Design of protein-binding proteins from the target structure alone.

The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge1-5. Here we describe a general solution to this problem that starts with a broad exploration of the vast space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate the broad applicability of this approach through the de novo design of binding proteins to 12 diverse protein targets with different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and, following experimental optimization, bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five closely match the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvements of both. Our approach enables the targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.

Active Genetic Neutralizing Elements for Halting or Deleting Gene Drives.

CRISPR-Cas9-based gene drive systems possess the inherent capacity to spread progressively throughout target populations. Here we describe two self-copying (or active) guide RNA-only genetic elements, called e-CHACRs and ERACRs. These elements use Cas9 produced in trans by a gene drive either to inactivate the cas9 transgene (e-CHACRs) or to delete and replace the gene drive (ERACRs). e-CHACRs can be inserted at various genomic locations and carry two or more gRNAs, the first copying the e-CHACR and the second mutating and inactivating the cas9 transgene. Alternatively, ERACRs are inserted at the same genomic location as a gene drive, carrying two gRNAs that cut on either side of the gene drive to excise it. e-CHACRs efficiently inactivate Cas9 and can drive to completion in cage experiments. Similarly, ERACRs, particularly those carrying a recoded cDNA-restoring endogenous gene activity, can drive reliably to fully replace a gene drive. We compare the strengths of these two systems.

Synchronous retreat of Thwaites and Pine Island glaciers in response to external forcings in the presatellite era.

Today, relatively warm Circumpolar Deep Water is melting Thwaites Glacier at the base of its ice shelf and at the grounding zone, contributing to significant ice retreat. Accelerating ice loss has been observed since the 1970s; however, it is unclear when this phase of significant melting initiated. We analyzed the marine sedimentary record to reconstruct Thwaites Glacier's history from the early Holocene to present. Marine geophysical surveys were carried out along the floating ice-shelf margin to identify core locations from various geomorphic settings. We use sedimentological data and physical properties to define sedimentary facies at seven core sites. Glaciomarine sediment deposits reveal that the grounded ice in the Amundsen Sea Embayment had already retreated to within ~45 km of the modern grounding zone prior to ca. 9,400 y ago. Sediments deposited within the past 100+ y record abrupt changes in environmental conditions. On seafloor highs, these shifts document ice-shelf thinning initiating at least as early as the 1940s. Sediments recovered from deep basins reflect a transition from ice proximal to slightly more distal conditions, suggesting ongoing grounding-zone retreat since the 1950s. The timing of ice-shelf unpinning from the seafloor for Thwaites Glacier coincides with similar records from neighboring Pine Island Glacier. Our work provides robust new evidence that glacier retreat in the Amundsen Sea was initiated in the mid-twentieth century, likely associated with climate variability.

Single-Cell Analysis of Rohon-Beard Neurons Implicates Fgf Signaling in Axon Maintenance and Cell Survival.

Peripheral sensory neurons are a critical part of the nervous system that transmit a multitude of sensory stimuli to the central nervous system. During larval and juvenile stages in zebrafish, this function is mediated by Rohon-Beard somatosensory neurons (RBs). RBs are optically accessible and amenable to experimental manipulation, making them a powerful system for mechanistic investigation of sensory neurons. Previous studies provided evidence that RBs fall into multiple subclasses; however, the number and molecular makeup of these potential RB subtypes have not been well defined. Using a single-cell RNA sequencing (scRNA-seq) approach, we demonstrate that larval RBs in zebrafish fall into three, largely nonoverlapping classes of neurons. We also show that RBs are molecularly distinct from trigeminal neurons in zebrafish. Cross-species transcriptional analysis indicates that one RB subclass is similar to a mammalian group of A-fiber sensory neurons. Another RB subclass is predicted to sense multiple modalities, including mechanical stimulation and chemical irritants. We leveraged our scRNA-seq data to determine that the fibroblast growth factor (Fgf) pathway is active in RBs. Pharmacological and genetic inhibition of this pathway led to defects in axon maintenance and RB cell death. Moreover, this can be phenocopied by treatment with dovitinib, an FDA-approved Fgf inhibitor with a common side effect of peripheral neuropathy. Importantly, dovitinib-mediated axon loss can be suppressed by loss of Sarm1, a positive regulator of neuronal cell death and axonal injury. This offers a molecular target for future clinical intervention to fight neurotoxic effects of this drug.

