Fragment-to-Lead Medicinal Chemistry Publications in 2023.

This Perspective summarizes successful fragment-to-lead (F2L) studies that were published in 2023 and is the ninth installment in an annual series. A tabulated summary of the relevant articles published in 2023 is provided (17 entries from 16 articles), and a comparison of the target classes, screening methods, and overall fragment or lead property trends for 2023 examples and for the combined entries over the years 2015-2023 is discussed. In addition, we identify several trends and innovations in the 2023 literature that promise to further increase the success of fragment-based drug discovery (FBDD), particularly in the areas of NMR and virtual screening, fragment library design, and fragment linking.

GnRH pulse generator activity in mouse models of polycystic ovary syndrome.

One in ten women in their reproductive age suffer from polycystic ovary syndrome (PCOS) that, alongside subfertility and hyperandrogenism, typically presents with increased luteinizing hormone (LH) pulsatility. As such, it is suspected that the arcuate kisspeptin (ARN) neurons that represent the GnRH pulse generator are dysfunctional in PCOS. We used here in vivo GCaMP fiber photometry and other approaches to examine the behavior of the GnRH pulse generator in two mouse models of PCOS.

Intraventricular Hemorrhage and Survival, Multimorbidity, and Neurodevelopment.

Importance: Intraventricular hemorrhage (IVH) has proven to be a challenging and enduring complication of prematurity. However, its association with neurodevelopment across the spectrum of IVH severity, independent of prematurity, and in the context of contemporary care remains uncertain.

Objective: To evaluate national trends in IVH diagnosis and the association with survival and neurodevelopmental outcomes at 2 years of age.

Association of radiation-induced normal tissue toxicity with a high genetic risk for rheumatoid arthritis.

Purpose: Overlapping genes are involved with rheumatoid arthritis (RA) and DNA repair pathways. Therefore, we hypothesised that patients with a high polygenic risk score (PRS) for RA will have an increased risk of radiotherapy (RT) toxicity given the involvement of DNA repair.

Methods: Primary analysis was performed on 1494 prostate cancer, 483 lung cancer and 1820 breast cancer patients assessed for development of RT toxicity in the REQUITE study.

Kinematics and directionality of body turning in water striders (Gerris argentatus) on the water surface.

Water striders inhabit the elastic surface tension film of water, sharing their environment with other aquatic organisms. Their survival relies heavily on swift maneuverability and navigation around floating obstacles, which aids in the exploration of their habitat and in escaping from potential threats. Their high agility is strongly based on the ability to execute precise turns, enabling effective directional control.

Elevated developmental temperatures below the lethal limit reduce Aedes aegypti fertility.

Aedes aegypti mosquitoes are the principal vectors of dengue and continue to pose a threat to human health, with ongoing urbanization, climate change, and trade all impacting the distribution and abundance of this species. Hot periods are becoming increasingly common and their impacts on insect mortality have been well established, but they may have even greater impacts on insect fertility. In this study, we investigated the impacts of high temperatures on Ae.

The Co-Occurrence of Autism and Avoidant/Restrictive Food Intake Disorder (ARFID): A Prevalence-Based Meta-Analysis.

Objective: Avoidant/restrictive food intake disorder (ARFID) is a feeding and eating disorder characterized by extensive avoidance and/or restriction of food. Existing research demonstrates that ARFID is over-represented in Autistic populations and vice-versa, with both groups exhibiting shared characteristics. This meta-analysis investigated the co-occurrence between ARFID and autism via determination of autism prevalence in ARFID populations, and ARFID prevalence in Autistic groups.

Oncocytic Carcinoma Ex-Pleomorphic Adenoma of the Lacrimal Gland.

Oncocytic carcinoma is a rare malignant neoplasm of oncocytic cells, such cells being characterized by abundant granular eosinophilic cytoplasm, invasive growth, and pronounced cellular pleomorphism. It may arise de novo, or through malignant transformation of a pre-existing benign oncocytoma. Oncocytic carcinoma most commonly occurs in the salivary glands, with rare involvement of the ocular adnexa where it mainly affects caruncle, conjunctiva, and lacrimal sac, and only very arises in the lacrimal gland.

EXPRESS: Pharmacokinetic advantages of lipophilic statins over rosuvastatin in COVID-19 management.

Not applicable.

Structure-Activity Relationships for s-Block Metal/Co(III) Heterodinuclear Catalysts in Cyclohexene Oxide Ring-Opening Copolymerizations.

In homogeneous catalysis, uncovering structure-activity relationships remains very rare but invaluable to understand and rationally improve performances. Here, generalizable structure-activity relationships apply to a series of heterodinuclear polymerization catalysts featuring Co(III) and s-block metals M(I/II) (M= Na(I), K(I), Ca(II), Sr(II), Ba(II)). These are shown to apply to polycarbonate production by the ring-opening copolymerizations (ROCOP) of cyclohexene oxide (CHO) and carbon dioxide (CO2), conducted at high (20 bar) and low (1 bar) CO2 pressures, and to polyester production by copolymerization of cyclohexene oxide and phthalic anhydride (PA).

Relatively high interest but limited active engagement in HIV cure research: Awareness, interest, and information-seeking among affected communities in the Netherlands.

Background: Community engagement is important for inclusive HIV cure development. This study evaluates current engagement in HIV cure research among affected communities in the Netherlands by analyzing awareness, interest, and information-seeking behavior. It also identifies participant characteristics and HIV-related illness perceptions linked to each engagement stage.

Trends in stroke-related mortality in atrial fibrillation patients in the United States: Insights from the CDC WONDER database.

