Hormonal Control of Blood Viscosity.

The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus. By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide.

Pediatric mental health emergency department visits from 2017 to 2022: A multicenter study.

BACKGROUND: The COVID-19 pandemic adversely affected children's mental health (MH) and changed patterns of MH emergency department (ED) utilization. Our objective was to assess how pediatric MH ED visits during the COVID-19 pandemic differed from expected prepandemic trends. METHODS: We retrospectively studied MH ED visits by children 5 to <18 years old at nine U.S. hospitals participating in the Pediatric Emergency Care Applied Research Network Registry from 2017 to 2022. We described visit length by time period: prepandemic (January 2017-February 2020), early pandemic (March 2020-December 2020), midpandemic (2021), and late pandemic (2022). We estimated expected visit rates from prepandemic data using multivariable Poisson regression models. We calculated rate ratios (RRs) of observed to expected visits per 30 days during each pandemic time period, overall and by sociodemographic and clinical characteristics. RESULTS: We identified 175,979 pediatric MH ED visits. Visit length exceeded 12 h for 7.3% prepandemic, 8.4% early pandemic, 15.0% midpandemic, and 19.2% late pandemic visits. During the early pandemic, observed visits per 30 days decreased relative to expected rates (RR 0.80, 95% confidence interval [CI] 0.78-0.84), were similar to expected rates during the midpandemic (RR 1.01, 95% CI 0.96-1.07), and then decreased below expected rates during the late pandemic (RR 0.92, 95% CI 0.86-0.98). During the late pandemic, visit rates were higher than expected for females (RR 1.10, 95% CI 1.02-1.20) and for bipolar disorders (RR 1.83, 95% CI 1.38-2.75), schizophrenia spectrum disorders (RR 1.55, 95% CI 1.10-2.59), and substance-related and addictive disorders (RR 1.50, 95% CI 1.18-2.05). CONCLUSIONS: During the late pandemic, pediatric MH ED visits decreased below expected rates; however, visits by females and for specific conditions remained elevated, indicating a need for increased attention to these groups. Prolonged ED visit lengths may reflect inadequate availability of MH services.

Chatbot Reliability in Managing Thoracic Surgical Clinical Scenarios.

BACKGROUND: Chatbot use in medicine is growing, and concerns have been raised regarding their accuracy. We assessed the performance of four different chatbots in managing thoracic surgical clinical scenarios. METHODS: Topic domains were identified and clinical scenarios were developed within each domain. Each scenario included three stems utilizing Key Feature methods related to diagnosis, evaluation, and treatment. Twelve scenarios were presented to ChatGPT-4, Bard, Perplexity, and Claude 2 in three separate runs. Up to 1 point was awarded for each stem, yielding a potential of 3 points per scenario. Critical failures were identified prior to scoring; if they occurred, the stem and overall scenario scores were adjusted to 0. We arbitrarily established a threshold of ≥2 points mean adjusted score per scenario as a passing grade and established a critical fail rate of ≥30% as failure to pass. RESULTS: The bot performances varied considerably within each run and their overall performance was a fail on all runs (critical mean scenario fails of 83%, 71%, and 71%). The bots trended towards "learning" from the first to the second run, but without improvement in overall raw (1.24 ± 0.47 vs 1.63 ± 0.76 vs 1.51 ± 0.60; p=0.29) and adjusted scenario scores (0.44 ± 0.54 vs 0.80 ± 0.94 vs 0.76 ± 0.81; p=0.48) after all runs. CONCLUSIONS: Chatbot performance in managing clinical scenarios was insufficient to provide reliable assistance. This is a cautionary note against reliance on the current accuracy of chatbots in complex Thoracic Surgery medical decision making.

The Association between Race and Extended Length of Stay in Low-energy Proximal Humerus Fractures in Elderly Patients.

