bluuebunny/crossref_metadata_2025 huggingface dataset:
BT09 Multicentre prospective clinical performance analysis of an artificial intelligence as a medical device deployed within urgent suspected skin cancer pathways
Authors: Brewer Felix , Kentley Jonathan , Kalsi Dilraj , Mullarkey Dan , Thomas Lucy
Published: June 2024

Over 25% of patients with suspected skin cancer in England waited over 4 weeks from urgent referral to diagnosis in October 2023. Implementation of artificial intelligence (AI) can augment this pathway to improve timely diagnosis. A prospective, postdeployment, multicentre clinical performance review of AIaMD was performed. AIaMD is a UKCA class IIa-approved artificial intelligence as a medical device intended for use in the screening, triage and assessment of skin lesions suspicious for skin cancer. AIaMD was deployed at four sites as part of the National Health Service AI in Health and Care Award. Patients assessed by the most recent version of AIaMD from April 2022 to November 2023 were eligible for inclusion. Outcomes were confirmed from histology reports for cancerous lesions and histology reports or consultant teledermatology assessment for premalignant and benign lesions. AIaMD assessed 3979 lesions with outcomes confirmed, including 38 melanomas, 68 squamous cell carcinomas, 181 basal cell carcinomas, 5 rare skin cancers, and 612 premalignant lesions such as Bowen disease and actinic keratoses. The negative predictive value – how often AIaMD labelled lesions as premalignant or benign and correctly ruled out cancer – was 99.8% (539 of 540). The sensitivities of AIaMD for melanoma, all skin cancer and premalignancy were 97% (37 of 38), 96.6% (282 of 292) and 86.3% (528 of 612), respectively. The specificity of AIaMD for benign lesions was 74.9% (2118 of 2827). For benign lesions confirmed by biopsy only, the specificity was 27.6% (105 of 381). One site reported a reduction in average wait time to first appointment by 11 days, a 10% reduction in biopsies and a 13% reduction in routine follow-up appointments. This postmarket service evaluation reported the clinical outcomes of AIaMD – an AI device used for assessment of skin lesions. The pathway was sensitive, identifying 282 out of 292 skin cancers, and specific, correctly identifying three out of every four benign lesions assessed and confirmed clinically or histologically. Moreover, implementation of AIaMD was linked to benefits to the pathway such as a reduction of biopsies. The integration of AIaMD into skin cancer diagnostic pathways could significantly improve the accuracy of urgent suspected skin cancer referrals, removing unnecessary specialist review of benign lesions. Part of the deployment period was funded as part of the NHS AI in Health and Care Award, and two of the authors are employed by one of the deployment sites. Three of the authors are employed by the AI provider.
BT11 Artificial intelligence and ethnically diverse skin: potential, pitfalls and a model for reducing risk
Authors: Lamche Lucas , Felton Jessie
Published: June 2024

There is increasing demand for artificial intelligence (AI) tools to manage skin cancer; however, there is minimal diversity in images used for AI training and validation (Wen D, Khan SM, Xu AJ et al. Characteristics of publicly available skin cancer image datasets: a systematic review. Lancet Digit Health 2022; 4: e64–74). Limited validation in ethnically diverse skin, in tandem with no human ‘sense check’ on photographic input and analysis by AI, increases the risk of misdiagnosis of skin cancers. We assessed AI bias and developed a cost-effective protocol to increase diagnostic accuracy in patients with ethnically diverse skin. A dermatology nurse collected clinical history and used videodermoscopy to capture optimized macro and dermoscopic images of lesions. Data were from consented patients with self-identified ethnically diverse skin, being assessed via the 2-week-wait skin cancer teledermatology pathway over 7 months. This was combined with clinical history. Histological diagnosis (where available) and consultant diagnosis were recorded for each lesion, used as gold standard to compare Moleanalyzer pro AI assessments of lesions. This ‘real-time AI’ is run at the bedside and clearly demarcates the lesion being analysed. We analysed 69 lesions from 64 patients (45 female, 19 male) with an age range of 18–81 years (mean 49.9). The AI malignancy threshold (MT) is 0–1 (1 being highest risk of malignancy). With MT on the Moleanalyzer pro AI at > 0.2, clinical–AI concordance was 75.4%, while AI sensitivity and specificity were 83.3% and 74.6%, respectively. Published results for Moleanalyzer pro AI in people with Fitzpatrick type II and III skin at MT 0.5 and above show sensitivity 81.6% and specificity 88.9%. In some cases in our study, AI picked out the incorrect darker area and not the index lesion in ethnically diverse skin. In addition, only rare subtypes of skin cancers were found in our patient population. We found that when using dermatological AI diagnostic tools, a nurse-led photography protocol is optimal. Incorporating clinical history alongside ‘real-time AI’ at the bedside, and a human ‘sense check’ on AI diagnosis, reduces risk. When using AI in an ethnically diverse population, a reduced MT must be considered to achieve a level of accuracy comparable with published data. With an effective protocol, AI can provide extensive savings and reduced waiting times. Each diagnostic AI tool developed for skin cancer should be validated with ethnically diverse skin images to reduce health inequality and potential harm to patients. We propose this is introduced into formal quality standards for AI used in skin cancer diagnosis.
BT14 (P026) Teledermatology from the other side: a clinical photographers’ perspective
Authors: Uthayakumar Aarthy , Searle Tamara , Elshimy Noha
Published: June 2024

