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Introduction: Situational awareness is essential during emergent procedures such as endotracheal intubation. Previous studies suggest that time distortion can occur during intubation. However, only in-hospital intubations performed by physicians have been studied. We aimed to determine whether time distortion affected paramedics performing intubation by examining the perceived vs actual total laryngoscopy time, defined as time elapsed from the laryngoscope blade entering the mouth until the endotracheal tube balloon passes the vocal cords.Methods: For this retrospective study we collected prehospital intubation data from a suburban, fire department-based emergency medical services (EMS) system from January 5, 2021–May 21, 2022. The perceived total laryngoscopy time was queried as a part of the electronic health record. Video laryngoscopy recordings were reviewed by a panel of experts to determine the actual time. Patients >18 years old who underwent intubation by paramedics with video laryngoscopy were included for analysis. The primary outcome was the difference between actual and perceived total laryngoscopy time. Secondary analysis examined the relationship between high time distortion, defined as the highest quartile of the primary outcome, and patient age, paramedic years of experience, perceived presence of difficult anatomy, excess secretions, use of rapid sequence intubation, and multiple intubation attempts. We conducted descriptive analysis followed by logistic regression analysis, chi-square tests, and Fisher exact tests when appropriate.Results: A total of 122 intubations were collected for analysis, and 10 were excluded due to lack of video recording. Final analysis included 112 intubations. Mean actual laryngoscopy time was 50.0 seconds (s)(95% confidence interval [CI] 43.7–56.3). Mean perceived laryngoscopy time was 27.8 s (95% CI 24.7–31.0). The median difference between actual and perceived time was 18 s (interquartile range 6–30). We calculated high time distortion as having a difference greater than 30 s between actual and perceived laryngoscopy time. None of the secondary variables had statistically significant associations with high time distortion. Overall, we show that the paramedic’s perception of total laryngoscopy time is significantly underestimated even when accounting for paramedic experience and perceived airway difficulty.Conclusion: This study suggests that time distortion may lead to an unrecognized prolonged procedure time. Limitations include use of a convenience sample, small sample size, and potential uncollected confounding variables.

Internal distraction devices are commonly used in congenital micrognathia. The eventual need for device and screw removal can be challenging, requiring extensive dissection and disturbance of bone regenerate. Bioabsorbable poly-L-lactide (PLLA) screws, compared to traditional titanium screws, simplify device removal. Previous in vivo studies have found that the maximal compressive force generated by mandibular distraction is 69.4N. We hypothesized that PLLA screws could support these compressive/distraction forces. Ten mandibles were obtained from 5 canine cadavers. Paired mandibles from the same cadaver were each fixated to a mandibular distractor with eight screws (either titanium or PLLA). Devices were each set to 15 and 30 mm of distraction distance. Compression force of 80 N was then generated parallel to the axis of the distraction device. Distractor displacement was measured to detect any mechanical failure during this pre-set load. Finally, if no failure was observed at 80 N, a load-to-failure compression test was done in the PLLA group to determine the mechanical failure point. All distractors in both the titanium and PLLA screw groups withstood 80 N of compression without failure. When the load-to-failure test was performed in the PLLA group, the average device failure point was 172.8 N (range 148-196 N). Review of high-frame-rate video demonstrated that all failures occurred due to the PLLA screws breaking or falling out. Bioabsorbable PLLA screws can withstand compressive forces more than double that of the maximal in vivo forces needed during mandibular distraction. These screws may be an acceptable alternative for the fixation of internal mandibular distractors.

Despite widespread and striking examples of physiological oscillations, their functional role is often unclear. Even glycolysis, the paradigm example of oscillatory biochemistry, has seen questions about its oscillatory function. Here, we take a systems approach to argue that oscillations play critical physiological roles, such as enabling systems to avoid desensitization, to avoid chronically high and therefore toxic levels of chemicals, and to become more resistant to noise. Oscillation also enables complex physiological systems to reconcile incompatible conditions such as oxidation and reduction, by cycling between them, and to synchronize the oscillations of many small units into one large effect. In pancreatic β-cells, glycolytic oscillations synchronize with calcium and mitochondrial oscillations to drive pulsatile insulin release, critical for liver regulation of glucose. In addition, oscillation can keep biological time, essential for embryonic development in promoting cell diversity and pattern formation. The functional importance of oscillatory processes requires a re-thinking of the traditional doctrine of homeostasis, holding that physiological quantities are maintained at constant equilibrium values, a view that has largely failed in the clinic. A more dynamic approach will initiate a paradigm shift in our view of health and disease. A deeper look into the mechanisms that create, sustain and abolish oscillatory processes requires the language of nonlinear dynamics, well beyond the linearization techniques of equilibrium control theory. Nonlinear dynamics enables us to identify oscillatory ('pacemaking') mechanisms at the cellular, tissue and system levels.

