Treatment Pathways Research Articles

Advances in CRISPR-Cas9 Technology for Tumor Therapy

Genome editing technology is an emerging toolbox that can specifically target genes. At present, the existing gene editing technologies include ZFN, TALEN, and CRISPR system editing technology with clusters of regularly spaced short palindromic repeats. However, ZFN and TALEN are no longer the preferred tools for gene editing due to some of their problems, and their complex protein design, high cost, and high difficulty are the main reasons that limit their use. The CRISPR system, on the other hand, is able to achieve specific binding by base complementary pairing of sgRNA to the target sequence. Traditional cancer treatment methods have limited efficacy and high recurrence rates, and the disease can be fundamentally treated by inactivating oncogenes or activating tumor suppressor genes through gene editing technology and then changing downstream signaling pathways for cancer treatment. With CRISPR-Cas9 technology, it is possible to have gene knockouts, insertions, and mutations. Here, we will investigate and explore the feasibility of the CRISPR system for tumor treatment, including the following three topics: oncogene knockout, augmentation of tumor suppressor gene expression, and enhancement of engineered T cell viability for effective tumor Through these methods, the CRISPR system is of great help and promising tumor therapy.

LncRNA evf-2 Exacerbates Podocyte Injury in Diabetic Nephropathy by Inducing Cell Cycle Re-entry and Inflammation Through Distinct Mechanisms Triggered by hnRNPU.

Albuminuria is a hallmark of diabetic nephropathy (DN). Podocyte injury significantly contributes to proteinuria in DN. Our study found that lncRNA EVF-2 is upregulated in podocytes of DN patients, correlating with cell cycle re-entry and inflammation. Specific knockout or knockdown of lncRNA evf-2 in diabetic mice or cultured podocytes alleviated podocyte injury associated with these processes. RNA sequencing of evf-2-overexpressing podocytes unveiled a predominant enrichment of upregulated mRNAs in cell cycle and inflammation pathways, with alternative splicing in cell cycle-related mRNAs Ccnb1 and Tacc3. Chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) analysis highlighted the involvement of ribonucleoprotein complex and mRNA processing-related proteins, with hnRNPU as the main binding partner of evf-2 in spliceosomes. Knockdown of hnRNPU partially restored the upregulation of mRNAs induced by evf-2 overexpression, altering splice variants of Ccnb1 and Tacc3. This study is the first to reveal the splice variants of cell cycle-related genes in DN and elucidate the interaction between lncRNA evf-2 and hnRNPU. This interaction culminates in the upregulation of cell cycle-related genes and inflammatory factors through diverse pathways, potentially involving transcriptional activation, RNA stability modulation, alternative splicing or translational regulation. This highlights potential novel pathways for DN treatment.

Evaluating Long-Term Outcomes of Children Undergoing Surgical Treatment for Congenital Heart Disease for National Audit in England and Wales.

There is strong interest in the evaluation of longer-term outcome metrics for congenital heart diseases (CHDs); however, registries focus on postoperative metrics. Informed by user online discussion forums and scoping of national data, we selected sentinel CHDs and long-term outcome metrics suitable for routine monitoring. We then developed sentinel CHD phenotypes and algorithms for identifying treatment pathway procedures using clinical codes. Finally, we calculated the metrics within a retrospective national cohort analysis. The 9 selected sentinel CHDs had a higher-than-average prevalence, typically involved surgery in infancy, and were associated with an increased risk of late mortality. The selected metrics of survival and reinterventions at 1, 5, and 10 years were both important and feasible. The cohort included 29 319 (41.3% of all operated CHD births) English and Welsh children born with sentinel CHDs in 2000 to 2022. Example metrics at age 10 years included: survival-hypoplastic left heart syndrome: 57.6% (95% CI, 54.9%-60.4%), functionally univentricular heart: 86.7% (95% CI, 84.6%-88.9%), transposition of the great arteries: 93.1% (95% CI, 92.2%-93.9%), pulmonary atresia: 81.0% (95% CI, 79.1%-82.9%), atrioventricular septal defect: 88.5% (95% CI, 87.5%-89.5%), tetralogy of Fallot: 95.1% (95% CI, 94.4%-95.8%), aortic stenosis: 94.4% (95% CI, 93.3%-95.6%), coarctation: 96.7% (95% CI, 96.2%-97.3%), and ventricular septal defect: 96.9% 95% CI, (96.4%-97.3%); and (2) cumulative incidence of reintervention-hypoplastic left heart syndrome : 54.5% (95% CI, 51.5%-57.3%), functionally univentricular heart: 57.3% (95% CI, 53.9%-60.5%), transposition of the great arteries: 20.9% (95% CI, 19.5%-22.3%), pulmonary atresia: 66.8% (95% CI, 64.2%-69.1%), atrioventricular septal defect: 21.6% (20.3%-23.0%), tetralogy of Fallot: 26.6% (95% CI, 25.2%-28.0%), aortic stenosis: 31.2% (95% CI, 28.8%-33.6%), coarctation: 19.8% (95% CI, 18.6%-21.1%), and ventricular septal defect: 6.1% (95% CI, 5.5%-6.8%). It is feasible to report important long-term outcomes of survival and reintervention for sentinel CHDs using routinely collected procedure records, adding value to national audit.

