Long-term Outcomes of Complete Tears of the Distal Biceps Tendon: An Analysis of Surgical Management at a Median Follow-up of 14.7 Years.

Background: Surgical repair of full thickness biceps tears has demonstrated adequate outcomes in short and mid-term studies. However, data on the long-term outcomes of full thickness distal biceps injuries and their treatment are currently lacking. Purpose/Hypothesis: The purpose of this study was to report on patient demographics, injury characteristics, and long-term outcomes for patients with full-thickness distal biceps tears. It was hypothesized that complete distal biceps tears managed operatively would demonstrate robust clinical success at long-term follow-up. Study Design: Case series; Level of evidence, 4. Methods: Patients with magnetic resonance imaging-confirmed, complete distal biceps tendon rupture sustained between 1996 and 2016 were identified. Patients were cross-referenced with a regional geographic database. Results: A total of 66 patients (3 female, 63 male) with a median age of 50.8 years (IQR, 41.5-60.4) and a median clinical follow-up of 14.7 years (IQR, 9.6-17.9 years) were included. Patients who sustained a full-thickness distal biceps tendon tear were likely to be in their early 50s, male, right-hand dominant, current/former smokers, and laborers with a history of traumatic injury during an intentional movement. Most of these patients had pain and supination weakness but no loss of range of motion. All included tears were treated operatively. At final follow-up, patients maintained a majority of near-normal range of motion (median total arc of flexion/extension 140° and supination/pronation 80°), excellent elbow flexion strength (91% of patients had full strength), and adequate elbow supination strength (76% of patients had full strength). The overall complication rate was 24%, with 16 out of 66 patients experiencing some type of complication between infection, rerupture, heterotopic ossification, reoperation, and nerve complications. Overall return to work was 98%, and 85% of those who returned to work did so without restrictions. Conclusion: Complete tears of the distal biceps were most common in patients 50 years of age, male sex, right-hand dominant, and current/former smokers. The most common profession was laborer, and injuries were primarily traumatic in nature during intentional activity. Patients managed operatively demonstrated high rates of success at long-term follow-up with respect to elbow function and clinical outcomes.

Postoperative Feeding in Cleft Surgery: A Systematic Review.

INTRODUCTION: Postoperative feeding is crucial for the recovery of children after cleft surgery. The literature outlines diverse feeding methods with varying recommendations on the duration of non-nipple feeding postsurgery. This study aims to explore reported postoperative feeding modalities for infants undergoing primary cleft lip/palate repair, concentrating on their influence on feeding improvement and complication reduction. METHODS: PubMed, Cochrane, and Web of Science databases were queried for original English articles without any date restrictions. This review was conducted in accordance with the 2020 PRISMA. The MINORS criteria was used to assess quality of studies. RESULTS: Of 696 abstracts, 9 full-text articles were included, consisting of 459 children with cleft lip (n = 221) & cleft lip/palate (n = 238). Feeding modalities included bottle, breastfeeding, spoon, syringe, and nasogastric tube. Two studies found a significant increase in weight with breastfeeding compared to spoon or cup. Two studies found partial wound dehiscence using spoons, and two studies reported dehiscence using bottles. Post-palatoplasty, two studies showed a decrease in hospital stay in infants breastfed (2.1 & 5.8 days) vs spoon-fed (6 days). Analgesia was reduced in the breastfed group vs spoon/nasogastric tube. CONCLUSION: This review highlights the importance of postoperative feeding in the recovery of infants with cleft lip/palate. Evidence suggests that breastfeeding may offer advantages in terms of weight gain and reduced hospital stay, while potentially minimizing the need for postoperative analgesia. The limited number of studies and variability in their outcomes underscore the need for further research to establish evidence-based guidelines for postoperative feeding.

Understanding the Scope of Acute Care Vascular Surgery at a Tertiary Academic Medical System.

