Molecular permeation through large pore channels: computational approaches and insights.

Computational methods such as molecular dynamics (MD) have illuminated how single-atom ions permeate membrane channels and how selectivity among them is achieved. Much less is understood about molecular permeation through eukaryotic channels that mediate the flux of small molecules (e.g. connexins, pannexins, LRRC8s, CALHMs). Here we describe computational methods that have been profitably employed to explore the movements of molecules through wide pores, revealing mechanistic insights, guiding experiments, and suggesting testable hypotheses. This review illustrates MD techniques such as voltage-driven flux, potential of mean force, and mean first-passage-time calculations, as applied to molecular permeation through wide pores. These techniques have enabled detailed and quantitative modeling of molecular interactions and movement of permeants at the atomic level. We highlight novel contributors to the transit of molecules through these wide pathways. In particular, the flexibility and anisotropic nature of permeant molecules, coupled with the dynamics of pore-lining residues, lead to bespoke permeation dynamics. As more eukaryotic large-pore channel structures and functional data become available, these insights and approaches will be important for understanding the physical principles underlying molecular permeation and as guides for experimental design.

An interprofessional postgraduate quality improvement curriculum: results and lessons learned over a 5-year implementation.

PROBLEM: Quality Improvement (QI) is interprofessional by nature; however, most academic QI programs occur in silos and do not leverage the opportunity to bring interprofessional learners together. INTERVENTION: To evaluate QI competencies of physician, nursing, pharmacy, behavioral health, and social work residents after participating in a longitudinal QI curriculum. Lessons learned are shared to guide educators in developing QI curriculum for interprofessional learners. CONTEXT: Cohorts of graduate students over 5 years participated in a QI curriculum that aligned with each professions' core quality competencies. Residents engaged in didactics and experiential learning in primary care clinics. IMPACT: All learners (N = 74) demonstrated improvement in QI knowledge measured by the QIKAT-R and applied their skills demonstrated by completion of a QI project presented at the Institute for Healthcare Improvement annual forums. Participation in QI curriculum resulted in knowledge and skill improvement. LESSONS LEARNED: An experiential QI curriculum is a natural place to bring diverse post-graduate learners together to improve QI knowledge and skills. Successful QI curriculum goals are to (a) align projects with institutional and stakeholder goals, (b) include coaches to promote teamwork and project management, (c) narrow project scope, (d) develop an improvement mindset that failures are learning opportunities, and (e) address needs for data access.

Infection following mini-open rotator cuff repair: a single surgeon experience.

BACKGROUND: Surgical technique has been shown to influence risk of surgical site infection following rotator cuff repair (RCR). Few studies have reported the rate of infection associated with mini-open RCR. The goal of this study was to report the postoperative infection rate and risk factors for infection among patients undergoing RCR performed by a single surgeon using a modified mini-open technique. Our hypothesis was that the rate of infection after mini-open RCR would be lower than previously reported for this surgical approach. METHODS: We retrospectively reviewed an institutional shoulder surgery database to identify patients who underwent mini-open RCR performed by one surgeon at an academic tertiary care institution between 2003 and 2020. Patient records were reviewed to determine which individuals returned within 3 months postoperatively with a superficial or deep surgical site infection requiring operative management. Patient demographics, preoperative clinical characteristics, intraoperative variables, microbiological findings, infection management, and clinical course after infection were recorded. Backward elimination multivariate regression was used to assess for significant risk factors for infection. RESULTS: Of the 925 patients identified, 823 (89%) had at least 3 months of follow-up and were included for further analysis. A majority of the patients undergoing RCR were men (57%). The mean age was 58.4 ± 9.9 years, and the mean body mass index was 29.3 ± 5.9 kg/m2. Fourteen cases (1.7%) of postoperative surgical site infection were identified in 13 patients. Ten infections (1.2%) were superficial and 4 (0.49%) were deep. The most commonly identified organisms were Staphylococcus aureus and Cutibacterium acnes. Male sex (odds ratio [OR] 4.3, 95% CI 1.2-15.3) and diabetes mellitus (OR 3.9, 95% CI 1.2-12.6) were found to be associated with greater risk of infection. The RCR construct was found to be intact in all 10 patients with superficial infections and 2 of the 4 patients with deep infections. All infections were successfully treated with 1 round of surgical débridement and wound irrigation, and with 6 or fewer weeks of intravenous antibiotic therapy. All patients with postoperative infections recovered with no sequelae at a median final follow-up of 63.5 months (range, 3-215 months). CONCLUSIONS: This single-surgeon series of a large patient cohort undergoing mini-open RCR over an 18-year period demonstrated a low overall infection rate of 1.7%. Only 4 infections were deep, which suggests that deep infection after mini-open RCR is uncommon and approximates infection rates seen with arthroscopic techniques.

