Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML.

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.

Spatial transcriptomics reveal neuron-astrocyte synergy in long-term memory.

Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala is a centre of salience networks that underlie emotional experiences and thus has a key role in long-term fear memory formation1. Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide and BDNF signalling, MAPK and CREB activation, ubiquitination pathways, and synaptic connectivity as key components of long-term memory. Notably, upon long-term memory formation, a neuronal subpopulation defined by increased Penk and decreased Tac expression constituted the most prominent component of the memory engram of the basolateral amygdala. These transcriptional changes were observed both with single-cell RNA sequencing and with single-molecule spatial transcriptomics in intact slices, thereby providing a rich spatial map of a memory engram. The spatial data enabled us to determine that this neuronal subpopulation interacts with adjacent astrocytes, and functional experiments show that neurons require interactions with astrocytes to encode long-term memory.

Successful kinetic impact into an asteroid for planetary defence.

Although no known asteroid poses a threat to Earth for at least the next century, the catalogue of near-Earth asteroids is incomplete for objects whose impacts would produce regional devastation1,2. Several approaches have been proposed to potentially prevent an asteroid impact with Earth by deflecting or disrupting an asteroid1-3. A test of kinetic impact technology was identified as the highest-priority space mission related to asteroid mitigation1. NASA's Double Asteroid Redirection Test (DART) mission is a full-scale test of kinetic impact technology. The mission's target asteroid was Dimorphos, the secondary member of the S-type binary near-Earth asteroid (65803) Didymos. This binary asteroid system was chosen to enable ground-based telescopes to quantify the asteroid deflection caused by the impact of the DART spacecraft4. Although past missions have utilized impactors to investigate the properties of small bodies5,6, those earlier missions were not intended to deflect their targets and did not achieve measurable deflections. Here we report the DART spacecraft's autonomous kinetic impact into Dimorphos and reconstruct the impact event, including the timeline leading to impact, the location and nature of the DART impact site, and the size and shape of Dimorphos. The successful impact of the DART spacecraft with Dimorphos and the resulting change in the orbit of Dimorphos7 demonstrates that kinetic impactor technology is a viable technique to potentially defend Earth if necessary.

A human brain vascular atlas reveals diverse mediators of Alzheimer's risk.

The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.

Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER-mitochondria-associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance.

Persistent transcriptional programmes are associated with remote memory.

The role of gene expression during learning and in short-term memories has been studied extensively1-3, but less is known about remote memories, which can persist for a lifetime4. Here we used long-term contextual fear memory as a paradigm to probe the single-cell gene expression landscape that underlies remote memory storage in the medial prefrontal cortex. We found persistent activity-specific transcriptional alterations in diverse populations of neurons that lasted for weeks after fear learning. Out of a vast plasticity-coding space, we identified genes associated with membrane fusion that could have important roles in the maintenance of remote memory. Unexpectedly, astrocytes and microglia also acquired persistent gene expression signatures that were associated with remote memory, suggesting that they actively contribute to memory circuits. The discovery of gene expression programmes associated with remote memory engrams adds an important dimension of activity-dependent cellular states to existing brain taxonomy atlases and sheds light on the elusive mechanisms of remote memory storage.

Physiological blood-brain transport is impaired with age by a shift in transcytosis.

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

Immediate smoking cessation support during lung cancer screening: long-term outcomes from two randomised controlled trials.

BACKGROUND: Immediate smoking cessation interventions delivered alongside targeted lung health checks (TLHCs) to screen for lung cancer increase self-reported abstinence at 3 months. The impact on longer term, objectively confirmed quit rates remains to be established. METHODS: We followed up participants from two clinical trials in people aged 55-75 years who smoked and took part in a TLHC. These randomised participants in the TLHC by day of attendance to either usual care (UC) (signposting to smoking cessation services) or an offer of immediate smoking cessation support including pharmacotherapy. In the QuLIT1 trial, this was delivered face to face and in QuLIT2, it was delivered remotely. Follow-up was conducted 12 months after the TLHC by telephone interview with subsequent biochemical verification of smoking cessation using exhaled CO. RESULTS: 430 people were enrolled initially (115 in QuLIT1 and 315 in QuLIT2), with 4 deaths before 12 months leaving 426 (62.1±5.27 years old and 48% women) participants for analysis. At 12 months, those randomised to attend on smoking cessation support intervention days had higher quit rates compared with UC adjusted for age, gender, deprivation, and which trial they had been in; self-reported 7-day point prevalence (20.0% vs 12.8%; adjusted OR (AOR)=1.78; 95% CI 1.04 to 2.89) and CO-verified quits (12.1% vs 4.7%; AOR=2.97; 95% CI 1.38 to 6.90). Those in the intervention arm were also more likely to report having made a quit attempt (30.2% vs UC 18.5%; AOR 1.90; 95% CI 1.15 to 3.15). CONCLUSION: Providing immediate smoking cessation support alongside TLHC increases long term, biochemically confirmed smoking abstinence. TRIAL REGISTRATION NUMBER: ISRCTN12455871.

