First-in-Class Mitogen-Activated Protein Kinase p38α: MAPK-Activated Protein Kinase-2 (MK2) Dual Signal Modulator with Anti-inflammatory and Endothelial-stabilizing Properties.

We previously identified a small molecule, UM101, predicted to bind to the substrate-binding groove of p38aMitogen-activated Protein Kinase (MAPK) near the binding site of its proinflammatory substrate, MAPK-activated protein kinase (MK2). UM101 exhibited anti-inflammatory, endothelial-stabilizing, and lung-protective effects. To overcome its limited aqueous solubility and p38a binding affinity, we designed an analog of UM101, GEn-1124, with improved aqueous solubility, stability, and p38a binding affinity. Compared with UM101, GEn-1124 has 18-fold greater p38a-binding affinity as measured by Surface Plasmon Resonance (SPR), 11-fold greater aqueous solubility, enhanced barrier-stabilizing activity in thrombin-stimulated human pulmonary artery endothelial cells (hPAEC) in vitro, and greater lung protection in vivo GEn-1124 improved survival from 10% to 40% in murine acute lung injury (ALI) induced by combined exposure to intratracheal bacterial endotoxin lipopolysaccharide (LPS) instillation and febrile-range hyperthermia (FRH) and from 0% to 50% in a mouse influenza pneumonia model. Gene expression analysis by RNASeq in TNFa-treated hPAEC showed that the gene-modifying effects of GEn-1124 were much more restricted to TNFa-inducible genes than the catalytic site p38 inhibitor, SB203580. Gene expression pathway analysis, confocal immunofluorescence analysis of p38aand MK2 subcellular trafficking, and SPR analysis of phosphorylated p38a:MK2 binding affinity supports a novel mechanism of action. GEn-1124 destabilizes the activated p38a:MK2 complex, dissociates nuclear export of MK2 and p38a, thereby promoting intranuclear retention and enhanced intranuclear signaling by phosphorylated p38a retention, and accelerated inactivation of p38-free cytosolic MK2 by unopposed phosphatases. Significance Statement We describe an analog of our first-in-class small molecule modulator of p38a/MK2 signaling targeted to a pocket near the ED substrate binding domain of p38a, which destabilizes the p38a:MK2 complex without blocking p38 catalytic activity or ablating downstream signaling. The result is a rebalancing of downstream pro- and anti-inflammatory signaling, yielding anti-inflammatory, endothelial-stabilizing, and lung-protective effects with therapeutic potential in ARDS.

Wide Variability of the Definitions Used for Native Vertebral Osteomyelitis: Walking the Path for a Unified Diagnostic Framework with a Meta-Epidemiological Approach.

BACKGROUND CONTEXT: Native Vertebral Osteomyelitis (NVO) has seen a rise in incidence, yet clinical outcomes remain poor with high relapse rates and significant long-term sequelae. The 2015 IDSA Clinical Practice Guidelines initiated a surge in scholarly activity on NVO, revealing a patchwork of definitions and numerous synonyms used interchangeably for this syndrome. PURPOSE: To systematically summarize these definitions, evaluate their content, distribution over time, and thematic clustering. STUDY DESIGN/SETTING: Meta-epidemiological study with a systematic review of definitions. PATIENTS SAMPLE: An extensive search of multiple databases was conducted, targeting trials and cohort studies dating from 2005 to present, providing a definition for NVO and its synonyms. OUTCOME MEASURES: Analysis of the diagnostic criteria that composed the definitions and the breaking up of the definitions in the possible combinations of diagnostic criteria. METHODS: We pursued a thematic synthesis of the published definitions with Boolean logic, yielding single or multiple definitions per included study. Using eight predefined diagnostic criteria, we standardized definitions, focusing on the minimum necessary combinations used. Definition components were visualized using Sankey diagrams. RESULTS: The literature search identified 8,460 references, leading to 171 studies reporting on 21,963 patients. Of these, 91.2% were retrospective, 7.6% prospective, and 1.2% RCTs. Most definitions originated from authors, with 29.2% referencing sources. We identified 92 unique combinations of diagnostic criteria across the literature. Thirteen main patterns emerged, with the most common being clinical features with imaging, followed by clinical features combined with imaging and microbiology, and lastly, imaging paired with microbiology. CONCLUSIONS: Our findings underscore the need for a collaborative effort to develop standardized diagnostic criteria. We advocate for a future Delphi consensus among experts to establish a unified diagnostic framework for NVO, emphasizing the core components of clinical features and MRI while incorporating microbiological and histopathological insights to improve both patient outcomes and research advancements.

