ABSTRACT
Coordinated spatio-temporal regulation of the determination and differentiation of neural stem cells is essential for brain development. Failure to integrate multiple factors leads to defective brain structures or tumour formation. Previous studies suggest changes of chromatin state are needed to direct neural stem cell differentiation, but the mechanisms are unclear. Analysis of Snr1, the Drosophila orthologue of SMARCB1, an ATP-dependent chromatin remodelling protein, identified a key role in regulating the transition of neuroepithelial cells into neural stem cells and subsequent differentiation of neural stem cells into the cells needed to build the brain. Loss of Snr1 in neuroepithelial cells leads to premature neural stem cell formation. Additionally, loss of Snr1 in neural stem cells results in inappropriate perdurance of neural stem cells into adulthood. Snr1 reduction in neuroepithelial or neural stem cells leads to the differential expression of target genes. We find that Snr1 is associated with the actively transcribed chromatin region of these target genes. Thus, Snr1 likely regulates the chromatin state in neuroepithelial cells and maintains chromatin state in neural stem cells for proper brain development.
Subject(s)
Drosophila Proteins , Transcription Factors , Animals , Transcription Factors/metabolism , Trans-Activators/genetics , Chromatin Assembly and Disassembly/genetics , Cell Cycle Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila/metabolism , Cell Differentiation/genetics , ChromatinABSTRACT
BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.
Subject(s)
Consensus , Delphi Technique , Desensitization, Immunologic , Food Hypersensitivity , Informed Consent , Humans , Desensitization, Immunologic/methods , Administration, Oral , Food Hypersensitivity/therapy , Food Hypersensitivity/immunologyABSTRACT
In summer 2022, a case of mpox was confirmed in a resident at the Cook County Jail (CCJ) in Chicago, Illinois, USA. We conducted in-depth interviews with CCJ residents and staff to assess mpox knowledge, attitudes, and practices; hygiene and cleaning practices; and risk behaviors. We characterized findings by using health belief model constructs. CCJ residents and staff perceived increased mpox susceptibility but were unsure about infection severity; they were motivated to protect themselves but reported limited mpox knowledge as a barrier and desired clear communication to inform preventive actions. Residents expressed low self-efficacy to protect themselves because of contextual factors, including perceived limited access to cleaning, disinfecting, and hygiene items. Our findings suggest correctional facilities can support disease prevention by providing actionable and tailored messages; educating residents and staff about risk and vaccination options; and ensuring access to and training for hygiene, cleaning, and disinfecting supplies.
Subject(s)
Health Knowledge, Attitudes, Practice , Mpox (monkeypox) , Humans , Health Belief Model , Illinois , JailsABSTRACT
Both peroxisomes and lipid droplets regulate cellular lipid homeostasis. Direct inter-organellar contacts as well as novel roles for proteins associated with peroxisome or lipid droplets occur when cells are induced to liberate fatty acids from lipid droplets. We have shown a non-canonical role for a subset of peroxisome-assembly [Peroxin (Pex)] proteins in this process in Drosophila. Transmembrane proteins Pex3, Pex13 and Pex14 were observed to surround newly formed lipid droplets. Trafficking of Pex14 to lipid droplets was enhanced by loss of Pex19, which directs insertion of transmembrane proteins like Pex14 into the peroxisome bilayer membrane. Accumulation of Pex14 around lipid droplets did not induce changes to peroxisome size or number, and co-recruitment of the remaining Peroxins was not needed to assemble peroxisomes observed. Increasing the relative level of Pex14 surrounding lipid droplets affected the recruitment of Hsl lipase. Fat body-specific reduction of these lipid droplet-associated Peroxins caused a unique effect on larval fat body development and affected their survival on lipid-enriched or minimal diets. This revealed a heretofore unknown function for a subset of Pex proteins in regulating lipid storage. This article has an associated First Person interview with Kazuki Ueda, joint first author of the paper.
