Search Results (118)

Background: Doppler-guided haemorrhoidal artery ligation with rectoanal repair (HAL-RAR) is a minimally invasive alternative to conventional haemorrhoidectomy. While associated with reduced postoperative pain and quicker recovery, data on its safety, recurrence rates, and applicability across haemorrhoid grades remain limited, particularly in Australian settings. Methods: A retrospective review was conducted on 128 consecutive patients who underwent elective HAL-RAR at a single institution between February 2022 and December 2024. Data on demographics, operative details, postoperative outcomes, and recurrence were collected. Outcomes were stratified by haemorrhoid grade. Multivariate logistic regression was used to identify predictors of recurrence, day-case completion, and conversion to excisional surgery. Results: The median age was 49 years, and 77.3% had Grade II or III haemorrhoids. HAL-RAR was completed as a day case in 76.6% of patients. Postoperative urinary retention occurred in 3.9%, return to theatre in 0.8%, and 30-day readmission in 7.0%. The symptomatic recurrence rate was 17.6%. Grade IV haemorrhoids were independently associated with increased recurrence (aOR 3.64, 95% CI 1.03–12.84), reduced likelihood of day-case management (aOR 0.14, 95% CI 0.03–0.93), and higher conversion to excisional haemorrhoidectomy (aOR 7.23, 95% CI 1.13–46.40). Conclusions: HAL-RAR is a safe, effective, and low-morbidity option for the management of Grade II and III haemorrhoids, suitable for day-case surgery. In selected Grade IV cases, it may offer benefit, although with higher recurrence and conversion risk. Careful patient selection is essential, and longer-term prospective studies are needed to assess durability. Full article

Background/Objectives: Prostate cancer (PCa) is diagnosed at an earlier median age, more advanced stage, and has worse clinical outcomes in African American (AA) men compared to European Americans (EA). Methods: To investigate the role of aberrant DNA methylation in tumor-adjacent stroma (TAS), methyl binding domain sequencing (MBD-seq) was performed on AA (n = 17) and EA (n = 15) PCa patients. This was independently confirmed using the long interspersed nuclear element-1 (LINE-1) assay. Pathway analysis was performed on statistically significantly differentially methylated genes for AA and EA TAS. DNA methylation profiles of primary cultured AA and EA carcinoma-associated fibroblasts (CAFs) were compared with AA and EA TAS. AA and EA CAFs were treated with demethylating agent 5-Azacytidine (5-AzaC). Results: AA TAS exhibited higher global DNA methylation than EA TAS (p-value < 0.001). Of the 3268 differentially methylated regions identified (DMRs, p-value < 0.05), 85% (2787 DMRs) showed increased DNA methylation in AA TAS, comprising 1648 genes, of which 1379 were protein-coding genes. Based on DNA methylation levels, two AA subgroups were identified. Notably, AA patients with higher DNA methylation were predominantly those with higher Gleason scores. Pathway analysis linked methylated genes in AA TAS to several key signaling pathways (p-value < 0.05), including immune response (e.g., IL-1, IL-15, IL-7, IL-8, IL-3, and chemokine), Wnt/β-catenin, androgen, PTEN, p53, TGF-β, and circadian clock regulation. A total of 168 concordantly methylated genes were identified, with 109 genes (65%) showing increased methylation in AA CAFs and TAS (p-value < 0.05). Treatment with 5-AzaC significantly reduced DNA methylation of concordant genes in AA CAFs (p-value < 0.001). Conclusions: These findings suggest a distinct stromal methylome in AA, providing a foundation for integrating demethylating agents into standard therapies. This approach targets the tumor microenvironment, potentially addressing PCa disparities in AA men. Full article

