New Guinea has the world's richest island flora.

New Guinea is the world's largest tropical island and has fascinated naturalists for centuries1,2. Home to some of the best-preserved ecosystems on the planet3 and to intact ecological gradients-from mangroves to tropical alpine grasslands-that are unmatched in the Asia-Pacific region4,5, it is a globally recognized centre of biological and cultural diversity6,7. So far, however, there has been no attempt to critically catalogue the entire vascular plant diversity of New Guinea. Here we present the first, to our knowledge, expert-verified checklist of the vascular plants of mainland New Guinea and surrounding islands. Our publicly available checklist includes 13,634 species (68% endemic), 1,742 genera and 264 families-suggesting that New Guinea is the most floristically diverse island in the world. Expert knowledge is essential for building checklists in the digital era: reliance on online taxonomic resources alone would have inflated species counts by 22%. Species discovery shows no sign of levelling off, and we discuss steps to accelerate botanical research in the 'Last Unknown'8.

A Common Variant in the Adaptor Mal Regulates Interferon Gamma Signaling.

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.

A Toolkit for Delirium Identification and Promoting Partnerships Between Carers and Nurses: A Pilot Pre-Post Feasibility Study.

BACKGROUND: Delirium is frightening for people experiencing it and their carers, and it is the most common hospital-acquired complication worldwide. Delirium is associated with higher rates of morbidity, mortality, residential care home admission, dementia, and carer stress and burden, yet strategies to embed the prevention and management of delirium as part of standard hospital care remain challenging. Carers are well placed to recognize subtle changes indicative of delirium, and partner with nurses in the prevention and management of delirium. OBJECTIVE: To evaluate a Prevention & Early Delirium Identification Carer Toolkit (PREDICT), to support partnerships between carers and nurses to prevent and manage delirium. DESIGN: A pre-post-test intervention and observation study. MAIN MEASURES: Changes in carer knowledge of delirium; beliefs about their role in partnering with nurses and intended and actual use of PREDICT; carer burden and psychological distress. Secondary measures were rates of delirium. PARTICIPANTS: Participants were carers of Indigenous patients aged 45 years and older and non-Indigenous patients aged 65 years and older. INTERVENTION: Nurses implemented PREDICT, with a view to provide carers with information about delirium and strategies to address caregiving stress and burden. KEY RESULTS: Participants included 25 carers (43% response rate) (n = 17, 68% female) aged 29-88 (M = 65, SD = 17.7 years). Carer delirium knowledge increased significantly from pre-to-post intervention (p = < .001; CI 2.07-4.73). Carers' intent and actual use of PREDICT was (n = 18, 72%; and n = 17, 68%). Carer burden and psychological distress did not significantly change. The incidence of delirium in the intervention ward although not significant, decreased, indicating opportunity for scaling up. CONCLUSION: The prevention and management of delirium are imperative for safe and quality care for patients, carers, and staff. Further comprehensive and in-depth research is required to better understand underlying mechanisms of change and explore facets of nursing practice influenced by this innovative approach.

Validating the safety of low-dose CTPA in pregnancy: results from the OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) Study.

BACKGROUND: Pulmonary embolism (PE) is a leading cause of pregnancy-related mortality. CT pulmonary angiogram (CTPA) is the first-line advanced imaging modality for suspected PE in pregnancy at institutes offering low-dose techniques; however, a protocol balancing safety with low dose remains undefined. The wide range of CTPA doses reported in pregnancy suggests a lack of confidence in implementing low-dose techniques in this group. PURPOSE: To define and validate the safety, radiation dose and image quality of a low-dose CTPA protocol optimised for pregnancy. MATERIALS AND METHODS: The OPTICA study is a prospective observational study. Pregnant study participants with suspected PE underwent the same CTPA protocol between May 2018 and February 2022. The primary outcome, CTPA safety, was judged by the reference standard; the 3-month incidence of venous thromboembolism (VTE) in study participants with a negative index CTPA. Secondary outcomes defined radiation dose and image quality. Absorbed breast, maternal effective and fetal doses were estimated by Monte-Carlo simulation on gestation-matched phantoms. Image quality was assessed by signal-to-noise and contrast-to-noise ratios and a Likert score for pulmonary arterial enhancement. RESULTS: A total of 116 CTPAs were performed in 113 pregnant women of which 16 CTPAs were excluded. PE was diagnosed on 1 CTPA and out-ruled in 99. The incidence of recurrent symptomatic VTE was 0.0% (one-sided 95% CI, 2.66%) at follow-up. The mean absorbed breast dose was 2.9 ± 2.1mGy, uterine/fetal dose was 0.1 ± 0.2mGy and maternal effective dose was 1.4 ± 0.9mSv. Signal-to-noise ratio (SNR) was 11.9 ± 3.7. Contrast-to-noise ratio (CNR) was 10.4 ± 3.5. CONCLUSION: The OPTICA CTPA protocol safely excluded PE in pregnant women across all trimesters, with low fetal and maternal radiation. CLINICAL RELEVANCE: OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) is the first prospective study to define the achievable radiation dose, image-quality and safety of a low-dose CT pulmonary angiogram protocol optimised for pregnancy (NCT04179487). It provides the current benchmark for safe and achievable CT pulmonary angiogram doses in the pregnant population. KEY POINTS: • Despite the increased use of CT pulmonary angiogram in pregnancy, an optimised low-dose protocol has not been defined and reported doses in pregnancy continue to vary widely. • The OPTICA (Optimised CT Pulmonary Angiography in Pregnancy) study prospectively defines the achievable dose, image quality and safety of a low-dose CT pulmonary angiogram protocol using widely available technology. • OPTICA provides a benchmark for safe and achievable CT pulmonary angiogram doses in the pregnant population.

Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.

The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.

Repair of lateral temporo-sphenoidal encephalocoele via an endoscopic transorbital approach: ex vivo 3D printed simulation followed by in vivo deployment.

BACKGROUND: A temporo-sphenoidal encephalocoele occurs when temporal lobe herniates through a defect in the greater wing of the sphenoid bone into the sphenoid air sinus. The natural history is not well-understood, though presentation in adulthood with CSF rhinorrhoea and/or meningitis is typical. Lateral pneumatisation of the sphenoid sinus and elevated BMI may be contributory. AIMS: We explored the feasibility of a transorbital approach (TOA) for repair, using a combination of 3D modelling and simulation. We then successfully deployed this technique in vivo. METHODS: CT imaging for three patients who had previously undergone transcranial repair of lateral temporo-sphenoidal encephalocoele was used to generate data allowing 3D printed models of the skull base to be produced. The transorbital approach was simulated by performing a lateral orbitotomy followed by drilling of the sphenoid wing to expose the antero-basal middle fossa. 3D object scanning was used to create virtual models of the skull base post-surgery, from which surgical access was quantified in two ways: the area (mm2) of the middle fossa exposed by the TOA and the vertical attack angle. RESULTS: The mean surface area of the cranial access window achieved by simulated TOA was 325mm2. The mean vertical attack angle was 25°. One patient was subsequently treated successfully via TOA with no recurrence of their CSF leak, no orbital morbidity, excellent cosmesis, but resolving V2 numbness (follow-up 7 months). CONCLUSIONS: We have shown that the transorbital approach provides adequate surgical access. In our single case, surgical repair of a lateral temporo-sphenoidal encephalocoele via TOA was feasible, safe, and effective. This approach may offer some advantages compared with transcranial or endonasal approaches.

Potassium Supplementation and Prevention of Atrial Fibrillation After Cardiac Surgery: The TIGHT K Randomized Clinical Trial.

