Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress.

Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.

Cost-effectiveness of eculizumab and efgartigimod for the treatment of anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.

BACKGROUND: Eculizumab and efgartigimod were approved to treat anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (anti-AChR Ab-positive gMG). These relatively new biological treatments provide a more rapid onset of action and improved efficacy compared with conventional immunosuppressive treatments, but at a higher cost. OBJECTIVE: To assess the cost-effectiveness of eculizumab and, separately, efgartigimod, each added to conventional therapy vs conventional therapy alone, among patients with refractory anti-AChR Ab-positive gMG and those with anti-AChR Ab-positive gMG, respectively. METHODS: A Markov model with 4 health states was developed, evaluating costs and utility with a 4-week cycle length and lifetime time horizon from a health care system perspective and a modified societal perspective including productivity losses from patients and caregiver burden. Model inputs were informed by key clinical trials and relevant publications identified from targeted literature reviews, and drug costs were identified from Micromedex Red Book. Costs and outcomes were discounted at 3% per year. Incremental cost-effectiveness ratios (ICERs; cost per quality-adjusted life-year [QALY] gained) were calculated for each comparison. RESULTS: Among the corresponding populations, lifetime costs and QALYs, respectively, for eculizumab were $5,515,000 and 11.85, and for conventional therapy, $308,000 and 10.29, resulting in an ICER of $3,338,000/QALY gained. For efgartigimod, lifetime costs and QALYs, respectively, were $6,773,000 and 13.22, and for conventional therapy, $322,000 and 9.98, yielding an ICER of $1,987,000/QALY gained. After applying indirect costs in a modified societal perspective, the ICERs were reduced to $3,310,000/QALY gained for eculizumab and $1,959,000/QALY gained for efgartigimod. CONCLUSIONS: Eculizumab and efgartigimod are rapidly acting and effective treatments for myasthenia gravis. However, at their current price, both therapies greatly exceeded common cost-effectiveness thresholds, likely limiting patient access to these therapies.

The Genesis of Schizophrenia: An Origin Story.

Schizophrenia is routinely referred to as a neurodevelopmental disorder, but the role of brain development in a disorder typically diagnosed during early adult life is enigmatic. The authors revisit the neurodevelopmental model of schizophrenia with genomic insights from the most recent schizophrenia clinical genetic association studies, transcriptomic and epigenomic analyses from human postmortem brain studies, and analyses from cellular models that recapitulate neurodevelopment. Emerging insights into schizophrenia genetic risk continue to converge on brain development, particularly stages of early brain development, that may be perturbed to deviate from a typical, normative course, resulting in schizophrenia clinical symptomatology. As the authors explicate, schizophrenia genetic risk is likely dynamic and context dependent, with effects of genetic risk varying spatiotemporally, across the neurodevelopmental continuum. Optimizing therapeutic strategies for the heterogeneous collective of individuals with schizophrenia may likely be guided by leveraging markers of genetic risk and derivative functional insights, well before the emergence of psychosis. Ultimately, rather than a focus on therapeutic intervention during adolescence or adulthood, principles of prediction and prophylaxis in the pre- and perinatal and neonatal stages may best comport with the biology of schizophrenia to address the early-stage perturbations that alter the normative neurodevelopmental trajectory.

Uncertainty cues amplify late positive potential responses to aversive emotional stimuli.

Uncertainty is unavoidable, and maladaptive responses to uncertainty may underlie the etiology and maintenance of psychopathology. A general tendency to associate uncertainty with aversive consequences, a type of covariation bias, can amplify aversive emotional experiences. To address questions about uncertainty during emotion regulation, we examined the Late Positive Potential (LPP) - an electrocortical marker of attention to and appraisal of motivationally relevant emotional stimuli - during a task designed to measure the effect of covariation bias and its emotional response consequences. Event-related potentials (ERPs) were recorded while participants (N = 52) were presented with a pre-stimulus cue that either conveyed information about the valence of an upcoming emotional image, or left them in ambiguity. We replicated findings that demonstrate expectancy biases in a priori and online expectancies of emotion-eliciting images, as well as in a posteriori estimates for concurrence of uncertainty cues and aversive images. Moreover, we demonstrate a novel finding that uncertainty cues amplify the LPP in response to subsequent aversive emotional stimuli. These findings advance research by conjoining existing emotion regulation research on the LPP with study of the effects of uncertainty on emotional appraisal and highlight the importance of accounting for stimulus uncertainty in emotion regulation research.

