Non-STEM majors COVID-19 vaccine impressions improve, and misconceptions resolve, after podcast assignment.

Misinformation regarding vaccine science decreased the receptiveness to COVID-19 vaccines, exacerbating the negative effects of the COVID-19 pandemic on society. To mitigate the negative societal impact of the COVID-19 pandemic, impactful and creative science communication was needed, yet little research has explored how to encourage COVID-19 vaccine acceptance and address misconceptions held by non-Science, Technology, Engineering and Mathematics majors (referred to as non-majors). We have previously demonstrated that including expert guest lectures in the vaccine module in the non-major introductory biology course helps combat students' vaccine hesitancy. In the present study, we further address how learning about vaccines impacts student knowledge and impressions of the COVID-19 vaccines through a podcast assignment. As a part of this assignment, non-majors created podcasts to address COVID-19 vaccine misconceptions of their choice. We coded pre and post, open-ended essay reflections (n = 40) to assess non-majors' knowledge and impressions of the COVID-19 vaccines. Non-majors' impressions of the vaccines improved following the podcast assignment with more than three times as many students reporting a positive view of the assignment than negative views. Notably, eight of the nine interviewed students still ended the course with misconceptions about the COVID-19 vaccines, such as the vaccines being unnecessary or causing fertility issues. In a post semi-structured interview following this assignment, students (n = 7) discussed the impact of looking into the specific misconceptions related to COVID-19 vaccines themselves, including improved science communication skills and understanding of different perspectives. Thus, podcasts can provide opportunities for students to improve engagement in valuable societal topics like vaccine literacy in the non-majors classroom.

GCN2 in Viral Defence and the Subversive Tactics Employed by Viruses.

The recent SARS-CoV-2 pandemic and associated COVID19 disease illustrates the important role of viral defence mechanisms in ensuring survival and recovery of the host or patient. Viruses absolutely depend on the host's protein synthesis machinery to replicate, meaning that impeding translation is a powerful way to counteract viruses. One major approach used by cells to obstruct protein synthesis is to phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α). Mammals possess four different eIF2α-kinases: PKR, HRI, PEK/PERK, and GCN2. While PKR is currently considered the principal eIF2α-kinase involved in viral defence, the other eIF2α-kinases have also been found to play significant roles. Unsurprisingly, viruses have developed mechanisms to counteract the actions of eIF2α-kinases, or even to exploit them to their benefit. While some of these virulence factors are specific to one eIF2α-kinase, such as GCN2, others target all eIF2α-kinases. This review critically evaluates the current knowledge of viral mechanisms targeting the eIF2α-kinase GCN2. A detailed and in-depth understanding of the molecular mechanisms by which viruses evade host defence mechanisms will help to inform the development of powerful anti-viral measures.

Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors. This article is featured in Selected Articles from This Issue, p. 897.

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

The Role of Immune Cells Driving Electropathology and Atrial Fibrillation.

Atrial fibrillation (AF) is the most common progressive cardiac arrhythmia worldwide and entails serious complications including stroke and heart failure. Despite decades of clinical research, the current treatment of AF is suboptimal. This is due to a lack of knowledge on the mechanistic root causes of AF. Prevailing theories indicate a key role for molecular and structural changes in driving electrical conduction abnormalities in the atria and as such triggering AF. Emerging evidence indicates the role of the altered atrial and systemic immune landscape in driving this so-called electropathology. Immune cells and immune markers play a central role in immune remodeling by exhibiting dual facets. While the activation and recruitment of immune cells contribute to maintaining atrial stability, the excessive activation and pronounced expression of immune markers can foster AF. This review delineates shifts in cardiac composition and the distribution of immune cells in the context of cardiac health and disease, especially AF. A comprehensive exploration of the functions of diverse immune cell types in AF and other cardiac diseases is essential to unravel the intricacies of immune remodeling. Usltimately, we delve into clinical evidence showcasing immune modifications in both the atrial and systemic domains among AF patients, aiming to elucidate immune markers for therapy and diagnostics.

Transfluthrin diffusers do not protect two-person US military tents from mosquitoes in open field and canopy warm-temperate habitats.