BACKGROUND: The restructuring of nonelective general surgery and nationwide implementation of the acute care surgery paradigm has improved patient outcomes and healthcare resource utilization. Although vascular surgery maintains one of the highest acuity rates among surgical specialties, the acute care vascular surgery (ACVS) practice model has not been widely accepted. In the present study, we investigate the scope and burden of ACVS at a tertiary academic medical system. METHODS: All vascular surgical procedures performed at three hospitals comprising a large tertiary academic medical system were retrospectively queried through electronic medical records. Data were collected on procedure, acuity, timing of intervention, primary service, admission type, and total costs and charges. Patients were stratified by acuity of surgical intervention, with ACVS being defined as urgent or emergent operation. RESULTS: A total of 12,689 vascular surgeries were performed from 2018 to 2022. ACVS procedures comprised 22.1% of this total (n = 2,803; 12.5% urgent, 9.6% emergent), with an annual burden ranging from 19.1% to 28.3%. Vascular surgeons served as primary surgeon in 91.3% of ACVS and cosurgeon in 8.7%. Fourteen separate surgical specialties requested acute vascular assistance, with the most frequently consulting specialties, including trauma or acute care surgery (ACS) (n = 109, 3.9%) and cardiac surgery (n = 74, 2.6%). ACVS cases were more frequently performed during after-hours (30.7% vs 11.6%) and on weekends (27.1% vs 2.0%) compared with elective vascular procedures (P < 0.0001 each). The majority of ACVS cases originated from inpatient (n = 2,353, 85.0%) and emergency department (n = 379, 13.5%) consultations. Overall, ACVS generated $37.5 million in charges, accounting for 14% of total procedure-related charges over the study period. CONCLUSIONS: ACVS comprises a substantial portion of modern vascular practice and is associated with significant human and healthcare resource expenditure. These data support the development of practice models dedicated to acute vascular surgical care.

Ultrasound Induces Similar Temporal Endothelial Expression Patterns of eNOS and KLF2 as Normal Flow.

OBJECTIVE: To determine the sensitivity of vascular endothelial cells to long durations of low-intensity pulsed ultrasound (LIPUS) compared to normal flow and identify the duration that maximizes expression of two mechanosensitive genes related to healthy endothelial function, endothelial nitric oxide synthase (eNOS) and Krüppel-like factor 2 (KLF2). METHODS: Custom ultrasound exposure tanks were developed and the acoustic field was characterized. Human umbilical vein endothelial cells were seeded into culture plates and exposed to LIPUS at a frequency of 1 MHz and acoustic pressure of 217 kPa for 20 min, 1 h, 6 h, 9 h, or 24 h. As a comparator, other cells were exposed to normal flow. RT-qPCR was used to assess mRNA expression of eNOS and KLF2. RESULTS: Maximum eNOS and KLF2 expression occurred at 6 h and was localized to the beam path. Both genes exhibited qualitatively similar patterns of expression under LIPUS compared to normal flow. LIPUS induced a more rapid beneficial response compared to normal flow, but flow induced higher expression of both genes. eNOS expression after 6 h of LIPUS was dependent on RNA yield and culture duration prior to experiments. CONCLUSION: Endothelial cells exposed to longer durations of LIPUS than typically employed exhibited greater expression of beneficial genes. The temporal gene expression patterns resulting from LIPUS and normal flow suggest activation of similar signaling pathways. However, LIPUS also caused increased RNA yield that may be linked to proliferation, which would suggest more of a wound healing than atheroprotective phenotype.

Acinetobacter baumannii transformants expressing oxacillinases and metallo-ß-lactamases that confer resistance to meropenem: new tools for anti-Acinetobacter drug development and AMR preparedness.

