PICH deficiency limits the progression of MYC-induced B-cell lymphoma.

Plk1-interacting checkpoint helicase (PICH) is a DNA translocase involved in resolving ultrafine anaphase DNA bridges and, therefore, is important to safeguard chromosome segregation and stability. PICH is overexpressed in various human cancers, particularly in lymphomas such as Burkitt lymphoma, which is caused by MYC translocations. To investigate the relevance of PICH in cancer development and progression, we have combined novel PICH-deficient mouse models with the Eµ-Myc transgenic mouse model, which recapitulates B-cell lymphoma development. We have observed that PICH deficiency delays the onset of MYC-induced lymphomas in Pich heterozygous females. Moreover, using a Pich conditional knockout mouse model, we have found that Pich deletion in adult mice improves the survival of Eµ-Myc transgenic mice. Notably, we show that Pich deletion in healthy adult mice is well tolerated, supporting PICH as a suitable target for anticancer therapies. Finally, we have corroborated these findings in two human Burkitt lymphoma cell lines and we have found that the death of cancer cells was accompanied by chromosomal instability. Based on these findings, we propose PICH as a potential therapeutic target for Burkitt lymphoma and for other cancers where PICH is overexpressed.

Feasibility of an artificial intelligence phone call for postoperative care following cataract surgery in a diverse population: two phase prospective study protocol.

INTRODUCTION: Artificial intelligence (AI) development has led to improvements in many areas of medicine. Canada has workforce pressures in delivering cataract care. A potential solution is using AI technology that can automate care delivery, increase effectiveness and decrease burdens placed on patients and the healthcare system. This study assesses the use of 'Dora', an example of an AI assistant that is able to deliver a regulated autonomous, voice-based, natural-language consultation with patients over the telephone. Dora is used in routine practice in the UK, but this study seeks to assess the safety, usability, acceptability and cost-effectiveness of using the technology in Canada. METHODS AND ANALYSIS: This is a two-phase prospective single-centred trial. An expected 250 patients will be recruited for each phase of the study. For Phase I of the study, Dora will phone patients at postoperative week 1 and for Phase II of the study, Dora will phone patients within 24hours of their cataract surgery and again at postoperative week 1. We will evaluate the agreement between Dora and a supervising clinician regarding the need for further review based on the patients' symptoms. A random sample of patients will undergo the System Usability Scale followed by an extended semi-structured interview. The primary outcome of agreement between Dora and the supervisor will be assessed using the kappa statistic. Qualitative data from the interviews will further gauge patient opinions about Dora's usability, appropriateness and level of satisfaction. ETHICS AND DISSEMINATION: Research Ethics Board William Osler Health System (ID: 22-0044) has approved this study and will be conducted by guidelines of Declaration of Helsinki. Master-linking sheet will contain the patient chart identification (ID), full name, date of birth and study ID. Results will be shared through peer-reviewed journals and presentations at conferences.

Investigating the Impact of Automation on the Health Care Workforce Through Autonomous Telemedicine in the Cataract Pathway: Protocol for a Multicenter Study.

BACKGROUND: While digital health innovations are increasingly being adopted by health care organizations, implementation is often carried out without considering the impacts on frontline staff who will be using the technology and who will be affected by its introduction. The enthusiasm surrounding the use of artificial intelligence (AI)-enabled digital solutions in health care is tempered by uncertainty around how it will change the working lives and practices of health care professionals. Digital enablement can be viewed as facilitating enhanced effectiveness and efficiency by improving services and automating cognitive labor, yet the implementation of such AI technology comes with challenges related to changes in work practices brought by automation. This research explores staff experiences before and after care pathway automation with an autonomous clinical conversational assistant, Dora (Ufonia Ltd), that is able to automate routine clinical conversations. OBJECTIVE: The primary objective is to examine the impact of AI-enabled automation on clinicians, allied health professionals, and administrators who provide or facilitate health care to patients in high-volume, low-complexity care pathways. In the process of transforming care pathways through automation of routine tasks, staff will increasingly "work at the top of their license." The impact of this fundamental change on the professional identity, well-being, and work practices of the individual is poorly understood at present. METHODS: We will adopt a multiple case study approach, combining qualitative and quantitative data collection methods, over 2 distinct phases, namely phase A (preimplementation) and phase B (postimplementation). RESULTS: The analysis is expected to reveal the interrelationship between Dora and those affected by its introduction. This will reveal how tasks and responsibilities have changed or shifted, current tensions and contradictions, ways of working, and challenges, benefits, and opportunities as perceived by those on the frontlines of the health care system. The findings will enable a better understanding of the resistance or susceptibility of different stakeholders within the health care workforce and encourage managerial awareness of differing needs, demands, and uncertainties. CONCLUSIONS: The implementation of AI in the health care sector, as well as the body of research on this topic, remain in their infancy. The project's key contribution will be to understand the impact of AI-enabled automation on the health care workforce and their work practices. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/49374.