Passivating the Background of Living Microbes with a Zwitterionic Peptide for Therapies.

Living microbial therapies have been proposed as a course of action for a variety of diseases. However, problematic interactions between the host immune system and the microbial organism present significant clinical concerns. Previously, we developed a genetically encoded superhydrophilic zwitterionic peptide, termed EKP, to mimic low-immunogenic zwitterionic materials, which have been used for the chemical modification of biologics such as protein and nucleic acid drugs to increase their in vivo circulation time and reduce their immunogenicity. Herein, we demonstrate the protective effects of the EKP polypeptide genetically cloaking the surface of Saccharomyces cerevisiae as a model microbe in both in vitro and in vivo systems. First, we show that EKP peptide cloaking suppresses the interactions between yeast cells and their specific antibodies, thereby illustrating its cloaking behavior. Then, we examine the in vitro interactions between EKP peptide surface cloaked yeast cells and murine macrophage cells, which exhibit phagocytotic behavior in the presence of foreign microbes. Our results indicate that EKP cloaking suppresses macrophage interactions and thus reduces phagocytosis. Furthermore, EKP cloaked yeast cells demonstrate a prolonged circulation time in mice in vivo.

High Heart Rate Variability Buffers the Effect of Attachment Insecurity on Sleep Quality.

OBJECTIVE: Sleep quality is an important health-protective factor. Psychosocial factors, including attachment orientation, may be valuable for understanding who is at risk of poor sleep quality and associated adverse health outcomes. High attachment anxiety is reliably associated with adverse health outcomes, whereas high attachment avoidance is associated with adverse health outcomes when co-occurring with poor self-regulatory capacity, indexed by heart rate variability (HRV). We examined the associations between attachment anxiety, attachment avoidance, HRV, and sleep quality. METHODS: Using longitudinal data from a sample of 171 older adults measured four times over 1 year ( M = 66.18 years old; 67.83% women), we separated the between-person variance (which we call "trait") and within-person variance (which we call "state") for attachment anxiety, attachment avoidance, and HRV (via the root mean square of successive differences). Sleep quality was measured with the Pittsburgh Sleep Quality Index. RESULTS: Higher trait attachment anxiety was associated with poorer global sleep quality ( B = 0.22, p = .005). Higher state attachment avoidance was associated with poorer sleep quality ( B = -0.13, p = .01), except for those with higher trait HRV. Higher state attachment anxiety was associated with poorer sleep quality ( B = -0.15, p = .002), except for those with higher or mean trait HRV. Higher trait attachment anxiety was associated with poorer sleep quality ( B = -0.31, p = .02), except for those with higher trait HRV. CONCLUSIONS: High trait HRV mitigated the adverse effects of attachment insecurity on sleep quality. Our results suggest that people with high trait HRV had greater self-regulation capacity, which may enable them to enact emotion regulation strategies effectively.

Applying Artificial Intelligence to Identify Common Targets for Treatment of Asthma, Eczema, and Food Allergy.

INTRODUCTION: Allergic disorders are common diseases marked by the abnormal immune response toward foreign antigens that are not pathogens. Often patients with food allergy also suffer from asthma and eczema. Given the similarities of these diseases and a shortage of effective treatments, developing novel therapeutics against common targets of multiple allergies would offer an efficient and cost-effective treatment for patients. METHODS: We employed the artificial intelligence-driven target discovery platform, PandaOmics, to identify common targets for treating asthma, eczema, and food allergy. Thirty-two case-control comparisons were generated from 15, 11, and 6 transcriptomics datasets related to asthma (558 cases, 315 controls), eczema (441 cases, 371 controls), and food allergy (208 cases, 106 controls), respectively, and allocated into three meta-analyses for target identification. Top-100 high-confidence targets and Top-100 novel targets were prioritized by PandaOmics for each allergic disease. RESULTS: Six common high-confidence targets (i.e., IL4R, IL5, JAK1, JAK2, JAK3, and NR3C1) across all three allergic diseases have approved drugs for treating asthma and eczema. Based on the targets' dysregulated expression profiles and their mechanism of action in allergic diseases, three potential therapeutic targets were proposed. IL5 was selected as a high-confidence target due to its strong involvement in allergies. PTAFR was identified for drug repurposing, while RNF19B was selected as a novel target for therapeutic innovation. Analysis of the dysregulated pathways commonly identified across asthma, eczema, and food allergy revealed the well-characterized disease signature and novel biological processes that may underlie the pathophysiology of allergies. CONCLUSION: Altogether, our study dissects the shared pathophysiology of allergic disorders and reveals the power of artificial intelligence in the exploration of novel therapeutic targets.

