Systematic multi-trait AAV capsid engineering for efficient gene delivery.

Broadening gene therapy applications requires manufacturable vectors that efficiently transduce target cells in humans and preclinical models. Conventional selections of adeno-associated virus (AAV) capsid libraries are inefficient at searching the vast sequence space for the small fraction of vectors possessing multiple traits essential for clinical translation. Here, we present Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait AAV capsids. By leveraging a capsid library that uniformly samples the manufacturable sequence space, reproducible screening data are generated to train accurate sequence-to-function models. Combining six models, we designed a multi-trait (liver-targeted, manufacturable) capsid library and validated 88% of library variants on all six predetermined criteria. Furthermore, the models, trained only on mouse in vivo and human in vitro Fit4Function data, accurately predicted AAV capsid variant biodistribution in macaque. Top candidates exhibited production yields comparable to AAV9, efficient murine liver transduction, up to 1000-fold greater human hepatocyte transduction, and increased enrichment relative to AAV9 in a screen for liver transduction in macaques. The Fit4Function strategy ultimately makes it possible to predict cross-species traits of peptide-modified AAV capsids and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits.

Outcomes of cobalt-chrome 3D-printed total talus replacement with and without combined total ankle replacement.

BACKGROUND: Collapse of the talus and peri-talar arthritis pose treatment challenges due to the anatomy and location of the talus as a keystone of the foot and ankle. Custom 3D-printed total talus replacement (TTR) and combined total ankle total talus replacement (TATTR) have emerged as treatment options for these pathologies. However, the safety and efficacy of these implants is unknown due to the limited number of cases and short follow-up durations. METHODS: This was a retrospective study to assess surgical outcomes of patients who underwent a TTR and TATTR with or without subtalar fusion. Patient demographics, intraoperative parameters, device related surgical and non-surgical events, imaging and clinical evaluations, and patient reported outcome (PRO) measures were compiled. RESULTS: A total of 38 patients received a custom 3D-printed implant with mean follow-up time of 22.1 (range: 12-45) months. In this cohort, 7 (18.4 %) required secondary surgery and 3 (7.9 %) required implant removal. Multivariate logistic regression revealed that patient diagnosis of depression was a significant predictor of secondary surgery with an OR 17.50 (p = 0.037). Significant postoperative improvements were observed in the talocalcaneal height (p = 0.005) and talar declination angle (p = 0.013) for the TATTR group. VAS and PROMIS pain interference (PI) scores demonstrated an initial significant improvement in pain, but this improvement did not maintain significance at most recent follow-up. However, there was a significant increase in the PROMIS physical function (PF) scores (p = 0.037) at most recent follow-up. CONCLUSION: These results demonstrate that TTR and TATTR provide significant improvement in post-operative radiographic foot and ankle alignment and physical function at the two-year timepoint. PRO findings suggest that patients are more active after surgery. Surgeons considering proceeding with either of these procedures should counsel patients about pain and functional outcomes as well as realistic expectations in patients with depression. LEVEL OF EVIDENCE: Level 3.

Academic Productivity at Orthopedic Spine Surgery Fellowships is Positively Correlated With Nonresearch Lifetime Industry Earnings: A Retrospective Study.