Antimicrobial resistance (AMR) in Acinetobacter baumannii is an unmet medical need. Multiple drug-resistant/extremely drug-resistant strains of A. baumannii do not display growth well in in vivo models, and consequently, their response to antibacterial therapy is inconsistent. We addressed this issue by engineering carbapenem resistance motifs into the highly virulent genetic background of A. baumannii AB5075. This strain has a chromosomally encoded oxa-23 that was deleted (Δoxa-23), then plasmids expressing oxa-23, oxa-24/40, oxa-58, imp-1, vim-2, and ndm-1 were introduced to create the mutant strains. Each transformant was used as a challenge strain in a neutropenic murine thigh infection model and assessed for the extent of growth and response to meropenem 200 mg/kg subcutaneously every 6 h (q6h). Pharmacodynamic analyses were performed by transforming drug exposure from dose (mg/kg) to the fraction of the dosing interval; free meropenem concentrations were >minimum inhibitory concentration (MIC) (fT > MIC). AB5075 and the AB5075Δoxa-23 mutant had a MICs of 32 and 4 mg/L, respectively. The transformants harboring oxacillinases oxa-24/40 and oxa-58 had an MIC of 64 mg/L. The metallo-ß-lactamases imp-1, vim-2, and ndm-1 had MICs of 128, 64, and 64 mg/L, respectively. All vehicle-treated transformants displayed in vivo growth in the range of 0.75-1.4 log. The response to meropenem was consistent with the varying fT > MIC of the transformants and was readily described by an inhibitory sigmoid Emax relationship. Stasis was achieved with a fT > MIC of 0.36. These A. baumannii transformants are invaluable new tools for the assessment of anti-Acinetobacter compounds and provide a new pathway for AMR preparedness.

Impact of Wound Closure Technique on Surgical Site Infection After Lower Extremity Bypass Surgery.

BACKGROUND: Surgical site infections (SSIs) are among the most common complications after lower extremity bypass (LEB). Both patient and hospital-related factors have been associated with SSI after LEB; however, the impact of surgical closure technique on SSI incidence remains unclear. METHODS: Institutional electronic medical records (EMRs) were retrospectively queried for all LEB procedures performed from 2018 to 2022. Data were collected on patient demographics, medical comorbidities, operative details, wound closure techniques, and postoperative outcomes. Closure techniques included skin staples, absorbable monofilament (Monocryl), nonabsorbable monofilament (Nylon), or left open to heal by secondary intention. Logistic regression analysis was utilized to identify risk factors and calculate adjusted odds ratios (ORs) for postoperative SSI. RESULTS: A total of 517 patients underwent LEB surgery over the study period. SSI was diagnosed in 120 (23.2%) patients over a median follow-up period of 1.5 years. The most common SSI locations were groin incision (40.0%), saphenectomy (31.7%), and leg incision (19.2%). The median onset of SSI was 18.5 d (interquartile range [IQR] 11-28 d) post-LEB surgery. Patients with SSI had higher body mass index (BMI) (28.2 [IQR 24.2-33.5] vs. 26.6 [23.1-31.5] kg/m2, P = 0.03) compared with non-SSI patients. Patient age, sex, and medical comorbidities were otherwise similar between groups. There were no differences in closure technique (79.2% vs. 78.1% staples, 18.3% vs. 19.7% Monocryl, 0.8% vs. 1.8% Nylon, 1.7% vs. 0.5% open; P = 0.53) in SSI versus non-SSI groups. On multivariate analysis, patient BMI (OR 1.04 per unit, 95% confidence interval [CI] 1.01-1.08, P = 0.02), reoperative field (OR 1.81, 95% CI 1.00-3.25, P = 0.03), and active smoking (OR 2.72, 95% CI 1.12-6.59, P = 0.048) were independently associated with increased SSI incidence. Postoperative SSI resulted in prolonged hospital length of stay (LOS) (7 vs. 6 days, P = 0.04), unplanned hospital readmission (49.2% vs. 12.3%, P < 0.001), and reoperation rates (64.7% vs. 8.1%, P < 0.001). Bypass graft infection rates were also higher among patients suffering postoperative SSI (9.2% vs. 0.0%, P < 0.001). On subset analysis of patients at increased risk of postoperative SSI, as found on multivariate modeling, there were no differences in closure technique between SSI and no SSI groups. CONCLUSIONS: This study provides insights on wound closure techniques and postoperative SSI made available through granular, operative data that are not found in large database analyses. Surgical wound closure technique was not associated with postoperative SSI after LEB surgery, even among patients at increased risk of infection. These data support individualization of wound closure techniques among patients undergoing LEB surgery.