How life events may confer vulnerability to addiction: the role of epigenetics.

Substance use disorder (SUD) represents a large and growing global health problem. Despite the strong addictive potency of drugs of abuse, only a minority of those exposed develop SUDs. While certain life experiences (e.g., childhood trauma) may increase subsequent vulnerability to SUDs, mechanisms underlying these effects are not yet well understood. Given the chronic and relapsing nature of SUDs, and the length of time that can elapse between prior life events and subsequent drug exposure, changes in SUD vulnerability almost certainly involve long-term epigenetic dysregulation. To validate this idea, functional effects of specific epigenetic modifications in brain regions mediating reinforcement learning (e.g., nucleus accumbens, prefrontal cortex) have been investigated in a variety of animal models of SUDs. In addition, the effects of epigenetic modifications produced by prior life experiences on subsequent SUD vulnerability have been studied, but mostly in a correlational manner. Here, we review how epigenetic mechanisms impact SUD-related behavior in animal models and summarize our understanding of the relationships among life experiences, epigenetic regulation, and future vulnerability to SUDs. Despite variations in study design, epigenetic modifications that most consistently affect SUD-related behavior are those that produce predominantly unidirectional effects on gene regulation, such as DNA methylation and histone phosphorylation. Evidence explicitly linking environmentally induced epigenetic modifications to subsequent SUD-related behavior is surprisingly sparse. We conclude by offering several directions for future research to begin to address this critical research gap.

High-Dose TXA Is Associated with Less Blood Loss Than Low-Dose TXA without Increased Complications in Patients with Complex Adult Spinal Deformity.

BACKGROUND: Tranexamic acid (TXA) is commonly utilized to reduce blood loss in adult spinal deformity (ASD) surgery. Despite its widespread use, there is a lack of consensus regarding the optimal dosing regimen. The aim of this study was to assess differences in blood loss and complications between high, medium, and low-dose TXA regimens among patients undergoing surgery for complex ASD. METHODS: A multicenter database was retrospectively analyzed to identify 265 patients with complex ASD. Patients were separated into 3 groups by TXA regimen: (1) low dose (<20-mg/kg loading dose with ≤2-mg/kg/hr maintenance dose), (2) medium dose (20 to 50-mg/kg loading dose with 2 to 5-mg/kg/hr maintenance dose), and (3) high dose (>50-mg/kg loading dose with ≥5-mg/kg/hr maintenance dose). The measured outcomes included blood loss, complications, and red blood cell (RBC) units transfused intraoperatively and perioperatively. The multivariable analysis controlled for TXA dosing regimen, levels fused, operating room time, preoperative hemoglobin, 3-column osteotomy, and posterior interbody fusion. RESULTS: The cohort was predominantly White (91.3%) and female (69.1%) and had a mean age of 61.6 years. Of the 265 patients, 54 (20.4%) received low-dose, 131 (49.4%) received medium-dose, and 80 (30.2%) received high-dose TXA. The median blood loss was 1,200 mL (interquartile range [IQR], 750 to 2,000). The median RBC units transfused intraoperatively was 1.0 (IQR, 0.0 to 2.0), and the median RBC units transfused perioperatively was 2.0 (IQR, 1.0 to 4.0). Compared with the high-dose group, the low-dose group had increased blood loss (by 513.0 mL; p = 0.022) as well as increased RBC units transfused intraoperatively (by 0.6 units; p < 0.001) and perioperatively (by 0.3 units; p = 0.024). The medium-dose group had increased blood loss (by 491.8 mL; p = 0.006) as well as increased RBC units transfused intraoperatively (by 0.7 units; p < 0.001) and perioperatively (by 0.5 units; p < 0.001) compared with the high-dose group. CONCLUSIONS: Patients with ASD who received high-dose intraoperative TXA had fewer RBC transfusions intraoperatively, fewer RBC transfusions perioperatively, and less blood loss than those who received low or medium-dose TXA, with no differences in the rates of seizure or thromboembolic complications. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

An open-source combined atomic force microscope and optical microscope for mechanobiology studies.

Atomic Force Microscopy (AFM) has become the gold standard tool for measuring mechanical properties of biological samples including proteins, single cells and tissues. However, investment in this specialized equipment and gaining expertise in its operation are significant obstacles for non-experts looking to adopt this technique. To address this, we have designed an AFM based mechanical measurement system for measuring cell mechanical properties which is combined with a custom inverted fluorescence microscope which can be used for characterizing mechanosensitive responses. This system, through its ease of use and low setup cost, will promote interdisciplinary research leading to new insights into the role of cell mechanics and mechanosensitive responses in physiology and disease.

Reassessing Glycemic Control: A Novel Method for 90-Day Major Complication Stratification Based on Hemoglobin A1c and Same-Day Glucose Levels for Patients Undergoing Total Knee Arthroplasty.