An inguinal bladder hernia (IBH) is an abnormal protrusion of the bladder into the inguinal canal accompanied by a peritoneum sheath that creates the hernia sac. Clinical presentations vary greatly from lower urinary tract symptoms (LUTS) and reduction in scrotal size after voiding to being entirely asymptomatic. Since inguinal bladder hernias are uncommon and often accompanied by varied and nonspecific symptoms, it is challenging to diagnose and rarely included in differentials. Currently, computerized tomography (CT) imaging with contrast or voiding cystourethrography is recommended for diagnosis. There is no consensus on the best treatment for inguinal bladder hernias, with options ranging from laparoscopic repair to catheterization. In this study, we report the case of inguinal bladder hernia in an 86-year-old male presenting with symptoms of recurrent hematuria and two failed voiding trials after a Foley catheter placement from prostatomegaly resulting in bladder diverticula, and IBH. He was treated with prostate artery embolization (PAE) to address LUTS related to benign prostatic hyperplasia (BPH). The resultant decreased prostatic volume resolved his symptoms of IBH, hematuria, and urinary retention.

Hematomas are often associated with benign processes such as sport-related injuries, postsurgical complications, and medications such as blood thinners. Rarely, hematomas can occur spontaneously without any identifiable cause or recollection of an inciting event. Such events can lead to inaccurately diagnosing a patient, which could delay or alter treatment and worsen the patient's prognosis. This patient reported sudden-onset abdominal pain with radiation to her back and denied any recent medication use or trauma while at home. The case highlights the key radiographic findings of magnetic resonance imaging (MRI) and contrast-enhanced ultrasound to eventually confirm an obscure case of hepatocellular carcinoma and help guide management.

Central nervous system (CNS) injury or disease states are often difficult to treat due to the closed system of the dura mater/blood-brain barrier and the bony skull and vertebrae. The closed system results in at least partial containment of any pro-inflammatory molecules, pathogens, or toxic byproducts in the case of brain or spinal cord lesions, which can result in a destructive feedback loop. Cervical-approach access techniques (lateral C1-C2, suboccipital and lateral atlanto-occipital space punctures) are less-common methods of cerebrospinal fluid (CSF) sampling due to the relative ease and safety of lumbar spinal taps. However, with improved image-guidance, these cervical-level CSF access points are still useful when there are certain contraindications and difficulties when attempting to sample the CSF via the typical lumbar spinal approach. With the advent of microcatheters and minimally invasive techniques, combined with body fluid filtration technology, the question arises: could dual microcatheters be introduced for inflow and outflow of purified or artificial CSF to break the destructive feedback loop and thus diminish CNS damage?. We hypothesize that intrathecal spinal catheters could be placed in 2 positions (e.g., via a cervical route and the typical lumbar spinal route) to allow for both an input and output to more effectively filter or flush the CSF. This could have broad implications in the treatment of strokes, traumatic brain or spinal cord injury, infections, autoimmune diseases, and even malignancies within the CNS-in short, any disease with abnormalities detectable in the CSF.

This study determined whether initiation of pharmacologic treatment was delayed for newly diagnosed osteoporosis patients during the COVID-19 pandemic. 1,189 patients ≥50 years with newly diagnosed osteoporosis using dual-energy x-ray absorptiometry (DXA) screening at a single academic institution were included. Patients with previous osteoporosis were excluded. Patients diagnosed between March 1, 2018-January 31, 2020 (pre-pandemic cohort, n = 576) were compared to those diagnosed between March 1, 2020-January 31, 2022 (pandemic cohort, n = 613). Age, sex, race, ethnicity, ordering providers (primary vs specialty), and pharmacological agents were evaluated. Primary outcomes included proportion of patients prescribed therapy within 3 and 6-months of diagnosis, and mean time from diagnosis to treatment initiation. The pre-pandemic cohort had more White patients (74.3 vs 68.4%, p = .02) and no differences between remaining demographic variables. Only 40.5% of newly diagnosed patients initiated pharmacologic therapy within 6 months. Patients treated at 3-months (31.8 vs 35.4%, p = 0.19) and 6-months (37.8 vs 42.9, p = 0.08) were comparable between cohorts (47.2 vs 50.2% p = 0.30). Mean time from diagnosis to treatment initiation was similar (46 vs 45 days, p = 0.72). There were no treatment differences based on gender, race, or ethnicity or between ordering providers (65.1 vs 57.4% primary care, p = 0.08). Bisphosphonates were most often prescribed in both cohorts (89% vs 82.1%). This is the first study assessing COVID-19's impact on pharmacologic treatment of newly diagnosed osteoporosis. 40.5% of newly diagnosed patients were treated pharmacologically within six months of diagnosis, and the pandemic did not significantly affect treatment rates.