Producing recombinant proteins in Vibrio natriegens.

The diversity of chemical and structural attributes of proteins makes it inherently difficult to produce a wide range of proteins in a single recombinant protein production system. The nature of the target proteins themselves, along with cost, ease of use, and speed, are typically cited as major factors to consider in production. Despite a wide variety of alternative expression systems, most recombinant proteins for research and therapeutics are produced in a limited number of systems: Escherichia coli, yeast, insect cells, and the mammalian cell lines HEK293 and CHO. Recent interest in Vibrio natriegens as a new bacterial recombinant protein expression host is due in part to its short doubling time of ≤ 10 min but also stems from the promise of compatibility with techniques and genetic systems developed for E. coli. We successfully incorporated V. natriegens as an additional bacterial expression system for recombinant protein production and report improvements to published protocols as well as new protocols that expand the versatility of the system. While not all proteins benefit from production in V. natriegens, we successfully produced several proteins that were difficult or impossible to produce in E. coli. We also show that in some cases, the increased yield is due to higher levels of properly folded protein. Additionally, we were able to adapt our enhanced isotope incorporation methods for use with V. natriegens. Taken together, these observations and improvements allowed production of proteins for structural biology, biochemistry, assay development, and structure-based drug design in V. natriegens that were impossible and/or unaffordable to produce in E. coli.

Practice patterns in utilization of atherectomy and embolic protection devices in inpatient and outpatient treatment settings.

OBJECTIVE: The frequency of atherectomy in lower extremity arterial disease has increased substantially over the past several years, specifically in the office-based laboratory (OBL) setting, yet the efficacy compared with other interventions and the consequences of distal embolization remain unknown. Embolic protection devices (EPDs) have been used at varying rates depending on physician and practice setting. Previous studies have described lesion characteristics to consider when weighing the benefits and drawbacks associated with device use. Our study focuses on the use of atherectomy and EPDs in femoropopliteal arterial disease to better characterize resource use trends and postoperative outcomes in the inpatient and OBL interventional settings. METHODS: We conducted a retrospective analysis on endovascular interventions performed for femoral-popliteal occlusive disease that were entered into the Vascular Quality Initiative data registry between 2017 and 2021. A one:one greedy match, adjusted analysis based on inpatient or OBL location of procedure was used to compare the groups. Hierarchical logistical regression with selective use of principal component analysis was used to further explore the differences in EPD use and immediate postoperative outcomes. A proportional hazard model was used to demonstrate differences in reintervention rates up to 2 years postoperatively between patients who underwent atherectomy in the inpatient vs OBL treatment setting. RESULTS: 2849 matched pairs were inlcuded in the final analysis. In our cohort, there was 22% EPD use overall, 40% in the hospital setting and 4.4% in the OBL setting (P < .001). Among the patients with available follow-up information, OBL intervention setting increased probability of reintervention by 18% at 2 years postoperatively compared with the inpatient setting; however, there was no difference associated with EPD placement and rate of reintervention. CONCLUSIONS: Use of EPDs in the OBL setting compared with the hospital setting is dramatically decreased; however, no increased incidence of postoperative complications was seen compared to procedures performed in the hospital setting when controlling for patient and lesion characteristics. Patients with available follow-up data were more likely to undergo ipsilateral reintervention between 6 months and 2 years postoperatively if atherectomy was done in the OBL setting. Dedicated studies are encouraged to ensure patient safety, effective resource allocation, and long-term efficacy of OBL atherectomy as an ever-growing number of peripheral arterial procedures are transitioned to the OBL setting.

Gluteus Maximus Distal Myotendinous Junction Tear in a Pickleball Player: A Case Report.

