All-Weather Dry Decontaminant Polymer-H2O2 Complex for HD Degradation.

Hydrogen peroxide (H2O2) is a highly effective decontaminant against chemical warfare agents (CWAs) when present both in a liquid and as a solid powder. For the latter, this can be in the form of H2O2 being complexed to a polymer, such as polyvinylpyrrolidone (PVP). While a H2O2-PVP complex is indeed effective at decontaminating CWAs, it is vulnerable to environmental conditions such as high relative humidities (RH), which can dissociate the H2O2 from the complex before it is given the opportunity to react with CWAs. In this paper, we demonstrate that the cross-linked version of PVP forms a highly stable complex with H2O2, which can withstand both high (40 °C) and low (-20 °C) temperatures as well as maintain stability at high RH up to 90% over several days. Collectively, this lays the framework for processing the H2O2-PVP complex in a variety of form factors that can maintain efficacy under a wide range of real-world environmental conditions.

Pool-Based Surfboard Elicits Activation of Posterior Shoulder Muscles During a Surfing Stroke.

ABSTRACT: Pexa, BS, Johnston, CD, Elder, EE, Ford, KR, Patterson, MQ, and Myers, JB. Pool-based surfboard elicits activation of posterior shoulder muscles during a surfing stroke. J Strength Cond Res 38(7): 1300-1304, 2024-Surfboard paddling may activate posterior shoulder muscles, which are critical to baseball pitchers' injury risk and performance. The purpose of this study was to measure posterior shoulder muscle activation during different phases of the surf stroke (propulsion vs. recovery) on a pool-based surfboard. Twenty healthy active adult subjects completed a familiarization and testing session with the pool-based surfboard. During the testing session, electromyography (EMG) sensors were placed on 6 posterior shoulder muscles: latissimus dorsi, infraspinatus, posterior deltoid, upper trapezius, middle trapezius, and lower trapezius. Subjects completed 4 laps in a pool at 3 separate resistances (low, moderate, and heavy) in a randomized order. The peak EMG signal during each phase (propulsion and recovery) was recorded. A 2-way within subject ANOVA (resistance-by-phase) with post hoc Bonferroni's corrections was used to identify differences in EMG activation. There was a significant main effect of phase for the latissimus dorsi (F = 91.3, p < 0.001), upper trapezius (F = 36.5, p < 0.001), middle trapezius (F = 33.8, p < 0.001), and lower trapezius (F = 21.6, p < 0.001). The latissimus dorsi demonstrated higher activation during the propulsion phase (p < 0.001), and all trapezius muscles demonstrated higher activation during the recovery phase (p < 0.001). There was a significant main effect of resistance for the posterior deltoid (F = 3.4, p = 0.043), with higher muscle activation in the low resistance trials compared with the heavy resistance trials (p = 0.036). Recreationally active individuals demonstrate activation of the posterior shoulder when using a pool-based surfboard. This pool-based surfboard may be beneficial to activate the posterior musculature and may be more accessible than standard surfing to baseball athletes.

Disinhibition by VIP interneurons is orthogonal to cross-modal attentional modulation in primary visual cortex.

Attentional modulation of sensory processing is a key feature of cognition; however, its neural circuit basis is poorly understood. A candidate mechanism is the disinhibition of pyramidal cells through vasoactive intestinal peptide (VIP) and somatostatin (SOM)-positive interneurons. However, the interaction of attentional modulation and VIP-SOM disinhibition has never been directly tested. We used all-optical methods to bi-directionally manipulate VIP interneuron activity as mice performed a cross-modal attention-switching task. We measured the activities of VIP, SOM, and parvalbumin (PV)-positive interneurons and pyramidal neurons identified in the same tissue and found that although activity in all cell classes was modulated by both attention and VIP manipulation, their effects were orthogonal. Attention and VIP-SOM disinhibition relied on distinct patterns of changes in activity and reorganization of interactions between inhibitory and excitatory cells. Circuit modeling revealed a precise network architecture consistent with multiplexing strong yet non-interacting modulations in the same neural population.

Psoas Abscess Precipitated by an Uncommon Pathogen: Pasteurella multocida.