STUDY DESIGN: Retrospective Analysis. OBJECTIVE: The objective of the study was to assess the impact of academic productivity at both individual and program levels on lifetime industry earnings within US orthopedic spine fellowships. SUMMARY OF BACKGROUND DATA: Physician-industry transparency was codified by the Physician Payments Sunshine Act (PSSA) in 2010. No study has explored the relationship between academic productivity and industry earnings at the fellowship level. METHODS: Inclusion criteria encompassed physicians with complete academic and industry data from orthopedic spine fellowship programs listed on the North American Spine Society (NASS) 2022-2023 fellowship directory. Academic productivity was defined via H-index on the Scopus website, and industry productivity by total lifetime earnings on the Open Payments Database (OPD). RESULTS: This analysis included 75 orthopedic spine fellowship programs with 320 individual physicians. Median individual physician lifetime earnings were $86,852.71 (mean: $666,580.23 ± $1,887,734.64; minimum-maximum: $10.86-$27,164,431.49) and the median individual physician (n=320 physicians) H-index was 17.0 (mean: 21.82 ± 19.28; minimum-maximum: 0-109). Median combined physician H-index per fellowship (n=75 fellowships) was 65.0 (mean: 93.08 ± 85.67; minimum-maximum: 3-434) and median combined physician lifetime earnings was $927,771.60 (mean: $2,844,075.64 ± $4,942,089.56; minimum-maximum: $1,112.32-$29,983,900.69). A positive correlation was observed between academic productivity and industry productivity at an individual level (P<0.001; Spearman's rho = 0.467). This correlation was stronger at the fellowship level (P<0.001; Spearman's rho = 0.734). There was no significant difference in total lifetime earnings (P=0.369) or H-index per fellowship (P=0.232) when stratified by region of the fellowship program in the United States. CONCLUSION: Orthopedic spine surgery fellowship programs in the United States exhibit a positive correlation between academic productivity and nonresearch industry lifetime earnings at both individual and program levels. This correlation is stronger at the program level, and regional differences among fellowship programs do not significantly impact academic or industry productivity.

Interpositional Arthroplasty for Hallux Rigidus: Surgical Technique and Outcomes Discussion.

Interpositional arthroplasty for the treatment of hallux rigidus (HR) involves resection of the diseased joint surface and placement of spacer material within the joint to preserve length at the metatarsophalangeal joint while still allowing for range of motion. The majority of studies available in the literature have focused on capsular interpositional arthroplasty, revealing generally positive outcomes. Other forms of interpositional arthroplasty are less supported by long-term follow-up and large sample sizes. Moreover, there exists substantial heterogeneity in the studies evaluating interpositional arthroplasty. Despite the limitations of the current data, interpositional arthroplasty seems to be a viable treatment option for HR.

Surgical Management of Failed First Metatarsophalangeal Joint Arthroplasty.

This article describes the etiology, clinical presentation, surgical management, and outcomes for treatment of the failed first metatarsophalangeal (MTP) joint arthroplasty. Failure following implant arthroplasty typically creates large osseous deficits and surgical management can be difficult. Salvage arthrodesis provides reliable joint stability while maintaining hallux length. Outcomes following conversion of a failed MTP joint arthroplasty to MTP joint arthrodesis have demonstrated consistent pain relief and high satisfaction: however, high rates of complication and nonunion have been reported. Bone graft may be necessary to fill large voids in the joint. Other revision options for failed arthroplasty have been described, but outcomes remain inconsistent and varied. Ultimately, conversion to MTP joint arthrodesis is the recommended intervention for treatment of the failed MTP arthroplasty implant, providing sufficient stability and pain relief.

GC × GC-HRMS with complementary ionization methods in the suspect screening analysis of fragrance allergens: overwhelming or justified?

Modern gas chromatography-mass spectrometry (GC-MS) allows for the analysis of complex samples, such as fragrances. However, identifying all the constituents in natural fragrance mixtures, especially allergens that need to be listed on product labels, is a significant challenge. This is primarily due to the high complexity of the sample and the fact that electron ionization, the most commonly used ionization method in GC-MS, produces numerous nonspecific fragment ions, often resulting in the absence or very low abundance of the molecular ion. These factors affect confidence in assigning the analyte. In this study, we demonstrate that the combination of GC × GC separation, with high mass resolution and accurate mass measurements, as well as chemical ionization in addition to traditional electron ionization, becomes an efficient tool for reliable qualitative analysis of a mixture containing 100 fragrance allergens, even when many of them are closely related species or isomers. The proposed approach expands the applicability of the comprehensive GC × GC-HRMS method, which includes complementary ionization techniques, from studies on anthropogenic priority pollutants and emerging contaminants to the analysis of natural products. Although targeted qualitative and quantitative analysis of allergens in the modern laboratories is well organized, GC × GC-HRMS, being a useful complement to routine quality control of volatile allergens in fragrances, definitely gives an additional contribution to the analytical cases when conventional 1D-GC-MS faces some problems or uncertainties.

