bluuebunny/crossref_metadata_2025 huggingface dataset:
Orismilast, a phosphodiesterase 4B/D inhibitor, in moderate-to-severe atopic dermatitis: efficacy and safety from a multicentre randomized placebo-controlled phase IIb dose-ranging study (ADESOS)
Authors: Silverberg Jonathan I , Eichenfield Lawrence F , Blauvelt Andrew , Irvine Alan D , Guttman-Yassky Emma , Langley Richard G , Warren Richard B , French Lars E , Felding Jakob , Weiss Anne , Pedersen Claus B , Jensen Morten L , Carlsson Anna , Sommer Morten O A , Kjøller Kim , Simpson Eric L
Published: January 2025

Background

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous skin lesions and pruritus. There is an unmet need for effective first-line systemic treatments with good safety profiles, particularly oral medications. Orismilast is a novel first-in-class oral phosphodiesterase 4 (PDE4) B/D inhibitor under investigation for the treatment of moderate-to-severe AD.

Objectives

To evaluate the optimal dose, efficacy and safety of twice-daily orismilast in patients with moderate-to-severe AD.

Methods

This 16-week, multicentre randomized placebo-controlled phase IIb dose-ranging study (NCT05469464) included patients from 48 centres in Europe and the USA. Adults with moderate-to-severe AD were given (1 : 1 : 1 : 1) orismilast 20 mg, 30 mg or 40 mg, or placebo, twice daily. The primary endpoint was percentage change in Eczema Area and Severity Index (EASI); the secondary endpoints (all at week 16) included achievement of a score of clear (0) or almost clear (1) with ≥ 2-point improvement on the Investigator Global Assessment (IGA 0/1); achievement of a Peak Pruritus Numerical Rating Scale (PP-NRS) reduction of ≥ 4 points; and achievement of a reduction in EASI of 75%, 90% and 100% from baseline.

Results

Overall, 233 patients were randomly assigned to orismilast 20 mg (n = 58), 30 mg (n = 61), 40 mg (n = 59) or placebo (n = 55). At week 16, reductions in EASI (percentage points) from baseline to week 16 were seen across orismilast groups and placebo (P > 0.05 for orismilast vs. placebo). Significantly more patients achieved IGA 0/1 with a ≥ 2-point improvement with orismilast 20 mg and 40 mg compared with placebo (P < 0.05). Significantly greater proportions of patients achieving a ≥ 4-point reduction in PP-NRS were demonstrated with orismilast at week 2. The safety profile was consistent with that of the PDE4 class, with no major safety concerns reported.

Conclusions

These data support the clinical relevance of selective PDE4B/D inhibition with orismilast, potentially offering a convenient, novel oral therapy for the treatment of AD.
[18F]F-DCFPyL PET/MRI radiomics for intraprostatic prostate cancer detection and metastases prediction using whole-gland segmentation
Authors: Mirshahvalad Seyed Ali , Basso Dias Adriano , Ortega Claudia , Abreu Gomez Jorge Andres , Krishna Satheesh , Perlis Nathan , Berlin Alejandro , van der Kwast Theodorus , Jhaveri Kartik , Ghai Sangeet , Metser Ur , Santiago Anna Theresa , Veit-Haibach Patrick
Published: January 2025

Objectives

To evaluate [18F]F-DCFPyL PET/MRI whole-gland-derived radiomics for detecting clinically significant (cs) prostate cancer (PCa) within the prostate gland and predicting extra-prostatic metastasis (N and M staging).

Methods

In this single-centre, retrospective study, therapy-naïve PCa patients who underwent [18F]F-DCFPyL PET/MRI were included. Whole-prostate segmentation was performed. Feature extraction from each modality was done. The selection of potential variables was made through regularized binomial logistic regression. The oversampled training data were used to train binomial logistic regression for each outcome. The estimates of the models were calculated, and the mean accuracy was reported. The trained models were assessed on the test data for comparative evaluation of performance.

Results

A total of 103 patients (mean age = 65; mean PSA = 23.4) were studied. Among them, 89 had csPCa and 20 had metastatic disease. There were five radiomics variables selected for the International Society of Urological Pathology Grade Group (ISUP GG) ≥ 2 from T2w, ADC, and PET. To detect N1, five radiomics variables were selected from the T2w and PET. For M1, four radiomics variables were selected from T2w and ADC. Regarding the performance of models for the prediction of csPCa, the imaging-based hybrid model (T2w + PET) provided the highest AUC (0.98). The performance of N1 models showed the highest AUC (0.80) for T2w + PET. To predict M1, the T2w + ADC model showed the highest AUC (0.93).

Conclusions

Whole-gland PET/MRI radiomics may provide a reliable model to predict csPCa. Also, acceptable performance was reached for predicting metastatic disease in our limited population. Our findings may support the value of whole-gland radiomics for non-invasive csPCa detection and prediction of metastatic disease.

Advances in knowledge

Whole-gland PET/MRI radiomics, a less operator-dependent segmentation method, can be potentially used for treatment personalization in PCa patients.