Exploring treatment decision-making at diagnosis for children with advanced cancer in low- and middle-income countries

PurposeGlobal childhood cancer survival outcomes correlate with regional contextual factors, yet upfront treatment decision-making for children with advanced or poor prognosis cancer in low- and middle-income countries (LMICs) is not well understood. This study aimed to (1) characterize the landscape of contextual factors that shape physician decision-making at diagnosis for these children in LMICs and (2) describe physician rationales for if/when to offer treatment with non-curative intent, including how they define “poor prognosis” during treatment decision-making.MethodsAn international panel of pediatric oncologists practicing in LMICs participated in two focus groups structured for the collaborative generation of factors influencing treatment decision-making, including consideration of non-curative treatment pathways at diagnosis. Thematic analysis of qualitative data was conducted, followed by member checking.ResultsEleven pediatric oncologists participated, representing all global regions defined by the World Health Organization. Participants identified a broad range of factors influencing decision-making across multiple levels, including the individual, hospital, health system, community, and country levels. All participants agreed that treatment with non-curative intent could be offered at diagnosis in certain contexts, and diverse definitions for poor prognosis were described.ConclusionsUpfront treatment decision-making for children with advanced or poor prognosis cancer in LMICs is variable and challenging. Difficulties with decision-making in LMICs may be amplified by inconsistent definitions of poor prognosis and underrepresentation of the factors that influence treatment decision-making within existing decision-making frameworks or childhood cancer treatment guidelines. Future research should explore decision-making approaches, preferences, and challenges in depth from the perspectives of pediatric cancer patients, families, and multidisciplinary clinicians.

Platinum Resistance in Ovarian Cancer: Is This the End of the Line?

Approximately 80% of females with ovarian cancer are diagnosed with advanced disease, and around 70% of these females relapse within 3 years of first-line treatment. Five-year survival for newly diagnosed advanced ovarian cancer is less than 50%. Platinum-based chemotherapy is the cornerstone of systemic treatment; however, it is not appropriate for patients with relapsed ovarian cancer who had disease progression during previous platinum treatment, early symptomatic progression post-platinum treatment, or who are platinum intolerant. New drugs are needed to address the unmet need in patients with relapsed ovarian cancer who are not eligible for platinum-based chemotherapy. This article presents highlights from a satellite symposium conducted as part of the European Society for Medical Oncology (ESMO) Congress 2024, which took place from 13th–17th September 2024 in Barcelona, Spain. The objectives of the symposium were to improve understanding of the current treatment pathways and unmet needs for patients with ovarian cancer who are ineligible for platinum-based therapies, to raise awareness of the rationale for targeting folate receptor α (FRα) in a variety of novel therapeutics for platinum-resistant ovarian cancer (PROC), and to review the efficacy outcomes and side effects from recent clinical trials involving antibody–drug conjugates (ADC) in PROC. In this symposium, Ana Oaknin, Vall d’Hebron University Hospital, Barcelona, Spain, described the current landscape in advanced ovarian cancer and the unmet need in relapsed disease; Philipp Harter, Evangelische Kliniken Essen-Mitte, Germany, explored FRα-targeted therapeutics in PROC; and Kathleen Moore, Stephenson Cancer Center, University of Oklahoma, Norman, USA, discussed ADC development beyond FRα in PROC. The symposium concluded with a lively discussion, including questions from the audience, key examples of which are included in this article.