Teledermatology has transformed the way we deliver our skin cancer service, with medical photographers playing a vital role in our trust. We sought to further streamline our existing teledermatology service and explore challenges faced by the photography team. Our teledermatology model involves patients directly attending the hospital for a professional photography appointment before consultant triage of the lesion(s). After observing teledermatology photography lists with detailed photographer feedback, 1 week of teledermatology clinics across all three sites of the trust were analysed. Referral type, discrepancies between the general practitioner (GP) referral and photos taken, and chaperone availability were explored, in addition to the referral pathway and patient information supplied. In total 122 teledermatology patients were included. Photographers highlighted difficulties with patients requesting lesions not specified on the GP referral to be photographed, and not having sufficient information prior to their teledermatology appointment, making it often difficult to manage expectations. Furthermore, due to minimal staffing, the availability of chaperones was often limited. In 19% of cases there was a discrepancy between the GP referred lesion and photograph taken, which was due to additional lesions being photographed (35%), patients having multiple moles (22%), and unlikely suitability for teledermatology and no GP referral being present (17%). Improvements have been implemented at different levels along the teledermatology pathway to further streamline the service and reduce some of the pressures faced by our clinical photographer colleagues. Modifications to the GP suspected skin cancer pathway referral make it clearer which patients are suitable for teledermatology, and request a mandatory lesion and locator photograph. The triage process has been altered to improve robustness, with an additional triage step to minimize patients inappropriate for teledermatology being booked in, such as those with more than three lesions, genital lesions and patients on stretchers. Patient information has been clearly displayed in the medical photography department, highlighting that only the referred lesion can be photographed, and a paper copy of the teledermatology patient information leaflet is provided to highlight the next steps to the patient. This minimizes questions directed at the photographers and aids management of patient expectations. Finally, a protocol for medical photographers has been implemented to standardize teledermatology images taken, with changes to include polarized and nonpolarized dermoscopy. With these changes we have minimized the challenges faced by our clinical photography colleagues, whose perspective and experience of a successful teledermatology service is critical, and we believe this should be explored in order to make meaningful improvements.
Poster presentationsBT15 Ethical implications of artificial intelligence in dermatology: use-case analysis of skin cancer diagnostic smartphone apps
Authors: Shah Fazal , Arecco Daniel , Draper Heather , Matin Rubeta
Published: June 2024

Skin cancer is the most common cancer worldwide. Early diagnosis is crucial for improving patient survival and morbidity. Artificial intelligence (AI)-assisted smartphone applications (apps) for skin cancer potentially offer accessible, early risk assessment of suspicious skin lesions. If harnessed to effective and responsive dermatology services, they may improve patient outcomes. The integration of novel technologies into dermatology raises ethical concerns. Ethical principles for acceptable AI governance are well known. Less well elucidated are how these should be applied to actual AI apps. Ethical use-case analysis can improve this understanding. Accordingly, we undertook an ethical use-case analysis of commercially available skin cancer apps. We applied previously described methods for ethical analysis of clinical AI applications to two popular skin cancer apps: SkinVision and Scanoma (Rogers WA, Draper H, Carter SM. Evaluation of artificial intelligence clinical applications: detailed case analyses show value of healthcare ethics approach in identifying patient care issues. Bioethics 2021; 35: 623–33). Systematic searches incorporating published literature, regulatory documents, and websites were undertaken to provide a detailed description of each app, and review the available evidence about their development, effectiveness and use. Screening for inclusion was undertaken by two researchers independently. Ethical concerns were identified with reference to previously described ethical concerns and principles for AI-assisted healthcare. These data were also independently checked and agreed on. By conceptualizing ethical principles within the use context of skin cancer apps, we identified specific ethical issues arising throughout the AI lifecycle of both apps. One company provided extensive detail regarding algorithm development and decision making; this information was insufficiently reported for the other app. Other concerns identified related to the number, quality, consistency and independence of studies assessing algorithm efficacy. Limited efforts to address potential skin tone biases and exclusion of patients with darker skin as target users by one app risk perpetuating existing inequalities. Inadequate regulatory requirements were highlighted. To the best of our knowledge, this study represents the first ethical use-case analysis of patient-facing AI-assisted skin cancer apps. Our findings suggest inadequate incorporation of bioethical norms such as justice, responsibility and transparency into the development and deployment of both apps. Improved regulation will increase accountability. Ensuring ethics by design through integration between technology developers, dermatologists, ethicists and patients is urgently needed to prevent the potential benefits of AI-assisted skin cancer apps being overshadowed by potential ethical harms.
BT16 BT17 Dermatology advice and guidance: a service evaluation
Authors: Sathanantham Kugili , Hickey Sian , Ellison Judith
Published: June 2024