A psoas abscess is a rare infection; it is an accumulation of purulent material within the psoas muscle. Common pathogens include Staphylococcus aureus, streptococci, Escherichia coli, and other enteric Gram-negative bacilli and anaerobes. These abscesses are thought to occur by either hematogenous spread, contiguous spread from adjacent organs, trauma, or local inoculation. Pasteurella multocida is a pathogen that usually infects a patient via a bite or scratch from dogs or cats and causes cellulitis at the site of the injury. Pasteurella multocida may also cause infection by the colonization of human respiratory and gastrointestinal (GI) tracts with spontaneous bacteremia seeding remote organs by the bacterial translocation process. Pasteurella multocida is highly susceptible to penicillins, cephalosporins, and other antibiotics. However, psoas abscesses usually require a drainage procedure as well as an extended course of antibiotics. We present a patient presenting with a psoas abscess due to P. multocida, an uncommon presentation of infection by this bacterium.

Recurrent Klebsiella pneumoniae Bacteremia Due to Endotipsitis.

Transjugular intrahepatic portosystemic shunt (TIPS) procedures are commonly performed in patients with cirrhosis to decrease the pressure in the portal system. An unusual complication of this procedure is endotipsitis, an infection of the shunt/stent with resultant sustained bacteremia caused by vegetation within the TIPS. The most commonly associated pathogens include staphylococci, enterococci, streptococci, and enteric Gram-negative bacilli. We present a patient who developed endotipsitis due to Klebsiella pneumoniae and presented with refractory K. pneumoniae bacteremia. Our patient had a progressively worsening clinical picture and after recognition of endotipsitis was transferred to another facility for liver transplantation and removal of the TIPS. Rapid diagnosis of endotipsitis in the setting of refractory bacteremia is essential to patient survival.

The effects of fish meal substitution by clam meal on the growth and health of Florida pompano (Trachinotus carolinus).

A 12-week feeding trial was conducted to evaluate the effects of fish meal (FM) substitution by clam meal (CM, at 10%, 20% and 30% of the diet) on the growth, feed utilization, hepatic antioxidant enzymes, plasma parameters, fatty acid and amino acid composition, and gut microbiome of juvenile Florida pompano, Trachinotus carolinus. The results indicated that: (1) juveniles fed 10% and 20% CM had a significantly higher final weight than the group fed the control (0% CM); and the control group also showed significantly lower weight gain, feed intake, protein retention value, whole-body crude protein and total amino acids composition, but higher hepatosomatic index and whole-body crude fat; (2) hepatic peroxide content and superoxide dismutase activity were not significantly affected by the substitution of CM, but it did affect glutathione peroxidase activity, with higher levels found in fish fed 30% CM compared to 0% and 10% CM; (3) plasma total protein, alkaline phosphatase, alanine aminotransferase, and immunoglobulin M showed no significant differences among the treatments; (4) there were no significant differences among treatments in terms of fatty acids composition and microbial diversity. Overall, this study concluded that CM has comparable benefit in the diet of Florida pompano as FM does.

Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

Influence of Baseball Training Load on Clinical Reach Tests and Grip Strength in Collegiate Baseball Players.

CONTEXT: A baseball-specific training load may influence strength or glenohumeral range of motion, which are related to baseball injuries. Glenohumeral reach tests and grip strength are clinical assessments of shoulder range of motion and upper extremity strength, respectively. OBJECTIVE: To examine changes in glenohumeral reach test performance and grip strength between dominant and nondominant limbs and high, moderate, and low baseball-specific training-load groups. DESIGN: Repeated-measures study. SETTING: University laboratory and satellite clinic. PATIENTS OR OTHER PARTICIPANTS: Collegiate baseball athletes (n = 18, age = 20.1 ± 1.3 years, height = 185.0 ± 6.5 cm, mass = 90.9 ± 10.2 kg). MAIN OUTCOME MEASURE(S): Participants performed overhead reach tests (OHRTs), behind-the-back reach tests (BBRTs), and grip strength assessments using the dominant and nondominant limbs every 4 weeks for 16 weeks. Percentage change scores were calculated between testing times. After each training session, participants provided their duration of baseball activity, throw count, and body-specific and arm-specific ratings of perceived exertion. We classified them in the high, moderate, or low training-load group based on each training-load variable: body-specific acute:chronic workload ratio (ACWR), arm-specific ACWR, body-specific cumulative load, and arm-specific cumulative load. Mixed models were used to compare training-load groups and limbs. RESULTS: The arm-specific ACWR group demonstrated as main effect for OHRT (F = 7.70, P = .001), BBRT (F = 4.01, P = .029), and grip strength (F = 8.89, P < .001). For the OHRT, the moderate training-load group demonstrated a 10.8% greater increase than the high group (P = .004) and a 13.2% greater increase than the low group (P < .001). For the BBRT, the low training-load group had a 10.1% greater increase than the moderate group (P = .011). For grip strength, the low training-load group demonstrated a 12.1% greater increase than the high group (P = .006) and a 17.7% greater increase than the moderate group (P < .001). CONCLUSIONS: Arm-specific ACWR was related to changes in clinical assessments of range of motion and strength. Clinicians may use arm-specific ACWR to indicate when a baseball athlete's physical health is changing.

