The 3D-Printed Custom Elbow Prosthesis for Salvage Treatment of Complex Intra-Articular Distal Humerus Fracture Malunion.

Intra-articular fractures of the distal humerus are complex injuries that often require surgery with the goal of restoring elbow range-of-motion and function. Open reduction and internal fixation has been the preferred surgical modality; however, restoration of the medial and/or lateral columns can be complicated in fractures involving a major loss of the articular surface and bony structure. Over the past decade, 3-dimensional (3D) printing has made significant advances in the field of orthopedic surgery, specifically in guiding surgeon preoperative planning. Recently, the incorporation of 3D-printing has proven to provide a safe and reliable construct for the restoration of anatomy in complex trauma cases. We present a 47-year-old woman who sustained a complex, intra-articular distal humerus fracture with associated shearing of the capitellum that went onto malunion. Patient was treated with a patient-specific 3D-printed custom elbow prosthesis with excellent outcomes. Our goal was to shed light on the use of 3D-printing technology as a viable salvage option in treating complex, intra-articular distal humeral fractures associated with lateral condylar damage that subsequently went onto malunion.

Materials for electronically controllable microactuators.

Abstract: Electronically controllable actuators have shrunk to remarkably small dimensions, thanks to recent advances in materials science. Currently, multiple classes of actuators can operate at the micron scale, be patterned using lithographic techniques, and be driven by complementary metal oxide semiconductor (CMOS)-compatible voltages, enabling new technologies, including digitally controlled micro-cilia, cell-sized origami structures, and autonomous microrobots controlled by onboard semiconductor electronics. This field is poised to grow, as many of these actuator technologies are the firsts of their kind and much of the underlying design space remains unexplored. To help map the current state of the art and set goals for the future, here, we overview existing work and examine how key figures of merit for actuation at the microscale, including force output, response time, power consumption, efficiency, and durability are fundamentally intertwined. In doing so, we find performance limits and tradeoffs for different classes of microactuators based on the coupling mechanism between electrical energy, chemical energy, and mechanical work. These limits both point to future goals for actuator development and signal promising applications for these actuators in sophisticated electronically integrated microrobotic systems.

Clinical reference dosimetry for the 0.5 T inline rotating biplanar Linac-MR.

BACKGROUND: The world's first clinical 0.5 T inline rotating biplanar Linac-MR system is commissioned for clinical use. For reference dosimetry, unique features to device, including an SAD = 120 cm, bore clearance of 60 cm × 110 cm, as well as 0.5 T inline magnetic field, provide some challenges to applying a standard dosimetry protocol (i.e., TG-51). PURPOSE: In this work, we propose a simple and practical clinical reference dosimetry protocol for the 0.5T biplanar Linac-MR and validated its results. METHODS: Our dosimetry protocol for this system is as follows: tissue phantom ratios at 20 and 10 cm are first measured and converted into %dd10x beam quality specifier using equations provided and Kalach and Rogers. The converted %dd10x is used to determine the ion chamber correction factor, using the equations in the TG-51 addendum for the Exradin A12 farmer chamber used, which is cross-calibrated with one calibrated at a standards laboratory. For a 0.5 T parallel field, magnetic field effect on chamber response is assumed to have no effect and is not explicitly corrected for. Once the ion chamber correction factor for a non-standard SAD (kQ,msr) is determined, TG-51 is performed to obtain dose at a depth of 10 cm at SAD = 120 cm. The dosimetry protocol is repeated with the magnetic field ramped down. To validate our dosimetry protocol, Monte Carlo (EGSnrc) simulations are performed to confirm the determined kQ,msr values. MC Simulations and magnetic Field On versus Field Off measurements are performed to confirm that the magnetic field has no effect. To validate our overall dosimetry protocol, external dose audits, based on optical simulated luminescent dosimeters, thermal luminescent dosimeters, and alanine dosimeters are performed on the 0.5 T Linac-MR system. RESULTS: Our EGSnrc results confirm our protocol-determined kQ,msr values, as well as our assumptions about magnetic field effects (kB = 1) within statistical uncertainty for the A-12 chamber. Our external dosimetry procedures also validated our overall dosimetry protocol for the 0.5 T biplanar Linac-MR hybrid. Ramping down the magnetic field has resulted in a dosimetric difference of 0.1%, well within experimental uncertainty. CONCLUSION: With the 0.5 T parallel magnetic field having minimal effect on the ion chamber response, a TPR20,10 approach to determine beam quality provides an accurate method to perform clinical dosimetry for the 0.5 T biplanar Linac-MR.