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive subtype of non-Hodgkin lymphoma, the monitoring of which is largely restricted to radiological methods. Diagnosis relies on identifying characteristic clinicopathological features, supported by the detection of recurrent somatic mutations in RHOA, TET2, IDH2 and DNMT3A. The characteristic molecular profile of AITL and the high levels of circulating tumour DNA (ctDNA) measurable in AITL before treatment makes this an attractive lymphoma subtype in which to further investigate the role of ctDNA monitoring. The detection of somatic mutations in pre-treatment AITL-containing tissue samples was compared to those detected in pre-treatment ctDNA samples in a cohort of 12 patients. Changes in ctDNA somatic mutation burden over time were then correlated with radiological response. All six paired pre-treatment ctDNA and tissue samples had variants in common. All (8/8) previously ctDNA-detectable IDH2 and RHOA variants were undetectable in ctDNA samples at the time of end-of-treatment complete metabolic response (CMR). In comparison, the majority of both previously ctDNA-detectable DNMT3A variants (3/4) and TET2 variants (6/11) were detectable in ctDNA samples at the time of end-of-treatment CMR. These observations suggest that IDH2/RHOA variants may be more reliable markers of measurable residual disease in AITL than DNMT3A/TET2 variants. Full article

Background: The Xpert MTB/RIF Ultra assay (Ultra) is a second-generation molecular diagnostic test for tuberculosis (TB). The “Trace Call” result was added as a semi-quantitative category for extremely low bacillary loads. The prevalence and interpretation of Trace Call results remains insufficiently elucidated in the context of community-based active case finding (ACF). Methods: We organized 56 days of mobile chest X-ray (CXR) screening events in Ho Chi Minh City, Viet Nam, between October 2020 and March 2021. Participants were screened verbally and by CXR and tested by Ultra, if eligible. Persons with a Trace Call were re-tested on Ultra per national guidelines. qXRv3 computer-aided detection software was used for post hoc quality control of CXR interpretation. We calculated descriptive statistics and fitted mixed-effect multivariate regression models to identify factors associated with Trace Call results and confirmatory diagnosis. Results: A total of 16,698 people were screened by CXR to detect 185 Ultra-positive participants, including 142 persons with a confirmed TB diagnosis. Among Ultra-positive participants, 38.4% (71/185) had Trace Call results. Of these, 85.9% (61/71) were re-tested, and 45.9% (28/61) were bacteriologically-confirmed, comprising 19.7% (28/142) of the final number of confirmed diagnoses. Having a low qXR abnormality score (<0.5) (aOR = 4.97; 95%CI: [1.88, 13.14]; p = 0.001) and a history of TB within 5 recent years (aOR = 3.53; 95%CI: [1.69, 7.35]; p = 0.001) were associated with an initial Trace Call. Conclusions: The Trace Call can improve ACF detection, particularly in earlier stages of disease with limited pulmonary deterioration. However, participants with a history of TB had higher rates of Trace Call, reinforcing the need to interpret test results in this group with caution. Full article

Fecal microbiota transplantation (FMT) is the most effective therapy for preventing recurrent Clostridioides difficile infection (rCDI). However, the impact of FMT formulations and storage conditions on bacterial viability, community structure, functionality, and clinical efficacy remains under-investigated. We studied the effect of different storage conditions on the bacterial viability (live/dead staining and cell sorting), community structure (16S rDNA analysis), and metabolic functionality (fermentation) of frozen and lyophilized FMT formulations. The clinical success rates of rCDI patients were correlated retrospectively with FMT formulations, storage durations, and host factors using the Edmonton FMT program database. Bacterial viability remained at 10–20% across various storage conditions and formulations and was comparable to that of fresh FMT. Live and dead bacterial fractions in both frozen and lyophilized FMT preparations exhibited distinct community structures. Storage durations, but not temperatures, negatively affected bacterial diversity. More short-chain fatty acids were found in the metabolomic profiling of in vitro fermentation products using lyophilized than frozen FMT. Clinical success rates in 537 rCDI patients receiving a single dose of FMT were not significantly different among the three formulations. However, longer storage durations and advanced recipient age negatively impacted clinical efficacy. Together, our findings suggest that FMT formulations and storage durations should be considered when establishing guidelines for product shelf life for optimal treatment outcomes. Full article

