Multiple neoplasms in patients with uveal melanoma: a systematic review.

PURPOSE: Uveal melanoma is the most prevalent intraocular malignancy in adults, derived from uveal tract melanocytes. This study focuses on the frequency and risk of second primary malignancies in UM patients. METHODS: A PubMed search (1980-2023) identified studies on SPM incidence in UM patients. From 191 references, 14 studies were chosen, focusing on UM, SPMs, and analysing data on demographics and types of neoplasms. RESULTS: Among 31,235 UM patients in 14 studies, 4695 had 4730 SPMs (15.03% prevalence). Prostate (15%), breast (12%), and colorectal (9%) cancers were most common. Digestive system malignancies were highest (19%), with colorectal cancer leading (51%). Breast and prostate cancers were prevalent in respective systems. Lung, bladder, and non-Hodgkin's lymphoma were also notable. The study observed an increasing trend in the frequency of SPMs over time, reflecting broader trends in cancer survivorship and the growing prevalence of multiple malignancies. CONCLUSION: The study highlights a significant presence of SPMs in UM patients, with an increasing trend in frequency over time, emphasizing prostate and breast cancers. This underscores the need for focused surveillance and tailored follow-up for UM survivors, considering their higher risk of additional malignancies. Future research should further investigate SPM aetiology in UM patients.

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.

Preserved VPS13A distribution and expression in Huntington's disease: divergent mechanisms of action for similar movement disorders?

VPS13A disease and Huntington's disease (HD) are two basal ganglia disorders that may be difficult to distinguish clinically because they have similar symptoms, neuropathological features, and cellular dysfunctions with selective degeneration of the medium spiny neurons of the striatum. However, their etiology is different. VPS13A disease is caused by a mutation in the VPS13A gene leading to a lack of protein in the cells, while HD is due to an expansion of CAG repeat in the huntingtin (Htt) gene, leading to aberrant accumulation of mutant Htt. Considering the similarities of both diseases regarding the selective degeneration of striatal medium spiny neurons, the involvement of VPS13A in the molecular mechanisms of HD pathophysiology cannot be discarded. We analyzed the VPS13A distribution in the striatum, cortex, hippocampus, and cerebellum of a transgenic mouse model of HD. We also quantified the VPS13A levels in the human cortex and putamen nucleus; and compared data on mutant Htt-induced changes in VPS13A expression from differential expression datasets. We found that VPS13A brain distribution or expression was unaltered in most situations with a decrease in the putamen of HD patients and small mRNA changes in the striatum and cerebellum of HD mice. We concluded that the selective susceptibility of the striatum in VPS13A disease and HD may be a consequence of disturbances in different cellular processes with convergent molecular mechanisms already to be elucidated.

Tirofiban versus aspirin to prevent in-stent thrombosis after emergent carotid artery stenting in acute ischemic stroke.

BACKGROUND: Several antithrombotic treatments during emergent carotid artery stenting (eCAS) have been proposed, but an appropriate protocol to balance risk-benefit is not well known. OBJECTIVE: To investigate the efficacy and safety of tirofiban compared with aspirin in patients with acute ischemic stroke undergoing eCAS. METHODS: We conducted a retrospective single-center study of the prospective ARTISTA Registry, including patients with atherosclerotic internal carotid artery occlusion treated with eCAS. Two groups, according to antiplatelet drug, were studied: aspirin (250-500 mg single-dose) versus tirofiban (500 µg bolus+200 µg/h). Primary outcomes were the rate of in-stent thrombosis and symptomatic intracranial hemorrhage (sICH) within the first 24 hours. RESULTS: During the period 2019-2023, 181 patients were included, 103 received aspirin, 78 tirofiban; 149 (82.3%) had tandem lesions. The primary efficacy outcome occurred in 9 (9.4%) in the aspirin group, as compared with 1 (1.3%) in the tirofiban group (adjusted odds ratio (aOR)=0.11, 95% CI 0.01 to 0.98; P=0.048). The primary safety outcome was detected in 12 (11.7%) in the aspirin group, as compared with 2 (2.6%) in the tirofiban group (aOR=0.16, 95% CI 0.03 to 0.87; P=0.034). The tirofiban group presented a lower risk of parenchymal hemorrhage (18 (17.4%) vs 4 (5.2%), aOR=0.27, 95% CI 0.09 to 0.88; P=0.029) and an increased rate of excellent recanalization (expanded Treatment in Cerebral Infarction (eTICI) 2c-3) (50 (48.5%) vs 54 (69.2%); aOR=2.15, 95% CI 1.12 to 4.13; P=0.02). There were no differences in functional outcomes or mortality at 3 months. CONCLUSIONS: Periprocedural antithrombotic therapy with tirofiban was associated with a lower risk of in-stent thrombosis and sICH at 24 hours from eCAS compared with aspirin. Prospective randomized clinical trials are needed to confirm our results.