Spatial repellents are volatile or volatilized chemicals that may repel arthropod vectors in free space, preventing bites and reducing the potential for pathogen transmission. In a 21-week field study, we investigated the efficacy of passive transfluthrin-impregnated diffusers placed in two-person United States (US) military tents located in canopy and open field habitats in north Florida to prevent mosquitoes from entering. Mosquito collections with US Centers for Disease Control and Prevention traps baited with light and carbon dioxide were conducted weekly for weeks 0-4, every two weeks for weeks 5-10, and monthly for weeks 11-21. Our results demonstrated that these transfluthrin-impregnated devices did not function as spatial repellents as expected and did not create a mosquito-free zone of protection. Instead, we observed consistently higher collections of mosquitoes from tents with transfluthrin-impregnated diffusers, and higher rates of mosquito mortality in collections from tents with transfluthrin diffusers, compared to untreated control tents. Based on these findings we do not recommend the use of passive transfluthrin-impregnated diffusers for mosquito protection in two-person US military tents in warm-temperate environments similar to north Florida.

Retrospective evaluation of surgical outcomes in canine patients with primary and secondary glaucoma following diode endoscopic cyclophotocoagulation.

OBJECTIVE: To evaluate the long-term outcome of endoscopic cyclophotocoagulation (ECP) for the treatment of primary and secondary glaucoma in dogs. ANIMALS STUDIED: Retrospective review of dogs that underwent ECP at two referral centers from 2004 to 2023. PROCEDURES: Medical records of 389 eyes (301 dogs) following ECP were reviewed. Outcomes evaluated included follow-up time, intraocular pressure (IOP), vision status, additional ECP procedures performed, number of medications, and complications. Patient and surgical variables and their association with IOP control and vision maintenance were evaluated. RESULTS: Median follow-up time was 18 months. IOP remained controlled in 90% and 95% of patients at 1 and 2 years, respectively, following ECP. IOP was controlled long-term (2 years) in cases with primary (88%) and secondary (99%) glaucoma. Post-operative vision was maintained in 63% and 49% of eyes at approximately 1 and 2 years, respectively. Median time to vision loss was 6.5 months. Repeat ECP was required in 15.4% of eyes at a median of 19 days post-operatively. Eyes that underwent more than one ECP surgery had a significantly longer median time to blindness (13.8 months) than those that underwent a single ECP procedure (3.6 months; p = .0003). The median number of anti-glaucoma medications decreased from three pre-operatively to one at 1- and 2-year post-operatively. Complications included corneal ulceration (28%), blinding hypotony (11%), retinal detachment (11%), and hyphema (10%). CONCLUSION: Endolaser cyclophotocoagulation is an effective surgery for maintaining long-term IOP control and extending vision in canine patients with glaucoma refractory to medical management.

Biatrial arrhythmogenic substrate in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF) in patients with hypertrophic obstructive cardiomyopathy (HOCM) may be caused by a primary atrial myopathy. Whether HOCM-related atrial myopathy affects mainly electrophysiological properties of the left atrium (LA) or also the right atrium (RA) has never been investigated. OBJECTIVE: The purpose of this study was to characterize atrial conduction and explore differences in the prevalence of conduction disorders, potential fractionation, and low-voltage areas (LVAs) between the RA and LA during sinus rhythm (SR) as indicators of potential arrhythmogenic areas. METHODS: Intraoperative epicardial mapping of both atria during SR was performed in 15 HOCM patients (age 50 ± 12 years). Conduction delay (CD) and conductin block (CB), unipolar potential characteristics (voltages, fractionation), and LVA were quantified. RESULTS: Conduction disorders and LVA were found scattered throughout both atria in all patients and did not differ between the RA and LA (CD: 2.9% [1.9%-3.6%] vs 2.6% [2.1%-6.4%], P = .541; CB: 1.7% [0.9%-3.1%] vs 1.5% [0.5%-2.8%], P = .600; LVA: 4.7% [1.6%-7.7%] vs 2.9% [2.1%-7.1%], P = .793). Compared to the RA, unipolar voltages of single potentials (SPs) and fractionated potentials (FPs) were higher in the LA (SP: P75 7.3 mV vs 10.9 mV; FP: P75 2.0 mV vs 3.7 mV). FP contained low-voltage components in only 18% of all LA sites compared to 36% of all RA sites. CONCLUSION: In patients with HOCM, conduction disorders, LVA, and FP are equally present in both atria, supporting the hypothesis of a primary atrial myopathy. Conceptually, the presence of a biatrial substrate and high-voltage FP may contribute to failure of ablative therapy of atrial tachyarrhythmias in this population.

Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study.

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC0-24/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.

Generation of precision preclinical cancer models using regulated in vivo base editing.

