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1.
J Vis Exp ; (208)2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38912778

ABSTRACT

Pancreatic islet transplantation is an emerging treatment for type I diabetes; however, it is limited by donor matching and availability. Porcine islet xenotransplantation offers a promising alternative to allotransplantation, with the potential for large-scale production of on-demand, functional islets. The yield and viability of isolated islets is highly susceptible to the quality of the donor pancreas and the method of procurement, particularly the duration of warm-ischemia time. To improve organ preservation and subsequent islet yield and viability, we have developed a protocol for surgical perfusion and resection of the porcine pancreas. This protocol employs direct infrarenal aortic cannulation and organ perfusion to both minimize warm-ischemia time and simplify the procedure for operators who do not have extensive surgical expertise. Subsequent arterial perfusion of the pancreas via the aorta flushes stagnant blood from the microvasculature, thereby reducing thrombosis and oxidative damage to the tissue. This manuscript provides a detailed protocol for surgical perfusion and resection of the porcine pancreas, followed by islet isolation and purification.


Subject(s)
Islets of Langerhans Transplantation , Islets of Langerhans , Pancreas , Perfusion , Animals , Swine , Islets of Langerhans/cytology , Islets of Langerhans Transplantation/methods , Perfusion/methods , Pancreas/surgery , Pancreas/blood supply , Pancreas/cytology , Transplantation, Heterologous/methods
2.
Front Oncol ; 14: 1415627, 2024.
Article in English | MEDLINE | ID: mdl-38919519

ABSTRACT

Background: The devastating scourge of cervical cancer in Africa is largely due to the absence of preventive interventions, driven by low awareness and poor perception of the disease in the continent. This work is a preliminary effort toward understanding key social drivers promoting this disease in our immediate environment with a view to mitigating it. Method: Female students of two tertiary health institutions in Azare, northeastern Nigeria, were approached to participate in this cross-sectional descriptive study. A structured self-administered questionnaire was administered to consenting participants and covered questions on their socio-demographics, awareness, perception, and attitude about/toward cervical cancer and its prevention. The responses were scrutinized for coherency and categorized into themes using summary statistics, while a chi-square test was used to determine the association between awareness of cervical cancer and participant age, marital status, religion, screening uptake, and willingness to undergo screen. Results: Awareness of cervical cancer was recorded among 174/230 (75.7%) respondents who enrolled in this study; 117 (67.2%) knew that it was preventable, but only three (1.3%) respondents had undergone screening. Among the aware participants, 91 (52.3%) and 131 (75.3%) knew that sexual intercourse and multiple sexual partners are risk factors for the disease, respectively. In contrast, knowledge of the etiology was poor; 82 (47.1%) respondents who knew it was preventable had heard about human papillomavirus (HPV), while 72 (41.4%) knew that HPV causes cervical cancer. Most (78%) of the participants expressed willingness to take a human papillomavirus vaccine or undergo screening (84.6%) if made available to them. Awareness was significantly associated with participants' age (p = 0.022) and willingness to undergo screening (p = 0.016). Conclusion: This study revealed discordance between awareness and knowledge about cervical cancer. Educational initiatives reflective of population perception/knowledge of cervical cancer are needed to mitigate the rising incidence of this disease, especially among female healthcare providers.

