CT Myocardial Perfusion and CT-FFR versus Invasive FFR for Hemodynamic Relevance of Coronary Artery Disease.

Background CT-derived fractional flow reserve (CT-FFR) and dynamic CT myocardial perfusion imaging enhance the specificity of coronary CT angiography (CCTA) for ruling out coronary artery disease (CAD). However, evidence on comparative diagnostic value remains scarce. Purpose To compare the diagnostic accuracy of CCTA plus CT-FFR, CCTA plus CT perfusion, and sequential CCTA plus CT-FFR and CT perfusion for detecting hemodynamically relevant CAD with that of invasive angiography. Materials and Methods This secondary analysis of a prospective study included patients with chest pain referred for invasive coronary angiography at nine centers from July 2016 to September 2019. CCTA and CT perfusion were performed with third-generation dual-source CT scanners. CT-FFR was assessed on-site. Independent core laboratories analyzed CCTA alone, CCTA plus CT perfusion, CCTA plus CT-FFR, and a sequential approach involving CCTA plus CT-FFR and CT perfusion for the presence of hemodynamically relevant stenosis. Invasive coronary angiography with invasive fractional flow reserve was the reference standard. Diagnostic accuracy metrics and the area under the receiver operating characteristic curve (AUC) were compared with the Sign test and DeLong test. Results Of the 105 participants (mean age, 64 years ± 8 [SD]; 68 male), 49 (47%) had hemodynamically relevant stenoses at invasive coronary angiography. CCTA plus CT-FFR and CCTA plus CT perfusion showed no evidence of a difference for participant-based sensitivities (90% vs 90%, P > .99), specificities (77% vs 79%, P > .99) and vessel-based AUCs (0.84 [95% CI: 0.77, 0.91] vs 0.83 [95% CI: 0.75, 0.91], P = .90). Both had higher participant-based specificity than CCTA alone (54%, both P < .001) without evidence of a difference in sensitivity between CCTA (94%) and CCTA plus CT perfusion (P = .50) or CCTA plus CT-FFR (P = .63). The sequential approach combining CCTA plus CT-FFR with CT perfusion achieved higher participant-based specificity than CCTA plus CT-FFR (88% vs 77%, P = .03) without evidence of a difference in participant-based sensitivity (88% vs 90%, P > .99) and vessel-based AUC (0.85 [95% CI: 0.77, 0.93], P = .78). Compared with CCTA plus CT perfusion, the sequential approach showed no evidence of a difference in participant-based sensitivity (P > .99), specificity (P = .06), or vessel-based AUC (P = .54). Conclusion There was no evidence of a difference in diagnostic accuracy between CCTA plus CT-FFR and CCTA plus CT perfusion for detecting hemodynamically relevant CAD. A sequential approach combining CCTA plus CT-FFR with CT perfusion led to improved participant-based specificity with no evidence of a difference in sensitivity compared with CCTA plus CT-FFR. ClinicalTrials.gov registration no.: NCT02810795 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Sinitsyn in this issue.

Ketamine Produces Antidepressant Effects by Inhibiting Histone Deacetylases and Upregulating Hippocampal Brain-Derived Neurotrophic Factor Levels in a Diisopropyl Fluorophosphate-Based Rat Model of Gulf War Illness.

Approximately one-third of Gulf War veterans suffer from Gulf War Illness (GWI), which encompasses mood disorders and depressive symptoms. Deployment-related exposure to organophosphate compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased brain-derived neurotrophic factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the Food and Drug Administration for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET's antidepressant effect in GWI-related depression. Here, we investigated whether KET's effect on histone mechanisms signals BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once daily with diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c., 5 days). At 6 months following DFP exposure, KET (10 mg/kg, i.p.) was injected, and brains were dissected 24 hours later. Western blotting was used for protein expression, and epigenetic studies used chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of histone deacetylase (HDAC) enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the Bdnf promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET's actions involve the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathologic synaptic plasticity and exerts an antidepressant effect in DFP rats. SIGNIFICANCE STATEMENT: This study offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated brain-derived neurotrophic factor expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.