Subject(s)
Drosophila , Lipid Droplets , Animals , Drosophila/metabolism , Humans , Lipid Droplets/metabolism , Lipids , Membrane Proteins/metabolism , Peroxins , Peroxisomes/metabolismABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic substantially impacted different age groups, with children and young people not exempted. Many have experienced enduring health consequences. Presently, there is no consensus on the health outcomes to assess in children and young people with post-COVID-19 condition. Furthermore, it is unclear which measurement instruments are appropriate for use in research and clinical management of children and young people with post-COVID-19. To address these unmet needs, we conducted a consensus study, aiming to develop a core outcome set (COS) and an associated core outcome measurement set (COMS) for evaluating post-COVID-19 condition in children and young people. Our methodology comprised of two phases. In phase 1 (to create a COS), we performed an extensive literature review and categorisation of outcomes, and prioritised those outcomes in a two-round online modified Delphi process followed by a consensus meeting. In phase 2 (to create the COMS), we performed another modified Delphi consensus process to evaluate measurement instruments for previously defined core outcomes from phase 1, followed by an online consensus workshop to finalise recommendations regarding the most appropriate instruments for each core outcome. In phase 1, 214 participants from 37 countries participated, with 154 (72%) contributing to both Delphi rounds. The subsequent online consensus meeting resulted in a final COS which encompassed seven critical outcomes: fatigue; post-exertion symptoms; work/occupational and study changes; as well as functional changes, symptoms, and conditions relating to cardiovascular, neuro-cognitive, gastrointestinal and physical outcomes. In phase 2, 11 international experts were involved in a modified Delphi process, selecting measurement instruments for a subsequent online consensus workshop where 30 voting participants discussed and independently scored the selected instruments. As a result of this consensus process, four instruments met a priori consensus criteria for inclusion: PedsQL multidimensional fatigue scale for "fatigue"; PedsQL gastrointestinal symptom scales for "gastrointestinal"; PedsQL cognitive functioning scale for "neurocognitive" and EQ-5D for "physical functioning". Despite proposing outcome measurement instruments for the remaining three core outcomes ("cardiovascular", "post-exertional malaise", "work/occupational and study changes"), a consensus was not achieved. Our international, consensus-based initiative presents a robust framework for evaluating post-COVID-19 condition in children and young people in research and clinical practice via a rigorously defined COS and associated COMS. It will aid in the uniform measurement and reporting of relevant health outcomes worldwide.
Subject(s)
COVID-19 , Post-Acute COVID-19 Syndrome , Adolescent , Child , Humans , Delphi Technique , Outcome Assessment, Health Care , Research Design , Treatment OutcomeABSTRACT
The mechanical and architectural properties of the three-dimensional (3D) tissue microenvironment can have large impacts on cellular behavior and phenotype, providing cells with specialized functions dependent on their location. This is especially apparent in macrophage biology where the function of tissue resident macrophages is highly specialized to their location. 3D bioprinting provides a convenient method of fabricating biomaterials that mimic specific tissue architectures. If these printable materials also possess tunable mechanical properties, they would be highly attractive for the study of macrophage behavior in different tissues. Currently, it is difficult to achieve mechanical tunability without sacrificing printability, scaffold porosity, and a loss in cell viability. Here, we have designed composite printable biomaterials composed of traditional hydrogels [nanofibrillar cellulose (cellulose) or methacrylated gelatin (gelMA)] mixed with porous polymeric high internal phase emulsion (polyHIPE) microparticles. By varying the ratio of polyHIPEs to hydrogel, we fabricate composite hydrogels that mimic the mechanical properties of the neural tissue (0.1-0.5 kPa), liver (1 kPa), lungs (5 kPa), and skin (10 kPa) while maintaining good levels of biocompatibility to a macrophage cell line.