Ensemble machine learning using hydrometeorological information to improve modeling of quality parameter of raw water supplying treatment plants.

Source and raw water quality may deteriorate due to rainfall and river flow events that occur in watersheds. The effects on raw water quality are normally detected in drinking water treatment plants (DWTPs) with a time-lag after these events in the watersheds. Early warning systems (EWSs) in DWTPs require models with high accuracy in order to anticipate changes in raw water quality parameters. Ensemble machine learning (EML) techniques have recently been used for water quality modeling to improve accuracy and decrease variance in the outcomes. We used three decision-tree-based EML models (random forest [RF], gradient boosting [GB], and eXtreme Gradient Boosting [XGB]) to predict two critical parameters for DWTPs, raw water Turbidity and UV absorbance (UV254), using rainfall and river flow time series as predictors. When modeling raw water turbidity, the three EML models (rRF-Tu2=0.87, rGB-Tu2=0.80 and rXGB-Tu2=0.81) showed very good performance metrics. For raw water UV254, the three models (rRF-UV2=0.89, rGB-UV2=0.85 and rXGB-UV2=0.88) again showed very good performance metrics. Results from this study suggest that EML approaches could be used in EWSs to anticipate changes in the quality parameters of raw water and enhance decision-making in DWTPs.

Oral Exposure to Titanium Dioxide E171 and Zinc Oxide Nanoparticles Induces Multi-Organ Damage in Rats: Role of Ceramide.

Food-grade titanium dioxide (E171) and zinc oxide nanoparticles (ZnO NPs) are common food additives for human consumption. We examined multi-organ toxicity of both compounds on Wistar rats orally exposed for 90 days. Rats were divided into three groups: (1) control (saline solution), (2) E171-exposed, and (3) ZnO NPs-exposed. Histological examination was performed with hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Ceramide (Cer), 3-nitrotyrosine (NT), and lysosome-associated membrane protein 2 (LAMP-2) were detected by immunofluorescence. Relevant histological changes were observed: disorganization, inflammatory cell infiltration, and mitochondrial damage. Increased levels of Cer, NT, and LAMP-2 were observed in the liver, kidney, and brain of E171- and ZnO NPs-exposed rats, and in rat hearts exposed to ZnO NPs. E171 up-regulated Cer and NT levels in the aorta and heart, while ZnO NPs up-regulated them in the aorta. Both NPs increased LAMP-2 expression in the intestine. In conclusion, chronic oral exposure to metallic NPs causes multi-organ injury, reflecting how these food additives pose a threat to human health. Our results suggest how complex interplay between ROS, Cer, LAMP-2, and NT may modulate organ function during NP damage.

Domestic access to water in a decentralized truck-to-cistern system: a case study in the Northern Village of Kangiqsualujjuaq, Nunavik (Canada).