Socioeconomic inequalities in cervical cancer mortality in Canada, 1990 and 2019: a trend analysis.

OBJECTIVE: It is increasingly recognized that those of lower socioeconomic status (SES) are disproportionately affected by cancer mortality. The association between cervical cancer mortality and SES have been reported; however, it remains poorly understood in the Canadian population. Thus, this study investigates trends in income and education inequalities in cervical cancer mortality in Canada over the last three decades. STUDY DESIGN: Trend analysis. METHODS: A dataset constructed at the census division level (n = 280), comprising the Canadian Vital Statistics Death Database, the Canadian Census of Population, and the National Household Survey was used to measure cervical cancer mortality in Canada. Income and education inequalities in cervical cancer mortality were measured using age-standardized Concentration index (C). RESULTS: Crude cervical cancer mortality rates decreased significantly during the study period. Age-standardized C values were negative for the majority of years for income and education inequalities, reaching significance in some years. Trend analyses indicated an increasing concentration of cervical cancer mortality amongst those with lower education levels. CONCLUSION: Despite recent decreases in cervical cancer mortality rates, socioeconomic inequalities in cervical cancer mortality in Canada are persistent. Notably, those of lower income and education levels are disproportionately affected, underscoring an opportunity to improve clinical outcomes by addressing these inequalities.

CT-derived fractional flow reserve (FFRct) for functional coronary artery evaluation in the follow-up of patients after heart transplantation.

OBJECTIVES: Invasively measured fractional flow reserve (FFR) is associated with outcome in heart transplant (HTx) patients. Coronary computed tomography angiography (CCTA)-derived FFR (FFRct) provides additional functional information from anatomical CT images. We describe the first use of FFRct in HTx patients. METHODS: HTx patients underwent CCTA with FFRct to screen for cardiac allograft vasculopathy. FFRct was measured distal to each coronary stenosis > 30% and FFRct ≤ 0.8 indicated hemodynamically significant stenosis. FFRct was also measured at the most distal location of each vessel. Overall distal FFRct was calculated as the mean of the distal values in the left, right, and circumflex coronary artery in each patient. RESULTS: Seventy-three patients (age 56 (42-65) years, 63% males) at 11 (8-16) years after HTx were included. Eighteen (25%) patients had a focal hemodynamically significant stenosis (stenosis > 30% with FFRct ≤ 0.8). In the 55 patients without a hemodynamically significant focal FFRct stenosis (FFRct > 0.80), the distal left anterior descending artery FFRct was < 0.90 in 74% of the patients and 10 (18%) patients had ≥ 1 coronary artery with a distal FFRct ≤ 0.8, including 1 with a distal FFRct ≤ 0.8 in all coronaries. Overall distal FFRct in patients without focal stenosis was 0.88 (0.86-0.91), 0.87 (0.86-0.90), and 0.88 (0.86-0.91) (median with 25th-75th percentile) at 5-9, 10-14, or ≥ 15 years post-transplantation, respectively (p = 0.93). CONCLUSIONS: FFRct performed on CCTA scans of HTx patients demonstrated that 25% of patients had a focal coronary stenosis with FFRct ≤ 0.8. Even without a focal stenosis, FFRct values are often abnormal in HTx patients. KEY POINTS: • This is the first report describing the use of FFRct in in heart transplant patients. • FFRct identifies patients after heart transplantation with hemodynamically significant coronary stenosis. • Even without a focal stenosis, FFRct values are often abnormal in heart transplant patients.

Histone acetylation at the sulfotransferase 1a1 gene is associated with its hepatic expression in normal aging.

