3D genome, on repeat: Higher-order folding principles of the heterochromatinized repetitive genome.

Nearly half of the human genome is comprised of diverse repetitive sequences ranging from satellite repeats to retrotransposable elements. Such sequences are susceptible to stepwise expansions, duplications, inversions, and recombination events which can compromise genome function. In this review, we discuss the higher-order folding mechanisms of compartmentalization and loop extrusion and how they shape, and are shaped by, heterochromatin. Using primarily mammalian model systems, we contrast mechanisms governing H3K9me3-mediated heterochromatinization of the repetitive genome and highlight emerging links between repetitive elements and chromatin folding.

High-throughput Oligopaint screen identifies druggable 3D genome regulators.

The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions1-3. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)-an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.

Cohesin-mediated loop anchors confine the locations of human replication origins.

DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)3-6, subTADs7 and loops8 in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.

Reproductive outcome in 326 women with unicornuate uterus.

OBJECTIVES: To study the reproductive outcomes of women with a unicornuate uterus and compare them to those of women with no congenital uterine anomaly. METHODS: This was a single-center, retrospective cohort study. Cases were women aged at least 16 years who were diagnosed with a unicornuate uterus on transvaginal/transrectal ultrasound between January 2008 and September 2021. Controls were women with no congenital uterine anomaly matched 1:1 by age and body mass index. The primary outcome was live-birth rate. Secondary outcomes were pregnancy loss (miscarriage, ectopic pregnancy, termination of pregnancy), preterm delivery, mode of delivery and concomitant gynecological abnormalities (endometriosis, adenomyosis, fibroids). RESULTS: Included in the study were 326 cases and 326 controls. Women with a unicornuate uterus had a significantly lower live-birth rate (184/388 (47.4%) vs 229/396 (57.8%); P = 0.004) and higher rates of overall miscarriage (178/424 (42.0%) vs 155/465 (33.3%); adjusted odds ratio (aOR), 2.21 (95% CI, 1.42-3.42), P < 0.001), ectopic pregnancy (26/424 (6.1%) vs 11/465 (2.4%); aOR, 2.52 (95% CI, 1.22-5.22), P = 0.01), preterm delivery (45/184 (24.5%) vs 17/229 (7.4%); aOR, 3.04 (95% CI, 1.52-5.97), P = 0.001) and Cesarean delivery (116/184 (63.0%) vs 70/229 (30.6%); aOR, 2.54 (95% CI, 1.67-3.88), P < 0.001). Rudimentary-horn pregnancies accounted for 7/26 (26.9%) ectopic pregnancies in the study group. Women with a unicornuate uterus were more likely to have endometriosis (17.5% vs 10.7%; P = 0.018) and adenomyosis (26.7% vs 15.6%; P = 0.001), but were not more likely to have fibroids compared with controls. Women with a functional rudimentary horn were more likely to have pelvic endometriosis compared to those without (odds ratio, 2.4 (95% CI, 1.4-4.1), P = 0.002). CONCLUSIONS: Pregnant women with a unicornuate uterus should be classified as high risk. Removal of a functional rudimentary horn should be discussed with the patient to prevent a rudimentary-horn ectopic pregnancy. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Examining the influence of social-environmental variables on self-injurious behaviour in adolescent boys with fragile X syndrome.

BACKGROUND: Individuals with fragile X syndrome (FXS), the most common known inherited form of intellectual disability, are at increased risk for showing specific forms of self-injurious behaviour (SIB) such as hand biting and head hitting, suggesting that biological factors associated with the syndrome confers increased risk for SIB. Few studies, however, have examined the extent to which social-environmental variables can influence the occurrence of these behaviours in this population. METHOD: Twenty-two adolescent boys with FXS, aged 10 to 18 years were systematically exposed to seven environmental conditions in functional analyses of SIB conducted over 2 days at our research centre. RESULTS: Fourteen (63.6%) boys with FXS engaged in SIB during the functional analyses. Ten (45.5%) boys engaged in SIB that was maintained by social-environmental variables, that is, gaining access to attention/tangibles and/or escaping from social interaction, task demands and/or transition demands. For two boys, SIB was undifferentiated across conditions, and for two boys, SIB appeared to be maintained by automatic reinforcement. CONCLUSIONS: Social-environmental variables appeared to maintain SIB in a significant proportion of boys with FXS. Given that pharmacological treatments for SIB have limited efficacy in this population, the potential role of social-environmental factors on SIB should be examined before pharmacological treatments are implemented for these behaviours.