Trial Registration

NCT03535831. Registered 2018; NCT03149861. Registered 2017
Cranio-cervical hyperpneumatization: a case report
Authors: Kueh Matthew , Behar Ramnik
Published: January 2025

Hyperpneumatization is a rare pathological process where air-filled cavitation form within solid bone architecture occurring at sites where physiological pneumatization is not seen. Extension of this process into the atlanto-occipital region is considered extremely rare and is only quoted several times in the literature. In this case report, we present a 66-year-old man who presented with an 8-month history of a worsening frontal headache and blocked sensation in his left ear. Subsequent CT head evaluation revealed hyperpneumatization affecting C1 vertebra, temporal and occipital bones with extension into the clivus. A rare complication of epidural emphysema was seen. The aetiology of hyperpneumatization is uncertain, although it is thought to be either congenital or acquired. In our case, clinical suggestion of eustachian tube dysfunction and radiological findings of thickened sinus mucosa and a unilateral nasal polyp point to chronic recurrent coryzal illnesses, which may indicate an acquired mechanism. Management is mostly conservative with surgical management reserved for high risk or refractory cases.
BHSo1 Establishing a chemical component separation service using botulinum toxin for abdominal wall reconstruction in a district general tertiary hernia referral unit
Authors: Curwen Oliver , Zhao Sarah , Ludden Rebecca , Gate Emilio Schweighart , Jakkalasaibaba Ravishankar , Parker Samuel , Thomas Rhys
Published: January 2025

Background

Botulinum toxin type A (BTA) is a valuable adjunct in abdominal wall reconstruction (AWR). Chemical component separation (CCS) involves injecting BTA into the lateral abdominal wall, leading to muscle relaxation and elongation. The aim is to achieve primary fascial closure of both anterior and posterior sheaths without the need for extensive dissection, associated with greater morbidity.

Aim

To present a standardised protocol for CCS in a tertiary hernia unit and to demonstrate the clinical benefit of BTA in AWR.

Methods

A retrospective analysis of a prospective dataset of all patients undergoing standardised pre-operative CCS between May 2021 and May 2024 for AWR were included in this study. Analysis of pre-operative multi-disciplinary team (MDT) planning, BTA administration, surgical procedure and outcomes was performed.

Results

During the 3-year-period, 45 patients underwent CCS in a standardised protocol with subsequent AWR, 4 were out of area referrals. The median age was 60, with a male:female of 2:3, median BMI was 32.1. Average hernia defect width was 8.7 cm. 23 patients underwent synthetic mesh repair and 20 had biosynthetic mesh repair. Anterior and posterior sheath closure was achieved in 84% of cases, with 36% avoiding the need for component separation. There were no complications following CCS, and the complication rate following AWR was 38%, including seroma (16%). Parastomal recurrence occurred in 2 patients.

Conclusions

The presented protocol of pre-operative BTA is a safe method of CCS. We demonstrate that its use reduces the need for extensive component dissection and is associated with good post-operative outcomes.
BHSo3 ‘Happy to close?’: the relationship between surgical experience and incisional hernia rates following abdominal wall closure in colorectal surgery
Authors: Smith Laurie , Coxon-Meggy Alexandra , Shinkwin Michael , Cornish Julie , Watkins Alan , Fegan Greg , Torkington Jared
Published: January 2025

Aim

Incisional Hernia (IH) is a common complication of colorectal surgery, affecting up to 30% of patients. There is an association between surgeon experience and outcomes in hernia surgery, yet little regarding impact of the surgeon performing abdominal wall closure (AWC) on IH rate.

We aimed to assess the rates of IH at 1 year following AWC between junior and senior surgeons in patients undergoing colorectal surgery.

Method

This is an exploratory analysis of patients who participated in the Hughes Abdominal Repair Trial (HART), a prospective, multicentre randomised control trial comparing AWC methods. Grade of surgeon performing AWC was categorised into ‘Trainee’ and ‘Consultant’ and compared to IH rate at 1 year.

Results

663 patients were included. The rate of IH in patients closed by trainees was 20%, compared to 12% in those closed by consultants (P = <0.001). Patients closed by trainees were more likely to have had rectal surgery. Patients closed by consultants were more likely to be younger and have a longer duration of surgery. On multivariate analysis, age, male sex and closure by a trainee were identified as risk factors for developing IH.

Conclusion

Patients who undergo AWC by a trainee have an increased risk of developing IH when compared to those closed by a consultant. Further work is needed to determine the impact of supervised and un-supervised trainees on IH rates. AWC should be regarded as a training opportunity in its own right, and closure time should be seen as training time, not coffee time.
BHSeP2 Light and heavy weight mesh comparison for incisional hernia repair
Authors: Sher Falak , Akbar Muhammad Bilal , Ahmad Muhammad Shabir , Imran Hafiz Muhammad
Published: January 2025

Introduction

Incisional hernia or surgical hernia is quite a common occurrence in large operative wounds.

Prosthetic mesh repair is imperative to tackle its high risk of recurrence. Conventional mesh (heavy weight) is considered thicker than is probably sufficient, with a volley of contradictory data regarding the outcomes of the light weight and the heavy weight mesh in incisional hernia repair.

Objective

To compare light and heavy weight mesh for foreign body sensation in the repair of incisional hernia.

Materials and methods

To proceed with this randomized controlled trial at the Surgical Unit III, Dept. ofSurgery, Lahore General Hospital, Lahore 260 patients based on inclusion criteria were selected from S-III ward. Then they were randomly and equally divided in two groups. Where group A was having light weight mesh (weight ≥35–<70 g/m2) repair and group B had a heavy weight mesh (≥140 g/m2) used in repair. At 7th post OP day, feeling of foreign body was noted. Then follow up for recurrence till 3 months.

