Design, Synthesis, and Pharmacological Evaluation of Nonsteroidal Tricyclic Ligands as Modulators of GABA Receptors.

GABA receptors (GABARs) are the major elements of inhibitory neurotransmission in the central nervous system (CNS). They are established targets for regulation by endogenous brain neuroactive steroids (NASs) such as pregnanolone. However, the complexity of de novo synthesis of NAS derivatives has hindered attempts to circumvent the principal limitations of using endogenous NASs, including selectivity and limited oral bioavailability.

Decoding the elite soccer player's psychological profile.

Soccer is arguably the most widely followed sport worldwide, and many dream of becoming soccer players. However, only a few manage to achieve this dream, which has cast a significant spotlight on elite soccer players who possess exceptional skills to rise above the rest. Originally, such attention was focused on their great physical abilities.

Independently engaging protein tethers of different length enhance synaptic vesicle trafficking to the plasma membrane.

Synaptic vesicle (SV) trafficking toward the plasma membrane (PM) and subsequent SV maturation are essential for neurotransmitter release. These processes, including SV docking and priming, are co-ordinated by various proteins, such as SNAREs, Munc13 and synaptotagmin (Syt), which connect (tether) the SV to the PM. Here, we investigated how tethers of varying lengths mediate SV docking using a simplified mathematical model.

Transperitoneal robot-assisted partial nephrectomy: a comparison of operative and oncological outcomes between posterior and anterolateral tumours.

Objective: To compare operative and oncological outcomes, as well as the risk of postoperative complications in patients who underwent transperitoneal robot-assisted partial nephrectomy (RAPN) for renal tumours located either posteriorly or anterolaterally.

Methods: Retrospective, consecutive study including 451 patients who underwent transperitoneal RAPN for non-metastatic, localised renal tumours from May 2016 to April 2023. Operative data included duration of the procedure, warm ischaemia time, and blood loss; oncological data included surgical margins and recurrence; and 90-day postoperative complications were classified according to the Clavien-Dindo classification.

Reconstruction of reverberant sound fields over large spatial domains.

Characterising acoustic fields in rooms is challenging due to the complexity of data acquisition. Sound field reconstruction methods aim at predicting the acoustic quantities at positions where no data are available, incorporating generalisable physical priors of the sound in a room. This study introduces a model that exploits the general time structure of the room impulse response, where a wave-based expansion addresses the direct sound and early reflections, localising their apparent origin, and kernel methods are applied to the late part.

Optimizing automated photo identification for population assessments.

Several legal acts mandate that management agencies regularly assess biological populations. For species with distinct markings, these assessments can be conducted noninvasively via capture-recapture and photographic identification (photo-ID), which involves processing considerable quantities of photographic data. To ease this burden, agencies increasingly rely on automated identification (ID) algorithms.

Advancing Principled Pharmacoepidemiologic Research to Support Regulatory and Healthcare Decision Making: The Era of Real-World Evidence.

A compilation of factors over the past decade-including the availability of increasingly large and rich healthcare datasets, advanced technologies to extract unstructured information from health records and digital sources, advancement of principled study design and analytic methods to emulate clinical trials, and frameworks to support transparent study conduct-has ushered in a new era of real-world evidence (RWE). This review article describes the evolution of the RWE era, including pharmacoepidemiologic methods designed to support causal inferences regarding treatment effects, the role of regulators and other health authorities in establishing distributed real-world data networks enabling analytics at scale, and the many global guidance documents on principled methods of producing RWE. This article also highlights the growing opportunity for RWE to support decision making by regulators, health technology assessment groups, clinicians, patients, and other stakeholders and provides examples of influential RWE studies.

Twisting nanoporous graphene on graphene: electronic decoupling and chiral currents.

Nanoporous graphene (NPG), laterally bonded carbon nanoribbons, is a promising platform for controlling coherent electron propagation in the nanoscale. However, for its successful device integration NPG should ideally be on a substrate that preserves or enhances its anisotropic transport properties. Here, using an atomistic tight-binding model combined with nonequilibrium Green's functions, we study NPG on graphene and show that their electronic coupling is modulated as a function of the interlayer twist angle.

Treatment of bile acid diarrhea with GLP-1 receptor agonists: A Promising Yet Understudied Approach.

Bile acid diarrhea (BAD) is a chronic and socially debilitating disease characterized by abdominal pain, diarrhea, urgency, and fecal incontinence. Recently, in a six-week randomized controlled trial (RCT), we showed that the glucagon-like peptide 1 receptor agonist (GLP-1RA) liraglutide is superior to bile acid sequestration (considered standard-of-care) using colesevelam in reducing BAD symptoms. The emergence of new, more potent, and longer-acting GLP-1RAs has spurred an interest in these treatments in BAD management.

Prospective validation study of a combined urine and plasma test for predicting high-grade prostate cancer in biopsy naïve men.

Objective: Early and accurate diagnosis of prostate cancer (PC) is crucial for effective treatment. Diagnosing  clinically insignificant cancers can lead to overdiagnosis and overtreatment, highlighting the importance of accurately selecting patients for further evaluation based on improved risk prediction tools. Novel biomarkers offer promise for enhancing this diagnostic process.

Association between Deficient MSH2/MSH6 vs MLH1/PMS2 Status and Survival Rates in Localized Colorectal Cancer: A Nationwide Cohort Study.