Subject(s)
Bioprinting , Tissue Scaffolds , Porosity , Tissue Engineering/methods , Hydrogels , Bioprinting/methods , Printing, Three-Dimensional , Biocompatible Materials , Polymers , Gelatin , Cellulose , Cell Culture Techniques, Three DimensionalABSTRACT
INTRODUCTION: An unprecedented shortage of infant formula occurred in the United States (U.S.) in 2022 and posed widespread challenges to infant feeding nationwide. The purpose of this study is to investigate mothers' experiences during the 2022 infant formula shortage and its perceived impacts on infants' diet and health. METHODS: Mothers (n = 45) of infants under 8 months old from Washington D.C. were invited to participate in a virtual study meeting during the summer of 2022. Mothers completed surveys regarding their demographics, infants' anthropometrics, infant feeding practices, information they have received about infant feeding, and knowledge about infant feeding practices. They then participated in a qualitative interview about their experiences during the infant formula shortage. RESULTS: Overarching themes were: the shortage (1) had adverse impacts on mothers' mental and emotional health; (2) had significant financial and intangible costs; (3) led to changes in infant feeding practices; (4) social and family networks were helpful in navigating the shortage; and (5) mothers felt fortunate to have resources to breastfeed and/or obtain formula. DISCUSSION: The infant formula shortage adversely impacted mothers' mental and emotional health, and was costly, in terms of financial and intangible costs. Findings demonstrate the need to develop clinical and policy approaches to support mothers in feeding their infants and provide education about safe infant feeding practices.
Subject(s)
Infant Formula , Mothers , Infant , Female , Humans , Washington , Mothers/psychology , Breast Feeding/psychology , Feeding Behavior , Health Knowledge, Attitudes, PracticeABSTRACT
BACKGROUND: Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). METHODS: The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants' feedback. RESULTS: The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. CONCLUSIONS: By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. TRIAL REGISTRATION: SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).
Subject(s)
Checklist , Research Design , Humans , Consensus , Reproducibility of Results , Research ReportABSTRACT
INTRODUCTION: Depression is strongly associated with obesity and is common among patients undergoing bariatric surgery. Little is known about the impact of depression on early postoperative outcomes or its association with substance use. METHODS: The Michigan Bariatric Surgery Collaborative is a statewide quality improvement program that maintains a large clinical registry. We evaluated patients undergoing primary Roux-en-Y gastric bypass or sleeve gastrectomy between 2017 and 2022. Patients self-reported symptoms of depression (PHQ-8) and use of alcohol (AUDIT-C), smoking, prescription opiates, and marijuana at baseline. Preoperative PHQ-8 scores stratified patients based on severity: no depression (0-4), mild (5-9), moderate (10-14), or severe (15-24). We compared 30-day outcomes and substance use between patients with and without depression. RESULTS: Among 44,301 patients, 30.8% had some level of depression, with 19.8% mild, 7.5% moderate, and 3.5% severe. Patients with depression were more likely to have an extended length of stay (LOS) (> 3 days) than those without depression (no depression 2.1% vs. severe depression 3.0%, p = 0.0452). There were no significant differences between no depression and severe depression groups in rates of complications (5.7% vs. 5.2%, p = 0.1564), reoperations (0.9%, vs. 0.8%, p = 0.7394), ED visits (7.7% vs. 7.8%, p = 0.5353), or readmissions (3.2% vs. 3.9%, p = 0.3034). Patients with severe depression had significantly higher rates of smoking (9.7% vs. 12.5%, p < 0.0001), alcohol use disorder (8.6% vs. 14.0%, p < 0.0001), opiate use (14.5% vs. 22.4%, p < 0.0001) and marijuana use (8.4%, vs. 15.5%, p = 0.0008). CONCLUSIONS: This study demonstrated that nearly one-third of patients undergoing bariatric surgery have depression, with over 10% in the moderate to severe range. There was a significant association between preoperative depressive symptoms and extended LOS after bariatric surgery, as well as higher rates of smoking and use of marijuana, prescription opiates and alcohol. There was no significant effect on adverse events or other measures of healthcare utilization.
