Advanced Therapy Research Articles

Omega Fatty Acid-Based Therapy for Healing of Recalcitrant Wounds in Patients with Complex Comorbidities.

The human body possesses the unique ability to repair itself after injury through complex, sequential phases. Current development of advanced wound care therapies generally focuses on addressing a single aspect of this biological process that can result in delayed or ineffective wound healing. When patients present with further systemic and local confounding pathologies it can result in painful, chronic wounds that are especially challenging to treat.In this case report, the authors demonstrate how treatment with a novel multimodal wound matrix expedited healing and decreased pain in two patients who had each been unresponsive to treatment with advanced modalities for more than 7 months. The first patient had factor V Leiden and the second patient had sickle cell disease. Use of a once-weekly treatment protocol with the multimodal wound matrix, combined with sharp debridement when deemed clinically necessary, resulted in elimination of pain and expedited wound healing to closure. The wound matrix's omega fatty acid-based formulation is designed to target multiple factors common among hard-to-heal wounds that when not addressed, can adversely inhibit the wound-healing cascade.

Material-driven immunomodulation and ECM remodeling reverse pulmonary fibrosis by local delivery of stem cell-laden microcapsules

Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.

Review Mechanisms for Advanced Medical Therapies in Japan and Thailand: A Proposal for the Use of Expert Clinical Benefit Assessments at Designated Institutions

AbstractAdvanced new therapies, such as stem cell and gene therapies and xenotransplantation, represent challenges for regulatory and ethical review. Major drug agencies, such as in the U.S., India, and Europe, have asserted regulatory authority and require ethics review by local ethics review committees, using the same strict requirements as those for standard drug approvals. In spite of this, unapproved and undocumented stem cell clinics flourish in all of these places, suggesting that current approaches do not offer patients sufficient protection. Japan has attempted another approach, requiring approvals at local levels for all regenerative medical procedures, and a faster approval of promising new interventions. The Japanese approach has, however, also been criticized as not striking a proper balance between early access and a proper assessment of safety and effectiveness. For smaller and less-resourced countries, such as Thailand, one major challenge is limited expertise to conduct the evaluation of these advanced new therapies. This article provides an overview of the issues facing regulators and proposes that countries should restrict the early adoption of advanced new therapies to specialized clinics with appropriate scientific and ethical expertise for review. Review in these institutions should focus on expert clinical benefit assessments for individual patients being offered such interventions, independently of whether they are offered as research or therapy.

Real-World Treatment Persistence Among Advanced Therapy-Naïve or -Experienced Patients with Ulcerative Colitis Initiated on Ustekinumab or Adalimumab.

Persistence on advanced therapies in ulcerative colitis (UC) is a useful real-world treatment performance measure. This study compared real-world persistence during the maintenance phase among advanced therapy-naïve and -experienced patients with UC initiated on ustekinumab or adalimumab. Claims data from the IQVIA PharMetrics® Plus de-identified database (01/01/2015-06/30/2022) were used to select adult patients with UC treated with ustekinumab or adalimumab based on the agent first initiated (index date) after 10/21/2019. Inverse probability of treatment weighting was used to balance cohorts on baseline characteristics. Persistence on the index agent (no gaps in days of supply of>120 days for ustekinumab or>60 days for adalimumab), persistence while corticosteroid-free, while on monotherapy, and persistence on the US labeled dose were described and compared during the 12-month period post-index using Kaplan-Meier analysis and Cox proportional hazards models. Outcomes were analyzed separately among advanced therapy-naïve and advanced therapy-experienced patients. At 12 months post-index, advanced therapy-naïve patients receiving ustekinumab (n=371) had higher persistence on the index agent [83.8% vs. 57.6%, hazard ratio (95% confidence interval) =3.09 (2.29-4.16); p<0.001), persistence while corticosteroid-free [2.00 (1.63-2.45); p<0.001], persistence while on monotherapy [2.67 (2.07-3.44); p<0.001], and persistence on the labeled dose [4.21 (2.76-6.44); p<0.001] versus those receiving adalimumab (n=1726). At 12 months post-index, advanced therapy-experienced patients receiving ustekinumab (n=693) had higher persistence on the index agent [78.1% vs. 59.2%, 2.44 (1.82-3.26); p<0.001], persistence while corticosteroid-free [1.24 (1.01-1.54); p=0.0447], persistence while on monotherapy [2.53 (2.00-3.21); p<0.001], and persistence on the labeled dose [4.77 (3.09-7.35); p<0.001] versus those receiving adalimumab (n=254). This claims-based analysis demonstrated significantly higher treatment persistence, including persistence while corticosteroid-free, persistence while on monotherapy, and persistence on the labeled dose, among both advanced therapy-naïve and advanced therapy-experienced patients with UC initiated on ustekinumab compared to adalimumab.