Factors influencing surgical treatment of De Quervain's tendinopathy: A retrospective cross-sectional observational study

BackgroundThe literature surrounding how different patient, sociodemographic, and anatomical factors influence surgical treatment of De Quervain's tendinopathy (DQT) is limited. PurposeWe hypothesised that different patient, anatomical, or sociodemographic factors influence the management of DQT with regard to non-operative vs. surgical management. MethodsThis retrospective cross-sectional study reviewed 155 cases of patients with DQT seen over a 10 year period. Patient-specific factors included age, gender, hand affected, dominant hand, steroid injection given and mean number of injections. Sociodemographic factors included ethnicity, employment, and deprivation, were measured using deprivation quintiles through The Index of Multiple Deprivation. Anatomical factors included the presence of subcompartmentalization, number of APL and EPB tendon slips, tendon thickening, exudative tenosynovitis, hypervascularization, and the presence of a sheath ganglion Patients were categorized into either non-operative or surgical cohort. Bivariate analysis was used to compare factors between the cohorts, and significant factors (p < 0.05) were included in the logistic regression model, used to predict factors influencing surgical management. ResultsBivariate analysis detected a significant difference in the mean number of steroids given between the non-operative and surgical cohort (p = 0.001) patient factors. For sociodemographic factors, a significant difference was found between deprivation quintiles (p = 0.02). From the anatomical factors, the surgical cohort had more patients with multiple APL tendon slips (p = 0.02) and the presence of a tendon ganglion sheath ganglion (p = 0.02). For patient and sociodemographic factors, logistic regression identified that the number of steroids (per patient) and being in deprivation quintile 4 were associated with surgical treatment. For anatomical factors, multiple APL tendon slips and the presence of a tendon sheath ganglion were associated with the surgical treatment. ConclusionThis study suggests that several factors are associated with the need for surgical treatment of DQT, including the number of steroid injections received, social deprivation, and anatomical factors, such as the presence of multiple tendon slips and a tendon sheath ganglion. Our findings add to the growing body of literature exploring factors that may influence treatment pathways for patients with DQT.

Altered intrinsic neural activity and its molecular analyses in first-episode schizophrenia with auditory verbal hallucinations.

Auditory verbal hallucinations (AVHs) are one of the signature positive symptoms of schizophrenia, affecting a substantial portion of patients with schizophrenia. These hallucinations seriously impact the lives of patients, resulting in a substantial social burden. Recent studies have shown a significant correlation between abnormal local brain activity and the neurobiological mechanisms of AVHs. However, it is not fully clear whether altered intrinsic brain activity in schizophrenia patients with AVHs is correlated with specific neurotransmitter systems. We included 50 first-episode, drug-naïve schizophrenia patients with AVHs, 50 patients without AVHs (NAVHs), and 50 age- and sex-matched healthy controls (HCs). The amplitude of low-frequency fluctuation (ALFF) was utilized to explore the altered intrinsic brain activity in the AVH group. Subsequently, we spatially correlated the altered ALFF with neurotransmitter maps using JuSpace. In our study, compared to HCs, the AVH group exhibited significantly reduced ALFF in multiple brain regions, mainly including the left precuneus, bilateral supplementary motor areas, bilateral paracentral lobules, bilateral precentral gyri, and bilateral postcentral gyri. The NAVH group showed significantly reduced ALFF in the left inferior occipital gyrus, left calcarine gyrus, and left lingual gyrus compared to HCs. Furthermore, the AVH group showed higher ALFF in the right inferior frontal gyrus compared to the NAVH group. Additionally, these ALFF alterations in the AVH group were closely related to three neurotransmitters, including dopamine, serotonin and norepinephrine. We link neurotransmitters to abnormal intrinsic brain activity in first-episode, drug-naïve schizophrenia patients with AVHs, contributing to a comprehensive understanding of the pathophysiological processes and treatment pathways underlying AVHs.

