APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

INTRODUCTION: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS: This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265 mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION: APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. Highlights: The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

Mechanistic insights and in vivo efficacy of thiosemicarbazones against methicillin-resistant Staphylococcus aureus.

Staphylococcus aureus poses a significant threat in both community and hospital settings due to its infective and pathogenic nature combined with its ability to resist the action of chemotherapeutic agents. Methicillin-resistant S. aureus (MRSA) poses a critical challenge. Metal-chelating thiosemicarbazones (TSCs) have shown promise in combating MRSA and while previous studies hinted at the antimicrobial potential of TSCs, their mechanisms of action against MRSA are still under investigation. We screened a chemical library for anti-staphylococcal compounds and identified a potent molecule named R91 that contained the NNSN structural motif found within TSCs. We identified that R91 and several structural analogs exhibited antimicrobial activity against numerous S. aureus isolates as well as other Gram-positive bacteria. RNAseq analysis revealed that R91 induces copper and oxidative stress responses. Checkerboard assays demonstrated synergy of R91 with copper, nickel, and zinc. Mutation of the SrrAB two-component regulatory system sensitizes S. aureus to R91 killing, further linking the oxidative stress response to R91 resistance. Moreover, R91 was found to induce hydrogen peroxide production, which contributed to its antimicrobial activity. Remarkably, no mutants with elevated R91 resistance were identified, despite extensive attempts. We further demonstrate that R91 can be used to effectively treat an intracellular reservoir of S. aureus in cell culture and can reduce bacterial burdens in a murine skin infection model. Combined, these data position R91 as a potent TSC effective against MRSA and other Gram-positive bacteria, with implications for future therapeutic development.

Familiarity enhances functional connectivity between visual and nonvisual regions of the brain during natural viewing.

We explored the neural correlates of familiarity with people and places using a naturalistic viewing paradigm. Neural responses were measured using functional magnetic resonance imaging, while participants viewed a movie taken from Game of Thrones. We compared inter-subject correlations and functional connectivity in participants who were either familiar or unfamiliar with the TV series. Higher inter-subject correlations were found between familiar participants in regions, beyond the visual brain, that are typically associated with the processing of semantic, episodic, and affective information. However, familiarity also increased functional connectivity between face and scene regions in the visual brain and the nonvisual regions of the familiarity network. To determine whether these regions play an important role in face recognition, we measured responses in participants with developmental prosopagnosia (DP). Consistent with a deficit in face recognition, the effect of familiarity was significantly attenuated across the familiarity network in DP. The effect of familiarity on functional connectivity between face regions and the familiarity network was also attenuated in DP. These results show that the neural response to familiarity involves an extended network of brain regions and that functional connectivity between visual and nonvisual regions of the brain plays an important role in the recognition of people and places during natural viewing.

Antennal transcriptome analysis reveals sensory receptors potentially associated with host detection in the livestock pest Lucilia cuprina.