OBJECTIVES: Phase II drug metabolism is poorly studied in advanced age and older adults may exhibit significant variability in their expression of phase II enzymes. We hypothesized that age-related changes to epigenetic regulation of genes involved in phase II drug metabolism may contribute to these effects. METHODS: We examined published epigenome-wide studies of human blood and identified the SULT1A1 and UGT1A6 genes as the top loci showing epigenetic changes with age. To assess possible functional alterations with age in the liver, we assayed DNA methylation (5mC) and histone acetylation changes around the mouse homologs Sult1a1 and Ugt1a6 in liver tissue from mice aged 4-32 months. RESULTS: Our sample shows a significant loss of 5mC at Sult1a1 (ß = -1.08, 95% CI [-1.8, -0.2], SE = 0.38, P = 0.011), mirroring the loss of 5mC with age observed in human blood DNA at the same locus. We also detected increased histone 3 lysine 9 acetylation (H3K9ac) with age at Sult1a1 (ß = 0.11, 95% CI [0.002, 0.22], SE = 0.05, P = 0.04), but no change to histone 3 lysine 27 acetylation (H3K27ac). Sult1a1 gene expression is significantly positively associated with H3K9ac levels, accounting for 23% of the variation in expression. We did not detect any significant effects at Ugt1a6. CONCLUSIONS: Sult1a1 expression is under epigenetic influence in normal aging and this influence is more pronounced for H3K9ac than DNA methylation or H3K27ac in this study. More generally, our findings support the relevance of epigenetics in regulating key drug-metabolizing pathways. In the future, epigenetic biomarkers could prove useful to inform dosing in older adults.

Clinical implementation of coronary computed tomography angiography for routine detection of cardiac allograft vasculopathy in heart transplant patients.

Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects long-term outcomes in heart transplant (HTx) patients. We prospectively evaluated the feasibility of coronary computed tomography angiography (CCTA) for the detection of CAV during clinical implementation at our center. All consecutive HTx patients >4 years post-transplant were actively converted from myocardial perfusion imaging to CCTA for the annual assessment of CAV. Between February 2018 and May 2019, 129/172 (75%) HTx patients underwent a CCTA. Renal impairment (n = 21/43) was the most frequent reason for patients could not undergo CCTA. CCTA image quality was good-excellent in 118/129 (92%) patients, and the radiation dose was 2.1 (1.6-2.8) mSv. CCTA showed obstructive CAV in 19/129 (15%) patients. Thirteen (10%) patients underwent additional tests, of which 8 patients underwent coronary revascularization within 90 days of CCTA. After 1 year, 3 additional coronary angiograms were performed, resulting in one revascularization in a patient with known severe CAV who developed ventricular tachycardia. One myocardial infarction after coronary stenting and 2 non-cardiac deaths were observed. CCTA can be successfully implemented for routine detection of CAV with good image quality and low radiation dose. CCTA allows CAV evaluation with the limited need for additional invasive testing.

Building a schizophrenia genetic network: transcription factor 4 regulates genes involved in neuronal development and schizophrenia risk.

The transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SCZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SCZ association findings. We identified 11 322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having ≥1 Ebox) and implicate a gene set enriched for genes downregulated in TCF4 small-interfering RNA (siRNA) knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among (1) gene ontology categories such as axon/neuronal development, (2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex and (3) genes downregulated in postmortem brain tissue from SCZ patients (odds ratio, OR = 2.8, permutation P < 4x10-5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA-binding proteins such as FOXP2 and the SCZ-associated EP300. TCF4 binding sites were modestly enriched among SCZ risk loci from the Psychiatric Genomic Consortium (OR = 1.56, P = 0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point toward functional interactions with potential relevance for SCZ.

Impact of machine-learning CT-derived fractional flow reserve for the diagnosis and management of coronary artery disease in the randomized CRESCENT trials.