We wish to present a service evaluation undertaken of the regional dermatology advice and guidance (A&G) service provided within our locale. As part of the national Elective Care Transformation Programme, A&G services were created, primarily as a consultant dermatologist-led service prior to referral. This was designed to transform the way in which primary care referrals are managed with continued access to specialist clinical advice. The process permits the streamlined conversion to National Health Service referral if required and is being advocated as a potential main referral pathway to dermatology in England. This has resulted in a 400% increase in dermatology A&G requests since the onset of the COVID-19 pandemic in 2020 across England. In real-world practice, this translated to 200 referrals over a 2-week period across four trusts. Our service evaluation analysed the practices across the region to capture the way this service is currently delivered. We focused on the grade of the provider of A&G, whether a rota system was in place, how this was job planned into clinical activity, the service platform utilized and the size of the region the service covered. Each referral was assessed to ascertain the grade of the referrer and whether appropriate imaging and an adequate past medical and medication history were provided. From our service evaluation, approximately 25% of A&G outcomes were directed to have a referral only, 30% of outcomes were advice followed by formal referral if advice did resolve the problem, and 25% of referrals were given advice only. Overall, 20% of referrals were rejected due to either inadequate imaging, inadequate history and imaging, or an inadequate history alone. In conclusion, 70% of the surveyed consultants felt the A&G referrals were subjectively useful to patients and as an educational tool to general practitioner colleagues. This service evaluation provided a baseline understanding of A&G: 25% of current referrals were managed via this service alone, and 30% of the referrals were given a trial of advice with safety-net formal referral advocated if advice did not resolve the issue. As a result, nearly 50% of referrals were managed via an electronic referral service where they would have previously been managed via a face-to-face clinic appointment.
BT20 Comparison of colour accuracy of a DSLR camera and mobile phone cameras used for dermoscopy images: a pilot study
Authors: Teo Daryl , Potluru Aparna , Salako Kazeem
Published: June 2024

Dermatology, being a visual specialty, lends itself well to the advent of telemedicine. Utilization of teledermatology has been greatly expanded since the COVID-19 pandemic. Patients are increasingly making use of their own personal devices to capture images of their skin conditions to show the clinician. Advances in cameras of mobile phone devices have also encouraged good-quality image capturing. However, mobile phone cameras have inbuilt software that is often calibrated to deliver appealing consumer photography. Each company has their own software and marketing regarding this. The present pilot study aims to compare the colour accuracy of DSLR and mobile phone cameras used in dermoscopy images. Dermoscopic images allow for consistent lighting to standardize comparison. We used a DSLR camera (Nikon D7200 body with the DermLite Foto II Pro dermoscopy lens) as the standard for comparison, which is likely to produce a better image. Four mobile phones were used (Apple iPhone 12 Pro, Samsung Galaxy Note 8, Samsung Galaxy S21 Ultra, and Google Pixel 7A) and dermoscopy images were captured through a Heine DELTAone. Three photos of a melanocytic naevus each from five participants were taken. All raw images were transferred to a computer and analysed with FIJI, ImageJ freeware. RGB images were converted to the CIELAB colour space. The CIELAB colour space was used as a device-independent model to compare colour difference, which was determined by the computation of total colour difference (ΔE). ΔE values in all participants were calculated, with the lowest mean difference for Pixel 7A (12.9), followed by iPhone 12 Pro (18.6), Note 8 (20.0) and S21 Ultra (26.1). Of note, there was a greater mean difference across all devices in our participants of Afro-Caribbean ethnicity (25.7) compared with other participants. There is variation in colour accuracy between mobile phone devices in comparison with DSLR photography for our dermoscopic images of melanocytic naevi. This difference appears more pronounced in Black individuals. It is important for dermatologists to be aware of the devices used in capturing these images when they are used as part of any telemedicine service. Careful consideration is required for assessing rashes in patients with darker skin tones, especially as those clinical photographs would not have consistent lighting and exposure factors, which can influence the final image. The study can be expanded to include more participants and images to further investigate these differences.
BT27 How reliable is teledermatology in diagnosing skin cancer? A retrospective analysis of skin cancer outcomes from a single centre
Authors: Moon Emily , Elkins Anna , Johnson Jo , Ahmad Maria , Peng Chenjing
Published: June 2024