ABSTRACT: A 72-year-old male presented for evaluation of a 2-wk history left buttock pain that began while playing pickleball. He sustained a left inversion ankle sprain while in a squatted position and landed on his left buttock. Four days after his injury, he developed extensive bruising involving his lower back, buttock, and left thigh. On examination, he had tenderness to palpation at the left side of the sacrum and in the region of the deep external rotators. Left hip range of motion was full in extension but limited to 90° of flexion, which reproduced left-sided buttock pain. External rotation provoked pain, but internal rotation was full and pain free. MRI of the pelvis demonstrated a grade 2 partial thickness tear of the left gluteus maximus muscle at its distal myotendinous junction with associated retraction and intramuscular hematoma. He was managed with compression with biking shorts, icing, acetaminophen, and physical therapy. He returned to pickleball approximately 4 wk after his injury, and at his 4-wk follow-up, he reported 99% improvement in his symptoms with the only remaining complaint being minimal discomfort with gluteal stretching.

Machine Learning of Cardiac Anatomy and the Risk of New-Onset Atrial Fibrillation After TAVR.

BACKGROUND: New-onset atrial fibrillation (NOAF) occurs in 5% to 15% of patients who undergo transfemoral transcatheter aortic valve replacement (TAVR). Cardiac imaging has been underutilized to predict NOAF following TAVR. OBJECTIVES: The objective of this analysis was to compare and assess standard, manual echocardiographic and cardiac computed tomography (cCT) measurements as well as machine learning-derived cCT measurements of left atrial volume index and epicardial adipose tissue as risk factors for NOAF following TAVR. METHODS: The study included 1,385 patients undergoing elective, transfemoral TAVR for severe, symptomatic aortic stenosis. Each patient had standard and machine learning-derived measurements of left atrial volume and epicardial adipose tissue from cardiac computed tomography. The outcome of interest was NOAF within 30 days following TAVR. We used a 2-step statistical model including random forest for variable importance ranking, followed by multivariable logistic regression for predictors of highest importance. Model discrimination was assessed by using the C-statistic to compare the performance of the models with and without imaging. RESULTS: Forty-seven (5.0%) of 935 patients without pre-existing atrial fibrillation (AF) experienced NOAF. Patients with pre-existing AF had the largest left atrial volume index at 76.3 ± 28.6 cm3/m2 followed by NOAF at 68.1 ± 26.6 cm3/m2 and then no AF at 57.0 ± 21.7 cm3/m2 (P < 0.001). Multivariable regression identified the following risk factors in association with NOAF: left atrial volume index ≥76 cm2 (OR: 2.538 [95% CI: 1.165-5.531]; P = 0.0191), body mass index <22 kg/m2 (OR: 4.064 [95% CI: 1.500-11.008]; P = 0.0058), EATv (OR: 1.007 [95% CI: 1.000-1.014]; P = 0.043), aortic annulus area ≥659 mm2 (OR: 6.621 [95% CI: 1.849-23.708]; P = 0.004), and sinotubular junction diameter ≥35 mm (OR: 3.891 [95% CI: 1.040-14.552]; P = 0.0435). The C-statistic of the model was 0.737, compared with 0.646 in a model that excluded imaging variables. CONCLUSIONS: Underlying cardiac structural differences derived from cardiac imaging may be useful in predicting NOAF following transfemoral TAVR, independent of other clinical risk factors.

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes.

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5'-cytosine-phosphate-guanine-3' loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10-14. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.

A novel approach to saline/contrast delivery in excimer laser coronary atherectomy (ELCA) to enhance efficacy: MAXCon ELCA technique.

The advent of excimer laser coronary atherectomy (ELCA) nearly four decades ago heralded a novel way to treat complex lesions, both coronary and peripheral, which were previously untraversable and thus untreatable. These complex lesions include heavily calcified lesions, ostial lesions, bifurcation lesions, chronic total occlusions, in-stent restenosis (including stent underexpansion), and degenerative saphenous vein grafts. We discuss the technology of ELCA, its indications, applications, and complications, and suggest the "MAXCon ELCA" technique for better outcomes without increased risk. Lastly, we present a case of MAXCon ELCA effectively treating a complex lesion.

