Patient with mediastinal carcinoma of unknown primary with RET fusion achieves durable response with RET inhibition.

Selective RET inhibitors have shown promise in thyroid cancer (TC) and nonsmall cell lung cancer (NSCLC) harboring RET fusions on next-generation sequencing (NGS), although rarity of the rearrangement has led to limited data for certain tumor types, such as carcinoma of unknown primary. We present a 65-year-old female with no history of malignancy, smoking or radiation exposure, who was found to have an anterior mediastinum malignancy of unknown primary, with metastases to supraclavicular lymph nodes. Core biopsy of the mediastinum revealed poorly differentiated carcinoma, while a biopsy of the thyroid revealed atypia of indeterminate significance (Bethesda III). PD-L1 immunohistochemistry was positive (90%), and liquid NGS revealed mutations in TP53 and the TERT promoter (c.-124C>T), as well as a CCDC6-RET fusion. This genetic profile resembled an anaplastic TC vs. NSCLC primary, although thymic primary and poorly differentiated TC remained on the differential. The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. At a reduced dosage, patient developed transaminitis, and selpercatinib was switched to pralsetinib. Brain MRI showed a nonenhancing temporal lobe signal abnormality, which on biopsy proved to be glioblastoma (GBM) with TERT promoter c.-124C>T mutation and FGFR3-TACC3 fusion by NGS. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.

Non-Small Cell Lung Cancer, Version 4.2024.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

Targeted Combination of Poly(ADP-ribose) Polymerase Inhibitors and Immune Checkpoint Inhibitors Lacking Evidence of Benefit: Focus in Ovarian Cancer.

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi's), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi's have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in BRCA wild-type, homologous recombination proficient (HRP) cancers. Therefore, attempts have been made at combination therapy involving PARPi to improve patient outcomes. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated underwhelming results involving ovarian cancer. Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.

Inactivated Poliovirus Vaccine Booster Reduces the Likelihood of COVID-19 Outcomes in Individuals Primed with Oral Poliovirus Vaccination.

Introduction: Prior research explores whether seasonal and childhood vaccines mitigate the risk of SARS-CoV-2 infection. Although there are trials investigating COVID-19 infection in response to the effects of the oral poliovirus vaccine (OPV), there has been no prior research assessing COVID-19 outcomes in recently immunized adults with the inactivated poliovirus vaccine (IPV). Methods: SARS-CoV-2 infection and COVID-19 symptoms were analyzed across a cohort of 282 adults who received an IPV booster. Bivariate and multivariate regression models explored associations among variables related to vaccination histories and COVID-19 outcomes. Results: One year post-IPV inoculation, participants who had never received OPV were more likely to test positive for SARS-CoV-2 and experience COVID-19 symptoms, compared to those who had previously received OPV (OR = 3.92, 95%CI 2.22-7.03, p < 0.001; OR = 4.45, 95%CI 2.48-8.17, p < 0.001, respectively). Those who had never received OPV experienced COVID-19 symptoms for 6.17 days longer than participants who had previously received OPV (95%CI 3.68-8.67, p < 0.001). Multivariate regression modeling indicated COVID-19 vaccination did not impact SARS-CoV-2 infection or COVID-19 symptoms in this sample of adults who had recently received IPV. Discussion: Findings suggest IPV may boost mucosal immunity among OPV-primed individuals, and COVID-19 vaccination may not provide additional protection among those who had received IPV. Future, larger-scale studies should measure the extent of protective effects against COVID-19 to inform public health policies in resource-deficient settings.

Triage of V-V ECMO referrals for COVID-19 respiratory failure.