Teledermatology has become a pivotal tool to meet the increasing demands on skin cancer services. Factors such as referral quality and clinical judgement need to be considered when evaluating its effectiveness and reliability. A single-centre retrospective study was conducted to evaluate the diagnostic accuracy of a pilot teledermatology service used to triage 2-week-wait skin cancer referrals from primary care. Between May and July 2023 (total 158 referrals), 45% of 2-week-wait teledermatology referrals were accepted into a face-to-face (F2F) clinic, of which 80% were seen in a 2-week-wait clinic, either by dermatology or plastic surgery. The remaining accepted cases were redirected into a general dermatology clinic. Of the 87 referrals returned, 31% were due to poor-quality photographs or insufficient information provided, and 69% were thought to be appropriate for primary care management. A detailed analysis of 100 referrals was conducted to assess the referral quality and clinical outcomes. Of the 51 patients with a suspected skin cancer diagnosed on teledermatology, 21% (5 of 24) of melanomas, 17% (4 of 23) of squamous cell carcinomas and 75% (3 of 4) of basal cell carcinomas were confirmed on histological analysis. Of the 21 patients who were suspected to have a precancerous or benign lesion on teledermatology, two were diagnosed with a malignancy on histology. When comparing the teledermatology diagnosis vs. histological diagnosis as the gold standard, diagnostic accuracy was 0.66 [95% confidence interval (CI) 0.51–0.78], with 92% sensitivity, 42% specificity and κ = 0.33 (95% CI 0.11–0.56). This was comparable with the diagnostic accuracy of a F2F clinic review, which was 0.66 (95% CI 0.51–0.79) with 96% sensitivity, 38% specificity and κ = 0.33 (95% CI 0.13–0.54). When only the F2F diagnosis was used as the gold standard, the diagnostic accuracy of teledermatology was higher at 0.78 (95% CI 0.66–0.87), with 91% sensitivity, 56% specificity and κ = 0.5 (95% CI 0.28–0.71). Our study demonstrated that teledermatology can be a useful tool to reduce unnecessary F2F clinic reviews, if adequate information and photographs are provided. It has demonstrated high skin cancer diagnostic sensitivity, but with compromised specificity. There was a moderate level of concordance between diagnoses made in teledermatology and the F2F clinic. Although teledermatology and F2F assessment had very comparable diagnostic accuracies, a higher sensitivity and lower specificity were noted on F2F assessment. This could be attributed to the initial diagnosis made on teledermatology influencing the subsequent clinical decision in a F2F clinic. Ongoing caution, critical reflection and more studies are warranted to elucidate teledermatology’s full potential in the diagnosis and management of skin cancer.
BT36 A cross-sectional study of social media content relating to cutaneous lupus
Authors: Murphy Lisa , Wynne Bairbre
Published: June 2024

Social media is now a well-recognized entity when it comes to accessing information quickly and at minimal cost. If patients could be directed towards reputable social media pages, they could have greater access to reliable information, as well as a forum to reach out to other patients with similar conditions. Systemic lupus erythematosus is a complex disease that can affect a number of organs. Some patients may become overwhelmed with the wealth of information being provided to them at diagnosis. Social media could play a key role in providing patients with more user-friendly information, while equally introducing a more interactive component to information sharing. As a result, the aim of this study was to establish the nature of the content available to patients on popular social media websites. Three popular social media sites were identified and included in this study: Instagram, X (formerly known as Twitter) and Facebook. The search words ‘cutaneous lupus’ were used on all three websites and the top 30 posts were included in data analysis. The content breakdown on Instagram could be stratified into the sharing of patients’ personal photographs, infographics, and the sharing of cutaneous lupus events and resources. Overall, 30% of the posts consisted of infographics with factual medical information for viewers, while 23% of patients posted personal photographs of their cutaneous lupus manifestations. The average number of people who had engaged with posts on Instagram was 1541. In terms of the site X, 47% of posts shared were to disseminate article links and publications in medical journals. Six posts were statements that contained factual medical knowledge, eight posts were images and two posts were infographics. The average number of views for these posts on X was 9797 people. Of the analysed posts on Facebook, 10 were links to article publications, 5 were statements, 5 were members seeking advice, 3 were infographics, 5 were images and 2 were videos. In total, 73% of posts on Facebook contained factual medical information regarding lupus. The average number of people to have engaged with posts on Facebook was 29. Social media has the potential to provide patients with increased access to healthcare information, medical developments, and support from other patients. This study highlights that social media may prove to be a useful adjunct for clinicians to direct their patients towards for further information. While it is important to warn patients of the potential for misinformation, if patients could be counselled on how to use social media sites appropriately, this could be an effective method for patients to garner support and knowledge about cutaneous lupus.
BT40 A case of low-grade angiosarcoma of the face: is teledermatology effective in early diagnosis of rare skin tumours?
Authors: Kubba Faris , Aliyeva-Derraz Pakiza
Published: June 2024

