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.

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.

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.

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.

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.

Pyridazine and pyridazinone derivatives as potent and selective factor XIa inhibitors.

Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability.

The Relationship Between the Push Off Ground Reaction Force and Ball Speed in High School Baseball Pitchers.

Oyama, S and Myers, JB. The relationship between the push off ground reaction force and ball speed in high school baseball pitchers. J Strength Cond Res 32(5): 1324-1328, 2018-Baseball pitching is a sequential movement that requires transfer of momentum from the lower extremity to the throwing arm. Therefore, the ground reaction force (GRF) during push off is suggested to play a role in production of ball speed. The purpose of this study was to investigate the correlation between GRF characteristics during push off and ball speed in high school baseball pitchers. A total of 52 pitchers performed fast pitches from an indoor pitching mound. A force plate embedded in an indoor mound was used to capture the push off GRF. The GRF characteristics (peak anterior, vertical, and resultant forces, vertical and resultant forces at the time of peak anterior GRF, and impulse produced by the anterior GRF) from the 3 fastest strike pitches from each pitcher were used for analyses. Spearman's rank correlation coefficients were used to describe the relationships between ball speed and the GRF characteristics. Ball speed was only weakly correlated with peak resultant force (ρ = 0.32, p = 0.02) and vertical (ρ = 0.45, p < 0.001) and resultant (ρ = 0.42, p = 0.002) forces at the time of peak anterior force. The ball speed was not correlated with other variables. The correlation between ball speed and push off force in high school pitchers was weak, especially when compared with what was reported for adult pitchers in other studies. Unlike for adult pitchers, higher push off force is only weakly correlated with ball velocity in high school pitchers, which suggests that training to better use body momentum may help high school pitchers improve ball speed.

The Influence of Verbal and Tactile Feedback on Electromyographic Amplitude of the Shoulder Musculature During Common Therapeutic Exercises.

CONTEXT: Verbal and tactile feedback (VTF) during rehabilitation exercises can increase muscle activation, thus improving the therapeutic benefits. However, it is unclear which feedback method elicits the greatest electromyographic (EMG) amplitude. OBJECTIVE: To determine if the addition of tactile to verbal feedback (VF) increases EMG amplitude of selected shoulder musculature during scapular plane elevation (Ys), shoulder horizontal abduction with external rotation (Ts), and scapular retraction with external rotation (Ws). DESIGN: Repeated-measures cross-over design. SETTING: Biomechanics laboratory. PARTICIPANTS: A total of 30 physically active adults volunteered for this study-age = 20.23 (1.25) years; height = 1.71 (0.073) m; and mass = 70.11 (15.14) kg. INTERVENTIONS: Electromyography of the serratus anterior; upper, middle, and lower trapezii; and anterior and posterior deltoids was recorded during Ys, Ts, and Ws with VTF and VF alone during separate testing sessions. Participants completed baseline trials without feedback, then received VTF and VF across 2 counterbalanced sessions. MAIN OUTCOME MEASURES: Difference scores were calculated between prefeedback and postfeedback interventions, and the difference score between baseline measurements was used as a control. One-way analysis of variance of the difference scores was used to evaluate the influence of VTF and VF on EMG amplitude during Ys, Ts, and Ws. RESULTS: There was a significant difference between conditions for EMG amplitude of the middle trapezius (F2,28 = 4.09, P = .02) and serratus anterior (F2,28 = 3.91, P = .03) during Ys, the middle trapezius (F2,28 = 7.82, P = .001) during Ws, and the upper (F2,28 = 3.61, P = .03) and middle trapezii (F2,28 = 5.81, P = .01) during Ts. Post hoc testing revealed that both feedback conditions elicited greater EMG amplitude compared with no feedback, but there were no significant differences between the feedback conditions. CONCLUSIONS: The addition of tactile feedback to VF does not increase EMG amplitude compared with VF alone. This study indicates that feedback, regardless of type, is more beneficial than providing no feedback, for increasing EMG amplitude.

Macrocyclic factor XIa inhibitors.

A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.

Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency.

Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.

Preseason screening of shoulder range of motion and humeral retrotorsion does not predict injury in high school baseball players.

BACKGROUND: Shoulder and elbow injuries are commonplace in high school baseball. Although altered shoulder range of motion (ROM) and humeral retrotorsion angles have been associated with injuries, the efficacy of preseason screening of these characteristics remains controversial. METHODS: We conducted preseason screenings for shoulder internal and external rotation ROM and humeral retrotorsion on 832 high school baseball players and tracked their exposure and incidence on throwing-related shoulder and elbow injuries during a subsequent season. Poisson regression with robust error variance was used to determine whether preseason screening could identify injury risk in baseball players and whether the injury risk was higher for pitchers compared with players who do not pitch. RESULTS: Shoulder rotation ROM or humeral retrotorsion at preseason did not predict the risk of throwing-related upper extremity injury (P = .15-.89). Injury risk was 3.84 higher for baseball players who pitched compared with those who did not (95% confidence interval, 1.72-8.56; P = .001). DISCUSSION: Preseason measures of shoulder ROM and humeral retrotorsion may not be effective in identifying players who are at increased injury risk. Because shoulder ROM is a measure that fluctuates under a variety of influences, future study should investigate whether taking multiple measurements during a season can identify at-risk players. The usefulness of preseason screening may also depend on rigor of participation in sports. Future studies should investigate how preseason shoulder characteristics and participation factors (ie, pitch count and frequency, competitive level, pitching in multiple leagues) interact to predict injury risk in baseball players.

Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group.

Pyridine-based Factor XIa (FXIa) inhibitor (S)-2 was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)-17 was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-17 with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)-24 which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-23. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.

The utility of the surgical safety checklist for wound patients.