Background: Although the Patient Protection and Affordable Care Act (ACA) has been associated with increased Medicaid coverage among prostate cancer patients, the association between Medicaid expansion with risk group at diagnosis, time to treatment initiation (TTI), and the refusal of locoregional treatment (LT) among patients requires further exploration. Methods: Using the National Cancer Database, we performed a retrospective cohort analysis of all patients aged 40 to 64 years diagnosed with localized prostate cancer from 2011 to 2016. Difference-in-difference (DID) analysis was used to compare changes in insurance status, risk group at diagnosis, TTI, and the refusal of LT among patients residing in Medicaid expansion versus non-expansion states. In a secondary analysis, we used DID to compare changes in the above outcomes among racial minorities versus White patients living in expansion states. Results: Of the 112,434 patients with prostate cancer in our analysis, 50,958 patients lived in Medicaid expansion states, and 61,476 patients lived in non-expansion states. In the adjusted analysis, we found that the proportion of uninsured patients (adjusted DID: −0.87%; 95% confidence interval [95% CI]: −1.28 to −0.46) and patients who refused radiation therapy (adjusted DID: −0.71%; 95% CI: −0.95 to −0.47) decreased more in expansion states compared to non-expansion states. Similarly, we observed that the racial disparity of select outcomes in expansion states narrowed, as racial minorities experienced larger absolute decreases in uninsured status and the refusal of radiation therapy (RT) regimens than White patients following ACA implementation (p < 0.01 for all). However, residence in a Medicaid expansion state was not associated with changes in risk group at diagnosis, TTI, nor the refusal of LT (p > 0.01 for all); racial disparities in TTI were also exacerbated in expansion states following ACA implementation. Conclusions: The association between Medicaid expansion and prostate cancer outcomes and disparities remains unclear. While ACA implementation was associated with increased insurance coverage and decreased refusal of RT, there was no significant association with earlier risk group at diagnosis, TTI within 180 days, or refusal of LT. Similarly, racial minorities in expansion states had larger decreases in uninsured status and the refusal of RT regimens, as well as smaller increases in intermediate-/high-risk disease at presentation than White patients following ACA implementation, but experienced no significant changes in TTI. More research is needed to understand how Medicaid expansion affects cancer outcomes and whether these effects are borne equitably among different populations. Full article

Serological surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies is important to monitor population COVID-19 immunity. Dried blood spots (DBS) are a valuable method for serosurveys, particularly in remote settings and in children. We compared the measurement of SARS-CoV-2 spike-specific IgG in paired blood samples collected using standard venepuncture (serum) and the hemaPEN^® microsampling DBS device from children and adults. A total of 83 participants (10 months to 65 years of age), comprising COVID-positive and -negative participants, were recruited. Paired serum and DBS samples were assayed for SARS-CoV-2 receptor-binding domain (RBD) and Spike (S1) antibodies using an established in-house ELISA. RBD and S1 IgG concentrations of paired hemaPEN DBS eluates and serum samples were compared using a non-parametric Wilcoxon matched-pairs signed ranked test. A Pearson’s correlation was used for RBD and S1 IgG concentrations and the level of agreement between the hemaPEN DBS eluates and serum samples was assessed by Bland–Altman analysis. A total of N = 41 adults (36 COVID-positive and 5 COVID-negative), and N = 42 children (37 COVID-positive, and 5 COVID-negative) have paired serum and DBS assayed. We found moderate to strong correlations between paired hemaPEN DBS eluates and serum SARS-CoV-2 IgG antibodies for RBD (r = 0.9472, p < 0.0001) and S1 proteins (r = 0.6892, p < 0.0001). Similar results were observed in both adult and paediatric populations. No significant differences in S1-specific IgG levels were observed in hemaPEN DBS samples stored for up to 35 weeks at room temperature. Eluted hemaPEN samples showed high specificity and sensitivity (100% and 89.89%, respectively) compared with serum. The use of the microsampling hemaPEN device for DBS sample collection is a feasible approach for assessing SARS-CoV-2 antibodies for serosurveillance studies, particularly in remote settings and in children. Full article