IMPORTANCE: Supplementing potassium in an effort to maintain high-normal serum concentrations is a widespread strategy used to prevent atrial fibrillation after cardiac surgery (AFACS), but is not evidence-based, carries risks, and is costly. OBJECTIVE: To determine whether a lower serum potassium concentration trigger for supplementation is noninferior to a high-normal trigger. DESIGN, SETTING, AND PARTICIPANTS: This open-label, noninferiority, randomized clinical trial was conducted at 23 cardiac surgical centers in the United Kingdom and Germany. Between October 20, 2020, and November 16, 2023, patients with no history of atrial dysrhythmias scheduled for isolated coronary artery bypass grafting (CABG) surgery were enrolled. The last study patient was discharged from the hospital on December 11, 2023. INTERVENTIONS: Patients were randomly assigned to a strategy of tight or relaxed potassium control (only supplementing if serum potassium concentration fell below 4.5 mEq/L or 3.6 mEq/L, respectively). Patients wore an ambulatory heart rhythm monitor, which was analyzed by a core laboratory masked to treatment assignment. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was clinically detected and electrocardiographically confirmed new-onset AFACS in the first 120 hours after CABG surgery or until hospital discharge, whichever occurred first. All primary outcome events were validated by an event validation committee, which was masked to treatment assignment. Noninferiority of relaxed potassium control was defined as a risk difference for new-onset AFACS with associated upper bound of a 1-sided 97.5% CI of less than 10%. Secondary outcomes included other heart rhythm-related events, clinical outcomes, and cost related to the intervention. RESULTS: A total of 1690 patients (mean age, 65 years; 256 [15%] females) were randomized. The primary end point occurred in 26.2% of patients (n = 219) in the tight group and 27.8% of patients (n = 231) in the relaxed group, which is a risk difference of 1.7% (95% CI, -2.6% to 5.9%). There was no difference between the groups in the incidence of at least 1 AFACS episode detected by any means or by ambulatory heart rhythm monitor alone, non-AFACS dysrhythmias, in-patient mortality, or length of stay. Per-patient cost for purchasing and administering potassium was significantly lower in the relaxed group (mean difference, $111.89 [95% CI, $103.60-$120.19]; P <.001). CONCLUSIONS AND RELEVANCE: For AFACS prophylaxis, supplementation only when serum potassium concentration fell below 3.6 mEq/L was noninferior to the current widespread practice of supplementing potassium to maintain a serum potassium concentration greater than or equal to 4.5 mEq/L. The lower threshold of supplementation was not associated with any increase in dysrhythmias or adverse clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04053816.

Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England.

OBJECTIVES: The National Health Service in England funds 12 months of weekly subcutaneous tocilizumab (qwTCZ) for patients with relapsing or refractory giant cell arteritis (GCA). During the COVID-19 pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. METHODS: Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. RESULTS: 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median (interquartile range, IQR) of 12 (12-17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0-5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6% respectively had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10-40) mg/day. 33.6% of relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017); in those not in remission at qwTCZ cessation (P = 0.0036); and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing, and conventional synthetic DMARD use were not associated with time to relapse. CONCLUSION: Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients.

Exploring the influence of nasal morbidity on quality of life following endoscopic endonasal skull base surgery: a retrospective cohort study of 95 patients.

The endoscopic endonasal approach is more disruptive to normal anatomy (particularly nasal mucosa) than the transseptal submucosal microscopic approach. This may result in greater postoperative nasal morbidity, in turn reducing quality of life. We aimed to assess the severity and time course of nasal morbidity, and its impact on quality of life, following endoscopic endonasal skull base surgery in this retrospective cohort study. We identified 95 patients who underwent endoscopic endonasal skull base surgery for anterior skull base pathologies. Nasal-specific questions from the Sino-Nasal Outcome Test-22 (SNOT-22) and the Anterior Skull Base inventory (ASB-12) were combined with quality-of-life questions. Patient demographics, diagnosis, and operative data were collected from electronic records. Age of the cohort ranged from 14-83 years. Time elapsed since surgery ranged from 3-85 months. 85/95 (89%) felt that nasal morbidity associated with surgery was acceptable, given the underlying reason for, and outcome of surgery; 10/95 (11%) did not. 71/95 (75%) reported no change or improvement in olfaction 3-months following surgery. 24/95 (25%) reported a deterioration in olfaction which was mild in 7%, moderate in 7%, and severe in 11%. Nasal crusting, nasal obstruction, and headache were moderately problematic symptoms but improved significantly by 3-month follow-up. Nasal discharge, nasal pain, and nasal whistling were mildly problematic and improved significantly by 3-months. 62/95 (65%) patients reported 'no change' in day-to-day activities due to the effects on their nose after surgery. 19/95 (20%) had 'mild inconvenience', 8/95 (8%) 'moderate inconvenience' and 6/95 (6%) 'severe inconvenience'. Endoscopic anterior skull base surgery is associated with nasal morbidity. Whilst 35% of patients appreciate a consequent negative impact on day-to-day life, the overwhelming majority feel that nasal morbidity is acceptable, given the wider surgical goals.

Emotional visual stimuli and simulated laparoscopic surgical performance: A pilot cohort study.