INTRODUCTION: Glucose levels obtained on day of surgery may be predictive of complications following total knee arthroplasty (TKA). Established glucose thresholds for TKA are either non-specific or have low predictive power. Therefore, the purpose of this study was to create data-driven hemoglobin A1c (HbA1c) and same-day glucose thresholds associated with varying risks of 90-day major and surgical site infection (SSI) complications following TKA. METHODS: Stratum-specific likelihood ratio analysis was conducted to determine data-driven HbA1c and glucose strata associated with varying risks of 90-day major and SSI complications. Each strata was then propensity-score matched to the lowest strata based on age, sex, hypertension, heart failure, chronic obstructive pulmonary disorder, and obesity. The risk ratio (RR) for complications in each stratum with respect to the lowest matched stratum was analyzed. RESULTS: Four data-driven HbA1c (%) strata (4.5 to 5.9, 6.0 to 6.4, 6.5 to 7.9, and 8.0+) and two same-day glucose (mg/dl) strata (60 to 189 and 190+) were identified that predicted 90-day major complications. When compared to the propensity-matched lowest strata (4.5 to 5.9%), the risk of 90-day major complications sequentially increased as the HbA1c (%) strata increased: 6.0 to 6.4 (RR: 1.23; P = 0.024), 6.5 to 7.9 (RR 1.38; P < 0.001), 8.0+ (RR 2.0; P < 0.001). When compared to the propensity-matched lowest strata (60 to 189 mg/dl), the 190+ mg/dl strata had a higher risk of 90-day major complications (RR: 1.18; P = 0.016). No HbA1c or same-day glucose strata had significantly different risks of 90-day SSI. CONCLUSION: The multiple strata identified for HbA1c demonstrate that a single HbA1c cut-off as identified in prior literature may be missing a larger picture for risk stratification. The threshold identified for same-day glucose can be utilized in day-of-surgery glycemic control guidelines to further reduce the risk of 90-day major complications.

No Difference in 30-day Mortality Between Patients Undergoing Bilateral Simultaneous Total Knee Arthroplasty With Technology Assistance Compared to Conventional Instrumentation.

Background: Bilateral simultaneous total knee arthroplasty (BSTKA) has decreased in frequency due to concerns about higher rates of early mortality and complications than unilateral or staged surgeries. Purpose: We sought to evaluate whether technology assistance (encompassing robotics and computer assistance) decreases early mortality following BSTKA. Methods: We conducted a retrospective cohort study using a national all-payer claims database. Patients who underwent BSTKA from October 2015 to December 2020 were identified. Univariate and multivariable analyses were conducted to compare outcomes in patients who underwent BSTKA with technology assistance compared to conventional instrumentation. The primary outcome was 30-day postoperative mortality. Secondary outcomes were respiratory failure and fat embolism. A post-hoc analysis was performed to evaluate length of stay, readmission, and other medical complications. Results: A total of 14,870 patients who underwent BSTKA were included in this study. Of these, 860 patients underwent technology-assisted BSTKA, and 14,010 patients underwent BSTKA without technology assistance. After a multivariable analysis, patients who underwent technology-assisted BSTKA had equivalent odds of 30-day mortality compared to those who underwent BSTKA without technology assistance. Technology assistance was not protective against the development of acute respiratory failure or fat embolism. Conclusion: This retrospective cohort study found no differences in the rates of 30-day mortality, respiratory failure, or fat embolism after technology-assisted BSTKA compared to conventional BSTKA. On the post-hoc analysis, technology use was associated with a decreased length of stay, lower readmission risk, and decreased rates of deep vein thrombosis, pulmonary embolism, and blood transfusion.

Magnitude and predictors of elasticity of demand for morphine are similar in male and female rats.

Introduction: Sex differences in vulnerability to opioid use disorder (OUD) have been reported in some clinical and preclinical studies, but findings are mixed and further research is needed in this area. The goal of this study was to compare elasticity of demand (reinforcement efficacy) in an i.v. morphine self-administration (SA) model in male and female rats using a translationally relevant behavioral economics approach. Rate of acquisition and predictors of individual differences in demand (e.g., cumulative morphine infusions during acquisition) were also evaluated in both sexes. Materials methods and results: Acquisition of morphine SA (0.4 mg/kg/infusion) under a fixed ratio (FR) 1 schedule of reinforcement was slower and infusions earned were lower in females than in males (n = 30-31/sex), but infusions earned did not differ between sexes during the FR 2 and FR 3 phases of acquisition. Increases in the FR response requirement across sessions during demand testing (FR 1-FR 96) resulted in a progressive reduction in morphine infusions in both sexes. Morphine consumption was well-described by an exponential demand function in both sexes and was associated with considerable individual vulnerability. There were no sex differences in elasticity of demand (rate of decline in morphine consumption with increasing price) or intensity of demand (consumption at zero price). A higher number of infusions earned during the FR 2 and FR 3 phases of acquisition and greater maximum response rates during demand testing were associated with lower demand elasticity (i.e., greater reinforcing efficacy) in both males and females, whereas other relationships were sex-specific (e.g., higher intensity of demand was associated with lower elasticity of demand in males but not in females). Conclusion: Our findings indicate similar elasticity of demand and predictors of individual differences in demand for morphine in male and female rats, although sex differences were observed in initial rate of acquisition and in some correlations between morphine SA measures. These data are consistent with findings of similar OUD vulnerability in males and females in some human and animal studies.