3.
Sci Rep ; 14(1): 12100, 2024 05 27.
Article in English | MEDLINE | ID: mdl-38802488

ABSTRACT

Field-derived metrics are critical for effective control of malaria, particularly in sub-Saharan Africa where the disease kills over half a million people yearly. One key metric is entomological inoculation rate, a direct measure of transmission intensities, computed as a product of human biting rates and prevalence of Plasmodium sporozoites in mosquitoes. Unfortunately, current methods for identifying infectious mosquitoes are laborious, time-consuming, and may require expensive reagents that are not always readily available. Here, we demonstrate the first field-application of mid-infrared spectroscopy and machine learning (MIRS-ML) to swiftly and accurately detect Plasmodium falciparum sporozoites in wild-caught Anopheles funestus, a major Afro-tropical malaria vector, without requiring any laboratory reagents. We collected 7178 female An. funestus from rural Tanzanian households using CDC-light traps, then desiccated and scanned their heads and thoraces using an FT-IR spectrometer. The sporozoite infections were confirmed using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR), to establish references for training supervised algorithms. The XGBoost model was used to detect sporozoite-infectious specimen, accurately predicting ELISA and PCR outcomes with 92% and 93% accuracies respectively. These findings suggest that MIRS-ML can rapidly detect P. falciparum in field-collected mosquitoes, with potential for enhancing surveillance in malaria-endemic regions. The technique is both fast, scanning 60-100 mosquitoes per hour, and cost-efficient, requiring no biochemical reactions and therefore no reagents. Given its previously proven capability in monitoring key entomological indicators like mosquito age, human blood index, and identities of vector species, we conclude that MIRS-ML could constitute a low-cost multi-functional toolkit for monitoring malaria risk and evaluating interventions.


Subject(s)
Anopheles , Machine Learning , Malaria, Falciparum , Mosquito Vectors , Plasmodium falciparum , Animals , Anopheles/parasitology , Malaria, Falciparum/epidemiology , Malaria, Falciparum/diagnosis , Malaria, Falciparum/parasitology , Plasmodium falciparum/isolation & purification , Mosquito Vectors/parasitology , Female , Humans , Tanzania/epidemiology , Sporozoites , Spectrophotometry, Infrared/methods , Spectroscopy, Fourier Transform Infrared/methods
4.
JTCVS Open ; 18: 80-86, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38690437

ABSTRACT

Objective: Open decannulation from femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) carries high risk of morbidity, including groin wound infection. This study evaluated the impact of percutaneous decannulation on rates of groin wound infection in patients decannulated from femoral VA-ECMO. Methods: Between January 1, 2022, and April 30, 2023, 47 consecutive patients received percutaneous femoral VA-ECMO and survived to decannulation. A percutaneous suture-mediated closure device was used for decannulation in patients with relatively smaller arterial cannulas. Patients with larger arterial cannulas or unsuccessful percutaneous closures underwent surgical cutdown and repair of the femoral artery. The primary outcome was arterial site wound infection following decannulation. Results: Among the 47 patients who survived to decannulation from VA-ECMO, 21 underwent percutaneous decannulation and 27 underwent surgical cutdown. One patient underwent 2 VA-ECMO runs, one with percutaneous decannulation and one with surgical cutdown. Percutaneous decannulation was attempted in 22 patients, with 21 of 22 (95.5%) success rate. Decannulation procedure length was significantly shorter in the percutaneous group (79 minutes vs 148 minutes, P = .0001). The percutaneous group had significantly reduced rates of groin wound complications (0% vs 40.7%, P = .001) and groin wound infections (0% vs 22.2%, P = .03) when compared with the surgical cutdown group. Three patients (14.3%) in the percutaneous group experienced vascular complications, including pseudoaneurysm at the distal perfusion catheter site and nonocclusive thrombus of the common femoral artery. Conclusions: Percutaneous decannulation may reduce decannulation procedure length and rate of groin wound infection in patients who survive to decannulation from VA-ECMO.

5.
Article in English | MEDLINE | ID: mdl-38747674

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) affects subpleural lung, but is considered to spare small airways. Micro-CT studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. We use EB-OCT to evaluate small airways in early IPF and control subjects in vivo. METHODS: EB-OCT was performed in 12 IPF and 5 control subjects (matched by age, sex, smoking-history, height, BMI). IPF subjects had early disease with mild restriction (FVC: 83.5% predicted), diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for UIP present) and less affected (some but not all criteria for UIP present) sites. Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site. RESULTS: Compared to control subjects (mean: 11.2 bronchioles/cm3; SD: 6.2), there was significant bronchiole reduction in IPF subjects (42% loss; mean: 6.5/cm3; SD: 3.4; p=0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; p<0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; p=0.024) sites. Stereology metrics showed IPF affected small airways were significantly larger and more distorted/irregular than in IPF less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (p=0.36-1.0). CONCLUSION: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30 and 50%), even in areas minimally affected by disease, compared to matched controls. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