User-acceptability of an automated telephone call for post-operative follow-up after uncomplicated cataract surgery.

BACKGROUND: Innovative technology is recommended to address the current capacity challenges facing the NHS. This study evaluates the patient acceptability of automated telephone follow-up after routine cataract surgery using Dora (Ufonia Limited, Oxford, United Kingdom), which to our knowledge is the first AI-powered clinical assistant to be used in the NHS. Dora has a natural-language, phone conversation with patients about their symptoms after cataract surgery. METHODS: This is a prospective mixed-methods cohort study that was conducted at Buckinghamshire Healthcare NHS Foundation Trust. All patients who were followed up using Dora were asked to give a Net Promoter Score (NPS), and 24 patients were randomly selected to complete the validated Telephone Usability Questionnaire (TUQ) as well as extended semi-structured interviews that underwent thematic analysis. RESULTS: A total of 170 autonomous calls were completed. The median NPS score was 9 out of 10. The TUQ (scored out of 5) showed high rates of acceptability, with an overall mean score of 4.0. Simplicity, time saving, and ease of use scored the highest with a median of 5, whilst 'speaking to Dora feels the same as speaking to a clinician' scored a median of 3. The main themes extracted from the qualitative data were 'I can see why you're doing it', 'It went quite well actually', 'I just trust human beings I suppose'. CONCLUSION: We found high levels of patient acceptability when using Dora across three acceptability measures. Dora provides a potential solution to reduce pressure on hospital capacity whilst also providing a convenient service for patients.

A Prospective Audit Comparing Optos Widefield Imaging to Fundus Examination for Von Hippel-Lindau Retinal Screening.

Background Von Hippel-Lindau (VHL) disease is an autosomal dominant multisystem disorder caused by germline mutations at chromosome 3p25-26 in the VHLtumour suppressor gene. Retinal manifestations include capillary haemangiomas that develop in up to 80% of gene carriers. Lifelong retinal surveillance involves yearly assessment usually by fundoscopy and often as part of a VHL multidisciplinary clinic. Optos ultra-widefield retinal imaging is now becoming more widely used in virtual retinal screening clinics. We aimed to assess discrepancies in the pickup rate of angioma and angiomatous-associated disease between slit-lamp fundoscopy and Optos ultra-widefield imaging. Methodology A total of 49 patients had both Optos ultra-widefield retinal imaging and slit-lamp fundoscopy over 16 months in VHL retinal surveillance clinics at the John Radcliffe Hospital, Oxford, UK. Optos images were analysed for image quality and presence of angioma(s) by a Consultant Ophthalmologist who was masked to the fundoscopy findings. The pickup rate was compared between slit-lamp fundoscopy and Optos imaging. Results In total, data on 94 eyes were collected. Of the total Optos retinal images, 12.8% were positive for angiomas compared to 11.7% from the slit-lamp examination. There was a discrepancy of 1.1% (one value) where the Optos image analysis suggested a possible angioma, which was not identified on slit-lamp examination. Optos imaging identified all angiomas in this cohort. Conclusions Optos imaging was non-inferior to slit-lamp examination in this sample of 94 eyes. In the current COVID-19 climate, reducing clinician-patient interaction is important. This research supports providing retinal imaging as an acceptable alternative to the yearly slit-lamp fundus examination.

Antisense Peptide Nucleic Acid-Diaminobutanoic Acid Dendron Conjugates with SbmA-Independent Antimicrobial Activity against Gram-Negative Bacteria.