Low-density lipoprotein cholesterol goal attainment with "inclisiran first" versus usual care in patients with atherosclerotic cardiovascular disease

Abstract Background Rapid and sustained attainment of guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals is critical for patients with atherosclerotic cardiovascular disease (ASCVD). In VICTORION-INITIATE, inclisiran administered twice-yearly by a healthcare professional earlier in the treatment pathway allowed more patients with ASCVD to achieve and sustain LDL-C goals vs current usual care (UC). Purpose To evaluate cumulative LDL-C exposure in the overall population and LDL-C goal attainment and safety in subgroups of participants (type of ASCVD, timing of ASCVD event, and history of statin intolerance) who received an "inclisiran first" implementation strategy (IF; adding inclisiran immediately on failure to achieve LDL-C &amp;lt;70 mg/dL [1.8 mmol/L] with maximally tolerated statins) compared with UC. Methods VICTORION-INITIATE was a 330-day, prospective, pragmatically designed trial that randomised participants 1:1 (stratified by insurance status) to IF (open-label inclisiran 284 mg at Days 0, 90 and 270 plus UC) or UC alone (lipid management directed by treating physician’s discretion). The study took place at 45 sites across 20 states in the USA. Treating physicians had access to LDL-C measurements and were encouraged to intensify treatment per clinical practice guidelines. This prespecified subgroup analysis evaluated LDL-C goal attainment by timing of the most recent ASCVD event (&amp;lt;1 year/≥1 year prior to consent), ASCVD subtype (coronary heart disease [CHD], peripheral arterial disease [PAD], and cerebrovascular disease [CVD]) and statin intolerance status. Cumulative LDL-C exposure over time in the overall population and safety by subgroup were also evaluated. Results Of 450 patients randomised to IF or UC, 11.1% and 84.2% had an ASCVD event &amp;lt;1 year or ≥1 year prior to consent, respectively; 91.8%, 18.2% and 14.7% had a history of CHD, CVD or PAD, and 25.8% were statin intolerant. Cumulative exposure to LDL-C to Day 330 was lower in patients treated with IF vs UC (mean time-adjusted LDL-C: 42.4 mg/dL vs 90.7 mg/dL, Figure). Significantly more patients who received IF achieved LDL-C goals of &amp;lt;70 mg/dL and &amp;lt;55 mg/dL at Day 330 vs UC, irrespective of subgroup (Table). Across subgroups, the incidence of treatment-emergent adverse events (TEAEs) and serious TEAEs were similar between IF and UC (IF: 52.6−71.2%, UC: 46.2−66.0% and IF: 10.7−28.3%, UC: 11.4−22.2%, respectively). Conclusions Participants with ASCVD and LDL-C &amp;gt;70 mg/dL who received IF had lower cumulative LDL-C exposure over the study period than those treated with UC. IF resulted in rapid and sustained achievement of LDL-C goals regardless of ASCVD subtype, event timing and statin intolerance. The safety profile of IF was consistent across the subgroups analysed.

Methodological insights into severity distribution of non-fatal cancer burden in Belgium using a microsimulation model (2004-2019)

Abstract This study leverages a registry-based microsimulation model to analyze the non-fatal burden of cancer in Belgium from 2004 to 2019, emphasizing the methodology for severity distribution. Utilizing incidence- and prevalence-based approaches, we estimated Years Lived with Disability (YLD) through detailed national cancer registry data coupled with tailored disease models. The microsimulation model employed enabled nuanced translation of cancer incidence into prevalence estimates, incorporating the longitudinal impacts of disease severity influenced by treatment. Methodologically, the model integrated expert elicitation to adjust for treatment-related disabilities, such as surgical aftereffects, enhancing the accuracy of disability weight assignment across different cancer stages. This approach allowed for a dynamic assessment of disease burden, reflecting real-world complexities of cancer prognosis and treatment pathways. Significant findings include a substantial increase in the age-standardized non-fatal burden for non-melanoma skin cancer, highlighting the model’s capability to detect shifts in disease impact over time. By focusing on the microsimulation’s capacity to delineate severity distributions within the cancer burden landscape, this analysis underscores the model’s utility in refining health policy decisions and resource allocation. Ultimately, this study presents a robust framework for national burden of disease studies, facilitating detailed evaluations of health interventions and their longitudinal effectiveness.