6.
JBI Evid Implement ; 2024 May 14.
Article in English | MEDLINE | ID: mdl-38738475

ABSTRACT

INTRODUCTION: Appropriate malignant fungating wound (MFW) care is challenging for oncology nurses, leading to increased stress, compromised care quality, and poor patient outcomes. OBJECTIVE: This study aimed to address best practice barriers and develop evidence-based guidelines for MFW care. METHODS: This project was guided by the JBI Evidence Implementation Framework, which follows a seven-phase process. Both nurses' skills and patient charts were audited to determine compliance with best practices for comprehensive MFW assessment, wound photo records, use of validated wound assessment tools, appropriate wound care, and patient pain and satisfaction. Bandura's social learning theory was used to guide the development of an online education program and an objective structured clinical examination for skill improvement to prompt behavior change in nurses. A follow-up audit was conducted to measure improvements in knowledge, skills, and self-efficacy among nurses to validate the effectiveness of the intervention. RESULTS: The project resulted in improvements in all four evidence-based practice criteria: (1) comprehensive MFW assessments increased from 27% to 98%; (2) the inclusion of wound photos in medical records increased from 50% to 100%; (3) use of a validated wound assessment tool increased from 0% to 100%; and (4) appropriate interventions to manage wounds and maintain patients' quality of life increased from 50% to 90%. CONCLUSIONS: The project integrated a flexible education program, multidisciplinary collaboration, and leadership support to empower nurses to effectively manage MFWs. In addition, Bandura's social learning theory was used to influence nurses' behavior and bring about sustainable changes to organizational culture and practices. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A205.

7.
Crit Rev Oncog ; 29(3): 99-112, 2024.
Article in English | MEDLINE | ID: mdl-38683157

ABSTRACT

Differences in tumor biology and genetic predisposition have been suggested as factors influencing overall survival and increased mortality in Black breast and ovarian cancer patients. Therefore, it is key to evaluate genetic susceptibilities in Afro-Caribbean patients because the black population in the US is not homogeneous. Identifying a high incidence of hereditary breast and ovarian cancer (HBOC) in Afro-Caribbean countries can lead to understanding the pattern of inherited traits in US-Caribbean immigrants and their subsequent generations. The paucity of projects studying the genetic landscape in these populations makes it difficult to design studies aimed at optimizing screening and prophylaxis strategies, which in turn, improve survival and mortality rates. This scoping review identifies and categorizes current research on the genetic paradigm of HBOC in the Afro-Caribbean population. We performed an evaluation of the evidence and generated a summary of findings according to preferred reporting items for systematic review and meta-analysis (PRISMA) Extension for Scoping Reviews guidelines. We included articles that assessed the incidence and prevalence of pathologic germline mutations and experience/barriers for genetic testing in Afro-Caribbean Countries and US-Caribbean patients. Our results highlight countries where genetic landscapes remain severely understudied and support recommending multigene testing in Caribbean-born patients. They highlight a need for further research on the genetic paradigm of HBOC in the Afro-Caribbean population to improve genetic testing/counseling and the subsequent adoption of early detection and risk reduction strategies.


Subject(s)
Genetic Predisposition to Disease , Female , Humans , Black People/genetics , Breast Neoplasms/genetics , Breast Neoplasms/epidemiology , Genetic Testing , Germ-Line Mutation , Hereditary Breast and Ovarian Cancer Syndrome/genetics , Hereditary Breast and Ovarian Cancer Syndrome/epidemiology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/epidemiology , United States , Black or African American
8.
Int J Nurs Stud ; 154: 104765, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38642473

