Saint Vincent's Catholic Medical Center

<title>Abstract</title> Psoriasis is characterized by a complex immune micro-environment, yet most spatial studies rely on two-dimensional (2D) immunohistochemistry (IHC) histology. We investigated whether routine immunohistochemistry coupled with three-dimensional (3D) digital reconstruction can provide quantitative insight into immune-epithelial architecture across the psoriatic spectrum. Skin biopsies from 15 patients with plaque psoriasis and 52 healthy donors were serially sectioned to generate 174 tissue stacks (10,700 whole-slide images). CD3 ⁺ , CD68 ⁺ and mast cell were labelled and their Euclidean distance to dermal–epidermal junction (DEJ) were calculated in 3D. Compared with controls, lesional skin showed pronounced super-ficialisation of immune clusters: median CD3 ⁺ and CD68 ⁺ cluster distance to DEJ significantly decreased. Mast cell distribution revealed a biphasic pattern: peri-lesional area displayed decreased cell density at deeper dermal levels, whereas established plaques demonstrated higher cell density at superficial dermis. Averaging multiple 2D sections obscured these distributional features, underlining the necessity of volumetric analysis. High-resolution 3D reconstruction reliably maps the spatial dynamics of T cells, macrophages and mast cells in psoriasis and detects subclinical immunological priming in peri-lesional skin. The proposed pipeline bridges routine pathology and advanced spatial omics, offering a scalable tool for early disease detection, patient stratification and therapeutic monitoring.

Background and ObjectivesStereoelectroencephalography (SEEG) is increasingly used worldwide for epilepsy presurgical evaluation. A data-driven view of SEEG practice evolution is lacking for any world region. We aimed to perform a nationwide survey of SEEG use in Australian adult epilepsy centers. We predicted that the proportion of nonlesional MRI cases, number of electrodes, and radiofrequency thermocoagulation (RF-TC) use would increase over time.MethodsAll epilepsy centers in Australia undertaking SEEG in patients older than 16 years at any time were invited to participate in a nationwide survey. Data were retrospectively and/or prospectively collected on patient demographics and SEEG exploration. Descriptive statistics were used.ResultsA total of 281 SEEG explorations were performed in 8 centers from 2012 until 2023, 278 of which (99%) are reported here. A definite epileptogenic MRI lesion was present in 30.6% with no overall significant growth in the proportion of nonlesional cases (χ² [1, N = 278] = 0.067, p = 0.79), although this varied per center. Patients identifying as Indigenous Australians comprised 1.6% of this national SEEG survey vs an estimated national indigenous population of 3.8%. The median number of electrodes increased from 8 in 2012 to 15 in 2023. A total of 174 patients (62.6%) were offered resective surgery after SEEG. Surgery was performed with 1-year follow-up in 114, of whom 72.8% were seizure-free at the last follow-up. The presence/absence of an MRI lesion was not associated with postoperative seizure-free outcomes (χ² [1, N = 114] = 0.06, p = 0.80). RF-TC use differed between centers and evolved, with a crossover to the majority use of RF-TC occurring 5 years after regulatory approval.DiscussionThis comprehensive nationwide and regional survey of SEEG practice comprises full ascertainment of all centers and allows analysis of changes in practice over time. Whole cohort results show a high proportion of nonlesional MRI cases achieving satisfactory surgical outcomes and evolution to increased RF-TC use. Indigenous access to SEEG seems to be lower than expected, consistent with broader health care access issues for this population group. Nationwide collaboration on SEEG data provides a basis for analysis of practice at the individual center and state and national levels to optimize health care planning and sharing of expertise.