An 87-year-old White man presented with a gradual swelling of the right side of the face. This was clinically diagnosed by his general practitioner via teledermatology as erysipelas refractory to antibiotic treatment, with a clinical course of around 10 months. The differential diagnosis included rosacea. The lesion was gradually involving the cheek and spreading to the left side of the face. The patient was referred to the dermatology clinic and on examination the lesion was found to be indurated, tender and warm with a wet texture. The patient had a previous history of bladder cancer, which was treated 5 years earlier. A 4-mm punch biopsy from the right cheek was taken, which showed a permeative vasoformative tumour within the dermis composed of anastomosing vascular spaces lined by a single layer of plump endothelial cells. Mitotic figures were identified. ERG immunohistochemical stain highlighted the endothelial cells. Human herpesvirus 8 stain was negative. The diagnosis was a grade 1 angiosarcoma. This was also reviewed in the specialized unit and the patient was urgently referred to a sarcoma service. Computed tomography and positron emission tomography scans were performed and he was be referred for chemotherapy. The role of teledermatology for skin lesion assessment has been a recent development, particularly since the COVID-19 pandemic, and has impacted the ability to assess patients in person. In recent research, 22 studies were reviewed to include basal cell carcinoma, squamous cell carcinoma and melanoma. The authors stated that anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Their results suggest that teledermatology can correctly identify the majority of malignant lesions. In another recent review of 45 publications, the authors concluded that teledermatology offers a comparable standard of effectiveness to in-person assessment. It can save significant time in expediting advice and management. Image quality and inclusion of dermoscopy have a considerable bearing on the overall effectiveness. However, our case shows that the diagnostic accuracy of teledermatology in similar rare tumours needs to be carefully evaluated. Any clinical suspicion about lesions with diffuse growth patterns that mimic dermatoses refractory to medications should be taken seriously and an urgent referral to a dermatologist is to be recommended. In conclusion, we have presented a case of angiosarcoma of the face initially diagnosed as erysipelas, which needed further referral after being refractory to antibiotics. As primary cutaneous angiosarcoma is one of the most aggressive skin tumours and carries a very poor prognosis, further assessment of teledermatology as a reliable diagnostic method needs to be evaluated, and confusion with inflammatory dermatosis remains a serious diagnostic pitfall.
Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes
Authors: Pasquini Lorenzo , Pereira Felipe L , Seddighi Sahba , Zeng Yi , Wei Yongbin , Illán-Gala Ignacio , Vatsavayai Sarat C , Friedberg Adit , Lee Alex J , Brown Jesse A , Spina Salvatore , Grinberg Lea T , Sirkis Daniel W , Bonham Luke W , Yokoyama Jennifer S , Boxer Adam L , Kramer Joel H , Rosen Howard J , Humphrey Jack , Gitler Aaron D , Miller Bruce L , Pollard Katherine S , Ward Michael E , Seeley William W
Published: June 2024

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution.

To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired.

We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes.

Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes.
Nav1.2 channel mutations preventing fast inactivation lead to SCN2A encephalopathy
Authors: Berecki Géza , Tao Elaine , Howell Katherine B , Coorg Rohini K , Andersen Erik , Kahlig Kris , Wolff Markus , Corry Ben , Petrou Steven
Published: June 2024

SCN2A gene-related early-infantile developmental and epileptic encephalopathy (EI-DEE) is a rare and severe disorder that manifests in early infancy. SCN2A mutations affecting the fast inactivation gating mechanism can result in altered voltage dependence and incomplete inactivation of the encoded neuronal Nav1.2 channel and lead to abnormal neuronal excitability.

In this study, we evaluated clinical data of seven missense Nav1.2 variants associated with DEE and performed molecular dynamics simulations, patch-clamp electrophysiology and dynamic clamp real-time neuronal modelling to elucidate the molecular and neuron-scale phenotypic consequences of the mutations.

The N1662D mutation almost completely prevented fast inactivation without affecting activation. The comparison of wild-type and N1662D channel structures suggested that the ambifunctional hydrogen bond formation between residues N1662 and Q1494 is essential for fast inactivation. Fast inactivation could also be prevented with engineered Q1494A or Q1494L Nav1.2 channel variants, whereas Q1494E or Q149K variants resulted in incomplete inactivation and persistent current. Molecular dynamics simulations revealed a reduced affinity of the hydrophobic IFM-motif to its receptor site with N1662D and Q1494L variants relative to wild-type. These results demonstrate that the interactions between N1662 and Q1494 underpin the stability and the orientation of the inactivation gate and are essential for the development of fast inactivation. Six DEE-associated Nav1.2 variants, with mutations mapped to channel segments known to be implicated in fast inactivation were also evaluated. Remarkably, the L1657P variant also prevented fast inactivation and produced biophysical characteristics that were similar to those of N1662D, whereas the M1501V, M1501T, F1651C, P1658S and A1659V variants resulted in biophysical properties that were consistent with gain-of-function and enhanced action potential firing of hybrid neurons in dynamic action potential clamp experiments. Paradoxically, low densities of N1662D or L1657P currents potentiated action potential firing, whereas increased densities resulted in sustained depolarization.

Our results provide novel structural insights into the molecular mechanism of Nav1.2 channel fast inactivation and inform treatment strategies for SCN2A-related EI-DEE. The contribution of non-inactivating Nav1.2 channels to neuronal excitability may constitute a distinct cellular mechanism in the pathogenesis of SCN2A-related DEE.
Automatic classification and segmentation of multiclass jaw lesions in cone-beam CT using deep learning
Authors: Liu Wei , Li Xiang , Liu Chang , Gao Ge , Xiong Yutao , Zhu Tao , Zeng Wei , Guo Jixiang , Tang Wei
Published: June 2024

Objectives

To develop and validate a modified deep learning (DL) model based on nnU-Net for classifying and segmenting five-class jaw lesions using cone-beam CT (CBCT).

Methods

A total of 368 CBCT scans (37 168 slices) were used to train a multi-class segmentation model. The data underwent manual annotation by two oral and maxillofacial surgeons (OMSs) to serve as ground truth. Sensitivity, specificity, precision, F1-score, and accuracy were used to evaluate the classification ability of the model and doctors, with or without artificial intelligence assistance. The dice similarity coefficient (DSC), average symmetric surface distance (ASSD), and segmentation time were used to evaluate the segmentation effect of the model.