On-campus student employment as a form of leadership development.

Student employment is a common co-curricular activity among undergraduate students. Previous studies have primarily focused on the impact of employment on academic outcomes and post-graduation labor market success. Although there is an assumption that on-campus student employment influences leadership learning, there is a lack of research directly exploring this topic. Therefore, this study explores how on-campus student employment influences leadership capacity development in undergraduate students who worked in a department in Student Affairs. Findings suggest that on-campus student employment influenced leadership capacity development in undergraduate students.

Sulfide oxidation by members of the Sulfolobales.

The oxidation of sulfur compounds drives the acidification of geothermal waters. At high temperatures (>80°C) and in acidic conditions (pH <6.0), oxidation of sulfide has historically been considered an abiotic process that generates elemental sulfur (S0) that, in turn, is oxidized by thermoacidophiles of the model archaeal order Sulfolobales to generate sulfuric acid (i.e. sulfate and protons). Here, we describe five new aerobic and autotrophic strains of Sulfolobales comprising two species that were isolated from acidic hot springs in Yellowstone National Park (YNP) and that can use sulfide as an electron donor. These strains significantly accelerated the rate and extent of sulfide oxidation to sulfate relative to abiotic controls, concomitant with production of cells. Yields of sulfide-grown cultures were ∼2-fold greater than those of S0-grown cultures, consistent with thermodynamic calculations indicating more available energy in the former condition than the latter. Homologs of sulfide:quinone oxidoreductase (Sqr) were identified in nearly all Sulfolobales genomes from YNP metagenomes as well as those from other reference Sulfolobales, suggesting a widespread ability to accelerate sulfide oxidation. These observations expand the role of Sulfolobales in the oxidative sulfur cycle, the geobiological feedbacks that drive the formation of acidic hot springs, and landscape evolution.

Beyond the prescription: trends and challenges in erectile dysfunction medications among young adult men.

We sought to assess erectile dysfunction (ED) medication use among males aged 18-40. Between June and July 2023, a cross-sectional survey on Qualtrics (Provo, UT) was disseminated via Research Match. Among 210 respondents, ED prevalence was 57.1% with 39.0% reporting prior ED medication use. Black or African American race (OR = 3.54, p < 0.001), Hispanic or Latino ethnicity (OR = 3.32, p = 0.01), and Medicare or Medicaid insurance status (OR = 6.07, p < 0.001) were associated with increased medication utilization. Income >$200,000 was associated with decreased medication usage (OR 0.23, p = 0.04). ED severity significantly correlated with higher medication usage. Primary care providers were the most common source of acquisition (47.6%), followed by online direct to consumer (DTC) platforms (31.7%) and personal connections (19.5%). Privacy (n = 51, 62.2%) and cost (n = 45, 54.9%) were key considerations in obtaining medications. Despite 73.2% of individuals receiving counseling regarding risks/benefits and 84.1% receiving instructions for proper use, only 28.0% correctly identified essential aspects of proper/appropriate use. Overall, we found a high ED prevalence and medication utilization rate. The preference for privacy in procuring medications suggests ongoing stigma around men's sexual health. Despite extensive counseling, a significant knowledge gap remains indicating a pressing need for enhanced patient education.

Advances in diagnosis and treatment of vestibular migraine and the vestibular disorders it mimics.

Dizziness is one of the most common chief complaints in both the ambulatory care setting and the emergency department. These symptoms may be representative of a broad range of entities. Therefore, any attempt at treatment must first start with determining the etiology. In this current perspective, we focus specifically on the diagnosis of and treatment of vestibular migraine, which is common and overlaps clinically with a variety of other diagnoses. We discuss the traditional treatments for vestibular migraine in addition to the recent explosion of novel migraine therapeutics. Because vestibular migraine can mimic, or co-exist with, a variety of other vestibular diseases, we discuss several of these disorders including persistent postural-perceptual dizziness, benign paroxysmal positional vertigo, post-concussive syndrome, Ménière's disease, and cerebrovascular etiologies. We discuss the diagnosis of each, as well as overlapping and distinguishing clinical features of which the reader should be aware. Finally, we conclude with evidence based as well as expert commentary on management, with a particular emphasis on vestibular migraine.

Is our understanding of aquatic ecosystems sufficient to quantify ecologically driven climate feedbacks?