Identification and characterization of diverse OTU deubiquitinases in bacteria.

Manipulation of host ubiquitin signaling is becoming an increasingly apparent evolutionary strategy among bacterial and viral pathogens. By removing host ubiquitin signals, for example, invading pathogens can inactivate immune response pathways and evade detection. The ovarian tumor (OTU) family of deubiquitinases regulates diverse ubiquitin signals in humans. Viral pathogens have also extensively co-opted the OTU fold to subvert host signaling, but the extent to which bacteria utilize the OTU fold was unknown. We have predicted and validated a set of OTU deubiquitinases encoded by several classes of pathogenic bacteria. Biochemical assays highlight the ubiquitin and polyubiquitin linkage specificities of these bacterial deubiquitinases. By determining the ubiquitin-bound structures of two examples, we demonstrate the novel strategies that have evolved to both thread an OTU fold and recognize a ubiquitin substrate. With these new examples, we perform the first cross-kingdom structural analysis of the OTU fold that highlights commonalities among distantly related OTU deubiquitinases.

Transferrin receptor targeting by de novo sheet extension.

The de novo design of polar protein-protein interactions is challenging because of the thermodynamic cost of stripping water away from the polar groups. Here, we describe a general approach for designing proteins which complement exposed polar backbone groups at the edge of beta sheets with geometrically matched beta strands. We used this approach to computationally design small proteins that bind to an exposed beta sheet on the human transferrin receptor (hTfR), which shuttles interacting proteins across the blood-brain barrier (BBB), opening up avenues for drug delivery into the brain. We describe a design which binds hTfR with a 20 nM Kd, is hyperstable, and crosses an in vitro microfluidic organ-on-a-chip model of the human BBB. Our design approach provides a general strategy for creating binders to protein targets with exposed surface beta edge strands.

Long-Term Neurodevelopmental Outcomes in Children with Gastroschisis: A Review of the Literature.

This study aimed to investigate and present a review of the literature on long-term neurodevelopmental outcomes in children with gastroschisis. Gastroschisis is the most common abdominal wall defect. Children with gastroschisis are at high risk for premature birth, intestinal failure, sepsis, and repeated anesthesia exposure, which collectively increase the risk for adverse long-term neurodevelopmental outcomes. The existing literature on neurodevelopmental outcomes is limited in number, quality, and generalizability, creating a gap in clinical knowledge and care. Five internet databases were searched by a professional research librarian: Ovid MEDLINE, Scopus, Web of Science, PsycINFO, and Cochrane Library. Included articles were (1) published in English, (2) included postneonatal hospital discharge neurodevelopmental outcomes of children with gastroschisis, and (3) included patients under the age of 18 years. No date parameters were applied. The paucity of literature on long-term neurodevelopmental outcomes in gastroschisis children has left large gaps in the body of knowledge on post-hospital care of such children. In this review, 37 articles were found evaluating neurodevelopmental outcomes in gastroschisis and, while conclusions were contradictory, the literature broadly indicated the potential for neurodevelopmental deficits in the gastroschisis pediatric population. A significant limitation of this review was the heterogeneous samples included in available literature, which confounded the ability to determine cognitive risk of gastroschisis independent of other abdominal wall defects. Findings of this review demonstrate potential risk for neurodevelopmental deficits in the pediatric gastroschisis population exist, yet additional research is needed to definitively predict the significance, type, onset, and trajectory of neurodevelopmental impairment in this population. The significant gaps in long-term outcomes data have elucidated the need for prospective, longitudinal investigation of various cognitive domains in homogenous gastroschisis populations to properly evaluate prevalence of neurodevelopmental deficits and guide recommendations for long-term clinical care. KEY POINTS: · Limited literature exists regarding long-term neurodevelopmental outcomes in gastroschisis.. · There is some evidence to suggest worse cognitive behavioral outcomes in gastroschisis over time.. · Developmental surveillance, screening, and evaluation may be beneficial for gastroschisis patients..

Neck scar perception after neck dissection in HPV-associated oropharyngeal squamous cell carcinoma.