Prolonged Inotrope Use After Surgery for Congenital Heart Disease: A Common Occurrence with a High Burden of Mortality.

Outcomes in patients requiring prolonged inotropes (PI) following surgery for congenital heart disease (CHD) have not been well studied. We aimed to describe the burden of PI use in the immediate postoperative period after CHD surgery and identify risk factors for in-hospital mortality. We conducted a retrospective cohort study using the Pediatric Health Information System® (PHIS) database. Patients 0-18years with CHD who underwent cardiovascular surgery from 2010 to 2020 were included. Patients who received inotropic medications for > 7 consecutive days after surgery were in the PI group and all others in the control group. Patients who died before 7days were excluded. Multivariable mixed-effect logistic regression was used to examine risk factors for in-hospital mortality. There were 110,271 patients from 48 centers included, 10,292 in the PI group and 99,979 in the control group. In-hospital mortality was significantly higher in the PI group (24.9% vs. 4.6%, p < 0.001). Ventricular assist device use was rare (1.6%). After adjustment, odds of in-hospital mortality in the PI group was 3.5 (95% CI 3.3-3.8) times higher than in controls. Independent risk factors for in-hospital mortality were age, non-White race, class of CHD, number of complex chronic conditions, preoperative inotrope, preoperative extracorporeal membrane oxygenation, sepsis, stroke, renal failure, number of inotropes at 7days, and discharge year (p < 0.01 for all). Postoperative PI use in CHD is common and carries a considerable burden of mortality. Additional work is needed to understand which risk factors are modifiable and which patients may benefit from reintervention or advanced heart failure therapies.

Comparative Analysis of Post-Authorization Measures for Advanced Medicinal Products Authorized in the European Union and in the United States of America Between 2009 and 2023.

In the current landscape, regulatory agencies face the challenge of reconciling timely authorizations for novel medicines addressing life-threatening conditions with thorough evaluations of their benefits and risks. This challenge is pronounced with advanced therapy medicinal products (ATMPs), where expedited approval mechanisms and orphan drug designations are often applied, making post-authorization measures a crucial mechanism to address uncertainties. We compared post-authorization measures imposed by the U.S. Food and Drug Administration and the European Medicines Agency on ATMPs approvals, from 2009 to 2023. A systematic extraction of FDA postmarketing requirements (PMRs) and EMA-imposed post-authorization measures (PAMs) from publicly available regulatory documents was conducted. Descriptive analysis focused on post-authorization measure categories, objectives, study designs, and their status and registration rates. A total of 15 ATMPs were approved in both jurisdictions over the study period. For these products, the EMA imposed 53 PAMs (34 Annex II conditions and 19 Specific Obligations), whereas the FDA imposed 27 PMRs. As of December 2023, 15 EMA-imposed PAMs were fulfilled, with no explicit fulfilments indicated for FDA PMRs. Both agencies promoted real-world data use in around half of the imposed PAMs (23 by EMA vs. 15 by FDA), marking regulators' growing recognition of Real-World Evidence for decision-making. This study highlights disparities between imposed PAMs: EMA imposed more PAMs, covering efficacy, safety, and quality aspects, while the FDA required fewer measures focusing on specific safety concerns. These discrepancies primarily reflect distinct regulatory structures and approaches to further post-authorization data collection between the EMA and FDA, rather than disparities in initial benefit/risk assessments.