The Earth functions as an integrated system-its current habitability to complex life is an emergent property dependent on interactions among biological, chemical, and physical components. As global warming affects ecosystem structure and function, so too will the biosphere affect climate by altering atmospheric gas composition and planetary albedo. Constraining these ecosystem-climate feedbacks is essential to accurately predict future change and develop mitigation strategies; however, the interplay among ecosystem processes complicates the assessment of their impact. Here, we explore the state-of-knowledge on how ecological and biological processes (e.g., competition, trophic interactions, metabolism, and adaptation) affect the directionality and magnitude of feedbacks between ecosystems and climate, using illustrative examples from the aquatic sphere. We argue that, despite ample evidence for the likely significance of many, our present understanding of the combinatorial effects of ecosystem dynamics precludes the robust quantification of most ecologically driven climate feedbacks. Constraining these effects must be prioritized within the ecological sciences for only by studying the biosphere as both subject and arbiter of global climate can we develop a sufficiently holistic view of the Earth system to accurately predict Earth's future and unravel its past.

La Terre fonctionne comme un système intégré­son habitabilité pour une vie complexe est une propriété émergente qui dépend des interactions entre les composantes biologiques, chimiques et physiques. Le réchauffement climatique affecte la structure et la fonction des écosystèmes, et en retour, la biosphère affecte également le climat en modifiant la composition des gaz atmosphériques et l'albédo planétaire. Il est essentiel de quantifier ces rétroactions entre les écosystèmes et le climat afin de prédire avec précision les changements futurs et élaborer des stratégies d'atténuation; cependant, l'interaction entre les processus écologiques complique l'évaluation de leurs impacts. Dans cet article, nous examinons l'état des connaissances sur la façon dont les processus écologiques et biologiques (par exemple, la concurrence, les interactions trophiques, le métabolisme, l'adaptation) affectent la directionnalité et l'ampleur des rétroactions entre les écosystèmes et le climat à l'aide d'exemples issus du monde aquatique. Nous soutenons que, malgré les nombreuses preuves de l'importance de plusieurs de ces rétroactions, notre compréhension limitée des effets additifs des processus écosystémiques empêche de faire une quantification robuste de la plupart des rétroactions climatiques d'origine écologique. Circonscrire ces effets doit être une priorité pour les sciences aquatiques, car ce n'est qu'en étudiant la biosphère en tant que sujet et arbitre du climat planétaire que nous pourrons développer une vision suffisamment holistique du système terrestre pour prédire avec précision l'avenir de la Terre et élucider son passé.

Cooperative growth in microbial communities is a driver of multistability.

Microbial communities often exhibit more than one possible stable composition for the same set of external conditions. In the human microbiome, these persistent changes in species composition and abundance are associated with health and disease states, but the drivers of these alternative stable states remain unclear. Here we experimentally demonstrate that a cross-kingdom community, composed of six species relevant to the respiratory tract, displays four alternative stable states each dominated by a different species. In pairwise coculture, we observe widespread bistability among species pairs, providing a natural origin for the multistability of the full community. In contrast with the common association between bistability and antagonism, experiments reveal many positive interactions within and between community members. We find that multiple species display cooperative growth, and modeling predicts that this could drive the observed multistability within the community as well as non-canonical pairwise outcomes. A biochemical screening reveals that glutamate either reduces or eliminates cooperativity in the growth of several species, and we confirm that such supplementation reduces the extent of bistability across pairs and reduces multistability in the full community. Our findings provide a mechanistic explanation of how cooperative growth rather than competitive interactions can underlie multistability in microbial communities.

Humidity and temperature preference in two Neotropical species of sand flies.