The retinal chromophore environment in an inward light-driven proton pump studied by solid-state NMR and hydrogen-bond network analysis.

Inward proton pumping is a relatively new function for microbial rhodopsins, retinal-binding light-driven membrane proteins. So far, it has been demonstrated for two unrelated subgroups of microbial rhodopsins, xenorhodopsins and schizorhodopsins. A number of recent studies suggest unique retinal-protein interactions as being responsible for the reversed direction of proton transport in the latter group. Here, we use solid-state NMR to analyze the retinal chromophore environment and configuration in an inward proton-pumping Antarctic schizorhodopsin. Using fully 13C-labeled retinal, we have assigned chemical shifts for every carbon atom and, assisted by structure modelling and molecular dynamics simulations, made a comparison with well-studied outward proton pumps, identifying locations of the unique protein-chromophore interactions for this functional subclass of microbial rhodopsins. Both the NMR results and molecular dynamics simulations point to the distinctive polar environment in the proximal part of the retinal, which may result in a hydration pattern dramatically different from that of the outward proton pumps, causing the reversed proton transport.

Validating the application of cyclic hydraulic pressure pulses to reduce breakdown pressure in granite.

As the geoenergy sector moves toward more sustainable practices, an emerging field of research is the proposed utilization of cyclic hydraulic pressure pulses to safely and efficiently enhance productivity. We demonstrate how cyclic hydraulic pressure pulses can reduce hydraulic breakdown pressure in granite using newly developed experimental equipment, which applies pulsed square waves of fluid pressure to large bench-top samples, monitored with dynamic high-resolution fiber optic strain sensors. Our results show a significant reduction in breakdown pressure can be achieved by cyclic pulsed pumping, and we explore the role of mean pressure and cyclic amplitude. Our results offer new insight into cyclic well-stimulation treatments and show potential for reducing peak power consumption during geothermal exploitation.

Cementless, Cruciate-Retaining Primary Total Knee Arthroplasty Using Conventional Instrumentation: Technical Pearls and Intraoperative Considerations.