Comparison of real-world healthcare resource utilization among advanced therapy-naïve and advanced therapy-experienced patients with ulcerative colitis initiated on ustekinumab or vedolizumab

Objectives To describe and compare healthcare resource utilization (HRU) among advanced therapy-naïve and advanced therapy-experienced patients with ulcerative colitis (UC) initiating ustekinumab or vedolizumab in the United States. Methods Claims data from IQVIA PharMetrics Plus de-identified database (01/01/2015–06/30/2022) were used to identify adult patients with UC initiating ustekinumab or vedolizumab (index date) after 10/21/2019. Baseline characteristics were balanced using inverse probability of treatment weighting. All-cause and UC-related HRU (number of inpatient admissions, inpatient days, emergency department visits, and outpatient visits) were described during the post-index period, and Poisson regression models were used to evaluate associations between index therapy and HRU outcomes. Analyses were performed separately among advanced therapy-naïve or advanced therapy-experienced patients. Results A total of 444 (ustekinumab) and 1,917 (vedolizumab) advanced therapy-naïve patients, and 647 (ustekinumab) and 1,152 (vedolizumab) advanced therapy-experienced patients were identified. In advanced therapy-naïve patients, higher rates of UC-related inpatient days (rate ratio [95% confidence interval] = 1.84 [1.15, 3.58]; p = 0.004), emergency department visits (1.39 [1.01, 2.17]; p = 0.044), and outpatient visits (1.81 [1.61, 2.04]; p < 0.001) were observed among patients initiating vedolizumab relative to ustekinumab. In advanced therapy-experienced patients, higher rates of UC-related inpatient admissions (1.47 [1.06, 2.12]; p = 0.012), inpatient days (2.18 (1.44, 3.71); p < 0.001), and outpatient visits (1.50 (1.19, 1.82); p < 0.001) were observed among patients initiating vedolizumab relative to ustekinumab. Results were similar when all-cause HRU was examined. Conclusions Among patients with UC with and without advanced therapy experience, higher rates of all-cause and UC-related HRU were observed among those treated with vedolizumab relative to ustekinumab.

Extraintestinal Manifestations in Inflammatory Bowel Disease: From Pathophysiology to Treatment.

The inflammatory bowel diseases (IBDs) are systemic conditions that affect not only the gastrointestinal tract but also other parts of the body. The presence of extraintestinal manifestations can significantly impact the quality of life in IBD patients. Peripheral arthritis, episcleritis, and erythema nodosum are frequently associated with active intestinal inflammation and often improve with standard treatment targeting intestinal inflammation. In contrast, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis typically occur independently of disease flares. The incidence of these conditions in individuals with IBD can reach up to 50% of patients over the course of their lifetime. In addition, some advanced therapies utilized for the treatment of IBD potentially result in side effects that may resemble extraintestinal manifestations. This review provides a thorough analysis of the pathophysiology and treatment of extraintestinal manifestations associated with Crohn's disease and ulcerative colitis.

Interleukin-33 and liver natural killer cells: A novel perspective on antitumor activity in liver fibrosis.

Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway. Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl4)-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity. The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n=385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence. Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis.

Methuosis Inducer SGI-1027 Cooperates with Everolimus to Promote Apoptosis and Pyroptosis by Triggering Lysosomal Membrane Permeability in Renal Cancer.

The mTOR inhibitor everolimus has been approved as a sequential or second-line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI-1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME-dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti-tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI-1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus-resistance overcoming.