Although single-nucleotide variants (SNVs) make up the majority of cancer-associated genetic changes and have been comprehensively catalogued, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a mouse system for temporal and regulatable in vivo base editing. The inducible base editing (iBE) mouse carries a single expression-optimized cytosine base editor transgene under the control of a tetracycline response element and enables robust, doxycycline-dependent expression across a broad range of tissues in vivo. Combined with plasmid-based or synthetic guide RNAs, iBE drives efficient engineering of individual or multiple SNVs in intestinal, lung and pancreatic organoids. Temporal regulation of base editor activity allows controlled sequential genome editing ex vivo and in vivo, and delivery of sgRNAs directly to target tissues facilitates generation of in situ preclinical cancer models.

The impact of cycling hypoxia on the phenotype of HPV-positive cervical cancer cells.

Cycling hypoxia (cycH) is a prevalent form of tumor hypoxia that is characterized by exposure of tumor cells to recurrent phases of hypoxia and reoxygenation. CycH has been associated with a particularly aggressive cellular phenotype of tumor cells and increased therapy resistance. By performing comparative analyses under normoxia, physoxia, chronic hypoxia, and cycH, we here uncover distinct effects of cycH on the phenotype of human papillomavirus (HPV)-positive cervical cancer cells. We show that-other than under chronic hypoxia-viral E6/E7 oncogene expression is largely maintained under cycH as is the E6/E7-dependent regulation of p53 and retinoblastoma protein. Further, cycH enables HPV-positive cancer cells to evade prosenescent chemotherapy, similar to chronic hypoxia. Moreover, cells under cycH exhibit a particularly pronounced resistance to the proapoptotic effects of Cisplatin. Quantitative proteome analyses reveal that cycH induces a unique proteomic signature in cervical cancer cells, which includes a significant downregulation of luminal lysosomal proteins. These encompass the potentially proapoptotic cathepsins B and cathepsin L, which, however, appear not to affect the response to Cisplatin under any of the O2 conditions tested. Rather, we show that the proapoptotic Caspase 8/BH3-interacting domain death agonist (BID) cascade plays a pivotal role for the efficiency of Cisplatin-induced apoptosis in HPV-positive cancer cells under all investigated O2 conditions. In addition, we provide evidence that BID activation by Cisplatin is impaired under cycH, which could contribute to the high resistance to the proapoptotic effects of Cisplatin. Collectively, this study provides the first insights into the profound phenotypic alterations induced by cycH in HPV-positive cancer cells, with implications for their therapeutic susceptibility.

Opposing, spatially-determined epigenetic forces impose restrictions on stochastic olfactory receptor choice.

Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in the mouse genome in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this 'privileged' repertoire. Our experiments identify early transcription as a potential 'epigenetic' contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.

Characterization of unipolar electrogram morphology: a novel tool for quantifying conduction inhomogeneity.

AIMS: Areas of conduction inhomogeneity (CI) during sinus rhythm may facilitate the initiation and perpetuation of atrial fibrillation (AF). Currently, no tool is available to quantify the severity of CI. Our aim is to develop and validate a novel tool using unipolar electrograms (EGMs) only to quantify the severity of CI in the atria. METHODS AND RESULTS: Epicardial mapping of the right atrium (RA) and left atrium, including Bachmann's bundle, was performed in 235 patients undergoing coronary artery bypass grafting surgery. Conduction inhomogeneity was defined as the amount of conduction block. Electrograms were classified as single, short, long double (LDP), and fractionated potentials (FPs), and the fractionation duration of non-single potentials was measured. The proportion of low-voltage areas (LVAs, <1 mV) was calculated. Increased CI was associated with decreased potential voltages and increased LVAs, LDPs, and FPs. The Electrical Fingerprint Score consisting of RA EGM features, including LVAs and LDPs, was most accurate in predicting CI severity. The RA Electrical Fingerprint Score demonstrated the highest correlation with the amount of CI in both atria (r = 0.70, P < 0.001). CONCLUSION: The Electrical Fingerprint Score is a novel tool to quantify the severity of CI using only unipolar EGM characteristics recorded. This tool can be used to stage the degree of conduction abnormalities without constructing spatial activation patterns, potentially enabling early identification of patients at high risk of post-operative AF or selection of the appropriate ablation approach in addition to pulmonary vein isolation at the electrophysiology laboratory.

Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency.

Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined TPMT genotypes (2016-2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. TPMT genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.

Distinctive Arbutin-Containing Markers: Chemotaxonomic Significance and Insights into the Evolution of Proteaceae Phytochemistry.

