Silicon Ether Ionizable Lipids Enable Potent mRNA Lipid Nanoparticles with Rapid Tissue Clearance.

The advent of mRNA for nucleic acid (NA) therapeutics has unlocked many diverse areas of research and clinical investigation. However, the shorter intracellular half-life of mRNA compared with other NAs may necessitate more frequent dosing regimens. Because lipid nanoparticles (LNPs) are the principal delivery system used for mRNA, this could lead to tolerability challenges associated with an accumulated lipid burden. This can be addressed by introducing enzymatically cleaved carboxylic esters into the hydrophobic domains of lipid components, notably, the ionizable lipid. However, enzymatic activity can vary significantly with age, disease state, and species, potentially limiting the application in humans. Here we report an alternative approach to ionizable lipid degradability that relies on nonenzymatic hydrolysis, leading to a controlled and highly efficient lipid clearance profile. We identify highly potent examples and demonstrate their exceptional tolerability in multiple preclinical species, including multidosing in nonhuman primates (NHP).

Implementation of an intervention aimed at deprescribing benzodiazepines in a large US healthcare system using patient education materials: a pre/post-observational study with a control group.

OBJECTIVES: Long-term benzodiazepine use is common despite known risks. In the original Eliminating Medications Through Patient Ownership of End Results (EMPOWER) Study set in Canada, patient education led to increased rates of benzodiazepine cessation. We aimed to determine the effectiveness of implementing an adapted EMPOWER quality improvement (QI) initiative in a US-based healthcare system. DESIGN: We used a pre-post design with a non-randomised control group. SETTING: A network of primary care clinics. PARTICIPANTS: Patients with ≥60 days' supply of benzodiazepines in 6 months and ≥1 risk factor (≥65 years of age, a concurrent high-risk medication prescribed or a diazepam equivalent daily dose ≥10) were eligible. INTERVENTION: In March 2022, we engaged 22 primary care physicians (PCPs), and 308 of their patients were mailed an educational brochure, physician letter and flyer detailing benzodiazepine risks; the control group included 4 PCPs and 291 of their patients. PRIMARY AND SECONDARY MEASURES: The primary measure was benzodiazepine cessation by 9 months. We used logistic regression and a generalised estimating equations approach to control for clustering by PCP, adjusting for demographics, frailty, number of risk factors, and diagnoses of arthritis, depression, diabetes, falls, and pain. RESULTS: Patients in the intervention and control groups were comparable across most covariates; however, a greater proportion of intervention patients had pain-related diagnoses and depression. By 9 months, 26% of intervention patients (81 of 308) had discontinued benzodiazepines, compared with 17% (49 of 291) of control patients. Intervention patients had 1.73 greater odds of benzodiazepine discontinuation compared with controls (95% CI: 1.09, 2.75, p=0.02). The unadjusted number needed to treat was 10.5 (95% CI: 6.30, 34.92) and the absolute risk reduction was 0.095 (95% CI: 0.03 to 0.16). CONCLUSIONS: Results from this non-randomised QI initiative indicate that patient education programmes using the EMPOWER brochures have the potential to promote cessation of benzodiazepines in primary care.

Periodontists and oral surgeons' peri-implantitis-related education, knowledge, attitudes, and professional behavior: A national survey.