BACKGROUND: Lucilia cuprina (Wiedemann, 1830) (Diptera: Calliphoridae) is the main causative agent of flystrike of sheep in Australia and New Zealand. Female flies lay eggs in an open wound or natural orifice, and the developing larvae eat the host's tissues, a condition called myiasis. To improve our understanding of host-seeking behavior, we quantified gene expression in male and female antennae based on their behavior. METHODS: A spatial olfactometer was used to evaluate the olfactory response of L. cuprina mated males and gravid females to fresh or rotting beef. Antennal RNA-Seq analysis was used to identify sensory receptors differentially expressed between groups. RESULTS: Lucilia cuprina females were more attracted to rotten compared to fresh beef (> fivefold increase). However, males and some females did not respond to either type of beef. RNA-Seq analysis was performed on antennae dissected from attracted females, non-attracted females and males. Transcripts encoding sensory receptors from 11 gene families were identified above a threshold (≥ 5 transcript per million) including 49 ATP-binding cassette transporters (ABCs), two ammonium transporters (AMTs), 37 odorant receptors (ORs), 16 ionotropic receptors (IRs), 5 gustatory receptors (GRs), 22 odorant-binding proteins (OBPs), 9 CD36-sensory neuron membrane proteins (CD36/SNMPs), 4 chemosensory proteins (CSPs), 4 myeloid lipid-recognition (ML) and Niemann-Pick C2 disease proteins (ML/NPC2), 2 pickpocket receptors (PPKs) and 3 transient receptor potential channels (TRPs). Differential expression analyses identified sex-biased sensory receptors. CONCLUSIONS: We identified sensory receptors that were differentially expressed between the antennae of both sexes and hence may be associated with host detection by female flies. The most promising for future investigations were as follows: an odorant receptor (LcupOR46) which is female-biased in L. cuprina and Cochliomyia hominivorax Coquerel, 1858; an ABC transporter (ABC G23.1) that was the sole sensory receptor upregulated in the antennae of females attracted to rotting beef compared to non-attracted females; a female-biased ammonia transporter (AMT_Rh50), which was previously associated with ammonium detection in Drosophila melanogaster Meigen, 1830. This is the first report suggesting a possible role for ABC transporters in L. cuprina olfaction and potentially in other insects.

Quality performance indicators for oesophageal and gastric cancer: ANZ expert Delphi consensus.

BACKGROUND: Quality performance indicators for the management of oesophagogastric cancer can be used to objectively measure and compare the performance of individual units and capture key elements of patient care to improve patient outcomes. METHODS: Two systematic reviews were completed to identify evidence-based quality performance indicators for the surgical management of oesophagogastric cancer. Based on the indicators identified, a two-round modified Delphi process with invitations was sent to all members of the Australia and Aotearoa New Zealand Gastric and Oesophageal Surgery Association. The expert working group discussed each suggested indicator and either removed, added, or adjusted the list of indicators of oesophagogastric cancer. RESULTS: The final list of both OG cancer indicators included Specialized Multi-disciplinary team discussion, Endoscopy documentation, Staging Contrast CT Chest/Abdomen and Pelvis, Neoadjuvant or Adjuvant chemo/radiotherapy administered in accordance with the Local multi-disciplinary team, Pathological margin clearance (R0 Resection), Lymphadenectomy retrieving 15 or more nodes, Formal review of pathological findings and documentation, Postoperative complications, 30-day and 90-day postoperative mortality, clinical surveillance and Specialized Dietetic guidance. Indicators specific to gastric cancer included Preoperative biopsy for pathological diagnosis and Staging Laparoscopy. Indicators specific to oesophageal cancer include positron emission tomography scan if CT negative for metastasis, Perioperative Oesophagectomy Care Pathway, length of stay of 21 days or more, and Unplanned readmission within 30 days. CONCLUSIONS: The results of this study present a core set of indicators for the surgical management of oesophagogastric cancer that can be used to measure quality and compare performance between different units.

Racial Differences in Stigmatizing and Positive Language in Emergency Medicine Notes.

OBJECTIVE: Language used by providers in medical documentation may reveal evidence of race-related implicit bias. We aimed to use natural language processing (NLP) to examine if prevalence of stigmatizing language in emergency medicine (EM) encounter notes differs across patient race/ethnicity. METHODS: In a retrospective cohort of EM encounters, NLP techniques identified stigmatizing and positive themes. Logistic regression models analyzed the association of race/ethnicity and themes within notes. Outcomes were the presence (or absence) of 7 different themes: 5 stigmatizing (difficult, non-compliant, skepticism, substance abuse/seeking, and financial difficulty) and 2 positive (compliment and compliant). RESULTS: The sample included notes from 26,363 unique patients. NH Black patient notes were less likely to contain difficult (odds ratio (OR) 0.80, 95% confidence interval (CI), 0.73-0.88), skepticism (OR 0.87, 95% CI, 0.79-0.96), and substance abuse/seeking (OR 0.62, 95% CI, 0.56-0.70) compared to NH White patient notes but more likely to contain non-compliant (OR 1.26, 95% CI, 1.17-1.36) and financial difficulty (OR 1.14, 95% CI, 1.04-1.25). Hispanic patient notes were less likely to contain difficult (OR 0.68, 95% CI, 0.58-0.80) and substance abuse/seeking (OR 0.78, 95% CI, 0.66-0.93). NH NA/AI patient notes had twice the odds as NH White patient notes to contain a stigmatizing theme (OR 2.02, 95% CI, 1.64-2.49). CONCLUSIONS: Using an NLP model to analyze themes in EM notes across racial groups, we identified several inequities in the usage of positive and stigmatizing language. Interventions to minimize race-related implicit bias should be undertaken.