Racial Disparities in Outcomes After Foot and Ankle Surgery: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis delved into the impact of race and ethnicity on outcomes following foot and ankle surgery, an area garnering increasing attention within the medical community. Despite significant literature on postsurgical clinical and functional outcomes, limited research has explored the influence of racial and ethnic factors on postoperative outcomes. In this study, data from 33 relevant studies, involving a total of 557,734 patients, were analyzed to assess outcomes across different racial and ethnic groups. Notably, only 6 studies met the criteria for inclusion in the final meta-analysis due to variations in outcome reporting. Findings revealed disparities in functional scores, pain levels, and resource utilization among different racial and ethnic cohorts. Specifically, non-White and minority patients exhibited higher rates of foot and ankle fractures and lower extremity surgeries, worse functional outcomes, increased pain, longer hospital stays, and a greater incidence of complications compared to their White counterparts. However, some studies presented contradictory results, emphasizing the necessity for further investigation to elucidate these discrepancies fully. This research underscores the importance of considering racial and ethnic factors in foot and ankle surgery outcomes and highlights the need for targeted interventions to address existing disparities.

EThcD as a Unique Tool for the Top-Down De Novo Sequencing of Intact Natural Ranid Amphibian Peptides.

De novo sequencing of any novel peptide/protein is a difficult task. Full sequence coverage, isomeric amino acid residues, inter- and intramolecular S-S bonds, and numerous other post-translational modifications make the investigators employ various chemical modifications, providing a variety of specific fragmentation MSn patterns. The chemical processes are time-consuming, and their yields never reach 100%, while the subsequent purification often leads to the loss of minor components of the initial peptide mixture. Here, we present the advantages of the EThcD method that enables establishing the full sequence of natural intact peptides of ranid frogs in de novo top-down mode without any chemical modifications. The method provides complete sequence coverage, including the cyclic disulfide section, and reliable identification of isomeric leucine/isoleucine residues. The proposed approach demonstrated its efficiency in the analysis of peptidomes of ranid frogs from several populations of Rana arvalis, Rana temporaria, and Pelophylax esculentus complexes.

Direct anterior compared to posterior approach for hip hemiarthroplasty following femoral neck fractures.

The differences in complication rates between the direct anterior and posterior approaches for hemiarthroplasty in elderly patients with femoral neck fractures are not yet fully understood. Dislocation, a severe complication associated with increased mortality and often requiring additional surgery, may occur less frequently with the direct anterior approach compared to the posterior approach. Careful consideration of patient demographics is essential when planning the surgical approach. Future research in this area should focus on robust randomized controlled trials involving elderly patients recovering from femoral neck fractures.

Impact of pre-existing depression and food insecurity on the trajectory of depressive symptomatology during the COVID-19 pandemic outbreak in South Africa: A panel analysis of nationally representative South African data.

We investigated the trajectory of depressive symptoms ("depression") from the start of the COVID-19 pandemic in South Africa (March 2020) until 2021, between individuals with and without pre-pandemic depression, specifically regarding the role of food security. Our investigation used publicly available panel data (N = 6,930) from the South African National Income Dynamics Study Coronavirus Rapid Mobile Survey (SA-NIDS-CRAM from 2020-2021) on those who had also participated in the pre-pandemic South African National Income Dynamics Study (SA-NIDS, 2017) depression interview. We investigated trends in depressive symptomatology (based on a 2-item Patient Health Questionnaire) at SA-NIDS-CRAM Wave 2 (July 2020), Wave 3 (February 2021) and Wave 5 (May 2021). Generalized estimating equations (GEE) with post-estimation linear combinations of estimators were fitted to investigate the roles of pre-pandemic depression (based on 2017 SA-NIDS data) and food insecurity during the pandemic on depressive symptomatology. During the pandemic, the highest levels of depression were observed consistently among those with pre-pandemic depression and food insecurity; and were lowest among those without pre-pandemic depression and food security. Depressive symptomatology rose in nearly equal magnitude during the early phases of the pandemic in two groups: those without pre-pandemic depression but food insecure during the pandemic; as well as those with pre-pandemic depression but food secure during the pandemic. However, this dynamic changed later in the pandemic, when higher depressive symptomatology was observed in the group with both pre-pandemic depression and food insecurity, widening the gap between them from Wave 3 (adj ß = 0.63, p < 0.01) to Wave 5 (adj ß = 0.79, p < 0.01). Our results highlight the importance of addressing both population mental health and food insecurity, particularly at the early stages of a crisis/disaster. As we showed that mental health impact is linked to food insecurity during a pandemic, strengthening social protection measures, especially around food and nutrition, would help build resilience to crises in the long term.