Background: Pharmacokinetic drug–drug interactions (DDIs) can be caused by the effect of a pharmaceutical compound on the activity of one or more subtypes of the Cytochrome P450 (CYP) family, UDP-glucuronosyltransferases (UGTs), and/or transporters. As the number of therapeutic areas with polypharmacy has increased, interest has grown in assessing the risk of DDIs during the early phases of drug development. Various lines of research have led to improved mathematical models to predict DDIs, culminating in the Food and Drug Administration’s (FDA) guidelines on evaluating pharmacokinetic DDI risks. However, the recommended static models are highly conservative and often result in false positive predictions. The current research aims to improve the workflow for assessing CYP-mediated DDI risk using Boehringer Ingelheim (BI) proprietary compounds. Methods: The Drug–drug Interaction Risk Calculator (PharmaPendium) was used to evaluate the mechanistic static model, and predictions were correlated with human pharmacokinetic studies from Phase I clinical trials. Results: The results demonstrated that the FDA formula performed well in predicting DDIs for BI proprietary compounds. Furthermore, the integration of either human renal excretion or preclinical species total excretion data into the mechanistic static model enhanced the predictive performance for candidate drugs as victims in DDIs. Conclusions: The basic static models (BSMs) for drug interactions should be used in early drug discovery to “rule out” DDI risks because of the minimal inputs required and the low rate of false negative predictions. Mechanistic static models (MSMs) can then be implemented for compounds that require additional evaluation. Full article

Background: Receptor Expressed in Lymphoid Tissues (RELT) is a TNFRSF member that has two paralogs, RELL1 and RELL2; the three proteins are collectively referred to as RELT family members (RELTfms). Methods: We sought to evaluate RELT expression in cancerous cells by using real-time PCR, western blotting, flow cytometry, and immunohistochemistry (IHC). The mechanism of RELT-induced cell death was assessed by western blotting, flow cytometry, luciferase assays, and morphology staining. RELT localization was detected through immunofluorescence and western blotting, and co-immunoprecipitation was used to test whether a mutated RELT interacts with the OXSR1 kinase. Results: RELT and RELL1 protein expression was significantly elevated in cell lines representing breast and lung cancer, whereas RELL2 protein expression was relatively consistent across different cell lines. The surface expression of RELT was highest in monocytes. IHC staining revealed increased RELT expression in malignant breast cancer biopsies compared to patient-matched benign tissue. RELTfm overexpression induced death in MDA-MB-231 (231) breast cancer cells, accompanied by increased phosphatidylserine externalization and Caspase-3/7 activation. The co-transfection of plasmids predicted to block the phosphorylation of RELT by the OXSR1 kinase did not abrogate RELT-induced apoptosis, indicating that the activation of p38 by RELT through the OXSR1 kinase is not required for RELT-induced cell death. Interestingly, nuclear localization of RELT was detected in 231 and HEK-293 cells. Conclusions: These results demonstrate that RELT induces death in breast cancer cells through an apoptotic pathway that does not require OXSR1 phosphorylation and that RELT possesses the ability to translocate to the nucleus, a novel finding that warrants further investigation. Full article

Diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus, is primarily characterized by damage to Schwann cells caused by oxidative stress under hyperglycemic conditions. Recently, we demonstrated the ability of coumarin-rich Ficus formosana Maxim. to alleviate DPN in ovariectomized diabetic mice. However, the underlying mechanisms remain unclear. In this study, we established an in vitro DPN model using RSC96 Schwann cells exposed to high glucose levels. Daphnetin, a natural coumarin found abundantly in Ficus formosana Maxim., was co-incubated with Schwann cells in a high-glucose medium to investigate its protective effects against DPN. The free radical scavenging capacity of daphnetin was evaluated, along with assessments of cell viability, apoptosis, H₂O₂ levels, and the expression of proteins by the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutamate–cysteine ligase catalytic subunit (GCLC) pathway in RSC96 Schwann cells. The results showed that daphnetin was non-toxic within the tested concentration range of 6.25 μM to 50 μM in RSC96 Schwann cells. Moreover, daphnetin significantly improved cell viability, exhibited strong antioxidant activity, reduced H₂O₂ levels, and regulated the Nrf2/GCLC pathway protein expressions in RSC96 cells cultured in high-glucose medium. Additionally, daphnetin influenced apoptosis-related proteins by decreasing the expression levels of Bax and Caspase 3, while increasing the Bcl-2 expression level in high-glucose-treated RSC96 cells. These findings suggest that daphnetin may alleviate oxidative stress induced by high glucose levels through activation of the Nrf2/GCLC pathway and inhibition of Schwann cell apoptosis, underscoring its potential as a therapeutic agent for DPN. Full article