The purpose of this study was to determine the frequency of changes in patient care resulting from the use of a surgical safety checklist. Data were retrospectively obtained from 233 patients. The number and types of changes made to the patients' intra-operative management, based on the use of the checklist, were recorded. The number of patients whose management was modified as a result of the checklist was 113 (48%) out of 233. The total number of changes made was 132, and 18 patients had more than one modification made to their care plan. Further stratification was identified: among the 132 changes made, antibiotics were held or administered in 73 (55%), changes related to anaemia involving type and screen or transfusion occurred in 27 (20%), modifications made regarding anti-coagulation occurred in 8 (7%), beta-blockers were held in 2 (2%), an allergy was identified in 7 (5%), modifications made to the surgical procedure were 3 (2%) and a category labelled 'other' encompassed 9 (7%) changes. The surgical safety checklist is a standardised form of team communication that leads to modifications of the patient care plan in a large percentage of cases. The ever-increasing complexity of medicine means that patients are at greater risk of oversight and harm without the use of a checklist.

Acute Effects of Posture Shirts on Rounded-Shoulder and Forward-Head Posture in College Students.

CONTEXT: Rounded-shoulder and forward-head posture can be contributing factors to shoulder pain. Corrective techniques such as manual therapy and exercise have been shown to improve these altered postures, but there is little evidence that corrective garments such as posture shirts can alter posture. OBJECTIVES: To determine the acute effects of corrective postureshirt use on rounded-shoulder and forward-head posture in asymptomatic college students. DESIGN: Repeated-measures intervention study with counterbalanced conditions. SETTING: Research laboratory. PARTICIPANTS: 24 members of the general student body of a university, 18-25 y old, with a forward shoulder angle (FSA) >52° and no history of upper-extremity surgery, scoliosis, active shoulder pain, or shoulder pain in the previous 3 mo that restricted participation for 3 consecutive days. INTERVENTIONS: Photographic posture assessment under a control condition, under a sham or treatment condition (counterbalanced), under another control condition, and treatment or sham. MAIN OUTCOME MEASURES: FSA and forward head angle (FHA) calculated from a lateral photograph. RESULTS: FSA decreased relative to the control condition while participants wore the sham shirt (P = .029) but not the corrective posture shirt (P = 1.00). FHA was unchanged between groups (P = .371). CONCLUSIONS: Application of a corrective posture shirt did not acutely alter FSA or FHA, while application of a sham shirt may decrease FSA at rest.

Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.

Mosaic tetrasomy 13q and phylloid hypomelanosis: a case report and review of the literature.

A 6-year-old girl presented for evaluation of skin discoloration. Examination revealed oval and oblong hypopigmented macules on her trunk and extremities. Cytogenetic studies and immunohistochemistry of biopsies from normally pigmented and hypopigmented skin revealed mosaicism for partial tetrasomy for 13q with low melanocyte levels in lesional skin. The patient was diagnosed with phylloid hypomelanosis (PH), a distinct clinical entity linked to abnormalities in chromosome 13. This article reviews the literature regarding PH and supports the notion that mosaicism of the melanocyte region of chromosome 13q is responsible for PH.

Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering.

Proprotein convertase subtilisin kexin-9 (PCSK9) is an important pharmacological target for decreasing low-density lipoprotein (LDL) in cardiovascular disease, although seemingly inaccessible to small molecule approaches. Compared with therapeutic IgG antibodies currently in development, targeting circulating PCSK9 with smaller molecular scaffolds could offer different profiles and reduced dose burdens. This inspired genesis of PCSK9-binding Adnectins, a protein family derived from human fibronectin-10th-type III-domain and engineered for high-affinity target binding. BMS-962476, an ∼11-kDa polypeptide conjugated to polyethylene glycol to enhance pharmacokinetics, binds with subnanomolar affinity to human. The X-ray cocrystal structure of PCSK9 with a progenitor Adnectin shows ∼910 Å(2) of PCSK9 surface covered next to the LDL receptor binding site, largely by residues of a single loop of the Adnectin. In hypercholesterolemic, overexpressing human PCSK9 transgenic mice, BMS-962476 rapidly lowered cholesterol and free PCSK9 levels. In genomic transgenic mice, BMS-962476 potently reduced free human PCSK9 (ED50 ∼0.01 mg/kg) followed by ∼2-fold increases in total PCSK9 before return to baseline. Treatment of cynomolgus monkeys with BMS-962476 rapidly suppressed free PCSK9 >99% and LDL-cholesterol ∼55% with subsequent 6-fold increase in total PCSK9, suggesting reduced clearance of circulating complex. Liver sterol response genes were consequently downregulated, following which LDL and total PCSK9 returned to baseline. These studies highlight the rapid dynamics of PCSK9 control over LDL and liver cholesterol metabolism and characterize BMS-962476 as a potent and efficacious PCSK9 inhibitor.

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.

Prediction-error signals in anterior cingulate cortex drive task-switching.

Task-switching is a fundamental cognitive ability that allows animals to update their knowledge of current rules or contexts. Detecting discrepancies between predicted and observed events is essential for this process. However, little is known about how the brain computes cognitive prediction-errors and whether neural prediction-error signals are causally related to task-switching behaviours. Here we trained mice to use a prediction-error to switch, in a single trial, between responding to the same stimuli using two distinct rules. Optogenetic silencing and un-silencing, together with widefield and two-photon calcium imaging revealed that the anterior cingulate cortex (ACC) was specifically required for this rapid task-switching, but only when it exhibited neural prediction-error signals. These prediction-error signals were projection-target dependent and were larger preceding successful behavioural transitions. An all-optical approach revealed a disinhibitory interneuron circuit required for successful prediction-error computation. These results reveal a circuit mechanism for computing prediction-errors and transitioning between distinct cognitive states.