The Influence of the Home Food Environment on the Eating Behaviors, Family Meals, and Academic Achievement of Adolescents in Schools in the UAE.

The eating behavior (EB) and habits developed during adolescence tend to persist into adulthood, with parents and caregivers playing a significant role in shaping their children's food choices. The home environment is a crucial setting for developing eating behavior during adolescence. This study aimed to explore the influence of the home food environment (HFE) and its correlates on EB, family meals (FMs), and academic achievement among adolescents in schools in the United Arab Emirates (UAE). A cross-sectional study was conducted with 304 school-aged adolescents from the UAE. The questionnaire included sociodemographic data, dietary habits, information related to the HFE (food availability and accessibility), physical activity, sleep patterns, and academic achievement. Several questionnaire items were combined to create an HFE score. These questions included the frequency of weekly family meals, meal preparation practices, and accessibility to healthy and unhealthy food products and snacks at home. The HFE score was dichotomized into favorable and unfavorable HFE scores. Similarly, EB and FM scores were generated by combining responses to various related questions. The participants' weights and heights were measured. The findings reported that more than half (55%) of the adolescents were either overweight or obese. The majority of the participants had favorable HFE (57.2%), EB (69.1%), and FM scores (58.2%). The significant correlates to the HFE were as follows: male participants whose parents attended college (OR: 0.31; 95% CI: 0.15-0.62; p < 0.001), high academic achievers (OR: 1.98; 95% CI: 1.02-3.82; p = 0.043), and those who were physically active (OR: 1.80; 95% CI: 1.14-2.85; p = 0.012), were more likely to have favorable HFE. Moreover, the HFE score showed a highly significant positive correlation with the EB score (r = 0.573, p < 0.001) and the FM score (r = 0.384, p < 0.001). These results underscore the critical role of a healthy HFE in shaping healthy positive eating behaviors and food choices among adolescents. They provide a foundation for developing effective, evidence-based policies that can impact the health and academic success of adolescents in the UAE.

Plasma Microbial Cell-free DNA Next-generation Sequencing Can Be a Useful Diagnostic Tool in Patients With Osteoarticular Infections.

Background: Recent advances in shotgun metagenomic sequencing (sMGS) for detecting microbial cell-free DNA (mcfDNA) in peripheral blood have shown promise across various patient populations. This study evaluates the application of sMGS for diagnosing osteoarticular infections (OAIs), a condition with significant diagnostic challenges. Methods: We conducted a retrospective analysis on 73 patients suspected of OAIs at the Mayo Clinic from 2019 to 2023, incorporating mcfDNA sMGS (Karius test [KT]) into their diagnostic evaluation. We categorized the clinical impact of KT on OAI diagnoses and management into 4 distinct outcomes. (1) KT was able to confirm an established diagnosis, (2) KT supported noninfectious diseases diagnosis, (3) KT established an unsuspected diagnosis, (4) KT did not add relevant information. Results: In our cohort, KT was performed in 73 patients. Among the infected individuals, KT yielded positive results in 22 of 43 (51.2%) cases. Of these 22 cases, 11 (50%) showed agreement with conventional diagnostic workup, whereas in 5 (22.7%) cases, the KT established an unsuspected diagnosis. Native vertebral osteomyelitis diagnosis (P < .001) or OAIs with concomitant presence of endocarditis or endovascular infection (P = .005) were statistically associated with a definite, probable, or possible diagnostic certainty of KT result. Conclusions: In complex OAIs, KT enhanced diagnostic accuracy by 11.6%, proving especially beneficial in diagnosing native vertebral osteomyelitis and infections with concurrent endocarditis or endovascular complications. Our findings underscore the utility of KT in the diagnostic workflow for challenging OAI cases, potentially altering clinical management for a significant subset of patients.

It is time for a unified definition of native vertebral osteomyelitis: a framework proposal.