S3 Guideline: Treating Chronic Respiratory Failure with Non-invasive Ventilation

The S3 guideline on non-invasive ventilation as a treatment for chronic respiratory failure was published on the website of the Association of the Scientific Medical Societies in Germany (AWMF) in July 2024. It offers comprehensive recommendations for the treatment of chronic respiratory failure in various underlying conditions, such as COPD, thoraco-restrictive diseases, obesity-hypoventilation syndrome, and neuromuscular diseases. An important innovation is the separation of the previous S2k guideline dating back to 2017, which included both invasive and non-invasive ventilation therapy. Due to increased scientific evidence and a significant rise in the number of affected patients, these distinct forms of therapy are now addressed separately in two different guidelines.The aim of the guideline is to improve the treatment of patients with chronic respiratory insufficiency using non-invasive ventilation and to make the indications and therapy recommendations accessible to all involved in the treatment process. It is based on the latest scientific evidence and replaces the previous guideline. This revised guideline provides detailed recommendations on the application of non-invasive ventilation, ventilation settings, and the subsequent follow-up of treatment.In addition to the updated evidence, important new features of this S3 guideline include new recommendations on patient care and numerous detailed treatment pathways that make the guideline more user-friendly. Furthermore, a completely revised section is dedicated to ethical issues and offers recommendations for end-of-life care. This guideline is an important tool for physicians and other healthcare professionals to optimize the care of patients with chronic respiratory failure. This version of the guideline is valid for three years, until July 2027.

Characteristic disease defects in circulating endothelial cells isolated from patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressures that can lead to right heart failure and death. No cure exists for this disease, but therapeutic advancements have extended its median survival from 2 to 7 years. Mechanistic research in PAH has been limited by factors including that a) animal models do not fully recapitulate the disease or provide insights into its pathogenesis, and b) cellular material from PAH patients is primarily obtained from donor lungs during autopsy or transplantation, which reflect end-stage disease. Therefore, there is a need to identify tools that can elucidate the specific mechanisms of human disease in individual patients, a critical step to guide treatment decisions based on specific pathway abnormalities. Here we demonstrate a simple method to isolate and culture circulating endothelial cells (CECs) obtained at the time of right heart catheterization in PAH patients. We tested these CECs using transcriptomics and found that they have typical traits of PAH, including those involving key treatment pathways, i.e. nitric oxide, endothelin, prostacyclin and BMP/activin pathways. CECs show important gene expression changes in other central PAH disease pathways. In summary, we present a new cellular model for the ex-vivo mechanistic evaluation of critical PAH pathways that participate in the pathogenesis of the disease and may help personalized therapeutic decisions.

Opportunistic screening of coronary artery calcification on non-gated conventional CT scans using artificial intelligence

Abstract Background Recent advancements in artificial intelligence (AI) led to the development of automatic Coronary artery calcification (CAC) analysis based on chest CT scans. The objective of this study is to assess the impact of AI-based CAC evaluation on improving the allocation of add-on therapies and further evaluation. Methods We used a novel propriety AI software to estimate CAC from non-gated, non-contrast chest CT scans. Patients were categorized into groups: low CAC 0-99 Agatston unit (AU), moderate CAC 100-399AU, and high CAC ≥ 400 AU. Exclusion criteria included prior myocardial infarction, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), and life expectancy &amp;lt; 2 years. Patients classified as high CAC were invited to a dedicated clinic to perform a risk factor and clinical assessment, initiate appropriate medication, and refer to further testing as needed. For low-moderate CAC, referring physicians were informed of CAC status, encouraging guideline-based optimal preventive management. Results 1272 eligible patients between January 1th, 2023 to February 29th, 2024 were evaluated for inclusion. 641/1272 (50.3%) were excluded. Out of 631 enrolled patients, 84 (13%) patients were classified as high CAC, 163 (26%) as moderate and 348 (61%) as low CAC. At the dedicated clinic, appropriate low-density lipoprotein (LDL) goals were assigned and statins were initiated or dose adjusted where necessary. Twenty patients were referred to myocardial perfusion imaging, of which 2 were referred for invasive coronary angiography, one of them underwent PCI (Figure), and the other was referred for CABG. Conclusion This ongoing study indicates routine CAC quantification using AI software on chest CT scans can identify patients who may benefit from preventive cardiology services and lead them to appropriate cardiac treatment pathway. Further follow-up is required to assess its clinical impact.