BACKGROUND: Exposure to stress prior to or during surgery can negatively impact performance. Management of stress is an essential non-technical skill required for safe practice. The effects of exposure to emotional visual stressors on surgical performance are poorly understood. This study aims to develop a model to investigate effects of emotive visual stimuli on simulated laparoscopic performance. METHODS AND MATERIALS: A single-centre cohort study. Thirty novice, simulator-naïve medical students were randomly allocated to view either positive, negative, or neutral emotional images (sourced from validated image registry). Participants focused for 5 s on the image before completing a peg-threading laparoscopic task. Time, instrument distance, speed, acceleration, motion smoothness, and ambidexterity were recorded automatically with instrument tracking software. 8 task cycles were completed; 3 control practices followed by 5 with the stimuli, according to group allocation. RESULTS: The final performance metrics of students (time, distance, speed, and motion smoothness) were not significantly different when comparing positive and neutral stimuli groups to those shown negative stimuli. However, changes were seen in the rate of performance improvements (positive: p = 0.711, p = 0.837, p = 0.297, and p = 0.393) (neutral: p = 0.285, p = 0.918, p = 0.835, and p = 0.396). Participation improved performance metrics overall (p=<0.001, p=<0.001, p = 0.088, p = 0.025, p=<0.001). CONCLUSION: Model systems may be valuable for investigating the impact of stress on surgeon performance. The effect of emotive visual stimuli on surgical performance is complex. This model may aid the further exploration of these relationships and ultimately can provide an environment in which surgeons can develop strategies to mitigate the adverse effect of stressors.

Emerging Experiences with Virtual Clinical Ethics Consultation: Case Studies from the United States and Malaysia.

AbstractThe COVID-19 pandemic has inspired numerous opportunities for telehealth implementation to meet diverse healthcare needs, including the use of virtual communication platforms to facilitate the growth of and access to clinical ethics consultation (CEC) services across the globe. Here we discuss the conceptualization and implementation of two different virtual CEC services that arose during the COVID-19 pandemic: the Clinical Ethics Malaysia COVID-19 Consultation Service and the Johns Hopkins Hospital Ethics Committee and Consultation Service. A common strength experienced by both platforms during virtual delivery included improved ability for local practitioners to address consultation needs for patient populations otherwise unable to access CEC services in their respective locations. Additionally, virtual platforms allowed for enhanced collaboration and sharing of expertise among ethics consultants. Both contexts encountered numerous challenges related to patient care delivery during the pandemic. The use of virtual technologies resulted in decreased personalization of patient-provider communication. We discuss these challenges with respect to contextual differences specific to each service and setting, including differences in CEC needs, sociocultural norms, resource availability, populations served, consultation service visibility, healthcare infrastructure, and funding disparities. Through lessons learned from a health system in the United States and a national service in Malaysia, we provide key recommendations for health practitioners and clinical ethics consultants to leverage virtual communication platforms to mitigate existing inequities in patient care delivery and increase capacity for CEC globally.

Social Support in Older Transgender and Gender Diverse Communities in the United Kingdom and Australia: A Comparative Study During COVID-19.

While the impact of the COVID-19 pandemic on older people has been recognized, there is limited understanding of its impact on older trans and gender diverse people who often have different experiences of care and support than the general population. This article examines older trans and gender diverse people's experience of social support during the COVID-19 pandemic, based on a comparative mixed method survey administered in Australia and the United Kingdom. Using a non-probability sample of 84 participants who were connected to social media and service organizations in the United Kingdom and Australia, we found some commonalities and differences between experiences in these countries. Some participants were isolated, including almost 1 in 5 participants who said that they did not have someone they could call upon in an emergency. However, participants had rich networks of friends, partners, and family members. Religious organizations and the community also played an important role. Friends were reported as the main emergency contacts and as the main people to whom support is provided. This research supports previous findings that friends of trans and gender diverse people play an important role in well-being.

Genomes shed light on the evolution of Begonia, a mega-diverse genus.

Clarifying the evolutionary processes underlying species diversification and adaptation is a key focus of evolutionary biology. Begonia (Begoniaceae) is one of the most species-rich angiosperm genera with c. 2000 species, most of which are shade-adapted. Here, we present chromosome-scale genome assemblies for four species of Begonia (B. loranthoides, B. masoniana, B. darthvaderiana and B. peltatifolia), and whole genome shotgun data for an additional 74 Begonia representatives to investigate lineage evolution and shade adaptation of the genus. The four genome assemblies range in size from 331.75 Mb (B. peltatifolia) to 799.83 Mb (B. masoniana), and harbor 22 059-23 444 protein-coding genes. Synteny analysis revealed a lineage-specific whole-genome duplication (WGD) that occurred just before the diversification of Begonia. Functional enrichment of gene families retained after WGD highlights the significance of modified carbohydrate metabolism and photosynthesis possibly linked to shade adaptation in the genus, which is further supported by expansions of gene families involved in light perception and harvesting. Phylogenomic reconstructions and genomics studies indicate that genomic introgression has also played a role in the evolution of Begonia. Overall, this study provides valuable genomic resources for Begonia and suggests potential drivers underlying the diversity and adaptive evolution of this mega-diverse clade.