Results

With light weight mesh feeling of foreign body was significantly low. (Light Weight Mesh: 14.6%vs. Heavy Weight Mesh: 36.9%, P-value = 0.000).

Conclusion

The lightweight meshes have benefits over the heavy weight mesh for incisional hernia repairs for having a reduced foreign body sensation.
BHSeP34 Reducing inappropriate hernia ultrasound requests: a quality improvement project
Authors: Hardy Kate , Lawden Emilia , Brown Joshua , Phillips Alexander
Published: January 2025

Introduction

The Royal College of Surgeons (RCS) Commissioning Guide states ‘diagnostic imaging should not be arranged at primary care level’ for suspected groin hernias. This quality improvement project aimed to evaluate the prevalence of inappropriate hernia ultrasound requests at Newcastle upon Tyne Hospitals NHS Foundation Trust (NUTH) and identify areas for improvement.

Methods

Data was collected from the PACS department for ultrasound (US) requests with 'hernia' in the indication or report from August to December 2023. Out of 251 requests from GP practices, 138 were relevant after excluding duplicates and non-hernia indications. Each patient’s notes were reviewed to determine the US report outcomes and subsequent clinical follow-up.

Results

Among the 138 US requests analysed, 95 confirmed hernias (47 small, 29 moderate, 19 large). Of these, 48 patients were referred to secondary care, with 33 seen in clinic and 24 undergoing surgery. The project identified a significant number of inappropriate scans based on RCS guidelines, resulting in an annual cost of £21 810 for 331 US slots.

Conclusions

Despite RCS guidelines, 331 US slots per year at NUTH were utilised for suspected hernias, incurring costs and delaying patient care. Direct referral to secondary care for clinically evident hernias could reduce costs, expedite treatment, and optimise US slot utilisation. These findings were presented at NUTH general surgery and radiology departmental meetings, with further presentations planned for local GP practices. The key recommendation is to educate GPs to refer patients with clinically evident hernias directly to secondary care, bypassing primary care imaging.
BHSeP37 Is routine clinic follow-up post-incisional hernia repair still needed, or should we transition to Patient Initiated Follow-Up ‘PIFU’?
Authors: Youssef Mark , Esa Abdelmonem , Hughes Belinda , Garg Yukti , Ebied Husam
Published: January 2025

Introduction

Patient Initiated Follow-Up (PIFU) pathway allows patients to control their follow-up care, enabling them to be seen quickly when necessary and avoiding the inconvenience of low clinical value appointments. This study reviews the outcomes of operatively managed incisional hernia cases and evaluates the first outpatient clinic outcomes to assess the suitability of PIFU for these cases.

Method

Retrospective data analysis was conducted for patients who underwent elective incisional hernia repair and were followed up as outpatients from January 2021 to May 2024. Data were collected on the type of surgical repair, postoperative complications and the outcome of the clinic review.

Results

49 cases were analysed (38 ventral hernias, 6 loin hernias post-nephrectomy, 2 parastomal hernias, and 3 combined ventral and parastomal hernias). The results showed that only 5 cases (10.2%) had a change in the management plan during the first outpatient clinic review (3 out of the 5 cases were the combined ventral and parastomal repairs). Management changes included arranging further follow-up, requesting a scan, or planning for another surgery. The median waiting time for the outpatient clinic review was 8 weeks. Additionally, 6 cases (12.2%) attended the emergency department with presentations such as pain, seroma, hematoma, and wound complications.

Conclusion

Considering that only 10.2% of the cases included in the study required change in the management plan during the first outpatient clinic appointment, PIFU pathway can be safely and effectively applied for these cases which will free up considerable capacity in outpatient service to reduce the care backlog.
The challenge of long-term stroke outcome prediction and how statistical correlates do not imply predictive value
Authors: Sperber Christoph , Gallucci Laura , Arnold Marcel , Umarova Roza M
Published: January 2025