Restless nights when sick: ectoparasite infections alter rest-activity cycles of diurnal fish hosts.

Circadian rhythms are timekeeping mechanisms responsible for an array of biological processes. Disruption of such cycles can detrimentally affect animal health. Circadian rhythms are critical in the co-evolution of host­parasite systems, as synchronization of parasite rhythms to the host can influence infection dynamics and transmission potential. This study examines the circadian rhythms in behaviour and activity of a model fish species (Poecilia reticulata) in isolation and in shoals, both when uninfected and infected with an ectoparasite (Gyrodactylus turnbulli). Additionally, the rhythmical variance of parasite activity under different light conditions as well as rhythmical variance in parasite transmissibility was explored. Overall, infection alters the circadian rhythm of fish, causing nocturnal restlessness. Increased activity of gyrodactylids on the host's skin at night could potentially contribute to this elevated host activity. Whilst migration of gyrodactylids across the host's skin may have caused irritation to the host resulting in nocturnal restlessness, the disruption in guppy activity rhythm caused by the expression of host innate immunity cannot be excluded. We discuss the wider repercussions such behavioural responses to infection have for host health, the implications for animal behaviour studies of diurnal species as well as the application of chronotherapeutic approaches to aquaculture.

Fibular Allograft Osteoplasty and Silicone Arthroplasty following Gunshot Injury of the Metacarpal.

The complexity of a gunshot wound to the hand with segmental bone loss and adjacent joint disruption presents a unique challenge for the reconstructive surgeon. There are several options for posttraumatic reconstruction of hand joint defects, ranging from arthrodesis, implants, and autologous arthroplasty. Despite the abundance of literature regarding guidelines for isolated osteoplasty and arthroplasty, there are only case reports describing management of bone and joint defects, all within the setting of cancer resection. This case report presents a 24-year-old, right-hand dominant man with a gunshot wound to his left hand involving the fifth metacarpal and metacarpal phalangeal joint. The metacarpal was reconstructed with a fibular bone allograft with simultaneous placement of a silicone arthroplasty implant, allowing preservation of motion at the metacarpal phalangeal joint with satisfactory functional outcomes. This illustrates the feasibility of successfully reconstructing segmental bone loss and adjacent joint defects simultaneously in the traumatic setting of firearm injuries.

Evidence-based Perioperative Practice Utilization among Various Racial Populations-A Retrospective Cohort Trending Analysis of Lower Extremity Total Joint Arthroplasty Patients.

