Future Options Research Articles

Epigenetics of Fear, Anxiety and Stress - Focus on Histone Modifications.

Fear-, anxiety- and stress-related disorders are among the most frequent mental disorders. Given substantial rates of insufficient treatment response and often a chronic course, a better understanding of the pathomechanisms of fear-, anxiety- and stress-related disorders is urgently warranted. Epigenetic mechanisms such as histone modifications - positioned at the interface between the biological and the environmental level in the complex pathogenesis of mental disorders - might be highly informative in this context. The current state of knowledge on histone modifications, chromatin-related pharmacology and animal models modified for genes involved in the histone-related epigenetic machinery will be reviewed with respect to fear-, anxiety- and stress-related states. Relevant studies, published until 30th June 2022, were identified using a multi-step systematic literature search of the Pub- Med and Web of Science databases. Animal studies point towards histone modifications (e.g., H3K4me3, H3K9me1/2/3, H3K27me2/3, H3K9ac, H3K14ac and H4K5ac) to be dynamically and mostly brain region-, task- and time-dependently altered on a genome-wide level or gene-specifically (e.g., Bdnf) in models of fear conditioning, retrieval and extinction, acute and (sub-)chronic stress. Singular and underpowered studies on histone modifications in human fear-, anxiety- or stress-related phenotypes are currently restricted to the phenotype of PTSD. Provided consistent validation in human phenotypes, epigenetic biomarkers might ultimately inform indicated preventive interventions as well as personalized treatment approaches, and could inspire future innovative pharmacological treatment options targeting the epigenetic machinery improving treatment response in fear-, anxiety- and stressrelated disorders.

Abstract 2847: Study of spatial and temporal epigenetic heterogeneity in neuroblastoma suggests role of H3K27me3-mediated repression

Abstract Introduction: Trimethylation of Histone 3 Lysine 27 (H3K27) is widely understood to be a mark associated with gene repression and linked to gene silencing during development. Neuroblastoma, a developmental pediatric extracranial solid malignancy, has a relatively silent mutational landscape. Therefore, epigenetic modifications, including H3K27me3 mediated repression, could explain underlying developmental origins and the wide clinical heterogeneity observed. While previous studies have focused on the role of distinct super enhancer histone marks and their core regulatory circuits, less is understood about repressive control. We aimed to therefore investigate the role of H3K27me3-mediated repression in Neuroblastoma patients. Methods: Genome-wide H3K27me3 ChIP-Seq profiles were obtained from 48 diagnostic tissue biopsies covering all clinical and molecular patient subgroups. Transcriptome sequencing, ChIP-Seq of additional histone marks and WES/WGS was also performed on the same samples and on a panel of Neuroblastoma cell line models, with multiomics integrative analysis to validate findings. HMCAN, deepTools, DiffBind and ROSE packages were used to analyze the ChIP-seq data. Results: A comparison of H3K27me3 regions across all patient ChIP-Seq profiles, identified commonly repressed genes specific to Neuroblastoma. These genes are enriched in development and differentiation pathways, with significantly lower RNA expression levels than other publicly available pediatric tumor datasets. When compared to publicly available single cell RNAseq of the healthy adrenal medulla, we can further highlight a potential role of H3K27me3-mediated repression in regulating cell lineage commitment and differentiation ability. In addition, we identified that patient samples cluster into their clinical subgroups based on H3K27me3 patterns and differentially repressed genes, specifically between MYCN-amplified and non-amplified high-risk groups. A CRISPR screen to further validate the functional role of these repressed genes is being carried out. Conclusions: To our knowledge, this study shows for the first time that understanding of H3K27me3 mediated repression in Neuroblastoma, can uncover new insights into both disease development and clinical subclassifications. This knowledge will be important when considering future potential novel treatment options. Citation Format: Charlotte Butterworth, Alexandra Saint-Charles, Yasmine Iddir, Jaydutt Bhalshankar, Angela Bellini, Charles Bobin, Elisa Wecht, Young-Gyu Park, Caroline Louis, Virginie Raynal, Dominique Plantaz, Hervé Sartelet, Valérie Combaret, Gaelle Pierron, Isabelle Janoueix-Lerosey, Kai-Oliver Henrich, Olivier Delattre, Frank Westermann, Gudrun Schleiermacher. Study of spatial and temporal epigenetic heterogeneity in neuroblastoma suggests role of H3K27me3-mediated repression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2847.

