bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potential Therapeutic drug Targets for Hypertension Identified using Proteomics and Mendelian Randomization
Authors: Pan Wei , Huang Daoxin , Lin Chunjin , Huang Haozhang , Chen Qing , Wang Liman , Li Min , Yu Huizhen 
Published: January 2025

Abstract

Background
Hypertension (HT) is the most prevalent risk factor for cardiovascular disease (CVD) worldwide. Despite being a highly heritable trait, the underlying mechanisms of HT remain elusive due to its complex genetic architecture. Discovering disease-associated proteins with causal genetic evidence offers a potential strategy for identifying therapeutic targets for HT.

Methods
We analyzed the plasma proteome of 4,657 plasma proteins from 7,213 European American (EA) participants in the ARIC study. Genome-wide association study (GWAS) data for HT were sourced from FinnGen R10, which includes 102,864 cases and 289,117 controls. Cis-Mendelian randomization (MR) was conducted to assess the causal effect of circulating proteins on the risk of HT. A multiverse sensitivity analysis was performed to evaluate the robustness of these causal relationships. Colocalization analysis was conducted to determine whether these features share the same associated single nucleotide polymorphisms (SNPs). The causal effects of HT-associated proteins were then validated using cis-protein quantitative trait loci (Cis-pQTL) genetic instruments from the deCODE database.

Results
Among 1,788 proteins, genetically predicted levels of 18 plasma proteins were associated with HT in the discovery stage. Seven of these proteins showed strong support for colocalization. After replication, only ERAP1 and ACVRL1 were validated as therapeutic candidates for HT, demonstrating a negative correlation with the risk of HT.

Conclusions
By combining cis-MR analysis with colocalization analysis, we identified ERAP1 and ACVRL1 as potential targets for interventions in the primary prevention of HT, with ERAP1 emerging as a particularly promising drug target after further validation.
Ceftobiprole: A therapeutic update
Authors: Hitt Emily M , Bowers Dana R 
Published: January 2025

Abstract

Purpose
The purpose of this therapy update is to highlight new clinical studies comparing ceftobiprole to current therapies and provide evidence for its suggested role in therapeutic management of selected infectious diseases.

Summary
Antimicrobial resistance continues to be a global health problem, and newer targeted antimicrobials are necessary to combat increasing rates of problematic infections. More specifically, targeted antimicrobials against methicillin-resistant Staphylococcus aureus are needed. Ceftobiprole has been marketed internationally for the treatment of complicated skin and skin structure infections, community-acquired pneumonia, and hospital-acquired pneumonia. While Food and Drug Administration approval was previously pursued for its use in acute bacterial skin and skin structure infections in the US, the Food and Drug Administration issued a complete response letter determining that study data were unreliable and recommended completion of additional studies. In April 2024, ceftobiprole was granted approval for 3 indications in the US based on updated clinical study data. Ceftobiprole is the second fifth-generation cephalosporin to be developed and approved for clinical use.

Conclusion
Ceftobiprole has been shown to be safe and effective in treating specific infectious diseases such as bloodstream infections, acute bacterial skin and skin structure infections, and community-acquired bacterial pneumonia. Its use should be considered when targeting infections caused by methicillin-resistant S. aureus where other therapeutic options may be limited. However, additional real-world data on the efficacy of ceftobiprole should be continually monitored as experience in the US increases.
Development of a highly sensitive method to detect translational infidelity
Authors: Hartmann Max , Neher Lisa , Grupp Benjamin , Cao Zhouli , Chiew Chloe , Iben Sebastian 
Published: January 2025

Abstract
Protein homeostasis (proteostasis) is the balance of protein synthesis, protein maintenance, and degradation. Loss of proteostasis contributes to the aging process and characterizes neurodegenerative diseases. It is well established that the processes of protein maintenance and degradation are declining with aging; however, the contribution of a declining quality of protein synthesis to the loss of proteostasis is less well understood. In fact, protein synthesis at the ribosome is an error-prone process and challenges the cell with misfolded proteins. Here, we present the development of a highly sensitive and reproducible reporter assay for the detection of translational errors and the measurement of translational fidelity. Using Nano-luciferase, an enzyme 3 times smaller and 50 times more sensitive than the hitherto used Firefly-luciferase, we introduced stop-codon and amino-acid exchanges that inactivate the enzyme. Erroneous re-activation of luciferase activity indicates ribosomal inaccuracy and translational infidelity. This highly sensitive and reproducible method has broad applications for studying the molecular mechanisms underlying diseases associated with defective protein synthesis and can be used for drug screening to modulate translational fidelity.
Composite likelihood inference for space-time point processes
Authors: Jalilian Abdollah , Cuevas-Pacheco Francisco , Xu Ganggang , Waagepetersen Rasmus 
Published: January 2025

ABSTRACT
The dynamics of a rain forest is extremely complex involving births, deaths, and growth of trees with complex interactions between trees, animals, climate, and environment. We consider the patterns of recruits (new trees) and dead trees between rain forest censuses. For a current census, we specify regression models for the conditional intensity of recruits and the conditional probabilities of death given the current trees and spatial covariates. We estimate regression parameters using conditional composite likelihood functions that only involve the conditional first order properties of the data. When constructing assumption lean estimators of covariance matrices of parameter estimates, we only need mild assumptions of decaying conditional correlations in space, while assumptions regarding correlations over time are avoided by exploiting conditional centering of composite likelihood score functions. Time series of point patterns from rain forest censuses are quite short, while each point pattern covers a fairly big spatial region. To obtain asymptotic results, we therefore use a central limit theorem for the fixed timespan—increasing spatial domain asymptotic setting. This also allows us to handle the challenge of using stochastic covariates constructed from past point patterns. Conveniently, it suffices to impose weak dependence assumptions on the innovations of the space-time process. We investigate the proposed methodology by simulation studies and an application to rain forest data.
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

Abstract

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 &gt; 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 &lt; 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

Abstract

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

Abstract
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

Abstract

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

Abstract

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 = &lt;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

Abstract

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–&lt;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

Abstract

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

Abstract

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.