OBJECTIVE: To determine the potential impact of on-site CT-derived fractional flow reserve (CT-FFR) on the diagnostic efficiency and effectiveness of coronary CT angiography (CCTA) in patients with obstructive coronary artery disease (CAD) on CCTA. METHODS: This observational cohort study included patients with suspected CAD who had been randomized to cardiac CT in the CRESCENT I and II trials. On-site CT-FFR was blindly performed in all patients with at least one ≥ 50% stenosis on CCTA and no exclusion criteria for CT-FFR. We retrospectively assessed the effect of adding CT-FFR to the CT protocol in patients with a stenosis ≥ 50% on CCTA in terms of diagnostic effectiveness, i.e., the number of additional tests required to determine the final diagnosis, reclassification of the initial management strategy, and invasive coronary angiography (ICA) efficiency, i.e., ICA rate without ≥ 50% CAD. RESULTS: Fifty-three patients out of the 372 patients (14%) had at least one ≥ 50% stenosis on CCTA of whom 42/53 patients (79%) had no exclusion criteria for CT-FFR. CT-FFR showed a hemodynamically significant stenosis (≤ 0.80) in 27/53 patients (51%). The availability of CT-FFR would have reduced the number of patients requiring additional testing by 57%-points compared with CCTA alone (37/53 vs. 7/53, p < 0.001). The initial management strategy would have changed for 30 patients (57%, p < 0.001). Reserving ICA for patients with a CT-FFR ≤ 0.80 would have reduced the number of ICA following CCTA by 13%-points (p = 0.016). CONCLUSION: Implementation of on-site CT-FFR may change management and improve diagnostic efficiency and effectiveness in patients with obstructive CAD on CCTA. KEY POINTS: • The availability of on-site CT-FFR in the diagnostic evaluation of patients with obstructive CAD on CCTA would have significantly reduced the number of patients requiring additional testing compared with CCTA alone. • The implementation of on-site CT-FFR would have changed the initial management strategy significantly in the patients with obstructive CAD on CCTA. • Restricting ICA to patients with a positive CT-FFR would have significantly reduced the ICA rate in patients with obstructive CAD on CCTA.

Minimal change disease: A case report.

Although minimal change disease (MCD) is a major cause of nephrotic syndrome in children, it's less common in adults. It develops from damage to the glomeruli with a loss of large amounts of protein in the urine. Early recognition and treatment is the key to a good outcome. This article describes the diagnosis, treatment, and nursing care of an adult with MCD.

Feasibility and acceptability of combining cognitive behavioural therapy techniques with swallowing therapy in head and neck cancer dysphagia.

BACKGROUND: Head and neck cancer squamous cell carcinoma (HNSSC) patients report substantial rates of clinically significant depression and/or anxiety, with dysphagia being a predictor of distress and poorer quality of life. Evidence-based dysphagia interventions largely focus on the remediation of physical impairment. This feasibility study evaluates an intervention which simultaneously uses a psychological therapy approach combined with swallowing impairment rehabilitation. METHODS: This prospective single cohort mixed-methods study, recruited HNSCC patients with dysphagia, from two institutions. The intervention combined Cognitive Behavioural Therapy with swallowing therapy (CB-EST), was individually tailored, for up to 10 sessions and delivered by a speech and language therapist. Primary acceptability and feasibility measures included recruitment and retention rates, data completion, intervention fidelity and the responsiveness of candidate outcome measures. Measures included a swallowing questionnaire (MDADI), EORTC-QLQH&N35, dietary restrictions scale, fatigue and function scales and the Hospital Anxiety and Depression Scale (HADS), administered pre-, post-CB-EST with three month follow-up and analysed using repeated measures ANOVA. Qualitative interviews were conducted to evaluate intervention processes. RESULTS: A total of 30/43 (70%) eligible patients agreed to participate and 25 completed the intervention. 84% were male, mean age 59 yrs. Patients were between 1 and 60 months (median 4) post-cancer treatment. All patients had advanced stage disease, treated with surgery and radiotherapy (38%) or primary chemoradiotherapy (62%). Pre to post CB-EST data showed improvements in MDADI scores (p = 0.002), EORTC-QLQH&N35 (p = 0.006), dietary scale (p < 0.0001), fatigue (p = 0.002) but no change in function scales or HADS. Barriers to recruitment were the ability to attend regular appointments and patient suitability or openness to a psychological-based intervention. CONCLUSIONS: CB-EST is a complex and novel intervention, addressing the emotional, behavioural and cognitive components of dysphagia alongside physical impairment. Preliminary results are promising. Further research is required to evaluate efficacy and effectiveness.