Extranodal diffuse large B-cell lymphoma involving the uterine cervix.

This is a case of primary diffuse large B-cell lymphoma involving the uterine cervix which presented with irregular vaginal bleeding. The diagnosis was confirmed following multiple cervical biopsies. Treatment with a combination of immunotherapy, chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)) and radiotherapy produced a good response.

Antireflux surgery in patients with gastroesophageal reflux but a negative 24-hour pH study: late outcomes.

PURPOSE: Patients with gastroesophageal reflux disease often undergo a 24-hour pH test to confirm pathologic reflux before surgery. However, a negative pH test can occur in some individuals with reflux, and a case might still be made for antireflux surgery based on symptoms of reflux even in the absence of endoscopic esophagitis. The long-term outcomes in patients who underwent antireflux surgery despite negative preoperative test results were determined. METHODS: Patients were selected from a prospective database. A total of 745 patients met the inclusion criteria, which included typical esophageal reflux symptoms, absence of a large hiatus hernia, preoperative 24-hour pH study performed, endoscopy, and postoperative symptom and satisfaction follow-up available at 5 years. Patients were divided into 3 groups based on 24-hour pH study and endoscopy results: negative pH and negative endoscopy (n = 65), negative pH and positive endoscopy (n = 72), and positive pH (n = 608). The negative pH and negative endoscopy group underwent surgery based on clinical assessment and typical esophageal reflux symptoms. Baseline and follow-up outcomes at 5 years were evaluated using 0 to 10 analog scores, which assessed heartburn, dysphagia, and satisfaction with the overall outcome. Data were analyzed to compare the groups. RESULTS: The groups were well matched for demographics and preoperative symptom scores. At the median 5-year follow-up, clinical outcome scores were similar among the groups for heartburn, dysphagia, and overall satisfaction. The mean heartburn scores were 1.80 in the negative pH and negative endoscopy group, 1.88 in the negative pH and positive endoscopy group, and 1.91 in the positive pH group (P = .663). The mean satisfaction scores were high in all groups: 8.13, 7.31, and 7.72, respectively (P = .293). CONCLUSION: No difference in clinical outcome scores was observed. The negative pH and negative endoscopy group had high satisfaction scores and low heartburn and dysphagia scores. Our findings support antireflux surgery in well-selected symptomatic patients with a negative preoperative pH test.

Management of fetal hyperthyroidism caused by persistent autoimmune antibodies in a case of previously treated maternal Graves' disease.

Maternal Graves' autoantibodies are well known to cause fetal and neonatal thyroid disturbances. Despite radioiodine therapy, Graves' autoantibodies are known to persist, which can cross the placenta and cause hyperthyroidism in the fetus. We present the case of a 26-year-old woman in her first pregnancy, clinically and biochemically euthyroid with history of treated Graves' disease, where the fetus showed signs of hyperthyroidism on antenatal scans. This was confirmed by amniotic fluid testing as fetal blood sampling was not feasible and successfully treated with maternal carbimazole whilst continuing thyroxine for the mother (block-replacement). We discuss the challenges in the diagnosis of fetal hyperthyroidism and treatment whilst maternal thyroid status is maintained on thyroxine.