BACKGROUND: Various studies have demonstrated racial disparities in perioperative care and outcomes. The authors hypothesize that among lower extremity total joint arthroplasty patients, evidence-based perioperative practice utilization increased over time among all racial groups, and that standardized evidence-based perioperative practice care protocols resulted in reduction of racial disparities and improved outcomes. METHODS: The study analyzed 3,356,805 lower extremity total joint arthroplasty patients from the Premier Healthcare database (Premier Healthcare Solutions, Inc., USA). The exposure of interest was race (White, Black, Asian, other). Outcomes were evidence-based perioperative practice adherence (eight individual care components; more than 80% of these implemented was defined as "high evidence-based perioperative practice"), any major complication (including acute renal failure, delirium, myocardial infarction, pulmonary embolism, respiratory failure, stroke, or in-hospital mortality), in-hospital mortality, and prolonged length of stay. RESULTS: Evidence-based perioperative practice adherence rate has increased over time and was associated with reduced complications across all racial groups. However, utilization among Black patients was below that for White patients between 2006 and 2021 (odds ratio, 0.94 [95% CI, 0.93 to 0.95]; 45.50% vs. 47.90% on average). Independent of whether evidence-based perioperative practice components were applied, Black patients exhibited higher odds of major complications (1.61 [95% CI, 1.55 to 1.67] with high evidence-based perioperative practice; 1.43 [95% CI, 1.39 to 1.48] without high evidence-based perioperative practice), mortality (1.70 [95% CI, 1.29 to 2.25] with high evidence-based perioperative practice; 1.29 [95% CI, 1.10 to 1.51] without high evidence-based perioperative practice), and prolonged length of stay (1.45 [95% CI, 1.42 to 1.48] with high evidence-based perioperative practice; 1.38 [95% CI, 1.37 to 1.40] without high evidence-based perioperative practice) compared to White patients. CONCLUSIONS: Evidence-based perioperative practice utilization in lower extremity joint arthroplasty has been increasing during the last decade. However, racial disparities still exist with Black patients consistently having lower odds of evidence-based perioperative practice adherence. Black patients (compared to the White patients) exhibited higher odds of composite major complications, mortality, and prolonged length of stay, independent of evidence-based perioperative practice use, suggesting that evidence-based perioperative practice did not impact racial disparities regarding particularly the Black patients in this surgical cohort.

Adherence and persistence to direct factor Xa inhibitors in the community following newly diagnosed venous thromboembolism: a retrospective pharmacy-linkage study.

OBJECTIVES: To assess adherence and persistence to the direct factor Xa inhibitor oral anticoagulants in the community following newly diagnosed venous thromboembolism (VTE). METHODS: We retrospectively reviewed community pharmacy dispensing data on all patients with newly diagnosed VTE who were prescribed direct factor Xa inhibitors, apixaban or rivaroxaban, between January 2018 and December 2019 at our institution. Proportion of days covered (PDC) was used to assess adherence at 90 days, and 6- and 12 months. Persistence was measured by participants having both dispensed supply of a factor Xa inhibitor at the end of the treatment period and no significant gaps (maximum of 60 days) in supply. KEY FINDINGS: There were 225 patients identified. Overall PDC at 90 days, 6- and 12 months were 84.6%, 86.2% and 86.1%, respectively. Apixaban had a higher mean overall PDC than rivaroxaban (86.2% and 80.6%, respectively). Females demonstrated higher PDC compared with males (87.3% versus 81.2%). Overall, 133 patients (64%) were persistent with therapy. CONCLUSIONS: In patients with newly diagnosed VTE treated with a factor Xa inhibitor, adherence rates are high at >80%, with females and those prescribed apixaban exhibiting higher adherence. These findings may assist clinicians in identifying those patients with VTE at risk of poor adherence.

Gas-phase microactuation using kinetically controlled surface states of ultrathin catalytic sheets.

Biological systems convert chemical energy into mechanical work by using protein catalysts that assume kinetically controlled conformational states. Synthetic chemomechanical systems using chemical catalysis have been reported, but they are slow, require high temperatures to operate, or indirectly perform work by harnessing reaction products in liquids (e.g., heat or protons). Here, we introduce a bioinspired chemical strategy for gas-phase chemomechanical transduction that sequences the elementary steps of catalytic reactions on ultrathin (<10 nm) platinum sheets to generate surface stresses that directly drive microactuation (bending radii of 700 nm) at ambient conditions (T = 20 °C; Ptotal = 1 atm). When fueled by hydrogen gas and either oxygen or ozone gas, we show how kinetically controlled surface states of the catalyst can be exploited to achieve fast actuation (600 ms/cycle) at 20 °C. We also show that the approach can integrate photochemically controlled reactions and can be used to drive the reconfiguration of microhinges and complex origami- and kirigami-based microstructures.

Passive Cycle Training Promotes Bone Recovery after Spinal Cord Injury without Altering Resting-State Bone Perfusion.

