Randomised controlled trial of resorbable versus non-resorbable sutures for lacerations of the face (TORN Face).

Facial lacerations are commonly encountered in emergency departments and require effective management to optimise aesthetic outcomes. Non-resorbable sutures are traditionally favoured for their tensile strength and minimal inflammatory response, despite the inconvenience of the required follow up for removal. This single-centre, single-blinded randomised controlled trial aimed to compare the clinical efficacy and cost-effectiveness of resorbable (Vicryl Rapide) versus non-resorbable (Ethilon) sutures for the closure of facial lacerations in adults. Between November 2021 and February 2023, 200 adult patients presenting with facial lacerations were randomly allocated to either resorbable or non-resorbable sutures. Outcomes assessed included aesthetic results via the Visual Analogue Scale (VAS) and Hamilton Scar Scale, patient-reported satisfaction using the Patient Scar Assessment Questionnaire (PSAQ), complication rates, and cost analysis. No significant differences were found in mean VAS scores between the two groups in both modified intention-to-treat and per-protocol analyses. The majority of patients reported high satisfaction levels. Early complication rates were significantly higher in the non-resorbable group at the one-week follow up, with no long-term differences noted. Preliminary cost analysis indicated a more than five-fold cost saving with resorbable sutures. Resorbable sutures provide a viable and cost-effective alternative to non-resorbable sutures for adult facial lacerations, with comparable aesthetic outcomes and patient satisfaction. Their use could reduce healthcare burdens by eliminating the need for follow-up suture removal, supporting broader adoption in clinical practice.

A cost analysis of sorafenib for desmoid tumors.

INTRODUCTION: A recent randomized trial demonstrated that sorafenib improved progression free survival (PFS) in patients with desmoid tumors despite many patients experiencing stable disease or spontaneous regression without treatment. Utilizing these trial data, we performed a cost analysis of sorafenib efficacy through two years of treatment. METHODS: Current Medicare Part D rates for sorafenib were utilized (dose 400 mg/day, cost $309/day). Annual costs per progression and objective response were calculated. Radiologic progression and response were defined using RECIST criteria. Patients with disease progression were separately analyzed in two groups: both clinical and radiologic (CAR), and radiologic alone. RESULTS: 84 previously randomized patients were analyzed (placebo: 35, sorafenib: 49). At one year, sorafenib was associated with a 43% absolute risk reduction (ARR) of CAR progression and number-needed-to-treat (NNT) of 2.3 patients/year, costing $259,406. At two years, ARR was 48% and NNT of 2.1 patients/year, costing $473,697. When evaluating only patients with RECIST defined radiologic progression, sorafenib patients experienced ARR of 13.9% with NNT 7.2 and estimated costs of $812,052 at one year. Two-year ARR was 17.5% with NNT 5.7 and estimated costs $1,285,052. Sorafenib patients experienced improved RECIST partial response rates at 1 and 2 years of 14.7% and 14.3%, with NNT 6.8 and 6.9, and costs of $766,938 and $1,556,433; respectively. CONCLUSION: For the treatment of desmoid tumors, Sorafenib led to improved PFS, but at a significant cost per patient. Favorable RECIST outcomes were less likely and costlier. Patients should be informed of possible benefits of treatment versus potential financial burden.

Effectiveness of Homologous and Heterologous COVID-19 Booster Doses Following 1 Ad.26.COV2.S (Janssen [Johnson & Johnson]) Vaccine Dose Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults - VISION Network, 10 States, December 2021-March 2022.