BACKGROUND: As the pandemic progressed, the use of extracorporeal membrane oxygenation (ECMO) for COVID-19-related acute respiratory distress syndrome increased, and patient triage and transfer to ECMO centers became important to optimize patient outcomes. Our objectives are to identify predictors of patient transfer for veno-venous extracorporeal membrane oxygenation (V-V ECMO) evaluation as well as to describe the outcomes of accepted patients. METHODS: This is a single-center, retrospective analysis of V-V ECMO transfer requests for adult patients with known or suspected COVID-19 and respiratory failure from March 2020 until March 2021. Data were collected prospectively during the triage process for transfer requests as part of clinical patient care at our institution. RESULTS: Of 341 referred patients, 112 (33%) were accepted for transfer to our facility, whereas 229 (67%) patients were declined for transfer. The Classification and Regression Tree analysis showed that patients' high pressure during airway pressure release ventilation (APRV) and age were the variables most significantly associated with the decision to accept or decline patients for transfer. CONCLUSIONS: Our triage process enabled one-third of referred patients to be transferred for evaluation, with nearly 70% of those patients ultimately receiving ECMO support. High ventilator settings on APRV and young age were associated with acceptance for transfer. Accepted patients also had a higher incidence of adjunctive therapies (proning and paralysis) prior to transfer request, less cardiac or renal dysfunction, and a shorter duration of mechanical ventilation. Further research is warranted to investigate the outcomes of nontransferred patients.

Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Vitamin D Supplementation and Prior Oral Poliovirus Vaccination Decrease Odds of COVID-19 Outcomes among Adults Recently Inoculated with Inactivated Poliovirus Vaccine.

BACKGROUND: Structural and functional commonalities between poliovirus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suggest that poliovirus inoculation may induce antibodies that mitigate the coronavirus disease (COVID-19). No known studies have evaluated COVID-19 risk factors in adults recently vaccinated against poliovirus. STUDY OBJECTIVE: Among adults with no history of COVID-19 infection or vaccination, who recently received an inactivated poliovirus vaccine (IPV), we sought to determine which biological factors and social determinants of health (SDOH) may be associated with (1) testing positive for SARS-CoV-2, (2) experiencing COVID-19 symptoms, and (3) a longer duration of COVID-19 symptoms. METHODS: The influence of biological factors and SDOH on SARS-CoV-2 infection and COVID-19 symptoms were evaluated among 282 adults recently inoculated with IPV. Participant-reported surveys were analyzed over 12 months post-enrollment. Bivariate and multivariate linear and logistic regression models identified associations between variables and COVID-19 outcomes. RESULTS: Adjusting for COVID-19 vaccinations, variants, and other SDOH, secondary analyses revealed that underlying conditions, employment, vitamin D, education, and the oral poliovirus vaccination (OPV) were associated with COVID-19 outcomes. The odds of testing positive for SARS-CoV-2 and experiencing symptoms were significantly reduced among participants who took vitamin D (OR 0.12 and OR 0.09, respectively). Unemployed or part-time working participants were 72% less likely to test positive compared with full-time workers. No prior dose of OPV was one of the strongest predictors of SARS-CoV-2 infection (OR 4.36) and COVID-19 symptoms (OR 6.95). CONCLUSIONS: Findings suggest that prophylactic measures and mucosal immunity may mitigate the risk and severity of COVID-19 outcomes. Larger-scale studies may inform future policies.

Pregnancy History at 40 Years of Age as a Marker of Cardiovascular Risk.

BACKGROUND: Individual pregnancy complications are associated with increased maternal risk of cardiovascular disease. We assessed the link between a woman's total pregnancy history at 40 years of age and her relative risk of dying from atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: This population-based prospective study combined several Norwegian registries covering the period 1967 to 2020. We identified 854 442 women born after 1944 or registered with a pregnancy in 1967 or later, and surviving to 40 years of age. The main outcome was the time to ASCVD mortality through age 69 years. The exposure was a woman's number of recorded pregnancies (0, 1, 2, 3, or 4) and the number of those with complications (preterm delivery <35 gestational weeks, preeclampsia, placental abruption, perinatal death, and term or near-term birth weight <2700 g). Cox models provided estimates of hazard ratios across exposure categories. The group with the lowest ASCVD mortality was that with 3 pregnancies and no complications, which served as the reference group. Among women reaching 40 years of age, risk of ASCVD mortality through 69 years of age increased with the number of complicated pregnancies in a strong dose-response fashion, reaching 23-fold increased risk (95% CI, 10-51) for women with 4 complicated pregnancies. Based on pregnancy history alone, 19% of women at 40 years of age (including nulliparous women) had an increased ASCVD mortality risk in the range of 2.5- to 5-fold. CONCLUSIONS: Pregnancy history at 40 years of age is strongly associated with ASCVD mortality. Further research should explore how much pregnancy history at 40 years of age adds to established cardiovascular disease risk factors in predicting cardiovascular disease mortality.