Progress towards a methodology for high throughput 3D reconstruction of soot nanoparticles via electron tomography.

The aim of this work is to make progress towards the development of 3D reconstruction as a legitimate alternative to traditional 2D characterization of soot. Time constraints are the greatest opposition to its implementation, as currently reconstruction of a single soot particle takes around 5-6 h to complete. As such, the accuracy and detail gains are currently insufficient to challenge 2D characterization of a representative sample (e.g. 200 particles). This work is a consideration of the optimization of the steps included within the computational reconstruction and manual segmentation of soot particles. Our optimal process reduced the time required by over 70% in comparison to a typical procedure, whilst producing models with no appreciable decrease in quality.

How well do services for young people with long term conditions deliver features proposed to improve transition?

BACKGROUND: For young people with long-term conditions, transition from child to adult-oriented health services is a critical period which, if not managed well, may lead to poor outcomes. There are features of transition services which guidance and research suggest improve outcomes. We studied nine such features, calling them 'proposed beneficial features': age-banded clinic; meet adult team before transfer; promotion of health self-efficacy; written transition plan; appropriate parent involvement; key worker; coordinated team; holistic life-skills training; transition manager for clinical team. We aimed to describe the extent to which service providers offer these nine features, and to compare this with young people's reported experience of them. METHODS: A longitudinal, mixed methods study followed 374 young people as their care moved from child to adult health services. Participants had type 1 diabetes, cerebral palsy or autism spectrum disorder with additional mental health difficulties. Data are reported from the first two visits, one year apart. RESULTS: Three hundred four (81.3%) of the young people took part in the second visit (128 with diabetes, 91 with autism, 85 with cerebral palsy). Overall, the nine proposed beneficial features of transition services were poorly provided. Fewer than half of services stated they provided an age-banded clinic, written transition plan, transition manager for clinical team, a protocol for promotion of health self-efficacy, or holistic life-skills training. To varying degrees, young people reported that they had not experienced the features which services said they provided. For instance, the agreement for written transition plan, holistic life-skills training and key worker, was 30, 43 and 49% respectively. Agreement was better for appropriate parent involvement, age-banded clinic, promotion of health self-efficacy and coordinated team at 77, 77, 80 and 69% respectively. Variation in the meaning of the features as experienced by young people and families was evident from qualitative interviews and observations. CONCLUSIONS: UK services provide only some of the nine proposed beneficial features for supporting healthcare transition of young people with long term conditions. Observational studies or trials which examine the influence of features of transition services on outcomes should ensure that the experiences of young people and families are captured, and not rely on service specifications.

Effects of HIV-1 Tat and Methamphetamine on Blood-Brain Barrier Integrity and Function In Vitro.