Personalized prediction of stroke outcome using lesion imaging markers is still too imprecise to make a breakthrough in clinical practice. We performed a combined prediction and brain mapping study on topographic and connectomic lesion imaging data to evaluate (i) the relationship between lesion-deficit associations and their predictive value and (ii) the influence of time since stroke. In patients with first-ever ischaemic stroke, we first applied high-dimensional machine learning models on lesion topographies or structural disconnection data to model stroke severity (National Institutes of Health Stroke Scale 24 h/3 months) and functional outcome (modified Rankin Scale 3 months) in cross-validation. Second, we mapped the topographic and connectomic lesion impact on both clinical measures. We retrospectively included 685 patients [age 67.4 ± 15.1, National Institutes of Health Stroke Scale 24 h median(IQR) = 3(1; 6), modified Rankin Scale 3 months = 1(0; 2), National Institutes of Health Stroke Scale 3 months = 0(0; 2)]. Predictions for acute stroke severity (National Institutes of Health Stroke Scale 24 h) were better with topographic lesion imaging (R² = 0.41) than with disconnection data (R² = 0.29, P = 0.0015), whereas predictions at 3 months (National Institutes of Health Stroke Scale/modified Rankin Scale) were generally close to chance level. In the analysis of lesion-deficit associations, the correlates of more severe acute stroke (National Institutes of Health Stroke Scale 24 h > 4) and poor functional outcome (modified Rankin Scale 3 months ≥ 2) were left-lateralized. The lesion location impact of both variables corresponded in right-hemisphere stroke with peaks in primary motor regions, but it markedly differed in left-hemisphere stroke. Topographic and disconnection lesion features predict acute stroke severity better than the 3-months outcome. This suggests a likely higher impact of lesion-independent factors in the longer term and highlights challenges in the prediction of global functional outcome. Prediction and brain mapping diverge, and the existence of statistically significant associations—as here for 3-months outcomes—does not imply predictive value. Routine neurological scores better capture left- than right-hemispheric lesions, further complicating the challenge of outcome prediction.
Characterization of different clinical presentation of Merkel cell carcinomas and their potential prognostic implications
Authors: Lai Michela , Piana Simonetta , Brancaccio Gabriella , Briatico Giulia , Mirra Marica , Raucci Margherita , Ronchi Andrea , Zerbini Alessandro , Carone Chiara , Banzi Maria , Kaleci Shaniko , Argenziano Giuseppe , Longo Caterina
Published: January 2025

Background

Recent studies analyzed the impact of Merkel cell polyomavirus (MCPyV) on the prognosis of Merkel cell carcinoma (MCC) patients. No data on specific morphological clinical differences of MCPyV+ or MCPyV- are currently available neither on the possible prognostic implication of different clinical presentation of MCC.

Objectives

1) to describe clinicopathological characteristics of MCC patients and the prevalence of MCPyV infection in an Italian cohort of patients; 2) to define possible differences in clinicopathological and prognostic features among MCPyV+ and MCPyV- MCCs.

Methods

Retrospective, multicenter, cohort study conducted in two Italian tertiary referral centers. MCPyV presence was detected by immunohistochemistry (IHC) and PCR with two different primers amplifying VP1 (VP1-PCR) and LT viral region (LT-PCR). Clinicopathological features were compared between MCPyV+ and MCPyV- tumors and between red exophytic nodules and subcutaneous cyst-like MCCs.

Results

62 MCCs were included, presenting as red exophytic nodules (69.3%) or with a subcutaneous cyst-like appearance (19.3%); MCPyV was detected in 40.3% of cases by IHC, 56.4% by VP1-PCR and 79% by LT-PCR. No correlation was found between clinical morphology and viral status. Mortality rate was 40.8% for MCPyV- and 23.1% for MCPyV+ (p-value 0.239) and 69.8% for red nodules and 25% for cyst-like lesions (p-value 0.005). By multivariable analysis, age at diagnosis, ki67 and treatment with surgery/radiotherapy remained the only factors significantly affecting the OS.

Conclusions

This study highlights the potential impact of clinical morphology of MCCs on prognosis. Subcutaneous cyst-like morphology may provide a survival benefit to the patients, regardless the presence of MCPyV.
The symbolic dimensions of waterfront regeneration projects: inter-referencing, legitimating strategies and circulating practices in three Latin American megaprojects
Authors: Jajamovich Guillermo , Silvestre Gabriel , Duque Franco Isabel
Published: January 2025

This paper provides a comparative analysis of three symbolic dimensions of waterfront regeneration projects in Latin American cities: the inter-referencing practices alluded to in relation to projects from elsewhere, legitimating strategies that are discursively and materially constructed to present these projects as socially distributive, and subsequent approaches to leverage lessons from these experiences and re-circulate practices to other places. Following recent literature on urban megaprojects, policy mobility and inter-referencing we postulate that urban megaprojects production and legitimation involves material and symbolic, as well as territorial and relational processes, including the mobilisation of symbols, representations and images that generate consensus and mitigate criticism and resistance.
Kidney replacement therapies in the older person: challenges to decide the best option
Authors: Selwood Jessica , Dani Melanie , Corbett Richard , Brown Edwina A
Published: January 2025

A multitude of challenges exist when supporting older adults in deciding on the optimal kidney replacement therapy (KRT), including frailty, comorbidity, cognitive impairment, dialysis modality, as well as local availability of services. The combination of these factors can determine treatment outcomes and quality of life (QoL), and as such the care of older people should be tailored to take these into account. Frailty in older people with chronic kidney disease (CKD) leads to higher rates of hospitalization, increased mortality, and a diminished QoL, while cognitive impairment, present in up to 50% of people with CKD, exacerbates these challenges and affects decision making.

Dialysis, particularly haemodialysis, can accelerate physical and cognitive decline in frail older adults. Conversely, peritoneal dialysis (PD) presents a home-based alternative that may better support QoL, particularly for people wanting to prioritize treatment flexibility and independence. Assisted PD programmes have emerged as a valuable option for older people who cannot manage home-based care independently, improving access to KRT.

Ultimately shared decision making should be employed when discussing KRT, incorporating patient goals, prognostic awareness, and QoL measures. There is also the emerging role of the geriatrician and the need for an integrated Comprehensive Geriatric Assessment. These elements support older adults to make informed choices that align with the individuals’ values and health needs.