Heterogeneity in the risk of cardiovascular disease mortality after the hypertensive disorders of pregnancy across mothers' lifetime reproductive history.

BACKGROUND: Prior studies on maternal cardiovascular disease (CVD) mortality and hypertensive disorders of pregnancy (HDP) have focused only on a woman's first birth and have not accounted for successive affected pregnancies. OBJECTIVES: The objective of this study is to identify mothers' risk of CVD mortality considering lifetime reproductive history. METHODS: We used data from the Medical Birth Registry of Norway, the Norwegian Cause of Death Registry, and the Norwegian National Population Register to identify all mothers who gave birth from 1967 to 2020. Our outcome was mothers' CVD death before age 70. The primary exposure was the lifetime history of HDP. The secondary exposure was the order of HDP and gestational age at delivery of pregnancies with HDP. We used Cox regression models to estimate hazard ratio (HR) and 95% confidence interval (CI), adjusting for education, mother's age, and year of last birth. These models were stratified by the lifetime number of births. RESULTS: Among 987,378 mothers, 86,294 had HDP in at least one birth. The highest CVD mortality, relative to mothers without HDP, was among those with a pre-term HDP in their first two births, although this represented 1.0% of mothers with HDP (HR 5.12, 95% CI 2.66, 9.86). Multiparous mothers with term HDP in their first birth only had no increased risk of CVD relative to mothers without HDP (36.9% of all mothers with HDP; HR 1.12, 95% CI 0.95, 1.32). All other mothers with HDP had a 1.5- to 4-fold increased risk of CVD mortality. CONCLUSIONS: This study identified heterogeneity in the risk of CVD mortality among mothers with a history of HDP. A third of these mothers are not at higher risk compared to women without HDP, while some less common patterns of HDP history are associated with severe risk of CVD mortality.

Conformational variants of the ternary complex of C5a, C5aR1, and G-protein.

The complement component fragment 5a (C5a) binds and activates two complement receptors like C5aR1 and C5aR2, which play a significant role in orchestrating the proinflammatory function of C5a in tissues through the recruitment of heterotrimeric G-proteins and ß-arrestins. Dysregulation of the complement induces excessive production of C5a, which triggers aberrant activation of the C5a-C5aR1-G-protein and C5a-C5aR2-ß-arrestin signalling axes in tissues, contributing to the pathology of numerous immune-inflammatory diseases. Thus, understanding the interaction of C5a with C5aR1 and C5aR2, as well as the interaction of G-protein and ß-arrestins, respectively, with C5a-C5aR1 and C5a-C5aR2, holds tremendous therapeutic value. In the absence of structural data, we have previously elaborated the binary complexes of C5a-C5aR1 and C5a-C5aR2, as well as the ternary complex of C5a-C5aR2-ß-arrestin1, in highly refined model structures. While our ternary model complex of C5a-C5aR1-G-protein was in progress, two cryo-electron microscopy-based ternary structural complexes of C5aR1 were made available by others. However, it is observed that the interaction of the crucial NT-peptide of C5aR1 with C5a, including the portion of the G⍺i-subunit that harbors the switch-I region, is not fully resolved in both complexes. The current study addresses the issues and provides two highly refined alternative model ternary complexes of C5a-C5aR1-G-protein. The study highlights the conformational heterogeneity in C5aR1 by comparing the two conformational variants of the model ternary complex in the context of C5a-C5aR2-ß-arrestin1 for further devising methods and molecules targeting both surface and intracellular C5aR1/C5aR2 for effectively mitigating the proinflammatory role of C5a in various disease settings.Communicated by Ramaswamy H. Sarma.