Checking the Status: The Evolutionary Explanations and Drug Resistance Prevalence to Dolutegravir for HIV Treatment (A Review)

Drug treatment advancements for HIV have dramatically advanced since the virus’ identification in the early 1980s. Integrase strand transfer inhibitors (INSTIs) are one of seven HIV treatment drug classes currently utilized to create an undetectable viral count in blood samples of people living with HIV (PLWH). First generation INSTIs are documented with low barriers of genetic resistance, which indicates that the number of mutations to lead to a drug resistant mutation is low. The introduction of dolutegravir, a second generation INSTI, shows a higher barrier of genetic resistance that will reduce drug resistant mutations to INSTIs and increase the overall effectiveness of this class of HIV treatment. PLWH can be categorized based on whether they received treatment previously/currently or have never received treatment. Therapy naive and previously treated (successfully or unsuccessfully) patients for HIV report different rates of drug resistant mutations compared to actual resistance to dolutegravir, 0.4-31% and 0.1-67.2% respectively. Evolutionary considerations of genetic resistance, including epistatic interactions and point mutations, suggest both non-polymorphic and polymorphic mutations for these drug resistant mutations. An incomplete understanding of how evolutionary factors contribute to HIV drug resistance highlights the importance of conducting further research. This research may help improve the efficacy of second generation INSTIs in future treatment options for PLWH. This review describes the landscape of existing research on drug resistance prevalence for dolutegravir and possible evolutionary explanations on how these mutations arise in the first place, leading to implications in developing more robust treatment modalities.

Research progress and future development direction of Alzheimer's therapy

Dementia has become a global crisis, numbering over 50 million people in the world, more than half of whom are Alzheimers disease (AD)s patients. AD is a heterogeneous disease that has complex pathobiologic properties. The exact AD mechanism is unclear at this point, but the pathological hallmarks constitute amyloid- (A) plaques and tau neurofibrillary tangles and most treatments are based on this. AD has a serious impact on society and on humanity, but drugs approved to treat AD are few and ineffective. The article analyzes the possible causes of pathological hallmarks and describes existing treatment options, as well as their shortcomings and potential future treatments. It also speculates on the direction of possible future therapeutic options providing reference for more new technologies and methods of treating AD in the future. However, there are still many unclear pathogenic mechanisms and more effective treatments are needed for further research on AD in the future.

Contemporary visions of the next apocalypse: Climate change and artificial intelligence

The ancient Greco-Roman and Judeo-Christian traditions are the main sources of the eschatological compositions of the apocalypse. Through the combination of various symbolic elements and a prefigured narrative, apocalyptic visions offer a script that can be applied in diverse historical situations to deal with the uncertainty of the present, to justify political action and to allocate resources. In contemporary society, the high complexity and significance of the socio-natural and socio-technical operations in the domains of climate change and artificial intelligence create a fertile ground for the proliferation of apocalyptic eschatologies. The analysis shows that while the use of the apocalyptic script indeed motivates action in the present to avoid a future posited as unavoidable, it also generates strong moral and political distinctions that emphasize a unilateral projection of the future and undervalue alternative possibilities. The article concludes that apocalyptic eschatology promotes a ritualistic action in the present that evades the explanation of the complex causalities underlying climate change and artificial intelligence. The magnetism of the apocalyptic narrative lies in its ability to motivate action based on a recognizable architecture, but in doing so, it precludes alternative future options.

Clostridioides difficile infection: history, epidemiology, risk factors, prevention, clinical manifestations, treatment, and future options.