ABSTRACT

BACKGROUND: Haemorrhoids are a common chronic anorectal disease, and haemorrhoidectomy is the standard treatment for advanced (grade III and IV) haemorrhoids. Warm water sitz has commonly been used to stimulate urination, cleanse wounds, and decrease pain. Although urinary retention and pain usually occur within the first 24 h after surgery, the warm water sitz bath is provided 24 h after haemorrhoidectomy, which might be a missed opportunity to optimize the quality and efficiency of the care provided. OBJECTIVE: To investigate the effect of early warm water sitz bath on the day of haemorrhoidectomy surgery on preventing urinary retention and reducing wound pain. DESIGN: This was a longitudinal double-blind study with a permuted block randomization design. SETTING(S): This study was conducted in a surgical ward of a medical center. An average of 18 patients receiving hemorrhoid surgery in that ward every month. PARTICIPANTS: A total of 64 participants (32 each in the experimental and control groups) were enrolled. (The first recruitment date is January 16, 2020.) METHODS: Patients who received haemorrhoidectomy for grade III or IV haemorrhoids from January to December 2020 were enrolled. The experimental and control groups received the same conventional treatment and care before the haemorrhoidectomy. The experimental group started warm-water sitz bath 6 h after the surgery, and the control group started warm water sitz bath on post-haemorrhoidectomy day 1 as usual. Urinary retention was defined as use of Foley catheter during the hospital stay or remaining urine volume ≧ 300 ml using the bladder scan. A numerical rating scale was used to rate the pain level. Each participant was evaluated 6 times in total until hospital discharge. The data were analysed by descriptive statistics, chi-square test, and independent samples t test. Generalized estimating equations and intention to treat were used to identify changes in urinary retention and pain over time and missing data, respectively. RESULTS: There was no significant difference in the degree of change in the number of people with urinary retention between groups. A change in the wound pain index was noted; the study group had a statistically significant lower pain score than the control group (B = -0.81, 95 % CI: -1.44 to -0.18). CONCLUSIONS: Early warm water sitz bath was a safe and effective strategy to decrease post-haemorrhoidectomy pain, but not urinary retention. Nurses could provide early warm water sitz bath for post-haemorrhoidectomy patients' comfort. REGISTRATION: ClinicalTrials.gov ID: NCT04535765.


Subject(s)
Hemorrhoidectomy , Urinary Retention , Humans , Urinary Retention/etiology , Male , Female , Hemorrhoidectomy/methods , Hemorrhoidectomy/adverse effects , Double-Blind Method , Middle Aged , Adult , Baths/methods , Pain, Postoperative , Water , Hemorrhoids/surgery , Aged , Hot Temperature , Longitudinal Studies
9.
J Cancer Surviv ; 2024 Apr 04.
Article in English | MEDLINE | ID: mdl-38573458

ABSTRACT

PURPOSE: Due to the increase in both cancer incidence and overall survival rates, more adolescents and young adults (AYAs) have to live with the effects that their cancer diagnosis and following treatments have on their bodies. This qualitative phenomenological study aimed to gain more insight into the way AYAs experience these effects and how they respond to these effects. METHODS: Semi-structured interviews with a sample of 11 AYAs with an age range of 25-41 years at the time of the interview, who were diagnosed with different types of cancer, were conducted. Participants were recruited via social media and patient associations until data saturation was reached. A topic guide with open-ended questions about lived experiences was used. Interpretative phenomenological analysis (IPA) was performed to analyse the transcripts. RESULTS: We identified six Group Experiential Themes based on different ways AYAs experience their bodies: (1) self-conscious body, (2) vulnerable body, (3) adapting to the body, (4) uncontrollable body, (5) remembering the body and (6) shared bodies. CONCLUSION: This study offers in-depth insight into the bodily experiences of AYAs after cancer and how they respond to these changes from a phenomenological point of view. IMPLICATIONS FOR CANCER SURVIVORS: This knowledge could be beneficial to provide more guidance for AYAs during and after their illness, by focussing on personalised psychological (after)care.