INTRODUCTION: Proximal humerus fractures (PHFs) are one of the most common fractures among patients aged 65 years and older, commonly due to low-energy mechanisms. It is essential to identify drivers of increased healthcare utilization in geriatric PHF patients and bring awareness to any disparities in care. Here, we identify factors associated with the likelihood of inpatient admission and prolonged hospital stay among patients aged 65 years and older who sustain PHF due to falls. METHODS: A national database was used to identify patients aged 65 years and older who suffered proximal humeral fractures due to a fall. Patient factors were analyzed for association with the likelihood of admission and odds of prolonged stay (≥5 days). RESULTS: In the study period, 75,385 PHF patients who met our inclusion criteria presented to the emergency department and 14,118 (18.7%) were admitted. Black race was significantly associated with decreased odds of admission (P < 0.001) and increased likelihood of prolonged stay (P = 0.007) compared with White patients. Patients aged 75 to 84 and 85+ were both more likely to be admitted (P < 0.001) and experienced a prolonged hospital stay (P = 0.015). Patients undergoing surgical intervention with reverse total shoulder arthroplasty were associated with admission and prolonged length of stay (P < 0.001). Hospitals in Midwestern (P < 0.001) and Western (P < 0.001) regions exhibited lower rates of admission and Northeastern hospitals were associated with prolonged stays (P = 0.001). Finally, trauma and nonmetropolitan (P < 0.001) centers were associated with admission. CONCLUSION: Our study highlights the notable influence of age and race on the likelihood of hospital admission and prolonged hospital stay. Specifically, Black patients exhibited prolonged hospital stay, which has been associated with lower-quality care, warranting additional exploration. Understanding these demographic and hospital-related factors is essential for optimizing resource allocation and reducing healthcare disparities in the care of PHF patients, especially as the population ages and the incidence of PHF continues to rise.

Public health surveillance of new psychoactive substances: recent developments.

PURPOSE OF REVIEW: New psychoactive substances (NPS) continue to emerge globally and present a threat to public health. This article summarizes the most recent literature on approaches for monitoring NPS use and adverse events related to use. RECENT FINDINGS: A variety of approaches have recently been employed for surveillance of NPS use and associated harms, including the use of toxicology testing of patients in emergency departments, surveys of sentinel populations, drug checking and syringe services programs, wastewater-based epidemiology, and retrospective analyses of clinical samples and toxicology reports. These studies cover a range of time periods and NPS examined across numerous countries. SUMMARY: Areas of particular interest for future research include the use of data from drug checking services to inform surveillance efforts of the illicit drug supply and the development of methods for wastewater-based monitoring of NPS. Studies that combine self-report data with toxicology testing in particular are important for capturing unintentional or unknown exposure to NPS including fentanyls and drugs like xylazine. Given the limitations associated with individual indicators of drug use and associated harms, the harmonization of multiple data sources can help present a more complete picture of both trends involving NPS to better inform public health responses.

Measuring the burden of hundreds of BioBricks defines an evolutionary limit on constructability in synthetic biology.

Engineered DNA will slow the growth of a host cell if it redirects limiting resources or otherwise interferes with homeostasis. Populations of engineered cells can rapidly become dominated by "escape mutants" that evolve to alleviate this burden by inactivating the intended function. Synthetic biologists working with bacteria rely on genetic parts and devices encoded on plasmids, but the burden of different engineered DNA sequences is rarely characterized. We measured how 301 BioBricks on high-copy plasmids affected the growth rate of Escherichia coli . Of these, 59 (19.6%) negatively impacted growth. The burden imposed by engineered DNA is commonly associated with diverting ribosomes or other gene expression factors away from producing endogenous genes that are essential for cellular replication. In line with this expectation, BioBricks exhibiting burden were more likely to contain highly active constitutive promoters and strong ribosome binding sites. By monitoring how much each BioBrick reduced expression of a chromosomal GFP reporter, we found that the burden of most, but not all, BioBricks could be wholly explained by diversion of gene expression resources. Overall, no BioBricks reduced the growth rate of E. coli by >45%, which agreed with a population genetic model that predicts such plasmids should be "unclonable" because escape mutants will take over during growth of a bacterial colony or small laboratory culture from a transformed cell. We made this model available as an interactive web tool for synthetic biology education and added our burden measurements to the iGEM Registry descriptions of each BioBrick.

Metagenome diversity illuminates the origins of pathogen effectors.