Association between bedtime and self-reported illness among college students: a representative nationwide study of China.

OBJECTIVE: This study was to examine the association between bedtime and self-reported illness among Chinese college students. METHODS: Participants were 11,942 students, who were identified through a multistage survey sampling process. Sleep and illness status were obtained by self report. Both unadjusted and adjusted methods were considered in the analyses. RESULTS: The logistic regression model found that late bedtime was positively associated with self reported short and long-term illness (OR: 3.70 and 1, 79) after adjusting for demographic characteristics, short sleep duration, and mental disorders. CONCLUSIONS: This study is the first to find a positive relationship between late bedtime and self reported illnesses in China or elsewhere. The findings underscore the importance of educating college students about the importance of sleep.

What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 2. Treatment and prevention.

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE). It provides a summary of key findings from 12 systematic reviews (SRs) that were published or indexed during 2014, and focuses on the treatment and prevention of AE. For an update of SRs on the epidemiology, mechanisms of disease and methodological issues, see Part 1 of this update. Although phototherapy and various systemic medications (including ciclosporin, azathioprine and methotrexate) are commonly used to treat AE, many of these have not been robustly assessed in head-to-head randomized controlled trials. Educational interventions may improve AE severity and quality of life for children and their families. Intake of probiotics prenatally and postnatally may help prevent AE, but there is little evidence to suggest a role in the treatment of AE. Although no benefit was found for allergen avoidance in preventing AE, the use of immunotherapy to treat AE-associated aeroallergen sensitivity requires further evaluation. There is insufficient evidence for Vitamin D supplementation for the treatment of AE This overview of reviews provides a succinct guide for clinicians and patients wishing to remain up to date with the most recent evidence for the treatment and prevention of AE.

What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 1. Epidemiology, risk factors and outcomes.

This review summarizes key findings from nine systematic reviews on atopic eczema (AE) published or first indexed in 2014. It focuses on epidemiology, disease processes and methodological issues. There is reasonable evidence to conclude that high birth weight (> 4000 g) is a risk factor for the development of AE. A lower socioeconomic position is associated with lower prevalence of AE. The effect of exposure to traffic-related air pollution in childhood on the development of AE is uncertain. CD14 polymorphisms do not appear to have an effect in AE. There may be a role for interleukin-18 in AE development. Patients with AE are at decreased risk of brain tumours, but at increased risk of developing attention deficit hyperactivity disorder. Evidence supports the view that normal-appearing skin in AE is in fact structurally abnormal. Lower success rates at inducing remission in AE are associated with increased risk of relapse during long-term follow-up. The Eczema Area Severity Index (EASI) has been agreed as the preferred core instrument to measure clinical signs in future research. There remains a lack of consensus on the definition of an AE flare.

The Insertion and Management of External Ventricular Drains: An Evidence-Based Consensus Statement : A Statement for Healthcare Professionals from the Neurocritical Care Society.