10.
Eur Urol Focus ; 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38631992

ABSTRACT

BACKGROUND AND OBJECTIVE: The implementation of quality assurance programs (QAPs) within urological practice has gained prominence; yet, their impact on outcomes after radical prostatectomy (RP) remains uncertain. This paper aims to systematically review the current literature regarding the implementation of QAPs and their impact on outcomes after robot-assisted RP, laparoscopic RP, and open prostatectomy, collectively referred to as RP. METHODS: A systematic Embase, Medline (OvidSP), and Scopus search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) process, on January 12, 2024. Studies were identified and included if these covered implementation of QAPs and their impact on outcomes after RP. QAPs were defined as any intervention seeking quality improvement through critically reviewing, analyzing, and discussing outcomes. Included studies were assessed critically using the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool, with results summarized narratively. KEY FINDINGS AND LIMITATIONS: Ten included studies revealed two methodological strategies: periodic performance feedback and surgical video assessments. Despite conceptual variability, QAPs improved outcomes consistently (ie, surgical margins, urine continence, erectile function, and hospital readmissions). Of the two strategies, video assessments better identified suboptimal surgical practice and technical errors. Although the extent of quality improvements did not appear to correlate with the frequency of QAPs, there was an apparent correlation with whether or not outcomes were evaluated collectively. CONCLUSIONS AND CLINICAL IMPLICATIONS: Current findings suggest that QAPs have a positive impact on outcomes after RP. Caution in interpretation due to limited data is advised. More extensive research is required to explore how conceptual differences impact the extent of quality improvements. PATIENT SUMMARY: In this paper, we review the available scientific literature regarding the implementation of quality assurance programs and their impact on outcomes after radical prostatectomy. The included studies offered substantial support for the implementation of quality assurance programs as an incentive to improve the quality of care continuously.

11.
Malar J ; 23(1): 86, 2024 Mar 26.
Article in English | MEDLINE | ID: mdl-38532415

ABSTRACT

BACKGROUND: The degree to which Anopheles mosquitoes prefer biting humans over other vertebrate hosts, i.e. the human blood index (HBI), is a crucial parameter for assessing malaria transmission risk. However, existing techniques for identifying mosquito blood meals are demanding in terms of time and effort, involve costly reagents, and are prone to inaccuracies due to factors such as cross-reactivity with other antigens or partially digested blood meals in the mosquito gut. This study demonstrates the first field application of mid-infrared spectroscopy and machine learning (MIRS-ML), to rapidly assess the blood-feeding histories of malaria vectors, with direct comparison to PCR assays. METHODS AND RESULTS: Female Anopheles funestus mosquitoes (N = 1854) were collected from rural Tanzania and desiccated then scanned with an attenuated total reflectance Fourier-transform Infrared (ATR-FTIR) spectrometer. Blood meals were confirmed by PCR, establishing the 'ground truth' for machine learning algorithms. Logistic regression and multi-layer perceptron classifiers were employed to identify blood meal sources, achieving accuracies of 88%-90%, respectively, as well as HBI estimates aligning well with the PCR-based standard HBI. CONCLUSIONS: This research provides evidence of MIRS-ML effectiveness in classifying blood meals in wild Anopheles funestus, as a potential complementary surveillance tool in settings where conventional molecular techniques are impractical. The cost-effectiveness, simplicity, and scalability of MIRS-ML, along with its generalizability, outweigh minor gaps in HBI estimation. Since this approach has already been demonstrated for measuring other entomological and parasitological indicators of malaria, the validation in this study broadens its range of use cases, positioning it as an integrated system for estimating pathogen transmission risk and evaluating the impact of interventions.


Subject(s)
Anopheles , Malaria , Animals , Humans , Female , Mosquito Vectors , Malaria/epidemiology , Machine Learning , Spectrophotometry, Infrared , Feeding Behavior
12.
Parasit Vectors ; 17(1): 143, 2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38500231