SUMMARYClostridioides difficile infection (CDI) is one of the major issues in nosocomial infections. This bacterium is constantly evolving and poses complex challenges for clinicians, often encountered in real-life scenarios. In the face of CDI, we are increasingly equipped with new therapeutic strategies, such as monoclonal antibodies and live biotherapeutic products, which need to be thoroughly understood to fully harness their benefits. Moreover, interesting options are currently under study for the future, including bacteriophages, vaccines, and antibiotic inhibitors. Surveillance and prevention strategies continue to play a pivotal role in limiting the spread of the infection. In this review, we aim to provide the reader with a comprehensive overview of epidemiological aspects, predisposing factors, clinical manifestations, diagnostic tools, and current and future prophylactic and therapeutic options for C. difficile infection.

Effectiveness of Combination Chemotherapy With Docetaxel, Nedaplatin, and 5-Fluorouracil for Advanced and Recurrent Esophageal Cancer.

Chemotherapy and immunotherapy have been recently developed as potentially useful first-line treatments for unresectable, advanced, or recurrent esophageal cancer. We performed a retrospective study of the therapeutic effectiveness of triplet chemotherapy with docetaxel, nedaplatin, and 5-fluorouracil therapy for advanced, recurrent, and unresectable advanced esophageal cancer at our hospital and compared the regimen's results with those of current and possible future treatment options. The study cohort comprised 101 patients who received docetaxel, nedaplatin, and 5-fluorouracil for advanced or recurrent esophageal cancer at Gunma University from May 2008 to December 2017. We retrospectively evaluated the results of this combination chemotherapy and postulated future treatment strategies. The overall response and disease control rates, the latter including stable disease, for docetaxel, nedaplatin, and 5-fluorouracil were 33.6% and 61.4%, respectively. The median overall survival and progression-free survival were 12.26 months and 5.1 months, respectively. In patients with recurrence, the median overall and progression-free survivals were 14.97 months (449 days) and 5.1 months (152 days), respectively. No study patients developed acute kidney injury and there were no treatment-related deaths. However, leukopenia and neutropenia were frequent hematologic toxicities. Treatment with docetaxel, nedaplatin, and 5-fluorouracil for advanced or recurrent esophageal cancer is particularly useful for recurrent cases and has the advantage of not causing severe renal dysfunction.

Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest.

In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.

The Future of Food Allergy Management: Advancements in Therapies.

To review current and future treatment options for IgE-mediated food allergy. Recent years have seen major developments in both allergen-specific and allergen-non-specific treatment options, with the first FDA-approved peanut oral immunotherapy (OIT) product becoming available in 2020. In addition to OIT, other immunotherapy modalities, biologics, adjunct therapies, and novel therapeutics are under investigation. Food allergy is a potentially life-threatening condition associated with a significant psychosocial impact. Numerous products and protocols are under investigation, with most studies focusing on OIT. A high rate of adverse events, need for frequent office visits, and cost remain challenges with OIT. Further work is needed to unify outcome measures, develop treatment protocols that minimize adverse events, establish demographic and clinical factors that influence candidate selection, and identify patient priorities.

Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT)

Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference-0.6%, 95% CI-3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P=0.08) over the entire follow-up period. A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. The National Institute for Health Research Health Technology Assessment programme.

Concerning Personality Tests and Human Resource Performance: Wataseuake.com Analysis System Literature Review

The potential of personality tests to enhance HR management and worker output has attracted a lot of interest. The Wataseuake.com Analysis System is a novel approach to assessing employees' personalities that makes use of adaptive testing processes, cutting-edge algorithms, and real-time data analytics. Integrating AI and ML allows us to evaluate the system's reliability and validity in comparison to widely used personality tests while also addressing privacy and ethics concerns. The research also discusses the constraints and future advancements in human resource management, as well as the long-term effects of using the Wataseuake.com Analysis System in different types of organizations. Future enhancements and customization options for the system are also addressed. This study adds to the ongoing discussion on how to enhance modern human resource practices by synthesizing existing research, calling attention to knowledge gaps, and discussing the real-world implications of this innovative strategy. The results imply that improving our knowledge of employee characteristics may improve recruiting, teamwork, and output. modern human resource practices by integrating previous research, highlighting gaps in knowledge, and providing insights into the practical consequences of this new approach. In this article, we will look at how personality testing has affected employment performance. It looks at the validity, reliability, and ethical concerns of these tests from a psychometric perspective. The findings of the research imply that a better grasp of employee personalities might boost recruitment efforts, collaboration, and productivity. Insights from the review help plan future studies.