Cost analysis of cardiac MRI for cardiac transplant surveillance

National health expenditures in the United States have risen steadily since 1960. While lifesaving therapies exist for acquired and congenital heart diseases, for some children heart transplantation is their only chance for a period of durable survival. Like many advanced therapies, however, heart transplantation confers a significant cost to families and the health care system at large. Current heart transplant health surveillance relies on frequent cardiac catheterization with endomyocardial biopsy (cath-EMB) as periodic assessment of graft health and detection of possible life-threatening acute rejection. Cardiac magnetic resonance imaging (MRI) has emerged as a diagnostic tool which can characterize the myocardium, providing insights into graft health and potentially acute/chronic graft rejection. The PEACE study (R01-HL164995-02) aims to systematically evaluate the potential for using cardiac MRI parametric mapping as a pre-cath-EMB screening tool to alleviate both patient anxiety and discomfort, as well as the financial burden of cath-EMB. The PEACE trial aims to establish definitive evidence and criteria for determining when cath EMB is needed. For a technique to be practical in the real world, though, it must also be cost effective.Therefore, the goal of this current research is to determine a minimal set of measurement properties (positive predictive value (PPV), etc.) that cardiac MRI must attain to be cost-effective. These data will guide the decision-making for the PEACE trial results. Consistent with the recent emphasis on “Value MRI,” we sought to understand the potential Medicare savings, through economic cost analysis modeling, if cardiac MRI is used for cardiac transplant surveillance rather than cath-EMB surveillance. At even the most pessimistic positive test rate for MRI considered, these modeling results suggest substantial Medicare cost savings when using cardiac MRI parametric mapping as a screening tool for detecting acute cardiac rejection. Longitudinal cost savings are notable too.

A Real-World Comparison of Clinical Effectiveness in Patients with Rheumatoid Arthritis Treated with Upadacitinib, Tumor Necrosis Factor Inhibitors, and Other Advanced Therapies After Switching from an Initial Tumor Necrosis Factor Inhibitor.

This study compared the clinical effectiveness of switching from tumor necrosis factor inhibitor (TNFi) to upadacitinib (TNFi-UPA), another TNFi (TNFi-TNFi), or an advanced therapy with another mechanism of action (TNFi-other MOA) in patients with rheumatoid arthritis (RA). Data were drawn from the Adelphi RA Disease Specific Programme™, a cross-sectional survey administered to rheumatologists and their consulting patients in Germany, France, Italy, Spain, the UK, Japan, Canada, and the USA from May2021 to January 2022. Patients who switched treatment from an initial TNFi were stratified by subsequent therapy of interest: TNFi-UPA, TNFi-TNFi, or TNFi-other MOA. Physician-reported clinical outcomes including disease activity (with formal DAS28 scoring available for 29% of patients) categorized as remission, low/moderate/high disease activity, as well as pain were recorded at initiation of current treatment and ≥ 6months from treatment switch. Fatigue and treatment adherence were measured ≥ 6months from treatment switch. Inverse-probability-weighted regression adjustment compared outcomes by subsequent class of therapy: TNFi-UPA versus TNFi-TNFi, or TNFi-UPA versus TNFi-other MOA. Of 503 patients who switched from their first TNFi, 261 were in TNFi-UPA, 128 in TNFi-TNFi, and 114 in TNFi-other MOA groups. At the time of switch, most patients had moderate/high disease activity (TNFi-UPA: 73%; TNFi-TNFi: 52%; TNFi-other MOA: 60%). After adjustment for differences in characteristics at point of switch, patients in TNFi-UPA group (n = 261) were significantly more likely to achieve physician-reported remission (67.7% vs. 40.3%; p = 0.0015), no pain (55.7% vs. 25.4%; p = 0.0007), and complete adherence (60.0% vs. 34.2%; p = 0.0049) compared with patients in TNFi-TNFi group (n = 121). Similar findings were observed for TNFi-UPA versus TNFi-other MOA groups (n = 111). Patients who switched from TNFi to UPA had significantly better clinical outcomes of remission, no pain, and complete adherence than those who cycled TNFi or switched to another MOA.

MDK promotes M2 macrophage polarization to remodel the tumour microenvironment in clear cell renal cell carcinoma

The efficacy of immunotherapy for clear cell renal cell carcinoma (ccRCC), especially advanced ccRCC, is limited, presenting a clinical challenge. This limitation is closely tied to the immune regulation network. Understanding the heterogeneity of the tumour microenvironment (TME) is crucial for developing advanced ccRCC therapies. Using publicly available ccRCC data (scRNA-seq, bulk RNA-seq, and somatic mutation data), a multiomics study was performed to explore TME heterogeneity. Three distinct ccRCC immune subtypes were identified through combined scRNA-seq and bulk RNA-seq analysis. A prognostic model based on unique cell signalling molecules in immunosuppressive tumour subtype was validated in the TCGA and CheckMate cohorts. MDK emerged as a critical regulatory gene in the immunosuppressive subtype, predicting a poor ccRCC prognosis and a poor immunotherapy response. MDK promotes M2 macrophage polarization via the MDK-LRP1 interaction, and the inhibition of MDK suppressed M2 polarization. This study revealed the heterogeneity of the ccRCC TME and a reliable prognostic model, shedding light on the vital role of MDK in the immunosuppressive TME and paving the way for optimized ccRCC immunotherapy.