Subject(s)
Bariatric Surgery , Gastric Bypass , Laparoscopy , Obesity, Morbid , Opiate Alkaloids , Substance-Related Disorders , Humans , Obesity, Morbid/complications , Obesity, Morbid/epidemiology , Obesity, Morbid/surgery , Depression/epidemiology , Depression/etiology , Weight Loss , Bariatric Surgery/adverse effects , Gastric Bypass/adverse effects , Risk Factors , Gastrectomy/adverse effects , Ethanol , Substance-Related Disorders/complications , Substance-Related Disorders/epidemiology , Patient Acceptance of Health Care , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/surgery , Retrospective Studies , Treatment Outcome , Laparoscopy/adverse effectsABSTRACT
While the historic management of food allergy includes avoidance strategies and allergic reaction treatment, oral immunotherapy (OIT) approaches have become more commonly integrated into therapeutic approaches. International guidelines, phase 3 trials and real-world experience have supported the implementation of this procedure. However, OIT is an elective, rarely curative procedure with inherent risks that necessitates an increased degree of health literacy for the patients and families. Families assume the responsibility of amateur healthcare providers to ensure the daily safe administration of the allergenic food. As such, it is incumbent upon physicians to ensure that families are prepared for this role. A thorough educational and shared decision-making approach is necessary during the counselling and consent process to adequately inform the families. Educated discussion about the efficacy and patient-centred effectiveness, therapeutic alternatives and family goals is required to align physician and patient expectations. A frank discussion about the struggles, practical challenges, risks and contraindications can help to develop an understanding of the risk mitigation strategies employed to maintain safety. Physicians should develop a proactive approach to educate families about this, at times, burdensome procedure. This educational approach should encourage ongoing support starting prior to consent through the maintenance visits. By preparing families for their unique management role, physicians can help ensure the safe and successful integration of OIT into the therapeutic offering for the management of food allergies.
Subject(s)
Desensitization, Immunologic , Food Hypersensitivity , Humans , Desensitization, Immunologic/adverse effects , Desensitization, Immunologic/methods , Allergens , Administration, Oral , ImmunotherapyABSTRACT
Knowledge about monkeypox transmission risk in congregate settings is limited. In July 2022, the Chicago Department of Public Health (CDPH) confirmed a case of monkeypox in a person detained in Cook County Jail (CCJ) in Chicago, Illinois. This case was the first identified in a correctional setting in the United States and reported to CDC during the 2022 multinational monkeypox outbreak. CDPH collaborated with CCJ, the Illinois Department of Public Health (IDPH), and CDC to evaluate transmission risk within the facility. Fifty-seven residents were classified as having intermediate-risk exposures to the patient with monkeypox during the 7-day interval between the patient's symptom onset and his isolation. (Intermediate-risk exposure was defined as potentially being within 6 ft of the patient with monkeypox for a total of ≥3 hours cumulatively, without wearing a surgical mask or respirator, or potentially having contact between their own intact skin or clothing and the skin lesions or body fluids from the patient or with materials that were in contact with the patient's skin lesions or body fluids.) No secondary cases were identified among a subset of 62% of these potentially exposed residents who received symptom monitoring, serologic testing, or both. Thirteen residents accepted postexposure prophylaxis (PEP), with higher acceptance among those who were offered counseling individually or in small groups than among those who were offered PEP together in a large group. Monkeypox virus (MPXV) DNA, but no viable virus, was detected on one surface in a dormitory where the patient had been housed with other residents before he was isolated. Although monkeypox transmission might be limited in similar congregate settings in the absence of higher-risk exposures, congregate facilities should maintain recommended infection control practices in response to monkeypox cases, including placing the person with monkeypox in medical isolation and promptly and thoroughly cleaning and disinfecting spaces where the person has spent time. In addition, officials should provide information to residents and staff members about monkeypox symptoms and transmission modes, facilitate confidential monkeypox risk and symptom disclosure and prompt medical evaluation for symptoms that are reported, and provide PEP counseling in a private setting.