IMPORTANCE: While there has been an increased understanding of the impact of visible neck scars in some patients with certain diseases, this has not yet been explored in the HPV+ OPSCC population. OBJECTIVE: To understand patients' perception of their scar and the impact on their quality of life (QOL) at least 6 months after neck dissection (ND) for HPV+ oropharyngeal squamous cell carcinoma (OPSCC). DESIGN, SETTING, AND PARTICIPANTS: In this retrospective case-control study, patients who underwent primary transoral robotic surgery (TORS) and ND for HPV+ OPSCC between 2016 and 2021 at a single tertiary care center were identified. Data analysis was performed in January 2022. MAIN OUTCOMES AND MEASURES: Dermatology Life Quality Index was modified (mDLQI) to assess patients' perceptions of their scars. The primary outcome was the mean mDLQI survey score with higher scores corresponding to worse perceptions. Three questions adapted from the Self-Consciousness Scale (SCS) were also included to assess awareness of appearance. All questions were scaled on a 0-3 Likert Scale. Tweedie generalized linear model was used to understand the relationship between mDLQI score and patient- and procedure-specific factors (including the three SCS survey questions). An additional exploratory logistic regression was performed to understand the risk factors for clinically significant mDLQI score change. RESULTS: A total of 67 patients (response rate 57 %) completed the survey with a mean mDLQI survey score of 0.84 (max 30). Although there was a statistically significant negative association between private insurance and mDLQI survey score (95 % Confidence Interval [CI]: -2.72 - -0.38), and a positive association between the SCS score and mDLQI survey score (95 % CI: 0.23-0.81) (p < 0.05), these variables were not found to be risk factors for a clinically significant difference in mDLQI on multivariable analysis. CONCLUSION: The majority of patients felt their neck scars did not interfere with their daily lives. Patient perceptions of neck scars were consistent despite differing patient characteristics and treatment regimens.

The type-I interferon response potentiates seeded tau aggregation and exacerbates tau pathology.

INTRODUCTION: Signatures of a type-I interferon (IFN-I) response are observed in the post mortem brain in Alzheimer's disease (AD) and other tauopathies. However, the effect of the IFN-I response on pathological tau accumulation remains unclear. METHODS: We examined the effects of IFN-I signaling in primary neural culture models of seeded tau aggregation and P301S-tau transgenic mouse models in the context of genetic deletion of the IFN-I receptor (IFNAR). RESULTS: Polyinosinic:polycytidylic acid (PolyI:C), a synthetic analog of viral nucleic acids, evoked a potent cytokine response that enhanced seeded aggregation of tau in an IFN-I-dependent manner. IFN-I-induced vulnerability could be pharmacologically prevented and was intrinsic to neurons. Aged P301S-tau mice lacking Ifnar1 had significantly reduced tau pathology compared to mice with intact IFN signaling. DISCUSSION: We identify a critical role for IFN-I in potentiating tau aggregation. IFN-I is therefore identified as a potential therapeutic target in AD and other tauopathies. HIGHLIGHTS: Type-I IFN (IFN-I) promotes seeded tau aggregation in neural cultures. IFNAR inhibition prevents IFN-I driven sensitivity to tau aggregation. IFN-I driven vulnerability is intrinsic to neurons. Tau pathology is significantly reduced in aged P301S-tau mice lacking IFNAR.

Persistent hypersomnia following repetitive mild experimental traumatic brain injury: Roles of chronic stress and sex differences.

Traumatic brain injury (TBI) is often more complicated than a single head injury. An extreme example of this point may be military service members who experience a spectrum of exposures over a prolonged period under stressful conditions. Understanding the effects of complex exposures can inform evaluation and care to prevent persistent symptoms. We designed a longitudinal series of non-invasive procedures in adult mice to evaluate the effects of prolonged mild stress and head injury exposures. We assessed anxiety, depression, and sleep-wake dysfunction as symptoms that impact long-term outcomes after mild TBI. Unpredictable chronic mild stress (UCMS) was generated from a varied sequence of environmental stressors distributed within each of 21 days. Subsequently, mice received a mild blast combined with closed-head mild TBI on 5 days at 24-h intervals. In males and females, UCMS induced anxiety without depressive behavior. A major finding was reproducible sleep-wake dysfunction through 6- to 12-month time points in male mice that received UCMS with repetitive blast plus TBI events, or surprisingly after just UCMS alone. Specifically, male mice exhibited hypersomnia with increased sleep during the active/dark phase and fragmentation of longer wake bouts. Sleep-wake dysfunction was not found with TBI events alone, and hypersomnia was not found in females under any conditions. These results identify prolonged stress and sex differences as important considerations for sleep-wake dysfunction. Furthermore, this reproducible hypersomnia with impaired wakefulness is similar to the excessive daytime sleepiness reported in patients, including patients with TBI, which warrants further clinical screening, care, and treatment development.