Results

The model achieved the dual task of classifying and segmenting jaw lesions in CBCT. For classification, the sensitivity, specificity, precision, and accuracy of the model were 0.871, 0.974, 0.874, and 0.891, respectively, surpassing oral and maxillofacial radiologists (OMFRs) and OMSs, approaching the specialist. With the model's assistance, the classification performance of OMFRs and OMSs improved, particularly for odontogenic keratocyst (OKC) and ameloblastoma (AM), with F1-score improvements ranging from 6.2% to 12.7%. For segmentation, the DSC was 87.2% and the ASSD was 1.359 mm. The model's average segmentation time was 40 ± 9.9 s, contrasting with 25 ± 7.2 min for OMSs.

Conclusions

The proposed DL model accurately and efficiently classified and segmented five classes of jaw lesions using CBCT. In addition, it could assist doctors in improving classification accuracy and segmentation efficiency, particularly in distinguishing confusing lesions (eg, AM and OKC).
A Deeper Understanding of the Constitutional Status of Māori and Their Rights Required: A Reply to Christian Riffel
Authors: Charters Claire
Published: June 2024

In his recent article, Christian Riffel makes the important argument that New Zealand’s free trade agreements (FTAs) with the European Union and the United Kingdom constitute a form of constitutional law-making. However, in my view, Riffel misconstrues Māori rights under domestic and international law and associated context and law. He does not take sufficiently seriously the unique right of Indigenous peoples to self-determination and, in relation to Māori specifically, to tino rangatiratanga under New Zealand’s founding constitutional document, te Tiriti o Waitangi. This means that Indigenous peoples have rights to exercise public and governance power alongside a state. In this way, Indigenous peoples’ rights are fundamentally and qualitatively different from other minorities or groups in New Zealand and must not be conflated. There are several consequences that result from Riffel’s omission. For example, Riffel’s argument that Indigenous peoples’ rights under the FTAs challenge democracy does not adequately address Indigenous peoples’ rights to govern or the state’s legally questionable claim to sovereignty. I have some other less fundamental gripes. For example, Riffel’s comments on whether Māori in this field have considered the importance of the ‘Māori provisions’ is somewhat condescending.
Acute myocardial infarction and ischaemic stroke: differences and similarities in reperfusion therapies—a review
Authors: Scheldeman Lauranne , Sinnaeve Peter , Albers Gregory W , Lemmens Robin , Van de Werf Frans
Published: June 2024

Acute ST-elevation myocardial infarction (STEMI) and acute ischaemic stroke (AIS) share a number of similarities. However, important differences in pathophysiology demand a disease-tailored approach. In both conditions, fast treatment plays a crucial role as ischaemia and eventually infarction develop rapidly. Furthermore, in both fields, the introduction of fibrinolytic treatments historically preceded the implementation of endovascular techniques. However, in contrast to STEMI, only a minority of AIS patients will eventually be considered eligible for reperfusion treatment. Non-invasive cerebral imaging always precedes cerebral angiography and thrombectomy, whereas coronary angiography is not routinely preceded by non-invasive cardiac imaging in patients with STEMI. In the late or unknown time window, the presence of specific patterns on brain imaging may help identify AIS patients who benefit most from reperfusion treatment. For STEMI, a uniform time window for reperfusion up to 12 h after symptom onset, based on old placebo-controlled trials, is still recommended in guidelines and generally applied. Bridging fibrinolysis preceding endovascular treatment still remains the mainstay of reperfusion treatment in AIS, while primary percutaneous coronary intervention is the strategy of choice in STEMI. Shortening ischaemic times by fine-tuning collaboration networks between ambulances, community hospitals, and tertiary care hospitals, optimizing bridging fibrinolysis, and reducing ischaemia–reperfusion injury are important topics for further research. The aim of this review is to provide insights into the common as well as diverging pathophysiology behind current reperfusion strategies and to explore new ways to enhance their clinical benefit.
Closed loop stimulation reduces the incidence of atrial high-rate episodes compared with conventional rate-adaptive pacing in patients with sinus node dysfunctions
Authors: Pisanò Ennio C L , Calvi Valeria , Viscusi Miguel , Rapacciuolo Antonio , Lazzari Ludovico , Bontempi Luca , Pelargonio Gemma , Arena Giuseppe , Caccavo Vincenzo , Wang Chun-Chieh , Merkely Béla , Lin Lian-Yu , Oh Il-young , Bertaglia Emanuele , Saporito Davide , Menichelli Maurizio , Nicosia Antonino , Carretta Domenico M , Coppolino Aldo , Ching Chi Keong , del Castillo Álvaro Marco , Su Xi , Del Maestro Martina , Giacopelli Daniele , Gargaro Alessio , Botto Giovanni L
Published: June 2024

Aims

Subclinical atrial fibrillation (AF) is associated with increased risk of progression to clinical AF, stroke, and cardiovascular death. We hypothesized that in pacemaker patients requiring dual-chamber rate-adaptive (DDDR) pacing, closed loop stimulation (CLS) integrated into the circulatory control system through intra-cardiac impedance monitoring would reduce the occurrence of atrial high-rate episodes (AHREs) compared with conventional DDDR pacing.