In recent years, there has been a notable increase in research output on native vertebral osteomyelitis (NVO), coinciding with a rise in its incidence. However, clinical outcomes remain poor, due to frequent relapse and long-term sequelae. Additionally, the lack of a standardized definition and the use of various synonyms to describe this condition further complicate the clinical understanding and management of NVO. We propose a new framework to integrate the primary diagnostic tools at our disposal. These collectively fall into three main domains: clinical, radiological, and direct evidence. Moreover, they and can be divided into seven main categories: (a) clinical features, (b) inflammatory biomarkers, (c) imaging techniques, microbiologic evidence from (d) blood cultures and (e) invasive techniques, (f) histopathology, and (g) empirical evidence of improvement following the initiation of antimicrobial therapy. We provide a review on the evolution of these techniques, explaining why no single method is intrinsically sufficient to formulate an NVO diagnosis. Therefore, we argue for a consensus-driven, multi-domain approach to establish a comprehensive and universally accepted definition of NVO to enhance research comparability, reproducibility, and epidemiological tracking. Ongoing research effort is needed to refine these criteria further, emphasizing collaboration among experts through a Delphi method to achieve a standardized definition. This effort aims to streamline research, expedite accurate diagnoses, optimize diagnostic tools, and guide patient care effectively.

Novel Topical Treatments for Itch.

The experience of itch often poses a burden on patient quality of life and has the capacity to inflict significant suffering. Topical therapies are a mainstay of treatment for many cutaneous and systemic diseases and afford patients the opportunity to manage their conditions without many of the systemic side effects of non-topical therapies. We review a multitude of new topical medications targeting the skin, immune system, and neural receptors. The list includes Janus kinase inhibitors, tyrosine kinase inhibitors, phosphodiesterase inhibitors, transient receptor vanilloid inhibitors, topical cannabinoids, and topical acetaminophen. Many of the topical therapies reviewed show promising data in phase 2-3 clinical trials, but further research is needed to compare therapies head-to-head and test their efficacy on a broader range of conditions.

Recent advances in the treatment of Ebola disease: A brief overview.

Ebola disease (EBOD) remains a significant and ongoing threat to African countries, characterized by a mortality rate of 25% to 90% in patients with high viral load and significant transmissibility. The most recent outbreak, reported in Uganda in September 2022, was declared officially over in January 2023. However, it was caused by the Sudan Ebola virus (SUDV), a culprit species not previously reported for a decade. Since its discovery in 1976, the management of EBOD has primarily relied on supportive care. Following the devastating outbreak in West Africa from 2014 to 2016 secondary to the Zaire Ebola virus (EBOV), where over 28,000 lives were lost, dedicated efforts to find effective therapeutic agents have resulted in considerable progress in treating and preventing disease secondary to EBOV. Notably, 2 monoclonal antibodies-Ebanga and a cocktail of monoclonal antibodies, called Inmazeb-received Food and Drug Administration (FDA) approval in 2020. Additionally, multiple vaccines have been approved for EBOD prevention by various regulatory bodies, with Ervebo, a recombinant vesicular stomatitis virus-vectored vaccine against EBOV being the first vaccine to receive approval by the FDA in 2019. This review covers the key signs and symptoms of EBOD, its modes of transmission, and the principles guiding supportive care. Furthermore, it explores recent advancements in treating and preventing EBOD, highlighting the unique properties of each therapeutic agent and the ongoing progress in discovering new treatments.

Patterns and predictors of positive multiplex polymerase chain reaction respiratory panel among patients with acute respiratory infections in a single center in Lebanon.