Assessing the combined effect of ageism and sexuality-related stigma on the mental health and well-being of older lesbian and gay adults.

OBJECTIVE: Relatively little research has examined ageism among older lesbian and gay adults. In this study, we investigated how ageism, as well as sexuality-related stigma, relate to mental health and well-being in these groups. METHOD: Six hundred and thirteen lesbian women and gay men aged 60+ in Australia completed a nationwide survey. We investigated how experiences of ageism, concerns about having one's sexual orientation accepted by others (as one broad indicator of sexuality-related stigma), and their interactions, predict psychological distress, positive mental health, and resilience. RESULTS: Among the lesbian women, experiences of ageism predicted greater psychological distress and lower positive mental health, while sexuality acceptance concerns predicted poorer outcomes on all three well-being measures. Among the gay men, experiences of ageism and sexuality acceptance concerns predicted poorer outcomes on all the well-being measures. In addition, the gay men who were higher on sexuality acceptance concerns had higher psychological distress and lower resilience, but only when they also had greater experiences of ageism. CONCLUSION: Findings suggest that those concerned with the well-being of lesbian and gay people should account for not only the potential impact of sexuality acceptance concerns but also ageism, and how these two factors may interact.

Metabolic regulation of NLRP3.

A shift in our understanding of macrophage biology has come about as a result of recent discoveries in the area of metabolic reprogramming of macrophages. The NLRP3 inflammasome drives the activation of caspase-1, leading to the production of IL-1ß, IL-18, and a type of cell death termed pyroptosis. The NLRP3 inflammasome has been shown to sense metabolites such as palmitate, uric acid, and cholesterol crystals and is inhibited by ketone bodies produced during metabolic flux. The NLRP3 inflammasome has also been shown to be regulated by mitochondrial reactive oxygen species and components of glycolysis, such as Hexokinase. Here, we review these findings and discuss their importance for inflammation and furthermore discuss potential therapeutic benefits of targeting NLRP3.

Factors Associated with Self-Reported PTSD Diagnosis among Older Lesbian Women and Gay Men.

Lesbian women and gay men are at greater risk of post-traumatic stress disorder (PTSD) than heterosexual people, however few studies have examined PTSD in older lesbian women and gay men. This study examined predictors of having ever been diagnosed with PTSD, as well as relationships to current quality of life, among 756 lesbian women and gay men aged 60 years and older in Australia. Participants were surveyed on their sociodemographic characteristics, experiences of sexual orientation discrimination over their lifetime, whether they had ever been diagnosed with PTSD, whether they were currently receiving treatment for PTSD, and their current quality of life. After adjusting for sociodemographic variables, participants who reported having a PTSD diagnosis (11.2%) had significantly more frequent experiences of discrimination over their lifetime and were significantly less likely to currently be in a relationship. Older lesbian women were significantly more likely than older gay men to report ever having had a PTSD diagnosis. Additionally, having ever been diagnosed with PTSD significantly predicted current poorer quality of life. These findings suggest that a history of PTSD among older lesbian women and gay men is linked to experiences of discrimination and other factors, with associated links to current quality of life.

Glutathione transferase Omega 1 confers protection against azoxymethane-induced colorectal tumour formation.

Inflammatory bowel disease (IBD) is characterized by multiple alterations in cytokine expression and is a risk factor for colon cancer. The Omega class glutathione transferase GSTO1-1 regulates the release of the pro-inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) by deglutathionylating NEK7 in the NLRP3 inflammasome. When treated with azoxymethane and dextran sodium sulphate (AOM/DSS) as a model of IBD, Gsto1-/- mice were highly sensitive to colitis and showed a significant increase in the size and number of colon tumours compared with wild-type (WT) mice. Gsto1-/- mice treated with AOM/DSS had significantly lower serum IL-1ß and IL-18 levels as well as significantly decreased interferon (IFN)-γ, decreased pSTAT1 and increased pSTAT3 levels in the distal colon compared with similarly treated WT mice. Histologically, AOM/DSS treated Gsto1-/- mice showed increased active chronic inflammation with macrophage infiltration, epithelial dysplasia and invasive adenocarcinoma compared with AOM/DSS treated WT mice. Thus, this study shows that GSTO1-1 regulates IL-1ß and IL-18 activation and protects against colorectal cancer formation in the AOM/DSS model of IBD. The data suggest that while GSTO1-1 is a new target for the regulation of the NLRP3 inflammasome-associated cytokines IL-1ß and IL-18 by small molecule inhibitors, there is a possibility that anti-inflammatory drugs targeting these cytokines may potentiate colon cancer in some situations.