Conspicuous coloration of toxin-resistant predators implicates additional trophic interactions in a predator-prey arms race.

Antagonistic coevolution between natural enemies can produce highly exaggerated traits, such as prey toxins and predator resistance. This reciprocal process of adaptation and counter-adaptation may also open doors to other evolutionary novelties not directly involved in the phenotypic interface of coevolution. We tested the hypothesis that predator-prey coevolution coincided with the evolution of conspicuous coloration on resistant predators that retain prey toxins. In western North America, common garter snakes (Thamnophis sirtalis) have evolved extreme resistance to tetrodotoxin (TTX) in the coevolutionary arms race with their deadly prey, Pacific newts (Taricha spp.). TTX-resistant snakes can retain large amounts of ingested TTX, which could serve as a deterrent against the snakes' own predators if TTX toxicity and resistance are coupled with a conspicuous warning signal. We evaluated whether arms race escalation covaries with bright red coloration in snake populations across the geographic mosaic of coevolution. Snake colour variation departs from the neutral expectations of population genetic structure and covaries with escalating clines of newt TTX and snake resistance at two coevolutionary hotspots. In the Pacific Northwest, bright red coloration fits an expected pattern of an aposematic warning to avian predators: TTX-resistant snakes that consume highly toxic newts also have relatively large, reddish-orange dorsal blotches. Snake coloration also seems to have evolved with the arms race in California, but overall patterns are less intuitively consistent with aposematism. These results suggest that interactions with additional trophic levels can generate novel traits as a cascading consequence of arms race coevolution across the geographic mosaic.

Impact of transcatheter mitral valve edge-to-edge repair on atrial fibrillation burden: Insights from a multicenter cohort.

BACKGROUND: Patients with significant mitralregurgitation (MR) often experience atrial fibrillation (AF). The effects of transcatheter edge-to-edge repair (TEER) for MR on AF burden is unknown. METHODS: Patients who underwent TEER atthree institutions who also had a cardiac implantable electronic device with aright atrial lead were retrospectively identified. In patients with baseline AF, device data onAF burden and echocardiographic changes were recorded at baseline and 3- and 12-month follow up time points when available. Data is expressed as number (%) and median (interquartile range), withpaired values analyzed using the Wilcoxon signed-rank test. RESULTS: Overall 66 patients wereidentified, of whom 54 (82%) had baseline data on AF available for review. Of these, 18 (33%) had a baseline burden ofAF (median burden 100% [54-100%]). Patients were 77 (71-83) years old, 10 (56%) male, 14 (78%) White, and 3 (17%) Black. A significant reduction in AF burdenwas observed at 3 months (11 patients, p = 0.03) which did not retainsignificance at 12 months (8 patients, p = 0.69). Indexed maximal left atrial volumes did not significantly change inthose with paired studies available (p > 0.35 for both time points). CONCLUSIONS: In this multicenter cohort, one thirdof patients with severe MR undergoing TEER had an AF burden at baseline, whichwas found to be significantly lower at 3 month follow up. Further investigation is needed to confirm thefindings of this small cohort and determine its effects on downstream sequelaeof AF.

Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice.

BACKGROUND: Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) gene cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Δ9) increases abundance of With-No-Lysine (K) Kinase 4 (WNK4), inappropriately activating sterile 20/SPS-1-related proline/alanine-rich kinase (SPAK), which then phosphorylates and hyperactivates the Na+Cl- cotransporter (NCC). The precise mechanism by which CUL3-Δ9 causes FHHt is unclear. We tested the hypothesis that reduced abundance of CUL3 and of Kelch-like 3 (KLHL3), the CUL3 substrate adaptor for WNK4, is mechanistically important. Because JAB1, an enzyme that inhibits CUL3 activity by removing the ubiquitin-like protein NEDD8, cannot interact with CUL3-Δ9, we also determined whether Jab1 disruption mimicked the effects of CUL3-Δ9 expression. METHODS: We used an inducible renal tubule-specific system to generate several mouse models expressing CUL3-Δ9, mice heterozygous for both CUL3 and KLHL3 (Cul3+/-/Klhl3+/- ), and mice with short-term Jab1 disruption (to avoid renal injury associated with long-term disruption). RESULTS: Renal KLHL3 was higher in Cul3-/- mice, but lower in Cul3-/-/Δ9 mice and in the Cul3+/-/Δ9 FHHt model, suggesting KLHL3 is a target for both WT and mutant CUL3. Cul3+/-/Klhl3+/- mice displayed increased WNK4-SPAK activation and phospho-NCC abundance and an FHHt-like phenotype with increased plasma [K+] and salt-sensitive blood pressure. Short-term Jab1 disruption in mice lowered the abundance of CUL3 and KLHL3 and increased the abundance of WNK4 and phospho-NCC. CONCLUSIONS: Jab1-/- mice and Cul3+/-/Klhl3+/- mice recapitulated the effects of CUL3-Δ9 expression on WNK4-SPAK-NCC. Our data suggest degradation of both KLHL3 and CUL3 plays a central mechanistic role in CUL3-Δ9-mediated FHHt.

