KRAS inhibitors: resistance drivers and combinatorial strategies.

In 1982, the RAS genes HRAS and KRAS were discovered as the first human cancer genes, with KRAS later identified as one of the most frequently mutated oncogenes. Yet, it took nearly 40 years to develop clinically effective inhibitors for RAS-mutant cancers. The discovery in 2013 by Shokat and colleagues of a druggable pocket in KRAS paved the way to FDA approval of the first covalently binding KRAS inhibitors, sotorasib and adagrasib, in 2021 and 2022, respectively.

Objective and Automated Facial Palsy Grading and Outcome Assessment After Facial Palsy Reanimation Surgery - A Prospective Observational Study.

Background: Facial palsy (FP) is a widespread condition affecting over 3 million people annually, with a complex etiology requiring tailored, multidisciplinary management. Despite advancements, there remains a lack of reliable, automated tools for objective pre- and postoperative assessment, limiting progress in treatment optimization. This study introduces the AI Research Metrics Model (CAARISMA ® ARMM) to evaluate FP severity and outcomes following microsurgical gracilis muscle transfer.

Expression of claudin-18.2 in cholangiocarcinoma: a comprehensive immunohistochemical analysis from a German tertiary centre.

Aims: Anti-claudin-18.2 (CLDN18.2) therapy was recently approved for the treatment of gastric or gastro-oesophageal junction adenocarcinoma.

Mesenchymal stromal cells reduce inflammation and improve lung function in a mouse model of cystic fibrosis lung disease.

Mesenchymal stromal cells (MSCs) are multipotent adult stem cells which possess immunomodulatory and repair capabilities. In this study, we investigated whether MSC therapy could modulate inflammation and lung damage in the lungs of Scnn1b-transgenic mice overexpressing the β-subunit of the epithelial sodium channel (β-ENaC), a model with features of Cystic Fibrosis lung disease. Human bone marrow derived MSC cells were intravenously delivered to mice, prior to collection of bronchoalveolar lavage (BALF) and tissue.

Automated 24-sector grid-map algorithm for prostate mpMRI improves precision and efficacy of prostate lesion location reporting.

Background: The Prostate Imaging-Reporting and Data System (PI-RADS) calls for reporting the prostate index lesion and the location within the transition (TZ) or peripheral zone (PZ) and location on a corresponding sector map. The aim of this study was to train a deep learning DL-based algorithm for automatic prostate sector mapping and to validate its' performance.

Methods: An automatic 24-sector grid-map (ASG) of the prostate was developed, based on an automatic zone-specific deep learning segmentation of the prostate.

Klebsiella pneumoniae Glycoconjugate Vaccine Leads Based on Semi-Synthetic O1 and O2ac Antigens.

Klebsiella pneumoniae (KP) is a common opportunistic pathogen that emerged as a new critical threat to human health, due to its hypervirulence and widespread resistance against many antibiotics, including carbapenems. Alternative intervention strategies such as vaccines are not available.  Cell-surface lipopolysaccharides (LPS) and capsular polysaccharides (CPS) are attractive targets for vaccine development.

A stratified treatment algorithm in psychiatry: a program on stratified pharmacogenomics in severe mental illness (Psych-STRATA): concept, objectives and methodologies of a multidisciplinary project funded by Horizon Europe.

Schizophrenia (SCZ), bipolar (BD) and major depression disorder (MDD) are severe psychiatric disorders that are challenging to treat, often leading to treatment resistance (TR). It is crucial to develop effective methods to identify and treat patients at risk of TR at an early stage in a personalized manner, considering their biological basis, their clinical and psychosocial characteristics. Effective translation of theoretical knowledge into clinical practice is essential for achieving this goal.

First Clinical Application of Aztreonam-Avibactam in Treating Carbapenem-Resistant Enterobacterales: Insights from Therapeutic Drug Monitoring and Pharmacokinetic Simulations.

: A novel fixed combination of aztreonam (ATM) and avibactam (AVI) offers promising potential to treat infections with carbapenem-resistant (CRE) producing metallo-β-lactamases (MBL). This study aimed to assess the accuracy of population pharmacokinetic (PK) models for ATM-AVI in predicting in vivo concentrations in a critically ill patient with CRE infection during its first clinical use. : A 70-year-old male with septic shock due to hospital-acquired pneumonia (HAP) caused by MBL-producing was treated with ATM-AVI.