Background: Total knee arthroplasty (TKA) is commonly indicated for patients with severe tibiofemoral osteoarthritis in whom nonoperative treatment has failed. TKA is one of the most commonly performed orthopaedic surgical procedures in the United States and is associated with substantial improvements in pain, function, and quality of life1-3. The procedure may be performed with cemented, cementless, or hybrid cemented and cementless components4,5. Cementless TKA utilizing contemporary implant designs has been demonstrated to have excellent long-term survival and outcomes in patients who are appropriately indicated for this procedure5-8. The preference of the senior author is to perform this procedure with use of a cruciate-retaining implant design when feasible, and according to the principles of mechanical alignment to guide osseous resection. It should be noted that nearly all recent studies on outcomes following cementless TKA utilize traditional mechanical alignment7-9. Alternative alignment strategies, such as gap balancing and kinematic alignment, have not been as well studied in cementless TKA; however, preliminary short-term studies suggest comparable survivorship with restricted kinematic alignment and gap balancing compared with mechanical alignment in patients undergoing cementless TKA10,11. Description: Our preferred surgical technique for cementless TKA begins with the patient in the supine position. A thigh tourniquet is applied, and a valgus post is set at the level of the tourniquet. A flexion pad is also placed at 90°, with a bar at 20°. After sterile skin preparation and draping, a time-out is conducted, and the tourniquet is raised. The surgeon makes a medial parapatellar incision, which begins from 1 cm medial to the medial edge of the patella, extending from the tibial tubercle to 2 fingers above the proximal pole of the patella, using a knife and with the knee at 90° of flexion. Scissors are then used to find the fat above the fascia and dissect distally in the same plane. A knife is used to perform a high vastus-splitting, medial parapatellar arthrotomy. Pickups and scissors are then used to perform a partial medial synovectomy, and electrocautery is used to perform a medial peel. As the procedure progresses further medial, the infrapatellar fat pad is excised, followed by the anterior femoral synovial tissue. The surgeon then cuts through the anterior cruciate ligament footprint and origin with the knee flexed before sawing through the tibial spines to decrease the height of the tibial bone block. To prepare the femur, a step drill is inserted into the femoral canal, and the intramedullary alignment guide is placed with the distal femoral cutting guide set to 5° of valgus. The distal femoral cutting guide is then pressed firmly against the distal femur, making sure that the medial side is touching bone, and threaded pins are inserted in the cutting guide under power. The distal femur is then precisely sectioned with use of an oscillating saw equipped with a 21 mm x 90 mm x 1.27-mm saw blade. The surgeon focuses on initiating the cut at the cortices before proceeding further, to avoid cortical blow-out. The resultant cut is meticulously assessed for uniformity and levelness, employing both the alignment rod and the distal cutting guide for verification. Following this assessment, the pins and guide are removed, and any remaining femoral condylar osteophytes are delicately excised with use of a rongeur. The surgeon uses the femoral sizing guide, measures the size of the femur, and double-checks rotation in preparation for the remaining distal femoral cuts. The holes are then drilled to set the rotation for the 4-in-1 cutting guide. When applying the 4-in-1 cutting guide, care is taken to align the guide with the drilled holes in order to avoid inadvertent malrotation. The secure fixation of the block is ensured through the judicious insertion of 2 threaded pins under power at full speed, followed by a more controlled, slower securing process to avoid stripping the threaded pins. Subsequently, the anterior cut is made with the oscillating saw, again with a focus on initiating the cut at the cortices before proceeding further. The posterior cuts are then made in a controlled manner, employing a gentle bouncing technique to facilitate tactile feedback, and keen attention is given to cutting both the medial and lateral cortices of each of the posterior condyles. The anterior chamfer and posterior chamfer are similarly osteotomized. Subsequently, the 4-in-1 cutting guide is gently removed. To complete this phase of the procedure, a curved osteotome and mallet are employed to delicately extract the resected posterior condyles and remove posterior osteophytes as needed. The concave side of the curved osteotome is used with precision to meticulously trace the contours of the condyles, ensuring a precise result. The surgeon places a bump under the knee and extends it to check the medial collateral ligament, quadriceps tendon, patellar tendon, and posterior cruciate ligament to ensure they are intact. To make the tibial cut, the extramedullary alignment guide is placed, and the height of the slot is set to the level of the subchondral bone, aligning the rotation and coronal axis with the 2nd metatarsal. The tibial slope is also set at this step, with the goal of the resection matching the patient's native tibial slope. Matching is usually achieved by visual inspection of the trajectory of the cutting jig, although the stylus can also be utilized to confirm the appropriate tibial slope. The tibial cut is then completed with use of an oscillating saw. A single-sided reciprocating saw is then used to cut perpendicular to the plateau in the medial compartment while making sure not to extend the cut into the unresected portion of the intact tibial plateau. After removal of the medial plateau fragment, a lamina spreader is placed in the medial compartment; this process is repeated with a second cut in a similar fashion in the lateral compartment to create a triangular bone block that fully preserves the insertion of the posterior cruciate ligament. The medial and lateral menisci are resected, and the gaps are checked with use of a spacer block and alignment rod. The surgeon then sizes the tibia and uses their index fingers to feel both medially and laterally for overhang. An alternative approach is to fully expose the tibia in flexion and to size the tibia under complete visualization of the tibial margins. The tibial trial is then pinned in place after ensuring appropriate external rotation and optimal tibial coverage without overhang. The femoral and tibial trial components are placed, and the surgeon tests 7 things: (1) overall varus-valgus alignment in full extension; (2) degree of extension (specifically noting any amount of recurvatum or flexion contracture); (3) flexion to gravity; (4) anteroposterior stability in flexion (using manual anterior-posterior translation of the tibia); (5) varus-valgus stability in extension, mid-flexion, and full flexion with use of a manual dynamic varus-valgus stress test; (6) patellar tracking; and (7) component rotation. At this point, if any of the above checkpoints are not within acceptable tolerances, additional ligamentous releases or cuts may be performed. After the surgeon is satisfied with the positioning and stability of the trial components, the tibial preparation is completed by seating the feet of the tibial bushing into the tray and drilling the tibia, then punching out the keel. The pins and the tray are removed, the retractors are taken out, and the knee is extended. The surgeon then performs a pulse lavage of the femur and tibia with normal saline solution. The final components are opened, attached to the inserters, and placed in plastic coverings. The final tibial baseplate is inserted and impacted, followed by the femoral component in a similar fashion. We ensure that no soft tissue is incarcerated under the components after impaction. A trial bearing is placed, and the knee is extended. The joint space is then bathed in approximately 