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Abstract Aims The multi‐systemic effects of heart failure (HF) resemble the spread observed during cancer. We propose a new score, named HLM, analogous to the TNM classification used in oncology, to assess the prognosis of HF. HLM refers to H: heart damage, L: lung involvement, and M: systemic multiorgan involvement. The aim was to compare the HLM score to the conventional New York Heart Association (NYHA) classification, American College of Cardiology/American Heart Association (ACC/AHA) stages, and left ventricular ejection fraction (LVEF), to assess the most accurate prognostic tool for HF patients. Methods and results We performed a multicentre, observational, prospective study of consecutive patients admitted for HF. Heart, lung, and other organ function parameters were collected. Each patient was classified according to the HLM score, NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography. The follow‐up period was 12 months. The primary endpoint was a composite of all‐cause death and rehospitalization due to HF. A total of 1720 patients who completed the 12 month follow‐up period have been enrolled in the study. 520 (30.2%) patients experienced the composite endpoint of all‐cause death and rehospitalization due to HF. 540 (31.4%) patients were female. The mean age of the study population was 70.5 ± 12.9. The mean LVEF at admission was 42.5 ± 13%. Regarding the population distribution across the spectrum of HLM score stages, 373 (21.7%) patients were included in the HLM‐1, 507 (29.5%) in the HLM‐2, 587 (34.1%) in the HLM‐3, and 253 (14.7%) in the HLM‐4. HLM was the most accurate score to predict the primary endpoint at 12 months. The area under the receiver operating characteristic curve (AUC) was greater for the HLM score compared with the NYHA classification, ACC/AHA stages, or LVEF, regarding the composite endpoint (HLM = 0.645; NYHA = 0.580; ACC/AHA = 0.589; LVEF = 0.572). The AUC of the HLM score was significantly better compared with the LVEF (P = 0.002), ACC/AHA (P = 0.029), and NYHA (P = 0.009) AUC. Conclusions The HLM score has a greater prognostic power compared with the NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography in terms of the composite endpoint of all‐cause death and rehospitalization due to HF at 12 months of follow‐up.

Abstract Understanding the behavior of mercury (Hg) in organic‐rich sediments as they undergo thermal maturation is important, for example, because enrichment of Hg in sedimentary deposits has become a widely used proxy for volcanism from Large Igneous Provinces (LIPs). In this study, we evaluate the effects of such processes on sedimentary Hg concentrations by investigating a common stratigraphic interval in three drill cores with different levels of thermal maturity (immature, mature and post‐mature) in Toarcian sediments (Posidonienschiefer Formation) from the Lower Saxony Basin, Germany. We present Hg concentrations, bulk organic geochemistry, and total sulfur data. Mercury concentrations in the mature and post‐mature sediments are increased >2‐fold relative to the immature material, which is greater than any potential differences in original Hg concentrations in the studied successions prior to burial. Organic‐carbon and host‐rock mass loss during thermal maturation may have concentrated Hg in the mature sediments to some extent, provided Hg is considered effectively immobile. The increased Hg, TOC‐normalized Hg, and TS‐normalized Hg are most likely linked to the “closed system” behavior of Hg in sedimentary basins and the relatively low temperatures (70–260°C) during maturation that resulted in limited Hg mobility. More speculatively, a certain degree of redistribution of Hg within the mature sediments is suggested by its enrichment in distinct stratigraphic levels. Regardless of the exact mechanisms at play, the elevated Hg concentrations in mature sediments amplify both Hg/TOC and Hg/TS, implying that thermal effects must be considered when using normalized Hg as a proxy for far‐field volcanic activity.

Abstract PyGPlates is an open‐source Python library to visualize and edit plate tectonic reconstructions created using GPlates. The Python API affords a greater level of flexibility than GPlates to interrogate plate reconstructions and integrate with other Python workflows. GPlately was created to accelerate spatio‐temporal data analysis leveraging pyGPlates and PlateTectonicTools within a simplified Python interface. This object‐oriented package enables the reconstruction of data through deep geologic time (points, lines, polygons and rasters), the interrogation of plate kinematic information (plate velocities, rates of subduction and seafloor spreading), the rapid comparison between multiple plate motion models, and the plotting of reconstructed output data on maps. All tools are designed to be parallel‐safe to accelerate spatio‐temporal analysis over multiple CPU processors.