BACKGROUND: Arthropods vector a multitude of human disease-causing organisms, and their geographic ranges are shifting rapidly in response to changing climatic conditions. This is, in turn, altering the landscape of disease risk for human populations that are brought into novel contact with the vectors and the diseases they carry. Sand flies in the genera Lutzomyia and Pintomyia are vectors of serious disease-causing agents such as Leishmania (the etiological agent of leishmaniasis) and may be expanding their range in the face of climate change. Understanding the climatic conditions that vector species both tolerate physiologically and prefer behaviorally is critical to predicting the direction and magnitude of range expansions and the resulting impacts on human health. Temperature and humidity are key factors that determine the geographic extent of many arthropods, including vector species. METHODS: We characterized the habitat of two species of sand flies, Lutzomyia longipalpis and Pintomyia evansi. Additionally, we studied two behavioral factors of thermal fitness-thermal and humidity preference in two species of sand flies alongside a key aspect of physiological tolerance-desiccation resistance. RESULTS: We found that Lu. longipalpis is found at cooler and drier conditions than Pi. evansi. Our results also show significant interspecific differences in both behavioral traits, with Pi. evansi preferring warmer, more humid conditions than Lu. longipalpis. Finally, we found that Lu. longipalpis shows greater tolerance to extreme low humidity, and that this is especially pronounced in males of the species. CONCLUSIONS: Taken together, our results suggest that temperature and humidity conditions are key aspects of the climatic niche of Lutzomyia and Pintomyia sand flies and underscore the value of integrative studies of climatic tolerance and preference in vector biology.

Objective Assessment of Cognitive Workload in Surgery: A Systematic Review.

OBJECTIVE: To systematically review technologies that objectively measure CWL in surgery, assessing their psychometric and methodological characteristics. SUMMARY BACKGROUND DATA: Surgical tasks involving concurrent clinical decision-making and the safe application of technical and non-technical skills require a substantial cognitive demand and resource utilization. Cognitive overload leads to impaired clinical decision-making and performance decline. Assessing cognitive workload (CWL) could enable interventions to alleviate burden and improve patient safety. METHODS: Ovid MEDLINE, OVID Embase, the Cochrane Library and IEEE Xplore databases were searched from inception to August 2023. Full-text, peer-reviewed original studies in a population of surgeons, anesthesiologists or interventional radiologists were considered, with no publication date constraints. Study population, task paradigm, stressor, Cognitive Load Theory (CLT) domain, objective and subjective parameters, statistical analysis and results were extracted. Studies were assessed for a) definition of CWL, b) details of the clinical task paradigm, and c) objective CWL assessment tool. Assessment tools were evaluated using psychometric and methodological characteristics. RESULTS: 10790 studies were identified; 9004 were screened; 269 full studies were assessed for eligibility, of which 67 met inclusion criteria. The most widely used assessment modalities were autonomic (32 eye studies and 24 cardiac). Intrinsic workload (e.g. task complexity) and germane workload (effect of training or expertize) were the most prevalent designs investigated. CWL was not defined in 30 of 67 studies (44.8%). Sensitivity was greatest for neurophysiological instruments (100% EEG, 80% fNIRS); and across modalities accuracy increased with multi-sensor recordings. Specificity was limited to cardiac and ocular metrics, and was found to be sub-optimal (50% and 66.67%). Cardiac sensors were the least intrusive, with 54.2% of studies conducted in naturalistic clinical environments (higher ecological validity). CONCLUSION: Physiological metrics provide an accessible, objective assessment of CWL, but dependence on autonomic function negates selectivity and diagnosticity. Neurophysiological measures demonstrate favorable sensitivity, directly measuring brain activation as a correlate of cognitive state. Lacking an objective gold standard at present, we recommend the concurrent use of multimodal objective sensors and subjective tools for cross-validation. A theoretical and technical framework for objective assessment of CWL is required to overcome the heterogeneity of methodological reporting, data processing, and analysis.

Microbial Composition of the Laryngotracheal Region: A Systematic Review.

INTRODUCTION: Microbiome research has predominantly focused on the oral cavity and oropharynx's role in disease, while the upper airway, specifically the larynx and trachea, has been relatively overlooked. Examining the microbial communities in these regions can shed light on how dysbiosis influences diseases and their management. This review evaluates laryngotracheal microbial compositions in both healthy and diseased patients. METHODS: We conducted a systematic review in EMBASE, MEDLINE, and Cochrane Central databases, yielding 1383 studies in the initial search. Inclusion criteria involved participants aged over 18 years and the use of next-generation 16s ribosomal sequencing methods. RESULTS: We included 10 studies-seven focused on larynx sequencing and four on trachea sequencing (one investigated both sites). In a healthy larynx, diverse species such as Streptococcus, Cloacibacterium, Prevotella, and Helicobacter were found. Benign laryngeal diseases exhibited reduced microbial diversity, mainly dominated by Streptococcus. Subglottic stenosis patients showed diminished diversity in both idiopathic and iatrogenic scars. Laryngeal squamous cell carcinoma displayed increased diversity, primarily featuring Fusobacterium. Among non-respiratory-compromised surgery patients, the tracheal microbiome was more diverse in diabetics and those later developing lower respiratory infections. Pneumonia patients exhibited an abundance of Prevotella and Streptococcus, linked to an increased 28-day survival rate, while Streptococcus and Haemophilus abundance correlated with successful extubation. CONCLUSIONS: The laryngotracheal region hosts a unique microbial community influenced by both benign and malignant conditions. Many lesions remain unexplored, underscoring the need for future studies encompassing diverse laryngotracheal conditions. Clinical trials assessing microbiome modifications may unveil novel therapeutic avenues. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Female non-obstetric urogenital fistula repair: long-term patient-reported outcomes and a scoping literature review.