Characteristics of patients with difficult-to-treat rheumatoid arthritis: a descriptive retrospective cohort study

BackgroundIn 2021, an EULAR task force published a definition of difficult-to-treat rheumatoid arthritis (D2T RA). Our current knowledge of D2T RA with the EULAR definition is based on European and Asian cohorts, and no North American cohort has yet to be published. The aim of this study was to compare D2T RA patients to non-D2T RA who are good responders to advanced therapy, and to describe their evolution in an university health center patient cohort.MethodsThis is a retrospective single centre study of the medical records of all adults with RA on at least one biologic or target synthetic DMARD (b/tsDMARD). D2T RA group was defined according to the EULAR definition of D2T RA. The non-D2T RA group was defined as a b/tsDMARD good responder who had low-disease activity or remission for at least one year on 1 or 2 b/tsDMARD mechanism of action. We compared the patients’ comorbidities, and history of b/tsDMARD use. Descriptive statistics and proportions were calculated. Kaplan-Meier analysis with log-rank test was used to estimate and compare median survival.ResultsAmong the 417 patients, 101 (24%) were D2T RA and 316 (76%) were non-D2T RA. D2T RA group was slightly younger (63 ± 9 years versus 65 ± 12 years, p = 0.045), more likely to have concomitant non-inflammatory pain (28% versus 8%, p < 0.0001) and to discontinue at least one b/tsDMARD due to intolerance (39% versus 10%, p < 0.0001). In the D2T RA group, JAK inhibitors were associated with longer drug continuation when used as the third b/tsDMARD. Fewer patients were using corticosteroid at their most recent follow-up in this Canadian cohort compared to others (16% versus from 29 to 74%).ConclusionConcomitant non-inflammatory pain was more prevalent in D2T RA patients compared to b/tsDMARD good responder non-D2T RA patients. Steroid-sparing strategies is possible even in D2T RA patients. Future prospective research may compare JAK inhibitors with other mechanisms of action in D2T RA.

Therapeutic applications of synthetic gene/genetic circuits: a patent review.

A significant limitation of numerous current genetic engineering therapy approaches is their limited control over the strength, timing, or cellular context of their therapeutic effect. Synthetic gene/genetic circuits are synthetic biology approaches that can control the generation, transformation, or depletion of a specific DNA, RNA, or protein and provide precise control over gene expression and cellular behavior. They can be designed to perform logical operations by carefully selecting promoters, repressors, and other genetic components. Patent search was performed in Espacenet, resulting in 38 selected patents with 15 most frequent international classifications. Patent embodiments were categorized into applications for the delivery of therapeutic molecules, treatment of infectious diseases, treatment of cancer, treatment of bleeding, and treatment of metabolic disorders. The logic gates of selected genetic circuits are described to comprehensively demonstrate their therapeutic applications. Synthetic gene circuits can be customized for precise control of therapeutic interventions, leading to personalized therapies that respond specifically to individual patient needs, enhancing treatment efficacy and minimizing side effects. They can be highly sensitive biosensors that provide real-time therapy by accurate monitoring various biomarkers or pathogens and appropriately synthesizing a therapeutic molecule. Synthetic gene circuits may also lead to the development of advanced regenerative therapies and to implantable biodevices that produce on-demand bioactive molecules. However, this technology faces challenges for commercial profitability. The genetic circuit designs need adjustments for specific applications, and may have disadvantages like toxicity from multiple regulators, homologous recombination, context dependency, resource overuse, and environmental variability.

Describing the practice of breast self-examination and associated factors among female healthcare workers in Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.