The isomer-sensitive electrochemical HER of ruthenium(II)-hydrido complexes involving redox-active azoheteroaromatics.

The article deals with the development of isomeric ruthenium(II)-hydrido complexes [RuII(H)(L1)(PPh3)2(CO)]ClO4 ([1a]ClO4-[1b]ClO4)/[RuII(H)(L2)(PPh3)2(CO)]ClO4 ([2a]ClO4-[2b]ClO4) involving azo coupled L1 [L1: (E)-1,2-bis(1-methyl-1H-pyrazol-3-yl)diazene]/L2 [L2: (E)-1,2-bis(4-iodo-1-methyl-1H-pyrazol-3-yl)diazene], respectively. Structural evaluation of the complexes affirmed the syn conformation of the coordinated/uncoordinated pyrazole groups of L and its unperturbed neutral azo (NN) state. Isomeric forms in [1a]ClO4/[1b]ClO4 or [2a]ClO4/[2b]ClO4 differed with respect to the cis and trans orientations of the coordinated CO and N(azo) donor of L, respectively. It also demonstrated the formation of intermolecular hydrogen-bonded dimeric or 1D-polymeric chains in [1a]ClO4/[2b]ClO4 or [1b]ClO4, respectively. Successive two-electron reductions of the complexes varied to an appreciable extent as a function of the heterocycles connected to L. The involvement of the azo function of L towards the reductions ([NN]0 → [NN]˙- → [NN]2-) was supported by the DFT calculated MOs and Mulliken spin density at the paramagnetic state, which was further validated by the radical EPR profile of the first reduced (S = 1/2) state. Isomeric [1a]ClO4/[1b]ClO4 or [2a]ClO4/[2b]ClO4 immobilised on the carbon cloth support underwent various electrochemical acidic HERs (hydrogen evolution reactions) with TOF/10-1 s-1: [1a]ClO4 (0.83) > [1b]ClO4 (0.68) > [2a]ClO4 (0.50) > [2b]ClO4 (0.37).

Plunging Into the PACIFIC: Outcomes of Patients With Unresectable KRAS-Mutated Non-Small Cell Lung Cancer Following Definitive Chemoradiation and Durvalumab Consolidation.

BACKGROUND: Immune checkpoint inhibitor (ICI) consolidation following concurrent chemoradiotherapy (CRT) substantially improved progression free survival (PFS) and overall survival (OS) in the PACIFIC trial becoming the standard of care in locally-advanced, unresectable NSCLC. KRAS mutation may influence response to ICI. METHODS: In this single-institution, retrospective analysis, we compared treatment outcomes for patients with unresectable KRAS mutated (KRAS-mt) and wild-type (KRAS-wt) NSCLC treated with CRT between October 2017 and December 2021. Kaplan-Meier analysis was conducted comparing median progression free survival and median overall survival from completion of radiotherapy in all KRAS-mt patients and KRAS-G12C-mutated patients. Outcomes were also compared with and without ICI consolidation. RESULTS: Of 156 patients, 42 (26.9%) were KRAS-mt and 114 (73.1%) were KRAS-wt. Baseline characteristics differed only in histology; KRAS-mt NSCLC more likely to be adenocarcinoma. KRAS-mt patients had worse PFS (median 6.3 vs. 10.7 months, P = .041) but similar OS (median 23.1 vs. 27.3 months, P = .237). KRAS-mt patients were more likely to not receive ICI due to rapid disease progression post-CRT (23.8% vs. 4.4%, P = .007). Among patients who received ICI (n = 114), KRAS-mt was not associated with inferior PFS (8.1 vs. 11.9 months, P = .355) or OS (30.5 vs. 31.7 months, P = .692). KRAS-G12C patients (n = 22) had similar PFS and OS to other KRAS-mt. CONCLUSION: In one of the largest post-CRT KRAS-mt cohort published, KRAS-mt was associated with inferior PFS, largely due to rapid progression prior to ICI consolidation, but did not affect OS. Among those who received ICI consolidation, outcomes were comparable regardless of KRAS-mt status.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Risk of adverse pregnancy outcomes in twin- and singleton-born women: An inter-generational cohort study.