Associations Between Testing and Treatment Pathways in a Case of Pediatric Nonlesional Epilepsy: A Census Survey of NAEC Center Directors.

Epilepsy surgery is vital in managing of children with drug-resistant epilepsy. Noninvasive and invasive testing modalities allow for evaluation and treatment of children with drug-resistant epilepsy. Evidence-based algorithms for this process do not exist. This study examines expert response to a vignette of pediatric nonlesional epilepsy to assess associations in evaluation and treatment choices. We analyzed annual report data and an epilepsy practice survey reported in 2020 from 135 pediatric epilepsy center directors in the United States. Characteristics of centers along with noninvasive and invasive testing and surgical treatment strategies were collected. Multivariable logistic regression modeling was performed. The response rate was 100% with 135 responses included in the analyses. Most used noninvasive testing modalities included Neuropsychology evaluation (90%), interictal brain fluorodeoxyglucose-positron emission tomography (85%), and functional magnetic resonance imaging (MRI) (72%) with nearly half obtaining genetic testing. Choosing functional MRI was associated with stereo electroencephalography (EEG) (P = .025) and selecting Wada with subdural grid/strips (P = .038). Directors from pediatric-only centers were more likely to choose stereo EEG as opposed to combined centers (P = .042). Laser interstitial thermal therapy was almost 7 times as likely to be chosen as a treatment modality compared with open resection in dedicated pediatric centers (OR 6.96, P = .002). In a vignette of nonlesional childhood drug-resistant epilepsy, epilepsy center directors' patterns of noninvasive testing, invasive testing, and treatment were examined. Management choices were associated with pediatric versus combined pediatric/adult center characteristics. Expert opinions demonstrated equipoise in evaluation and management of children with drug-resistant epilepsy and the need for evidence-based management strategies.

Expert consensus on the optimal management of BRAFV600E-mutant metastatic colorectal cancer in the Asia-Pacific region.

The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.

Cost-Effectiveness of Treating Hepatitis C in Clients on Opioid Agonist Therapy in Community Pharmacies Compared to Primary Healthcare in Australia.

Meeting the World Health Organisation 2030 target of treating 80% of people with hepatitis C virus (HCV) in Australia requires accessible testing and treatment services for at-risk populations. Previous clinical trials, including those in Australia, have demonstrated the efficacy of outreach programmes to community pharmacies offering opioid agonist therapy (OAT). This analysis evaluates the potential cost-effectiveness of introducing an outreach programme in community pharmacies. Using a decision analytic model, we estimated the impact of adding a temporary hepatitis C outreach and treatment programme in community pharmacies to the standard treatment pathway available through general practice. We compared the expected number of tests, diagnoses, cures and costs occurring through the addition of this outreach and treatment programme to those expected through general practice alone over a 12-month time horizon. We examined costs from the perspective of the health system and conducted one-way and probabilistic sensitivity analyses to assess uncertainty in model parameters and test key assumptions. In the model adding the outreach programme pathway increased the number of tests from 4178 to 8737, the number of diagnoses from 615 to 1285 and the number of cures from 223 to 777 among people on OAT over a 12-month period. Each additional cure achieved through the addition of the outreach programme was estimated to incur $48,964 (AUD 2023) to the health system, with > 85% of these costs attributable to medication and dispensing expenses. The average cost per cure was estimated to be $49,152 through routine care and $49,018 in the outreach programme. Although outreach models of care incur large upfront costs, they can capture otherwise unreached populations and result in comparable or favourable cost per cure, due to higher levels of engagement and lower rates of loss to follow-up.

Socioeconomic Determinants of Health and Reflux Management: Insights from a Tertiary Medical Center.