Human immunodeficiency (HIV) infection results in neurocognitive deficits in about one half of infected individuals. Despite systemic effectiveness, restricted antiretroviral penetration across the blood-brain barrier (BBB) is a major limitation in fighting central nervous system (CNS)-localized infection. Drug abuse exacerbates HIV-induced cognitive and pathological CNS changes. This study's purpose was to investigate the effects of the HIV-1 protein Tat and methamphetamine on factors affecting drug penetration across an in vitro BBB model. Factors affecting paracellular and transcellular flux in the presence of Tat and methamphetamine were examined. Transendothelial electrical resistance, ZO-1 expression, and lucifer yellow (a paracellular tracer) flux were aspects of paracellular processes that were examined. Additionally, effects on P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP-1) mRNA (via quantitative PCR [qPCR]) and protein (via immunoblotting) expression were measured; Pgp and MRP-1 are drug efflux proteins. Transporter function was examined after exposure of Tat with or without methamphetamine using the P-gp substrate rhodamine 123 and also using the dual P-gp/MRP-1 substrate and protease inhibitor atazanavir. Tat and methamphetamine elicit complex changes affecting transcellular and paracellular transport processes. Neither Tat nor methamphetamine significantly altered P-gp expression. However, Tat plus methamphetamine exposure significantly increased rhodamine 123 accumulation within brain endothelial cells, suggesting that treatment inhibited or impaired P-gp function. Intracellular accumulation of atazanavir was not significantly altered after Tat or methamphetamine exposure. Atazanavir accumulation was, however, significantly increased by simultaneous inhibition of P-gp and MRP. Collectively, our investigations indicate that Tat and methamphetamine alter aspects of BBB integrity without affecting net flux of paracellular compounds. Tat and methamphetamine may also affect several aspects of transcellular transport.

Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome.

BACKGROUND: With the exception of the presence of the FIP1L1-PDGFRA fusion gene, little is known about predictors of imatinib response in clinically-defined hypereosinophilic syndrome (HES). METHODS: Subjects with FIP1L1-PDGFRA-myeloid neoplasm (FP; n =12), PDGFRA-negative HES with ≥4 criteria suggestive of a myeloid neoplasm (MHES; n =10), or steroid-refractory PDGFRA-negative HES with <4 myeloid criteria (SR; n = 5) were enrolled in a prospective study of imatinib therapy (NCT00044304: registered at clinicaltrials.gov). The primary outcome was an eosinophil count <1.5 × 109/L at one month and improvement of clinical symptoms. Clinical, molecular, and bone marrow responses to imatinib were assessed. A retrospective cohort of 18 subjects with clinically-defined HES who received imatinib (300-400 mg daily ≥ 1 month) were classified according to the criteria used in the prospective study. RESULTS: Overall, imatinib response rates were 100% in the FP group (n = 16), 54% in the MHES group (n = 13) and 0% in the SR group (n = 16). The presence of ≥ 4 myeloid features was the sole predictor of response. After ≥ 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MHES subjects. Seven subjects (6 FP, 1 MHES) remain in remission off therapy for a median of 29 months (range 14-36). CONCLUSIONS: Clinical features of MHES predict imatinib response in PDGFRA-negative HES.

Ag-catalysed cutting of multi-walled carbon nanotubes.

In this work, the cutting of carbon nanotubes is investigated using silver nanoparticles deposited on arc discharge multi-walled carbon nanotubes. The composite is subsequently heated in air to fabricate shortened multi-walled nanotubes. Complementary transmission electron microscopy and spectroscopy techniques shed light on the cutting mechanism. The nanotube cutting is catalysed by the fundamental mechanism based on the coordination of the silver atoms to the π-bonds of carbon nanotubes. As a result of the metal coordination, the strength of the carbon-carbon bond is reduced, promoting the oxidation of carbon at lower temperature when heated in air, or lowering the activation energy required for the removal of carbon atoms by electron beam irradiation, assuring in both cases the cutting of the nanotubes.

Health-related quality of life among Indigenous Australians diagnosed with cancer.