Abstract Coral reef islands are vulnerable landforms to environmental change. Constructed of largely unconsolidated reef‐derived sediments, they are highly sensitive to variations in metocean boundary conditions, raising global concern about their future resilience and stability in the face of increased natural hazards, sea‐level rise and anthropogenic climate change. This study examines the evolution of an inshore turbid reef island from the southern Pilbara region of Western Australia (Indo‐Pacific) using detailed analyses of island chronostratigraphy (composition, texture) and geochronology (21 in‐situ radiometric dates) from Eva Island. Downcore, composition of island‐grade (reef‐derived) sediments were homogenous, dominated by molluscan (37%–42%) and coral (32%–37%) constituents. The 14C radiometric dating of island sediments, beachrock and coral microatolls identified five stages of island formation across changing sea‐level regimes over the mid to late Holocene: (1) limestone platform accretion at ca 6,000 cal yr BP, coinciding with reef decline or ‘give‐up’ on neighbouring Exmouth Gulf reefs; (2) sand cay (i.e. core) initiation and vertical aggregation at ca 5,000 cal yr BP during the point of sea‐level regression to current levels; (3) major accretion and lateral progradation of the island between 3,500 cal yr BP and 2,500 cal yr BP including the modification of island shorelines through alongshore reworking of sediment; (4) lateral accretion and minor expansion to the north and formation of beachrock pavement between 2,500 and 650 cal yr BP; and (5) planform adjustment (erosion of the north‐west island) and backstepping under stabilised sea levels over the past 650 years. While this model is comparative to studies on island formation following incremental sea‐level fall following the mid‐Holocene highstand, it demonstrates active landform readjustment under stabilised sea levels over the past 2,000 years, probably the influence of local‐scale metocean boundary conditions within climate windows across the mid to late Holocene period (i.e. independent of sea‐level fluctuations). Importantly, while sediment production rates are predicted to be lower in turbid‐water reef systems than clear water, Eva Island shows no change in carbonate producers (i.e. proportion of mollusc and coral) over the course of island building, indicating the carbonate factory has not experienced significant adjustments in reef ecology, but has remained stable despite low water quality.

Abstract Sedimentary mercury (Hg) has become a widely used proxy for paleo‐volcanic activity. However, scavenging and drawdown of Hg by organic‐matter (OM) and sulfides are important non‐volcanic factors determining variability in such records. Most studies, therefore, normalize total Hg (HgT) to a Hg “host‐phase” proxy (e.g., HgT/TOC for OM, HgT/TS for sulfides), with the dominant host‐phase determined based on the strongest observed (linear) correlations. This approach suffers from various non‐linearities in Hg‐host‐phase behavior and does not account for succession‐level, let alone sample‐level, Hg speciation changes. Thermal desorption characteristics or “profiles” (TDPs) for many Hg species during pyrolysis analysis are well‐established with applications including distinguishing between OM‐bound Hg and different Hg sulfides and oxides in (sub‐)recent sediments. We explore the use of TDPs for geological sediment (rock) samples and illustrate the presence of multiple release phases (Hg species)—correlated to geochemical host‐phase—in (almost) all the 65 analyzed Tithonian (146–145 Ma) silt and mudrock samples. By quantifying the Hg in each release phase for every sample, we find TOC concentration may determine ∼60% of the variability in the first (lower temperature) Hg TDP release phase: a stark difference with the total Hg released from these samples, where ∼20% of variation is explained by TOC variability. TDPs provide insight on sample‐level Hg speciation and demonstrate that, while the common assumption of single‐phase Hg speciation in sedimentary rocks is problematic, differences in Hg speciation can be detected, quantified, and accounted for using commonly applied techniques—opening potential for routine assessment.

Abstract INTRODUCTION Long‐term improvements in physical inactivity and other behavioral risk factors are integral to dementia risk reduction; however, sustained behavior change is challenging. Apathy, depression, and fatigue may impact engagement in health behaviors, but their presentation overlaps. This study investigates whether these symptoms are differentially associated with multiple health behaviors. METHODS In 1037 community‐dwelling older adults without dementia (aged 70–90, 55% women), regression analyses examined apathy, depression, and fatigue as predictors of health behaviors (physical activity, diet, alcohol, smoking) and a behavioral risk index. RESULTS Apathy was associated with reduced physical activity and alcohol use, and one or multiple behavioral risk factors. No or inconsistent relations were found between depression or fatigue and health behaviors. DISCUSSION Apathy is relevant to multiple health behaviors and should be considered when designing health promotion for older adults, including interventions for dementia risk reduction. Findings highlight the importance of distinguishing apathy from comorbid symptoms. Highlights Novel theory‐based perspective on behavioural risk factors for dementia. Higher apathy predicted less physical activity and alcohol use, and increased odds of lifestyle risk factors. Depressive symptoms were not associated with any health behavior. Apathy may be a determinant of multiple health behaviors in older adults, distinct from depression and fatigue. Considering apathy in precision prevention of dementia appears warranted.