Current and Future Treatment of Food Allergies

Food allergy prevalence is rapidly growing among school-age children in the United States, posing a significant health concern in school settings. This article aims to provide an overview of the current state of food allergy treatment options, emergency food allergy care plans, and using epinephrine autoinjectors. In addition, it explores potential future treatment options, including immunotherapy and novel therapeutic approaches. This article emphasizes the crucial role of school nurses in recognizing the treatment options currently available to students and their families, as well as fostering a safe environment for students with food allergies.

(267) The Prevalence of Conditions Involving Aberrant Mast Cell Activity in Patients with Neuroproliferative Vestibulodynia

Abstract Introduction Neuroproliferative vestibulodynia (NPV) is a provoked vestibular pain, shown to be associated with excess immunohistochemical staining for CD117 and PGP9.5, consistent with mast cells and nerves, respectively. It is hypothesized that NPV occurs in genetically predisposed patients in whom mast cells accumulate in the vestibular sub-epithelial stroma where they release various cytokines/growth factors that stimulate the growth of nerves, causing severe allodynia and hyperalgesia throughout the entire vestibule. Objective To assess, in our patient cohort with histopathologically confirmed diagnosis of NPV, the prevalence of concomitant conditions involving aberrant mast cell activity. Methods Medical records from people with vulvas who underwent vestibulectomy between June 1, 2019 and December 31, 2022 were retrospectively reviewed. This research protocol was IRB-exempt. Histories from these patients, all of whom had histopathologically confirmed NPV after observing > 8 immunopositive CD117 stained cells per high-power field in the sub-epithelial stroma, were reviewed. The prevalence was noted for the presence of concomitant conditions where aberrant mast cell activity has been reported to play a critical role in symptomatology. The focus was on the following eight conditions: asthma, chronic sinusitis, endometriosis, food allergy/intolerance, interstitial cystitis, irritable bowel syndrome, migraine, and postural orthostatic tachycardia syndrome. Results A total of 65 NPV patients were included in this chart review. While 24 (37%) reported none, 41 (63%) had at least one other concomitant condition involving aberrant mast cell activity. A total of 25 (38%), 10 (15%), 4 (6%) and 2 (3%) had one, two, three and five other conditions, respectively, involving aberrant mast cell activity. The most common such condition was migraine (n=14; 22%), followed by endometriosis (n=12; 19%), food allergy/intolerance (n=11; 17%), interstitial cystitis (n=10; 15%), irritable bowel syndrome (n=8; 12%), asthma (n=7; 11%), chronic sinusitis (n=5; 8%) and postural orthostatic tachycardia syndrome (n=2; 3%). There was no correlation between the number of concomitant conditions with aberrant mast cell activity reported and the density of CD117-immunopositive staining in the overall cohort of patients with NPV or within the subgroups of those with either lifelong or acquired NPV. Conclusions Patients with histopathologically confirmed NPV have a high prevalence of concomitant conditions associated with aberrant mast cell activity. While more studies are needed, NPV is likely part of a broader systemic collection of conditions associated with aberrant mast cell activity. This finding is relevant in terms of future diagnostic and treatment options for patients with NPV. Disclosure No.