In designing future health services to meet the needs of increasing numbers of older people, there needs to be increased access to assisted PD as well as multidisciplinary working to ensure patient-focused care surrounding KRT in older adults.
Dragonfly larvae rearing: experimental insights and best practices
Authors: Bílková Eva , Kornová Veronika , Ožana Stanislav , Pyszko Petr , Schindlerová Hana , Chytilová Radana , Dolný Aleš
Published: January 2025

Understanding and optimizing rearing conditions for dragonfly larvae is crucial for ecological research and conservation efforts, yet optimal rearing conditions and general rearing practices are lacking. In this study, we investigated the effect of temperature, amount of oxygen in water, presence of (artificial) plants, and age of eggs on hatchability, survival, and development of dragonfly larvae using the model species Sympetrum striolatum. We conducted three independent experiments and assessed variability between egg clutches of individual females, as well as the occurrence of cannibalism among larvae. Our results showed that egg hatchability varied significantly between individual females and was negatively affected by egg aging and the presence of artificial plants. Larval survival was negatively affected by water temperatures above 24°C, the presence of artificial plants, and egg aging, and positively affected by high feeding frequency, in certain instars. Notably, cannibalism was observed among later instar larvae, especially under higher density conditions. Based on these findings, we provide practical recommendations for optimizing dragonfly larvae rearing protocols, emphasizing the importance of maintaining optimal temperature, appropriate feeding regimes, and managing larval density to reduce cannibalism. This study offers experimental, evidence-based guidelines for dragonfly larvae rearing, contributing to improved research methodologies and conservation efforts.
Sinus arrest and syncope in a young patient with Epstein–Barr virus infection: a case report
Authors: Sarto Gianmarco , Simeone Beatrice , Bernardi Marco , Frati Giacomo , Sciarretta Sebastiano
Published: January 2025

Background

Emerging evidence suggests a potential link between Epstein–Barr virus (EBV) infection and cardiovascular diseases. However, the impact of EBV infection on the development of arrhythmias and conduction abnormalities remains to be fully clarified.

Case summary

We present a case report of a healthy 38-year-old Caucasian male who underwent an occupational medicine visit, during which a resting electrocardiogram (ECG) showed numerous premature ventricular contractions. He was later prescribed a stress test. During the test, he experienced a sinus arrest of 6.5 seconds with true syncope during the recovery phase. EBV infection was the only concomitant pathological finding observed during subsequent diagnostic investigations. Initially, it was necessary to rule out all possible cardiac causes of the event, especially in such a young patient. Comprehensive cardiac evaluations, including ECG, echocardiography, cardiac computed tomography, cardiac magnetic resonance, and electrophysiological studies, were normal. After 2 months, both the resting ECG and stress test were completely normal. The final diagnosis for the patient was ‘reflex cardioinhibitory syncope’. Accordingly, a pacemaker (PMK) device was not implanted, as the patient was under 40 years old and had no history of recurrent syncope, in accordance with European Guidelines.

Discussion

Temporary conditions that may cause conduction abnormalities are a contraindication to PMK implantation. Therefore, it is crucial to always consider EBV infection in the differential diagnosis of cardiac conduction disorders. One hypothesis is that EBV may have specifically affected the sinoatrial node and a few right ventricular outflow tract cells without causing myocarditis signs.
Transcatheter aortic valve replacement for left ventricular assist device-related aortic regurgitation and prohibitive surgical risk: a case report
Authors: Barragán-Amado Andrés F , Manzur Barbur María , Holguín Diego , Obando Carlos , Rodríguez-González María J
Published: January 2025

Background

Aortic regurgitation (AR) is a prevalent complication following left ventricular assist device (LVAD) implantation, which elevates the risk of mortality. Prompt recognition and intervention are crucial to mitigate this risk.

Case summary

A 52-year-old male with severe left ventricular dysfunction secondary to Chagas cardiomyopathy and severe pulmonary hypertension underwent implantation of a HeartMate 3 device as a bridge to transplant candidacy. Post-implantation, he developed progressive AR and a decline in overall health, characterized by right ventricular dysfunction, worsening mitral regurgitation, and elevated pulmonary pressures. Given the very high surgical risk, transcatheter aortic valve replacement was successfully performed, yielding excellent outcomes, including normalization of right ventricular function, reduction in pulmonary pressures, and a decrease in mitral regurgitation.

Discussion

Aortic regurgitation is a progressive complication in patients with continuous flow-LVAD, limits effective blood flow, and can lead to severe outcomes like biventricular failure, high rates of hospitalization, and mortality. Managing AR is challenging, often requiring percutaneous interventions due to high surgical risks. Treatment choices depend on centre expertise and patient specifics.
Enhancing gamma-aminobutyric acid (GABA) synthesis from defatted rice bran extract by lactobacillus brevis VTCC-B397: technical parameters analysis
Authors: Lai Quoc Dat , Doan Ngoc Thuc Trinh , Nguyen Thi Hien
Published: January 2025