Background: Patients with skin lesions suspicious for skin cancer or atypical melanocytic nevi of uncertain malignant potential often present to dermatologists, who may have variable dermoscopy triage clinical experience. Objective: To evaluate the clinical utility of a digital dermoscopy image-based artificial intelligence algorithm (DDI-AI device) on the diagnosis and management of skin cancers by dermatologists. Methods: Thirty-six United States board-certified dermatologists evaluated 50 clinical images and 50 digital dermoscopy images of the same skin lesions (25 malignant and 25 benign), first without and then with knowledge of the DDI-AI device output. Participants indicated whether they thought the lesion was likely benign (unremarkable) or malignant (suspicious). Results: The management sensitivity of dermatologists using the DDI-AI device was 91.1%, compared to 84.3% with DDI, and 70.0% with clinical images. The management specificity was 71.0%, compared to 68.4% and 64.9%, respectively. The diagnostic sensitivity of dermatologists using the DDI-AI device was 86.1%, compared to 78.8% with DDI, and 63.4% with clinical images. Diagnostic specificity using the DDI-AI device increased to 80.7%, compared to 75.9% and 73.6%, respectively. Conclusion: The use of the DDI-AI device may quickly, safely, and effectively improve dermoscopy performance, skin cancer diagnosis, and management when used by dermatologists, independent of training and experience. Full article

Background/Objectives: This retrospective study evaluates outcomes of 66 patients who underwent reirradiation (re-RT) with proton beam therapy (PBT) for recurrent non-small cell lung cancer. Methods: Toxicity was scored via the CTCAE v5.0, and outcomes estimated using the Kaplan–Meier method, with associations evaluated via Cox proportional hazards and logistic regression analyses. Results: Patients were treated to a median re-RT prescription of 66 Gy/33 fxs (BED10 = 79 Gy; IQR: 71–84 Gy) at an interval of 1.4 years from prior RT. Half (50%) received concurrent chemotherapy. At 14 months follow-up, the median OS and PFS were 5 months (95%CI: 13–17) and 12.5 months (95%CI: 10–15), respectively. On multivariable analysis, a higher RT dose (BED10 > 70 Gy) [HR0.37; 95%CI: 0.20–0.68, p = 0.001] and concurrent chemotherapy (HR0.48; 95%CI: 0.28–0.81, p = 0.007) were associated with improved PFS, while treatment site overlap was adversely associated (HR1.78; 95%CI: 1.05–3.02, p = 0.031). The median PFS for definitive RT with concurrent chemotherapy (n = 28), definitive RT alone (BED10 > 70 Gy) [n = 22], and lower prescription RT (BED10 < 70 Gy) [n = 16] was 15.5 months (95%CI: 7.3–23.7), 14.1 months (95%CI: 10.9–17.3), and 3.3 months (95%CI: 0–12.3), respectively (log-rank, p = 0.006), with corresponding 2-year estimates of 37% (±9), 18% (±8), and 12.5% (±8), respectively. The incidence of Grade 3+ toxicity was 10.5% (6% pulmonary; 3% esophageal; and 1.5% skin), including one Grade 4 bronchopulmonary hemorrhage but no Grade 5 events. Cases with central site overlap had higher composite Dmax to the esophagus (median 87 Gy [IQR:77–90]), great vessels (median 120 Gy [IQR:110–138]), and proximal bronchial tree (median 120 Gy [IQR:110–138]) as compared to other cases (p ≤ 0.001 for all). However, no significant associations were identified with Grade 3+ events. Conclusions: Thoracic re-RT with PBT is an option for recurrent NSCLC with acceptable outcomes and toxicity for select patients. When feasible, higher prescription doses (BED10 > 70 Gy) should be delivered for definitive intent, and concurrent chemotherapy may benefit individual cases. Full article