Abstract WP227: Deep Medullary Vein Thrombosis in Neonates

Introduction: Deep medullary vein(DMV) thrombosis is a rare cause of neurological damage noted in both term and preterm infants. Although their incidence in children is not know, DMV thrombosis can occur isolated or in association with cerebral sinovenous thrombosis (CSVT). The spectrum of parenchymal radiological findings in DMV thrombosis includes edema and hemorrhage of variable extent. No clinical trials or definite treatment algorithms are available for DMV thrombosis in neonates. The choice of antithrombotic therapy is therefore based on the experience of the single centers or on indications extrapolated from available guidelines on CSVT. Aims: There are limited guidelines for the management of DMV thrombosis in literature. Recently published systematic review in neonates found a total of only 75 cases in literature. In none of these cases treatment options were described. We aim to present a single institute experience describing 3 cases of neonatal DMV thrombosis and different management methods. Methods and findings: Between July-August 2023, we prospectively studied 3 neonates with deep medullary vein thrombosis as evidenced by characteristic hemorrhage noted on MRI. For the 1st patient no anticoagulation was initially started given co-morbid conditions and critical illness. However, repeat imaging showed worsening of hemorrhage, thereby indicating progression of thrombosis resulting in venous hemorrhage. Pt was therefore stared on AC with LMWH. No worsening hemorrhage was noted thereafter. For the 2nd patient, AC was not started & no progression of thrombosis was noted. For the 3rd patient AC was started from a cardiac standpoint and no worsening in hemorrhage was noted. Observation: 1. Anticoagulation in patient with progression of DMV thrombosis did not worsen existing hemorrhage and prevented further propagation of clot. 2. No anticoagulation did not result in worsening of thrombosis and it likely self resolved in the absence of other comorbid conditions. 3. Anticoagulation used for a different indication did not worsen existing intraparenchymal hemorrhage. Next steps: 1. To conduct a retrospective chart review on a larger cohort of patients. This will help future studies and management options for this rare condition.

Qualitative focus group discussions exploring PrEP method and service delivery preferences among female sex workers and their managers in four Zambian provinces

ObjectivesTo describe the experiences of oral HIV pre-exposure prophylaxis (PrEP) use, preferences comparing oral PrEP to future long-acting PrEP products (the dapivirine vaginal ring (PrEP ring) and injectable cabotegravir (CAB...

Implied roughness in the term structure of oil market volatility

This paper analyses the attributes and the significance of the roughness of oil market volatility. We employ unspanned stochastic volatility models driven by rough Brownian motions that yield semi-analytical prices for future options entailing efficient calibration applications. By performing a Monte Carlo simulation study, we show that the semi-analytical pricing performs well thus establishing its efficiency for calibration applications. Thus we calibrate option prices written on oil futures and provide empirical evidence of the roughness in oil volatility. Introducing just one additional parameter, the Hurst parameter, indicating the roughness of the volatility improves the calibration by almost a factor of 10. The calibrated option-implied Hurst parameter varies over time, but the entire set of parameters becomes more stable than in the non-rough case corresponding to a fixed Hurst parameter 1/2. These results underscore the importance to model the time dependency of the roughness of oil market volatility.

Kynurenines, Neuronal Excitotoxicity, and Mitochondrial Oxidative Stress: Role of the Intestinal Flora.

The intestinal flora has been the focus of numerous investigations recently, with inquiries not just into the gastrointestinal aspects but also the pathomechanism of other diseases such as nervous system disorders and mitochondrial diseases. Mitochondrial disorders are the most common type of inheritable metabolic illness caused by mutations of mitochondrial and nuclear DNA. Despite the intensive research, its diagnosis is usually difficult, and unfortunately, treating it challenges physicians. Metabolites of the kynurenine pathway are linked to many disorders, such as depression, schizophrenia, migraine, and also diseases associated with impaired mitochondrial function. The kynurenine pathway includes many substances, for instance kynurenic acid and quinolinic acid. In this review, we would like to show a possible link between the metabolites of the kynurenine pathway and mitochondrial stress in the context of intestinal flora. Furthermore, we summarize the possible markers of and future therapeutic options for the kynurenine pathway in excitotoxicity and mitochondrial oxidative stress.