Cardiomyopathies have unresolved genotype-phenotype relationships and lack disease-specific treatments. Here we provide a framework to identify genotype-specific pathomechanisms and therapeutic targets to accelerate the development of precision medicine. We use human cardiac electromechanical in-silico modelling and simulation which we validate with experimental hiPSC-CM data and modelling in combination with clinical biomarkers. We select hypertrophic cardiomyopathy as a challenge for this approach and study genetic variations that mutate proteins of the thick (MYH7R403Q/+) and thin filaments (TNNT2R92Q/+, TNNI3R21C/+) of the cardiac sarcomere. Using in-silico techniques we show that the destabilisation of myosin super relaxation observed in hiPSC-CMs drives disease in virtual cells and ventricles carrying the MYH7R403Q/+ variant, and that secondary effects on thin filament activation are necessary to precipitate slowed relaxation of the cell and diastolic insufficiency in the chamber. In-silico modelling shows that Mavacamten corrects the MYH7R403Q/+ phenotype in agreement with hiPSC-CM experiments. Our in-silico model predicts that the thin filament variants TNNT2R92Q/+ and TNNI3R21C/+ display altered calcium regulation as central pathomechanism, for which Mavacamten provides incomplete salvage, which we have corroborated in TNNT2R92Q/+ and TNNI3R21C/+ hiPSC-CMs. We define the ideal characteristics of a novel thin filament-targeting compound and show its efficacy in-silico. We demonstrate that hybrid human-based hiPSC-CM and in-silico studies accelerate pathomechanism discovery and classification testing, improving clinical interpretation of genetic variants, and directing rational therapeutic targeting and design.

The tumor suppressor p53 oscillates in response to DNA double-strand breaks, a behavior that has been suggested to be essential to its anti-cancer function. Nearly all human cancers have genetic alterations in the p53 pathway; a number of these alterations have been shown to be oncogenic by experiment. These alterations include somatic mutations and copy number variations as well as germline polymorphisms. Intriguingly, they exhibit a mixed pattern of interactions in tumors, such as co-occurrence, mutual exclusivity, and paradoxically, mutual antagonism. Using a differential equation model of p53-Mdm2 dynamics, we employ Hopf bifurcation analysis to show that these alterations have a common mode of action, to abolish the oscillatory competence of p53, thereby, we suggest, impairing its tumor suppressive function. In this analysis, diverse genetic alterations, widely associated with human cancers clinically, have a unified mechanistic explanation of their role in oncogenesis.

Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the T wave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation. However, more recent evidence indicates that PVCs also can arise from the T wave itself. In the latter case, the PVC initiating reentry is not a separate event from the T wave but rather is causally generated from the repolarization gradient that manifests as the T wave. We call the former an R-to-T mechanism and the latter an R-from-T mechanism, which are initiation mechanisms distinct from each other. Both are important components of the R-on-T phenomenon and need to be taken into account when designing antiarrhythmic strategies. Strategies targeting suppression of triggers alone or vulnerable substrate alone may be appropriate in some instances but not in others. Preventing R-from-T arrhythmias requires suppressing the underlying dynamic tissue instabilities responsible for producing both triggers and substrate vulnerability simultaneously. The same principles are likely to apply to supraventricular arrhythmias.

Circadian rhythms in core body temperature (CBT) have been widely studied, but fewer studies have explored higher-frequency (ultradian) rhythms in detail. We analyzed CBT recordings from young and middle-aged wild-type mice as well as from the Q175 model of Huntington's disease (HD), at sufficient temporal resolution to address the question of ultradian rhythms. We used model selection methods to show that the overall circadian pattern was better fit by a square wave than a sine wave. Then, using Fourier analysis of the CBT rhythms, we identified the spectral signature of an 8-hour oscillation that occurs in the night but not the day, an observation that can be confirmed by direct inspection of the rhythms. This diurnal amplitude modulation of the 8-hour rhythm was lost with aging as well as in the HD model. Thus, the impact of aging and disease is seen here in the loss of the ability to separate rhythms into a daytime phase and a nighttime phase. These findings raise the possibility that ultradian rhythms in CBT may be a useful biomarker for the pathology within the central nervous system.