Opioid-free anesthesia for patients undergoing mastectomy: A matched comparison.

Opioid-free anesthesia (OFA) is being implemented in breast surgery due to increased awareness of adverse effects and the national opioid crisis. The objective of this study was to examine the effect of OFA on postoperative pain and postoperative nausea and vomiting (PONV) in mastectomy patients. A single-institution matched-cohort study was conducted from 2014 to 2017 on 48 women undergoing mastectomy, with the majority also undergoing immediate prosthetic-based reconstruction. Patients received either conventional anesthesia (CA) or a novel OFA regimen. Primary outcomes included postoperative pain scores, opioid use, and need for antiemetics that were evaluated both in the PACU and on the hospital floors. No significant differences were found in PACU opioid or antiemetic use between OFA and CA. Pain scores in PACU and on POD0 were not significantly different. There was a significant but modest decrease on POD1 in OFA patients (3.9 vs. 5.1, P = .046). Additionally, patients with higher intraoperative opioid regimens experienced significantly increased PONV (P = .023). This study demonstrated the efficacy of OFA in controlling postoperative pain and nausea compared to a traditional opioid-based regimen. Regardless of intraoperative opioids, patients experienced similar postoperative opioid requirements and PONV with decreased pain scores. Thus, OFA is feasible in mastectomy patients and should be further evaluated in select patients.

Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies.

Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.

Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species.

Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f, a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.

Quality Improvement Project to Promote Identification and Treatment of Children With Obesity Admitted to Hospital.

Among children hospitalized for acute problems, comorbid obesity is commonly unaddressed. The objective was to improve identification and initial management of obesity among hospitalized children. In collaboration with nurses and dietitians, pediatric hospitalists of 2 children's hospitals conducted a quality improvement project to improve body mass index (BMI) documentation, obesity diagnosis, diet, and nutrition consultation through clinician education, development of computerized clinical decision-support system tools, and workflow modifications. Participants received monthly performance feedback. Among those with elevated BMI, diagnosis rose to 70.2%; a documented obesity diagnosis was associated with being 35 times more likely (P < .001) to receive at least 1 intervention while hospitalized. Participants reported an increase in skill in (27%), comfort with (27%), and knowledge of (33%) obesity management. Improvement in health care provider recognition and management of obesity in the inpatient setting is achievable. Additional work is needed to identify how best to sustain desired practice patterns.

Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa.

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.

Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.

Variability in the identification and reporting of overuse injuries among sports injury surveillance data collectors.

PURPOSE: This study examined variability in identifying and reporting overuse injuries among Certified Athletic Trainers (ATs). METHODS: This cross-sectional study of ATs participating in the National Collegiate Athletic Association's Injury Surveillance Program, utilized a novel online-only survey, consisting of seven hypothetical clinical scenarios representing various clinical presentations including overuse and acute elements. Participants reported clinical opinions regarding the role overuse played in each scenario (major contributor, not a major contributor, not enough information) and probability (0-100%) of classifying each scenario as having an overuse injury mechanism, then completed open-ended questions addressing their decision-making process. RESULTS: 74 ATs (25%) completed the survey. Six of the seven scenarios generated discordance in responses among the participating ATs. Variability in AT decisions involved: the progression of injury, duration of symptoms, and activity at time of injury. CONCLUSION: Developing a formalized definition of overuse injury may improve consistency and standardize methods for identifying and reporting overuse injuries within injury research.