Methods and results

Patients with sinus node dysfunctions (SNDs) and an implanted pacemaker or defibrillator were randomly allocated to dual-chamber CLS (n = 612) or accelerometer-based DDDR pacing (n = 598) and followed for 3 years. The primary endpoint was time to the composite endpoint of the first AHRE lasting ≥6 min, stroke, or transient ischaemic attack (TIA). All AHREs were independently adjudicated using intra-cardiac electrograms. The incidence of the primary endpoint was lower in the CLS arm (50.6%) than in the DDDR arm (55.7%), primarily due to the reduction in AHREs lasting between 6 h and 7 days. Unadjusted site-stratified hazard ratio (HR) for CLS vs. DDDR was 0.84 [95% confidence interval (CI), 0.72–0.99; P = 0.035]. After adjusting for CHA2DS2-VASc score, the HR remained 0.84 (95% CI, 0.71–0.99; P = 0.033). In subgroup analyses of AHRE incidence, the incremental benefit of CLS was greatest in patients without atrioventricular block (HR, 0.77; P = 0.008) and in patients without AF history (HR, 0.73; P = 0.009). The contribution of stroke/TIA to the primary endpoint (1.3%) was low and not statistically different between study arms.

Conclusion

Dual-chamber CLS in patients with SND is associated with a significantly lower AHRE incidence than conventional DDDR pacing.
Academic orientation and cannabis use—findings from a population-based study of Swedish adolescents in upper secondary school
Authors: Gripe Isabella , Ramstedt Mats , Karlsson Patrik , Thor Siri
Published: June 2024

Aim

To examine the association between academic orientation and frequent cannabis use among Swedish adolescents in upper secondary school and include pupils from introductory programs (IPs), a large group of adolescents previously overlooked in research on adolescent cannabis use.

Methods

We used cross-sectional data from two anonymous school surveys carried out in upper secondary school in 2021. The samples consisted of pupils from all academic orientations, and the analysis included 3151 pupils in higher education preparatory programs (HEPs), 1010 pupils in vocational programs (VPs), and 819 pupils in IPs. The association between the exposure academic orientation and the outcome frequent (21+ times) cannabis was analyzed using multi-level mixed-effects Poisson regression.

Results

Estimates from the first model showed a significant (P < 0.05) 2.45 times higher risk of frequent cannabis use among pupils in IPs compared with in HEPs [incidence rate ratio (IRR) 2.45, 95% confidence interval (CI) 1.28–4.66] and 82% higher in VPs (IRR 1.82, 95% CI 1.09–3.04) compared with in HEPs. However, the associations between academic orientation and frequent (21+ times) cannabis use were attenuated and no longer significant when socioeconomic status, truancy, school dissatisfaction, and early onset of substance use were adjusted for.

Conclusions

There was a higher risk of frequent (21+ times) cannabis use among pupils in IPs, and this differential was explained by higher exposure to risk factors in this group. This result is important from a policy perspective as it provides knowledge of a previously neglected risk group for frequent cannabis use.
DNA Methylation Mediates the Association Between Cardiometabolic Risk Factors and Cognition: Findings From the Health and Retirement Study
Authors: Wan Zengyi , Chibnik Lori B , Valeri Linda , Hughes Timothy M , Blacker Deborah , Ma Yuan
Published: June 2024

The association between cardiometabolic risk factors and cognitive function has been well documented, but the underlying mechanisms are not fully understood. This longitudinal study aimed to investigate the potential mediating role of DNA methylation in this association. We conducted the analyses in 3 708 participants (mean [standard deviation {SD}] age: 67.3 [9.5], women: 57.9%) from the Health and Retirement Study who were assessed in the 2014–2020 waves, had Infinium Methylation EPIC BeadChip methylation assays from the 2016 Venous Blood Study, and had cognitive assessment between 2016 and 2020. Causal mediation analyses were used to test the mediation role of DNA methylation in the associations between cardiometabolic risk factors and cognition, adjusting for demographic, socioeconomic, and lifestyle factors. Hypertension (−0.061 in composite cognitive z-score; 95% confidence interval [CI: −0.119, −0.004]) and diabetes (−0.134; 95% CI: [−0.198, −0.071]) were significantly associated with worse cognitive function while abnormal body weight and hypercholesterolemia were not. An increased number of cardiometabolic risk factors was associated with worse cognitive function (p = .002). DNA methylation significantly mediated the association of hypertension (mediated effect on composite cognitive z-score: −0.023; 95% CI: −0.033, −0.014), diabetes (−0.022; 95% CI: −0.032, −0.014), and obesity (−0.021; 95% CI: −0.033, −0.011) with cognitive function, whereas the mediation effect was not observed for having hypercholesterolemia. The estimated proportions mediated were 37.4% for hypertension and 16.7% for diabetes. DNA methylation may be an important mediator linking cardiometabolic risk factors to worse cognition and might even provide a potential target for dementia prevention.
Experimental Studies of Bioinspired Shark Denticles for Drag Reduction
Authors: Graybill Marshall T , Xu Nicole W
Published: June 2024