Coamplification of miR-4728 protects HER2-amplified breast cancers from targeted therapy.

HER2 (ERBB2) amplification is a driving oncogenic event in breast cancer. Clinical trials have consistently shown the benefit of HER2 inhibitors (HER2i) in treating patients with both local and advanced HER2+ breast cancer. Despite this benefit, their efficacy as single agents is limited, unlike the robust responses to other receptor tyrosine kinase inhibitors like EGFR inhibitors in EGFR-mutant lung cancer. Interestingly, the lack of HER2i efficacy occurs despite sufficient intracellular signaling shutdown following HER2i treatment. Exploring possible intrinsic causes for this lack of response, we uncovered remarkably depressed levels of NOXA, an endogenous inhibitor of the antiapoptotic MCL-1, in HER2-amplified breast cancer. Upon investigation of the mechanism leading to low NOXA, we identified a micro-RNA encoded in an intron of HER2, termed miR-4728, that targets the mRNA of the Estrogen Receptor α (ESR1). Reduced ESR1 expression in turn prevents ERα-mediated transcription of NOXA, mitigating apoptosis following treatment with the HER2i lapatinib. Importantly, resistance can be overcome with pharmacological inhibition of MCL-1. More generally, while many cancers like EGFR-mutant lung cancer are driven by activated kinases that when drugged lead to robust monotherapeutic responses, we demonstrate that the efficacy of targeted therapies directed against oncogenes active through focal amplification may be mitigated by coamplified genes.

The gender gap in European neurosurgical conference presentations.

OBJECTIVE: Within neurosurgery, there are fewer women than men at all levels. The authors aimed to assess whether opportunities and representation within neurosurgery are proportional to the existing gender gap. METHODS: The authors analyzed the program of the 2019 joint European Association of Neurosurgical Societies (EANS)/Society of British Neurological Surgeons (SBNS) conference to assess the proportions of presentations given through abstract submission and invitation by men and women. They compared proportions to the previous joint conference in 2007 and to the gender proportions of board-certified European neurosurgeons. RESULTS: Women delivered 75/577 (13%) presentations at the 2019 EANS/SBNS conference: 54/283 (19%) abstract submissions and 21/294 (7%) invited presentations. Fifteen of 152 (10%) session chairs were women. This increased significantly from 4/121 (3%) presentations delivered by women in 2007. When only presentations given by neurosurgeons (residents or consultants) were analyzed, the proportion of female speakers increased from 1/111 (1%) in 2007 to 60/545 (11%) in 2019. Pediatrics was the subspecialty with the highest proportion of invited female speakers. Across subspecialties, there were no differences in gender proportions for presentations from abstract submissions. Across the top 5 participating European countries, the proportion of female invited speakers (8%) and chairs (8%) was half the proportion of female board-certified neurosurgeons (16%). CONCLUSIONS: The proportion of women delivering invited presentations and chairing sessions at a European neurosurgical conference is lower than expected from the available pool of board-certified neurosurgeons. The proportion of women participating is higher through application (abstract submission) than through invitation. The higher proportion of presentations from abstract submission may reflect submission from a pool of trainees with a higher proportion of women. The authors suggest implementation of strategies that increase invited speakers from minority groups and have been shown to be effective in other disciplines, such as improving minority group representation in organizing committees.

Older lesbian and gay men's perceptions on lesbian and gay youth in Australia.

Older lesbian and gay people are increasingly open about their sexuality but have also experienced a lifetime of discrimination. These groups have experienced a long history of changes to lesbian and gay rights, and many were also at the forefront of activist movements during the latter half of the 20th century. A deeper knowledge is needed of the life experiences of these groups, including how they view their lives in relation to younger lesbian and gay people. This would assist agencies working with older lesbian and gay people, such as health and support services, to provide more informed engagement, support, understanding, and culturally safe services. Drawing on 33 qualitative interviews with older (60+ years) lesbian and gay people, we explored their experiences during their younger years and their perspectives on how these experiences compare with those of younger lesbian and gay people today. Our findings note that older lesbian and gay people feel life is, in some ways, easier, and in others, still challenging for young lesbian and gay people, and they articulate a need for mutual respect across age groups.