To assess the correlation of social determinants of health (SDOH) with the general care patterns related to gastroesophageal reflux disease and laryngopharyngeal reflux. Determine correlation of SDOH on utilization rates for medication, reflux testing and surgical intervention for patients diagnosed with reflux. Describe overall care patterns for gastroesophageal reflux disease care at a tertiary academic facility. Retrospective chart review. Patient demographics (age, sex, race, ethnicity, and insurance status) were extracted for adults diagnosed with reflux between 2009 and 2019. Odds ratios (ORs) for the associations between sociodemographic factors and reflux treatment pathways were determined by chi-square analyses. A total of 143,786 patients were evaluated during the study period with a diagnosis code of reflux. A subgroup of 40,754 patients had objective reflux testing including Bravo, dual pH-impedance, manometry, esophagogastroduodenoscopy (EGD) and esophagram, but no significant difference in utilization rates was found. A total of 239 patients who failed medical management underwent fundoplication. White (OR 2.43, 95% confidence interval [CI] 1.56-3.70) and female (OR 1.37, 95% CI 1.05-1.79) patients were more likely to undergo fundoplication than Black (OR 0.42, 95% CI 0.25-0.70) and male (OR 0.72, 95% CI 0.55-0.95) patients. Patients with private insurance (OR 1.58, 95% CI 1.23-2.04) were more likely to undergo fundoplication than those with public insurance (OR 0.65, 95% CI 0.50-0.84). Male patients were less likely to undergo fundoplication (OR 0.69, 95% CI 0.49-0.98) among patients evaluated for reflux with EGD. SDOH correlate with patterns of reflux evaluation and management at our tertiary care center. IV Laryngoscope, 2024.

Cycling versus swapping strategies with TNF-α inhibitors and IL-17 inhibitors in psoriatic arthritis in clinical practice

The availability of a number of bDMARDs with different mechanism of action increases potential treatment pathways in psoriatic arthritis (PsA). In clinical practice, following the failure of one bDMARD, it is normal to consider which options are the best for switching strategy. In most cases this choice involves IL17i and TNFi. The main aim of this study was to compare the effectiveness of cycling (from TNFi to another TNFi) and swapping (from TNFi to IL17i or vice versa) strategies. In this monocentric retrospective observational study, all PsA patients treated with TNFi or IL17i between January 2016 and January 2022 were enrolled. The prescriptions were clustered in one cycling group (CG), and two swap groups: from TNFi to IL17i (SG1) and from IL17i to TNFi (SG2). The Kaplan–Meier method and Cox regression models were applied to compare the drug retention rates and to identify factors affecting treatment persistence. A total of 122 patients were enrolled. The CG, SG1 and SG2 2-years retention rates were 51%, 58% and 34% (p = 0.1), respectively. SG1 strategy (HR 0.53; CI 0.31–0.89; p = 0.02), age (HR 0.98; CI 0.96–0.99; p = 0.003), Disease Activity PsA (HR 1.11; CI 1.08–1.13; p < 0.0001), year of switch (HR 1.78; CI 1.39–2.22; p < 0.0001) influenced the retention rate. The findings of this real-world study, even if burdened by bias related to its observational nature, support the hypothesis that in PsA patients swapping from TNFi to IL17i might be more effective than cycling TNFis.

The SUMO Family: Mechanisms and Implications in Thyroid Cancer Pathogenesis and Therapy.

(1) Background: Small ubiquitin-like modifiers (SUMOs) are pivotal in post-translational modifications, influencing various cellular processes, such as protein localization, stability, and genome integrity. (2) Methods: This review explores the SUMO family, including its isoforms and catalytic cycle, highlighting their significance in regulating key biological functions in thyroid cancer. We discuss the multifaceted roles of SUMOylation in DNA repair mechanisms, protein stability, and the modulation of receptor activities, particularly in the context of thyroid cancer. (3) Results: The aberrant SUMOylation machinery contributes to tumorigenesis through altered gene expression and immune evasion mechanisms. Furthermore, we examine the therapeutic potential of targeting SUMOylation pathways in thyroid cancer treatment, emphasizing the need for further research to develop effective SUMOylation inhibitors. (4) Conclusions: By understanding the intricate roles of SUMOylation in cancer biology, we can pave the way for innovative therapeutic strategies to improve outcomes for patients with advanced tumors.