BACKGROUND: Infectious agents associated with community-acquired acute respiratory infections (ARIs) remain understudied in Lebanon. We aim to assess the microbiological profiles of ARIs by employing polymerase chain reaction (PCR) and identifying predictors of positive PCR results among patients admitted for ARI. METHODS AND RESULTS: We conducted a retrospective single-center study at the American University of Beirut Medical Center, including all respiratory PCR panels performed on pediatric (< 18) and adult (≥ 18) patients presenting with an ARI from January 2015 to March 2018, prior to the onset of the COVID-19 pandemic. We aimed to identify the epidemiological patterns of ARIs and the factors associated with positive PCRs in both adult and pediatric patients. Among 281 respiratory PCRs, 168 (59.7%) were positive for at least one pathogen, with 54.1% positive PCR for viruses, 7.8% for bacteria species, and 3.9% with virus-bacteria codetection. Almost 60% of the patients received antibiotics prior to PCR testing. PCR panels yielded more positive results in pediatric patients than in adults (P = 0.005). Bacterial detection was more common in adults compared to pediatrics (P < 0.001). The most common organism recovered in the entire population was Human Rhinovirus (RhV) (18.5%). Patients with pleural effusion on chest CT were less likely to have a positive PCR (95% Cl: 0.22-0.99). On multivariate analysis, pediatric age group (P < 0.001), stem cell transplant (P = 0.006), fever (P = 0.03) and UTRI symptoms (P = 0.004) were all predictive of a positive viral PCR. CONCLUSION: Understanding the local epidemiology of ARI is crucial for proper antimicrobial stewardship. The identification of factors associated with positive respiratory PCR enhances our understanding of clinical characteristics and potential predictors of viral detection in our population.

Valorization of Citrus peels: GC/MS-based metabolites profiling, multivariate analysis, and antiaging potential.

Aging and agro-waste are major challenges. Natural ingredients are preferred in skincare. This study intended to isolate the essential oils (EO) from the leftover peels obtained from three commonly edible Citrus species fruit peels, namely Citrus paradisi (grapefruit), Citrus sinensis (sweet orange), and Citrus deliciosa (mandarin). Gas chromatography/mass spectrometry analysis identified volatile constituents in EO and headspace aroma. Multivariate analysis distinguished between the three species. The antiaging effects of Citrus EO were assessed in vitro and in silico, studying volatile interactions with target enzymes. C. sinensis peels had the highest oil yield, rich in monoterpenes. C. paradisi and C. deliciosa contained sesquiterpenes. Limonene dominated the hydrodistilled EO: 94.50% in C. paradisi, 96.80% in C. sinensis, and 80.66% in C. deliciosa. Unsupervised multivariate analysis of Citrus species revealed that  d-limonene, γ-terpinene, and ß-pinene are the key phytochemical markers contributing to their diverse chemical composition. C. paradisi exhibited the highest enzyme inhibitory activity, with IC50 values of 12.82, 27.58, and 18.16 µg/mL for tyrosinase, elastase, and collagenase, respectively. In silico studies showed that the volatiles can inhibit the tested antiaging enzymes. According to these findings, the investigated agro-waste might slow aging in skin care.

Locally Advanced Gastric Cancer Management: A Cost-Effectiveness Analysis.

Across the nation, patients with locally advanced gastric cancer (LAGC) are managed with modalities including upfront surgery (US) and perioperative chemotherapy (PCT). Preoperative therapies have demonstrated survival benefits over US and thus long-term outcomes are expected to vary between the options. However, as these 2 modalities continue to be regularly employed, we sought to perform a decision analysis comparing the costs and quality-of-life associated with the treatment of patients with LAGC to identify the most cost-effective option. We designed a decision tree model to investigate the survival and costs associated with the most commonly utilized management modalities for LAGC in the United States: US and PCT. The tree described costs and treatment strategies over a 6-month time horizon. Costs were derived from 2022 Medicare reimbursement rates using the third-party payer perspective for physicians and hospitals. Effectiveness was represented using quality-adjusted life-years (QALYs). One-way, two-way, and probabilistic sensitivity analyses were utilized to test the robustness of our findings. PCT was the most cost-effective treatment modality for patients with LAGC over US with a cost of $40,792.16 yielding 3.11 QALYs. US has a cost of $55,575.57 while yielding 3.15 QALYs; the incremental cost-effectiveness ratio (ICER) was $369,585.25. One-way and two-way sensitivity analyses favored PCT in all variations of variables across their standard deviations. Across 100,000 Monte Carlo simulations, 100% of trials favored PCT. In our model simulating patients with LAGC, the most cost-effective treatment strategy was PCT. While US demonstrated improved QALYs over PCT, the associated cost was too great to justify its use.

Intravenous difelikefalin for the treatment of hemodialysis pruritus.