OBJECTIVE: To investigate long-term and patient-reported outcomes, including sexual function, in women undergoing urogenital fistula (UGF) repair, addressing the lack of such data in Western countries, where fistulas often result from iatrogenic causes. PATIENTS AND METHODS: We conducted a retrospective analysis at a tertiary referral centre (2010-2023), classifying fistulas based on World Health Organisation criteria and evaluating surgical approaches, aetiology, and characteristics. Both objective (fistula closure, reintervention rates) and subjective outcomes (validated questionnaires) were assessed. A scoping review of patient-reported outcome measures in UGF repair was also performed. RESULTS: The study included 50 patients: 17 (34%) underwent transvaginal and 33 (66%) transabdominal surgery. History of hysterectomy was present in 36 patients (72%). The median (interquartile range [IQR]) operating time was 130 (88-148) min. Fistula closure was achieved in 94% of cases at a median (IQR) follow-up of 50 (16-91) months and reached 100% after three redo fistula repairs. Seven patients (14%) underwent reinterventions for stress urinary incontinence after transvaginal repair (autologous fascial slings). Patient-reported outcomes showed median (IQR) scores on the International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules (ICIQ-FLUTS) of 5 (3-7) for filling symptoms, 1 (0-2) for voiding symptoms and 4.5 (1-9) for incontinence symptoms. The median (IQR) score on the ICIQ Female Sexual Matters Associated with Lower Urinary Tract Symptoms Module (ICIQ-FLUTSsex) was 3 (1-5). The median (IQR) ICIQ Satisfaction (ICIQ-S) outcome score and overall satisfaction with surgery item score was 22 (18.5-23.5) and 10 (8.5-10), respectively. Higher scores indicate higher symptom burden and treatment satisfaction, respectively. Our scoping review included 1784 women, revealing mixed aetiology and methodological and aetiological heterogeneity, thus complicating cross-study comparisons. CONCLUSIONS: Urogenital fistula repair at a specialised centre leads to excellent outcomes and high satisfaction. Patients with urethrovaginal fistulas are at increased risk of stress urinary incontinence, possibly due to the original trauma site of the fistula.

Data-driven gating (DDG)-based motion match for improved CTAC registration.

BACKGROUND: Respiratory motion artefacts are a pitfall in thoracic PET/CT imaging. A source of these motion artefacts within PET images is the CT used for attenuation correction of the images. The arbitrary respiratory phase in which the helical CT ( CT helical ) is acquired often causes misregistration between PET and CT images, leading to inaccurate attenuation correction of the PET image. As a result, errors in tumour delineation or lesion uptake values can occur. To minimise the effect of motion in PET/CT imaging, a data-driven gating (DDG)-based motion match (MM) algorithm has been developed that estimates the phase of the CT helical , and subsequently warps this CT to a given phase of the respiratory cycle, allowing it to be phase-matched to the PET. A set of data was used which had four-dimensional CT (4DCT) acquired alongside PET/CT. The 4DCT allowed ground truth CT phases to be generated and compared to the algorithm-generated motion match CT (MMCT). Measurements of liver and lesion margin positions were taken across CT images to determine any differences and establish how well the algorithm performed concerning warping the CT helical to a given phase (end-of-expiration, EE). RESULTS: Whilst there was a minor significance in the liver measurement between the 4DCT and MMCT ( p = 0.045 ), no significant differences were found between the 4DCT or MMCT for lesion measurements ( p = 1.0 ). In all instances, the CT helical was found to be significantly different from the 4DCT ( p < 0.001 ). Consequently, the 4DCT and MMCT can be considered equivalent with respect to warped CT generation, showing the DDG-based MM algorithm to be successful. CONCLUSION: The MM algorithm successfully enables the phase-matching of a CT helical to the EE of a ground truth 4DCT. This would reduce the motion artefacts caused by PET/CT registration without requiring additional patient dose (required for a 4DCT).