Precision antisense antibacterial agents may be developed into novel antibiotics in the fight against multidrug-resistant Gram-negative bacteria. In this study, a series of diaminobutanoic acid (DAB) dendrons are presented as novel carriers for the delivery of antisense antibacterial peptide nucleic acids (PNAs). The dendron-PNA conjugates targeting the essential acpP gene exhibit specific antisense antimicrobial bactericidal activity against Escherichia coli and Klebsiella pneumoniae at one-digit micromolar concentrations, while showing low toxicity to human cells. One compound selected from a structure-activity relationship series showed high stability in mouse and human serum (t1/2 ≫ 24 h) as well as in vivo activity against a multidrug-resistant, extended spectrum beta-lactamase-producing E. coli in a murine peritonitis model. The compound was also well tolerated in mice upon i.v. administration up to a dose of 20 mg/kg, and in vivo fluorescence imaging indicated clearance via renal excretion with slight accumulation in the kidneys and liver. Thus, DAB-based dendrons constitute a promising new chemistry platform for development of effective delivery agents for antibacterial drugs with possible in vivo use.

Primary intraventricular tumors - Imaging characteristics, post-treatment changes and relapses.

Primary intraventricular neoplasms are rare tumors that originate from the ependymal or subependymal, septum pellucidum, choroid plexus and the supporting arachnoid tissue. Knowledge of the common locations of these tumors within the ventricular system, together with key imaging characteristics and presentation age, can significantly narrow the differential diagnosis. In 2016, the WHO reorganized the classification of several primary CNS tumors by combining histopathological and molecular data. This study highlights the imaging characteristics, histopathological and molecular data, treatment strategies and post-treatment changes of primary intraventricular tumors. Molecular-based diagnosis can not only aid in patient stratification and personalized treatment, but it can also provide prognostic and predictive value independent of WHO classification.

Distinguishing Intramedullary Spinal Cord Neoplasms from Non-Neoplastic Conditions by Analyzing the Classic Signs on MRI in the Era of AI.

Intramedullary lesions can be challenging to diagnose, given the wide range of possible pathologies. Each lesion has unique clinical and imaging features, which are best evaluated using magnetic resonance imaging. Radiological imaging is unique with rich, descriptive patterns and classic signs-which are often metaphorical. In this review, we present a collection of classic MRI signs, ranging from neoplastic to non-neoplastic lesions, within the spinal cord. The Differential Diagnosis (DD) of intramedullary lesions can be narrowed down by careful analysis of the classic signs and patterns of involvement in the spinal cord. Furthermore, the signs are illustrated memorably with emphasis on the pathophysiology, mimics, and pitfalls. Artificial Intelligence (AI) algorithms, particularly deep learning, have made remarkable progress in image recognition tasks. The classic signs and related illustrations can enhance a pattern recognition approach in diagnostic radiology. Deep learning can potentially be designed to distinguish neoplastic from non-neoplastic processes by pattern recognition of the classic MRI signs.

Patient and clinician perspectives of ophthalmology emergency attendances during the COVID 19 pandemic.

Introduction: To explore patient and clinician perspectives on acute ophthalmology presentations during the COVID pandemic. To ascertain whether the pandemic had differentially impacted access to care based on patient demographics and postcodes. Methods: A single-centre, cross-sectional prospective study in a busy metropolitan eye casualty between April-June 2020 recording patient demographics, distance travelled to access healthcare, diagnosis and outcome compared to the equivalent period in 2019. A further two-part survey was conducted to explore patient and clinician's perceptions around delays in attendances, views on remote consultation and severity of the condition. Results: There was a 68% decrease in April 2020 compared to previous year's ED attendance. The diagnosis tended towards more visually significant pathology. From 2019 to 2020, there was a significant decrease in average distance travelled to the eye emergency department (eye ED). working-age adults (18-59) and white patients travelling from very far pre-pandemic contributed most to this change. 513 Patient responses (12%) out of 4433 attendances during the study period were received, 89% (456/513) of the completed surveys also had matching clinician surveys. 29% (149/513) patients felt COVID-19 stopped them from attending earlier. Clinicians thought a video consultation would have been suitable for 40% (182/456) of patients compared to only 13% (58/456) of patients preferring a video consultation. Discussion: Although our findings were limited by low response rates, COVID-19 may have caused a delay in presentation for emergency eye care. Demographic changes and attitudes towards video consultations have implications for planning of emergency eye care in future pandemics.