Reflections on resilience.

Resilience research has long sought to understand how factors at the child, family, school, community, and societal levels shape adaptation in the face of adversities such as poverty and war. In this article we reflect on three themes that may prove to be useful for future resilience research. First is the idea that mental and physical health can sometimes diverge, even in response to the same social process. A better understanding of explanations for this divergence will have both theoretical and public health implications when it comes to efforts to promote resilience. Second is that more recent models of stress suggest that stress can accelerate aging. Thus, we suggest that research on resilience may need to also consider how resilience strategies may need to be developed in an accelerated fashion to be effective. Third, we suggest that if psychological resilience interventions can be conducted in conjunction with efforts to enact system-level changes targeted at adversities, this may synergize the impact that any single intervention can have, creating a more coordinated and effective set of approaches for promoting resilience in young people who confront adversity in life.

Mass spectrometric identification of immunogenic SARS-CoV-2 epitopes and cognate TCRs.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections elicit both humoral and cellular immune responses. For the prevention and treatment of COVID-19, the disease caused by SARS-CoV-2, it has become increasingly apparent that T cell responses are equally if not more important than humoral responses in mediating recovery and immune protection. One major challenge in developing T cell-based therapies for infectious and malignant diseases has been the identification of immunogenic epitopes that can elicit a meaningful T cell response. Traditionally, this has been achieved using sophisticated in silico methods to predict putative epitopes deduced from binding affinities. Our studies find that, in contrast to current convention, "immunodominant" SARS-CoV-2 peptides defined by such in silico methods often fail to elicit T cell responses recognizing naturally presented SARS-CoV-2 epitopes. We postulated that immunogenic epitopes for SARS-CoV-2 are best defined empirically by directly analyzing peptides eluted from the naturally processed peptide-major histocompatibility complex (MHC) and then validating immunogenicity by determining whether such peptides can elicit T cells recognizing SARS-CoV-2 antigen-expressing cells. Using a tandem mass spectrometry approach, we identified epitopes derived from not only structural but also nonstructural genes in regions highly conserved among SARS-CoV-2 strains, including recently recognized variants. Finally, there are no reported T cell receptor-engineered T cell technology that can redirect T cell specificity to recognize and kill SARS-CoV-2 target cells. We report here several SARS-CoV-2 epitopes defined by mass spectrometric analysis of MHC-eluted peptides, provide empiric evidence for their immunogenicity, and demonstrate engineered TCR-redirected killing.

Biologics for inherited disorders of keratinisation: A systematic review.

BACKGROUND/OBJECTIVES: Recent literature highlights the potential of biologics in the management of inherited disorders of keratinisation. In this study, we conducted a systematic review of existing literature on treatment outcomes of inherited keratinisation disorders treated with biologics. METHODS: Eligible records were retrieved through searches of the electronic databases MEDLINE, Embase, PubMed and Scopus. Databases were searched from inception to July 2023 for eligible records. A snowballing method was employed to search the references of the retrieved records for the identification of potentially relevant articles. RESULTS: One hundred and four eligible studies consisting of a total of 166 patients with an inherited disorder of keratinisation were included. Patients had a median age of 19 years (range: 0.5 to 70 years). The most common disorders were Netherton syndrome (n = 63; 38%), autosomal recessive congenital ichthyoses (n = 27; 16%), CARD14-associated papulosquamous eruptions (n = 17; 10%) and familial pityriasis rubra pilaris (PRP) (n = 15; 9%).Of the 207 times biologics were employed, the three most frequently employed biologics were secukinumab (n = 47; 23%), dupilumab (n = 44; 21%) and ustekinumab (n = 37; 18%). Complete remission was observed in 10 (5%) instances, partial remission in 129 (62%), no or limited response to biologic therapy in 68 (32%) cases, and results are still pending in one case. A total of 33 adverse events were reported. CONCLUSIONS: Whilst biologics may be considered in cases of inherited keratinisation disorders recalcitrant to standard therapy, definitive conclusions are prohibited by the low-level of evidence and substantial heterogeneity in methodology across the included studies. Establishment of consensus definitions, and randomised clinical trials may help ascertain the efficacy and safety of biologic therapy in this context and establish the best agent and dosing protocol for each disorder.