Heatwaves and mortality in Queensland 2010-2019: implications for a homogenous state-wide approach.

Heatwaves are a significant cause of adverse health outcomes and mortality in Australia, worsening with climate change. In Queensland, the northeastern-most state, little is known about the impact of heatwaves outside of the capital city of Brisbane. This study aims to explore the impact of heatwaves on mortality across various demographic and environmental conditions within Queensland from 2010 to 2019. The Excess Heat Factor was used to indicate heatwave periods at the Statistical Area 2 (SA2) level. Registered deaths data from the Australian Bureau of Statistics and heatwave data from the Bureau of Meteorology were matched using a case-crossover approach. Relative risk and 95% confidence intervals were calculated across years, regions, age, sex, rurality, socioeconomic status, and cause of death. Heatwaves were associated with a 5% increase in all-cause mortality compared to deaths on non-heatwave days, with variability across the state. The risk of death on a heatwave day versus a non-heatwave day varied by heatwave severity. Individuals living in urban centers, the elderly, and those living in regions of lower socioeconomic status were most impacted by heatwave mortality. The relative risk of dying from neoplasms, nervous system conditions, respiratory conditions, and mental and behavioral conditions increased during heatwaves. As heatwaves increase in Queensland due to climate change, understanding the impact of heatwaves on mortality across Queensland is important to tailor public health messages. There is considerable variability across communities, demographic groups, and medical conditions, and as such messages need to be tailored to risk.

HOPE and DREAM: A Two-Clinic NICU Follow-up Model.

OBJECTIVE: The natural extension of inpatient-focused neonatal neurocritical care (NNCC) programs is the evaluation of long-term neurodevelopmental outcomes in the same patient population. CLINICAL DESIGN: A dedicated and collaborative team of neonatologists, neonatal neurologists, neuropsychologists, neurosurgeons, physical medicine and rehabilitation physicians, and psychologists are necessary to provide personalized medicine, developmental assessments, and parental education for NNCC graduates. To achieve this goal, we devised a two-clinic follow-up model at Children's Wisconsin: HOPE (Healthy Outcomes Post-ICU Engagement) and DREAM: Developmentally Ready: Engagement for Achievement of Milestones) clinics. Those infants with significant neurologic diagnoses attend DREAM clinic, while all other high-risk neonatal intensive care unit (NICU) infants are seen in the HOPE clinic. CONCLUSION: These clinic models allow for a targeted approach to post-NICU care, which has improved family engagement and perceptions of value. KEY POINTS: · Infants with neurologic compromise are a specialized population with increasing survival.. · Interdisciplinary NICU follow-up brings together previously separated outpatient service lines.. · Our novel clinic model allows for specialized developmental assessments..

Hemodynamic response and safety of vasodilator stress cardiovascular magnetic resonance in patients with permanent pacemakers or implantable cardioverter-defibrillators.