PURPOSE: Health-related quality of life (HRQoL) and associated factors were assessed among 155 Indigenous Australian adult cancer patients 6 months post-diagnosis. METHODS: The Assessment of Quality of Life-4D Questionnaire was used to assess HRQoL. Differences in the median utility score among subgroups of interest were examined using nonparametric tests. Factors associated with excellent HRQoL were assessed through logistic regression. RESULTS: Participants' mean age was 52 years (range 20-78), and the majority were female (60 %), unemployed (72 %), and recruited from outpatients clinics (64 %). Breast cancer (27 %) was the most common diagnosis. The median HRQoL score was 0.62; 14 % of participants reported excellent HRQoL (>0.90). After adjusting for age, admission status, and treatment, excellent HRQoL was more likely among participants of Torres Strait Islander origin [adjusted odds ratio (AOR) 3.68; 95 % CI 1.23-11.01], those living in regional areas (AOR 5.59; 95 % CI 1.42-22.06), and those whose main language spoken at home was not English (AOR 3.60; 95 % CI 1.08-11.99) and less likely among those reporting less contact with Indigenous people (AOR 0.23; 95 % CI 0.68-0.81). CONCLUSION: Assessing HRQoL is important to identifying and improving the length and quality of cancer survivorship, especially in groups that have significantly poorer cancer outcomes, such as Indigenous Australians. Acknowledging the study's observational nature, we found HRQoL was lower than reported for other Australians, and we identified some socio-demographic factors that were associated with excellent HRQoL. Such assessments are an important component of identifying and evaluating appropriate interventions to improve the health and well-being of Indigenous cancer patients.

Genome-wide analysis of hepatic DNA methylation reveals impact of epigenetic aging on xenobiotic metabolism and transport genes in an aged mouse model.

Hepatic xenobiotic metabolism and transport decline with age, while intact xenobiotic metabolism is associated with longevity. However, few studies have examined the genome-wide impact of epigenetic aging on these processes. We used reduced representation bisulfite sequencing (RRBS) to map DNA methylation changes in liver DNA from mice ages 4 and 24 months. We identified several thousand age-associated differentially methylated sites (a-DMS), many of which overlapped genes encoding Phase I and Phase II drug metabolizing enzymes, in addition to ABC and SLC classes of transporters. Notable genes harboring a-DMS were Cyp1a2, Cyp2d9, and Abcc2 that encode orthologs of the human drug metabolizing enzymes CYP1A2 and CYP2D6, and the multidrug resistance protein 2 (MRP2) transporter. Cyp2d9 hypermethylation with age was significantly associated with reduced gene expression, while Abcc2 expression was unchanged with age. Cyp1a2 lost methylation with age while, counterintuitively, its expression also reduced with age. We hypothesized that age-related dysregulation of the hepatic transcriptional machinery caused down-regulation of genes despite age-related hypomethylation. Bioinformatic analysis of hypomethylated a-DMS in our sample found them to be highly enriched for hepatic nuclear factor 4 alpha (HNF4α) binding sites. HNF4α promotes Cyp1a2 expression and is downregulated with age, which could explain the reduction in Cyp1a2 expression. Overall, our study supports the broad impact of epigenetic aging on xenobiotic metabolism and transport. Future work should evaluate the interplay between hepatic nuclear receptor function and epigenetic aging. These results may have implications for studies of longevity and healthy aging.

Universal pre-mixing dry-film stickers capable of retrofitting existing microfluidics.

Integrating microfluidic mixers into lab-on-a-chip devices remains challenging yet important for numerous applications including dilutions, extractions, addition of reagents or drugs, and particle synthesis. High-efficiency mixers utilize large or intricate geometries that are difficult to manufacture and co-implement with lab-on-a-chip processes, leading to cumbersome two-chip solutions. We present a universal dry-film microfluidic mixing sticker that can retrofit pre-existing microfluidics and maintain high mixing performance over a range of Reynolds numbers and input mixing ratios. To attach our pre-mixing sticker module, remove the backing material and press the sticker onto an existing microfluidic/substrate. Our innovation centers around the multilayer use of laser-cut commercially available silicone-adhesive-coated polymer sheets as microfluidic layers to create geometrically complex, easy to assemble designs that can be adhered to a variety of surfaces, namely, existing microfluidic devices. Our approach enabled us to assemble the traditional yet difficult to manufacture "F-mixer" in minutes and conceptually extend this design to create a novel space-saving spiral F-mixer. Computational fluid dynamic simulations and experimental results confirmed that both designs maintained high performance for 0.1 < Re < 10 and disparate input mixing ratios of 1:10. We tested the integration of our system by using the pre-mixer to fluorescently tag proteins encapsulated in an existing microfluidic. When integrated with another microfluidic, our pre-mixing sticker successfully combined primary and secondary antibodies to fluorescently tag micropatterned proteins with high spatial uniformity, unlike a traditional pre-mixing "T-mixer" sticker. Given the ease of this technology, we anticipate numerous applications for point-of-care devices, microphysiological-systems-on-a-chip, and microfluidic-based biomedical research.