500 mL of sterile 0.35% povidone-iodine solution, followed by pulsatile lavage with 1 L of sterile isotonic sodium chloride solution without antibiotics. Stability is then tested again, testing the (7) checkpoints previously discussed. At this point, the only modification that can be made is an increase or decrease in the polyethylene component. Our belief is that any additional changes that require removal or repositioning of the previously implanted cementless femoral and tibial components warrant modification to the cemented TKA. Once satisfied with the stability of the real implants and the trial tibial articular surface, the final polyethylene component is inserted. Finally, the tourniquet is released. The surgeon then irrigates the wound again and closes the arthrotomy and skin. Our preference is to utilize a knotless barbed suture for the arthrotomy closure, followed by 2-0 Vicryl (Ethicon) for subcutaneous closure and 2-0 monofilament knotless barbed suture for skin closure. Some surgeons may choose to utilize a non-barbed suture; however, the use of a barbed suture has been shown to be faster and equally as effective as a non-barbed suture in a large meta-analysis of patients undergoing TKA12. Before final closure, the peri-incisional iodophor-impregnated antimicrobial incise drape is peeled back, and sterile 10% povidone-iodine is applied to the skin surrounding the incision. After subcuticular closure, adhesive skin glue is applied, followed by a waterproof dressing with the knee in flexion. Alternatives: There are numerous nonoperative treatments available for tibiofemoral osteoarthritis. According to the 2021 American Academy of Orthopaedic Surgeons Management of Osteoarthritis of the Knee (Non-Arthroplasty) Clinical Practice Guideline, these include bracing, nonsteroidalanti-inflammatory drugs, acetaminophen, supervised exercise, patient education, weight loss, and intra-articular corticosteroid injection, among others13. When nonoperative treatment has failed, surgical treatment is then indicated for patients who continue to have symptoms that interfere with quality of life. Surgical treatments for tibiofemoral osteoarthritis primarily include unicompartmental knee arthroplasty or TKA, although proximal tibial osteotomy can be performed in some select cases according to disease severity and patient age. Each of these treatments is supported by the recent 2022 American Academy of Orthopaedic Surgeons Management of Osteoarthritis of the Knee (Non-Arthroplasty) Clinical Practice Guideline. Rationale: Historically, the initial generation of cementless TKA implant designs was associated with relatively high rates of failure and poor clinical outcomes when compared with cemented arthroplasty14,15. However, there has been a renewed interest in cementless TKA with modern implant designs that incorporate newer biomaterials and porous coatings, with several recent studies demonstrating equivalence to cemented components at short-term, mid-term, and in some studies long-term follow-up4,6-8. In a recent study, Kim et al. demonstrated 98% survival free from revision for aseptic loosening at 22 to 25 years postoperatively7. In addition to at least equivalent long-term functional outcomes compared with cemented TKA, across multiple studies4,7, several short-term benefits of cementless fixation have been reported, including decreased costs and the avoidance of complications associated with cement debris8,16,17. Additionally, because there is no need to mix cement, there is a reduced burden of staff training and the elimination of possible variables that may affect cement integrity, in turn leading to improved operative efficiency and shorter operative time8. Bone cement implantation syndrome (BCIS) has been reported in up to 28% of cases of cemented TKA, and has a substantial risk of morbidity and mortality16. Cement debris can also remain in the knee if not retrieved after cement curing and prior to closure17, which is believed to cause discomfort and polyethylene wear. This complication is also avoided when cementless implants are utilized. Additional factors leading to our preference for cementless TKA, when indicated, have not yet been proven in the literature but are intuitive concepts. For example, the lack of cement leads to easier removal of components during revision surgery, and preservation of bone stock is important for performing a successful revision TKA. Expected Outcomes: Cementless TKA using modern implant designs has excellent long-term outcomes at up to 25 years. Kim et al. evaluated 261 patients who underwent bilateral simultaneous TKA with random assignment of cemented and cementless components in contralateral knees. In that study, the mean age was 63 years and the mean follow-up was 24 years. The authors found 98% survival without revision for aseptic loosening at 25 years7. Similar findings have also been shown in older patients. For example, in a 2022 study by Goh et al., 7-year survivorship of modern implant designs was 100%. In that study of patients >75 years old, 120 cementless TKAs were matched in a 1:3 ratio with TKAs using cemented implants of the same modern design. Ultimately, no difference was seen in final postoperative scores or improvement in scores at 2 years. Seven-year survivorship free from aseptic revision was 99.4% for patients with cemented implants and 100% for patients with cementless implants4. Important Tips: When deciding to perform cementless TKA, we consider a variety of preoperative factors, such as a history of osteoporosis, preoperative radiographs showing areas of bone loss, and a history of conditions associated with low bone mineral density.Intraoperative factors can also be considered when deciding between cementless and cemented implants. For example, tactile feedback when sawing can help to determine if bone is hard and sclerotic, which we believe indicates a better candidate for cementless implants.○ Note that during tibial preparation in a varus knee, you will typically have substantial sclerosis of the medial tibial plateau and relative osteopenia in the lateral tibial plateau because of longstanding differences in joint loading. This pattern is reversed in valgus knees.○ In general, we believe that the decision regarding bone integrity should be made primarily on the basis of the non-sclerotic side.With use of the techniques described in the present article, we do not have a preoperative alignment threshold or knee range-of-motion criteria for cementless TKA. More research is needed, however, on the long-term outcomes of cementless TKA when utilizing personalized alignment strategies, which may dictate the placement of components in substantial varus or valgus relative to the anatomic axis.When utilizing keeled tibial implants, we recommend drilling in reverse to pack the walls of the drill hole with bone rather than milling it out, which we believe increases support for bone growth.If there is almost no resistance while drilling in reverse, we believe this to be a poor prognostic sign for cementless TKA, and cementing should be considered.When sizing the tibial baseplate, the goal is to maximize the size of the tibia to fit on top of the rim of cortical bone without overhanging. Undersizing may increase the potential for implant subsidence.Osseous cuts with cementless components need to be perfect. Dome-shaped cuts are at risk for rocking and/or toggling, which could contribute to loosening over time.All 4 quadrants of the tibia should be checked to confirm a flat surface.Soft tissues can get incarcerated under the implant, which is of particular concern for cementless implants as this could impair osseous ingrowth.During trialing, ensure that the trial is completely flush on bone, which is an additional check to guard against toggling and/or loosening.When impacting the femoral component, we recommend applying an extension force so that the weight of the inserter does not pull the component into flexion; however, excessive extension force could also cause a fracture. Acronyms and Abbreviations: IV = intravenousAP = anteroposterior.