Safety and Acceptability of a Natural Language Artificial Intelligence Assistant to Deliver Clinical Follow-up to Cataract Surgery Patients: Proposal.

BACKGROUND: Due to an aging population, the demand for many services is exceeding the capacity of the clinical workforce. As a result, staff are facing a crisis of burnout from being pressured to deliver high-volume workloads, driving increasing costs for providers. Artificial intelligence (AI), in the form of conversational agents, presents a possible opportunity to enable efficiency in the delivery of care. OBJECTIVE: This study aims to evaluate the effectiveness, usability, and acceptability of Dora agent: Ufonia's autonomous voice conversational agent, an AI-enabled autonomous telemedicine call for the detection of postoperative cataract surgery patients who require further assessment. The objectives of this study are to establish Dora's efficacy in comparison with an expert clinician, determine baseline sensitivity and specificity for the detection of true complications, evaluate patient acceptability, collect evidence for cost-effectiveness, and capture data to support further development and evaluation. METHODS: Using an implementation science construct, the interdisciplinary study will be a mixed methods phase 1 pilot establishing interobserver reliability of the system, usability, and acceptability. This will be done using the following scales and frameworks: the system usability scale; assessment of Health Information Technology Interventions in Evidence-Based Medicine Evaluation Framework; the telehealth usability questionnaire; and the Non-Adoption, Abandonment, and Challenges to the Scale-up, Spread and Suitability framework. RESULTS: The evaluation is expected to show that conversational technology can be used to conduct an accurate assessment and that it is acceptable to different populations with different backgrounds. In addition, the results will demonstrate how successfully the system can be delivered in organizations with different clinical pathways and how it can be integrated with their existing platforms. CONCLUSIONS: The project's key contributions will be evidence of the effectiveness of AI voice conversational agents and their associated usability and acceptability. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/27227.

Fundus Autofluorescence Imaging in Macular Telangiectasia Type 2: MacTel Study Report Number 9.

PURPOSE: To investigate the role of fundus autofluorescence (FAF) imaging in the diagnosis of macular telangiectasia type 2 (MacTel) and to describe disease-associated FAF patterns and their origin. DESIGN: Cross-sectional multicenter study METHODS: FAF images were collected from the multicenter MacTel Natural History Observation and Registry Study. In a first qualitative approach, common FAF phenotypes were defined and correlated with multimodal imaging. We then evaluated how many eyes showed FAF changes, and temporal vs nasal asymmetry of FAF changes was graded. Finally, 100 eyes of MacTel patients and 100 control eyes (50 normal eyes and 50 eyes with other macular diseases) were combined and 2 masked graders assessed the presence of MacTel based on FAF images alone. RESULTS: The study included 807 eyes of 420 patients (33 eyes were excluded owing to poor image quality). Loss of macular pigment, cystoid spaces, pigment plaques, neovascular membranes, and ectatic vascular changes commonly caused characteristic changes on FAF images. All MacTel patients had macular FAF changes in at least 1 eye. In 95% of eyes, these changes were more pronounced temporally than nasally. Common FAF patterns were increased (60%) and mixed/decreased FAF (38%) and/or visibility of vascular changes such as blunted vessels or ectatic capillaries (79%). Based on those features, high diagnostic performance was achieved for detection of the disease based on FAF alone (Youden index up to 0.91). CONCLUSIONS: The study demonstrates that MacTel is consistently associated with disease-specific changes on FAF imaging. Those changes are typically more pronounced in the temporal parafovea.

Radiological Signs in Traumatic Cervical Facet Joint Dislocations.

Unilateral cervical facet joint dislocation (UCFJD) is the most frequently missed cervical spine injury on plain radiographs. If left untreated, UCFJD can progress to bilateral cervical facet joint dislocation. Given the complexity of cervical facet joint dislocations, radiologists rely on metaphorical signs to identify them on radiographs. The "Bow-tie" and "laminar space" signs represent UCFJD on plain radiographs. The "reversed hamburger", "naked facet" and "headphones" signs represent cervical facet joint dislocations on axial cross-sectional imaging. Illustrating these signs in an engaging manner facilitates pattern-based recognition, which can benefit trainees and radiologists. Moreover, pattern-based recognition can be applied to machine learning.