Breast cancer is the most frequently occurring cancer in women and is a global health problem. Yet, it can be a manageable disease with early diagnosis and sufficient treatment protocols, such as advanced surgical intervention, chemotherapy, and radiation therapies. Breast self-examination (BSE) is a screening technique that involves examining one's breasts for lumps, distortions, or swelling, and contributes to early diagnosis of the disease. The aim of this study was to assess the practice of BSE and associated factors among female healthcare workers in Saint Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia, 2022. An institution-based cross-sectional study was carried out at St. Paul's Hospital Millennium Medical College. A stratified and systematic random sampling technique was utilized to obtain respondents for the study. The data for this study were collected by professional nurses using a structured questionnaire. Data were analyzed using SPSS (version 20) software. Logistic regression analysis was utilized to assess relevant factors. Predictors with a p-value of < 0.05 were considered as statistically significant. Four hundred respondents participated giving a 100% response rate. The median age of study participants was 28 years, with an inter-quartile range of six years. About two-thirds (63.8%) of the study participants had good knowledge about BSE, 46.3% had a positive attitude toward BSE, and 76.25% reported they practised BSE. Significant associations were observed with the practice of BSE and the factors of age, monthly income, and knowledge about BSE. Compared to participants 40 years and above, participants between 25-29 years [AOR=0.10; 95%CI: 0.01, 0.88] and 35-39 years [AOR=0.09; 95%CI: 0.01, 0.92] were less likely to practise BSE; those with monthly income less than 5250 ETB [AOR=0.19; 95%CI: 0.035, 0.996], and between 5251-7800 [AOR=0.16; 95%CI: 0.032, 0.78], and 7801-10900ETB [AOR=0.18; 95%CI: 0.04, 0.83] were less likely to practise BSE; and those with good knowledge about BSE [AOR=2.08; 95%CI: 1.23, 3.53] were more apt to practise BSE. The study showed that about three-quarters of the health workers practised BSE. Statistically significant associations were observed between BSE and the factors of age in years, monthly income, and knowledge about BSE.

Glutathione hybrid poly (beta-amino ester)-plasmid nanoparticles for enhancing gene delivery and biosafety

IntroductionCRISPR/Cas9 gene editing technology has significantly advanced gene therapy, with gene vectors being one of the key factors for its success. Poly (beta-amino ester) (PBAE), a distinguished non-viral cationic gene vector, is known to elevate intracellular reactive oxygen species (ROS) levels, which may cause cytotoxicity and, consequently, impact gene transfection efficacy (T.E.). ObjectivesTo develop a simple but efficient strategy to improve the gene delivery ability and biosafety of PBAE both in vivo and in vitro. MethodsWe used glutathione (GSH), a clinically utilized drug with capability to modulating intracellular ROS level, to prepare a hybrid system with PBAE-plasmid nanoparticles (NPs). This system was characterized by flow cytometry, RNA-seq, Polymerase Chain Reaction (PCR) and Sanger sequencing in vitro, and its safety and efficacy in vivo was evaluated by imaging, PCR, Sanger sequencing and histology analysis. ResultsThe particle size of GSH-PBAE-plasmid NPs were 168.31 nm with a ζ-potential of 15.21 mV. An enhancement in T.E. and gene editing efficiency, ranging from 10 % to 100 %, was observed compared to GSH-free PBAE-plasmid NPs in various cell lines. In vitro results proved that GSH-PBAE-plasmid NPs reduced intracellular ROS levels by 25 %–40 %, decreased the total number of upregulated/downregulated genes from 4,952 to 789, and significantly avoided the disturbance in gene expression related to cellular oxidative stress-response and cell growth regulation signaling pathway compared to PBAE-plasmid NPs. They also demonstrated lower impact on the cell cycle, slighter hemolysis, and higher cell viability after gene transfection. Furthermore, GSH hybrid PBAE-plasmid NPs exhibited superior safety and improved tumor suppression ability in an Epstein–Barr virus (EBV)-infected murine tumor model, via targeting cleavage the EBV related oncogene by delivering CRISPR/Cas9 gene editing system and down-regulating the expression levels. This simple but effective strategy is expected to promote clinical applications of non-viral vector gene delivery.

A comprehensive overview of radiation therapy impacts of various cancer treatments and pivotal role in the immune system.