Routine Prescription of Proton Pump Inhibitors in the Perioperative Period is Associated With Decreased Rates of 2-Year Revision Surgery After Total Hip and Knee Arthroplasty.

BACKGROUND: Proton pump inhibitors (PPIs) are often prescribed in conjunction with nonsteroidal anti-inflammatory drugs after total hip arthroplasty (THA) and total knee arthroplasty (TKA) due to their gastroprotective effects. In animal studies, it has been suggested that PPIs have immunosuppressive effects and impair fracture healing; however, the association between PPI use and adverse events following THA and TKA has not been well-studied. METHODS: An administrative claims database was queried for patients who underwent elective THA from 2010 to 2019. The experimental group consisted of patients who did not have a prior history of gastrointestinal bleeding or gastroesophageal reflux disease and who received a PPI prescription in the perioperative period. A 1:1 propensity score matching was used to create control cohorts of patients who did not have any PPI prescription filled, also matching for age, sex, and the Charlson Comorbidity Index. This same cohort selection and matching procedure was then repeated for patients undergoing elective TKA. In total, 11,450 patients were studied (3,103 TKA + PPI, 2,622 THA + PPI, 3,103 TKA controls, and 2,622 THA controls). The mean age was 64 years (range, 38 to 94), and 57% were women. Significance was considered at P < 0.05. RESULTS: Perioperative PPI prescription in TKA patients was associated with significantly lower rates of all-cause revision (3.0 versus 4.1%, P < 0.01) and periprosthetic joint infection (1.0 versus 1.8%, P < 0.01). In THA patients, PPI prescription was associated with a lower all-cause revision rate (2.8 versus 4.0%, P = 0.02). No significant differences were found between PPI and non-PPI groups for aseptic loosening, periprosthetic fracture, gastrointestinal bleeding, or surgical site infection in either cohort. CONCLUSIONS: Patients receiving routine PPI prescriptions in the perioperative period surrounding TKA and THA have a lower risk of all-cause revision surgery, and perioperative PPI use is associated with a decreased risk of PJI in patients undergoing TKA. As these results conflict with the few previous studies performed on this topic, additional controlled studies are warranted to fully elucidate the relationship between PPI use and adverse events after THA and TKA.

Establishing a Graft-Versus-Host Disease (GVHD)-Focused Multidisciplinary Telehealth Clinic.