P830 The potential role of artificial intelligence in selecting the modality of biological therapy in patients with inflammatory bowel disease

Abstract Background Selecting an appropriate treatment strategy for inflammatory bowel disease (IBD) is an important task that can significantly alter the clinical course of the disease. Advanced artificial intelligence language models, such as ChatGPT, represent a potential future option that can assist practitioners. ChatGPT can help search the internet for medical facts by summarizing information from medical sources and providing concise explanations, simplifying the process of accessing and understanding medical information. Methods A ChatGPT-guided analysis of 89 IBD patients treated at the Clinical Department of Gastroenterology and Hepatology at University Medical Center "Zvezdara", Belgrade was conducted, considering further treatment with some biological drugs. A treatment modality proposal was obtained through communication with the interactive software ChatGPT (OpenAI, CA USA) and providing complete clinical and laboratory data. The alignment of decisions was analyzed, along with an assessment of treatment success in the group with matching and differing choices. Results In 72 patients (81%), there was concordance in the choice of therapy between ChatGPT and the medical consultation, while in 17 patients, ideas about the treatment approach differed. The most common difference in the choice of therapeutic modality related to the software's selection of ustekinumab compared to our choice of vedolizumab in patients with Crohn's disease who were not biologically naive, affecting seven patients with these characteristics. In 4 patients with severe ulcerative colitis, ChatGPT recommended using cyclosporine in combination with vedolizumab, contrary to the medical consultation's decision to use Anti-TNFα therapy. The group of patients in whom the artificial intelligence advice differed from the medical consultation was in a clinically more severe stage of the disease (CRP 10.4 vs. 9.1, p=0.0293), with worse endoscopic findings (proportion of severe endoscopic disease SES CD≥33/Mayo score>2, 53% vs. 24%, p=0.019). Taking into account the baseline differences in these patient groups, multiple analyses of covariance did not reveal a significant difference in the ultimate treatment outcome - proportions of endoscopic (p=0.773) and clinical remission (p=0.296) between patient groups. Conclusion The integration of advanced artificial intelligence language models may represent a future tactic with the potential to assist practitioners in making decisions about the treatment modality for IBD patients, but clinical experience should be considered.

Pulmonary toxicity of immune checkpoint immunotherapy.

Cancer remains a leading cause of mortality on a global scale. Lung cancer, specifically non-small cell lung cancer (NSCLC), is a prominent contributor to this burden. The management of NSCLC has advanced substantially in recent years, with immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), leading to improved patient outcomes. Although generally well tolerated, the administration of ICIs can result in unique side effects known as immune-related adverse events (irAEs). The occurrence of irAEs involving the lungs, specifically checkpoint inhibitor pneumonitis (CIP), can have a profound effect on both future therapy options and overall survival. Despite CIP being one of the more common serious irAEs, limited treatment options are currently available, in part due to a lack of understanding of the underlying mechanisms involved in its development. In this Review, we aim to provide an overview of the epidemiology and clinical characteristics of CIP, followed by an examination of the emerging literature on the pathobiology of this condition.

Erosive Hand Osteoarthritis: Recent Advances and Future Treatments.

Erosive hand osteoarthritis (EHOA) is an aggressive form of hand osteoarthritis that leads to significant disability, and recent data suggests that it is increasing in prevalence. This review provides an update of our current understanding of epidemiology, genetic associations, biomarkers, pathogenesis, and treatment of EHOA, with particular focus on studies published within the last 5 years. New studies of EHOA have identified new genetic loci associated with disease, including variants in genes involved in inflammation and bone remodeling. Preclinical studies implicate pathways of innate immunity, including some that may be causal in the condition. Recent novel studies showed that inflammatory features identified by ultrasound and MRI are associated with development of erosive lesions over time on conventional radiography. In the future, these imaging modalities may be useful in identifying patients at risk of adverse outcomes. Promising new findings in genetics, biomarkers, and treatment targets will hopefully allow for future therapeutic options for this debilitating condition.