INTRODUCTION: Vasodilator stress cardiovascular magnetic resonance (CMR) is a powerful diagnostic modality, but data toward its use in patients with permanent pacemakers (PPMs) or implantable cardioverter-defibrillators (ICDs) is limited. METHODS AND RESULTS: Patients with ICDs (>1% pacing) or PPMs who underwent regadenoson single photon emission computed tomography (SPECT) and all patients with ICDs or PPMs who underwent stress CMR were retrospectively identified. SPECT tests were analyzed for hemodynamic responses and new pacing requirements; CMR studies were examined for safety, device characteristics and programming, hemodynamic responses, and image quality. Changes from baseline were evaluated with the Related-Samples Wilcoxon Signed Rank Test. Of 67 patients (median age 65 [IQR 58-72] years, 31 [46%] female, 31 [46%] Black), 47 underwent SPECT and 20 CMR. With regadenoson SPECT, 89% of patients experienced tachycardic responses above resting heart rates (+19 [13-32] beats per minute, p < .01). During stress CMR, 10 (50%) devices were asynchronously paced approximately 10 beats per minute above resting rates, and the remaining were temporarily deactivated. Those with asynchronous pacing had no changes in heart rates, whereas patients with deactivated devices had near uniform heart rate accelerations. Image quality was diagnostic in the majority of stress CMR sequences, with nonconditional ICDs contributing 40 of 57 (70%) of nondiagnostic segments. CONCLUSION: This data supports the safety of vasodilator stress CMR with promising diagnostic quality images in patients with CMR conditional ICDs and PPMs. Despite a near uniform tachycardic response to regadenoson in the SPECT environment, high rates of asynchronous pacing during vasodilator stress CMR did not result in competitive pacing or adverse arrhythmic events. Further studies are needed to validate these findings and confirm the diagnostic and prognostic performance of stress CMR in these individuals.

Mid-trimester uterine electromyography in patients with a short cervix.

BACKGROUND: Preterm birth is the largest single cause of infant death in the United States. A cervical length of <2.5 cm, measured in the mid-trimester, has been shown to identify individuals at increased risk. Uterine electromyography is an emerging technology for noninvasively assessing uterine bioelectrical activity. With its ability to characterize nuanced differences in myometrial signals, uterine electromyography assessments during the mid-trimester may provide insight into the mechanisms of cervical shortening. OBJECTIVE: This study aimed to characterize uterine bioelectrical activity in pregnant individuals with short cervices in the mid-trimester compared with that of pregnant individuals of the same gestational age with normal cervical lengths. STUDY DESIGN: This is a prospective cohort study of subjects with singleton, nonanomalous pregnancies between 16 weeks and 0 days and 22 weeks and 6 days of gestational age. Subjects with normal cervical length (≥3.0 cm) were compared with subjects with short cervical length (<2.5 cm). The short-cervical-length cohort was further stratified by history of preterm birth. Multichannel uterine electromyography recordings were obtained for ∼60 minutes using proprietary, directional electromyography sensors on the abdomen. Uterine electromyography signals were observed and classified in groups as spikes, short bursts, and bursts. Primary outcomes were relative expression of spike, short-burst, and burst uterine electromyography signals. Subgroup analyses assessed each signal percentage by cervical length, history of preterm birth, and gestational age at delivery. Differences in percentage of uterine electromyography signals according to cervical length were analyzed using nonparametric tests of significance. RESULTS: Of the 28 included subjects, 10 had normal and 18 had short cervical length. There were 9 subjects with short cervical length and a history of preterm birth. Spikes were the most commonly recorded signals and were higher in the normal-cervical-length cohort (96.3% [interquartile range, 93.1%-100.0%]) than the short-cervical-length cohort (75.2% [interquartile range, 66.7%-92.0%], P=.001). In contrast, median percentages of short-bursts and bursts were significantly higher in subjects with a short cervical length (17.3% [interquartile range, 13.6%-23.9%] vs 2.5% for normal cervical length [interquartile range, 0%-5.5%], P=.001 and 6.6% [interquartile range, 0%-13.4%] vs 0% for normal cervical length [interquartile range, 0%-2.8%], P=.014, respectively). Within subgroup analyses, cervical length was inversely proportional to percentage of observed short-bursts (P=.013) and bursts (P=.014). Subjects with short cervical length and history of preterm birth had higher burst percentages (12.8% [interquartile range, 9.0%-15.7%]) than those with short cervical length and no history of preterm birth (3.3% [interquartile range, 0%-5.0%], P=.003). CONCLUSION: Short-burst and burst uterine electromyography signals are observed more frequently in mid-trimester patients with short cervical lengths. This relationship provides insight into abnormal myometrial activation in the mid-trimester and offers a plausible biophysiological link to cervical shortening.

Trends in quality of care among children with sickle cell anemia.