Clinical Performance of Technetium-99m-Sestamibi SPECT/CT Imaging in Differentiating Oncocytic Tumors From Renal Cell Carcinoma in Routine Clinical Practice.

PURPOSE: Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data from a large institutional cohort of patients who underwent technetium-99m-sestamibi scans during evaluation of renal masses. MATERIALS AND METHODS: Patients who underwent technetium-99m-sestamibi single-photon emission CT/x-ray CT between February 2020 and December 2021 were included in the analysis. Scans were defined as "hot" for oncocytic tumor when technetium-99m-sestamibi uptake was qualitatively equivalent or higher between the mass of interest and normal renal parenchyma, suggesting oncocytoma, hybrid oncocytic/chromophobe tumor, or chromophobe renal cell carcinoma. Demographic, pathological, and management strategy data were compared between "hot" and "cold" scans. For individuals who underwent diagnostic biopsy or extirpative procedures, the concordance between radiological findings and pathology was indexed. RESULTS: A total of 71 patients (with 88 masses) underwent technetium-99m-sestamibi imaging with 60 (84.5%) patients having at least 1 "cold" mass on imaging and 11 (15.5%) patients exhibiting only "hot" masses. Pathology was available for 7 "hot" masses, with 1 biopsy specimen (14.3%) being discordant (clear cell renal cell carcinoma). Five patients with "cold" masses underwent biopsy. Out of 5 biopsied masses, 4 (80%) were discordant oncocytomas. Of the extirpated specimens, 35/40 (87.5%) harbored renal cell carcinoma and 5/40 (12.5%) yielded discordant oncocytomas. In sum, 20% of pathologically sampled masses that were "cold" on technetium-99m-sestamibi imaging still harbored oncocytoma/hybrid oncocytic/chromophobe tumor/chromophobe renal cell carcinoma. CONCLUSIONS: Further work is needed to define utility of technetium-99m-sestamibi in real-world clinical practice. Our data suggest this imaging strategy is not yet ready to replace biopsy.

Minimally Invasive Surgery in the United States, 2022: Understanding Its Value Using New Datasets.

INTRODUCTION: While minimally invasive surgery (MIS) has transformed the treatment landscape of surgical care, its utilization is not well understood. The newly released Nationwide Ambulatory Surgery Sample allows for more accurate estimates of MIS volume in the United States-in combination with inpatient datasets. MATERIALS AND METHODS: Multiple nationwide databases from the Healthcare Cost and Utilization Project (HCUP) were used: the Nationwide Ambulatory Surgery Sample and National Inpatient Sample. The volume of MIS and robotic procedures were calculated from 2016 to 2018. An online query system, HCUPNet, was queried for inpatient stays from 1993 to 2014. RESULTS: In 2017, 9.8 million inpatient major operating room procedures were analyzed, of which 11.1% were MIS and 2.5% were robotic-assisted, compared with 9.6 million inpatient operating room procedures (11.2% MIS and 2.9% robotic-assisted) in 2018. There were 10.6, 10.6, and 10.7 million ambulatory procedures in 2016, 2017, and 2018, respectively. Ambulatory MIS procedures showed an increasing trend across years, representing 16.9%, 17.4%, and 18%, respectively. HCUPNet data revealed an increase in inpatient MIS cases from 529,811 (8.9%) in 1993 to 1,443,446 (20.7%) in 2014. CONCLUSIONS: This study is the first to estimate national MIS volume across specialties in both inpatient and ambulatory hospital settings. We found a trend toward a higher proportion of MIS and robotic cases from 1997 to 2018. These data may help contribute to a more comprehensive understanding of MIS value within surgery and highlight limitations of current databases, especially when categorizing robotic cases on a national scale.

Resilience in children with chronic illness: Tests of the shift-and-persist and skin-deep resilience theories.

This study investigated, and discusses the integration of, the shift-and-persist (SAP) and skin-deep resilience (SDR) theories. The SAP theory states that the combination of shifting (adjusting oneself to stressful situations through strategies like emotion regulation) and persisting (enduring adversity with strength by finding meaning and maintaining optimism) will be beneficial to physical health in children experiencing adversity. The SDR theory states that high striving/self-control will be beneficial to mental health but detrimental to physical health among those confronting adversity. This study investigated 308 children ages 8-17 experiencing the adversity of a chronic illness (asthma). SAP and SDR (striving/self-control) were assessed via questionnaires, and physical health (asthma symptoms, inflammatory profiles), mental health (anxiety/depression, emotional functioning), and behavioral (medication adherence, activity limitations, collaborative relationships with providers) outcomes were measured cross-sectionally. SAP was associated with better physical health, whereas SDR was associated with worse physical health. Both were associated with better mental health. Only SDR was associated with better behavioral outcomes. Implications of findings and discussion of how to integrate these theories are provided. We suggest that future interventions might seek to cultivate both SAP and SDR to promote overall better health and well-being across multiple domains in children experiencing adversity.