OBJECTIVES: Each year, approximately 5 million dental implants are placed in the United States and one out of three patients is likely to experience peri-implantitis (PI). The objectives were to compare the PI-related education, knowledge, attitudes, and professional behavior of periodontists and oral maxillofacial surgeons (OMS), and to explore relationships between these constructs of interest. METHODS: A total of 389 periodontists and 161 OMS responded to a web-based survey. Descriptive and inferential statistical analyses (independent sample t-tests, chi-square tests, and correlational analyses) were conducted. RESULTS: On average, periodontists reported a higher percentage of time spent in residency on implant surgery (21.02% vs. 7.27%; p < 0.001), better education about PI (5-point scale with 1 = not at all well: means: 2.86 vs. 2.59; p < 0.001), and better knowledge of risk factors (4.07 vs. 3.86; p < 0.001) than OMS. Periodontists argued that oral hygiene-related treatment (4.45 vs. 4.22; p = 0.001) and regeneration-focused treatments such as guided tissue regeneration (3.62 vs. 3.20; p < 0.001) contributed more to successfully treating PI and used these treatments more in their practices (4.86 vs. 4.56; p < 0.001/3.06 vs. 2.68; p < 0.001) than OMS. They also considered PI as a more serious problem than OMS (4.55 vs. 3.80; p < 0.001). The better the respondents' PI-related knowledge was, the more they considered PI as a serious problem (r = 0.19; p < 0.001). The more cases they treated per month, the more they considered PI as a serious problem (r = 0.19; p < 0.001). CONCLUSIONS: The results of the present study highlight the lack of standardization in the specialty training of periodontists and OMS. Best practice guidelines for the diagnosis and treatment of PI are needed to optimize graduate education about this important topic.

Actinomycetoma in a patient with pre-existing sensorineural hearing loss: a linezolid-based treatment paradigm.

Mycetoma is a chronic granulomatous infectious disease with a triad of subcutaneous swelling, discharging sinuses and the presence of granules. The infection may occur following minor trauma or penetrating thorn injury. We report a case of a man in his 40s with a history of thorn prick 9 years ago, followed by the formation of painless discharging sinuses on the right foot for the past 2 years. Clinical, local epidemiological, histopathological examination and Gram stain confirmed the diagnosis of actinomycetoma. Prior to initiating the Welsh regimen, a pretreatment assessment of the patient's auditory function was conducted through pure tone audiometry, indicating the existence of pre-existing high-frequency bilateral sensorineural hearing loss. The patient was treated with linezolid as an alternative to amikacin, at a dosage of 600 mg two times per day, leading to complete resolution within 3 weeks. This underscores linezolid's efficacy as a safe and cost-effective alternative for actinomycetoma, without causing ototoxic side effects.

Importance of targeting various cell signaling pathways in solid cancers.

Most adult human cancers are solid tumors prevailing in vital organs and lead to mortality all over the globe. Genetic and epigenetic alterations in cancer genes or genes of associated signaling pathways impart the most common characteristic of malignancy, that is, uncontrolled proliferation. Unless the mechanism of action of these cells signaling pathways (involved in cell proliferation, apoptosis, metastasis, and the maintenance of the stemness of cancer stem cells and cancer microenvironment) and their physiologic alteration are extensively studied, it is challenging to understand tumorigenesis as well as develop new treatments and precision medicines. Targeted therapy is one of the most promising strategies for treating various cancers. However, cancer is an evolving disease, and most patients develop resistance to these drugs by acquired mutations or mediation of microenvironmental factors or due to tumor heterogeneity. Researchers are striving to develop novel therapeutic options like combinatorial approaches targeting multiple responsible pathways effectively. Thus, in-depth knowledge of cell signaling and its components remains a critical topic of cancer research. This chapter summarized various extensively studied pathways in solid cancer and how they are targeted for therapeutic strategies.

Targeting signaling pathways in cancer stem cells: A potential approach for developing novel anti-cancer therapeutics.

Cancer stem cells (CSCs) have emerged as prime players in the intricate landscape of cancer development, progression, and resistance to traditional treatments. These unique cellular subpopulations own the remarkable capability of self-renewal and differentiation, giving rise to the diverse cellular makeup of tumors and fostering their recurrence following conventional therapies. In the quest for developing more effective cancer therapeutics, the focus has now shifted toward targeting the signaling pathways that govern CSCs behavior. This chapter underscores the significance of these signaling pathways in CSC biology and their potential as pivotal targets for the development of novel chemotherapy approaches. We delve into several key signaling pathways essential for maintaining the defining characteristics of CSCs, including the Wnt, Hedgehog, Notch, JAK-STAT, NF-κB pathways, among others, shedding light on their potential crosstalk. Furthermore, we highlight the latest advancements in CSC-targeted therapies, spanning from promising preclinical models to ongoing clinical trials. A comprehensive understanding of the intricate molecular aspects of CSC signaling pathways and their manipulation holds the prospective to revolutionize cancer treatment paradigms. This, in turn, could lead to more efficacious and personalized therapies with the ultimate goal of eradicating CSCs and enhancing overall patient outcomes. The exploration of CSC signaling pathways represents a key step towards a brighter future in the battle against cancer.