Osteoporosis and fracture as risk factors for self-harm and suicide: a systematic review and meta-analysis.

BACKGROUND: Increase in presentations of self-harm to primary care, a risk factor of suicide, has led to a growing interest in identifying at-risk populations. AIM: To examine whether osteoporosis or fractures are risk factors for self-harm, suicidal ideation, and suicide. DESIGN AND SETTING: This was a systematic review of observational studies in adults (>18 years) that had examined the role of osteoporosis and/or fractures in subsequent self-harm, suicidal ideation, and/or suicide. METHOD: Six databases were searched from inception to July 2019. Additional citation tracking of eligible studies was undertaken in November 2022. Screening, data extraction, and quality assessment of full-text articles were performed independently by at least two authors. Where possible, meta-analysis was run on comparable risk estimates. RESULTS: Fifteen studies were included: two examined the outcome of self-harm, three suicidal ideation, and 10 suicide. In approximately half of studies on osteoporosis, the risk of suicidal ideation and suicide remained significant. However, pooling of adjusted odds ratios from three studies indicated no association between osteoporosis and suicide (1.14, 95% confidence interval = 0.88 to 1.49). Nine studies examined the risk of a mixture of fracture types across different outcomes, limiting comparisons. However, all studies examining vertebral fracture (n = 3) reported a significant adjusted negative association for self-harm and suicide. CONCLUSION: Patients with vertebral fractures, a risk potential factor for suicide, may benefit from clinical case finding for mood disorders with personalised primary care management. However, because of the limited number and quality of studies and mixed findings, further examination of these associations is warranted.

Association of Migraine Headache With Depression, Anxiety, and Stress in the Population of Makkah City, Saudi Arabia: A Cross-Sectional Study.

Introduction Migraine is characterized by persistent headaches and a wide range of symptoms, such as nausea, vomiting, and photophobia. The chance of developing a chronic migraine might be increased by lifestyle variables like obesity, stress, and excessive medication use. According to previous studies in Saudi Arabia, migraines are more common there than they are globally. The study aimed to examine the migraine associations with depression, anxiety, and stress in the population of Makkah City, Saudi Arabia. Methods The study employed a descriptive cross-sectional design with a non-probability snowball sampling technique and an online questionnaire that included sociodemographic characteristics, the International Classification of Headache Disorders-3 (ICHD-3) criteria for migraine assessment, and the Depression, Anxiety, and Stress Scale-21 (DASS-21) measure for depression, anxiety, and stress. Results Our study included 418 participants, out of whom 73.7% were female and 26.3% were male. Regarding migraine, only 8.9% of participants met the ICHD-3 criteria for migraine headache screening, with a female predominance (78.4%). The study showed a high prevalence of depression, anxiety, and stress among the population (63.9%, 63.6%, and 55%, respectively), with females having a higher prevalence. Depression, anxiety, and stress had an equal prevalence of 78.4% among migraineurs, which was significantly higher than that of non-migraineurs. Conclusions The study found significant associations between migraine and depression, anxiety, and stress. This study provides insights into the association between these conditions. The study's findings suggest the need for screening and management of mental health conditions in patients with migraine. However, extensive efforts are needed to be applied in different cities and demographics for a more precise understanding of the association.