Subject(s)
Mpox (monkeypox) , Chicago/epidemiology , DNA , Humans , Illinois/epidemiology , Jails , Male , Mpox (monkeypox)/diagnosis , Mpox (monkeypox)/epidemiology , United StatesABSTRACT
Nuclear-cytoplasmic localization is an efficient way to regulate transcription factors and chromatin remodelers. Altering the location of existing protein pools also facilitates a more rapid response to changes in cell activity or extracellular signals. There are several examples of proteins that are regulated by nucleo-cytoplasmic shuttling, which are required for Drosophila neuroblast development. Disruption of the localization of homologs of these proteins has also been linked to several neurodegenerative disorders in humans. Drosophila has been used extensively to model the neurodegenerative disorders caused by aberrant nucleo-cytoplasmic localization. Here, we focus on the role of alternative nucleo-cytoplasmic protein localization in regulating proliferation and cell fate decisions in the Drosophila neuroblast and in neurodegenerative disorders. We also explore the analogous role of RNA binding proteins and mRNA localization in the context of regulation of nucleo-cytoplasmic localization during neural development and a role in neurodegenerative disorders.
Subject(s)
Drosophila , Neurons/cytology , Nuclear Proteins , Animals , Cell Nucleus , Cytoplasm , Drosophila/genetics , Nuclear Proteins/genetics , Transcription Factors/geneticsABSTRACT
OBJECTIVES: Listening effort may be defined as the attentional and cognitive resources needed to understand an auditory message, modulated by motivation. Despite the use of hearing devices such as hearing aids or cochlear implants (CIs), the requirement for high listening effort remains a challenge for individuals with hearing loss. The Listening Effort Questionnaire-Cochlear Implant (LEQ-CI) is a hearing-specific patient-reported outcome measure (PROM), which has been designed for use in the CI candidacy and rehabilitation process to assess perceived listening effort in everyday life in adults with severe-profound hearing loss. The LEQ-CI has been developed in line with international consensus-based standards for best practice in PROM construction. The aim of this study was to improve the measurement precision of the LEQ-CI and to assess its psychometric measurement properties. DESIGN: A field test was undertaken with 330 CI patients from five National Health Service auditory implant centers in the United Kingdom. Participants were adults (≥18 years of age), had a severe-profound hearing loss, and met the UK candidacy criteria for cochlear implantation specified by the National Institute for Health and Care Excellence (NICE). Participants completed and returned an anonymized 29-item (each with a 5- or 7-point response option), draft version of the LEQ-CI (LEQ-CI29) and a demographic questionnaire. Rasch analysis was undertaken using Winsteps software and the partial credit model to assess rating scale function and item fit. Results informed refinements to produce a 21-item version (LEQ-CI21), which underwent a further Rasch analysis. RESULTS: The sample was predominantly female: 60.3% (n = 191). Median age of participants was 66 (range 21 to 89) years, with 7.3% (n = 24) of respondents being CI candidates and 92.7% (n = 306) being CI recipients. Mean duration of implantation was 3.8 (SD = 4.8) years. Initial Rasch analysis of the LEQ-CI29 revealed poor rating scale functioning. Collapsing the 5- and 7-point rating scales to 3- and 4-point scales and removing eight items produced a 21-item PROM (LEQ-CI21). Rasch analysis of the LEQ-CI21 showed good fit to the Rasch measurement model. No items showed misfit and dimensionality analysis supported the existence of a single Rasch dimension, defined as perceived listening effort in daily life. Person reliability was 0.91 and the person separation index was 3.28, establishing four levels of person ability. The item separation index was 9.69, confirming the item hierarchy. No items showed differential item functioning for gender or age. The item difficulty range was -0.81 to 1.05, the person ability range for nonextreme persons was -3.54 to 2.49, and the mean person ability was -0.31. CONCLUSIONS: Overall, the LEQ-CI21 was found to meet the Rasch model criteria for interval-level measurement. The LEQ-CI21 is the first PROM to be developed specifically for the measurement of perceived listening effort and one of the first patient-reported outcome measures for use with CI patients to be developed using Rasch analysis. The LEQ-CI21 has the potential to be used as a research tool and in clinical practice to evaluate perceived listening effort in daily life. Further psychometric evaluation of the LEQ-CI21 is planned.