Radiographic and Advanced Imaging Evaluation of Posterior Shoulder Instability.

PURPOSE OF REVIEW: Posterior shoulder instability is an uncommon but important cause of shoulder dysfunction and pain which may occur as the result of seizure, high energy trauma, or repetitive stress related to occupational or sport-specific activities. This current review details the imaging approach to the patient with posterior shoulder instability and describes commonly associated soft tissue and bony pathologies identified by radiographs, CT, and MR imaging. RECENT FINDINGS: Advances in MR imaging technology and techniques allow for more accurate evaluation of bone and soft tissue pathology associated with posterior shoulder instability while sparing patients exposure to radiation. Imaging can contribute significantly to the clinical management of patients with posterior shoulder instability by demonstrating the extent of associated injuries and identifying predisposing anatomic conditions. Radiologic evaluation should be guided by clinical history and physical examination, beginning with radiographs followed by CT and/or MRI for assessment of osseous and soft tissue pathology. Synthesis of a patient's clinical history, physical exam findings, and radiologic examinations should guide clinical management.

Unexpected tobacco etch virus (TEV) protease cleavage of recombinant human proteins.

The tobacco etch virus (TEV) protease is a commonly used reagent for removal of solubility and purification tags from recombinant proteins and is cited as being highly specific for its canonical cleavage site. Flexibility in some amino acids within this recognition sequence has been described in the literature but researchers generally assume few native human proteins will carry off-target sequences for TEV cleavage. We report here the aberrant cleavage of three human proteins with non-canonical TEV protease cleavage sites and identify broader sequence specificity rules that can be used to predict unwanted cleavage of recombinant proteins. Using these rules, 456 human proteins were identified that could be substrates for unwanted TEV protease cleavage.

Is There Utility in Preoperative Testing of Hemoglobin Before Primary Cheiloplasty?

OBJECTIVE: To examine whether a preoperative hemoglobin of less than 10 g/dL is associated with a higher rate of perioperative complications. DESIGN: Retrospective review. SETTING: Tertiary academic hospital at Arkansas Children's Hospital of Little Rock, Arkansas. PATIENTS: A retrospective chart review evaluated patients undergoing primary cleft lip surgery from 2012 to 2017. INTERVENTIONS: No prospective intervention was performed for this study care. MAIN OUTCOME MEASURES: Age, sex, medical history, weight, and perioperative complications. Hemoglobin level was collected in the preoperative area. The primary outcome was rate of perioperative complications including infection, dehiscence, return to the operating room, unplanned admission, and emergency department visit within two weeks postoperatively. RESULTS: 105 patients undergoing primary cheiloplasty met inclusion criteria. Hemoglobin levels were obtained on all patients. 93.3% (n = 98) of patients had a hemoglobin of >10 g/dL before surgery, and 6.6% (n = 7) had levels <10 g/dL. 1 of 7 patients with a hemoglobin of <10 g/dL experienced a postoperative complication (Tet spell) and one patient with a hemoglobin of >10 g/dL experienced a postoperative complication (unplanned intensive care admission for respiratory distress). CONCLUSIONS: Post-operative complications are rare after primary cheiloplasty in patients with low or normal hemoglobin levels. The results of this study show that a preoperative hemoglobin of <10 g/dL does not predict perioperative complications in patients undergoing primary cheiloplasty.

Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.

Molecular pharmacodynamics of meropenem for nosocomial pneumonia caused by Pseudomonas aeruginosa.