Multimodality imaging and treatment strategy for malignant scalp neoplasms in adults.

Malignant scalp masses deserve much attention as they have the potential to destroy local structures, recur and metastasize to distant organs. Moreover, malignant scalp lesions are known to be more aggressive in behavior than their counterparts elsewhere in the body. Multimodality imaging is essential in narrowing the differential diagnoses of scalp masses, as well as in differentiating benign from malignant masses. Furthermore, imaging is important in (1) evaluating the extent of tumor invasion in the scalp, (2) staging the disease, (3) guiding surgical biopsy and/or resection of the tumor, (4) preoperative planning and post-treatment surveillance of scalp tumors. An interdisciplinary treatment approach is crucial for the management of scalp malignancies given their complex and aggressive nature. This review seeks to describe the unique clinical and imaging characteristics of various types of malignant scalp masses, as well as to review their current treatment strategies.

Approaches for Systemic Delivery of Dystrophin Antisense Peptide Nucleic Acid in the mdx Mouse Model.

Antisense-mediated exon skipping constitutes a promising new modality for treatment of Duchenne Muscular Dystrophy (DMD), which is caused by gene mutations that typically introduce a translation stop codon in the dystrophin gene, thereby abolishing production of functional dystrophin protein. The exon removal can restore translation to produce a shortened, but still partially functional dystrophin protein. Peptide nucleic acid (PNA) as a potential antisense drug has previously been shown to restore the expression of functional dystrophin by splice modulation in the mdx mouse model of DMD. In this study, we compare systemic administration of a 20-mer splice switching antisense PNA oligomer through intravenous (i.v.) and subcutaneous (s.c.) routes in the mdx mice. Furthermore, the effect of in situ forming depot technology (BEPO®) and PNA-oligonucleotide formulation was studied. In vivo fluorescence imaging analysis showed fast renal/bladder excretion of the PNA (t½ ∼ 20 min) for i.v. administration, while s.c. administration showed a two to three times slower excretion. The release from the BEPO depot exhibited biphasic kinetics with a slow release (t½ ∼ 10 days) of 50% of the dose. In all cases, some accumulation in kidneys and liver could be detected. Formulation of PNA as a duplex hybridization complex with a complementary phosphorothioate oligonucleotide increased the solubility of the PNA. However, none of these alternative administration methods resulted in significantly improved antisense activity. Therefore, either more sophisticated formulations such as designed nanoparticles or conjugation to delivery ligands must be utilized to improve both pharmacokinetics as well as tissue targeting and availability. On the other hand, the results show that s.c. and BEPO depot administration of PNA are feasible and allow easier, higher, and less frequent dosing, as well as more controlled release, which can be exploited both for animal model studies as well as eventually in the clinic in terms of dosing optimization.

Insights From Survival Analyses During 12 Years of Anti-Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration.