CDC recommends that all persons aged ≥18 years receive a single COVID-19 vaccine booster dose ≥2 months after receipt of an Ad.26.COV2.S (Janssen [Johnson & Johnson]) adenovirus vector-based primary series vaccine; a heterologous COVID-19 mRNA vaccine is preferred over a homologous (matching) Janssen vaccine for booster vaccination. This recommendation was made in light of the risks for rare but serious adverse events following receipt of a Janssen vaccine, including thrombosis with thrombocytopenia syndrome and Guillain-Barré syndrome† (1), and clinical trial data indicating similar or higher neutralizing antibody response following heterologous boosting compared with homologous boosting (2). Data on real-world vaccine effectiveness (VE) of different booster strategies following a primary Janssen vaccine dose are limited, particularly during the period of Omicron variant predominance. The VISION Network§ determined real-world VE of 1 Janssen vaccine dose and 2 alternative booster dose strategies: 1) a homologous booster (i.e., 2 Janssen doses) and 2) a heterologous mRNA booster (i.e., 1 Janssen dose/1 mRNA dose). In addition, VE of these booster strategies was compared with VE of a homologous booster following mRNA primary series vaccination (i.e., 3 mRNA doses). The study examined 80,287 emergency department/urgent care (ED/UC) visits¶ and 25,244 hospitalizations across 10 states during December 16, 2021-March 7, 2022, when Omicron was the predominant circulating variant.** VE against laboratory-confirmed COVID-19-associated ED/UC encounters was 24% after 1 Janssen dose, 54% after 2 Janssen doses, 79% after 1 Janssen/1 mRNA dose, and 83% after 3 mRNA doses. VE for the same vaccination strategies against laboratory-confirmed COVID-19-associated hospitalizations were 31%, 67%, 78%, and 90%, respectively. All booster strategies provided higher protection than a single Janssen dose against ED/UC visits and hospitalizations during Omicron variant predominance. Vaccination with 1 Janssen/1 mRNA dose provided higher protection than did 2 Janssen doses against COVID-19-associated ED/UC visits and was comparable to protection provided by 3 mRNA doses during the first 120 days after a booster dose. However, 3 mRNA doses provided higher protection against COVID-19-associated hospitalizations than did other booster strategies during the same time interval since booster dose. All adults who have received mRNA vaccines for their COVID-19 primary series vaccination should receive an mRNA booster dose when eligible. Adults who received a primary Janssen vaccine dose should preferentially receive a heterologous mRNA vaccine booster dose ≥2 months later, or a homologous Janssen vaccine booster dose if mRNA vaccine is contraindicated or unavailable. Further investigation of the durability of protection afforded by different booster strategies is warranted.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Development and implementation of the ECHO model in a school setting to address youth electronic cigarette use in Kansas: A protocol.

Introduction: Schools remain at the frontlines of addressing issues, such as e-cigarette use, that impact students. Despite e-cigarette use remaining a significant public health concern in the U.S., schools have limited resources (e.g., staff, capacity, programming) to address it, especially in rural and frontier areas. This ECHO Pilot Project aimed to build capacity and equip schools and school staff in the state of Kansas to address high rates of youth e-cigarette use by providing prevention support and information on best practices for e-cigarette cessation. Methods and analysis: The pilot used the established Project ECHO model to disseminate evidence-based strategies for e-cigarette prevention and cessation among youth to schools across Kansas. The pilot selected 20 interdisciplinary school teams representing both rural and urban middle and high schools across the state to participate in seven ECHO sessions. ECHO sessions proceeded throughout Fall 2021, with the final session in Spring 2022. School participants completed pre-post surveys as well as component-specific surveys following each ECHO session. In addition, each school team created an individualized action plan to comprehensively address e-cigarette use at their school based on the information provided throughout the ECHO. Survey data, school tobacco/nicotine policies, and action plans will be analyzed to assess process and final outcomes. Discussion: If successful, this pilot will demonstrate that the ECHO model is an effective platform for building school staff knowledge and skills to implement evidence-based strategies in both urban and rural settings. It is anticipated that the pilot will build capacity and equip schools and school staff to address high rates of youth e-cigarette use by providing support for school-based prevention programs and referrals for e-cigarette cessation which will lessen the burden of nicotine-related problems in Kansas schools and communities. Finally, the pilot will provide evidence that the ECHO model can be successfully and equitably applied in a school setting and may be a viable method for addressing other public health-related issues faced by schools.

Insulin Infusion Is Linked to Increased NPPC Expression in Muscle and Plasma C-type Natriuretic Peptide in Male Dogs.