Graft-versus-host disease (GVHD) is a complication following allogeneic hematopoietic cell transplant that frequently causes multiorgan affection and decrease in quality of life. Global assessment and care of these patients require a multidisciplinary approach, but access to focused clinics is limited given their scarcity and location in major cities, as well as mobility and transportation challenges that frequently affect these patients. Thus, we established a multispecialty GVHD telehealth (TH) clinic and hypothesized that a virtual platform will expand access to clinical care in children and adults. The clinic team members included BMT specialist, nursing, dermatologist, dentist, nutritionist, physiatrist, research personnel, and others as needed. We evaluated all GVHD-related visits (in-person and TH) conducted in a single center from 01/2022 to 12/2022. Ninety-three patients received a total of 308 visits, and one-third were via TH. Approximately half of the in-person group had at least 1 TH visit, and 10 patients were seen exclusively via TH. Most patients had advanced chronic GVHD. More male patients were seen in GVHD clinic, but female patients had increased in clinic visits via TH (41% TH versus 32% in-person). One-third of clinic visits were from patients of racial and ethnic minorities. While only 6% (n = 12/217) of in-person visits were for patients living >100 miles from the center, 34% (n = 31/91) of TH visits were from far distances including out-of-state. At baseline, the most common patient-reported symptoms in a subset of patients included fatigue, disturbed sleep, and distress. Fifteen patients completed a follow-up symptom survey and reported significantly reduced distress regarding their GVHD (P = .02), although other symptoms remained stable. A multidisciplinary TH clinic provided care for adult and pediatric patients with GVHD. We demonstrated preliminary feasibility of building a robust TH platform with a collaborative multispecialty approach that allowed access and continuity of medical care. Gender inequalities were reduced, and distance to our center represented a lesser barrier to attending specialized care via TH. Additionally, patients reported a significant reduction in distress. Our findings support the ongoing development of a virtual platform to improve access to specialized GVHD care.

Quantifying Efficacy of Video Interventions about Adverse Events in Medical Student Education.

OBJECTIVES: The coronavirus disease 2019 pandemic catalyzed a rapid shift toward remote learning in medicine. This study hypothesized that using videos on adverse events and patient safety event reporting systems could enhance education and motivation among healthcare professionals, leading to improved performance on quizzes compared with those exposed to standard, in-person lectures. METHODS: Participants were randomly assigned to a group both watching the video and attending an in-person lecture or a group that received only the in-person lecture in this study performed in 2022. Surveys gathered demographic information, tested knowledge, and identified barriers to reporting adverse events. RESULTS: A total of 83 unique participants responded to the survey out of the 130 students enrolled (64%; 83/130). Among the students completing all of the surveys, the group who watched the Osmosis video had a higher average quiz score (6.46/7) than the lecture group (6.31/7) following the first intervention. Only 25% of respondents agreed or strongly agreed that they knew what to include in a patient safety report and only 10% agreed or strongly agreed that they knew how to access the reporting system. CONCLUSIONS: This study suggests virtual preclass video learning can be a beneficial tool to complement traditional lecture-based learning in medical education. Further research is needed to determine the efficacy of long-term video interventions in adverse events.

An AUA Workforce Report: Data From the AUA Census Regarding Workplace Experiences Based on Gender.

INTRODUCTION: The AUA Workforce Workgroup contributes workforce-related questions to the annual AUA Census to better understand factors impacting the urologic community. This study aims to highlight pertinent gender differences potentially impacting career satisfaction and identify areas in which intervention could improve gender discrepancies. We hypothesize significant differences between males and females exist regarding responses to gender-related AUA Census questions. METHODS: The 2016 to 2021 AUA Censuses were examined to collate gender-specific data between self-identified male and female urologists. Up until 2021, the words male and female were used to define gender. The language was changed in the 2022 Census. Answers to AUA Census questions on topics with potential gender differences were grouped into major categories of workplace treatment and job satisfaction. RESULTS: Females were more likely than males to report negative differential treatment in primary practices (66.3% vs 2.7%, P < .001), felt they had limitations in seeing certain patients due to their gender (25.9% vs 2.4%, P = .021), experience gender bias in their practice (39.3% vs 1.2%, P < .001), and experience conflict regarding work and personal responsibility (95.4% vs 75%, P < .001). Females felt more barriers to professional success (93% vs 75%, P < .001) and felt a lack of control over staffing decisions or scheduling to be the greatest barriers (46.2%, P < .001). In contrast, males felt lack of time (33.7%, P = .060) to be the most significant barrier. Females were less likely than males to report feeling satisfied or very satisfied with their work-life balance (39.9% vs 57.7%, P < .001) and more likely to feel they do not have enough time for personal/family life (57.7% vs 33.6, P < .001). Females were also more likely than males to feel burnout (49.2% vs 35.3%, P < .001), which increased notably between 2016 and 2021. Females were also more likely to carry substantial education debt (18% vs 9%) and feel this contributed to burnout (38% vs 21.6%, P < .001). Notably, males and females demonstrated little difference in average worked hours (h) per week (mean 45.7 h for males, 43.7 h for females) and choosing medicine again as a career (88% males, 83.3% females; P= .143) and urology again as a specialty (93.3% males, 90.8% females; P = .307). CONCLUSIONS: Significant differences exist in career perceptions based on gender. Females report unique challenges in the workplace, and these factors contribute to less job satisfaction. Future work is needed to help characterize and address these differential workplace experiences.

Large-pore connexin hemichannels function like molecule transporters independent of ion conduction.

Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.