Dementia Rehabilitation Training for General Practitioners and Practice Nurses: Does It Make a Difference?

Rehabilitation helps reduce disability in dementia. The Australian National Dementia Action Plan identifies a gap in clear treatment pathways post-diagnosis, affecting the quality of life for those with dementia. This study assessed the impact of a one-day dementia training course and follow-up on GPs' and practice nurses' knowledge, attitudes, and confidence regarding dementia rehabilitation. The training, led by two experienced GPs and an academic physiotherapist, covered dementia diagnosis, allied health roles, care planning, and referrals. The follow-up involved applying the learnt material and completing a reflective task. Three longitudinal surveys (Dementia Knowledge Assessment Scale-DKAS, General Practitioners' Attitudes and Confidence towards Dementia Survey-GPACS-D, and Dementia Rehabilitation Scale) and Likert-scale statements were conducted pre-course, post-course, and at four-month follow-up, alongside a focus group. Descriptive and regression analyses were applied to survey data, and content analysis was used for focus group data. Seventeen participants (14 GPs, 3 nurses) completed the pre-post-course survey, with eight (6 GPs, 2 nurses) participating in follow-up and focus group discussions. Post-course, DKAS scores increased by 12.1%, GPACS-D by 10.1%, and the dementia rehabilitation scale by 9.4%. Likert-scale statements improved by 8-79%. At the four-month follow-up, there was a slight, non-significant decline in most measures. Focus groups highlighted the training's impacts, useful components, barriers, and suggestions for improvement. Training GPs and practice nurses in dementia rehabilitation enhances knowledge, awareness, and confidence. Ongoing efforts are needed to sustain benefits and address referral barriers for better access to dementia rehabilitation services.

A telemedicine-enabled intravenous thrombolytic treatment pathway for patients with hyperacute non-arteritic central retinal artery occlusion

PurposeTo describe the visual acuity (VA) outcomes from a telemedicine-enabled pathway allowing for rapid diagnosis and administration of intravenous (IV) thrombolytic treatment for non-arteritic central retinal artery occlusion (naCRAO) within 4.5 hours (4.5 h) of visual loss. DesignRetrospective observational case series. MethodsSetting: A large managed healthcare consortium.Patient Population: Eighty-five patients with naCRAO and vision loss for less than 4.5 h presenting between 2021 and 2023. Thirty-five patients received IV thrombolytic therapy and 50 patients were closely observed.Intervention: A collaborative telemedicine-enabled pathway employing fundus photography was previously established by Ophthalmology, Emergency Medicine, and Stroke services to rapidly evaluate and manage patients presenting with acute painless monocular vision loss and allow for administration of IV tenecteplase (0.25 mg/kg) for eligible consenting patients diagnosed with naCRAO within 4.5 h. Retrospective chart review was conducted to collect data on demographics, vascular risk factors, clinical features, VA outcomes, and adverse events. Comparison was made between patients who received intravenous thrombolysis and those who were observed.Main Outcome Measures: Improvement in VA of at least 0.3 logarithm of the minimum angle of resolution (logMAR) and/or from 20/200 or worse to 20/100 or better. ResultsA greater percentage of patients in the treated group had VA improvement of ≥0.3 logMAR (54.3 % vs 28 %, p = .014), and a greater percentage of patients in the untreated group had VA worsening of ≥0.3 logMAR (30 % vs 5.7 %, p = .006). Twice the percentage of treated versus untreated patients had improved VA from 20/200 or worse to 20/100 or better, but this difference was not statistically significant (20 % vs 10 %, p = .192). There was a significantly shorter mean time to treatment for those patients who had VA improvement from 20/200 or worse to 20/100 or better compared to those who did not (118 versus 171 min, p = .031). Two patients experienced intracranial bleeding after IV thrombolysis. ConclusionsThe evaluation and treatment of hyperacute naCRAO is possible on a large scale via an integrated telemedicine-enabled approach utilizing fundus photography. The use of IV thrombolytic was associated with better VA outcomes compared to observation alone. Prospective randomized controlled trials are needed to confirm these findings and determine optimal management.