ABSTRACT

BACKGROUND: Accurately determining the age and survival probabilities of adult mosquitoes is crucial for understanding parasite transmission, evaluating the effectiveness of control interventions and assessing disease risk in communities. This study was aimed at demonstrating the rapid identification of epidemiologically relevant age categories of Anopheles funestus, a major Afro-tropical malaria vector, through the innovative combination of infrared spectroscopy and machine learning, instead of the cumbersome practice of dissecting mosquito ovaries to estimate age based on parity status. METHODS: Anopheles funestus larvae were collected in rural south-eastern Tanzania and reared in an insectary. Emerging adult females were sorted by age (1-16 days old) and preserved using silica gel. Polymerase chain reaction (PCR) confirmation was conducted using DNA extracted from mosquito legs to verify the presence of An. funestus and to eliminate undesired mosquitoes. Mid-infrared spectra were obtained by scanning the heads and thoraces of the mosquitoes using an attenuated total reflection-Fourier transform infrared (ATR-FT-IR) spectrometer. The spectra (N = 2084) were divided into two epidemiologically relevant age groups: 1-9 days (young, non-infectious) and 10-16 days (old, potentially infectious). The dimensionality of the spectra was reduced using principal component analysis, and then a set of machine learning and multi-layer perceptron (MLP) models were trained using the spectra to predict the mosquito age categories. RESULTS: The best-performing model, XGBoost, achieved overall accuracy of 87%, with classification accuracy of 89% for young and 84% for old An. funestus. When the most important spectral features influencing the model performance were selected to train a new model, the overall accuracy increased slightly to 89%. The MLP model, utilizing the significant spectral features, achieved higher classification accuracy of 95% and 94% for the young and old An. funestus, respectively. After dimensionality reduction, the MLP achieved 93% accuracy for both age categories. CONCLUSIONS: This study shows how machine learning can quickly classify epidemiologically relevant age groups of An. funestus based on their mid-infrared spectra. Having been previously applied to An. gambiae, An. arabiensis and An. coluzzii, this demonstration on An. funestus underscores the potential of this low-cost, reagent-free technique for widespread use on all the major Afro-tropical malaria vectors. Future research should demonstrate how such machine-derived age classifications in field-collected mosquitoes correlate with malaria in human populations.


Subject(s)
Anopheles , Malaria , Animals , Female , Humans , Infant , Child, Preschool , Child , Infant, Newborn , Anopheles/parasitology , Mosquito Vectors/parasitology , Spectroscopy, Fourier Transform Infrared , Tanzania
13.
Nat Commun ; 15(1): 1876, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38485924

ABSTRACT

Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8- derived variants performed efficiently. This study demonstrates the potential of using normothermic liver perfusion as a model for early-stage testing of liver-focused gene therapies. The results offer preliminary insights that could help inform the development of more effective translational strategies.


Subject(s)
Dependovirus , Genetic Vectors , Humans , Genetic Vectors/genetics , Dependovirus/genetics , Antibodies, Neutralizing , Liver , Perfusion
14.
J Endovasc Ther ; : 15266028241231513, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-38357736

ABSTRACT

CLINICAL IMPACT: The study establishes a rapid, technically straightforward, and reproducible porcine large animal model for acute iliocaval deep vein thrombosis (DVT). The procedure can be performed with basic endovascular skillsets. With its procedural efficiency and consistency, the platform is promising for comparative in vivo testing of venous thrombectomy devices in a living host, and for future verification and validation studies to determine efficacy of novel thrombectomy devices relative to predicates.

15.
Mol Ther ; 32(3): 818-836, 2024 Mar 06.
Article in English | MEDLINE | ID: mdl-38297833

ABSTRACT

Directed evolution of natural AAV9 using peptide display libraries have been widely used in the search for an optimal recombinant AAV (rAAV) for transgene delivery across the blood-brain barrier (BBB) to the CNS following intravenous ( IV) injection. In this study, we used a different approach by creating a shuffled rAAV capsid library based on parental AAV serotypes 1 through 12. Following selection in mice, 3 novel variants closely related to AAV1, AAV-BBB6, AAV-BBB28, and AAV-BBB31, emerged as top candidates. In direct comparisons with AAV9, our novel variants demonstrated an over 270-fold improvement in CNS transduction and exhibited a clear bias toward neuronal cells. Intriguingly, our AAV-BBB variants relied on the LY6A cellular receptor for CNS entry, similar to AAV9 peptide variants AAV-PHP.eB and AAV.CAP-B10, despite the different bioengineering methods used and parental backgrounds. The variants also showed reduced transduction of both mouse liver and human primary hepatocytes in vivo. To increase clinical translatability, we enhanced the immune escape properties of our new variants by introducing additional modifications based on rational design. Overall, our study highlights the potential of AAV1-like vectors for efficient CNS transduction with reduced liver tropism, offering promising prospects for CNS gene therapies.