External ventricular drains (EVDs) are commonly placed to monitor intracranial pressure and manage acute hydrocephalus in patients with a variety of intracranial pathologies. The indications for EVD insertion and their efficacy in the management of these various conditions have been previously addressed in guidelines published by the Brain Trauma Foundation, American Heart Association and combined committees of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. While it is well recognized that placement of an EVD may be a lifesaving intervention, the benefits can be offset by procedural and catheter-related complications, such as hemorrhage along the catheter tract, catheter malposition, and CSF infection. Despite their widespread use, there are a lack of high-quality data regarding the best methods for placement and management of EVDs to minimize these risks. Existing recommendations are frequently based on observational data from a single center and may be biased to the authors' view. To address the need for a comprehensive set of evidence-based guidelines for EVD management, the Neurocritical Care Society organized a committee of experts in the fields of neurosurgery, neurology, neuroinfectious disease, critical care, pharmacotherapy, and nursing. The Committee generated clinical questions relevant to EVD placement and management. They developed recommendations based on a thorough literature review using the Grading of Recommendations Assessment, Development, and Evaluation system, with emphasis placed not only on the quality of the evidence, but also on the balance of benefits versus risks, patient values and preferences, and resource considerations.

Problem behaviour in adolescent boys with fragile X syndrome: relative prevalence, frequency and severity.

BACKGROUND: A large proportion of boys with fragile X syndrome (FXS), the most common known inherited form of intellectual disability (ID), exhibit problem behaviours (e.g. aggression, self-injury, property destruction and stereotypy) that can negatively impact the health and safety of others as well as the individual concerned. However, data are limited concerning the relative prevalence, frequency and severity of problem behaviours exhibited by boys with FXS compared with those by boys with mixed-aetiology ID who also exhibit problem behaviours. METHOD: As part of a larger study on problem behaviour, we obtained survey data on 85 adolescent boys with FXS and 155 age-matched boys with mixed-aetiology ID who exhibited at least one form of problem behaviour. RESULTS: For boys with FXS, stereotypy was reported to be more prevalent (χ2 = 4.52, P = 0.012), self-injury was reported to more frequent (U = 2525, P = 0.010) and aggression was reported to be less severe (U = 4176, P = 0.029) than for boys with mixed-aetiology ID. Ratings of aggression and property destruction were highly correlated in each group in terms of both frequency and severity (r = 0.60 to 0.71). Examination of the data by age indicated that the relative frequency of self-injury decreased with age in boys with FXS (χ2 = 8.29, P = 0.040). CONCLUSIONS: Taken together, these results refine and extend previous studies concerning the specificity of the behavioural phenotype in FXS and indicate that specific forms of problem behaviour shown by boys with FXS appear to differ from those exhibited by boys with mixed-aetiology ID in terms of prevalence, frequency and severity. Studies employing more objective measures of frequency and severity, including direct observations, are needed to confirm these findings.

Emergency Neurologic Life Support: Meningitis and Encephalitis.

Bacterial meningitis and viral encephalitis, particularly herpes simplex encephalitis, are severe neurological infections that, if not treated promptly and effectively, lead to poor neurological outcome or death. Because treatment is more effective if given early, the topic of meningitis and encephalitis was chosen as an Emergency Neurological Life Support protocol. This protocol provides a practical approach to recognition and urgent treatment of bacterial meningitis and encephalitis. Appropriate imaging, spinal fluid analysis, and early empiric treatment is discussed. Though uncommon in its full form, the typical clinical triad of headache, fever, and neck stiffness should alert the clinical practitioner to the possibility of a central nervous system infection. Early attention to the airway and maintaining normotension is crucial in treatment of these patients, as is rapid treatment with anti-infectives and, in some cases, corticosteroids.

Parsimonious inference of hybridization in the presence of incomplete lineage sorting.