Municipal water supply through truck-to-cistern systems is common in northern Canada. Household satisfaction and concerns about water services likely impact user preferences and practices. This case study explores household perspectives and challenges with regard to domestic access to water in a decentralized truck-to-cistern system. A case study was conducted in the Northern Village of Kangiqsualujjuaq, Nunavik (Quebec, Canada). A paper-based questionnaire was completed by 65 households (one quarter of the population). Many households (37%) reported not drinking tap water from the truck-to-cistern system. Chlorine taste was a frequently reported concern, with those households being significantly less likely to drink water directly from the tap (p = 0.002). Similarly, households that reported a water shortage in the previous week (i.e., no water from the tap at least once) (33%) were more likely to express dissatisfaction with delivered water quantity (rs = 0.395, p = 0.004). Interestingly, 77% of households preferred using alternative drinking water sources for drinking purposes, such as public tap at the water treatment plant, natural sources or bottled water. The study underscores the importance of considering household perspectives to mitigate the risks associated with service disruptions and the use of alternative sources for drinking purposes.

Optimizing sampling location for water quality degradation monitoring in distribution systems: Assessing global representativeness and potential health risk.

Selecting the optimal monitoring points in a water distribution network is challenging due to the complex spatiotemporal variability of water quality degradation. The lack of a standardized methodology for monitoring point selection forces operators to rely on general recommendations, historical data and professional experience, which can mask water quality problems and increase the risk to consumers. This study proposes a new methodology to optimize the selection of monitoring points in distribution networks. The method considers the spatiotemporal degradation of water quality, the definition of representative zones and two selection criteria: global representativeness and potential health risk. Representative zones were determined for each node of the network based on hydraulic paths and their water quality spatial variability. Part of the distribution network in Quebec City, Canada was used as the case study, in which four water quality parameters were investigated: free chlorine residual (FRC), heterotrophic plate counts (HPC), trihalomethanes (THMs) and haloacetic acids (HAAs). Seasonal variabilities (summer and winter) were also analyzed. The results obtained for the two criteria and for both seasons were compared, and methodological and practical recommendations were established for dynamic monitoring programs that respond to the needs of operators.

Characterizing Hepatitis Delta in Spain and the gaps in its management.

BACKGROUND AND AIMS: Chronic hepatitis D (CHD) is a severe form of chronic viral hepatitis. The estimated hepatitis delta prevalence in Spain is around 5% of patients with hepatitis B. Reimbursement of new antiviral therapies (Bulevirtide, BLV) was delayed in our country until February 2024. We aimed to characterize the clinical profile of patients with HDV/HBV infection in Spain and current barriers in their management at the time of BLV approval. METHOD: Multicenter registry including patients with positive anti-HDV serology actively monitored in 30 Spanish centers. Epidemiological, clinical and virological variables were recorded at the start of follow-up and at the last visit. RESULTS: We identified 329 anti-HDV patients, 41% were female with median age 51 years. The most common geographical origin was Spain (53%) and East Europe (24%). Patients from Spain were older and had HCV and HIV coinfection probably associated to past drug injection (p<0.01). HDV-RNA was positive in 138 of 221 assessed (62%). Liver cirrhosis was present at diagnosis in 33% and it was more frequent among viremic patients (58% vs 25%, p<0.01). After a median follow-up of 6 (3-12) years, 44 (16%) resolved infection (18 spontaneously and 26 after Peg-INF). An additional 10% of patients developed cirrhosis (n=137) during follow-up (45% had portal hypertension and 14% liver decompensation). Liver disease progression was associated to persisting viremia. CONCLUSION: One-third of the patients with CHD already have cirrhosis at diagnosis. Persistence of positive viremia is associated to rapid liver disease progression. Importantly, barriers to locally determine/quantify HDV-RNA were present.

Exploring the nexus of urban form, transport, environment and health in large-scale urban studies: A state-of-the-art scoping review.