Tunnel Technique in Bone Augmentation Procedures for Dental Implant Rehabilitation: A Systematic Review.

: This systematic review aimed to compare the tunnel technique for pre-implant bone regeneration with traditional flap techniques also involving a crestal incision, in terms of procedure success, graft healing, postoperative course, patient satisfaction, and implant follow-up. : A systematic search was conducted on MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials following PRISMA guidelines, searching for comparative prospective and retrospective studies in English, published between January 2002 and April 2024. The population of interest consisted of patients with edentulous ridge atrophy requiring pre-implant bone regeneration.

Development of a Tablet-Based Outpatient Care Application for People With Dementia: Interview and Workshop Study.

Background: Dementia management presents a significant challenge for individuals affected by dementia, as well as their families, caregivers, and health care providers. Digital applications may support those living with dementia; however only a few dementia-friendly applications exist.

Objective: This paper emphasizes the necessity of considering multiple perspectives to ensure the high-quality development of supportive health care applications.

Prediction of Central Post-Stroke Pain by Quantitative Sensory Testing.

Objective: Among patients with acute stroke, we aimed to identify those who will later develop central post-stroke pain (CPSP) versus those who will not (non-pain sensory stroke [NPSS]) by assessing potential differences in somatosensory profile patterns and evaluating their potential as predictors of CPSP.

Methods: In a prospective longitudinal study on 75 acute stroke patients with somatosensory symptoms, we performed quantitative somatosensory testing (QST) in the acute/subacute phase (within 10 days) and on follow-up visits for 12 months. Based on previous QST studies, we hypothesized that QST values of cold detection threshold (CDT) and dynamic mechanical allodynia (DMA) would differ between CPSP and NPSS patients before the onset of pain.

Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence.

Background: Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.

European biologic training course for type 2 inflammation by EUFOREA in 2024: key facts and lessons learned.

The European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized the first European Biologic Training Course (EBTC) in Brussels on 1st March 2024. The aim of this hybrid EBTC including both face-to-face and web-based participation was to address the educational needs of physicians dealing with asthma and Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) on the clinically relevant aspects of diagnosing and treatment with biologics. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic respiratory diseases through the implementation of optimal patient care via educational, research, and advocacy activities.

Depression and health literacy among adolescents and adults in Germany: findings from two representative samples.

Introduction: Depressive disorders constitute a significant public health challenge. Health literacy might be an important factor to consider in prevention strategies for depressive disorders, which is why this study aimed at exploring the association between depressive symptom levels and severity and health literacy, along with additional sociodemographic factors.

Materials And Methods: Data were collected from two large samples of adults ( = 3,011) and adolescents ( = 1,021) representative of the German-speaking population in Germany.

Seroprevalence of spp. and Rift Valley fever virus infections in communal pastoral cattle at the wildlife-livestock interface, Zambezi region, Namibia.

Introduction: Brucellosis and Rift Valley fever (RVF) are neglected zoonotic diseases (NZD) that threaten public health, animal health, and production in resource-limited countries including Namibia.

Methods: The objective of this cross-sectional study was to determine spp. and RVFV seroprevalence in cattle at the wildlife-livestock interface in the Kabbe South constituency (Zambezi region) of Namibia.

The association between different timeframes of air pollution exposure and COVID-19 incidence, morbidity and mortality in German counties in 2020.

Background: Ambient air pollution is a known risk factor for several chronic health conditions, including pulmonary dysfunction. In recent years, studies have shown a positive association between exposure to air pollutants and the incidence, morbidity, and mortality of a COVID-19 infection, however the time period for which air pollution exposure is most relevant for the COVID-19 outcome is still not defined. The aim of this study was to analyze the difference in association when varying the time period of air pollution exposure considered on COVID-19 infection within the same cohort during the first wave of the pandemic in 2020.

High-resolution DNA methylation changes reveal biomarkers of heart failure with preserved ejection fraction versus reduced ejection fraction.

Novel biomarkers are needed to better identify-and distinguish-heart failure with preserved ejection fraction (HFpEF) from other clinical phenotypes. The goal of our study was to identify epigenetic-sensitive biomarkers useful to a more accurate diagnosis of HFpEF. We performed a network-oriented genome-wide DNA methylation study of circulating CD4 T lymphocytes isolated from peripheral blood using reduced representation bisulfite sequencing (RRBS) in two cohorts (i.