Critical success factors for creating sustainable digital health applications: A systematic review of the German case.

Objective: The Covid-19 pandemic has accelerated the adoption of digital technologies to address social needs, leading to increased investments in digital healthcare applications. Germany implemented a special law called the "Digitales Versorgungsgesetz" (DVG-Digital Supply Act) in 2019, which enables the reimbursement of digital health applications, including digital therapeutics (DTx), through a fast-track process. The Federal Institute for Drugs and Medical Devices (BfArM), the German federal authority responsible for overseeing digital health applications, has implemented legislative adjustments since the law's introduction, which have increased requirements for these applications and potentially led to the removal of some from the directory as well as a slowdown in the addition of new ones. To counteract this trend, this work aimed to identify key success factors for digital health applications (DiGAs). Methods: This research identifies critical success factors through a structured literature review for developing sustainable digital health applications within the European healthcare systems, specifically DiGAs. The study aims to support the ongoing digital transformation in healthcare. Results: The identified success factors that significantly impact the sustainability of DiGAs include patient-centered design, application effectiveness, user-friendliness, and adherence to data protection and information security regulations using standardized approaches. These factors are crucial in preventing the failure of DiGA manufacturers in European countries. Conclusion: By considering and implementing these critical success factors, DiGA manufacturers can enhance their chances of long-term success and contribute to the digital transformation of the healthcare system in Europe.

Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay.

Developing an effective mRNA therapeutic often requires maximizing protein output per delivered mRNA molecule. We previously found that coding sequence (CDS) design can substantially affect protein output, with mRNA variants containing more optimal codons and higher secondary structure yielding the highest protein outputs due to their slow rates of mRNA decay. Here, we demonstrate that CDS-dependent differences in translation initiation and elongation rates lead to differences in translation- and deadenylation-dependent mRNA decay rates, thus explaining the effect of CDS on mRNA half-life. Surprisingly, the most stable and highest-expressing mRNAs in our test set have modest initiation/elongation rates and ribosome loads, leading to minimal translation-dependent mRNA decay. These findings are of potential interest for optimization of protein output from therapeutic mRNAs, which may be achieved by attenuating rather than maximizing ribosome load.

Microneedle-mediated nanomedicine to enhance therapeutic and diagnostic efficacy.

Nanomedicine has been extensively explored for therapeutic and diagnostic applications in recent years, owing to its numerous advantages such as controlled release, targeted delivery, and efficient protection of encapsulated agents. Integration of microneedle technologies with nanomedicine has the potential to address current limitations in nanomedicine for drug delivery including relatively low therapeutic efficacy and poor patient compliance and enable theragnostic uses. In this Review, we first summarize representative types of nanomedicine and describe their broad applications. We then outline the current challenges faced by nanomedicine, with a focus on issues related to physical barriers, biological barriers, and patient compliance. Next, we provide an overview of microneedle systems, including their definition, manufacturing strategies, drug release mechanisms, and current advantages and challenges. We also discuss the use of microneedle-mediated nanomedicine systems for therapeutic and diagnostic applications. Finally, we provide a perspective on the current status and future prospects for microneedle-mediated nanomedicine for biomedical applications.

3D bioprinted aged human post-infarct myocardium tissue model.