Abstract Serpentinization is among the most important, and ubiquitous, geological processes in crustal–upper mantle conditions (

Abstract Butyrophilin 1A1 (BTN1A1) is implicated in the secretion of lipid droplets from mammary epithelial cells as a membrane receptor, which forms a secretion complex with the redox enzyme, xanthine oxidoreductase (XDH). The first evidence that BTN1A1 functions in this process was the generation of Btn1a1−/− mouse lines, in which lipid secretion was disrupted and large unstable droplets were released into alveolar spaces with fragmented surface membranes. We have revisited one of these mutant mouse lines using RNAseq and proteomic analysis to assess the consequences of ablating the Btn1a1 gene on the expression of other genes and proteins. Disruption of intact Btn1a1 protein expression led to a large build‐up of Xdh in the cytoplasm, induction of acute phase response genes and Lif‐activation of Stat3 phosphorylation. At peak lactation, approx. 10% of the cells were dying, as assessed by TUNEL‐analysis of nuclear DNA. Possible cell death pathways included expression of caspase 8 and activated caspase 3, autophagy, Slc5a8‐mediated inactivation of survivin (Birc5), and pStat3‐mediated lysosomal lysis, the latter of which is the principal death route in involuting wild type cells. Milk secretion was prolonged by renewal of the secretory epithelium, as evidenced by the upregulation of Ki67 in approx. 10% of cell nuclei and expression of cyclins and Fos/Jun. These data highlight the plasticity of the mammary epithelium and the importance of functional BTN1A1 expression for maintenance of terminally differentiated secretory cells and optimal milk production throughout lactation.

Abstract Background Community science is increasingly utilized to track important vectors of companion animal disease, providing a scalable, cost‐effective strategy for identifying new foci, changing phenology, and disease prevalence across wide geographies. Objectives We examined photographs of ticks found attached to predominately dogs and cats reported to a photograph‐based tick surveillance program to identify potential areas for improvements in tick prevention education and risk intervention. Methods We compared estimated days of tick attachment using a Kruskal–Wallis one‐way analysis of variance, and a Pearson's chi‐square analysis of variance on the number of submissions by host type submitted for each season. Results The blacklegged tick (Ixodes scapularis) was the most common species reported (39.8%). Tick photographs submitted were almost entirely adults (89.5%), and ticks found on companion animals exhibited an estimated median engorgement time of 2.5 days. Ixodes scapularis displayed the highest median engorgement of the top tick species found feeding on companion animals (χ2 = 98.96, p