INTRODUCTION: Spinal cord injury (SCI) produces diminished bone perfusion and bone loss in the paralyzed limbs. Activity-based physical therapy (ABPT) modalities that mobilize and/or reload the paralyzed limbs (e.g., bodyweight-supported treadmill training (BWSTT) and passive-isokinetic bicycle training) transiently promote lower-extremity blood flow (BF). However, it remains unknown whether ABPT alter resting-state bone BF or improve skeletal integrity after SCI. METHODS: Four-month-old male Sprague-Dawley rats received T 9 laminectomy alone (SHAM; n = 13) or T 9 laminectomy with severe contusion SCI ( n = 48). On postsurgery day 7, SCI rats were stratified to undergo 3 wk of no ABPT, quadrupedal (q)BWSTT, or passive-isokinetic hindlimb bicycle training. Both ABPT regimens involved two 20-min bouts per day, performed 5 d·wk -1 . We assessed locomotor recovery, bone turnover with serum assays and histomorphometry, distal femur bone microstructure using in vivo microcomputed tomography, and femur and tibia resting-state bone BF after in vivo microsphere infusion. RESULTS: All SCI animals displayed immediate hindlimb paralysis. SCI without ABPT exhibited uncoupled bone turnover and progressive cancellous and cortical bone loss. qBWSTT did not prevent these deficits. In comparison, hindlimb bicycle training suppressed surface-level bone resorption indices without suppressing bone formation indices and produced robust cancellous and cortical bone recovery at the distal femur. No bone BF deficits existed 4 wk after SCI, and neither qBWSTT nor bicycle altered resting-state bone perfusion or locomotor recovery. However, proximal tibia BF correlated with several histomorphometry-derived bone formation and resorption indices at this skeletal site across SCI groups. CONCLUSIONS: These data indicate that passive-isokinetic bicycle training reversed cancellous and cortical bone loss after severe SCI through antiresorptive and/or bone anabolic actions, independent of locomotor recovery or changes in resting-state bone perfusion.

Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures.

Ischemic stroke causes brain endothelial cell (BEC) death and damages tight junction integrity of the blood-brain barrier (BBB). We harnessed the innate mitochondrial load of BEC-derived extracellular vesicles (EVs) and utilized mixtures of EV/exogenous 27 kDa heat shock protein (HSP27) as a one-two punch strategy to increase BEC survival (via EV mitochondria) and preserve their tight junction integrity (via HSP27 effects). We demonstrated that the medium-to-large (m/lEV) but not small EVs (sEV) transferred their mitochondrial load, that subsequently colocalized with the mitochondrial network of the recipient primary human BECs. Recipient BECs treated with m/lEVs showed increased relative ATP levels and mitochondrial function. To determine if the m/lEV-meditated increase in recipient BEC ATP levels was associated with m/lEV mitochondria, we isolated m/lEVs from donor BECs pre-treated with oligomycin A (OGM, mitochondria electron transport complex V inhibitor), referred to as OGM-m/lEVs. BECs treated with naïve m/lEVs showed a significant increase in ATP levels compared to untreated OGD cells, OGM-m/lEVs treated BECs showed a loss of ATP levels suggesting that the m/lEV-mediated increase in ATP levels is likely a function of their innate mitochondrial load. In contrast, sEV-mediated ATP increases were not affected by inhibition of mitochondrial function in the donor BECs. Intravenously administered m/lEVs showed a reduction in brain infarct sizes compared to vehicle-injected mice in a mouse middle cerebral artery occlusion model of ischemic stroke. We formulated binary mixtures of human recombinant HSP27 protein with EVs: EV/HSP27 and ternary mixtures of HSP27 and EVs with a cationic polymer, poly (ethylene glycol)-b-poly (diethyltriamine): (PEG-DET/HSP27)/EV. (PEG-DET/HSP27)/EV and EV/HSP27 mixtures decreased the paracellular permeability of small and large molecular mass fluorescent tracers in oxygen glucose-deprived primary human BECs. This one-two punch approach to increase BEC metabolic function and tight junction integrity may be a promising strategy for BBB protection and prevention of long-term neurological dysfunction post-ischemic stroke.

Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1.