Background and Aims: Fibrotic tissue formed after myocardial infarction (MI) can be as detrimental as MI itself. However, current in vitro cardiac fibrosis models fail to recapitulate the complexities of post-MI tissue. Moreover, although MI and subsequent fibrosis is most prominent in the aged population, the field suffers from inadequate aged tissue models. Herein, an aged human post-MI tissue model, representing the native microenvironment weeks after initial infarction, is engineered using three-dimensional bioprinting via creation of individual bioinks to specifically mimic three distinct regions: remote, border, and scar. Methods: The aged post-MI tissue model is engineered through combination of gelatin methacryloyl, methacrylated hyaluronic acid, aged type I collagen, and photoinitiator at variable concentrations with different cell types, including aged human induced pluripotent stem cell-derived cardiomyocytes, endothelial cells, cardiac fibroblasts, and cardiac myofibroblasts, by introducing a methodology which utilizes three printheads of the bioprinter to model aged myocardium. Then, using cell-specific proteins, the cell types that comprised each region are confirmed using immunofluorescence. Next, the beating characteristics are analyzed. Finally, the engineered aged post-MI tissue model is used as a benchtop platform to assess the therapeutic effects of stem cell-derived extracellular vesicles on the scar region. Results: As a result, high viability (>74%) was observed in each region of the printed model. Constructs demonstrated functional behavior, exhibiting a beating velocity of 6.7 µm/s and a frequency of 0.3 Hz. Finally, the effectiveness of hiPSC-EV and MSC-EV treatment was assessed. While hiPSC-EV treatment showed no significant changes, MSC-EV treatment notably increased cardiomyocyte beating velocity, frequency, and confluency, suggesting a regenerative potential. Conclusion: In conclusion, we envision that our approach of modeling post-MI aged myocardium utilizing three printheads of the bioprinter may be utilized for various applications in aged cardiac microenvironment modeling and testing novel therapeutics.

Current approaches in smart nano-inspired drug delivery: A narrative review.

Background and Aim: The traditional drug delivery approach involves systemic administration of a drug that could be nonspecific in targeting, low on efficacy, and with severe side-effects. To address such challenges, the field of smart drug delivery has emerged aiming at designing and developing delivery systems that can target specific cells, tissues, and organs and have minimal off-target side-effects. Methods: A literature search was done to collate papers and reports about the currently available various strategies for smart nano-inspired drug delivery. The databases searched were PubMed, Scopus, and Google Scholar. Based on selection criteria, the most pertinent and recent items were included. Results: Smart drug delivery is a cutting-edge revolutionary intervention in modern medicines to ensure effective and safe administration of therapeutics to target sites. These hold great promise for targeted and controlled delivery of therapeutic agents to improve the efficacy with reduced side-effects as compared to the conventional drug delivery approaches. Current smart drug delivery approaches include nanoparticles, liposomes, micelles, and hydrogels, each with its own advantages and limitations. The success of these delivery systems lies in engineering and designing them, and optimizing their pharmacokinetics and pharmacodynamics properties. Conclusion: Development of drug delivery systems that can get beyond various physiological and clinical barriers, as observed in conventionally administered chemotherapeutics, has been possible through recent advancements. Using multifunctional targeting methodologies, smart drug delivery tries to localize therapy to the target location, reduces cytotoxicity, and improves the therapeutic index. Rapid advancements in research and development in smart drug delivery provide wider and more promising avenues to guarantee a better healthcare system, improve patient outcomes, and achieve higher levels of effective medical interventions like personalized medicine.

Treatment of relapsed/refractory chronic lymphocytic leukemia with Zanubrutinib after progressing on other BTK inhibitors.

Chronic Lymphocytic Leukemia (CLL) is the most common type of leukemia in the US, representing approximately 1.1% of all new cancers diagnosed. Most patients with CLL can be monitored without treatment, and the indicated treatment options include a CD20 monoclonal antibody with or without bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL2) antagonists. We review the case of a 77-year-old female with a long-standing history of CLL predominant lymphocytosis, transfusion -independent anemia, and thrombocytopenia. Patient responded to zanubrutinib after initial failure of idelalisib, rituximab, and acalabrutinib and venetoclax.

Fibroblast Stromal Support Model for Predicting Human Papillomavirus-Associated Cancer Drug Responses.

Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV+OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERα) is overexpressed in HPV+OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV+ specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV+ keratinocytes and HPV+ cancer cells in vitro. Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV+ specific estrogen growth responses. Continuing to monopolize on the HPV+ specific overexpression of ERα, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro. Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery.