Gabapentin Decreases Narcotic Usage: Enhanced Recovery after Surgery Pathway in Free Autologous Breast Reconstruction.

The opioid crisis is public health emergency, in part due to physician prescribing practices. As a result, there is an increased interest in reducing narcotic use in the postsurgical setting. METHODS: From January 1, 2018, to October 31, 2018, we employed a multidisciplinary, multimodal Enhanced Recovery After Surgery (ERAS) pathway abdominally based free tissue transfer involving the rectus. Preoperative, intraoperative, and postoperative nonnarcotic modalities were emphasized. Factors in reducing narcotic consumption, pain scores, and antiemetic use were identified. RESULTS: Forty-two patients were included for a total of 66 free flaps, with a 98.4%(65/66) success rate. Average postoperative in-hospital milligram morphine equivalent (MME) use was 37.5, but decreased 85% from 80.9 MME per day to 12.9 MME per day during the study period. Average pain scores and antiemetic doses also decreased. Postoperative gabapentin was associated with a significant 59.8 mg decrease in postoperative MME use, 21% in self-reported pain, and a 2.5 fewer doses of antiemetics administered but increased time to ambulation by 0.89 days. Postoperative acetaminophen was associated with a significant 3.0 point decrease in self-reported pain. CONCLUSIONS: This study represents our early experience. A shift in the institutional mindset of pain control was necessary for adoption of the ERAS protocol. While the ERAS pathway functions to reduce stress and return patients to homeostasis following surgery, postoperative gabapentin resulted in the greatest reduction in postoperative opioid use, self-reported pain, and postoperative nausea vomiting compared to any other modality.

Structure based design of macrocyclic factor XIa inhibitors: Discovery of cyclic P1 linker moieties with improved oral bioavailability.

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.

Infraspinatus Cross-Sectional Area and Shoulder Range of Motion Change Following Live-Game Baseball Pitching.

CONTEXT: Following a baseball pitching bout, changes can occur to glenohumeral range of motion that could be linked to injury. These effects are in part due to the posterior shoulder's eccentric muscle activity, which can disrupt muscle contractile elements and lead to changes in muscle cross-sectional area (CSA), as measured by ultrasound. OBJECTIVE: To assess changes in muscle CSA, and range of motion immediately before and after pitching, and days 1 to 5 following pitching. DESIGN: Repeated measures. SETTING: Satellite athletic training room. PATIENTS: Ten elite college baseball pitchers participating in the fall season (age: 18.8 [1.2] y, height: 189.2 [7.3] cm, mass: 93.1 [15.3] kg, 8 starters, 2 long relievers). INTERVENTION: A pitching bout of at least 25 pitches (63.82 [17.42] pitches). MAIN OUTCOME MEASURES: Dominant and nondominant infraspinatus CSA, as measured by ultrasound, and glenohumeral range of motion including internal rotation (IRROM), external rotation (ERROM), and total rotation range of motion (TROM) before pitching, after pitching, and days 1 to 5 following the pitching bout. RESULTS: Dominant limb CSA significantly increased day 1 after pitching, and returned to baseline on day 2 (P < .001). Dominant and nondominant TROM did not change until day 5 (4.4°, P < .001) and day 3 (4.5°, P < .001), respectively, where they increased. Dominant IRROM was significantly decreased for 3 days (day 1: 1.9°, P < .001; day 2: 3.1°, P < .001; day 3: 0.3°, P < .001) following pitching and returned to baseline on day 4, with no such changes in the nondominant limb. Dominant external rotation significantly increased immediately post pitching (4.4°, P < .001) but returned to baseline by day 1. CONCLUSIONS: The results of the study demonstrate that infraspinatus CSA does not recover until 2 days following pitching, and IRROM does not recover until 4 days following pitching. Baseball pitching elicits damage to the posterior shoulder muscle architecture, resulting in changes to physical characteristics that last up to 4 days following pitching.