Hybridization plays an important evolutionary role in several groups of organisms. A phylogenetic approach to detect hybridization entails sequencing multiple loci across the genomes of a group of species of interest, reconstructing their gene trees, and taking their differences as indicators of hybridization. However, methods that follow this approach mostly ignore population effects, such as incomplete lineage sorting (ILS). Given that hybridization occurs between closely related organisms, ILS may very well be at play and, hence, must be accounted for in the analysis framework. To address this issue, we present a parsimony criterion for reconciling gene trees within the branches of a phylogenetic network, and a local search heuristic for inferring phylogenetic networks from collections of gene-tree topologies under this criterion. This framework enables phylogenetic analyses while accounting for both hybridization and ILS. Further, we propose two techniques for incorporating information about uncertainty in gene-tree estimates. Our simulation studies demonstrate the good performance of our framework in terms of identifying the location of hybridization events, as well as estimating the proportions of genes that underwent hybridization. Also, our framework shows good performance in terms of efficiency on handling large data sets in our experiments. Further, in analysing a yeast data set, we demonstrate issues that arise when analysing real data sets. Although a probabilistic approach was recently introduced for this problem, and although parsimonious reconciliations have accuracy issues under certain settings, our parsimony framework provides a much more computationally efficient technique for this type of analysis. Our framework now allows for genome-wide scans for hybridization, while also accounting for ILS.

Spinor dynamics in an antiferromagnetic spin-1 thermal Bose gas.

We present experimental observations of coherent spin-population oscillations in a cold thermal, Bose gas of spin-1 23Na atoms. The population oscillations in a multi-spatial-mode thermal gas have the same behavior as those observed in a single-spatial-mode antiferromagnetic spinor Bose-Einstein condensate. We demonstrate this by showing that the two situations are described by the same dynamical equations, with a factor of 2 change in the spin-dependent interaction coefficient, which results from the change to particles with distinguishable momentum states in the thermal gas. We compare this theory to the measured spin population evolution after times up to a few hundreds of ms, finding quantitative agreement with the amplitude and period. We also measure the damping time of the oscillations as a function of magnetic field.

Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.

PURPOSE: To examine patterns of use, efficacy, and safety of intravenous ketamine for the treatment of refractory status epilepticus (RSE). METHODS: Multicenter retrospective review of medical records and electroencephalography (EEG) reports in 10 academic medical centers in North America and Europe, including 58 subjects, representing 60 episodes of RSE that were identified between 1999 and 2012. Seven episodes occurred after anoxic brain injury. KEY FINDINGS: Permanent control of RSE was achieved in 57% (34 of 60) of episodes. Ketamine was felt to have contributed to permanent control ("possible" or "likely" responses) in 32% (19 of 60) including seven (12%) in which ketamine was the last drug added (likely responses). Four of the seven likely responses, but none of the 12 possible ones, occurred in patients with postanoxic brain injury. No likely responses were observed when infusion rates were lower than 0.9 mg/kg/h, when ketamine was introduced at least 8 days after SE onset, or after failure of seven or more drugs. Ketamine was discontinued due to possible adverse events in five patients. Complications were mostly attributed to concurrent drugs, especially other anesthetics. Mortality rate was 43% (26 of 60), but was lower when SE was controlled within 24 h of ketamine initiation (16% vs. 56%, p = 0.0047). SIGNIFICANCE: Ketamine appears to be a relatively effective and safe drug for the treatment of RSE. This retrospective series provides preliminary data on effective dose and appropriate time of intervention to aid in the design of a prospective trial to further define the role of ketamine in the treatment of RSE.

Emergency neurologic life support: meningitis and encephalitis.

Bacterial meningitis and viral encephalitis, particularly herpes simplex encephalitis (HSE), are severe neurological infections that, if not treated promptly and effectively, lead to poor neurological outcome or death. Because treatment is more effective if given early, the topic of meningitis and encephalitis was chosen as an Emergency Neurological Life Support protocol. This protocol provides a practical approach to recognition of and urgent treatment for bacterial meningitis and HSE, including imaging and spinal fluid analysis, and discusses the choice of empirical treatments until the cause of infection is determined. Though uncommon in its full form, the typical clinical triad of headache, fever, and neck stiffness should alert the clinical practitioner to the syndromes. Early attention to the airway and maintaining normotension is crucial in treatment of these patients, as is rapid treatment with anti-infectives and, in some cases, corticosteroids.