The purpose of this study was to assess insulin-stimulated gene expression in canine skeletal muscle with a particular focus on NPPC, the gene that encodes C-type natriuretic peptide, a key hormonal regulator of cardiometabolic function. Four conscious canines underwent hyperinsulinemic, euglycemic clamp studies. Skeletal muscle biopsy and arterial plasma samples were collected under basal and insulin-stimulated conditions. Bulk RNA sequencing of muscle tissue was performed to identify differentially expressed genes between these 2 steady-state conditions. Our results showed that NPPC was the most highly expressed gene in skeletal muscle in response to insulin infusion, rising 4-fold between basal and insulin-stimulated conditions. In support of our RNA sequencing data, we found that raising the plasma insulin concentration 15-fold above basal elicited a 2-fold (P = 0.0001) increase in arterial plasma concentrations of N-terminal prohormone C-type natriuretic peptide. Our data suggest that insulin may play a role in stimulating secretion of C-type natriuretic peptide by skeletal muscle. In this context, C-type natriuretic peptide may act in a paracrine manner to facilitate muscle-vascular bed crosstalk and potentiate insulin-mediated vasodilation. This could serve to enhance insulin and glucose delivery, particularly in the postprandial absorptive state.

Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2.

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593-596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251-262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.

The impact of additional resistance and balance training in exercise-based cardiac rehabilitation in older patients after valve surgery or intervention: randomized control trial.

BACKGROUND: To evaluate the short- and mid-term effect of a specially tailored resistance and balance training provided in addition to usual cardiac rehabilitation (CR) care program in older patients after valve surgery/intervention. METHODS: Single-center (inpatient CR clinic in Lithuania) randomized controlled trial. Two hundred fifty-two patients were assessed for eligibility on the first day of admittance to CR early after (14.5 ± 5.9 days) valve surgery/intervention between January 2018 and November 2019. Participants were coded centrally in accordance with randomization 1:1 using a computerized list. Control group (CG) patients were provided with usual care phase-II-CR inpatient multidisciplinary CR program, while intervention group (IG) patients received additional resistance and balance training (3 d/wk). Patients participated in a 3-month follow-up. Main outcome measures were functional capacity (6 min walk test (6MWT, meters), cardiopulmonary exercise testing), physical performance (Short Physical Performance Battery (SPPB, score) and 5-m walk test (5MWT, meters/second)), strength (one repetition maximum test for leg press), physical frailty (SPPB, 5MWT). RESULTS: One hundred sixteen patients (76.1 ± 6.7 years, 50% male) who fulfilled the study inclusion criteria were randomized to IG (n = 60) or CG (n = 56) and participated in CR (18.6 ± 2.7 days). As a result, 6MWT (IG 247 ± 94.1 vs. 348 ± 100.1, CG 232 ± 102.8 vs. 333 ± 120.7), SPPB (IG 8.31 ± 2.21 vs. 9.51 ± 2.24, CG 7.95 ± 2.01 vs. 9.08 ± 2.35), 5MWT (IG 0.847 ± 0.31 vs. 0.965 ± 0.3, CG 0.765 ± 0.24 vs 0.879 ± 0.29) all other outcome variables and physical frailty level improved significantly (p < 0.05) in both groups with no significant difference between groups. Improvements were sustained over the 3-month follow-up for 6MWT (IG 348 ± 113 vs. CG 332 ± 147.4), SPPB (IG 10.37 ± 1.59 vs CG 9.44 ± 2.34), 5MWT (IG 1.086 ± 0. 307 vs CG 1.123 ± 0.539) and other variables. Improvement in physical frailty level was significantly more pronounced in IG (p < 0.05) after the 3-month follow-up. CONCLUSION: Exercise-based CR improves functional and exercise capacity, physical performance, and muscular strength, and reduces physical frailty levels in patients after valve surgery/intervention in the short and medium terms. SPPB score and 5MWT were useful for physical frailty assessment, screening and evaluation of outcomes in a CR setting. Additional benefit from the resistance and balance training could not be confirmed. TRIAL REGISTRATION: NCT04234087 , retrospectively registered 21 January 2020.

Blunt Thoracic Trauma-Induced Mitral Papillary Muscle Avulsion with Pericardial Rupture and Cardiac Herniation: Difficult and Delayed Diagnoses.