Interface-modulated kinetic differentials in electron and hole transfer rates as a key design principle for redox photocatalysis by Sb2VO5/QD heterostructures.

The efficient conversion of solar energy to chemical energy represents a critical bottleneck to the energy transition. Photocatalytic splitting of water to generate solar fuels is a promising solution. Semiconductor quantum dots (QDs) are prime candidates for light-harvesting components of photocatalytic heterostructures, given their size-dependent photophysical properties and band-edge energies. A promising series of heterostructured photocatalysts interface QDs with transition-metal oxides which embed midgap electronic states derived from the stereochemically active electron lone pairs of p-block cations. Here, we examine the thermodynamic driving forces and dynamics of charge separation in Sb2VO5/CdSe QD heterostructures, wherein a high density of Sb 5s2-derived midgap states are prospective acceptors for photogenerated holes. Hard-x-ray valence band photoemission spectroscopy measurements of Sb2VO5/CdSe QD heterostructures were used to deduce thermodynamic driving forces for charge separation. Interfacial charge transfer dynamics in the heterostructures were examined as a function of the mode of interfacial connectivity, contrasting heterostructures with direct interfaces assembled by successive ion layer adsorption and reaction (SILAR) and interfaces comprising molecular bridges assembled by linker-assisted assembly (LAA). Transient absorption spectroscopy measurements indicate ultrafast (<2 ps) electron and hole transfer in SILAR-derived heterostructures, whereas LAA-derived heterostructures show orders of magnitude differentials in the kinetics of hole (<100 ps) and electron (∼1 ns) transfer. The interface-modulated kinetic differentials in electron and hole transfer rates underpin the more effective charge separation, reduced charge recombination, and greater photocatalytic efficiency observed for the LAA-derived Sb2VO5/CdSe QD heterostructures.

Mucosal impedance as a diagnostic tool for gastroesophageal reflux disease: an update for clinicians.

Mucosal impedance is a marker of esophageal mucosal integrity and a novel technique for assessing esophageal function and pathology. This article highlights its development and clinical application for gastroesophageal reflux disease (GERD), Barrett's esophagus, and eosinophilic esophagitis. A narrative review of key publications describing the development and use of mucosal impedance in clinical practice was conducted. A low mean nocturnal baseline impedance (MNBI) has been shown to be an independent predictor of response to anti-reflux therapy. MNBI predicts medication-responsive heartburn better than distal esophageal acid exposure time. Patients with equivocal evidence of GERD using conventional methods, with a low MNBI, had an improvement in symptoms following the initiation of PPI therapy compared to those with a normal MNBI. A similar trend was seen in a post fundoplication cohort. Strong clinical utility for the use of mucosal impedance in assessing eosinophilic esophagitis has been repeatedly demonstrated; however, there is minimal direction for application in Barrett's esophagus. The authors conclude that mucosal impedance has potential clinical utility for the assessment and diagnosis of GERD, particularly when conventional investigations have yielded equivocal results.

Modulatory actions of Echinococcus granulosus antigen B on macrophage inflammatory activation.