Importance: Although multiple imputation models for missing data and the use of mixed-effects models generally provide better outcome estimates than using only observed data or last observation carried forward in clinical trials, such approaches usually cannot be applied to visual outcomes from retrospective analyses of clinical practice settings, also called real-world outcomes. Objective: To explore the potential usefulness of survival analysis techniques for retrospective clinical practice visual outcomes. Design, Setting, and Participants: This retrospective cohort study covered a 12-year observation period at a tertiary eye center. Of 10 744 eyes with neovascular age-related macular degeneration receiving anti-vascular endothelial growth factor (VEGF) therapy between October 28, 2008, and February 1, 2020, 7802 eyes met study criteria (treatment-naive, first-treated eyes starting anti-VEGF therapy). Eyes were excluded from the analysis if they received photodynamic therapy or macular laser, any previous anti-VEGF therapy, treatment with anti-VEGF agents other than ranibizumab or aflibercept, or had an unknown date or visual acuity (VA) value at first injection. Main Outcomes and Measures: Kaplan-Meier estimates and Cox proportional hazards modeling were used to consider VA reaching an Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 70 (Snellen equivalent, 20/40) or better, duration of VA sustained at or better than 70 (20/40), and VA declining to 35 (20/200) or worse. Results: A total of 7802 patients (mean [SD] age, 78.7 [8.8] years; 4776 women [61.2%]; and 4785 White [61.3%]) were included in the study. The median time to attaining a VA letter score greater than or equal to 70 (20/40) was 2.0 years (95% CI, 1.87-2.32) after the first anti-VEGF injection. Predictive features were baseline VA (hazard ratio [HR], 1.43 per 5 ETDRS letter score or 1 line; 95% CI, 1.40-1.46), baseline age (HR, 0.88 per 5 years; 95% CI, 0.86-0.90), and injection number (HR, 1.12; 95% CI, 1.10-1.15). Of the 4439 of 7802 patients (57%) attaining this outcome, median time sustained at an ETDRS letter score of 70 (20/40) or better was 1.1 years (95% CI, 1.1-1.2). Conclusions and Relevance: In this cohort study, patients with neovascular age-related macular degeneration beginning anti-VEGF therapy were more likely to experience positive visual outcomes within the first 2.0 years after treatment, typically maintaining this outcome for 1.1 years but then deteriorating to poor vision within 8.7 years. These findings demonstrate the potential usefulness of the proposed analyses. This data set, combined with the statistical approach for retrospective analyses, may provide long-term prognostic information for patients newly diagnosed with this condition.

The accuracy of healthcare worker versus self collected (2-in-1) Oropharyngeal and Bilateral Mid-Turbinate (OPMT) swabs and saliva samples for SARS-CoV-2.

BACKGROUND: Self-sampling for SARS-CoV-2 would significantly raise testing capacity and reduce healthcare worker (HCW) exposure to infectious droplets personal, and protective equipment (PPE) use. METHODS: We conducted a diagnostic accuracy study where subjects with a confirmed diagnosis of COVID-19 (n = 401) and healthy volunteers (n = 100) were asked to self-swab from their oropharynx and mid-turbinate (OPMT), and self-collect saliva. The results of these samples were compared to an OPMT performed by a HCW in the same patient at the same session. RESULTS: In subjects confirmed to have COVID-19, the sensitivities of the HCW-swab, self-swab, saliva, and combined self-swab plus saliva samples were 82.8%, 75.1%, 74.3% and 86.5% respectively. All samples obtained from healthy volunteers were tested negative. Compared to HCW-swab, the sensitivities of a self-swab sample and saliva sample were inferior by 8.7% (95%CI: 2.4% to 15.0%, p = 0.006) and 9.5% (95%CI: 3.1% to 15.8%, p = 0.003) respectively. The combined detection rate of self-swab and saliva had a sensitivity of 2.7% (95%CI: -2.6% to 8.0%, p = 0.321). The sensitivity of both the self-collection methods are higher when the Ct value of the HCW swab is less than 30. The specificity of both the self-swab and saliva testing was 100% (95% CI 96.4% to 100%). CONCLUSION: Our study provides evidence that sensitivities of self-collected OPMT swab and saliva samples were inferior to a HCW swab, but they could still be useful testing tools in the appropriate clinical settings.

The Effectiveness of Artificial Intelligence Conversational Agents in Health Care: Systematic Review.