Blunt thoracic trauma (BTT) and the resultant isolated mitral papillary muscle avulsion, pericardial rupture, and cardiac herniation injuries are each rarely diagnosed clinical entities. We describe the first case of combined pericardial tear with cardiac herniation and ruptured mitral papillary muscles following BTT. Preoperative transesophageal echocardiography (TEE) diagnosed the delayed mitral papillary muscle rupture while all previous diagnostic modalities failed to delineate the pericardial rupture and cardiac herniation. Particular emphasis is placed on the clinical and radiologic aspects of the case that would heighten clinical suspicion in the emergency setting where blunt cardiac injury sequelae are suspected and frequently missed.

Diagnostic test accuracy of self-reported screening instruments in identifying frailty in community-dwelling older people: A systematic review.

Against a backdrop of aging populations worldwide, it has become increasingly important to identify frailty screening instruments suitable for community settings. Self-reported and/or administered instruments might offer significant simplicity and efficiency advantages over clinician-administered instruments, but their comparative diagnostic test accuracy has yet to be systematically examined. The aim of this systematic review was to determine the diagnostic test accuracy of self-reported and/or self-administered frailty screening instruments against two widely accepted frailty reference standards (the frailty phenotype and the Frailty Index) within community-dwelling older adult populations. We carried out a systematic search of the Embase, CINAHL, MEDLINE, PubMed, Web of Science, PEDro, PsycINFO, ProQuest Dissertations, Open Grey and GreyLit databases up to April 2017 (with an updated search carried out over May-July 2018) to identify studies reporting comparison of self-reported and/or self-administered frailty screening instruments against an appropriate reference standard, with a minimum sensitivity threshold of 80% and specificity threshold of 60%. We identified 24 studies that met our selection criteria. Four self-reported screening instruments across three studies met minimum sensitivity and specificity thresholds. However, in most cases, study design considerations limited the reliability and generalizability of the results. Additionally, meta-analysis was not carried out, because no more than three studies were available for any of the unique combinations of index tests and reference standards. Although the present study has shown that a number of self-reported frailty screening instruments reported sensitivity and specificity within a desirable range for community application, additional diagnostic test accuracy studies are required. Geriatr Gerontol Int 2020; 20: 14-24.

Ion current and action potential alterations in peripheral neurons subject to uniaxial strain.

Peripheral nerves, subject to continuous elongation and compression during everyday movement, contain neuron fibers vital for movement and sensation. At supraphysiological strains resulting from trauma, chronic conditions, aberrant limb positioning, or surgery, conduction blocks occur which may result in chronic or temporary loss of function. Previous in vitro stretch models, mainly focused on traumatic brain injury modelling, have demonstrated altered electrophysiological behavior during localized deformation applied by pipette suction. Our aim was to evaluate the changes in voltage-activated ion channel function during uniaxial straining of neurons applied by whole-cell deformation, more physiologically relevant model of peripheral nerve trauma. Here, we quantified experimentally the changes in inwards and outwards ion currents and action potential (AP) firing in dorsal root ganglion-derived neurons subject to uniaxial strains, using a custom-built device allowing simultaneous cell deformation and patch clamp recording. Peak inwards sodium currents and rectifying potassium current magnitudes were found to decrease in cells under stretch, channel reversal potentials were found to be left-shifted, and half-maximum activation potentials right-shifted. The threshold for AP firing was increased in stretched cells, although neurons retained the ability to fire induced APs. Overall, these results point to ion channels being damaged directly and immediately by uniaxial strain, affecting cell electrophysiological activity, and can help develop prevention and treatment strategies for peripheral neuropathies caused by mechanical trauma.

Structure and Biocatalytic Scope of Coclaurine N-Methyltransferase.

Benzylisoquinoline alkaloids (BIAs) are a structurally diverse family of plant secondary metabolites, which have been exploited to develop analgesics, antibiotics, antitumor agents, and other therapeutic agents. Biosynthesis of BIAs proceeds via a common pathway from tyrosine to (S)-reticulene at which point the pathway diverges. Coclaurine N-methyltransferase (CNMT) is a key enzyme in the pathway to (S)-reticulene, installing the N-methyl substituent that is essential for the bioactivity of many BIAs. In this paper, we describe the first crystal structure of CNMT which, along with mutagenesis studies, defines the enzymes active site architecture. The specificity of CNMT was also explored with a range of natural and synthetic substrates as well as co-factor analogues. Knowledge from this study could be used to generate improved CNMT variants required to produce BIAs or synthetic derivatives.