Assessing extremely negative online patient reviews and complaints of musculoskeletal oncology surgeons in the United States: a retrospective analysis.

INTRODUCTION: Physician-review websites (PRWs) are commonly used by patients while searching for a surgeon. There is no current literature investigating the factors that contribute to online one-star reviews of musculoskeletal oncology surgeons. This retrospective study aims to identify these factors to determine areas of care affecting patient's subjective reviews. METHODS: Patient ratings and comments regarding musculoskeletal oncology surgeons from the Musculoskeletal Tumor Society (MSTS) were collected from Vitals.com. One-star reviews with comments were then classified as either operative or nonoperative. These complaints were then further classified based on content including wait time, uncontrolled pain, time spent with the physician, surgical outcomes, medical staff/institutional complaints, and bedside manner. RESULTS: A total of 169 reviews (375 complaints) from 181 physicians were included. Of these complaints, 198 were from patients in the operative category while 177 were from patients in the nonoperative category. Bedside manner was the most common complaint. Operative patients reported higher instances of uncontrolled pain in their reviews, whereas nonoperative patients more frequently cited wait time. No significant difference in the complaints that mentioned the amount of time spent with the physician, bedside manner, a disagreement with the plan, or the medical staff or institution was found. CONCLUSION: Online one-star reviews of musculoskeletal oncology surgeons on Vitals.com referenced both surgical and non-surgical aspects of patient encounters, with bedside manner being the most popular complaint overall. Surgical patients were more likely to complain of uncontrolled pain whereas non-operative patients were more likely to complain of wait time. TYPE OF STUDY: Outcomes 2c.

Twelve-Year Progression of Osteochondral Lesions of the Talus Observed Using Magnetic Resonance Imaging.

Osteochondral lesions of the talus are common injuries that are most often the result of trauma. The natural progression of osteochondral lesions is not well understood. It is still unclear which lesions eventually lead to joint degeneration and osteoarthritic changes and if the treatment method affects the progression. The existing literature surrounding this topic is sparse, with inconsistent findings. The presented images are taken from a 72-year-old man with bilateral osteochondral lesions of the talus. To our knowledge, this is the first published series of images illustrating the natural progression of a patient with bilateral osteochondral lesions of the talus over a 12-year time period.

Evaluation of the Efficacy of a Novel Dermatotomy Device for Central Venous Cannulation.

OBJECTIVE: To test the effectiveness of a novel wire-guided scalpel (Guideblade) to create a precise dermatotomy incision for central venous catheter (CVC) insertion. DESIGN: Prospective, nonrandomized interventional study. SETTING: Stanford University, single-center teaching hospital. PARTICIPANTS: Cardiac and vascular surgical patients (n = 100) with planned CVC insertion for operation. INTERVENTIONS: A wire-guided scalpel was used during CVC insertion. RESULTS: A total of 188 CVCs were performed successfully with a wire-guided scalpel without the need for additional equipment in 100 patients, and 94% of CVCs were accomplished with only a single dermatotomy attempt. "No bleeding" or "minimal bleeding" at the insertion site was observed in 90% of patients 30 minutes after insertion and 80.7% at the conclusion of surgery. CONCLUSION: The wire-guided scalpel was effective in performing dermatotomy for CVC with a 100% success rate and a very high first-attempt rate. The wire-guided scalpel may decrease bleeding at the CVC insertion site.

Ankle Osteoarthritis.