Background/Objectives: This retrospective cohort study evaluated the relative vaccine effectiveness (rVE) of two bivalent (original/Omicron BA.4/BA.5) vaccines mRNA-1273.222 versus the BNT162b2 Bivalent in preventing COVID-19-related outcomes in adults with underlying medical conditions associated with increased risk for severe COVID-19. Methods: In a linked electronic health record/claims dataset, US adults (≥18 years) with ≥1 underlying medical condition of interest who received either the bivalent vaccine between 31 August 2022 and 28 February 2023 were identified. The inverse probability of treatment weighting was used to adjust for cohort differences. Cohorts were followed up for COVID-19-related hospitalizations and outpatient encounters until 31 May 2023. Hazard ratios and rVEs were estimated using Cox regression. Subgroup analyses were performed on individuals with pre-specified comorbid conditions. Results: 757,572 mRNA-1273.222 and 1,204,975 BNT162b2 Bivalent recipients were identified. The adjusted rVE over a median follow-up of 198 days was 10.9% (6.2%–15.2%) against COVID-19-related hospitalization and 3.2% (1.7%–4.7%) against COVID-19-related outpatient encounters. rVE estimates for COVID-19 hospitalizations among subgroups with comorbid conditions were as follows: diabetes 15.1% (8.7%–21.0%), cerebro- and cardiovascular disease 14.7% (9.0%–20.1%), chronic lung disease 11.9% (5.1%–18.2%), immunocompromised 15.0% (7.2%–22.2%), chronic kidney disease 8.4% (0.5%–15.7%). Conclusions: Overall, among adults with underlying medical conditions, mRNA-1273.222 was more effective than BNT162b2 Bivalent, especially in preventing COVID-19-related hospitalizations. Full article

Some preterm and sick neonates have altered biochemical profiles and follow-up newborn screening (NBS) collections are recommended. The Victorian NBS program historically recommended repeat collections for babies with birth weight < 1500 g (managed by the maternity service provider) and 3 weeks post-transfusion (managed by the laboratory). We aimed to determine adherence to current guidelines and review the guidelines to improve NBS performance. To do this, we audited data from 348,584 babies between January 2018 and June 2022. Babies with a recorded birth weight of <1500 g were filtered for inclusion. For the overall review and visualization of the protocol, we sourced information from the literature, our professional society and tertiary hospital services. A total of 2647 babies had a birth weight recorded between 200 and 1499 g. Of these, 2036 (77%) had a second sample collected, indicating that >1 in 5 babies were not receiving a follow-up collection. Our timing of repeat collections for transfused babies, requiring a 3-week follow-up collection, was longer than in other Australasian jurisdictions. A new combined “sick–prem protocol” was launched to support repeat collections and after a 1-year review achieved 95% compliance. We recommend NBS laboratories audit preterm and sick neonate repeat collections to ensure appropriate follow-up. This should be supported with a visual process map to aid education and compliance. Full article

Vietnam is a country most at risk for experiencing climate change effects, especially increasing temperatures. Agricultural production is one of the biggest contributors to Vietnam’s economy. Recent research has explored how climate change will impact agriculture in Vietnam. However, the impact of climate change to the health, safety, and wellbeing of Vietnamese farmers is often overlooked. In this study, we conducted five focus groups with 46 farmers representing three provinces of Vietnam. We used a convergent mixed-methods design and a Total Worker Health^® framework to assess how farmers in Vietnam experience climate-change-related hazards and describe how famers associate these hazards with impacts to their health, safety, and wellbeing. Multi-dimensional scaling suggests farmers conceptualize hazards separately from health, safety, and wellbeing outcomes, but a thematic analysis of our data indicated that farmers perceive both direct and indirect impacts of climate change to their health, safety, and wellbeing. Direct impacts of climate change described included physical health effects such as heat stress. Indirect impacts included mental health stressors due to productivity demands. Gaps in available health and safety trainings for farmers were also identified. This project demonstrates the need to co-develop safety and health trainings with farmers. System-level approaches both at the societal and community levels are needed. The local governments, cooperatives, Women’s Unions, and Farmers’ Unions are trusted sources of information that could implement and disseminate these trainings. Full article