INTRODUCTION: For decades, it has been recommended that children with sickle cell anemia (SCA) receive antibiotic prophylaxis to prevent serious infections and undergo transcranial Doppler (TCD) screening to identify those at highest risk of overt stroke. We assessed recent temporal trends in antibiotic prophylaxis prescription fills and TCD screening among children with SCA using validated quality measures. PROCEDURE: Using validated claims-based definitions, we identified children with SCA who were enrolled in Michigan or New York State (NYS) Medicaid programs (2011-2018). Among recommended age groups, two outcomes were assessed yearly: (a) filling of ≥300 days of antibiotics, and (b) receipt of greater than or equal to one TCD. The proportion of children with each outcome was calculated by state. Temporal trends in each preventive service were assessed using generalized linear models. RESULTS: A total of 1784 children were eligible for antibiotic prophylaxis (Michigan: 384; NYS: 1400), contributing 3322 person-years. Annual rates of filling ≥300 days of antibiotics ranged from 16% to 22% and were similar by state. There was no change in rates of antibiotic filling over time in Michigan (p-value: .10), but there was a decrease in NYS (p-value: .02). A total of 3439 children with SCA were eligible for TCD screening (Michigan: 710; NYS: 2729), contributing 10,012 person-years. Annual rates of TCD screening ranged from 39% to 45%, were similar by state, and did not change over time (p-values >.05). CONCLUSIONS: Most children with SCA do not receive recommended antibiotic prophylaxis and/or TCD screening. New, sustainable, and coordinated interventions across preventive services are urgently needed.

Parental presence at the bedside of critically ill children in the pediatric intensive care unit: A scoping review.

Parental presence at the bedside (PPB) of critically ill children in the pediatric intensive care unit (PICU) is necessary for operationalizing family-centred care. Previous evidence syntheses emphasize parent-healthcare provider interactions at rounds and resuscitation; our focus is the parent-child dyad. Prior to embarking on further study, we performed a scoping review to determine the breadth and scope of the literature addressing PPB of critically ill children in the PICU. We searched five online databases (MEDLINE, EMBASE, CINAHL, Cochrane Library, and PSYCHINFO) and the grey literature to identify English and French reports from January 1960 to June 2020 addressing physical parental presence with children (birth to 18 years) in intensive care units, without limitation by methodology. Screening, reference selection, and data extraction were performed by two independent reviewers. Data were extracted into a researcher-designed tool. We identified 204 publications (81 quantitative, 68 qualitative, 22 mixed methods, and 9 descriptive case or practice change studies, and a further 24 non-study reports). PPB was directly assessed in 78 (38%) reports, and was the primary objective in 64 (31%). Amount or quality of presence was addressed by 114 reports, barriers and enablers by 152 sources, and impacts and outcomes by 134 sources. While only 6 reports were published in the first two decades of our search (1960-1980), 17 reports were published in 2019 alone. Conclusions: A relatively large body of literature exists addressing PPB of critically ill children. Separate systematic evidence syntheses to assess each element of PPB are warranted. Scoping review protocol registration: Open science framework, protocol nx6v3, registered 9-September-2019. What is Known: • Parental presence at the bedside of critically ill children must be enabled to facilitate family centeredness in care. • Systematic evidence syntheses have focused on parental presence at rounds or resuscitation, rather than with the child throughout the intensive care journey. What is New: • Many reports (n=204) address parental presence at the bedside in the pediatric intensive care unit, though most do as incidental findings • Identifies studies addressing key elements of parental presence in the PICU including barriers and enablers to, amount and quality of, and impact and outcomes of parental presence, and demonstrates trends over time and geography.

Assessing the validity of mobile device data for estimating visitor demographics and visitation patterns in Yellowstone National Park.

Monitoring visitor demographics and temporal visitation patterns can help national park managers understand their visitors and allocate resources more effectively. Traditional approaches, such as visitor surveys or vehicle counts, are limited by time, space, labor, and financial resources. More recently, mobile device data have been adopted for monitoring visitors in park-related or tourism research. However, few studies validated mobile device data with traditional visitor surveys or count data. Combining mobile device data with the American Community Survey (ACS), this study assessed mobile device data's validity in a national park context with three approaches: Points of Interest (POIs), visitor demographics, and temporal visitation patterns. The results revealed that only half of the POIs inside Yellowstone National Park are valid. Compared to traditional visitor surveys, mobile device data are limited due to platform bias and the exclusion of international visitors, resulting in discrepancies in visitor demographics, such as education and income levels. Conversely, mobile device data have strong correlations with count data regarding monthly and daily visitation patterns. The results suggest that with careful consideration, mobile device data can serve as an additional and complementary source of information to traditional survey data for understanding visitor demographics and temporal visitation patterns.