BACKGROUND: As the world becomes increasingly urbanised, there is recognition that public and planetary health relies upon a ubiquitous transition to sustainable cities. Disentanglement of the complex pathways of urban design, environmental exposures, and health, and the magnitude of these associations, remains a challenge. A state-of-the-art account of large-scale urban health studies is required to shape future research priorities and equity- and evidence-informed policies. OBJECTIVES: The purpose of this review was to synthesise evidence from large-scale urban studies focused on the interaction between urban form, transport, environmental exposures, and health. This review sought to determine common methodologies applied, limitations, and future opportunities for improved research practice. METHODS: Based on a literature search, 2958 articles were reviewed that covered three themes of: urban form; urban environmental health; and urban indicators. Studies were prioritised for inclusion that analysed at least 90 cities to ensure broad geographic representation and generalisability. Of the initially identified studies, following expert consultation and exclusion criteria, 66 were included. RESULTS: The complexity of the urban ecosystem on health was evidenced from the context dependent effects of urban form variables on environmental exposures and health. Compact city designs were generally advantageous for reducing harmful environmental exposure and promoting health, with some exceptions. Methodological heterogeneity was indicative of key urban research challenges; notable limitations included exposure and health data at varied spatial scales and resolutions, limited availability of local-level sociodemographic data, and the lack of consensus on robust methodologies that encompass best research practice. CONCLUSION: Future urban environmental health research for evidence-informed urban planning and policies requires a multi-faceted approach. Advances in geospatial and AI-driven techniques and urban indicators offer promising developments; however, there remains a wider call for increased data availability at local-levels, transparent and robust methodologies of large-scale urban studies, and greater exploration of urban health vulnerabilities and inequities.

Squeezed from the top: "Social Outburst" (2019) and elite overproduction. A study of the dynamics of Chilean political instability from the approach of Structural Demographic Theory.

On October 18, 2019, Chile experienced the most important social upheaval since the country regained democracy in the late 1980s. The "Social Outbreak" surprised economic and political elites and seemed paradoxical to the international community who had often praised Chile as a model of successful development. In this paper, we used structural-demographic theory to analyze the interaction between the overproduction of elites and the stagnation in the relative income of the population as the underlying structural cause of Chilean political instability. This theory was able to predict the three most significant instances of political tension in the recent history of Chile: the crisis of the late 1960s that culminated in the coup d'état of 1973, popular mobilizations during the 1980s, and the recent student mobilizations and social upheaval. Our results suggest that, at least during the period 1938-2019, Chilean sociopolitical dynamics is determined by the same structural drivers.

Oral phytate supplementation on the progression of mild cognitive impairment, brain iron deposition and diabetic retinopathy in patients with type 2 diabetes: a concept paper for a randomized double blind placebo controlled trial (the PHYND trial).

Type 2 diabetes mellitus has a worldwide prevalence of 10.5% in the adult population (20-79 years), and by 2045, the prevalence is expected to keep rising to one in eight adults living with diabetes. Mild cognitive impairment has a global prevalence of 19.7% in adults aged 50 years. Both conditions have shown a concerning increase in prevalence rates over the past 10 years, highlighting a growing public health challenge. Future forecasts indicate that the prevalence of dementia (no estimations done for individuals with mild cognitive impairment) is expected to nearly triple by 2050. Type 2 diabetes mellitus is a risk factor for the development of cognitive impairment, and such impairment increase the likelihood of poor glycemic/metabolic control. High phytate intake has been shown to be a protective factor against the development of cognitive impairment in observational studies. Diary phytate intake might reduce the micro- and macrovascular complications of patients with type 2 diabetes mellitus through different mechanisms. We describe the protocol of the first trial (the PHYND trial) that evaluate the effect of daily phytate supplementation over 56 weeks with a two-arm double-blind placebo-controlled study on the progression of mild cognitive impairment, cerebral iron deposition, and retinal involvement in patients with type 2 diabetes mellitus. Our hypothesis proposes that phytate, by inhibiting advanced glycation end product formation and chelating transition metals, will improve cognitive function and attenuate the progression from Mild Cognitive Impairment to dementia in individuals with type 2 diabetes mellitus and mild cognitive impairment. Additionally, we predict that phytate will reduce iron accumulation in the central nervous system, mitigate neurodegenerative changes in both the central nervous system and retina, and induce alterations in biochemical markers associated with neurodegeneration.