Cestodes use own lipid-binding proteins to capture and transport hydrophobic ligands, including lipids that they cannot synthesise as fatty acids and cholesterol. In E. granulosus s.l., one of these lipoproteins is antigen B (EgAgB), codified by a multigenic and polymorphic family that gives rise to five gene products (EgAgB8/1-5 subunits) assembled as a 230 kDa macromolecule. EgAgB has a diagnostic value for cystic echinococcosis, but its putative role in the immunobiology of this infection is still poorly understood. Accumulating research suggests that EgAgB has immunomodulatory properties, but previous studies employed denatured antigen preparations that might exert different effects than the native form, thereby limiting data interpretation. This work analysed the modulatory actions on macrophages of native EgAgB (nEgAgB) and the recombinant form of EgAg8/1, which is the most abundant subunit in the larva and was expressed in insect S2 cells (rEgAgB8/1). Both EgAgB preparations were purified to homogeneity by immunoaffinity chromatography using a novel nanobody anti-EgAgB8/1. nEgAgB and rEgAgB8/1 exhibited differences in size and lipid composition. The rEgAgB8/1 generates mildly larger lipoproteins with a less diverse lipid composition than nEgAgB. Assays using human and murine macrophages showed that both nEgAgB and rEgAgB8/1 interfered with in vitro LPS-driven macrophage activation, decreasing cytokine (IL-1ß, IL-6, IL-12p40, IFN-ß) secretion and ·NO generation. Furthermore, nEgAgB and rEgAgB8/1 modulated in vivo LPS-induced cytokine production (IL-6, IL-10) and activation of large (measured as MHC-II level) and small (measured as CD86 and CD40 levels) macrophages in the peritoneum, although rEgAgB8/1 effects were less robust. Overall, this work reinforced the notion that EgAgB is an immunomodulatory component of E. granulosus s.l. Although nEgAgB lipid's effects cannot be ruled out, our data suggest that the EgAgB8/1 subunit contributes to EgAgB´s ability to regulate the inflammatory activation of macrophages.

The Brazilian version of the Inventory of Depression and Anxiety Symptoms-Expanded Version: Internal structure, invariance by sex and race, and associations with pathological personality traits.

The Inventory of Depression and Anxiety Symptoms-Expanded version (IDAS-II) is one of the few tools designed to assess internalizing symptoms based on dimensional models. We conducted two studies, the first testing internal validity aspects of the IDAS-II and the second testing the external validity of the scales. In the first study we adapted the IDAS-II to Brazilian Portuguese and tested its internal structure, including a higher order factorial solution coherent with the internalizing spectrum, the stability of the factor structure, and its measurement invariance for sex and racial groups. Participants were 2,379 Brazilian adults. In the second study, we investigated the IDAS-II scales' associations with broad pathological personality traits in Brazilian (N = 245) and North American (N = 402) samples. The results of the first study indicated that the IDAS-II scales are grouped into three first-order factors (Distress, Obsessions/Fear, and Positive Mood), replicating Wester et al. (2022) and Petre et al. (2023). Our results also suggested the plausibility of an internalizing second-order factor for the IDAS-II Brazilian version. The multigroup confirmatory factor analysis shows that this scale is invariant for males and females and for White and Black/Brown people. In the second study, the IDAS-II scales demonstrated mostly coherent associations with broad domains of pathological personality traits. Besides the internal validity of the Brazilian IDAS-II, our results also provide information about its external validity and expand its nomological network, as it is the first study reporting its associations with broad domains of pathological personality traits. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Quality of life following repair of large hiatal hernia is not influenced by the use of mesh-Longer-term follow-up from a randomized trial.

INTRODUCTION: The use of prosthetic mesh in laparoscopic repair of large hiatus hernias remains controversial. Clinical and quality of life outcomes from a randomized controlled trial of mesh versus suture repair previously showed few differences at early follow-up. This study evaluated longer-term quality of life outcomes from that trial. METHODS: A prospective, multicentre, double blind randomized controlled trial assessed three methods of repair for large hiatus hernias: sutures-only versus absorbable mesh versus non-absorbable mesh. Quality of life was assessed using the Short-Form 36 (SF-36) questionnaire which was completed preoperatively and then at 3, 6, 12 months following surgery and annually thereafter. SF-36 outcomes were compared across the three repair techniques at longer-term follow-up (3-6 years), and to earlier baseline and 12-month outcomes. RESULTS: 126 patients were randomized; 43-suture-only, 41-absorbable mesh and 42-non-absorbable mesh. Questionnaires were completed by 118 patients preoperatively, 115 at 12 months and 98 at longer-term follow-up (median 5 years). There were no significant differences between the repair techniques for the subscale and composite scores at longer-term follow-up. The mental component score improved significantly after surgery and was sustained across follow-up for all techniques. The physical component score also improved significantly but was lower at longer-term follow-up compared to the 12-month follow up in both mesh groups. CONCLUSION: Surgical repair of large hiatus hernias provides sustained long-term improvement in quality of life. The addition of mesh does not improve quality of life. TRIAL REGISTRATION: This trial is registered with the Australia and New Zealand Clinical Trials Registry ACTRN12605000725662.