Synopsis

Shark skin is composed of denticles, or complex scale-like features, which have been shown to reduce drag in turbulent and laminar flow. The denticle crown features undulating structures called riblets that interact with the turbulent boundary layer to reduce drag. Two mechanisms thought to contribute to the drag-reducing properties of riblets include the lifting of streamwise vortices and the hampering of spanwise vortex interactions to reduce crossflow, which could translate to similar flow mechanisms for denticles. Because of the varied morphologies of dermal denticles on different shark species, which also depend on body location, the impact of these denticle geometries on flow is of interest to the biology community, including related fields such as fluid mechanics and oceanography. This review highlights the past 15 years of manufacturing techniques and experimental measurements of drag over denticle-inspired surface structures, including real shark skin samples and engineered denticles and riblets. State-of-the-art additive manufacturing and other techniques are primarily limited to mm-length denticle scales, which have demonstrated drag reduction in lower flow speeds, under 1 m s−1. New manufacturing approaches can create sub-mm length denticles and nanotextured surface structures, which have achieved reported drag reductions of up to 31%. We synthesize results from the literature to illustrate the drag reduction properties of bioinspired denticles and riblets according to their geometry and flow conditions. Using these trends, we suggest design features and focus areas for future research, such as increasing studies of different denticle morphologies, hydrophobicity, antifouling properties, and acoustic noise reduction. Continued work on bioinspired denticles for drag reduction has wider implications in comparative biology and applications to design more energy-efficient, persistent vehicles for environmental monitoring.
Relative Contributions of the Novel Diarylquinoline TBAJ-876 and its Active Metabolite to the Bactericidal Activity in a Murine Model of Tuberculosis
Authors: Mudde Saskia E , Ammerman Nicole C , ten Kate Marian T , Fotouhi Nader , Lotlikar Manisha U , Bax Hannelore I , de Steenwinkel Jurriaan E M
Published: June 2024

Background

TBAJ-876 is a next-generation diarylquinoline. In vivo, diarylquinoline metabolites are formed with activity against Mycobacterium tuberculosis. Species-specific differences in parent drug-to-metabolite ratios might impact the translational value of animal model-based predictions. This study investigates the contribution of TBAJ-876 and its major active metabolite, TBAJ-876-M3 (M3), to the total bactericidal activity in a mouse tuberculosis model.

Methods

In vitro activity of TBAJ-876 and M3 was investigated and compared to bedaquiline. Subsequently, a dose-response study was conducted in M. tuberculosis-infected BALB/c mice treated with TBAJ-876 (1.6/6.3/25 mg/kg) or M3 (3.1/12.5/50 mg/kg). Colony-forming units in the lungs and TBAJ-876 and M3 plasma concentrations were determined. M3's contribution to TBAJ-876's bactericidal activity was estimated based on M3 exposure following TBAJ-876 treatment and corresponding M3 activity observed in M3-treated animals.

Results

TBAJ-876 and M3 demonstrated profound bactericidal activity. Lungs of mice treated for 4 weeks with 50 mg/kg M3 were culture negative. Following TBAJ-876 treatment, M3 exposures were 2.2 to 3.6-fold higher than for TBAJ-876. TBAJ-876 activity was substantially attributable to M3, given its high exposure and potent activity.

Conclusions

These findings emphasize the need to consider metabolites and their potentially distinct exposure and activity profiles compared to parent drugs to enhance the translational value of mouse model-driven predictions.
Field efficacy of a biopesticide and a predatory mite for suppression of Scirtothrips dorsalis (Thysanoptera: Thripidae) in strawberry
Authors: Lahiri Sriyanka , Kaur Gagandeep , Busuulwa Allan
Published: June 2024

Chilli thrips, Scirtothrips dorsalis Hood (Thysanoptera: Thripidae) has emerged as a severe invasive pest of strawberry Fragaria × ananassa Duchesne in the United States. The objective of this study was to assess the field efficacy of a biopesticide and thrips predator, Amblyseius swirskii Athias-Henriot for S. dorsalis management in field grown strawberry compared to synthetic insecticide applications that are current industry standard (spinetoram) conducted at UF/IFAS GCREC, FL during 2021–2022 and 2022–2023 in a 2-year field study. The following treatments were applied in the field: (1) biopesticide, capsicum oleoresin extract + garlic oil + canola oil application at maximum label rate; (2) predatory mite of thrips, A. swirskii released at 30 predators per plot; (3) spinetoram applied at maximum label rate; and (4) biopesticide applied 24 h before release of A. swirskii. A control plot with no insecticide or predatory mite releases was maintained. Results show that the capsicum extract can be used for management of S. dorsalis, especially during the latter stages of strawberry field season when resistance to spinetoram is high. The field performance of A. swirskii was variable and extensive research is needed to highlight factors affecting field performance of predatory mites for thrips management.