Subject(s)
Cochlear Implantation , Cochlear Implants , Hearing Loss , Adult , Aged , Aged, 80 and over , Female , Hearing Loss/rehabilitation , Humans , Listening Effort , Male , Middle Aged , Psychometrics , Reproducibility of Results , State Medicine , Surveys and Questionnaires , Young AdultABSTRACT
BACKGROUND AND AIM: No marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity. METHODS: At baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as <1, 1-2, 2-3 and >3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI). RESULTS: Fifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN <1 L/day than for FE and all PN >1 L/day), patients' death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2-3 and PN >3 L/day). CONCLUSIONS: The type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.
Subject(s)
Fat Emulsions, Intravenous/administration & dosage , Fluid Therapy/methods , Intestinal Diseases , Intestines/physiopathology , Parenteral Nutrition, Home , Administration, Intravenous/methods , Adult , Catheter-Related Infections/complications , Chronic Disease , Drug Dosage Calculations , Female , Humans , Intestinal Absorption , Intestinal Diseases/etiology , Intestinal Diseases/physiopathology , Intestinal Diseases/therapy , Liver Failure/complications , Male , Parenteral Nutrition, Home/adverse effects , Parenteral Nutrition, Home/methods , Pharmaceutical Solutions/administration & dosage , Severity of Illness IndexABSTRACT
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Genetic studies in susceptible individuals have linked this ocular disease to deregulated complement activity that culminates in increased C3 turnover, retinal inflammation and photoreceptor loss. Therapeutic targeting of C3 has therefore emerged as a promising strategy for broadly intercepting the detrimental proinflammatory consequences of complement activation in the retinal tissue. In this regard, a PEGylated second-generation derivative of the compstatin family of C3-targeted inhibitors is currently in late-stage clinical development as a treatment option for geographic atrophy, an advanced form of AMD which lacks approved therapy. While efficacy has been strongly suggested in phase 2 clinical trials, crucial aspects still remain to be defined with regard to the ocular bioavailability, tissue distribution and residence, and dosing frequency of such inhibitors in AMD patients. Here we report the intraocular distribution and pharmacokinetic profile of the fourth-generation compstatin analog, Cp40-KKK in cynomolgus monkeys following a single intravitreal injection. Using a sensitive surface plasmon resonance (SPR)-based competition assay and ELISA, we have quantified both the amount of inhibitor and the concentration of C3 retained in the vitreous of Cp40-KKK-injected animals. Cp40-KKK displays prolonged intraocular residence, being detected at C3-saturating levels for over 3 months after a single intravitreal injection. Moreover, we have probed the distribution of Cp40-KKK within the ocular tissue by means of immunohistochemistry and highly specific anti-Cp40-KKK antibodies. Both C3 and Cp40-KKK were detected in the retinal tissue of inhibitor-injected animals, with prominent co-localization in the choroid one-month post intravitreal injection. These results attest to the high retinal tissue penetrance and target-driven distribution of Cp40-KKK. Given its subnanomolar binding affinity and prolonged ocular residence, Cp40-KKK constitutes a promising drug candidate for ocular pathologies underpinned by deregulated C3 activation.
Subject(s)
Complement C3/antagonists & inhibitors , Eye/chemistry , Aged , Animals , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Intravitreal Injections , Macaca fascicularis , Retina/chemistry , Time Factors , Tissue DistributionABSTRACT
PURPOSE: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied. METHODS: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers. RESULTS: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers. CONCLUSION: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.