Natural products isolation studies of eight endemic Tasmanian Proteaceae species - Agastachys odorata, Persoonia juniperina, Hakea megadenia, Hakea epiglottis, Orites diversifolius, Orites acicularis, Orites revolutus, and Telopea truncata - and three endemic Australian Proteaceae species Banksia serrata, Banksia praemorsa, and Banksia marginata were undertaken. Two previously unreported glycoside-derived natural products were identified, in addition to four other tremendously rare arbutin esters. The results of this study provide further evidence consistent with the proposal that these distinctive arbutin esters represent markers that can provide valuable insights into the chemical evolution of plant species within the family Proteaceae.

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses.

Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that drive electrical conduction disorders and AF (i.e., electropathology). Insights into AF-induced transcriptomic alterations may aid in a deeper understanding of electropathology. Specifically, RNA sequencing (RNA-seq) facilitates transcriptomic analyses and discovery of differences in gene expression profiles between patient groups. In the last decade, various RNA-seq studies have been conducted in atrial tissue samples of patients with AF versus controls in sinus rhythm. Identified differentially expressed molecular pathways so far include pathways related to mechanotransduction, ECM remodeling, ion channel signaling, and structural tissue organization through developmental and inflammatory signaling pathways. In this review, we provide an overview of the available human AF RNA-seq studies and highlight the molecular pathways identified. Additionally, a comparison is made between human RNA-seq findings with findings from experimental AF model systems and we discuss contrasting findings. Finally, we elaborate on new exciting RNA-seq approaches, including single-nucleotide variants, spatial transcriptomics and profiling of different populations of total RNA, small RNA and long non-coding RNA.

Another Day, Another 82 Cents: A National Survey Assessing Gender-based Wage Differences in Board-certified Plastic Surgeons.

Background: Of 7461 actively practicing United States American Board of Plastic Surgery certified plastic surgeons, only 17% are women. In relation to this small number, gender inequities within the field have been the source of national discussions. Our study assessed the status of the gender-based wage-gap in plastic surgery and sought to identify possible causes. Methods: An anonymous 43-question survey was distributed to 2981 members of the American Society of Plastic Surgeons in 2021. Male and female responses were compared; an analysis also considering board-certification year was performed. Chi-square and Fisher exact tests were used for bivariate analysis. Continuous variables were compared with two-sample t tests and Wilcoxon rank sum tests. Results: Ten percent of contacted American Society of Plastic Surgeons members responded to our survey. Of the 288 respondents, 111 (38.5%) were women, and 177 (61.5%) were men. Men were more likely to have salaries over $400K USD per year (P < 0.0001). Earlier certification year was associated with pay greater than $400K per year (P = 0.0235) but was insignificant once stratified by gender (women: P = 0.2392, men: P = 0.7268). Earlier certification year was associated with production-based and self-determined wages (P = 0.0097), whereas later board-certification year was associated with nonnegotiable salaries (P < 0.0001). Conclusions: Women are significantly less likely to make salaries comparable to those of male plastic surgeons, related to shorter careers on average. An increase in female representation and career duration within the field is needed to improve the current wage-gap.

Prevention of Atrial Fibrillation: Putting Proteostasis Derailment Back on Track.

Despite the many attempts to treat atrial fibrillation (AF), the most common cardiac tachyarrhythmia in the Western world, the treatment efficacy of AF is still suboptimal. A plausible reason for the suboptimal efficacy is that the current treatments are not directed at the underlying molecular mechanisms that drive AF. Recent discoveries revealed that the derailment of specific molecular proteostasis pathways drive electrical conduction disorders, contractile dysfunction and AF. The degree of this so-called 'electropathology' corresponds to the response to anti-AF treatment. Hence, to develop effective therapies to prevent AF, understanding the molecular mechanisms is of key importance. In this review, we highlight the key modulators of proteostasis derailment and describe the mechanisms that explain how they affect electrical and contractile function in atrial cardiomyocytes and AF. The key modulators of proteostasis derailment include (1) exhaustion of cardioprotective heat shock proteins (HSPs), (2) excessive endoplasmic reticulum (ER) stress and downstream autophagic protein degradation, (3) histone deacetylase 6 (HDAC6)-induced microtubule disruption, (4) activation of DNA damage-PARP1 activation and NAD+ axis and (5) mitochondrial dysfunction. Furthermore, we discuss druggable targets within these pathways that are involved in the prevention of proteostasis derailment, as well as the targets that aid in the recovery from AF. Finally, we will elaborate on the most favorable druggable targets for (future) testing in patients with AF, as well as drugs with potential benefits for AF recovery.