Gamma aminobutyric acid (GABA) is a biologically active compound that has attracted significant attention in recent years due to its beneficial effects on the nervous system and its role in brain synthesis processes. GABA is widely produced by fermentation method, and its microbial biosynthesis can be improved by adjusting operational parameters and supplementing nutrients during fermentation. However, the optimal fermentation conditions for GABA production vary depending on raw materials and microbial strain used. Rice bran is known as a low-cost and nutritious raw material, capable of producing greater GABA content than other substrates. This study aimed to enhance GABA production from rice bran slurry fermented by Lactobacillus brevis VTCC-B397 by adjusting fermentation conditions, including temperature (25–37 °C), pH (3.0–6.0), monosodium glutamate (MSG) concentration (0–1 M) and fermented time (0–72 hours). The effects of these factors on bacterial cell density and GABA content were assessed over the fermentation period. Furthermore, response surface methodology (RSM) was applied to optimize the medium and fermentation parameters, as well as to investigate the interactions between factors that influence the fermentation process. The biosynthesis pathway of GABA was considerably impacted by temperature, pH and MSG content. The optimal conditions for GABA production from defatted rice bran solution was found to be 0.56 M MSG, 34 °C and pH 5.12. Under optimized conditions, the highest GABA yield achieved was 7.69 g/L.
CD209d/e promotes inflammation and lung injury during influenza virus infection
Authors: Gopal Radha , Marinelli Michael A , Rago Flavia , Richwalls Lacee J , Constantinesco Nicholas J , Debnath Deepa , Kupul Saran , Garcia-Hernandez Maria de la Luz , Rangel-Moreno Javier , Kolls Jay K , Alcorn John F
Published: January 2025

Influenza virus infects millions each year, contributing greatly to human morbidity and mortality. Upon viral infection, pathogen-associated molecular patterns activate pattern recognition receptors on host cells, triggering an immune response. The CD209 protein family, homologs of DC-SIGN (dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin), is thought to modulate immune responses to viruses. The effects of the mouse functional DC-SIGN homolog CD209d/e on the lung immune responses during influenza viral infection are not known. Therefore, we generated mice that lack both CD209d and e isoforms to determine the role in influenza viral infection. We infected wild-type and CD209d/e gene–deficient (CD209d/e−/−) mice with influenza virus and measured the cellular response in bronchoalveolar lavage, the expression of proinflammatory cytokines, antiviral genes, toll-like receptors (TLRs) in the lung, and lung pathology. We found CD209d/e−/− mice had decreased viral burden, TLR3 and TLR9 expression, interferon response, macrophages in bronchoalveolar lavage, and parenchymal lung inflammation compared with control mice. We also found less influenza viral uptake in alveolar macrophages and bone marrow–derived macrophages isolated from CD209d/e−/− mice when compared with control mice. We further investigated the role CD209d/e by treating bone marrow–derived macrophages from control and CD209d/e−/− mice with TLR agonists. We found that lacking CD209d/e decreased the expression of TLR3, TLR9, RIG1, STAT1, and STAT2 compared with controls. Collectively these results show that CD209d/e plays an important role in viral sensing/uptake and inflammatory immune responses during influenza viral infection.
Beneficial effects on T cells by photodynamic therapy with talaporfin enhance cancer immunotherapy
Authors: Ezzaldeen Ehab M , Yaguchi Tomonori , Imagawa Ryotaro , Soltan Mohamed A , Hirata Akira , Murakami Kosaku , Tsukamoto Hirotake , Muto Manabu , Honjo Tasuku , Chamoto Kenji
Published: January 2025

Photodynamic therapy (PDT), a local cancer treatment using photosensitizers, has been reported to enhance antitumor immune responses by inducing immunogenic cell death. Although several studies have demonstrated the synergistic antitumor effects of PDT and immune checkpoint blockage (ICB), the detailed underlying mechanisms remain poorly understood. In this study, we investigated the immunological effects of PDT with talaporfin (Tal-PDT), a clinically approved photosensitizer, using bilateral tumor-bearing mouse models. Treatment with Tal-PDT on the tumor on one side of the mouse resulted in tumor growth inhibition on the untreated opposite side. This phenomenon, accompanied by tumor antigen-specific immune reactions, is indicative of an abscopal effect. When combined with anti PD-L1 antibody, synergistic antitumor effects were observed on both the laser-treated and untreated sides. Mechanistically, Tal-PDT enhanced the induction of XCR-1+ dendritic cells in the proximal draining lymph node likely through the induction of ferroptosis in tumor cells. This, in turn, led to the systemic generation of precursor-exhausted CD8+ T cells. Moreover, talaporfin was selectively incorporated into tumor cells rather than into tumor-infiltrating T cells in vivo, leading to targeted tumor killing while preserving T cells. These beneficial effects of Tal-PDT on antitumor immunity collectively enhance ICB cancer immunotherapy. Our study demonstrates the potential of combining Tal-PDT with ICB therapy for clinical applications.
Could the Artist Not Be Wrong? A Critical Notice of Sherri Irvin's Immaterial: The Rules of Contemporary Art (Oxford: Oxford University Press, 2022)
Authors: Costello Diarmuid
Published: January 2025

