mean (SD) duration was 12.5 (7.1) months (range, 2-48 months). Of those who expressed milk at work, only 7.6% felt they "always" had sufficient time to pump; 32% felt they "always" had what they considered to be an appropriate location to pump. Breastfeeding duration rate of at least 6 months was higher for those (66%) who "sometimes" to "always" had access to what they felt were appropriate locations to pump than for those (34%) who "never" or "occasionally" did (98 vs 85%, P = 0.048). Eighty-six percent of respondents who had never breastfed reported being "very supportive" of expressing milk at work. CONCLUSIONS: Breastfeeding PEM physicians have high 6-month breastfeeding rates, and many express milk at work. Although colleagues report being supportive, barriers of perceived lack of sufficient time to pump and appropriate pumping locations remain.

GPER Agonist G1 Prevents Wnt-Induced JUN Upregulation in HT29 Colorectal Cancer Cells.

Women consistently show lower incidence and mortality rates for colorectal cancer (CRC) compared to men. Epidemiological evidence supports a pivotal role for estrogen in protecting women against CRC. Estrogen protective effects in CRC have been mainly attributed to the estrogen receptor beta (ERß) however its expression is lost during CRC progression. The role of the G-protein coupled membrane estrogen receptor (GPER/GPER1/GPR30), which remains expressed after ERß loss in CRC, is currently under debate. We hypothesise that estrogen can protect against CRC progression via GPER by modulating the Wnt/ß-catenin proliferative pathway which is commonly hyperactivated in CRC. We sought evidence of sexual dimorphism within the Wnt/ß-catenin pathway by conducting Kaplan-Meier analyses based on gene expression of the Wnt receptor FZD1 (Frizzled 1) in multiple public domain CRC patient data sets. High expression of FZD1 was associated with poor relapse-free survival rates in the male but not the female population. In female-derived HT29 CRC cell lines, we show that ß-catenin nuclear translocation was not affected by treatment with the GPER agonist G1. However, G1 prevented the Wnt pathway-induced upregulation of the JUN oncogene. These novel findings indicate a mechanistic role for GPER in protecting against CRC progression by selectively reducing the tumorigenic effects of hyperactive Wnt/ß-catenin signalling pathways in CRC.

Precise Targeting of miRNA Sites Restores CFTR Activity in CF Bronchial Epithelial Cells.

MicroRNAs that are overexpressed in cystic fibrosis (CF) bronchial epithelial cells (BEC) negatively regulate CFTR and nullify the beneficial effects of CFTR modulators. We hypothesized that it is possible to reverse microRNA-mediated inhibition of CFTR using CFTR-specific target site blockers (TSBs) and to develop a drug-device combination inhalation therapy for CF. Lead microRNA expression was quantified in a series of human CF and non-CF samples and in vitro models. A panel of CFTR 3' untranslated region (UTR)-specific locked nucleic acid antisense oligonucleotide TSBs was assessed for their ability to increase CFTR expression. Their effects on CFTR activity alone or in combination with CFTR modulators were measured in CF BEC models. TSB encapsulation in poly-lactic-co-glycolic acid (PLGA) nanoparticles was assessed as a proof of principle of delivery into CF BECs. TSBs targeting the CFTR 3' UTR 298-305:miR-145-5p or 166-173:miR-223-3p sites increased CFTR expression and anion channel activity and enhanced the effects of ivacaftor/lumacaftor or ivacaftor/tezacaftor in CF BECs. Biocompatible PLGA-TSB nanoparticles promoted CFTR expression in primary BECs and retained desirable biophysical characteristics following nebulization. Alone or in combination with CFTR modulators, aerosolized CFTR-targeting TSBs encapsulated in PLGA nanoparticles could represent a promising drug-device combination therapy for the treatment for CFTR dysfunction in the lung.

Plant-based Medicines (Phytoceuticals) in the Treatment of Psychiatric Disorders: A Meta-review of Meta-analyses of Randomized Controlled Trials: Les médicaments à base de plantes (phytoceutiques) dans le traitement des troubles psychiatriques: une méta-revue des méta-analyses d'essais randomisés contrôlés.

OBJECTIVES: Plant-based medicines have had a long-standing history of use in psychiatric disorders. Highly quantified and standardized extracts or isolates may be termed "phytoceuticals," in a similar way that medicinal nutrients are termed as "nutraceuticals." Over the past 2 decades, several meta-analyses have examined the data for a range of plant-based medicines in the treatment of psychiatric disorders. The aim of this international project is to provide a "meta-review" of this top-tier evidence. METHODS: We identified, synthesized, and appraised all available up to date meta-analyses... of randomized controlled trials (RCTs) reporting on the efficacy and effectiveness of individual phytoceuticals across all major psychiatric disorders. RESULTS: Our systematic search identified 9 relevant meta-analyses of RCTs, with primary analyses including outcome data from 5,927 individuals. Supportive meta-analytic evidence was found for St John's wort for major depressive disorder (MDD); curcumin and saffron for MDD or depression symptoms, and ginkgo for total and negative symptoms in schizophrenia. Kava was not effective in treating diagnosed anxiety disorders. We also provide details on 22 traditional Chinese herbal medicine formulas' meta-analyses (primarily for depression studies), all of which revealed highly significant and large effect sizes. Their methodology, reporting, and potential publication bias were, however, of marked concern. The same caveat was noted for the curcumin, ginkgo, and saffron meta-analyses, which may also have significant publication bias. CONCLUSIONS: More rigorous international studies are required to validate the efficacy of these phytoceuticals before treatment recommendations can be made. In conclusion, the breadth of data tentatively supports several phytoceuticals which may be effective for mental disorders alongside pharmaceutical, psychological therapies, and standard lifestyle recommendations.

Adverse Neuropsychiatric Events and Recreational Use of Efavirenz and Other HIV-1 Antiretroviral Drugs.

Efavirenz is a highly effective HIV-1 antiretroviral; however, it is also frequently associated with neuropsychiatric adverse events (NPAE) that include abnormal dreams, sleep disturbances, nervousness, anxiety, depression, and dizziness. The incidence of NPAEs upon initiation of treatment with efavirenz-containing medications is high, exceeding 50% in most studies. Although the NPAEs tend to decrease after the first month in many patients, they persist for long periods of time in others. Efavirenz-based treatment is generally well-tolerated in children, although some experience persistent concentration problems, as well as sleep disturbances, psychotic reactions, and seizures. In an effort to link basic with clinical research, parameters associated with efavirenz brain exposure are discussed, and factors that increase efavirenz levels are explored in depth as they are expected to contribute to NPAE risk. These include the role of modifiable and nonmodifiable risk factors such as diet, weight, and drug-drug interactions and sex, age, and ethnicity/pharmacogenetics. In addition to NPAEs, this review explores what is known about antiretroviral (ARV) drugs being used for recreational purposes. Although multiple ARV drugs are covered, special attention is devoted to efavirenz given that the majority of reports of NPAEs and illicit use of ARV drugs concern efavirenz. The evolving molecular mechanistic basis of NPAEs and abuse of efavirenz point to a complex and polymodal receptor pharmacology. Animal studies to date primarily point to a serotonergic mechanism of action. Recently emerging associations between HIV-associated neurocognitive disorder and efavirenz use, and possible contributions of the mitochondrial-immune-inflammatory-redox cascade are explored in the context of the signaling mechanisms that appear to be involved.