AIMS: Brain-derived neurotrophic factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, tropomyosin-related kinase receptor (TrkB), are expressed in cardiomyocytes; however, the role of myocardial BDNF signalling in cardiac pathophysiology is poorly understood. Here, we investigated the role of BDNF/TrkB signalling in cardiac stress response to exercise and pathological stress. METHODS AND RESULTS: We found that myocardial BDNF expression was increased in mice with swimming exercise but decreased in a mouse heart failure model and human failing hearts. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unravelled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signalling pathway, the pleiotropic transcription factor Yin Yang 1. CONCLUSION: Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.

Microscopic robots with onboard digital control.

Autonomous robots-systems where mechanical actuators are guided through a series of states by information processing units to perform a predesigned function-are expected to revolutionize everything from health care to transportation. Microscopic robots are poised for a similar revolution in fields from medicine to environmental remediation. A key hurdle to developing these microscopic robots is the integration of information systems, particularly electronics fabricated at commercial foundries, with microactuators. Here, we develop such an integration process and build microscopic robots controlled by onboard complementary metal oxide semiconductor electronics. The resulting autonomous, untethered robots are 100 to 250 micrometers in size, are powered by light, and walk at speeds greater than 10 micrometers per second. In addition, we demonstrate a microscopic robot that can respond to an optical command. This work paves the way for ubiquitous autonomous microscopic robots that perform complex functions, respond to their environments, and communicate with the outside world.

Cilia metasurfaces for electronically programmable microfluidic manipulation.

Cilial pumping is a powerful strategy used by biological organisms to control and manipulate fluids at the microscale. However, despite numerous recent advances in optically, magnetically and electrically driven actuation, development of an engineered cilial platform with the potential for applications has remained difficult to realize1-6. Here we report on active metasurfaces of electronically actuated artificial cilia that can create arbitrary flow patterns in liquids near a surface. We first create voltage-actuated cilia that generate non-reciprocal motions to drive surface flows at tens of microns per second at actuation voltages of 1 volt. We then show that a cilia unit cell can locally create a range of elemental flow geometries. By combining these unit cells, we create an active cilia metasurface that can generate and switch between any desired surface flow pattern. Finally, we integrate the cilia with a light-powered complementary metal-oxide-semiconductor (CMOS) clock circuit to demonstrate wireless operation. As a proof of concept, we use this circuit to output voltage pulses with various phase delays to demonstrate improved pumping efficiency using metachronal waves. These powerful results, demonstrated experimentally and confirmed using theoretical computations, illustrate a pathway towards fine-scale microfluidic manipulation, with applications from microfluidic pumping to microrobotic locomotion.

Endothelial superoxide dismutase 2 is decreased in sickle cell disease and regulates fibronectin processing.

Sickle cell disease (SCD) is a genetic red blood cell disorder characterized by increased reactive oxygen species (ROS) and a concordant reduction in antioxidant capacity in the endothelium. Superoxide dismutase 2 (SOD2) is a mitochondrial-localized enzyme that catalyzes the dismutation of superoxide to hydrogen peroxide. Decreased peripheral blood expression of SOD2 is correlated with increased hemolysis and cardiomyopathy in SCD. Here, we report for the first time that endothelial cells exhibit reduced SOD2 protein expression in the pulmonary endothelium of SCD patients. To investigate the impact of decreased SOD2 expression in the endothelium, SOD2 was knocked down in human pulmonary microvascular endothelial cells (hPMVECs). We found that SOD2 deficiency in hPMVECs results in endothelial cell dysfunction, including reduced cellular adhesion, diminished migration, integrin protein dysregulation, and disruption of permeability. Furthermore, we uncover that SOD2 mediates changes in endothelial cell function via processing of fibronectin through its inability to facilitate dimerization. These results demonstrate that endothelial cells are deficient in SOD2 expression in SCD patients and suggest a novel pathway for SOD2 in regulating fibronectin processing.

A1 Pulley Tenderness as a Modification to Tenderness along the Flexor Sheath in Diagnosing Pyogenic Flexor Tenosynovitis.