Background: Stroke associated with atrial fibrillation (AF) is a significant cause of mortality. This study analyzed demographic trends and disparities in mortality rates due to stroke in AF patients aged ≥25 years.

Methods: A retrospective analysis was conducted to acquire death data using the Centers for Disease Control and Prevention database from 1999 to 2020.

Perspectives of old-age and dementia researchers on communication with policymakers and public research funding decision-makers: an international cross-sectional survey.

Introduction: Society commonly believes that research knowledge is complementary to public decision-making. This study aimed to understand the perspectives and implications of dementia researchers communicating with policymakers and public research decision-makers (public officials).

Methods: This study uses 24 questions from an anonymous, online survey, which was received by 392 members of nine European, Latin American, and United States medical researcher associations/networks in the fields of age-related neurological degeneration and dementia medicine.

The clinical efficacy of a novel smartphone-based salivary self-test for the prediction of pre-eclampsia, pregnancy-induced hypertension and intrauterine growth restriction: a prospective cohort study.

Introduction: This study investigated the efficacy of a digital health solution utilizing smartphone images of colorimetric test-strips for home-based salivary uric acid (sUA) measurement to predict pre-eclampsia (PE), pregnancy-induced hypertension (PIH), and intrauterine growth restriction (IUGR).

Methods: 495 pregnant women were included prospectively at Zealand University Hospital, Denmark. They performed weekly self-tests from mid-pregnancy until delivery and referred these for analysis by a smartphone-app.

Achievements, priorities and strategies in pediatric nephrology in Europe: need for unifying approaches or acceptance of differences?

Background: There is a lack of information on the current healthcare systems for children with kidney diseases across Europe. The aim of this study was to explore the different national approaches to the organization and delivery of pediatric nephrology services within Europe.

Methods: In 2020, the European society for Paediatric Nephrology (ESPN) conducted a cross-sectional survey to identify the existing pediatric nephrology healthcare systems in 48 European countries covering a population of more than 200 million children.

Management of metastatic colorectal cancer: consensus in the Gulf Cooperation Council countries.

Colorectal cancer (CRC) represents a major public health challenge globally, particularly in the Gulf Cooperation Council (GCC) countries, where it is identified as the second most prevalent form of cancer. Despite advancements in management strategies, tailored guidelines specific to the Gulf region are lacking. This paper presents consensus recommendations developed by a panel of experts from the GCC countries to address this gap.

Refractory fungal infection: Three case reports highlighting good practice.

Refractory invasive fungal disease is a significant clinical problem, with high morbidity, mortality and costs. The complex causes of refractory infection include breakthrough infection due to antifungal resistance (both innate and acquired), suboptimal therapy and impaired immune responses in critically ill or immunocompromised patients. This case series details three reports on the identification and management of refractory fungal infections, two cases of azole resistance and one case of resistant candidiasis, highlighting the importance of accurate diagnosis, monitoring, implementation of biomarkers (serological markers, PCR), antifungal susceptibility testing and antifungal stewardship to optimise management and minimise risks of emergence of drug resistance.

Accidental Organophosphate Poisoning in a Patient Due to a Bed Bug Pesticide in the United Kingdom: A Case Report.

Organophosphate (OP) compounds, developed during World War II, are a group of chemicals used as pesticides, insecticides and herbicides. As irreversible inhibitors of the enzyme acetylcholinesterase (AChE), they reduce anti-cholinesterase activity and therefore increase acetylcholine (ACh) levels at the neuromuscular junction (NMJ). Diazinon, the OP leading to the patient's symptoms in this report, is an amber-brown liquid that was once the most widely used insecticide in the United States of America.

Use of Magtrace as an Alternative Approach in Staging the Axilla in Early-Stage Breast Cancer: A Single-Center Experience.

Background The sentinel lymph node biopsy (SLNB) is the standard method used to determine the stage of breast cancer in patients with no clinical signs of axillary involvement. The current gold standard for the intraoperative assessment of the axilla involves the use of dual radioisotope and patent blue dye. However, researchers have been studying the use of superparamagnetic iron oxide Magtrace® (Endomagnetics Limited, Cambridge, United Kingdom) agents as an alternative to overcome the limitations of the standard SLNB technique.

Learning delays through gradients and structure: emergence of spatiotemporal patterns in spiking neural networks.

We present a Spiking Neural Network (SNN) model that incorporates learnable synaptic delays through two approaches: per-synapse delay learning via Dilated Convolutions with Learnable Spacings (DCLS) and a dynamic pruning strategy that also serves as a form of delay learning. In the latter approach, the network dynamically selects and prunes connections, optimizing the delays in sparse connectivity settings. We evaluate both approaches on the Raw Heidelberg Digits keyword spotting benchmark using Backpropagation Through Time with surrogate gradients.

Impact of surrogates for insulin resistance on mortality and life expectancy in primary care: a nationwide cross-sectional study with registry linkage (LIPIDOGRAM2015).

Background: Insulin resistance (IR) is an important risk factor for multiple chronic diseases, increasing mortality and reducing life expectancy. The associations between emerging surrogates for IR, triglyceride-glucose index (TyG) and TyG-related indicators, with all-cause mortality and life expectancy in middle-aged and older patients in primary care are unclear.

Methods: This study originated from the Polish primary care cohort LIPIDOGRAM2015, including patients aged ≥45 years.

Operationalizing goal setting as an outcome measure in trials involving patients with frailty, multimorbidity or complexity.

Background/aims: In the absence of disease-modifying therapies for Parkinson's disease, much research focuses on improving quality of life, health and wellbeing. It is important to evaluate potential treatments and innovative care models in a robust and standardised way. Disease-specific outcomes have limitations in older people, those with cognitive impairment, multimorbidity, disability or short life expectancy.