Methotrexate Use and Risk of Interstitial Lung Disease in Dermatomyositis.

This cohort study examines the association between methotrexate use and interstitial lung disease in patients with dermatomyositis.

Erectile function preservation after salvage radiation therapy for biochemically recurrent prostate cancer after prostatectomy: Five-year results of the SAKK 09/10 randomized phase 3 trial.

Objectives: To evaluate effects of dose intensified salvage radiotherapy (sRT) on erectile function in biochemically recurrent prostate cancer (PC) after radical prostatectomy (RP). Materials and methods: Eligible patients had evidence of biochemical failure after RP and a PSA at randomization of ≤ 2 ng/ml. Erectile dysfunction (ED) was investigated as secondary endpoint within the multicentre randomized trial (February 2011 to April 2014) in patients receiving either 64 Gy or 70 Gy sRT. ED and quality of life (QoL) were assessed using CTCAE v4.0 and the EORTC QoL questionnaires C30 and PR25 at baseline and up to 5 years after sRT. Results: 344 patients were evaluable. After RP 197 (57.3 %) patients had G0-2 ED while G3 ED was recorded in 147 (42.7 %) patients. Subsequently, sexual activity and functioning was impaired. 5 years after sRT, 101 (29.4 %) patients noted G0-2 ED. During follow-up, 44.2 % of patients with baseline G3 ED showed any improvement and 61.4 % of patients with baseline G0-2 ED showed worsening. Shorter time interval between RP and start of sRT (p = 0.007) and older age at randomization (p = 0.005) were significant predictors to more baseline ED and low sexual activity in the long-term. Age (p = 0.010) and RT technique (p = 0.031) had a significant impact on occurrence of long-term ED grade 3 and worse sexual functioning. During follow-up, no differences were found in erectile function, sexual activity, and sexual functioning between the 64 Gy and 70 Gy arm. Conclusion: ED after RP is a known long-term side effect with significant impact on patients' QoL. ED was further affected by sRT, but dose intensification of sRT showed no significant impact on erectile function recovery or prevalence of de novo ED after sRT. Age, tumor stage, prostatectomy and RT-techniques, nerve-sparing and observation time were associated with long-term erectile function outcome.ClinicalTrials.gov. Identifier: NCT01272050.

Repellent activity of essential oils to the Lone Star tick, Amblyomma americanum.

BACKGROUND: The Lone Star tick, Amblyomma americanum is important to human health because of a variety of pathogenic organisms transmitted to humans during feeding events, which underscores the need to identify novel approaches to prevent tick bites. Thus, the goal of this study was to test natural and synthetic molecules for repellent activity against ticks in spatial, contact and human fingertip bioassays. METHODS: The efficacy of essential oils and naturally derived compounds as repellents to Am. americanum nymphs was compared in three different bioassays: contact, spatial and fingertip repellent bioassays. RESULTS: Concentration response curves after contact exposure to 1R-trans-chrysanthemic acid (TCA) indicated a 5.6 µg/cm2 concentration required to repel 50% of ticks (RC50), which was five- and sevenfold more active than DEET and nootkatone, respectively. For contact repellency, the rank order of repellency at 50 µg/cm2 for natural oils was clove > geranium > oregano > cedarwood > thyme > amyris > patchouli > citronella > juniper berry > peppermint > cassia. For spatial bioassays, TCA was approximately twofold more active than DEET and nootkatone at 50 µg/cm2 but was not significantly different at 10 µg/cm2. In spatial assays, thyme and cassia were the most active compounds tested with 100% and 80% ticks repelled within 15 min of exposure respectively and was approximately twofold more effective than DEET at the same concentration. To translate these non-host assays to efficacy when used on the human host, we quantified repellency using a finger-climbing assay. TCA, nootkatone and DEET were equally effective in the fingertip assay, and patchouli oil was the only natural oil that significantly repelled ticks. CONCLUSIONS: The differences in repellent potency based on the assay type suggests that the ability to discover active tick repellents suitable for development may be more complicated than with other arthropod species; furthermore, the field delivery mechanism must be considered early in development to ensure translation to field efficacy. TCA, which is naturally derived, is a promising candidate for a tick repellent that has comparable repellency to commercialized tick repellents.