Laryngopharyngeal reflux: is laparoscopic fundoplication an effective treatment?

INTRODUCTION: Laryngopharyngeal reflux (LPR) is difficult to diagnose and treat owing to uncertainty relating to the underlying pathology. The initial management of LPR includes lifestyle modifications and oral medications. In patients who have failed to respond to proton pump inhibitor (PPI) therapy, anti-reflux surgery is considered; laparoscopic fundoplication is the surgery of choice. The primary aim of this review is to identify whether fundoplication is effective in improving signs and symptoms of LPR. The secondary aim is to identify whether patients who have had a poor response to PPIs are likely to have symptom improvement with surgery. The objective of the study is to establish the effect of laparoscopic fundoplication on the reflux symptom index score (RSI). METHODS: PubMed, Embase, Medline and Cochrane databases were used to search according to the PRISMA guidelines. Original articles assessing the efficacy of fundoplication in relieving symptoms of LPR were included. For each study, the efficacy endpoints and safety outcomes were recorded. FINDINGS: Nine studies from 844 initial records met the inclusion criteria: one prospective case control study, one retrospective case-control study, four prospective case series and three retrospective case series involving 287 fundoplications. All nine studies found fundoplication to be effective in improving symptoms of LPR (p < 0.05). CONCLUSION: Current evidence suggests laparoscopic fundoplication is an effective treatment for LPR and should be considered if medical management is unsuccessful.

Laryngopharyngeal reflux: is laparoscopic fundoplication an effective treatment?

INTRODUCTION: Laryngopharyngeal reflux (LPR) is difficult to diagnose and treat owing to uncertainty relating to the underlying pathology. The initial management of LPR includes lifestyle modifications and oral medications. In patients who have failed to respond to proton pump inhibitor (PPI) therapy, anti-reflux surgery is considered; laparoscopic fundoplication is the surgery of choice. The primary aim of this review is to identify whether fundoplication is effective in improving signs and symptoms of LPR. The secondary aim is to identify whether patients who have had a poor response to PPIs are likely to have symptom improvement with surgery. The objective of the study is to establish the effect of laparoscopic fundoplication on the reflux symptom index score (RSI). METHODS: PubMed, Embase, Medline and Cochrane databases were used to search according to the PRISMA guidelines. Original articles assessing the efficacy of fundoplication in relieving symptoms of LPR were included. For each study, the efficacy endpoints and safety outcomes were recorded. FINDINGS: Nine studies from 844 initial records met the inclusion criteria: one prospective case control study, one retrospective case-control study, four prospective case series and three retrospective case series involving 287 fundoplications. All nine studies found fundoplication to be effective in improving symptoms of LPR (p < 0.05). CONCLUSION: Current evidence suggests laparoscopic fundoplication is an effective treatment for LPR and should be considered if medical management is unsuccessful.

The Family Level Assessment of Screen Use-Mobile Approach: Development of an Approach to Measure Children's Mobile Device Use.