Fluid transport in the neurovascular unit is essential for maintaining brain health through nutrient delivery and waste clearance. However, these systems are complex and the inter-dependencies between elements of these systems and how they may change through aging is not well understood. MRI outcomes provide insight into the underlying biological mechanisms of these systems in vivo, including water exchange rate through the neurovascular unit (BBB kw), enlarged perivascular spaces (ePVS), cerebral blood flow (CBF), free water (FW), and white matter hyperintensities (WMH). To explore the relationships between functional elements of the neurovascular unit, this study investigated relationships between these MRI measures using Bayesian mixed models, and their variation with chronological age or atrophy-related brain age (brainageR) using linear regression. In 132 non-clinical older adults (mean age = 67 years; 68% female), BBB kw positively associated with CBF (β^ = 0.08, 95% credible interval (CI) = [0.02, 0.15]). FW positively associated with both ePVS (β^ = 0.44, CI = [0.30, 0.63]) and WMH (β^ = 0.13, CI = [0.04, 0.21]). BBB kw, CBF and ePVS decreased with age, while FW and WMH increased (all p < 0.05). There were no associations with atrophy-related brain age (all p > 0.05). Relationships between FW, ePVS and WMH likely reflect interconnectivity of fluid regulation within different compartments, while the relationship between BBB kw and CBF indicates a link between neurovascular fluid flow and vessel function. While individual metrics of neurovascular integrity are associated with age, their inter-relationships appear stable, providing a baseline for future research in fluid transport and vascular health in neurodegenerative disease.Graphical

Renal ischemia-reperfusion injury (IRI) is a common complication in several clinical scenarios including kidney transplantation. Mannan-binding lectin-associated serine proteinase (MASP)-2 is essential for activation of the complement lectin pathway, which has been implicated in the pathogenesis of renal IRI and therefore represents a potential therapeutic target. We developed a new, affinity-enhanced MASP-2 inhibitor, EVO24, by directed evolution of the D2 domain of human tissue factor pathway inhibitor. EVO24 was fused with a human IgG1-Fc to create the homodimer EVO24L, which potently and selectively inhibited the lectin pathway in human and mouse serum in vitro. EVO24L was tested in a mouse model of unilateral warm renal IRI. EVO24L administered before and after ischemia significantly protected against IRI, with improved renal function as well as reduced tubular injury and inflammatory cell infiltration at 24 h compared to vehicle-treated mice. Immunofluorescence analyses showed reduced deposition of complement components (C3d, C4d, and C9) and reduced expression of VCAM-1, indicating a decrease in complement activation and endothelial cell activation. Additionally, EVO24L treatment lowered plasma levels of complement C5a, hyaluronan (a marker of endothelial glycocalyx shedding), and the proinflammatory cytokines IL-6 and TNF-α. Our findings indicate that EVO24L inhibits acute inflammatory responses in renal IRI by blocking the lectin pathway, confirming the important role of this pathway in acute ischemic kidney injury and warranting further investigation of EVO24L in clinical settings.

Abstract Background Prostate-specific membrane antigen (PSMA) receptor expression alters in response to androgen receptor blockade in metastatic castrate resistant prostate cancer (mCRPC). The ENZA-p trial (ANZUP 1901) demonstrated that the addition of [177Lu]Lu-PSMA-617 to enzalutamide improved overall survival (OS) in mCRPC. In this preplanned imaging substudy, we evaluated the frequency and clinical significance of early changes in PSMA-PET standardised uptake value (SUV) mean with enzalutamide ± [177Lu]Lu-PSMA-617. Materials and Methods Participants in ENZA-p had mCRPC not previously treated with chemotherapy or AR antagonist (abiraterone permitted), [68Ga]Ga-PSMA-avid disease, and at least two risk factors for early progression on enzalutamide alone. Participants were randomised (1:1) to either enzalutamide 160 mg daily or enzalutamide 160 mg daily plus adaptive-dosed [177Lu]Lu-PSMA-617 7.5 GBq (2 or 4 doses). Participants underwent a 68Ga-PSMA-PET/CT at baseline and day 15 after commencing enzalutamide, with [177Lu]Lu-PSMA-617 administered subsequently in the experimental arm. All 68Ga-PSMA-PET/CT were analysed with semi-automated software to derive PSMA SUVmean. The study investigated the relationship between early change in SUVmean and the following clinical outcomes: 50% PSA decline (PSA-50), PSA progression-free survival (PSA-PFS), and OS. Results We randomised 162 pts from Aug 2020 to Jul 2022, all of whom underwent baseline imaging. Of the treated participants 96% (154 out of 160) received a PSMA PET/CT at day 15 after commencing enzalutamide. The median age was 71 years (interquartile range, IQR: 65-76), with 53% having received prior docetaxel and 14% prior abiraterone. An increase in SUVmean at day 15, regardless of magnitude was recorded in 105 out of 154 (68%). Among these participants, the median increase in SUVmean was 13% (IQR: 6.0% - 22%). The median PSA-PFS in pts with increasing SUVmean by treatment arm was 5.8 months vs 13.1 months for enzalutamide monotherapy vs enzalutamide plus [177Lu]Lu-PSMA-617 respectively (Log-rank p &lt; 0.001). By contrast, in those with decreasing SUVmean, median PSA-PFS was 12.5 vs 13.3 months for enzalutamide monotherapy vs enzalutamide plus [177Lu]Lu-PSMA-617 (Log-rank p = 0.5). The p-value for an interaction between early increase or decrease in SUVmean and treatment arm for PSA-PFS was p=0.055. Conclusions An early increase in PSMA SUVmean is common with first line enzalutamide in mCRPC, and predictive for shorter PSA-PFS with enzalutamide alone. The addition of [177Lu]Lu-PSMA-617 to enzalutamide mitigated the shorter PSA-PFS in those with early increase in PSMA SUVmean.