Ankle osteoarthritis (OA) is less common than knee and hip OA, and 75% to 80% of all presentations are posttraumatic in nature, resulting from either ligamentous or bony injury to the ankle. While the ankle joint cartilage demonstrates capacity for self-restoration, the ankle joint is sensitive to aberrancies in biomechanics and the inflammatory milieu after an injury is thought to contribute to the onset of posttraumatic ankle OA. Conservative care for ankle OA is currently centered on pain reduction, and derivatives that may delay the progression of ankle OA are the subject of ongoing investigation. Surgical management for end-stage ankle OA currently focuses on ankle arthrodesis and total ankle arthroplasty. Specific indication for one procedure over the other is the topic of much debate. While total ankle arthroplasty has become more frequently used with the advent of newer generation systems, ankle arthrodesis may still be favored in younger patients with high-demand occupations.

Polyvinyl Alcohol Hydrogel Hemiarthroplasty of First Metatarsophalangeal Joint Hallux Rigidus.

Background Hallux rigidus (HR) is the most common arthritic condition of the foot. Although first metatarsophalangeal joint (MTPJ) arthrodesis has been the historical gold-standard treatment, polyvinyl alcohol (PVA) hydrogel implants have gained popularity as a joint-sparing technique. However, recent studies have shown variable failure rates of PVA hydrogel implants. The purpose of this study was to report the five-year experience with PVA hydrogel implants performed by a single surgeon. Methodology Health records were queried from August 2016 to 2021 for patients who underwent primary PVA hydrogel implant hemiarthroplasty for symptomatic late-stage HR. Patient demographics and postoperative outcomes variables were evaluated. Kaplan-Meier analysis was used to evaluate implant survival. A total of 146 PVA hydrogel implant procedures were performed with a minimum six-month follow-up. Results The majority of patients were female (n = 103, 70.5%), with a mean age of 58.1 (±10.1) years, body mass index of 27.3 (±5.2) kg/m2, and American Society of Anesthesiologists score <3 (n = 131, 89.7%). The majority had stage II or III disease (n = 115, 78.8%). Patients experienced significant improvement in visual analog scale score (p < 0.0001) and hallux dorsiflexion (p = 0.0005). There were 22 (15.1%) complications, including implant subsidence (n = 15, 10.3%), deep infection (n = 6, 4.1%), and hypertrophic ossification (n = 1, 0.7%). Revision surgeries were required in 12.3% (n = 18) of patients at an average of 9.4 (±9.2) months postoperatively. This included nine (6.2%) revision PVA hydrogel implant procedures and nine (6.2%) first MTJP arthrodesis. The one- and two-year survival rates for MTPJ arthrodesis (n = 9) were 95.9% and 86.3%, respectively. Conclusions In the largest single-surgeon series reported, first MTPJ hemiarthroplasty with a PVA hydrogel implant significantly improved pain and hallux dorsiflexion at an average of 14.5 months postoperatively. There was a high two-year survivorship of 86.3% until failure which required first MTPJ arthrodesis. Future studies should be performed to refine the indications for PVA hydrogel implants and identify risk factors.

Mucolytic Drugs Ambroxol and Bromhexine: Transformation under Aqueous Chlorination Conditions.

Bromhexine and ambroxol are among the mucolytic drugs most widely used to treat acute and chronic respiratory diseases. Entering the municipal wastewater and undergoing transformations during disinfection with active chlorine, these compounds can produce nitrogen- and bromine-containing disinfection by-products (DBPs) that are dangerous for aquatic ecosystems. In the present study, primary and deep degradation products of ambroxol and bromhexine obtained in model aquatic chlorination experiments were studied via the combination of high-performance liquid and gas chromatography with high-resolution mass spectrometry. It was shown that at the initial stages, the reactions of cyclization, hydroxylation, chlorination, electrophilic ipso-substitution of bromine atoms with chlorine, and oxidative N-dealkylation occur. Along with known metabolites, a number of novel primary DBPs were tentatively identified based on their elemental compositions and tandem mass spectra. Deep degradation of bromhexine and ambroxol gives twenty-four identified volatile and semi-volatile compounds of six classes, among which trihalomethanes account for more than 50%. The specific class of bromhexine- and ambroxol-related DBPs are bromine-containing haloanilines. Seven of them, including methoxy derivatives, were first discovered in the present study. One more novel class of DBPs associated with bromhexine and ambroxol is represented by halogenated indazoles formed through dealkylation of the primary transformation products containing pyrazoline or tetrahydropyrimidine cycle in their structure.