This article is a critical notice of Sherri Irvin’s Immaterial: Rules in Contemporary Art (2022). After introducing Irvin’s project, notably how she understands the role of “custom rules” for the display and conservation of, and participation in, works of contemporary art, I focus on two case studies that motivate her argument: Jan Dibbets’ work, All shadows that occurred to me (1969) and Sarah Sze’s Migrateurs (1997). According to Irvin, both works require the participation of museum conservators not merely for their preservation, but also realization. Granting the latter, I consider its implications. Prior to the involvement of conservators the works in question appear indeterminate in crucial respects. The conservators’ role is to seek enough clarity about various rules governing the work to afford future installations of the work without consulting the artist. But both case studies reveal considerable artistic whimsy when it comes to abiding by the rules supposedly underwriting these works’ identity, raising worries for their persistence over time. Given their constitutive role, I consider whether there is room, on Irvin’s account, for the conservators to be right and the artist wrong about the nature of the works in question.
Population pharmacokinetic analysis of teicoplanin in paediatric patients, including those receiving continuous kidney replacement therapy: a prospective cohort study
Authors: Butragueño-Laiseca Laura , García-Orueta Gastón , Riva Natalia , Trocóniz Iñaki F , Fernández Sarah N , Camacho Vicente Verónica , Padilla Belén , Slöcker María , Santiago María José
Published: January 2025

Objectives

Teicoplanin is a commonly used antibiotic in critically ill children. However, teicoplanin dosing is often inaccurate, especially in children undergoing continuous kidney replacement therapy (CKRT). This study aims to develop a population pharmacokinetic (PK) model to optimize teicoplanin dosing in critically ill children, including those on CKRT.

Methods

Data from 26 critically ill children (12 with CKRT) receiving the standard dosing regimen were analysed. In total, 172 teicoplanin concentration measurements from plasma, pre- and post-filter ports were modelled simultaneously using NONMEM 7.4. Simulations were conducted to assess the target attainment (Cmin = 10 mg/L and AUC24/MIC > 800 h) of the current standard dosing regimen and of different alternative dosing regimens.

Results

A two-compartment model was selected. Weight significantly affected renal clearance and volume of distribution of the central compartment, while filter surface area affected haemofilter clearance. Only 16 patients (59%) achieved a Cmin of >10 mg/L with the standard dosing regimen, and only 1 achieved the target AUC/MIC. Based on simulation results, 3 × 15 mg/kg q12h + 10 mg/kg q24h (CKRT) and 3 × 15 mg/kg q12h + 15 mg/kg q24h (no CKRT) could be better alternative regimens.

Conclusions

This population model is a good proof of concept to develop modelling approaches that could help in an individualized dosing approach that needs to be adopted in critically ill paediatric patients. The standard paediatric dosage for teicoplanin could be insufficient for optimal exposure, and higher doses may benefit both CKRT and non-CKRT patients.
P02 Exploring medical students’ knowledge, attitudes, and motivation towards antimicrobial resistance efforts in Eastern Uganda
Authors: Babuya Jonathan , Waruingi Daniel , Mungujakisa Douglas , Ahimbisibwe Osmas , Ruth Kako Victoria , Aporu Faith , Mugume Emmanuel , Nyamupachitu Julian , Kiyimba Kennedy
Published: January 2025

Objectives

To assess knowledge, attitudes, and key motivational drivers influencing medical students’ participation in antimicrobial resistance (AMR)-related extracurricular initiatives at Busitema University, Uganda.

Methods

A descriptive cross-sectional study was conducted among 193 undergraduate students. A semi-structured, pre-tested questionnaire was used to assess knowledge, attitudes, and motivations. Bloom cut-off method was used to evaluate knowledge, and χ2 and multivariate regression analyses were employed to identify engagement factors.

Results

Overall, 71.5% of students had sufficient knowledge of AMR. Ninety percent supported integrating AMR into curricula, and 87.5% favoured a One Health Approach to training. Peer influence, university support and mentorship were top motivators for AMR club engagement. Male students and those in higher academic years were more engaged. Sufficient AMR knowledge was strongly associated with extracurricular involvement.

Conclusions

Medical students demonstrated good knowledge and positive attitudes toward AMR, but deeper training is needed. Extracurricular activities play a pivotal role in motivating engagement. Embedding AMR and antimicrobial stewardship into curricula, along with peer mentorship, is critical for preparing future healthcare professionals to combat AMR.
P10 Development of a database to enable real time efficient recording of antimicrobial ward round stewardship interventions and support ongoing measurement of antimicrobial stewardship improvement
Authors: Rodger Rachael , Kinnaird Fiona , White Beth , Downie Karen
Published: January 2025

Background

Antimicrobial stewardship (AS) initiatives are crucial in the fight against antimicrobial resistance (AMR).1 Using quality improvement (QI) methodology we can adapt our AS initiatives to meet the demands of the complex healthcare environment.2 To determine if our AS initiatives are effective, we need to measure if improvement has occurred, but this can be time consuming and challenging in the acute hospital setting. Antimicrobial consumption is often used as an indicator measure of AS, however, using technology we can develop more reliable and specific measures of AS and patient-centred care improvement.3 An infectious diseases (ID) physician and antimicrobial pharmacist (AMP) ward round (AWR) service was recently introduced to the Royal Alexandra Hospital. To enable measurement of the impact of this service on AS within the hospital it was decided to develop an antimicrobial ward round (AWR) database.

Objectives

To develop a database to enable real time efficient data collection of AWR outcomes and AS interventions to enable more accurate measurement of AS improvement.

Methods

The AMP, data analyst and ID physician worked collectively to co-design the format of the database using an Access® system. Outcome definitions4 and AS intervention definitions were agreed and standardized. The database was piloted over a two month period with continuous feedback and adjustments to improve ease and efficiency of data input. The updated database was then used to collect outcome and AS interventions from over 200 AWR consultations. This data was compiled and used to measure AS improvement following introduction of the AWR service.