Human strongyloidiasis is often underdiagnosed or misdiagnosed, which can relate to a lack of knowledge or recognition of the importance of particular developmental/larval stages of Strongyloides stercoralis in making an accurate diagnosis using parasitological methods (a morphological approach or morphological features/characters). Here, we report the identification of S. stercoralis autoinfective fourth-stage larvae (L4a) in naturally infected humans, encountered in two clinical cases in Australia. These larvae were identified in sputum (Case 1) and bronchoalveolar lavage (Case 2) specimens by direct wet-mount microscopy. The L4a of S. stercoralis can be morphologically differentiated from autoinfective third-stage larvae by its conical and pointed tail and a relatively mature genital primordium with an enlarged genital rudiment and the formation of a vulva within cuticle layers. This study emphasizes the need to consider these morphological features of the L4a stage for an accurate diagnosis of S. stercoralis infection. A detailed morphological description of this stage is given to guide laboratory practitioners and researchers in the identification and differentiation of this unique but neglected life-cycle stage of S. stercoralis.

SummaryBased on a small number of predominantly low-to-moderate quality studies with moderate-to-high risk of bias, the FLS-to-primary care transition is portrayed as a challenging time for patients, GPs, and FLS clinicians, who experience numerous barriers to care continuation and coordination at this care juncture.PurposeContinuity and coordination of care between fracture liaison services (FLS) and primary care is required for optimal long-term osteoporosis care. This study aims to explore (1) how patients and healthcare providers (HCPs) experience the FLS to primary care transition, (2) the barriers and facilitators to primary care follow-up after FLS, and (3) interventions that enhance integration of FLS with primary care.MethodsAn integrative review was performed and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) Statement 2020. Online bibliographic databases were searched using the terms “osteoporosis”, “primary care”, and “fracture liaison services” and related terms for original English-language studies conducted between January 1, 2003 and December 29, 2023. Manuscripts were assessed for relevance using pre-defined criteria, and for quality and bias using validated instruments. Thematic analysis was used to extract key themes relevant to each research question.ResultsOverall, 14 relevant manuscripts were identified. Among the four studies that addressed patient and HCP experience of the FLS-to-primary care transition, five key themes emerged: (1) time and workload pressures, (2) limited confidence in primary care follow-up, (3) GP knowledge gaps, (4) siloed or disconnected care, and (5) communication issues. Twelve studies addressed barriers and facilitators to primary care follow-up after FLS, which fell into five themes: (1) patient knowledge and understanding (2) miscommunication and misinformation, (3) understanding roles and responsibilities, (4) GP engagement, and (5) GP-patient relationship. Additionally, single studies suggested healthcare policies and funding, accessing primary care from residential facilities, and GP gender influenced primary care follow-up. Five studies detailed interventions to enhance FLS-to-primary care integration. GP education and patient reminders, delivered as part of a multifaceted intervention, appeared to improve integration of acute and primary post-fracture care; however, the contribution of these individual interventions to outcomes remains unclear. While telephone coaching and bone marker monitoring were identified as potential interventions, there was insufficient evidence to conclude they are effective.ConclusionAvailable evidence was generally low-to-moderate quality with moderate-to-high risk of bias. Integration of the available evidence portrays the FLS-to-primary care transition as a challenging time for patients, GPs, and FLS clinicians, who experience a multitude of barriers to care continuation and coordination. There is insufficient data to support any single intervention as effective for enhancing care coordination beyond those considered standard components of FLS models. Knowledge gaps exist regarding the patient experience of the FLS-to-primary care transition, facilitators to primary care follow-up, interventions to support FLS integration with primary care, and how such information may be integrated to optimise care for patients with osteoporosis.