INTRODUCTION: Patients with chronic kidney disease (CKD) undergoing hemodialysis often experience significant itch secondary to their condition and a subsequent reduction in their overall quality of life. Current treatments are underwhelming, necessitating the search for new, effective therapeutic options to combat itch in this population. AREAS COVERED: The purpose of this review is to explore the available data for the use of intravenous difelikefalin in patients with CKD undergoing hemodialysis. The pathophysiology of CKD-associated itch is multifactorial, with one proposed mechanism involving an imbalance in the endogenous opioid system, favoring upregulation of itch-activating µ-opioid receptors (MORs) and downregulation of itch-inhibiting κ-opioid receptors (KORs). Dysregulation of the immune system is also involved. Difelikefalin is a recent FDA approved treatment that functions as peripherally acting KOR agonist, targeting this imbalance in the endogenous opioid system seen in CKD patients with itch and having an anti-inflammatory effect on immune cells. Clinical data on intravenous difelikefalin is promising regarding its ability to reduce itch in CKD patients on hemodialysis and improve patient quality of life, with few, mild adverse side effects. EXPERT OPINION: As intravenous difelikefalin becomes more widely used in the clinical setting, further studies assessing long-term efficacy and safety will be needed.

Pruritus in keloid scars: mechanisms and treatments.

Keloids occur after cutaneous injury and can cause distress due to physical appearance and associated symptoms such as pain and pruritus. Keloid-associated pruritus is a common manifestation and has negative impacts on quality of life. The mechanism underlying this type of pruritus is multifactorial and thought to involve small nerve fiber damage, neurogenic inflammation, and a Th2-predominant inflammatory response. Various agents have been shown to reduce keloid pruritus, including intralesional corticosteroids, botulinum toxin A, 5-fluorouracil, and bleomycin. Other treatment modalities such as cryotherapy and hyperbaric oxygen therapy are also effective. Future treatments targeting the mechanisms involved in keloid-associated itch could provide improvements in pruritus and quality of life in these patients, but further studies on the efficacy of these agents are needed.

Itch: from the skin to the brain - peripheral and central neural sensitization in chronic itch.

Similar to chronic pain, chronic itch is frequently linked to neural sensitization, a phenomenon wherein the nervous system becomes hypersensitive to stimuli. This process of neural sensitization of chronic itch is orchestrated by various signaling pathways and mediators in both the peripheral and central nervous systems. At the level of the peripheral nervous system, inflammation and neuroimmune interactions induce plastic changes to peripheral nerve fibers, thereby amplifying the transmission of itch signaling. Neural sensitization in the central nervous system occurs at both the spinal cord and brain levels. At the level of the spinal cord, it involves hyperactivity of itch-activating spinal pathways, dysfunction of spinal inhibitory circuits, and attenuation of descending supraspinal inhibitory pathways. In the brain, neural sensitization manifests as structural and functional changes to itch-associated brain areas and networks. Currently, we have a diverse array of neuroimmune-modulating therapies targeting itch neural sensitization mechanisms to help with providing relief to patients with chronic itch. Itch research is a dynamic and continually evolving field, and as we grow in our understanding of chronic itch mechanisms, so will our therapeutic toolbox. Further studies exploring the peripheral and central neural sensitization mechanisms in the context of chronic itch are needed.

Prevalence of Chronic Pruritus in Elderly Black and White Inpatients: A Comparative Population Study.

BACKGROUND: Black and geriatric patients were reported in small scale studies to have more intense chronic pruritus (CP). Studies comparing itch across geriatric racial groups are lacking. OBJECTIVES: To compare the prevalence of CP in Black and White inpatients ≥ 65 years old as well as the top primary diagnoses of these populations. METHODS: We used data from the National Inpatient Sample from 2016-2019 to analyze CP prevalence and ICD10-CM to identify diseases. The top five primary diagnoses were calculated for a subpopulation with CP. Sample characteristics were described, and the data was pooled and analyzed using IBM SPSS® Complex Sample modules. RESULTS: Among hospitalized Black inpatients ≥ 65 years old, the prevalence of CP was 0.26% while in the White cohort it was 0.22%. The top five primary diagnoses in the Black population with itch were sepsis (4.2%); hypertensive heart and chronic kidney disease (CKD) with heart failure (HF) and stage 1-4 CKD, or unspecified CKD (4.1%); acute kidney failure (4.0%); hypertensive heart and CKD with HF with stage 5 CKD, or end-stage renal disease (2.1%); and hypertensive heart disease with HF (1.7%). The top five primary diagnoses in the White population were sepsis (4.25%); acute kidney failure (3.0%); hypertensive heart and CKD with HF and stage 1-4 CKD, or unspecified CKD (2.5%); cellulitis of left lower limb (1.9%); and unilateral primary osteoarthritis, right knee (1.9%). CONCLUSIONS: Geriatric hospitalized Black patients demonstrated a higher prevalence of chronic itch compared with the White cohort, which may be related to the higher prevalence of chronic kidney disease in different stages of severity in this population.