Objective: This study investigated the association between loss of MSH2/MSH6 versus loss of MLH1/PMS2 expression and overall survival and disease-free survival in patients with localized colorectal cancer.

Background: The risk of developing colorectal cancer varies depending on the expression of mismatch repair proteins. However, it is unknown if the prognosis differs accordingly.

The aerial epidermis is a major site of quinolizidine alkaloid biosynthesis in narrow-leafed lupin.

Lupins are promising protein crops that accumulate toxic quinolizidine alkaloids (QAs) in the seeds, complicating their end-use. QAs are synthesized in green organs (leaves, stems, and pods) and a subset of them is transported to the seeds during fruit development. The exact sites of biosynthesis and accumulation remain unknown; however, mesophyll cells have been proposed as sources, and epidermal cells as sinks.

The impact of allergic rhinitis on future educational outcomes: a Danish real-world register study.

Objective: The symptom burden associated with allergic rhinitis (AR) negatively impacts the life of people living with the condition. Although the impact of AR on educational outcomes and the effect of AR-relieving medication have been investigated, the availability of up-to-date, population-based, real-world evidence is limited. Therefore, the aim was to investigate the impact of AR and AR-relieving medication on educational outcomes.

Accurate Estimation of Diffusion Coefficients and their Uncertainties from Computer Simulation.

Self-diffusion coefficients, *, are routinely estimated from molecular dynamics simulations by fitting a linear model to the observed mean squared displacements (MSDs) of mobile species. MSDs derived from simulations exhibit statistical noise that causes uncertainty in the resulting estimate of *. An optimal scheme for estimating * minimizes this uncertainty, i.

Effects of therapy in experimental models of Peyronie's disease: a scoping review.

Background: Peyronie's disease (PD) is a fibrotic disorder affecting the penile tunica albugínea, with unclear pathophysiology despite centuries of recognition.

Aim: This scoping review maps the effects of interventions in basic PD research, synthesizing evidence from in vivo and in vitro studies to guide future investigation.

Methods: In October-November 2023, a systematic search was conducted across PubMed, Embase (Ovid), Science of Web, and Scopus, following SRYCLE's guidelines.

Prevalence and Regional Variations of Visual and Auditory Impairments Among Elderly Individuals in the Faroe Islands: A Cross-Sectional Study.

Introduction: Aging is associated with the potential onset of vision and hearing problems, affecting the quality of life and functional independence of older adults. This study sought to investigate the prevalence of various vision and hearing problems in 76-year-old Faroese individuals and examine possible regional variations in these health issues.

Materials And Methods: A cross-sectional study design was used, surveying 175 participants, all 76-year-olds, from different regions in the Faroe Islands.

The "SES NXT" digital intervention for children of relationship dissolution: Study protocol for a randomized controlled trial study.

Parental relationship dissolution is among the most prevalent life crises for youths and is associated with both short- and long-term intra- and interpersonal struggles. Extant support programs tend to be in-person and in a group format. However, the structure and personnel needed for these programs make them costly to implement, less accessible, and difficult to scale.

MicroRNA-142-3p chemo-sensitizing breast cancer to docetaxel: apoptosis and cell cycle arrest induction, and migration suppression.

Docetaxel (DTX) is widely utilized in breast cancer treatment. However, cancer cell resistance has limited its anti-tumor efficacy. Some molecules called microRNAs (miRNAs), acting like fine-tuned switches, can influence how breast cancer develops and spreads.

Respiratory delivered vaccines: Current status and perspectives in rational formulation design.

The respiratory tract is susceptible to various infections and can be affected by many serious diseases. Vaccination is one of the most promising ways that prevent infectious diseases and treatment of some diseases such as malignancy. Direct delivery of vaccines to the respiratory tract could mimic the natural process of infection and shorten the delivery path, therefore unique mucosal immunity at the first line might be induced and the efficiency of delivery can be high.

Rigidity Aspects of Penrose's Singularity Theorem.

In this paper, we study rigidity aspects of Penrose's singularity theorem. Specifically, we aim to answer the following question: if a spacetime satisfies the hypotheses of Penrose's singularity theorem except with weakly trapped surfaces instead of trapped surfaces, then what can be said about the global spacetime structure if the spacetime is null geodesically complete? In this setting, we show that we obtain a foliation of MOTS which generate totally geodesic null hypersurfaces. Depending on our starting assumptions, we obtain either local or global rigidity results.

Iron deficiency and infection risk in Danish blood donors.

Background: We aimed to investigate if iron deficiency was associated with infection susceptibility in a large cohort of healthy individuals.

Study Design And Methods: The Danish Blood Donor Study is a national ongoing prospective study of blood donors. We included 94,628 donors with 338,290 ferritin measurements from March 2010 to October 2022.

Cardiac function and coronary plaque development following masculinizing gender-affirming hormone therapy: A prospective cohort study.

Introduction: Myocardial dysfunction and the presence of calcified and non-calcified coronary plaques are predictors of cardiovascular disease. Masculinizing gender-affirming hormone therapy may increase cardiovascular risk, highlighting the need for prospective studies to evaluate cardiovascular outcomes during gender-affirming hormone therapy.

Objectives: To evaluate changes in cardiac morphology, systolic and diastolic function, and development of coronary plaques after masculinizing gender-affirming hormone therapy.

Identifying genetic differences between bipolar disorder and major depression through multiple genome-wide association analyses.

Background: Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).

Aims: We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.