BACKGROUND: There is a strong association between increased mobile device use and worse dietary habits, worse sleep outcomes, and poor academic performance in children. Self-report or parent-proxy report of children's screen time has been the most common method of measuring screen time, which may be imprecise or biased. OBJECTIVE: The objective of this study was to assess the feasibility of measuring the screen time of children on mobile devices using the Family Level Assessment of Screen Use (FLASH)-mobile approach, an innovative method that leverages the existing features of the Android platform. METHODS: This pilot study consisted of 2 laboratory-based observational feasibility studies and 2 home-based feasibility studies in the United States. A total of 48 parent-child dyads consisting of a parent and child aged 6 to 11 years participated in the pilot study. The children had to have their own or shared Android device. The laboratory-based studies included a standardized series of tasks while using the mobile device or watching television, which were video recorded. Video recordings were coded by staff for a gold standard comparison. The home-based studies instructed the parent-child dyads to use their mobile device as they typically use it over 3 days. Parents received a copy of the use logs at the end of the study and completed an exit interview in which they were asked to review their logs and share their perceptions and suggestions for the improvement of the FLASH-mobile approach. RESULTS: The final version of the FLASH-mobile approach resulted in user identification compliance rates of >90% for smartphones and >80% for tablets. For laboratory-based studies, a mean agreement of 73.6% (SD 16.15%) was achieved compared with the gold standard (human coding of video recordings) in capturing the target child's mobile use. Qualitative feedback from parents and children revealed that parents found the FLASH-mobile approach useful for tracking how much time their child spends using the mobile device as well as tracking the apps they used. Some parents revealed concerns over privacy and provided suggestions for improving the FLASH-mobile approach. CONCLUSIONS: The FLASH-mobile approach offers an important new research approach to measure children's use of mobile devices more accurately across several days, even when the child shares the device with other family members. With additional enhancement and validation studies, this approach can significantly advance the measurement of mobile device use among young children.

Hydrofoam and oxygen headspace bioreactors improve cell-free therapeutic protein production yields through enhanced oxygen transport.

Protein therapeutics are powerful tools in the fight against diabetes, cancers, growth disorders, and many other debilitating diseases. However, availability is limited due to cost and complications of production from living organisms. To make life-saving protein therapeutics more available to the world, the possibility of magistral or point-of-care protein therapeutic production has gained focus. The recent invention and optimization of lyophilized "cell-free" protein synthesis reagents and its demonstrated ability to produce highly active versions of FDA-approved cancer therapeutics have increased its potential for low-cost, single-batch, magistral medicine. Here we present for the first time the concept of increased oxygen mass transfer in small-batch, cell-free protein synthesis (CFPS) reactions through air-water foams. These "hydrofoam" reactions increased CFPS yields by up to 100%. Contrary to traditional protein synthesis using living organisms, where foam bubbles cause cell-lysis and production losses, hydrofoam CFPS reactions are "cell-free" and better tolerate foaming. Simulation and experimental results suggest that oxygen transfer is limiting in even small volume batch CFPS reactors and that the hydrofoam format improved oxygen transfer. This is further supported by CFPS reactions achieving higher yields when oxygen gas replaces air in the headspace of batch reactions. Improving CFPS yields with hydrofoam reduces the overall cost of biotherapeutic production, increasing availability to the developing world. Beyond protein therapeutic production, hydrofoam CFPS could also be used to enhance other CFPS applications including biosensing, biomanufacturing, and biocatalysis.

Rapid sensing of clinically relevant glutamine concentrations in human serum with metabolically engineered E. coli-based cell-free protein synthesis.

Bioavailable glutamine (Gln) is critical for metabolism, intestinal health, immune function, and cell signaling. Routine measurement of serum Gln concentrations could facilitate improved diagnosis and treatment of severe infections, anorexia nervosa, chronic kidney disease, diabetes, and cancer. Current methods for quantifying tissue Gln concentrations rely mainly on HPLC, which requires extensive sample preparation and expensive equipment. Consequently, patient Gln levels may be clinically underutilized. Cell-free protein synthesis (CFPS) is an emerging sensing platform with promising clinical applications, including detection of hormones, amino acids, nucleic acids, and other biomarkers. In this work, in vitro E. coli amino acid metabolism is engineered with methionine sulfoximine to inhibit glutamine synthetase and create a CFPS Gln sensor. The sensor features a strong signal-to-noise ratio and a detection range ideally suited to physiological Gln concentrations. Furthermore, it quantifies Gln concentration in the presence of human serum. This work demonstrates that CFPS reactions which harness the metabolic power of E. coli lysate may be engineered to detect clinically relevant analytes in human samples. This approach could lead to transformative point-of-care diagnostics and improved treatment regimens for a variety of diseases including cancer, diabetes, anorexia nervosa, chronic kidney disease, and severe infections.