Abstract Background The consequences for children born with birth defects and developmental disabilities encompassed by foetal alcohol spectrum disorder (FASD) are profound, affecting all areas of social, behavioural and cognitive functioning. Given the strong evidence for a core deficit in executive functioning, underpinned by impaired self‐regulation skills, there has been a growing focus on the development of interventions that enhance or support the development of executive functions (EFs). Objectives The primary objective of this review is to synthesise the evidence for structured psychological interventions that explicitly aim to improve EF in children. The review also sought to ascertain if the effectiveness of interventions were influenced by characteristics of the intervention, participants or type of EF targeted by the intervention. Search Methods Sixteen databases, 18 grey literature search locations and 9 trial registries were systematically searched to locate eligible studies (up to December 2020). These searches were supplemented with reference harvesting, forward citation searching, hand searches of topic‐relevant journals and contact with experts. Selection Criteria Studies were included in the review if they reported on an impact evaluation of a psychological intervention aiming to improve EF in children 3–16 years who either had confirmed prenatal alcohol exposure or a formal diagnosis falling under the umbrella term of FASDs. Eligible study designs included randomised controlled trials (RCTs) and quasi‐experimental designs with either no treatment, wait list control or an alternative treatment as a comparison condition. Single‐group pre‐post designs were also included. Data Collection and Analysis Standard methodological procedures expected by the Campbell Collaboration were used at all stages of this review. Standardised mean differences (SMDs) were used to estimate intervention effects, which were combined with random effects meta‐analysis (data permitting). Risk of bias was assessed using the Cochrane Risk of Bias Tool (RoB2) and Cochrane Risk of Bias in Non‐Randomised Studies‐Interventions tool (ROBINS‐I). Main Results The systematic search identified 3820 unique records. After title/abstract and full‐text screening, 11 eligible studies (reported in 21 eligible documents) were deemed eligible, with a combined 253 participants. Of the 11 studies, 6 were RCTs, 1 was a quasi‐experiment and 4 were single‐group pre‐post intervention designs. All studies were rated as having an overall high or serious risk of bias, with some variation across domains for RCTs. For RCT and quasi‐experimental studies, the overall effect of EF interventions on direct and indirect measures of EF generally favoured the experimental condition, but was not statistically significant. There was no difference between intervention and comparison groups on direct measures of auditory attention (k = 3; SMD = 0.06, 95% confidence interval [CI] = −1.06, 1.18), visual attention (k = 2; SMD = 0.90, 95% CI = −1.41, 3.21), cognitive flexibility (k = 2; SMD = 0.23, 95% CI = −0.40, 0.86), attentional inhibition (k = 2; SMD = 0.04, 95% CI = −0.58, 0.65), response inhibition (k = 3; SMD = 0.47, 95% CI = −0.04, 0.99), or verbal working memory (k = 1; d = 0.6827; 95% CI = −0.0196, 1.385). Significant heterogeneity was found across studies on measures of auditory attention and visual attention, but not for measures of cognitive flexibility, attentional inhibition or response inhibition. Available data prohibited further exploration of heterogeneity. There was no statistical difference between intervention and comparison groups on indirect measures of global executive functioning (k = 2; SMD = 0.21, 95% CI = −0.40, 0.82), behavioural regulation (k = 2; SMD = 0.18, 95% CI = −0.43, 0.79), or emotional control (k = 3; SMD = 0.01, 95% CI = −0.33, 0.36). Effect sizes were positive and not significant for meta‐cognition (k = 1; SMD = 0.23, 95% CI = −0.72, 1.19), shifting (k = 2; SMD = 0.04, 95% CI = −0.35, 0.43), initiation (k = 1; SMD = 0.04, 95% CI = −0.40, 0.49), monitoring (k = 1; SMD = 0.25, 95% CI = −0.20, 0.70) and organisation of materials (k = 1; SMD = 0.25, 95% CI = −0.19, 0.70). Effect sizes were negative and not statistically different for effortful control (k = 1; SMD = −0.53, 95% CI = −1.50, 0.45), inhibition (k = 2; SMD = −0.08, 95% CI = −0.47, 0.31), working memory (k = 1; SMD = 0.00, 95% CI = −0.45, 0.44), and planning and organisation (k = 1; SMD = −0.10, 95% CI = −0.55, 0.34). No statistically significant heterogeneity was found for any of the syntheses of indirect measures of EF. Based on pre‐post single‐group designs, there was evidence for small to medium sized improvements in EF based on direct measures (cognitive flexibility, verbal working memory and visual working memory) and indirect measures (behavioural regulation, shifting, inhibition and meta‐cognition). However, these results must be interpreted with caution due to high risk of bias. Authors' Conclusions This review found limited and uncertain evidence for the effectiveness of interventions for improving executive functioning in children with FASD across 8 direct and 13 indirect measures of EF. The findings are limited by the small number of high‐quality studies that could be synthesised by meta‐analysis and the very small sample sizes for the included studies.

Abstract Introduction Otitis media is an umbrella term for middle ear inflammation; ranging from acute infection to chronic mucosal disease. It is a leading cause of antimicrobial therapy prescriptions and surgery in children. Despite this, treatments have changed little in over 50 years. Research has been limited by the lack of physiological models of middle ear epithelium. Methods We develop a novel human middle ear epithelial culture using an air‐liquid interface (ALI) system; akin to the healthy ventilated middle ear in vivo. We validate this using immunohistochemistry, immunofluorescence, scanning and transmission electron microscopy, and membrane conductance studies. We also utilize this model to perform a pilot challenge of middle ear epithelial cells with SARS‐CoV‐2. Results We demonstrate that human middle ear epithelial cells cultured at an ALI undergo mucociliary differentiation to produce diverse epithelial subtypes including basal (p63+), goblet (MUC5AC+, MUC5B+), and ciliated (FOXJ1+) cells. Mature ciliagenesis is visualized and tight junction formation is shown with electron microscopy, and confirmed by membrane conductance. Together, these demonstrate this model reflects the complex epithelial cell types which exist in vivo. Following SARS‐CoV‐2 challenge, human middle ear epithelium shows positive viral uptake, as measured by polymerase chain reaction and immunohistochemistry. Conclusion We describe a novel physiological system to study the human middle ear. This can be utilized for translational research into middle ear diseases. We also demonstrate, for the first time under controlled conditions, that human middle ear epithelium is susceptible to SARS‐CoV‐2 infection, which has important clinical implications for safe otological surgery. Level of Evidence NA.