Frailty prevalence and factors associated with the Frailty Phenotype and Frailty Index: Findings from the North West Adelaide Health Study.

OBJECTIVE: To determine the prevalence of frailty and associated factors in the North West Adelaide Health Study (2004-2006) using the Frailty Phenotype (FP) and Frailty Index (FI). METHODS: Frailty was measured in 909 community-dwelling participants aged ≥65 years using the FP and FI. RESULTS: The FP classified 18% of participants as frail and the FI 48%. The measures were strongly correlated (r = 0.76, P < 0.001) and had a kappa agreement of 0.38 for frailty classification, with 37% of participants classified as non-frail by the FP being classified as frail by the FI. Being older, a current smoker, and having multimorbidity and polypharmacy were associated with higher frailty levels by both tools. Female, low income, obesity and living alone were associated with the FI. CONCLUSION: Frailty prevalence was higher when assessed using the FI. Socioeconomic factors and other health determinants contribute to higher frailty levels.

Clinical efficacy and effectiveness of 3D printing: a systematic review.

OBJECTIVE: To evaluate the clinical efficacy and effectiveness of using 3D printing to develop medical devices across all medical fields. DESIGN: Systematic review compliant with Preferred Reporting Items for Systematic Reviews and Meta-Analyses. DATA SOURCES: PubMed, Web of Science, OVID, IEEE Xplore and Google Scholar. METHODS: A double-blinded review method was used to select all abstracts up to January 2017 that reported on clinical trials of a three-dimensional (3D)-printed medical device. The studies were ranked according to their level of evidence, divided into medical fields based on the International Classification of Diseases chapter divisions and categorised into whether they were used for preoperative planning, aiding surgery or therapy. The Downs and Black Quality Index critical appraisal tool was used to assess the quality of reporting, external validity, risk of bias, risk of confounding and power of each study. RESULTS: Of the 3084 abstracts screened, 350 studies met the inclusion criteria. Oral and maxillofacial surgery contained 58.3% of studies, and 23.7% covered the musculoskeletal system. Only 21 studies were randomised controlled trials (RCTs), and all fitted within these two fields. The majority of RCTs were 3D-printed anatomical models for preoperative planning and guides for aiding surgery. The main benefits of these devices were decreased surgical operation times and increased surgical accuracy. CONCLUSIONS: All medical fields that assessed 3D-printed devices concluded that they were clinically effective. The fields that most rigorously assessed 3D-printed devices were oral and maxillofacial surgery and the musculoskeletal system, both of which concluded that the 3D-printed devices outperformed their conventional comparators. However, the efficacy and effectiveness of 3D-printed devices remain undetermined for the majority of medical fields. 3D-printed devices can play an important role in healthcare, but more rigorous and long-term assessments are needed to determine if 3D-printed devices are clinically relevant before they become part of standard clinical practice.

Ultrasound-Guided Cannulation of the Brachiocephalic Vein in Infants and Children is Useful and Stable.

OBJECTIVE: Ultrasound-guided (USG) cannulation of the brachiocephalic vein (BCV) has been shown to be technically easy. We hypothesised that adoption of USG in-plane cannulation of the BCV as the primary approach to central venous cannulation at our institution would lead to central venous cannulation for a greater variety of indications. METHODS: We performed retrospective, descriptive comparison of all central lines placed in patients aged <16 years who underwent any surgical operation during calendar years 2012-2014 at a small, free-standing children's hospital. The use and management of a central line was reviewed until the patient was discharged from the hospital. Analysis of the data was performed using simple comparative statistical methods. RESULTS: Forty-nine patients were identified, 20 who weighed <10 kg and 29 who weighed >10 kg. Cannulation was successful in all patients. No significant late complications occurred. Catheters were well tolerated post-operatively, with no accidental dislodgement and no removal because of discomfort. The average duration of insertion was 6.3 (3-20±3.77) days. Nine catheters were placed for access during emergency surgery. 15 were placed in patients with difficult peripheral intravenous (PIV) access. The central lines remained in place until discharge in 79.6% of patients. In 40% of patients, the PIV catheter was removed, and the central line was retained because of preference. Total parenteral nutrition (TPN) was administered in 11 (22.4%) patients. CONCLUSION: Cannulation of BCV was well tolerated by children, with an average insertion duration of 6.3 days, which often lasted beyond the removal/failure of the PIV cannula. Catheters were useful for primary venous access during hospitalisation and for short TPN courses.