Hospital-acquired pneumonia (HAP) is a leading cause of morbidity and mortality, commonly caused by Pseudomonas aeruginosa. Meropenem is a commonly used therapeutic agent, although emergent resistance occurs during treatment. We used a rabbit HAP infection model to assess the bacterial kill and resistance pharmacodynamics of meropenem. Meropenem 5 mg/kg administered subcutaneously (s.c.) q8h (±amikacin 3.33-5 mg/kg q8h administered intravenously[i.v.]) or meropenem 30 mg/kg s.c. q8h regimens were assessed in a rabbit lung infection model infected with P. aeruginosa, with bacterial quantification and phenotypic/genotypic characterization of emergent resistant isolates. The pharmacokinetic/pharmacodynamic output was fitted to a mathematical model, and human-like regimens were simulated to predict outcomes in a clinical context. Increasing meropenem monotherapy demonstrated a dose-response effect to bacterial kill and an inverted U relationship with emergent resistance. The addition of amikacin to meropenem suppressed the emergence of resistance. A network of porin loss, efflux upregulation, and increased expression of AmpC was identified as the mechanism of this emergent resistance. A bridging simulation using human pharmacokinetics identified meropenem 2 g i.v. q8h as the licensed clinical regimen most likely to suppress resistance. We demonstrate an innovative experimental platform to phenotypically and genotypically characterize bacterial emergent resistance pharmacodynamics in HAP. For meropenem, we have demonstrated the risk of resistance emergence during therapy and identified two mitigating strategies: (i) regimen intensification and (ii) use of combination therapy. This platform will allow pre-clinical assessment of emergent resistance risk during treatment of HAP for other antimicrobials, to allow construction of clinical regimens that mitigate this risk.IMPORTANCEThe emergence of antimicrobial resistance (AMR) during antimicrobial treatment for hospital-acquired pneumonia (HAP) is a well-documented problem (particularly in pneumonia caused by Pseudomonas aeruginosa) that contributes to the wider global antimicrobial resistance crisis. During drug development, regimens are typically determined by their sufficiency to achieve bactericidal effect. Prevention of the emergence of resistance pharmacodynamics is usually not characterized or used to determine the regimen. The innovative experimental platform described here allows characterization of the emergence of AMR during the treatment of HAP and the development of strategies to mitigate this. We have demonstrated this specifically for meropenem-a broad-spectrum antibiotic commonly used to treat HAP. We have characterized the antimicrobial resistance pharmacodynamics of meropenem when used to treat HAP, caused by initially meropenem-susceptible P. aeruginosa, phenotypically and genotypically. We have also shown that intensifying the regimen and using combination therapy are both strategies that can both treat HAP and suppress the emergence of resistance.

Retrospective evaluation of MRI findings in arthroscopically confirmed cases of hypermobile lateral meniscus.

OBJECTIVE: To identify preoperative MRI findings in patients with arthroscopically confirmed hypermobile lateral meniscus utilizing a standard MRI knee protocol, with comparison to normal control and lateral meniscal tear groups. SUBJECTS AND METHODS: All patients with arthroscopically confirmed hypermobile lateral meniscus diagnosed at our institution were retrospectively identified. The following structures were evaluated on preoperative knee MRIs: superior and inferior popliteomeniscal fascicles, lateral meniscus and meniscocapsular junction, popliteal hiatus, and soft tissue edema around the popliteal hiatus. The same MRI features were evaluated in the normal control and lateral meniscal tear groups. RESULTS: Study, normal control, and lateral meniscal tear patients (18 each) were included. In the study group, 94.4% had superior popliteomeniscal fascicle abnormality, 89.0% had inferior popliteomeniscal fascicle abnormality, and 72.2% had lateral meniscal abnormality. Incidence of these abnormalities was significantly higher than in the normal control group. Meniscal abnormalities in the study group all involved the posterior horn meniscocapsular junction, 12/13 of which had vertical signal abnormality at the junction and 1/13 with anterior subluxation of the entire posterior horn. Popliteus hiatus measurements were largest in the lateral meniscal tear group. CONCLUSION: In patients with hypermobile lateral meniscus, the combination of popliteomeniscal fascicle abnormality and vertical signal abnormality at the meniscocapsular junction was seen in the majority of patients. Popliteomeniscal fascicle signal abnormality without identifiable lateral meniscal injury was the next most common imaging appearance. Radiologists may provide valuable information by suggesting the diagnosis of hypermobile lateral meniscus in such cases.

Treatment of calcific arterial disease via enhancement of autophagy using GSK343.

Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp-/-) and small (Abcc6-/-) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.