Australian women's experiences of post-partum rectus diastasis: A qualitative study.

BACKGROUND: Post-partum rectus diastasis, or the separation of the abdominal muscles after pregnancy, occurs in conjunction with physical symptoms and impaired quality of life. In Australia, health funding for surgery to treat diastasis was ceased in 2016, but reinstated in mid-2022, providing a unique context from which women's experiences of this condition can be analysed. OBJECTIVES: The objective is to examine the experiences of Australian women with post-partum rectus diastasis. DESIGN: This is an interview-style study with qualitative content analysis. METHODS: Women diagnosed with rectus diastasis were recruited to complete a baseline questionnaire (n = 45). Twenty-three responded to invitation for one-on-one interview via Zoom® between November 2021 and May 2022. Interviews were recorded, transcribed, and analysed using qualitative content analysis to identify key themes. RESULTS: Eighteen women had undergone caesarean section and eight had twins. Thirteen had private health insurance. Women were most often diagnosed by a physiotherapist (n = 10). Key themes identified included changed physical appearance and function; issues with self-esteem and intimacy; barriers to treatment; lack of recognition as a medical condition; and overall frustration. The impact of rectus diastasis extended beyond physical and psychological symptoms to affect women's social functioning, child rearing, and return to work. There was a complex interaction between healthcare providers' knowledge of rectus the removal of funding for surgical treatment, and limitations of conservative therapy, with women's lived experiences and symptoms. The lack of an established medical definition also influenced the experiences of these women and their engagement with treatment. CONCLUSION: This study contextualizes women's experience of post-partum rectus diastasis with respect to the unique landscape of Australia's healthcare economy and provides evidence of women's absorption of health policy surrounding this condition. Our qualitative analysis provides critical knowledge for future quantitative studies, the results of which in combination could advance the definition of rectus diastasis and inform healthcare policy surrounding treatment.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

The effect of mephedrone on human neuroblastoma and astrocytoma cells.

Mephedrone is an illegal drug that is used recreationally. Few studies have been conducted to investigate the mechanisms by which mephedrone is harming cells. In this research, we investigated the effect of mephedrone using toxicology coupled with LC-MS/MS based metabolomics in the two CNS derived cell lines. Methods of assessment such as neutral red (NR) assay, dimethylthiazolyl diphenyltetrazolium bromide (MTT), lactose dehydrogenase (LDH) measurement, and morphology were performed to identify the effect on cell viability and to identify the best concentration to be used in a metabolomics study. A concentration of 100 µM of mephedrone was used in the metabolomic experiment because at this concentration mephedrone had induced several intracellular changes. Although there no clear indicators of cellular damage caused by mephedrone. In astrocytes there was a clear indication that cell membrane function might be impaired by depletion of ether lipids.

Mapping the functional and structural connectivity of the scene network.

The recognition and perception of places has been linked to a network of scene-selective regions in the human brain. While previous studies have focussed on functional connectivity between scene-selective regions themselves, less is known about their connectivity with other cortical and subcortical regions in the brain. Here, we determine the functional and structural connectivity profile of the scene network. We used fMRI to examine functional connectivity between scene regions and across the whole brain during rest and movie-watching. Connectivity within the scene network revealed a bias between posterior and anterior scene regions implicated in perceptual and mnemonic aspects of scene perception respectively. Differences between posterior and anterior scene regions were also evident in the connectivity with cortical and subcortical regions across the brain. For example, the Occipital Place Area (OPA) and posterior Parahippocampal Place Area (PPA) showed greater connectivity with visual and dorsal attention networks, while anterior PPA and Retrosplenial Complex showed preferential connectivity with default mode and frontoparietal control networks and the hippocampus. We further measured the structural connectivity of the scene network using diffusion tractography. This indicated both similarities and differences with the functional connectivity, highlighting biases between posterior and anterior regions, but also between ventral and dorsal scene regions. Finally, we quantified the structural connectivity between the scene network and major white matter tracts throughout the brain. These findings provide a map of the functional and structural connectivity of scene-selective regions to each other and the rest of the brain.