The Impact of COVID-19 on the Epidemiology and Outcomes of Candidemia: A Retrospective Study from a Tertiary Care Center in Lebanon.

Invasive fungal infections, notably candidemia, have been associated with COVID-19. The epidemiology of candidemia has significantly changed during the COVID-19 pandemic. We aim to identify the microbiological profile, resistance rates, and outcomes of COVID-19-associated candidemia (CAC) compared to patients with candidemia not associated with COVID-19. We retrospectively collected data on patients with candidemia admitted to the American University of Beirut Medical Center between 2004 and 2022. We compared the epidemiology of candidemia during and prior to the COVID-19 pandemic. Additionally, we compared the outcomes of critically ill patients with CAC to those with candidemia without COVID-19 from March 2020 till March 2022. Among 245 candidemia episodes, 156 occurred prior to the pandemic and 89 during the pandemic. Of the latter, 39 (43.8%) were CAC, most of which (82%) were reported from intensive care units (ICU). Non-albicans Candida (NAC) spp. were predominant throughout the study period (67.7%). Candida auris infection was the most common cause of NAC spp. in CAC. C. glabrata had decreased susceptibility rates to fluconazole and caspofungin during the pandemic period (46.1% and 38.4%, respectively). The mortality rate in the overall ICU population during the pandemic was 76.6%, much higher than the previously reported candidemia mortality rate observed in studies involving ICU patients. There was no significant difference in 30-day mortality between CAC and non-CAC (75.0% vs. 78.1%; p = 0.76). Performing ophthalmic examination (p = 0.002), CVC removal during the 48 h following the candidemia (p = 0.008) and speciation (p = 0.028) were significantly associated with a lower case-fatality rate. The epidemiology of candidemia has been significantly affected by the COVID-19 pandemic at our center. Rigorous infection control measures and proper antifungal stewardship are essential to combat highly resistant species such as C. auris.

Burden of Disease and Unmet Needs in the Diagnosis and Management of Atopic Dermatitis in the Arabic Population of the Middle East.

Atopic dermatitis (AD) affects diverse ethnic groups with significant disparities in prevalence, disease progression, clinical outcomes, and access to care. There are limited data on AD in the Arabic population of the Middle East, yet there is a substantial economic and psychosocial burden of AD in this region with a large unmet need with regards to disease management that is critical to address. There is a trend of increasing prevalence of AD in the Arab Middle East; however, due to the large environmental, socioeconomic, and sociocultural heterogeneity of this region, prevalence varies greatly across and within countries. Similarly, clinical differences in disease presentations exist across the region, although data are limited. In this review, we will present clinical phenotypes of AD common in different regions of the Arab Middle East, and data on prevalence, genetic variations, and challenges of treatment. Further studies exploring molecular biomarkers, genetic polymorphisms, immune factors, and the microbiome of patients in the region will help to elucidate the mechanism behind ethnic differences in AD in this population as well as to understand susceptibilities and treatment response.

Current and Emerging Therapies for Chronic Spontaneous Urticaria: A Narrative Review.

Chronic spontaneous urticaria (CSU) is a condition in which wheals, angioedema, and pruritus occur spontaneously and recurrently for at least 6 weeks. The etiology of this disease is partially dependent on production of autoantibodies that activate and recruit inflammatory cells. Although the wheals can resolve within 24 h, symptoms have a significant detrimental impact on the quality of life of these patients. Standard therapy for CSU includes second-generation antihistamines and omalizumab. However, many patients tend to be refractory to these therapies. Available treatments such as cyclosporine, dapsone, dupilumab, and tumor necrosis factor alpha (TNFa) inhibitors have been used with success in some cases. Furthermore, various biologics and other novel drugs have emerged as potential treatments for this condition, and many more are currently under investigation in randomized clinical trials.