Metastatic neuroendocrine prostate cancer (NEPC) is a highly aggressive disease, whose incidence is rising. Long noncoding RNAs (lncRNAs) represent a large family of disease‐ and tissue‐specific transcripts, most of which are still functionally uncharacterized. Thus, we set out to identify the highly conserved lncRNAs that play a central role in NEPC pathogenesis. To this end, we performed transcriptomic analyses of donor‐matched patient‐derived xenograft models (PDXs) with immunohistologic features of prostate adenocarcinoma (AR+/PSA+) or NEPC (AR−/SYN+/CHGA+) and through differential expression analyses identified lncRNAs that were upregulated upon neuroendocrine transdifferentiation. These genes were prioritized for functional assessment based on the level of conservation in vertebrates. Here, LINC00261 emerged as the top gene with over 3229‐fold upregulation in NEPC. Consistently, LINC00261 expression was significantly upregulated in NEPC specimens in multiple patient cohorts. Knockdown of LINC00261 in PC‐3 cells dramatically attenuated its proliferative and metastatic abilities, which are explained by parallel downregulation of CBX2 and FOXA2 through distinct molecular mechanisms. In the cell cytoplasm, LINC00261 binds to and sequesters miR‐8485 from targeting the CBX2 mRNA, while inside the nucleus, LINC00261 functions as a transcriptional scaffold to induce SMAD‐driven expression of the FOXA2 gene. For the first time, these results demonstrate hyperactivation of the LINC00261‐CBX2‐FOXA2 axes in NEPC to drive proliferation and metastasis, and that LINC00261 may be utilized as a therapeutic target and a biomarker for this incurable disease.

The use of digital health products has gained considerable interest as a new way to improve therapeutic research and development. Although these products are being adopted by various industries and stakeholders, their incorporation in clinical trials has been slow due to a disconnect between the promises of digital products and potential risks in using these new technologies in the absence of regulatory support. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium hosted a public workshop to address challenges and opportunities in this field. Important characteristics of tool development were addressed in a series of presentations, case studies, and open panel sessions. The workshop participants endorsed the usefulness of an evidentiary criteria framework, highlighted the importance of early patient engagement, and emphasized the potential impact of digital monitoring tools and precompetitive collaborations. Concerns were expressed about the lack of real‐life validation examples and the limitations of legacy standards used as a benchmark for novel tool development and validation. Participants recognized the need for novel analytical and statistical approaches to accommodate analyses of these novel data types. Future directions are to harmonize definitions to build common methodologies and foster multidisciplinary collaborations; to develop approaches toward integrating digital monitoring data with the totality of the data in clinical trials, and to continue an open dialog in the community. There was a consensus that all these efforts combined may create a paradigm shift of how clinical trials are planned, conducted, and results brought to regulatory reviews.

Abstract Aims Perioperative blood transfusions are common among patients undergoing left ventricular assist device (LVAD) implantation. The association between blood product transfusion at the time of LVAD implantation and mortality has not been described. Methods and results This was a retrospective cohort study of all patients who underwent continuous flow LVAD implantation at a single, large, tertiary care, academic centre, from 2008 to 2014. We assessed used of packed red blood cells (pRBCs), platelets, and fresh frozen plasma (FFP). Outcomes of interest included all‐cause mortality and acute right ventricular (RV) failure. Standard regression techniques were used to examine the association between blood product exposure and outcomes of interest. A total of 170 patients were included in this study (mean age: 56.5 ± 15.5 years, 79.4% men). Over a median follow‐up period of 11.2 months, for every unit of pRBC transfused, the hazard for mortality increased by 4% [hazard ratio (HR) 1.04; 95% CI 1.02–1.07] and odds for acute RV failure increased by 10% (odds ratio 1.10; 95% CI 1.05–1.16). This association persisted for other blood products including platelets (HR for mortality per unit 1.20; 95% CI 1.08–1.32) and FFP (HR for mortality per unit 1.08; 95% CI 1.04–1.12). The most significant predictor of perioperative blood product exposure was a lower pre‐implant haemoglobin. Conclusions Perioperative blood transfusions among patients undergoing LVAD implantation were associated with a higher risk for all‐cause mortality and acute RV failure. Of all blood products, FFP use was associated with worst outcomes. Future studies are needed to evaluate whether pre‐implant interventions, such as intravenous iron supplementation, will improve the outcomes of LVAD candidates by decreasing need for transfusions.