Phosphate steering by Flap Endonuclease 1 promotes 5'-flap specificity and incision to prevent genome instability.

DNA replication and repair enzyme Flap Endonuclease 1 (FEN1) is vital for genome integrity, and FEN1 mutations arise in multiple cancers. FEN1 precisely cleaves single-stranded (ss) 5'-flaps one nucleotide into duplex (ds) DNA. Yet, how FEN1 selects for but does not incise the ss 5'-flap was enigmatic. Here we combine crystallographic, biochemical and genetic analyses to show that two dsDNA binding sites set the 5'polarity and to reveal unexpected control of the DNA phosphodiester backbone by electrostatic interactions. Via 'phosphate steering', basic residues energetically steer an inverted ss 5'-flap through a gateway over FEN1's active site and shift dsDNA for catalysis. Mutations of these residues cause an 18,000-fold reduction in catalytic rate in vitro and large-scale trinucleotide (GAA)n repeat expansions in vivo, implying failed phosphate-steering promotes an unanticipated lagging-strand template-switch mechanism during replication. Thus, phosphate steering is an unappreciated FEN1 function that enforces 5'-flap specificity and catalysis, preventing genomic instability.

Blood loss and transfusion requirements with epsilon-aminocaproic acid use during cranial vault reconstruction surgery.

OBJECTIVE: To determine whether epsilon-aminocaproic acid (EACA) load of 50 mg∙kg-1 before skin incision, and infusion of 25 mg∙kg-1∙h-1 until skin closure during cranial vault reconstruction (CVR) were associated with decreased estimated blood loss and transfusion requirements. BACKGROUND: Antifibrinolytic medications decrease bleeding and transfusion requirements during cardiothoracic and orthopedic surgeries with high blood loss, but practical reductions in blood loss and transfusion requirements have not been consistently realized in children undergoing CVR. Current dosing recommendations are derived from adult extrapolations, and may or may not have clinical relevance. METHOD: Retrospective case-controlled study of 45 consecutive infants and children undergoing primary craniosynostosis surgery at Covenant Children's Hospital during years 2010-2014. Exclusion criteria included revision surgery, and chromosomal abnormalities associated with bleeding disorders. Blood loss and blood transfusion volumes as a percent of estimated blood volume were compared in the presence of EACA while controlling for age, suture phenotype, use of bone grafting, and length of surgery. Secondary outcomes measures included volume of crystalloid infused, length of hospital stay, and any postoperative intubation requirement. RESULTS: When analyzed based on length of surgery, EACA did reduce blood loss and blood transfusion (R2=0.19, P=.005 and R2=0.18, P=.010, respectively) with shorter surgeries. CONCLUSIONS AND RELEVANCE: Using a standardized dosing regimen of EACA during craniosynostosis surgery, we found statistical significance in blood loss and transfusion requirements in surgeries of the shortest duration. We suspect this may be due to our selected dosing regimen, which may be lower than recently recommended. This study contributes to the growing body of evidence supporting EACA in CVR for craniosynostosis.

Cellularly active N-hydroxyurea FEN1 inhibitors block substrate entry to the active site.

The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA. Other compounds were more competitive with substrate. Cellular thermal shift data showed that both inhibitor types engaged with hFEN1 in cells, and activation of the DNA damage response was evident upon treatment with inhibitors. However, cellular EC50 values were significantly higher than in vitro inhibition constants, and the implications of this for exploitation of hFEN1 as a drug target are discussed.