Novel breakthroughs in advanced prostate cancer management.

INTRODUCTION: Although PSA screening has been rationalized, prostate cancer continues to have the highest incidence rate in 2021, and alone accounts for 26% of cancer diagnoses in men. A thorough review of the medical literature highlights a vast array of approved and investigational treatments for prostate cancer. Thus, selecting the best treatment option for the appropriate patient at the right time is crucial. Hence, biomarkers help in defining optimal patient stratification, revealing potential processes through which a drug might exert its impact and aid in the tailoring of treatments for efficient personalized medicine. AREAS COVERED: This article is a pragmatic review of novel prostate cancer therapies that can help guide clinicians in tackling prostate cancer with the latest treatments. EXPERT OPINION: Local radiotherapy has proven to be a game changer for low burden, de novo metastatic prostate cancer. Androgen deprivation therapy continues to be the ultimate treatment. Delaying resistance to these agents will undoubtedly be a breakthrough in the treatment of prostate cancer. When it comes to metastatic castrate-resistant disease, treatment options become narrower. PARP inhibitors and N-terminal domain inhibitors offer new hope and have a synergistic effect, with immunotherapy adding promising agents to the therapeutic arsenal.

A 59-Year-Old Woman With Progressive Shortness of Breath, Intermittent Fevers, and Restrictive Lung Disease.

CASE PRESENTATION: A 59-year-old woman sought treatment for 5 weeks of progressive exercise intolerance. At the time of presentation, dyspnea limited her ability to speak in complete sentences. She also reported new orthopnea. Her respiratory symptoms improved with rest and while standing. She endorsed associated intermittent low-grade fevers, cough productive of scant clear sputum, lower extremity swelling, bloating, weight loss, and reduced appetite. She had undergone two recent admissions with similar symptoms to other hospitals, during which she was treated empirically for community-acquired pneumonia and discharged after workups for infectious disease were unrevealing. She had a history notable for systemic lupus erythematosus (SLE) diagnosed in 2006, complicated by lupus nephritis in 2009. Most recently, her SLE had been quiescent while she was taking hydroxychloroquine (400 mg daily) and mycophenolate mofetil (MMF; 1 g twice daily). She reported baseline mild dyspnea with exertion since she received a diagnosis of SLE, but her symptoms had not previously affected her activities of daily living. The patient did not smoke, drink alcohol, or use recreational drugs, and her family history was unremarkable.

MHD flow of time-fractional Casson nanofluid using generalized Fourier and Fick's laws over an inclined channel with applications of gold nanoparticles.

Gold nanoparticles are commonly used as a tracer in laboratories. They are biocompatible and can transport heat energy to tumor cells via a variety of clinical techniques. As cancer cells are tiny, properly sized nanoparticles were introduced into the circulation for invasion. As a result, gold nanoparticles are highly effective. Therefore, the current research investigates the magnetohydrodynamic free convection flow of Casson nanofluid in an inclined channel. The blood is considered as a base fluid, and gold nanoparticles are assumed to be uniformly dispersed in it. The above flow regime is formulated in terms of partial differential equations. The system of derived equations with imposed boundary conditions is non-dimensionalized using appropriate dimensionless variables. Fourier's and Fick's laws are used to fractionalize the classical dimensionless model. The Laplace and Fourier sine transformations with a new transformation are used for the closed-form solutions of the considered problem. Finally, the results are expressed in terms of a specific function known as the Mittag-Leffler function. Various figures and tables present the effect of various physical parameters on the achieved results. Graphical results conclude that the fractional Casson fluid model described a more realistic aspect of the fluid velocity profile, temperature, and concentration profile than the classical Casson fluid model. The heat transfer rate and Sherwood number are calculated and presented in tabular form. It is worth noting that increasing the volume percentage of gold nanoparticles from 0 to 0.04 percent resulted in an increase of up to 3.825% in the heat transfer rate.