Subject(s)
Breast Neoplasms , Stomach Neoplasms , alpha Catenin/genetics , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Genetic Predisposition to Disease , Humans , Penetrance , Stomach Neoplasms/diagnosis , Stomach Neoplasms/geneticsABSTRACT
In this article, we examine ecological validity in hearing science from a qualitative methodological perspective. We present an overview of qualitative methods, presenting their key characteristics and contrasting these techniques with quantitative approaches to enquiry. We argue that ecological validity sits at the heart of the qualitative paradigm and seek to clearly emphasize the methodological gap that could be effectively filled by qualitative or mixed methods. In doing so, we discuss qualitative methods that may work particularly well in enhancing ecological validity in hearing science and explore their range of applications in this field. These approaches can be applied to a wide range of hearing health research questions to present a unique understanding of people's experiences of disease and disability, indicating gradations of personal health and illness in nuanced ways. We acknowledge and commend the current expansion of qualitative methods within hearing science and present recommendations for increasing ecological validity, both in the design of future studies and in the context of the wider research cycle. We call on qualitative researchers to strive for transparency, rigor, and trustworthiness and highlight challenges to be overcome if qualitative methods are to contribute to effective, efficient research strategies. To facilitate the transference of high-quality research findings into practice, we stress the need for joined-up working to create a research culture that promotes coproduction of ecologically valid research designs, involving not only hearing researchers but also implementation scientists, hearing healthcare professionals and, most importantly, people with hearing loss for whom these efforts could make a difference.
Subject(s)
Health Personnel , Hearing , Humans , Qualitative ResearchABSTRACT
OBJECTIVES: Hearing loss (HL) affects a significant proportion of adults aged >50 years by impairing communication and social connectedness and, due to its high prevalence, is a growing global concern. Cochlear implants (CIs) are effective devices for many people with severe or greater sensorineural HL who experience limited benefits from hearing aids. Despite this, uptake rates globally are low among adults. This multimethod, multicountry qualitative study aimed to investigate the barriers and facilitators to CI uptake among adults aged ≥50 years. DESIGN: Adult CI and hearing aid users with postlingual severe or greater sensorineural HL, general practitioners, and audiologists were recruited in Australia using purposive sampling, and a comparative sample of audiologists was recruited in England and Wales in the United Kingdom. Participants were interviewed individually, or in a focus group, completed a demographic questionnaire and a qualitative survey. Data were analyzed using thematic analysis. RESULTS: A total of 143 data capture events were collected from 55 participants. The main barriers to CI uptake related to patients' concerns about surgery and loss of residual hearing. Limited knowledge of CIs, eligibility criteria, and referral processes acted as barriers to CIs assessment referrals by healthcare professionals. Facilitators for CI uptake included patients' desire for improved communication and social engagement, and increased healthcare professional knowledge and awareness of CIs. CONCLUSIONS: There are numerous complex barriers and facilitators to CI uptake. Knowledge of these can inform the development of targeted strategies to increase CI referral and surgery for potential beneficiaries.
Subject(s)
Cochlear Implantation , Cochlear Implants , Hearing Aids , Adult , Australia , England , Humans , United KingdomABSTRACT
BACKGROUND: Cochlear implants (CIs) can provide a sound sensation for those with severe sensorineural hearing loss (SNHL), benefitting speech understanding and quality of life. Nevertheless, rates of implantation remain low, and limited research investigates journeys from traditional hearing aids to implantable devices. METHOD: Fifty-five adults (≥ 50 years), hearing aid users and/or CI users, General Practitioners, and Australian and United Kingdom audiologists took part in a multi-methods study. Focus groups, interviews, and surveys were thematically analysed. RESULTS: One hundred forty-three data-capture events disclosed 2 themes: 1) "The burden of hearing loss and the impact of Cochlear Implants", and 2) "Professional Support and Practice, and HCPs Roles and Responsibilities". CONCLUSIONS: Care experience can include convoluted, complex journeys towards cochlear implantation. The significant impact of this, as hearing loss progresses, motivates people to consider implants, but they and healthcare professionals need clear supported with defined referral pathways, and less system complexity.