BackgroundMeniere’s disease (MD) is a disabling disease of the inner ear, having a substantial effect on a patient’s quality of life. While various postulations regarding its aetiology exists, due to the difficulty with accessing inner ear tissue, there have been limited histological studies in patients with active MD.MethodsTissue was collected during labyrinthectomy from 8 patients with intractable MD who had failed medical therapy (22 samples), and 9 patients undergoing translabyrinthine resection of vestibular schwannoma (19 samples). 20 additional samples were obtained from 2 cadavers without a history of inner ear disease. Samples were assessed with routine histology and a panel of immunohistochemical markers to assess any differences between the groups.ResultsNo MD samples demonstrated significant inflammatory infiltrate, evidence of denervation of the sensory epithelium, fibrosis, or thickening of blood vessel wall stroma. Novel findings included confirmation that no lymphatic channels of usual type were present and that the subepithelial stromal cells are strongly positive for S100, suggesting possible perineurial origin. There were no consistent differences in expression of Claudin or Aquaporin between the MD and VS patient samples.ConclusionThis is one of the largest comparative histological study utilising operative samples from inner ear of living donors with active intractable MD and control patients with VS. There were no significant morphological differences between the two groups, suggesting that the aetiology lies elsewhere within the vestibular system. Examination of endolymphatic sac tissue is therefore a priority for future work.

BackgroundNegative perceptions about palliative care (PC), held by patients with cancer and their families, are a barrier to early referral and the associated benefits. This review examines the approaches that support the task of introducing PC to patients and families and describes any evaluations of these approaches.MethodsA systematic review with a systematic search informed by the Preferred Reporting Items for Systemic Reviews and Meta-Analyses guidelines was performed on the online databases MEDLINE, PsychInfo and CINAHL from May 2022 to July 2022. Identified studies were screened by title and abstract, and included if they were empirical studies and described an approach that supported the introduction of PC services for adult patients. A narrative-synthesis approach was used to extract and present the findings.ResultsSearches yielded 1193 unique manuscripts, which, following title and abstract screening, were reduced to 31 papers subject to full-text review, with a final 12 studies meeting eligibility criteria. A diverse range of included studies described approaches used to introduce palliative care, which may be broadly summarised by four categories: education, clinical communication, building trust and rapport and integrative system approaches.ConclusionWhile educational approaches were helpful, they were less likely to change behaviours, with focused communication tasks also necessary to facilitate PC introduction. An established relationship and trust between patient and clinician were foundational to effective PC discussions. A framework to assist clinicians in this task is likely to be multidimensional in nature, although more quantitative research is necessary to establish the most effective methods and how they may be incorporated into clinical practice.

Introduction: In the USA, endometrial cancer incidence rose by 4.5% annually from 1999 to 2015, reaching 18 per 100,000 women, with a disproportionate impact on African American women. Despite advancements in endometrial cancer research, racial disparities in mortality rates persist. Our retrospective cohort study aimed to investigate the mortality trends and disparities among patients with endometrial cancer in the USA. Methods: Patients with endometrial cancer mortality from 1999 to 2020 were analyzed from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER). Age-adjusted mortality rates (AAMRs) per 100,000 individuals were compared across different races and geographical regions. Results: From 1999 to 2020, endometrial cancer accounted for 90,145 deaths in the USA. Overall, the AAMRs of endometrial cancer increased significantly from 2.50 (95% CI, 2.41–2.58) in 1999 to 3.94 (95% CI, 3.85–4.04) per 100,000 individuals in 2020, with an AAPC of +2.23 (95% CI, 1.39–3.07). The highest AAMR was observed among African Americans (2.69 [95% CI, 2.65–2.74]), followed by whites (1.44 [95% CI, 1.43–1.45]), Hispanics (1.16 [95% CI, 1.13–1.20]), Asians (1.00 [95% CI, 0.96–1.04]), and American Indians (0.99 [95% CI, 0.88–1.10]). The highest AAMR from endometrial cancer was recorded in the Northeast region (1.73 [95% CI, 1.71–1.76]). Conclusion: There was an increasing trend of mortality rates from endometrial cancer in the last 2 decades, which disproportionately affected African Americans. Targeted interventions are warranted to address the mortality disparities among patients with endometrial cancer.