OBJECTIVE: To compare the risk of adverse pregnancy outcomes between twin-born and singleton-born women. We also evaluated whether in utero exposure to pre-eclampsia or preterm delivery affected adverse pregnancy outcomes in women's own pregnancies. DESIGN: Population-based cohort study. SETTING: Medical Birth Registry of Norway 1967-2020. POPULATION: 9184 twin-born and 492 894 singleton-born women during 1967-2005, with their later pregnancies registered during 1981-2020. METHODS: Data from an individual's birth were linked to their later pregnancies. We used generalised linear models with log link binomial distribution to obtain exponentiated regression coefficients that estimated relative risks (RRs) with 95% confidence intervals (CIs) for associations between twin- or singleton-born women and later adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Pre-eclampsia, preterm delivery or perinatal loss in twin-born compared with singleton-born women. RESULTS: There was no increased risk for adverse outcomes in twin-born compared with singleton-born women: adjusted RRs for pre-eclampsia were 1.00 (95% CI 0.93-1.09), for preterm delivery 0.96 (95% CI 0.90-1.02) and for perinatal loss 1.00 (95% CI 0.84-1.18). Compared with singleton-born women exposed to pre-eclampsia in utero, twin-born women exposed to pre-eclampsia had lower risk of adverse outcomes in their own pregnancies; the aRR for pre-eclampsia was 0.73 (95% CI 0.58-0.91) and for preterm delivery was 0.71 (95% CI 0.56-0.90). Compared with preterm singleton-born women, preterm twin-born women did not differ in terms of risk of pre-eclampsia (aRR 1.05, 95% CI 0.92-1.21) or perinatal loss (aRR 0.99, 95% CI 0.71-1.37) and had reduced risk of preterm delivery (RR 0.83, 95% CI 0.74-0.94). CONCLUSIONS: Twin-born women did not differ from singleton-born women in terms of risk of adverse pregnancy outcomes. Twin-born women exposed to pre-eclampsia in utero, had a lower risk of pre-eclampsia and preterm delivery compared with singleton-born women exposed to pre-eclampsia.

Patterns of Failure in Metastatic NSCLC Treated With First Line Pembrolizumab and Use of Local Therapy in Patients With Oligoprogression.

INTRODUCTION: The patterns of failure (POF) for metastatic non-small-cell lung cancer (mNSCLC) treated with immunotherapy are not well established. METHODS: We conducted a retrospective cohort study of mNSCLC that received first-line pembrolizumab with or without chemotherapy at a single academic center from 2015 to 2021. We defined POF with 2 classifications: 1) local, regional, or distant failure, or 2) failure in existing lesions, new lesions, or a combination. Oligoprogression was defined as disease progression (PD) in ≤3 sites of failure. Overall survival (OS) was measured via Kaplan-Meier and modelled with Cox regression. RESULTS: Of 298 patients identified, 198 had PD. Using POF classification 1, most failures were distant (43.9%) or a combination of locoregional and distant (34.4%). For POF classification 2, failures occurred in a combination of new and existing lesions (45.0%), existing lesions alone (33.3%), or in new lesions only (21.7%). Oligoprogression occurred in 39.9% (n = 79) cases. Median OS was higher in the following: PD in existing lesions vs. new or new + existing lesions (28.7 vs. 20.2 vs. 13.9 months, P < .001) and oligoprogression vs. polyprogression (35.1 vs. 12.2 months, P < .001). In oligoprogression, median OS was better for those who received radiation to all sites of PD (62.2 months) than for those who changed systemic therapy (22.9 months, P = .007). On multivariable analysis, radiation for oligoprogression (HR 0.35, 95% CI: 0.20-0.62, P < .001) was associated with improved OS. CONCLUSIONS: In mNSCLC treated with pembrolizumab, oligoprogression is relatively common. Randomized data are needed to define the benefits of radiation in oligoprogressive mNSCLC.