BACKGROUND: The high demand for health care services and the growing capability of artificial intelligence have led to the development of conversational agents designed to support a variety of health-related activities, including behavior change, treatment support, health monitoring, training, triage, and screening support. Automation of these tasks could free clinicians to focus on more complex work and increase the accessibility to health care services for the public. An overarching assessment of the acceptability, usability, and effectiveness of these agents in health care is needed to collate the evidence so that future development can target areas for improvement and potential for sustainable adoption. OBJECTIVE: This systematic review aims to assess the effectiveness and usability of conversational agents in health care and identify the elements that users like and dislike to inform future research and development of these agents. METHODS: PubMed, Medline (Ovid), EMBASE (Excerpta Medica dataBASE), CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Science, and the Association for Computing Machinery Digital Library were systematically searched for articles published since 2008 that evaluated unconstrained natural language processing conversational agents used in health care. EndNote (version X9, Clarivate Analytics) reference management software was used for initial screening, and full-text screening was conducted by 1 reviewer. Data were extracted, and the risk of bias was assessed by one reviewer and validated by another. RESULTS: A total of 31 studies were selected and included a variety of conversational agents, including 14 chatbots (2 of which were voice chatbots), 6 embodied conversational agents (3 of which were interactive voice response calls, virtual patients, and speech recognition screening systems), 1 contextual question-answering agent, and 1 voice recognition triage system. Overall, the evidence reported was mostly positive or mixed. Usability and satisfaction performed well (27/30 and 26/31), and positive or mixed effectiveness was found in three-quarters of the studies (23/30). However, there were several limitations of the agents highlighted in specific qualitative feedback. CONCLUSIONS: The studies generally reported positive or mixed evidence for the effectiveness, usability, and satisfactoriness of the conversational agents investigated, but qualitative user perceptions were more mixed. The quality of many of the studies was limited, and improved study design and reporting are necessary to more accurately evaluate the usefulness of the agents in health care and identify key areas for improvement. Further research should also analyze the cost-effectiveness, privacy, and security of the agents. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/16934.

In Vivo Administration of Splice Switching PNAs Using the mdx Mouse as a Model System.

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy and is caused by gene mutations that abolish production of functional dystrophin muscle protein. A promising new treatment exploits specifically targeted RNA-acting drugs that are able to partially restore the dystrophin protein. The mdx mouse model (animal model of DMD) serves as a good in vivo model for testing these antisense drugs. The simplest in vivo test, which circumvents the systemic circulation, is intramuscular administration of the compound. After 7 days it is possible to detect exon skipping by reverse transcriptase PCR, and newly synthesized dystrophin-positive fibers by immunohistochemistry and western blotting. All muscles, including the heart, are affected by the disease and must be treated. Therefore the use of antisense therapy for treatment of DMD requires systemic administration, and the model is also useful for systemic administration.

Near-Infrared In Vivo Whole-Body Fluorescence Imaging of PNA.

Using near-infrared fluorophore Alexa Fluor 680 labeled peptide nucleic acids (PNAs) the biodistribution of such antisense agents can be analyzed in real time in live mice using in vivo imaging. Using the fluorescence intensity emitted from the mouse at different time points following administration, the systemic distribution and organ accumulation of PNA can be tracked. In addition, an estimation of the body half-life of the compound can be obtained by the change in fluorescence intensity over time. With this technique, the distribution of compounds can be monitored real time, while reducing the number of animals and amount of compounds required.

Hippocampal CA2 Lewy pathology is associated with cholinergic degeneration in Parkinson's disease with cognitive decline.

Although the precise neuropathological substrates of cognitive decline in Parkinson's disease (PD) remain elusive, it has long been regarded that pathology in the CA2 hippocampal subfield is characteristic of Lewy body dementias, including dementia in PD (PDD). Early non-human primate tracer studies demonstrated connections from the nucleus of the vertical limb of the diagonal band of Broca (nvlDBB, Ch2) to the hippocampus. However, the relationship between Lewy pathology of the CA2 subfield and cholinergic fibres has not been explored. Therefore, in this study, we investigated the burden of pathology in the CA2 subsector of PD cases with varying degrees of cognitive impairment and correlated this with the extent of septohippocampal cholinergic deficit. Hippocampal sections from 67 PD, 34 PD with mild cognitive impairment and 96 PDD cases were immunostained for tau and alpha-synuclein, and the respective pathology burden was assessed semi-quantitatively. In a subset of cases, the degree of CA2 cholinergic depletion was quantified using confocal microscopy and correlated with cholinergic neuronal loss in Ch2. We found that only cases with dementia have a significantly greater Lewy pathology, whereas cholinergic fibre depletion was evident in cases with mild cognitive impairment and this was significantly correlated with loss of cholinergic neurons in Ch2. In addition, multiple antigen immunofluorescence demonstrated colocalisation between cholinergic fibres and alpha-synuclein but not tau pathology. Such specific Lewy pathology targeting the cholinergic system within the CA2 subfield may contribute to the unique memory retrieval deficit seen in patients with Lewy body disorders, as distinct from the memory storage deficit seen in Alzheimer's disease.