Background: Pyogenic flexor tenosynovitis (PFT) is frequently diagnosed by physical examination according to the Kanavel signs. This study proposes a modification of the Kanavel sign "tenderness over the course of the flexor sheath" by including palpation of the A1 pulley to increase specificity for diagnosis. Methods: A retrospective review was performed over 8 months for patients in the emergency department who received a consult to hand surgery to rule out PFT. Two cohorts, nonPFT infections and PFT infections, were studied for the presence or absence of the four Kanavel signs, as well as tenderness specifically over the A1 pulley on the affected digit(s) or T1 pulley of the thumb. Results: There were a total of 33 patients in the two cohorts (21 nonPFT, 12 PFT) with statistically significant differences with regard to the presence of all the Kanavel signs. A1 pulley tenderness had the greatest odds ratio, positive predictive value, specificity, and accuracy when compared with all Kanavel signs. When used in conjunction with each Kanavel sign, there was an increase in specificity in all four signs. Receiver operating characteristic analysis revealed increased area under the curve with A1 pulley tenderness added, indicating improved ability to classify hand infections as PFT versus nonPFT. Conclusion: Although the classic Kanavel signs have shown reliable clinical utility, this study finds that tenderness at the A1 pulley can be a useful specification of "tenderness over the course of the flexor sheath" to help with the diagnosis of PFT.

SOD2 V16A amplifies vascular dysfunction in sickle cell patients by curtailing mitochondria complex IV activity.

Superoxide dismutase 2 (SOD2) catalyzes the dismutation of superoxide to hydrogen peroxide in mitochondria, limiting mitochondrial damage. The SOD2 amino acid valine-to-alanine substitution at position 16 (V16A) in the mitochondrial leader sequence is a common genetic variant among patients with sickle cell disease (SCD). However, little is known about the cardiovascular consequences of SOD2V16A in SCD patients or its impact on endothelial cell function. Here, we show SOD2V16A associates with increased tricuspid regurgitant velocity (TRV), systolic blood pressure, right ventricle area at systole, and declined 6-minute walk distance in 410 SCD patients. Plasma lactate dehydrogenase, a marker of oxidative stress and hemolysis, significantly associated with higher TRV. To define the impact of SOD2V16A in the endothelium, we introduced the SOD2V16A variant into endothelial cells. SOD2V16A increases hydrogen peroxide and mitochondrial reactive oxygen species (ROS) production compared with controls. Unexpectedly, the increased ROS was not due to SOD2V16A mislocalization but was associated with mitochondrial complex IV and a concomitant decrease in basal respiration and complex IV activity. In sum, SOD2V16A is a novel clinical biomarker of cardiovascular dysfunction in SCD patients through its ability to decrease mitochondrial complex IV activity and amplify ROS production in the endothelium.

The Influence of Posture on Attention.

Smith et al. (2019) found standing resulted in better performance than sitting in three different cognitive control paradigms: a Stroop task, a task-switching, and a visual search paradigm. Here, we conducted close replications of the authors' three experiments using larger sample sizes than the original work. Our sample sizes had essentially perfect power to detect the key postural effects reported by Smith et al. The results from our experiments revealed that, in contrast to Smith et al., the postural interactions were quite limited in magnitude in addition to being only a fraction of the size of the original effects. Moreover, our results from Experiment 1 are consistent with two recent replications (Caron et al., 2020; Straub et al., 2022), which reported no meaningful influences of posture on the Stroop effect. In all, the current research provides further converging evidence that postural influences on cognition do not appear to be as robust, as was initially reported in prior work.

Complications After Clinic-Based Wide Awake Local Anesthesia No Tourniquet Hand Surgery at a Single Private Practice.

BACKGROUND: This study was designed to analyze the results of all wide awake local anesthesia no tourniquet (WALANT) procedures performed on the hand and wrist at a single practice hand surgery practice with a focus on quantifying and qualifying complications. METHODS: This retrospective chart review included 424 patients who underwent WALANT hand procedures in the minor procedure room of our private practice between 2015 and 2017. Patients were divided into groups based on the type of procedure, including carpal tunnel release, A1 pulley release, first dorsal compartment release, extensor tendon repair, mass excision, and foreign body removal. Data pertaining to patient demographics and complications were recorded. RESULTS: The overall complication rate for all procedures was 2.8% for 424 patients: A1 pulley release (n = 314, 2.5%), first dorsal compartment release (n = 11, 9%), extensor tendon repairs (5.5%), and mass excision (4%). The carpal tunnel release and foreign body removal groups experienced no complications. No adverse events (arrhythmias, vasovagal, etc.) were observed during the use of the WALANT technique. CONCLUSIONS: Clinic-based WALANT hand surgery procedures are equally safe compared to the same procedures performed in the operating room at an ambulatory surgery center or hospital.