Preliminary construct validity of a memory concerns scale derived from a PROMIS® item bank in a spanish-speaking sample.

This study examined preliminary evidence of construct validity in a stand-alone memory concerns scale constructed from the Patient-Reported Outcomes Measurement Information System (PROMIS®) Cognitive Function item bank. A sample of 396 individuals, ages 18-75 (M = 33.7, SD = 12.7), from Spain and Latin America completed an online survey regarding lifetime exposure to factors associated with neurological compromise. The sample was 69.4% female. Respondents completed 8 items from the PROMIS® Cognitive Function item bank v1.0 dealing with memory concerns (MCS-8) along with the PROMIS® 8-item short form reflecting general cognitive concerns (CCS-8). The MCS-8 had high internal consistency reliability (Cronbach's alpha = 0.90), and represented a factor distinct from general cognitive concerns items on the CCS-8 in confirmatory factor analysis. Analysis of covariance controlling for sex, age, and education, showed that individuals endorsing history of exposure to sources of neurological compromise scored significantly lower T-scores on the MCS-8 than those who did not report any such history, F(1,390) = 6.4, p = 0.012. Older age was significantly associated with greater memory concerns, a relationship with age not observed with the CCS-8. As a stand-alone self-report measure, the MCS-8 appears to measure a construct distinct from general cognitive concerns that may be of interest for further research in clinical populations.

The appendix in endometriosis.

BACKGROUND: In the most severe stage of endometriosis, Stage IV, intestinal involvement is common. The true prevalence of endometriotic disease of the appendix in this population is not well described. A macroscopically normal looking appendix may harbour endometriosis. AIMS: Our study aims to assess the role of routinely performing appendicectomy in Stage IV endometriosis surgery, and the histopathological prevalence of true appendiceal endometriosis in this population. METHODS: This is a retrospective study of women undergoing surgery for Stage IV endometriosis between 2018 to 2022 in a tertiary public hospital in New South Wales, Australia. Patient demographics, age and post-operative complications were retrospectively retrieved from hospital medical records. Inclusion criteria were women with Stage IV endometriosis who underwent routine appendicectomy as part of their endometriosis surgery. Exclusion criteria were women who did not have Stage IV endometriosis, those who had cancer surgery or emergency surgery for endometriosis. The primary outcome of this study was to determine the incidence of appendiceal endometriosis. Secondary outcomes included post-operative complications and length of stay. RESULTS: Sixty-seven patients were included. The mean age was 36 years. All patients also underwent bowel resection for colorectal endometriosis. There were 35.8% who had confirmed appendiceal endometriosis on histopathology. Post-operative complications included port site infections, colitis, urinary tract infection and ureteric injury. There were no complications related to appendicectomy. Mean length of stay was 4.4 days. CONCLUSION: Laparoscopic appendicectomy can be safely performed at time of laparoscopic surgical excision of Stage IV endometriosis and should be routinely considered in a subset of Stage IV endometriosis patients with colorectal involvement undergoing surgery.

A Gentle Introduction to Bayesian Network Meta-Analysis Using an Automated R Package.

Network meta-analysis is an extension of standard meta-analysis. It allows researchers to build a network of evidence to compare multiple interventions that may have not been compared directly in existing publications. With a Bayesian approach, network meta-analysis can be used to obtain a posterior probability distribution of all the relative treatment effects, which allows for the estimation of relative treatment effects to quantify the uncertainty of parameter estimates, and to rank all the treatments in the network. Ranking treatments using both direct and indirect evidence can provide guidance to policy makers and clinicians for making decisions. The purpose of this paper is to introduce fundamental concepts of Bayesian network meta-analysis (BNMA) to researchers in psychology and social sciences. We discuss several essential concepts of BNMA, including the assumptions of homogeneity and consistency, the fixed and random effects models, prior specification, and model fit evaluation strategies, while pointing out some issues and areas where researchers should use caution in the application of BNMA. Additionally, using an automated R package, we provide a step-by-step demonstration on how to conduct and report the findings of BNMA with a real dataset of psychological interventions extracted from PubMed.