Rate of Upper Extremity Injury in High School Baseball Pitchers Who Played Catcher as a Secondary Position.

CONTEXT: Many high school pitchers play another position after they have finished pitching for the day or on their rest days from pitching. Because of the cumulative demands on the arm, pitchers who also play catcher may have a greater risk of developing a throwing-related shoulder or elbow injury. OBJECTIVE: To compare the rate of throwing-related upper extremity injuries between high school baseball pitchers who also played catcher as a secondary position and those who did not play catcher. DESIGN: Prospective cohort study. SETTING: Field laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 384 male high school baseball pitchers were recruited from 51 high school teams. Pitchers who reported their secondary position as catcher were classified into the pitcher/catcher group and those who did not report playing catcher as a secondary position were classified into the other group. MAIN OUTCOME MEASURE(S): Participants completed a demographic questionnaire preseason and then athlete participation and injury status were tracked during the subsequent season. Athlete-exposures were monitored and the shoulder and elbow injury proportion rates were calculated. RESULTS: Athlete-exposures did not differ between groups ( P = .488). The pitcher/catcher group's risk of shoulder or elbow injury was 2.9 times greater than that of the other pitchers (15% versus 5%; injury proportion rate = 2.9; 95% confidence interval = 1.03, 8.12). CONCLUSIONS: Pitchers who reported also playing catcher were at a greater risk of sustaining a throwing-related shoulder or elbow injury than the other pitchers. These findings suggest that pitchers should consider not playing catcher as their secondary position in order to allow adequate time for recovery and to decrease their overall throwing load. Serial physical examinations of pitchers/catchers during the season may be useful in determining if their physical characteristics are changing during the season because of the cumulative throwing load.

Medial Elbow Joint Space Increases With Valgus Stress and Decreases When Cued to Perform A Maximal Grip Contraction.

BACKGROUND: Previous research indicates that the amount of valgus torque placed on the elbow joint during overhead throwing is higher than the medial ulnar collateral ligament (UCL) can tolerate. Wrist and finger flexor muscle activity is hypothesized to make up for this difference, and in vitro studies that simulated activity of upper extremity musculature, specifically the flexor digitorum superficialis and flexor carpi ulnaris, support this hypothesis. PURPOSE: To assess the medial elbow joint space at rest, under valgus stress, and under valgus stress with finger and forearm flexor contraction by use of ultrasonography in vivo. STUDY DESIGN: Controlled laboratory study. METHODS: Participants were 22 healthy males with no history of elbow dislocation or UCL injury (age, 21.25 ± 1.58 years; height, 1.80 ± 0.08 m; weight, 79.43 ± 18.50 kg). Medial elbow joint space was measured by use of ultrasonography during 3 separate conditions: at rest (unloaded), under valgus load (loaded), and with a maximal grip contraction under a valgus load (loaded-contracted) in both limbs. Participants lay supine with their arm abducted 90° and elbow flexed 30° with the forearm in full supination. A handgrip dynamometer was placed in the participants' hand to grip against during the contracted condition. Images were reduced in ImageJ to assess medial elbow joint space. A 2-way (condition × limb) repeated-measures analysis of variance and Cohen's d effect sizes were used to assess changes in medial elbow joint space. Post hoc testing was performed with a Bonferroni adjustment to assess changes within limb and condition. RESULTS: The medial elbow joint space was significantly larger in the loaded condition (4.91 ± 1.16 mm) compared with the unloaded condition (4.26 ± 1.23 mm, P < .001, d = 0.712) and the loaded-contracted condition (3.88 ± 0.94 mm, P < .001, d = 1.149). No significant change was found between the unloaded and loaded-contracted conditions ( P = .137). CONCLUSION: Medial elbow joint space increases under a valgus load and then decreases when a maximal grip contraction is performed. This indicates that wrist and finger flexor muscle contraction may assist in limiting medial elbow joint space, a result similar to findings of previous research in vitro. CLINICAL RELEVANCE: Muscle activation of the upper extremity limits the medial elbow joint space, suggesting that injury prevention programs for throwing athletes should incorporate exercises for the elbow, wrist, and hand to limit excessive medial elbow joint space gapping during activities that create high valgus load.