A Narrative Review of Advancements in Understanding and Treating Varicose Veins.

Chronic venous disease, with varicose veins as its archetypal manifestation, stands as a pervasive and intricate health quandary, encompassing a vast array of contributing factors. Age, genetics, obesity, pregnancy, and prolonged immobility weave a complex tapestry, underscoring the omnipresence of this ailment. Its societal and economic footprint is undeniably formidable, as diverse classifications underscore its multifaceted character. The intricate interplay of chronic venous disease with diabetes mellitus and neuropathy compounds the challenge, fostering soaring healthcare expenditures and a palpable erosion of quality of life, particularly among women harboring cardiometabolic risk factors. Despite research shedding light on heightened susceptibility within certain demographics, the enigmatic determinants orchestrating the transition from mild to severe chronic venous disease continue to elude us. Varicose veins, marked by the presence of dilated and tortuous subcutaneous vessels, precipitate both physical discomfort and cosmetic concerns, frequently necessitating meticulous clinical evaluation coupled with ultrasound studies to secure a precise diagnosis. Treatment strategies are strategically crafted to ameliorate distressing symptoms, enhance aesthetic concerns, and forestall potential complications. Nevertheless, the prognostication of chronic venous disease remains ensconced in a degree of ambiguity, hinting at the vast terrain yet to be charted in this medical domain. The quest to fathom the intricacies of this condition uncovers an ever-evolving panorama where conservative interventions play an indispensable role in managing mild cases, while interventional procedures like endovenous laser ablation and sclerotherapy step onto the stage for patients grappling with severe symptoms, thus treading the fine line between efficacy and invasiveness. Moreover, a meticulous economic analysis underscores the cost-effectiveness of various therapeutic modalities, thereby bolstering the imperative of a patient-centered approach. As we navigate the labyrinthine complexities of chronic venous disease and varicose vein management, we are inexorably drawn to the pivotal role of customized treatment approaches, as well as the dynamic interplay between scientific progress, patient preferences, and therapeutic innovations in the relentless pursuit of optimized outcomes and an enhanced quality of life.

The Functional Implications of Broad Spectrum Bioactive Compounds Targeting RNA-Dependent RNA Polymerase (RdRp) in the Context of the COVID-19 Pandemic.

BACKGROUND: As long as COVID-19 endures, viral surface proteins will keep changing and new viral strains will emerge, rendering prior vaccines and treatments decreasingly effective. To provide durable targets for preventive and therapeutic agents, there is increasing interest in slowly mutating viral proteins, including non-surface proteins like RdRp. METHODS: A scoping review of studies was conducted describing RdRp in the context of COVID-19 through MEDLINE/PubMed and EMBASE. An iterative approach was used with input from content experts and three independent reviewers, focused on studies related to either RdRp activity inhibition or RdRp mechanisms against SARS-CoV-2. RESULTS: Of the 205 records screened, 43 studies were included in the review. Twenty-five evaluated RdRp activity inhibition, and eighteen described RdRp mechanisms of existing drugs or compounds against SARS-CoV-2. In silico experiments suggested that RdRp inhibitors developed for other RNA viruses may be effective in disrupting SARS-CoV-2 replication, indicating a possible reduction of disease progression from current and future variants. In vitro, in vivo, and human clinical trial studies were largely consistent with these findings. CONCLUSIONS: Future risk mitigation and treatment strategies against forthcoming SARS-CoV-2 variants should consider targeting RdRp proteins instead of surface proteins.