Recent metagenome-assembled genome (MAG) analyses have profoundly impacted Rickettsiology systematics. The discovery of basal lineages (novel families Mitibacteraceae and Athabascaceae) with predicted extracellular lifestyles exposed an evolutionary timepoint for the transition to host dependency, which seemingly occurred independent of mitochondrial evolution. Notably, these basal rickettsiae carry the Rickettsiales vir homolog (rvh) type IV secretion system and purportedly use rvh to kill congener microbes rather than parasitize host cells as described for later-evolving rickettsial pathogens. MAG analysis also substantially increased diversity for the genus Rickettsia and delineated a sister lineage (the novel genus Tisiphia) that stands to inform on the emergence of human pathogens from protist and invertebrate endosymbionts. Herein, we probed Rickettsiales MAG and genomic diversity for the distribution of Rickettsia rvh effectors to ascertain their origins. A sparse distribution of most Rickettsia rvh effectors outside of Rickettsiaceae lineages illuminates unique rvh evolution from basal extracellular species and other rickettsial families. Remarkably, nearly every effector was found in multiple divergent forms with variable architectures, indicating profound roles for gene duplication and recombination in shaping effector repertoires in Rickettsia pathogens. Lateral gene transfer plays a prominent role in shaping the rvh effector landscape, as evinced by the discovery of many effectors on plasmids and conjugative transposons, as well as pervasive effector gene exchange between Rickettsia and Legionella species. Our study exemplifies how MAGs can yield insight into pathogen effector origins, particularly how effector architectures might become tailored to the discrete host cell functions of different eukaryotic hosts.IMPORTANCEWhile rickettsioses are deadly vector-borne human diseases, factors distinguishing Rickettsia pathogens from the innumerable bevy of environmental rickettsial endosymbionts remain lacking. Recent metagenome-assembled genome (MAG) studies revealed evolutionary timepoints for rickettsial transitions to host dependency. The rvh type IV secretion system was likely repurposed from congener killing in basal extracellular species to parasitizing host cells in later-evolving pathogens. Our analysis of MAG diversity for over two dozen rvh effectors unearthed their presence in some non-pathogens. However, most effectors were found in multiple divergent forms with variable architectures, indicating gene duplication and recombination-fashioned effector repertoires of Rickettsia pathogens. Lateral gene transfer substantially shaped pathogen effector arsenals, evinced by the discovery of effectors on plasmids and conjugative transposons, as well as pervasive effector gene exchanges between Rickettsia and Legionella species. Our study exemplifies how MAGs yield insight into pathogen effector origins and evolutionary processes tailoring effectors to eukaryotic host cell biology.

Staphylococcus aureus skin colonization is mediated by SasG lectin variation.

Staphylococcus aureus causes the majority of skin and soft tissue infections, but this pathogen only transiently colonizes healthy skin. However, this transient skin exposure enables S. aureus to transition to infection. The initial adhesion of S. aureus to skin corneocytes is mediated by surface protein G (SasG). Here, phylogenetic analyses reveal the presence of two major divergent SasG alleles in S. aureus: SasG-I and SasG-II. Structural analyses of SasG-II identify a nonaromatic arginine in the binding pocket of the lectin subdomain that mediates adhesion to corneocytes. Atomic force microscopy and corneocyte adhesion assays indicate that SasG-II can bind to a broader variety of ligands than SasG-I. Glycosidase treatment results in different binding profiles between SasG-I and SasG-II on skin cells. In addition, SasG-mediated adhesion is recapitulated using differentiated N/TERT keratinocytes. Our findings indicate that SasG-II has evolved to adhere to multiple ligands, conferring a distinct advantage to S. aureus during skin colonization.

How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a functional assessment.

BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic disorders. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs remain key challenges to study human nociception in vitro. Here, we report a detailed functional characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Anatomic's commercially available RealDRG™ were further characterized for both functional and expression phenotyping of key nociceptor markers. METHODS: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Manual patch clamp was used to functionally characterize both control and patient-derived neurons. High throughput techniques were further used to demonstrate that RealDRGs™ derived from the Anatomic protocol are amenable to high throughput technologies for disease modelling. RESULTS: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. Chambers protocol results in predominantly tonic firing when compared to Anatomic protocol. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. RealDRG™ sensory neurons show heterogeneity of nociceptive markers indicating that the cells may be useful as a humanized model system for translational studies. CONCLUSIONS: We validated the efficiency of two differentiation protocols and their potential application for functional assessment and thus understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

CT Imaging Computed Tomography/Computed Tomography Angiography/Perfusion in Acute Ischemic Stroke and Vasospasm.