Year-round monitoring of three water sources in Québec, Canada, reveals site-specific differences in conditions for Cryptosporidium and Giardia contamination.

Cryptosporidium and Giardia are protozoan parasites responsible for gastrointestinal illnesses in humans and in animal species. The main way these parasites are transmitted is by ingestion of their (oo)cysts in drinking water. Monitoring (oo)cysts in water sources is beneficial to evaluate the quality of raw water supplying treatment plants. Currently, the only standardized protocol to enumerate these parasites from water samples is United States Environmental Protection Agency (USEPA) Method 1623.1. With this method, we monitored three major water sources in Quebec over a year to assess temporal and geographical variations of these parasite (oo)cysts. These three water sources have independent watersheds despite being in the same region. We found a general pattern for Giardia, with high concentrations of cysts during cold and transition periods, and significantly lower concentrations during the warm period. Cryptosporidium's concentration was more variable throughout the year. Statistical correlations (Pearson's correlation coefficients) were established between the concentration of each parasite and various environmental parameters. The three study sites each showed unique factors correlating with the presence of both protozoa, supporting the idea that each water source must be seen as a unique entity with its own particular characteristics and therefore, must be monitored independently. Although some environmental parameters could be interesting proxies to the parasitic load, no parameter was strongly correlated throughout the whole sampling year and none of the parameters could be used as a single proxy for all three studies sources.

Development of a Risk Prediction Nomogram for Carotid Re-Stenosis in the One Year RECAST Registry.

OBJECTIVE: The long term benefit of carotid angioplasty and stenting (CAS) can be reduced by recurrent stroke related to in stent re-stenosis (ISR). An individualised predictive tool is needed to identify ISR events. A nomogram for individual risk assessment of ISR ≥ 70% after CAS is proposed. METHODS: A national observational, prospective, multicentre registry was conducted between January 2015 and December 2020. Cohorts of patients with symptomatic or asymptomatic severe carotid stenosis who underwent CAS with a follow up of at least one year after CAS were included. Duplex ultrasound was used to assess in stent re-stenosis. Pre-operative factors were compared between the non-ISR and ISR groups. Kaplan-Meier and Cox regression were used for variable selection. The nomogram was formulated and validated by concordance indices and calibration curves. An in stent re-stenosis risk table was generated for risk stratification. RESULTS: A total of 354 patients were included in the analysis. The ISR rate of ≥ 70% was 7.6% (n = 27). Peripheral arterial disease (hazard ratio [HR] 3.18, 95% confidence interval [CI] 1.23 - 8.24, p = .017), anterior communicating artery absence (HR 3.38, 95% CI 1.27 - 8.94, p = .016), diabetes mellitus (HR 3.34, 95% CI 1.21 - 9.26, p = .020), female sex (HR 2.99, 95% CI 1.04 - 8.60, p = .041), and pre-procedure pathological ultrasound vasoreactivity (HR 3.87, 95% CI 1.43 -10.50, p = .008), as independent risk factors for ISR of ≥ 70%, were included in the nomogram. The concordance index at 12 and 24 months was 0.83. In low risk groups, ISR of ≥ 70% occurred in 4.8% of patients during follow up compared with 56.2% of patients in the high risk groups (p < .001). CONCLUSION: The nomogram and risk evaluation score have good predictive ability for ISR. They can be used as practical clinical tools for individualised risk assessment.

Real-life effectiveness of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients previously treated with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir.