We analyze a dynamic, two-country model that highlights the various trade-offs each country faces between current consumption and competing investments in its future productive and military capacities as it prepares for a possible conflict in the future. Our focus is on the circumstances under which the effects of current trade between the two countries on the future balance of power render trade unappealing to one of them. We find that a positive probability of future conflict induces the country with less resource wealth to “prey” on the relatively more “prudent” behavior of its larger rival, and more so as conflict becomes more likely. While a shift from autarky to trade always raises the current incomes of both countries, the smaller country realizes the relatively larger income gain from trade and also devotes a relatively larger share of its income gain towards arming. Our analysis shows that the larger country rationally chooses not to trade today when the difference in initial resource wealth is sufficiently large and is more likely to prefer autarky when the probability of future conflict is higher.

There is a growing realization that traditional "Calculus for Life Sciences" courses do not show their applicability to the Life Sciences and discourage student interest. There have been calls from the AAAS, the Howard Hughes Medical Institute, the NSF, and the American Association of Medical Colleges for a new kind of math course for biology students, that would focus on dynamics and modeling, to understand positive and negative feedback relations, in the context of important biological applications, not incidental "examples." We designed a new course, LS 30, based on the idea of modeling biological relations as dynamical systems, and then visualizing the dynamical system as a vector field, assigning "change vectors" to every point in a state space. The resulting course, now being given to approximately 1400 students/year at UCLA, has greatly improved student perceptions toward math in biology, reduced minority performance gaps, and increased students' subsequent grades in physics and chemistry courses. This new course can be customized easily for a broad range of institutions. All course materials, including lecture plans, labs, homeworks and exams, are available from the authors; supporting videos are posted online.

Calculus is typically one of the first college courses encountered by science, technology, engineering, and mathematics (STEM) majors. Calculus often presents major challenges affecting STEM student persistence, particularly for students from groups historically underrepresented in STEM. For life sciences majors, calculus courses may not offer content that is relevant to biological systems or connect with students' interests in biology. We developed a transformative approach to teaching college-level math, using a dynamical systems perspective that focuses first on demonstrating why students need math to understand living systems, followed by providing quantitative and computational skills, including concepts from calculus, that students need to build and analyze mathematical models representing these systems. We found that students who complete these new math courses perform better in subsequent science courses than their counterparts who take traditional calculus courses. We also provide evidence that the new math curriculum positively impacts students' academic performance, with data that show narrowing of the achievement gap, based on students' math grades, between student subgroups in the new math courses. Moreover, our results indicate that students' interest in the concepts and skills critical to the quantitative preparation of 21st-century life sciences majors increases after completing the new contextualized math curriculum.

On the basis of a single-period, guns-versus-butter, complete-information model in which two agents dispute control over an insecure portion of their combined output, we study the choice between a peace agreement that maintains the status quo without arming (or unarmed peace) and open conflict (or war) that is possibly destructive. With a focus on outcomes that are immune to both unilateral deviations and coalitional deviations, we find that, depending on war's destructive effects, the degree of output security and the initial distribution of resources, peace can, but need not necessarily, emerge in equilibrium. We also find that, ex ante resource transfers without commitments can improve the prospects for peace, but only when the configuration of parameters describing the degree of output security and the degree of war's destruction ensures the possibility of peace without such transfers at least for some sufficiently even initial resource distributions.

An invasive biopsy followed by histological staining is the benchmark for pathological diagnosis of skin tumors. The process is cumbersome and time-consuming, often leading to unnecessary biopsies and scars. Emerging noninvasive optical technologies such as reflectance confocal microscopy (RCM) can provide label-free, cellular-level resolution, in vivo images of skin without performing a biopsy. Although RCM is a useful diagnostic tool, it requires specialized training because the acquired images are grayscale, lack nuclear features, and are difficult to correlate with tissue pathology. Here, we present a deep learning-based framework that uses a convolutional neural network to rapidly transform in vivo RCM images of unstained skin into virtually-stained hematoxylin and eosin-like images with microscopic resolution, enabling visualization of the epidermis, dermal-epidermal junction, and superficial dermis layers. The network was trained under an adversarial learning scheme, which takes ex vivo RCM images of excised unstained/label-free tissue as inputs and uses the microscopic images of the same tissue labeled with acetic acid nuclear contrast staining as the ground truth. We show that this trained neural network can be used to rapidly perform virtual histology of in vivo, label-free RCM images of normal skin structure, basal cell carcinoma, and melanocytic nevi with pigmented melanocytes, demonstrating similar histological features to traditional histology from the same excised tissue. This application of deep learning-based virtual staining to noninvasive imaging technologies may permit more rapid diagnoses of malignant skin neoplasms and reduce invasive skin biopsies.