Computed tomography (CT), CT angiography (CTA), and CT perfusion (CTP) play crucial roles in the comprehensive evaluation and management of acute ischemic stroke, aneurysmal subarachnoid hemorrhage (SAH), and vasospasm. CTP provides functional data about cerebral blood flow, allowing radiologists, neurointerventionalists, and stroke neurologists to more accurately delineate the volume of core infarct and ischemic penumbra allowing for patient-specific treatment decisions to be made. CTA and CTP are used in tandem to evaluate for vasospasm associated with aneurysmal SAH and can help provide an insight into the physiologic impact of angiographic vasospasm, better triaging patients for medical and interventional treatment.

Vessel Wall Characterization Using Quantitative MR Imaging.

MR imaging's exceptional capabilities in vascular imaging stem from its ability to visualize and quantify vessel wall features, such as plaque burden, composition, and biomechanical properties. The application of advanced MR imaging techniques, including two-dimensional and three-dimensional black-blood MR imaging, T1 and T2 relaxometry, diffusion-weighted imaging, and dynamic contrast-enhanced MR imaging, wall shear stress, and arterial stiffness, empowers clinicians and researchers to explore the intricacies of vascular diseases. This array of techniques provides comprehensive insights into the development and progression of vascular pathologies, facilitating earlier diagnosis, targeted treatment, and improved patient outcomes in the management of vascular health.

Dual-Energy Computed Tomography in the Evaluation and Management of Subarachnoid Hemorrhage, Intracranial Hemorrhage, and Acute Ischemic Stroke.

Dual-energy computed tomography (DECT) has emerged as a valuable imaging modality in the diagnosis and management of various cerebrovascular pathologies, including subarachnoid hemorrhage, intracranial hemorrhage, and acute ischemic stroke. This article reviews the principles of DECT and its applications in the evaluation and management of these conditions. The authors discuss the advantages of DECT over conventional computed tomography, as well as its limitations, and provide an overview of current research and future directions in the field.

Three-Dimensional Instrumented Gait Analysis for Children With Cerebral Palsy: An Evidence-Based Clinical Practice Guideline.

BACKGROUND: Children with cerebral palsy (CP) who walk have complex gait patterns and deviations often requiring physical therapy (PT)/medical/surgical interventions. Walking in children with CP can be assessed with 3-dimensional instrumented gait analysis (3D-IGA) providing kinematics (joint angles), kinetics (joint moments/powers), and muscle activity. PURPOSE: This clinical practice guideline provides PTs, physicians, and associated clinicians involved in the care of children with CP, with 7 action statements on when and how 3D-IGA can inform clinical assessments and potential interventions. It links the action statement grades with specific levels of evidence based on a critical appraisal of the literature. CONCLUSIONS: This clinical practice guideline addresses 3D-IGA's utility to inform surgical and non-surgical interventions, to identify gait deviations among segments/joints and planes and to evaluate the effectiveness of interventions. Best practice statements provide guidance for clinicians about the preferred characteristics of 3D-IGA laboratories including instrumentation, staffing, and reporting practices.Video Abstract: Supplemental digital content available at http://links.lww.com/PPT/A524.

Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB. RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients. CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

Longitudinal changes in adverse effects reporting in multiple dietary supplement classifications: The US military dietary supplement use study.

Over 70% of United States military service members (SMs) regularly use dietary supplements (DSs) and about 18% have reported adverse effects (AEs) associated with use. This investigation examined longitudinal changes in AEs reporting among DS users. On two separate occasions 1.3 ± 0.2 years apart (mean ± standard deviation), 5778 SMs completed identical questionnaires on DS use and associated AEs. Among SMs reporting DS use ≥1 time/week, ≥1 AE was reported by 19% and 15% in the baseline and follow-up phases, respectively. The risk of reporting DS use at follow-up was similar among those reporting and not reporting AEs at baseline for most DS categories including prohormones, proteins/amino acids, individual vitamins and minerals, multivitamin/multiminerals, herbals, fish oils, joint health products, and other DSs. An exception was combination products where those reporting AEs at baseline had an increased risk of use at follow-up (risk ratio = 1.13, 95% confidence interval = 1.06-1.09). Those reporting AEs at baseline and continuing DS use in the follow-up were more likely to report AEs at follow-up compared to those not reporting baseline AEs. In conclusion, AEs reported at baseline did not deter many participants from using DSs in the follow-up period, and many SMs reporting AEs at baseline continued reporting them at follow-up.

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody.

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.