BACKGROUND: Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct-acting antivirals (DAAs). Data are limited on the effectiveness of this treatment after the current first-line therapies. Our aim was to analyse the effectiveness and safety of SOF/VEL/VOX among patients failing sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). METHODS: Retrospective multicentre study (26 Spanish hospitals), including chronic hepatitis C patients unsuccessfully treated with SOF/VEL or GLE/PIB, and retreated with SOF/VEL/VOX ± ribavirin for 12 weeks between December 2017 and December 2022. RESULTS: In total, 142 patients included: 100 (70.4%) had failed SOF/VEL and 42 (29.6%) GLE/PIB. Patients were mainly men (84.5%), White (93.9%), with hepatitis C virus genotype (GT) 3 (49.6%) and 47.2% had liver cirrhosis. Sustained virological response (SVR) was evaluated in 132 patients who completed SOF/VEL/VOX and were followed 12 weeks after end of treatment; 117 (88.6%) achieved SVR. There were no significant differences in SVR rates according to initial DAA treatment (SOF/VEL 87.9% vs. GLE/PIB 90.2%, p = 0.8), cirrhosis (no cirrhosis 90% vs. cirrhosis 87.1%, p = 0.6) or GT3 infection (non-GT3 91.9% vs. GT3 85.5%, p = 0.3). However, when considering the concurrent presence of SOF/VEL treatment, cirrhosis and GT3 infection, SVR rates dropped to 82.8%. Ribavirin was added in 8 (6%) patients, all achieved SVR. CONCLUSION: SOF/VEL/VOX is an effective rescue therapy for failures to SOF/VEL or GLE/PIB, with an SVR of 88.6%. Factors previously linked to lower SVR rates, such as GT3 infection, cirrhosis and first-line therapy with SOF/VEL were not associated with lower SVRs.

Microscale Chiral Rectennas for Energy Harvesting.

Wireless radiofrequency rectifiers have the potential to power the billions of "Internet of Things" (IoT) devices currently in use by effectively harnessing ambient electromagnetic radiation. However, the current technology relies on the implementation of rectifiers based on Schottky diodes, which exhibit limited capabilities for high-frequency and low-power applications. Consequently, they require an antenna to capture the incoming signal and amplify the input power, thereby limiting the possibility of miniaturizing devices to the millimeter scale. Here, the authors report wireless rectification at the GHz range in a microscale device built on single chiral tellurium with extremely low input powers. By studying the crystal symmetry and the temperature dependence of the rectification, the authors demonstrate that its origin is the intrinsic nonlinear conductivity of the material. Additionally, the unprecedented ability to modulate the rectification output by an electrostatic gate is shown. These results open the path to developing tuneable microscale wireless rectifiers with a single material.

Reproductive physiology of the boar: What defines the potential fertility of an ejaculate?

Despite decades of research and handling of semen for use in artificial insemination (AI) and other assisted reproductive technologies, 5-10% of selected boar sires are still considered sub-fertile, escaping current assessment methods for sperm quality and resilience to preservation. As end-product, the ejaculate (emitted spermatozoa sequentially exposed to the composite seminal plasma, the SP) ought to define the homeostasis of the testes, the epididymis, and the accessory sexual glands. Yet, linking findings in the ejaculate to sperm production biology and fertility is suboptimal. The present essay critically reviews how the ejaculate of a fertile boar can help us to diagnose both reproductive health and resilience to semen handling, focusing on methods -available and under development- to identify suitable biomarkers for cryotolerance and fertility. Bulk SP, semen proteins and microRNAs (miRNAs) have, albeit linked to sperm function and fertility after AI, failed to enhance reproductive outcomes at commercial level, perhaps for just being components of a complex functional pathway. Hence, focus is now on the interaction sperm-SP, comparing in vivo with ex vivo, and regarding nano-sized lipid bilayer seminal extracellular vesicles (sEVs) as priority. sEVs transport fragile molecules (lipids, proteins, nucleic acids) which, shielded from degradation, mediate cell-to-cell communication with spermatozoa and the female internal genital tract. Such interaction modulates essential reproductive processes, from sperm homeostasis to immunological female tolerance. sEVs can be harvested, characterized, stored, and manipulated, e.g. can be used for andrological diagnosis, selection of breeders, and alternatively be used as additives to improve cryosurvival and fertility.

Breaking Bad Proteins-Discovery Approaches and the Road to Clinic for Degraders.

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.