Examining the Evidence Regarding Smoking and Patient Outcomes for Isolated Meniscus Pathology: A Comprehensive Systematic Review and Meta-Analysis.

Smoking is a well-known cause of impairment in wound healing and postoperative outcomes; however, its effects on treating meniscus issues remain unclear. This study assesses the relationship between smoking and meniscus treatment outcomes. PubMed, Scopus, Cochrane, and CINAHL were searched from inception to 24 December 2023. Inclusion criteria encompassed studies examining smoking's impact on patient outcomes regarding meniscus pathology. A secondary PubMed search targeted randomized controlled trials (RCTs) in the top ten orthopedic journals focusing on meniscus pathology and smoking as a demographic variable. Meta-analysis of six studies (n = 528) assessed meniscus failure rate based on smoking status. Eighteen observational studies (n = 8353 patients; 53.25% male; mean age: 51.35 ± 11.53 years; follow-up: 184.11 ± 117.34 months) were analyzed, covering meniscus repair, meniscectomy, allograft transplant, conservative care, and arthroscopy. Results showed four studies (36.36%) linked smoking with worse meniscus repair outcomes, while seven studies (63.64%) did not find significant associations. Meta-analysis from six studies showed no significant impact of smoking on repair failure (p = 0.118). Regarding meniscectomy, one study (33.33%) identified a significant association with smoking, but two did not. Only one (3.8%) of the RCTs in leading orthopedic journals included smoking as a factor. The evidence on smoking's effect on meniscus treatment is mixed, necessitating further investigation.

Mechanism of Injury for Traumatic Mid-Foot Lisfranc Injuries: Impact of the COVID-19 Pandemic.

Background During the COVID-19 pandemic, Americans transitioned away from their normal routines, drove in motor vehicles less, and reduced their physical activity, ultimately influencing the incidence and nature of orthopedic injuries that were operatively managed. The purpose of this study was to evaluate the effect of the COVID-19 pandemic lockdown and subsequent deconditioning on the mechanism of injury and severity of Lisfranc injury. Methods This retrospective study included patients with a traumatic Lisfranc injury who were surgically treated by a foot and ankle fellowship-trained orthopedic surgeon between 2015 and 2021. Electronic health records were queried for patient demographics, mechanism of injury, physical exam findings, and pain scores. Preoperative radiographs were reviewed to grade Lisfranc injuries using the previously described Nunley-Vertullo classification system. Descriptive and univariate statistics were performed to compare 15 patients in the pre-COVID-19 cohort and 15 patients in the post-COVID-19 cohort. Results In the pre-COVID-19 cohort, 80% (n=12/15) of the patients were female, the mean age was 46±15 years, the mean BMI was 29.7±7 kg/m2, and the mean follow-up period was 18.1±12 months. In the post-COVID-19 cohort, 53% (n=8/15) of the patients were female, the mean age was 48.5±17 years, the mean BMI was 31.4±7 kg/m2, and the mean follow-up period was 9.5±4 months. Significantly higher proportions of plantar ecchymosis (n=8/15, 53%), neuropathic pain (n=7/15, 47%), and swelling (n=12/15, 80%) were present in the post-COVID-19 cohort. A low-energy mechanism of injury was sustained by 73% (n=11/15) of the pre-COVID-19 cohort and 80% (n=12/15) of the post-COVID-19 cohort. Lisfranc injuries for the pre-COVID-19 cohort and the post-COVID-19 cohort demonstrated the following classifications: Grade 1 (33%, n=5/15 vs. 40%, n=6/15), Grade 2 (60%, n=9/15 vs. 53%, n=8/15), and Grade 3 (7%, n=1/15 vs. 7%, n=1/15). Conclusion Although a higher proportion of plantar ecchymosis, neuropathic pain, and swelling was observed, there was no association between a low mechanism of injury and a higher grade of Lisfranc injury following the COVID-19 pandemic.