Lessons from a population-based bladder cancer registry: exploring why survival is not improving.

OBJECTIVE: To explore the causes of the decrease in bladder cancer survival that has occurred over the past four decades. METHODS: We extracted data from the South Australian Cancer Registry. Data from the period 1 January 1977 to 31 December 2020 were extracted to explore changes in incidence and survival among a total of 8356 patients diagnosed with ≥pT1 disease. Invasive bladder cancer was defined as ≥pT1 in this study. RESULTS: Invasive bladder cancer age-standardized incidence decreased from 7.20 cases per 100 000 people in 1977 to 5.85 cases per 100 000 in 2020. The mean age at diagnosis increased from 68 years to 76 years. The crude incidence for patients aged 80 years and over increased by 3.3% per year (95% confidence interval [CI] 2.1 to 4.6). Overall survival decreased over the study period (hazard ratio [HR] 1.22 [95% CI 1.09 to 1.35]), however, survival increased after adjusting for age at diagnosis (HR 0.80 [95% CI 0.76 to 0.94]). Despite a decrease in non-bladder cancer-specific deaths in older people, there was no change in the bladder cancer-specific death rate in older people (HR 0.94 [95% CI 0.70 to 1.26]). Male sex was associated with higher survival (HR 0.87 [95% CI 0.83 to 0.92]), whereas socioeconomic advantage was not. CONCLUSIONS: Invasive bladder cancer survival has decreased over the past 40 years, with the age structure of the population being a significant contributing factor. PATIENT SUMMARY: We looked at why bladder cancer survival is decreasing using a large cancer registry with information from 1977 to 2020. We found that people are now more likely to be diagnosed at an older age. Older people often live for a shorter time with bladder cancer compared to younger people. Bladder cancer survival has decreased because there are more older people with the disease than previously.

Quantifying Perioperative Risks for Antireflux and Hiatus Hernia Surgery: A Multicenter Cohort Study of 4301 Patients.

OBJECTIVE: Using a comprehensive Australian cohort, we quantified the incidence and determined the independent predictors of intraoperative and postoperative complications associated with antireflux and hiatus hernia surgeries. In addition, we performed an in-depth analysis to understand the complication profiles associated with each independent risk factor. BACKGROUND: Predicting perioperative risks for fundoplication and hiatus hernia repair will inform treatment decision-making, hospital resource allocation, and benchmarking. However, available risk calculators do not account for hernia anatomy or technical aspects of surgery in estimating perioperative risk. METHODS: Retrospective analysis of all elective antireflux and hiatus hernia surgeries in 36 Australian hospitals over 10 years. Hierarchical multivariate logistic regression analyses were performed to determine the independent predictors of intraoperative and postoperative complications accounting for patient, surgical, anatomic, and perioperative factors. RESULTS: A total of 4301 surgeries were analyzed. Of these, 1569 (36.5%) were large/giant hernias and 292 (6.8%) were revisional procedures. The incidence rates of intraoperative and postoperative complications were 12.6% and 13.3%, respectively. The Charlson Comorbidity Index, hernia size, revisional surgery, and baseline anticoagulant usage independently predicted both intraoperative and postoperative complications. These risk factors were associated with their own complication profiles. Finally, using risk matrices, we visualized the cumulative impact of these 4 risk factors on the development of intraoperative, overall postoperative, and major postoperative complications. CONCLUSIONS: This study has improved our understanding of perioperative morbidity associated with antireflux and hiatus hernia surgery. Our findings group patients along a spectrum of perioperative risks that inform care at an individual and institutional level.