Results

The database enabled efficient real time data collection and a more accurate and standardized approach to AS data collection and report generation. Using the database we have been able to show that the introduction of AWR consultations (n=204) resulted in reduced antibiotic exposure (IVOST, de-escalated, stopped) in 46% of patients. Although 39% of consultations did not result in a change in antimicrobial therapy, a number of AS interventions to improve AS, patient safety and patient care, were actioned during these consultations. The most commonly recorded interventions were ongoing infection management advice, antimicrobial course length confirmation/advice and patient counselling and monitoring advice. Using the AWR database we were also able to calculate the total proportion of IV antimicrobial therapy prescribed pre (83%) and post (54%) consultation highlighting improved IV to oral switch (IVOST).

Conclusions

Development of the database has supported more timely data collection, measurement and feedback of the impact of the AWR service on AS and patient-centred care. This is important in supporting a continuous QI approach to AS and patient-centred care in the acute hospital setting.
VIEWER: an extensible visual analytics framework for enhancing mental healthcare
Authors: Wang Tao , Codling David , Msosa Yamiko Joseph , Broadbent Matthew , Kornblum Daisy , Polling Catherine , Searle Thomas , Delaney-Pope Claire , Arroyo Barbara , MacLellan Stuart , Keddie Zoe , Docherty Mary , Roberts Angus , Stewart Robert , McGuire Philip , Dobson Richard , Harland Robert
Published: January 2025

Objective

A proof-of-concept study aimed at designing and implementing Visual & Interactive Engagement With Electronic Records (VIEWER), a versatile toolkit for visual analytics of clinical data, and systematically evaluating its effectiveness across various clinical applications while gathering feedback for iterative improvements.

Materials and Methods

VIEWER is an open-source and extensible toolkit that employs natural language processing and interactive visualization techniques to facilitate the rapid design, development, and deployment of clinical information retrieval, analysis, and visualization at the point of care. Through an iterative and collaborative participatory design approach, VIEWER was designed and implemented in one of the United Kingdom’s largest National Health Services mental health Trusts, where its clinical utility and effectiveness were assessed using both quantitative and qualitative methods.

Results

VIEWER provides interactive, problem-focused, and comprehensive views of longitudinal patient data (n = 409 870) from a combination of structured clinical data and unstructured clinical notes. Despite a relatively short adoption period and users’ initial unfamiliarity, VIEWER significantly improved performance and task completion speed compared to the standard clinical information system. More than 1000 users and partners in the hospital tested and used VIEWER, reporting high satisfaction and expressed strong interest in incorporating VIEWER into their daily practice.

Discussion

VIEWER provides a cost-effective enhancement to the functionalities of standard clinical information systems, with evaluation offering valuable feedback for future improvements.

Conclusion

VIEWER was developed to improve data accessibility and representation across various aspects of healthcare delivery, including population health management and patient monitoring. The deployment of VIEWER highlights the benefits of collaborative refinement in optimizing health informatics solutions for enhanced patient care.
Memory-like NK cell differentiation, inhibitory NKG2A blockade, and improved recognition via antibody or CAR engineering combine to enhance NK cell attack against multiple myeloma
Authors: Zhou Alice Y , Marin Nancy D , Afrin Sadia , Wong Pamela , Tran Jennifer , Jacobs Miriam T , Becker-Hapak Michelle , Marsala Lynne , Foster Mark , Foltz Jennifer A , Neal Carly C , Russler-Germain David A , Morina Lyra , Paik Yeeun , Cubitt Celia C , Schappe Timothy , Pence Patrick , McClain Ethan , Kelley Sarah , Fortier Julie , Fiala Mark , Slade Michael , Schroeder Mark , Stockerl-Goldstein Keith , Vij Ravi , Gao Feng , Berrien-Elliott Melissa M , Fehniger Todd A
Published: January 2025

Natural killer (NK) cells are a promising approach for cellular cancer immunotherapy and are being investigated to treat patients with multiple myeloma (MM). We found that MM patient blood NK cell frequencies were normal with increased activating receptors and cytotoxic granules, without evidence of functional exhaustion. Despite this activated state, MM target cells were resistant to conventional NK cells by unclear mechanisms. Memory-like (ML) NK cells are generated after brief activation via the interleukin (IL)-12, IL-15, and IL-18 receptors and exhibit multiple enhanced antitumor properties. ML NK cell differentiation improved healthy donor and MM patient NK cell responses against MM target cells, in vitro and in vivo in immunodeficient murine xenograft models. Moreover, incorporating NKG2A checkpoint blockade to overcome HLA-E–induced inhibition further enhanced ML NK cell responses against MM in vitro and in vivo. Because activating receptor recognition of MM by ML NK cells was inadequate, strategies to improve this were investigated. Utilizing anti-SLAMF7 monoclonal antibody (elotuzumab) or anti-BCMA chimeric antigen receptors resulted in robust increases in ML NK cell functional responses against MM. In summary, ML differentiation enhances NK cell attack against myeloma, and combination with approaches to block inhibitory checkpoints and promote MM-specific activation are promising translational NK cell strategies for MM immunotherapy.