Heme stimulates platelet mitochondrial oxidant production to induce targeted granule secretion.

Hemolysis, a pathological component of many diseases, is associated with thrombosis and vascular dysfunction. Hemolytic products, including cell-free hemoglobin and free heme directly activate platelets. However, the effect of hemolysis on platelet degranulation, a central process in not only thrombosis, but also inflammatory and mitogenic signaling, remains less clear. Our group showed that hemoglobin-induced platelet activation involved the production of mitochondrial reactive oxygen species (mtROS). However, the molecular mechanism by which extracellular hemolysis induces platelet mtROS production, and whether these mtROS regulate platelet degranulation remains unknown. Here, we demonstrate using isolated human platelets that cell free heme is a more potent agonist for platelet activation than hemoglobin, and stimulates the release of a specific set of molecules, including the glycoprotein thrombospondin-1 (TSP-1), from the α-granule of platelets. We uncover the mechanism of heme-mediated platelet mtROS production which is dependent on the activation of platelet toll-like receptor 4 (TLR4) signaling and leads to the downstream phosphorylation and inhibition of complex-V by the serine kinase Akt. Notably, inhibition of platelet TLR4 or Akt, or scavenging of mtROS prevents heme-induced granule release in vitro. Further, heme-dependent granule release is significantly attenuated in vivo in mice lacking TLR4 or those treated with the mtROS scavenger MitoTEMPO. These data elucidate a novel mechanism of TLR4-mediated mitochondrial regulation, establish the mechanistic link between hemolysis and platelet degranulation, and begin to define the heme and mtROS-dependent platelet secretome. These data have implications for hemolysis-induced thrombo-inflammatory signaling and for the consideration of platelet mitochondria as a therapeutic target in hemolytic disorders.

Mitochondrial Respiration Defects in Single-Ventricle Congenital Heart Disease.

Background: Congenital heart disease (CHD) with single-ventricle (SV) physiology is now survivable with a three-stage surgical course ending with Fontan palliation. However, 10-year transplant-free survival remains at 39-50%, with ventricular dysfunction progressing to heart failure (HF) being a common sequela. For SV-CHD patients who develop HF, undergoing the surgical course would not be helpful and could even be detrimental. As HF risk cannot be predicted and metabolic defects have been observed in Ohia SV-CHD mice, we hypothesized that respiratory defects in peripheral blood mononuclear cells (PBMCs) may allow HF risk stratification in SV-CHD. Methods: SV-CHD (n = 20), biventricular CHD (BV-CHD; n = 16), or healthy control subjects (n = 22) were recruited, and PBMC oxygen consumption rate (OCR) was measured using the Seahorse Analyzer. Respiration was similarly measured in Ohia mouse heart tissue. Results: Post-Fontan SV-CHD patients with HF showed higher maximal respiratory capacity (p = 0.004) and respiratory reserve (p < 0.0001), parameters important for cell stress adaptation, while the opposite was found for those without HF (reserve p = 0.037; maximal p = 0.05). This was observed in comparison to BV-CHD or healthy controls. However, respiration did not differ between SV patients pre- and post-Fontan or between pre- or post-Fontan SV-CHD patients and BV-CHD. Reminiscent of these findings, heart tissue from Ohia mice with SV-CHD also showed higher OCR, while those without CHD showed lower OCR. Conclusion: Elevated mitochondrial respiration in PBMCs is correlated with HF in post-Fontan SV-CHD, suggesting that PBMC respiration may have utility for prognosticating HF risk in SV-CHD. Whether elevated respiration may reflect maladaptation to altered hemodynamics in SV-CHD warrants further investigation.