Negative valence in Obsessive-Compulsive Disorder: A worldwide mega-analysis of task-based functional neuroimaging data of the ENIGMA-OCD consortium.

Objective: Obsessive-compulsive disorder (OCD) is associated with altered brain function related to processing of negative emotions. To investigate neural correlates of negative valence in OCD, we pooled fMRI data of 633 individuals with OCD and 453 healthy controls from 16 studies using different negatively-valenced tasks across the ENIGMA-OCD Working-Group.

Methods: Participant data were processed uniformly using HALFpipe, to extract voxelwise participant-level statistical images of one common first-level contrast: negative vs.

Predicting cisplatin tolerability in older adults with head and neck cancer - Insights for improved chemoradiation outcomes.

Purpose: Cumulative cisplatin doses of ≥ 200 mg/m improve survival in adults with head-and-neck squamous cell carcinoma (HNSCC) undergoing chemoradiation, but many older adults with HNSCC cannot receive this prognostically relevant dose due to toxicities. This study aims to develop predictive models to assess the likelihood of older adults with HNSCC receiving ≥ 200 mg/m cisplatin during chemoradiation.

Methods: 366 patients from the SENIOR database, an international cohort of adults ≥ 65 years with HNSCC, received definitive chemoradiation with single-agent cisplatin and were analyzed.

Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines.

Over the past two decades, guidelines for the on-demand treatment of hereditary angioedema (HAE) attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly.

Neuropsychiatric manifestations of sarcoidosis.

Background: There has been significant progress in understanding neurosarcoidosis (NS) as a distinct disorder, which encompasses a heterogeneous group of clinical and radiological alterations which can affect patients with systemic sarcoidosis or manifest isolated.

Rationale And Aim Of The Study: The healthcare challenges posed by NS and sarcoidosis in general extend beyond their physical symptoms and can include a variety of psychosocial factors, therefore the recognition of main neuropsychiatric symptoms can be useful to approach patients with NS. Methods: For this purpose, databases such as Pubmed, Medline and Pubmed Central (PMC) have been searched.

Practical recommendations for therapy and monitoring of mogamulizumab patients in Germany.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of the heterogeneous group of cutaneous T-cell lymphomas (CTCL). With the expansion of the biologic treatment landscape, new treatment options have become available in recent years, most notably the C-C chemokine receptor 4 (CCR4)-directed monoclonal antibody mogamulizumab. Based on the phase III pivotal trial, mogamulizumab is recommended by the German S2k guidelines for the second-line treatment of stage IB and above SS and MF, after at least one prior systemic therapy.

The role of vorasidenib in the treatment of isocitrate dehydrogenase-mutant glioma.

Isocitrate dehydrogenase (IDH)-mutant gliomas are the most common malignant primary brain tumors in young adults. This condition imposes a substantial burden on patients and their caregivers, marked by neurocognitive deficits and high mortality rates due to tumor progression, coupled with significant morbidity from current treatment modalities. Although surgery, radiation therapy, and chemotherapy improve survival, these treatments can adversely affect cognitive function, quality of life, finances, employment status, and overall independence.

Impact of genetic test interpretation on a missense variant in Cohen syndrome.

Introduction: Cohen syndrome (CS) is an early-onset pediatric neurodevelopmental disorder characterized by postnatal microcephaly and intellectual disability. An accurate diagnosis for individuals with CS is crucial, particularly for their caretakers and future prospects. CS is predominantly caused by rare homozygous or compound heterozygous pathogenic variants in the vacuolar protein sorting-associated 13B () gene, which disrupt protein translation and lead to a loss of function (LoF) of the encoded VPS13B protein.

Femoral or Radial Secondary Access in TAVR: A Subanalysis From the Multicenter PULSE Registry.

Background: Transradial secondary access (TR-SA) may serve as an alternative to the traditional femoral secondary access (TF-SA) for pigtail placement in transcatheter aortic valve replacement (TAVR).

Objectives: The aim of this study was to assess the incidence of secondary access-related vascular complications after TR-SA or TF-SA in TAVR.

Methods: The PULSE (Plug or sUture based vascuLar cloSurE after TAVR) registry retrospectively evaluated data of 10,120 patients who underwent transfemoral TAVR at 10 heart centers from 2016 to 2021.