Abstract Aims The recent coronavirus disease 19 (COVID‐19) pandemic outbreak forced the adoption of restraint measures, which modified the hospital admission patterns for several diseases. The aim of the study is to investigate the rate of hospital admissions for heart failure (HF) during the early days of the COVID‐19 outbreak in Italy, compared with a corresponding period during the previous year and an earlier period during the same year. Methods and results We performed a retrospective analysis on HF admissions number at eight hospitals in Italy throughout the study period (21 February to 31 March 2020), compared with an inter‐year period (21 February to 31 March 2019) and an intra‐year period (1 January to 20 February 2020). The primary outcome was the overall rate of hospital admissions for HF. A total of 505 HF patients were included in this survey: 112 during the case period, 201 during intra‐year period, and 192 during inter‐year period. The mean admission rate during the case period was 2.80 admissions per day, significantly lower compared with intra‐year period (3.94 admissions per day; incidence rate ratio, 0.71; 95% confidence interval [CI], 0.56–0.89; P = 0.0037), or with inter‐year (4.92 admissions per day; incidence rate ratio, 0.57; 95% confidence interval, 0.45–0.72; P

Abstract A common goal of population genomics and molecular ecology is to reconstruct the demographic history of a species of interest. A pair of powerful tools based on the sequentially Markovian coalescent have been developed to infer past population sizes using genome sequences. These methods are most useful when sequences are available for only a limited number of genomes and when the aim is to study ancient demographic events. The results of these analyses can be difficult to interpret accurately, because doing so requires some understanding of their theoretical basis and of their sensitivity to confounding factors. In this practical review, we explain some of the key concepts underpinning the pairwise and multiple sequentially Markovian coalescent methods (PSMC and MSMC, respectively). We relate these concepts to the use and interpretation of these methods, and we explain how the choice of different parameter values by the user can affect the accuracy and precision of the inferences. Based on our survey of 100 PSMC studies and 30 MSMC studies, we describe how the two methods are used in practice. Readers of this article will become familiar with the principles, practice, and interpretation of the sequentially Markovian coalescent for inferring demographic history.

Prostate cancer (PCa) is driven by the androgen receptor (AR)‐signaling axis. Hormonal therapy often mitigates PCa progression, but a notable number of cases progress to castration‐resistant PCa (CRPC). CRPC retains AR activity and is incurable. Long noncoding RNA (lncRNA) represent an uncharted region of the transcriptome. Several lncRNA have been recently described to mediate oncogenic functions, suggesting that these molecules can be potential therapeutic targets. Here, we identified CRPC‐associated lncRNA by analyzing patient‐derived xenografts (PDXs) and clinical data. Subsequently, we characterized one of the CRPC‐promoting lncRNA, HORAS5, in vitro and in vivo. We demonstrated that HORAS5 is a stable, cytoplasmic lncRNA that promotes CRPC proliferation and survival by maintaining AR activity under androgen‐depleted conditions. Most strikingly, knockdown of HORAS5 causes a significant reduction in the expression of AR itself and oncogenic AR targets such as KIAA0101. Elevated expression of HORAS5 is also associated with worse clinical outcomes in patients. Our results from HORAS5 inhibition in in vivo models further confirm that HORAS5 is a viable therapeutic target for CRPC. Thus, we posit that HORAS5 is a novel, targetable mediator of CRPC through its essential role in the maintenance of oncogenic AR activity. Overall, this study adds to our mechanistic understanding of how lncRNA function in cancer progression.

Abstract This review aims to first enhance and update existing reviews by comprehensively synthesising the full array of psychosocial, pharmacological and legal interventions that aim to improve the psychosocial outcomes of children with substance misusing parents. Second, the review aims to use network meta‐analysis to integrate and examine the comparative impact of these interventions. Specifically, the review will address the following research questions: (1) What is the comparative impact of psychosocial, pharmacological, and legal interventions for improving the psychosocial outcomes of children with substance misusing parents? (2) Does the impact of interventions vary according to the child developmental period (e.g., infancy, early childhood, adolescence) or the type of (a) outcome measure; (b) substance misuse; (c) practitioner implementing the intervention; or (d) intervention setting? (3) Does the impact of interventions vary by the country of implementation?