The cancer treatment landscape is significantly evolving, focusing on advanced radiation therapy methods to maximize effectiveness and minimize the adverse effects. Recognized as a pivotal component in cancer and disease treatment, radiation therapy (RT) has drawn attention in recent research that delves into its intricate interplay with inflammation and the immune response. This exploration unveils the underlying processes that significantly influence treatment outcomes. In this context, the potential advantages of combining bronchoscopy with RT across diverse clinical scenarios, alongside the targeted impact of brachytherapy, are explored. Concurrently, radiation treatments serve multifaceted roles such as DNA repair, cell elimination, and generating immune stress signaling molecules known as damage-associated molecular patterns, elucidating their effectiveness in treating various diseases. External beam RT introduces versatility by utilizing particles such as photons, electrons, protons, or carbon ions, each offering distinct advantages. Advanced RT techniques contribute to the evolving landscape, with emerging technologies like FLASH, spatially fractionated RT, and others poised to revolutionize the field. The comprehension of RT, striving for improved treatment outcomes, reduced side effects, and facilitating personalized and innovative treatments for cancer and noncancer patients. After navigating these advancements, the goal is fixed to usher in a new era in which RT is a cornerstone of precision and effectiveness in medical interventions. In summarizing the myriad findings, the review underscores the significance of understanding the differential impacts of radiation approaches on inflammation and immune modulation, offering valuable insights for developing innovative therapeutic interventions that harness the immune system in conjunction with RT.

Factors Associated with Delays in Initiating Biologic Therapy in Patients with Inflammatory Bowel Disease.

Expeditious initiation of biologic therapy is important in patients with inflammatory bowel disease (IBD). However, initiation of biologics in the outpatient setting may be delayed by various clinical, social, and financial variables. To evaluate the delay in initiation of an advanced therapy in IBD and to identify factors that contributed to this delay. This was a multi-center retrospective study. Outpatients who were initiated on a biologic therapy from 3/1/2019 to 9/30/20 were eligible for the study. Univariate and multivariate linear regression analyses were performed to identify variables associated with a delay in biologic treatment initiation. Delay was defined as the days from decision date (prescription placement) to first infusion or delivery of medication. In total 411 patients (Crohn's disease, n = 276; ulcerative colitis, n = 129) were included in the analysis. The median [interquartile range-(IQR)] delay for all drugs was 20 [12-37] days (infliximab, 19 [13-33] days; adalimumab, 10 [5-26] days; vedolizumab, 21 [14-42] days; and ustekinumab, 21 [14-42] days). Multivariate linear regression analysis identified that the most important variables associated with delays in biologic treatment initiation was self-identification as Black, longer distance from treatment site, and lack of initial insurance coverage approval. There may be a significant delay in biologic treatment initiation in patients with IBD. The most important variables associated with this delay included self-identification as Black, longer distance from site, and lack of initial insurance coverage approval.

Trends in heart transplant outcomes for patients over the age of 70 years in the United States: An analysis of the scientific registry of transplant recipients database

BackgroundPatients of advanced age are often considered to be poor candidates for heart transplant (HT). As the U.S. population continues to age, it is important for clinicians to understand how best to select patients for advanced therapies. MethodsThis was a retrospective analysis of the U.S. Scientific Registry of Transplant Recipients data from 2006 to August 2022 in adult recipients. Patients were excluded if they were multiorgan transplant, re-do transplants, or less than 1 year post transplant. ResultsRecipients ≥70 had a one-year survival of 87.5%, compared to 91.1% for <60, and 88.4% for 60-69 years (p<0.001). Survival improved numerically, but not significantly, as transplant eras progressed for those ≥70 years. Survival by Kaplan-Meier analysis was greatest at five years for <60 years (80.6%), compared to 60-69 years (78.2%) and ≥70 years (77.1%). When comparing 60-69 years to ≥70 years by this same metric, there was significant difference (p=0.12). One year survival for those ≥70 years has improved from 2000-2009 (80.7%) to 88.5% since October 2018 (p<0.001). As recipients increased in age, they were more likely to be male, and less likely to be Black or Hispanic/Latino (p<0.001). ConclusionOverall, HT outcomes are excellent for carefully selected patients ≥70 years, and transplanting patients in this age cohort can be considered.