Subject(s)
Blood-Brain Barrier , Genetic Therapy , Humans , Animals , Mice , Genetic Therapy/methods , Capsid , Liver , Peptides/genetics , Dependovirus , Genetic Vectors/genetics , Transduction, Genetic
17.
Nature ; 626(7997): 151-159, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38233525

ABSTRACT

Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease1-3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb4. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly4-6. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.


Subject(s)
Enhancer Elements, Genetic , Extremities , Polydactyly , Proto-Oncogene Proteins c-ets , Humans , Enhancer Elements, Genetic/genetics , Extremities/embryology , Extremities/pathology , Gain of Function Mutation , Homeodomain Proteins/metabolism , Interferon Regulatory Factors/metabolism , Organ Specificity/genetics , Penetrance , Phenotype , Polydactyly/embryology , Polydactyly/genetics , Polydactyly/pathology , Polymorphism, Single Nucleotide , Protein Binding , Proto-Oncogene Proteins c-ets/metabolism , Transcription Factor AP-1/metabolism
18.
Nurse Educ Pract ; 75: 103895, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38232676

ABSTRACT

AIM: The purpose of this study was to evaluate the effectiveness of ECMO care board games facilitated teaching approach (ECMO care board games) in enhancing ECMO care knowledge, clinical reasoning and learning engagement among intensive care unit (ICU) nurses. BACKGROUND: ECMO is a highly complex, relatively low-incidence, high-risk clinical life support device system used in the intensive care unit (ICU). Its usage has increased nearly tenfold over the past 30 years. Traditionally, ECMO education has been delivered through classroom teaching, which has demonstrated limited effectiveness in promoting nurses' learning engagement, clinical reasoning competency and confidence. The literature suggests that well-designed board games can enhance learning engagement, stimulate higher-level thinking and improve the effectiveness and confidence of nurses' learning. DESIGN: A quasi-experimental study two-group repeated measure design. METHODS: A purposive sample of 73 ICU nurses from two campuses of one medical center was recruited (37 in the experimental group and 36 in the control group). The experimental group received ECMO care training through ECMO care board games facilitated teaching approach, whereas the control group completed the training through a traditional teaching approach. Instruments used for data collection include a demographic information sheet, ECMO Care Knowledge Scale, Clinical Reasoning Scale (Huang et al., 2023) and Learning Engagement Scale (Ciou , 2020). Both groups completed a pre-test before the training, a post-test one week after the training and a second post-test three weeks after the training. RESULTS: Prior to the intervention, there were no significant differences between the two groups in ECMO care knowledge and learning engagement. However, there was a significant difference in clinical reasoning. One week after the intervention, the experimental group demonstrated significantly higher scores in ECMO care knowledge, clinical reasoning and learning engagement than the control group (p <0.01). Three weeks after the intervention, the experimental group showed significantly higher scores in ECMO care knowledge, clinical reasoning and learning engagement (p <0.001). CONCLUSIONS: The content for ECMO care is complex and difficult. Board games can enhance ECMO care knowledge, clinical reasoning and learning engagement. This teaching strategy may be applied to learning challenging subjects in the future to improve learning effectiveness. The clinical reasoning framework is conducive to guiding nurses' learning. In future continuing education, board games designed based on the clinical reasoning framework and tailored to the focus of in-service education can effectively enhance nurses' learning effectiveness.


Subject(s)
Extracorporeal Membrane Oxygenation , Humans , Extracorporeal Membrane Oxygenation/education , Intensive Care Units , Learning , Clinical Competence , Educational Status
20.
Popul Health Manag ; 27(1): 94-95, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38079279
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