Allogeneic platelet-rich plasma for knee osteoarthritis in patients with primary immune thrombocytopenia: A randomized clinical trial.

The treatment of painful KOA in adult patients with ITP has not been well studied yet. We conducted a prospective, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of intra-articular allogeneic PRP injections on symptoms and joint structure in patients with KOA and ITP. 80 participants were randomly allocated in a 1:1 ratio to allogeneic PRP group or saline group. The primary outcome was the WOMAC total score at 12 months post-injection. The number of patients in each group who achieved MCID of primary outcome showed a statistically significant difference only at 3-month (27/39 vs. 5/39, p = 0.001) and 6-month (15/39 vs. 3/38, p = 0.032). The difference in WOMAC total score exceeded the MCID only at 3 month (mean difference of -15.1 [95% CI -20.7 to -9.5], p < 0.001). Results suggest that allogeneic PRP was superior to placebo only with respect to symptoms at 3-month of follow-up.

Paratesticular metastasis from colorectal adenocarcinoma presenting as hydrocele: a rare case report and literature review.

Colorectal cancer, with the liver being the most common site of distant metastasis, followed by the lungs and bones. Although reports of metastasis to the testis exist, paratesticular metastasis is extremely rare. A 37-year-old male presented with scrotal swelling. Ultrasound revealed hydrocele of the tunica vaginalis. The patient underwent routine surgical treatment, and postoperative pathology of the tunica vaginalis indicated adenocarcinoma of gastrointestinal origin. Colonoscopic biopsy confirmed adenocarcinoma of the sigmoid colon. After six months of systemic therapy, tumor reduction surgery was performed in conjunction with tunica vaginalis excision. Postoperative pathology suggested histological similarity in both sites, with immunohistochemistry results supporting the diagnosis of sigmoid colon adenocarcinoma metastasizing to the tunica vaginalis. We conducted a literature review, summarizing and discussing clinical presentations, metastatic pathways, and diagnostic approaches.

Artificial intelligence and medical education: application in classroom instruction and student assessment using a pharmacology & therapeutics case study.

BACKGROUND: Artificial intelligence (AI) tools are designed to create or generate content from their trained parameters using an online conversational interface. AI has opened new avenues in redefining the role boundaries of teachers and learners and has the potential to impact the teaching-learning process. METHODS: In this descriptive proof-of- concept cross-sectional study we have explored the application of three generative AI tools on drug treatment of hypertension theme to generate: (1) specific learning outcomes (SLOs); (2) test items (MCQs- A type and case cluster; SAQs; OSPE); (3) test standard-setting parameters for medical students. RESULTS: Analysis of AI-generated output showed profound homology but divergence in quality and responsiveness to refining search queries. The SLOs identified key domains of antihypertensive pharmacology and therapeutics relevant to stages of the medical program, stated with appropriate action verbs as per Bloom's taxonomy. Test items often had clinical vignettes aligned with the key domain stated in search queries. Some test items related to A-type MCQs had construction defects, multiple correct answers, and dubious appropriateness to the learner's stage. ChatGPT generated explanations for test items, this enhancing usefulness to support self-study by learners. Integrated case-cluster items had focused clinical case description vignettes, integration across disciplines, and targeted higher levels of competencies. The response of AI tools on standard-setting varied. Individual questions for each SAQ clinical scenario were mostly open-ended. The AI-generated OSPE test items were appropriate for the learner's stage and identified relevant pharmacotherapeutic issues. The model answers supplied for both SAQs and OSPEs can aid course instructors in planning classroom lessons, identifying suitable instructional methods, establishing rubrics for grading, and for learners as a study guide. Key lessons learnt for improving AI-generated test item quality are outlined. CONCLUSIONS: AI tools are useful adjuncts to plan instructional methods, identify themes for test blueprinting, generate test items, and guide test standard-setting appropriate to learners' stage in the medical program. However, experts need to review the content validity of AI-generated output. We expect AIs to influence the medical education landscape to empower learners, and to align competencies with curriculum implementation. AI literacy is an essential competency for health professionals.