Functional genomic screens with death rate analyses reveal mechanisms of drug action.

A common approach for understanding how drugs induce their therapeutic effects is to identify the genetic determinants of drug sensitivity. Because 'chemo-genetic profiles' are performed in a pooled format, inference of gene function is subject to several confounding influences related to variation in growth rates between clones. In this study, we developed Method for Evaluating Death Using a Simulation-assisted Approach (MEDUSA), which uses time-resolved measurements, along with model-driven constraints, to reveal the combination of growth and death rates that generated the observed drug response. MEDUSA is uniquely effective at identifying death regulatory genes. We apply MEDUSA to characterize DNA damage-induced lethality in the presence and absence of p53. Loss of p53 switches the mechanism of DNA damage-induced death from apoptosis to a non-apoptotic death that requires high respiration. These findings demonstrate the utility of MEDUSA both for determining the genetic dependencies of lethality and for revealing opportunities to potentiate chemo-efficacy in a cancer-specific manner.

Regulation and function of transposable elements in cancer genomes.

Over half of human genomic DNA is composed of repetitive sequences generated throughout evolution by prolific mobile genetic parasites called transposable elements (TEs). Long disregarded as "junk" or "selfish" DNA, TEs are increasingly recognized as formative elements in genome evolution, wired intimately into the structure and function of the human genome. Advances in sequencing technologies and computational methods have ushered in an era of unprecedented insight into how TE activity impacts human biology in health and disease. Here we discuss the current views on how TEs have shaped the regulatory landscape of the human genome, how TE activity is implicated in human cancers, and how recent findings motivate novel strategies to leverage TE activity for improved cancer therapy. Given the crucial role of methodological advances in TE biology, we pair our conceptual discussions with an in-depth review of the inherent technical challenges in studying repeats, specifically related to structural variation, expression analyses, and chromatin regulation. Lastly, we provide a catalog of existing and emerging assays and bioinformatic software that altogether are enabling the most sophisticated and comprehensive investigations yet into the regulation and function of interspersed repeats in cancer genomes.

Persistent transcriptional changes in cardiac adaptive immune cells following myocardial infarction: New evidence from the re-analysis of publicly available single cell and nuclei RNA-sequencing data sets.

INTRODUCTION: Chronic immunopathology contributes to the development of heart failure after a myocardial infarction. Both T and B cells of the adaptive immune system are present in the myocardium and have been suggested to be involved in post-MI immunopathology. METHODS: We analyzed the B and T cell populations isolated from previously published single cell RNA-sequencing data sets (PMID: 32130914, PMID: 35948637, PMID: 32971526 and PMID: 35926050), of the mouse and human heart, using differential expression analysis, functional enrichment analysis, gene regulatory inferences, and integration with autoimmune and cardiovascular GWAS. RESULTS: Already at baseline, mature effector B and T cells are present in the human and mouse heart, having increased activity in transcription factors maintaining tolerance (e.g. DEAF1, JDP2, SPI-B). Following MI, T cells upregulate pro-inflammatory transcript levels (e.g. Cd11, Gzmk, Prf1), while B cells upregulate activation markers (e.g. Il6, Il1rn, Ccl6) and collagen (e.g. Col5a2, Col4a1, Col1a2). Importantly, pro-inflammatory and fibrotic transcription factors (e.g. NFKB1, CREM, REL) remain active in T cells, while B cells maintain elevated activity in transcription factors related to immunoglobulin production (e.g. ERG, REL) in both mouse and human post-MI hearts. Notably, genes differentially expressed in post-MI T and B cells are associated with cardiovascular and autoimmune disease. CONCLUSION: These findings highlight the varied and time-dependent dynamic roles of post-MI T and B cells. They appear ready-to-go and are activated immediately after MI, thus participate in the acute wound healing response. However, they subsequently remain in a state of pro-inflammatory activation contributing to persistent immunopathology.

Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.

Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.

A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer.

BACKGROUND: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. METHODS: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). RESULTS: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. CONCLUSIONS: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.

The role of alternative autophagy in cell viability and response to paclitaxel treatment in v-Ha-ras-transformed NIH 3T3 cells.

In confluent v-Ha-ras-transformed NIH 3T3 fibroblasts (Ras-NIH 3T3), LC3 downregulation may precede a decrease in canonical autophagy, thus contributing to cell survival. Herein, we aimed to investigate the role of alternative autophagy in the viability of long-term cultures of Ras-NIH 3T3 cells and their parental NIH 3T3 cells. As cell confluence increased with the culture period, the level of alternative autophagy, as assessed through Lamp2-Rab9 co-localization, gradually decreased in both cell lines. However, Ras-NIH 3T3 cells maintained higher levels of alternative autophagy than the parental cells did. Rab9 knockdown minimally affected NIH 3T3 cells while drastically reducing the viability of Ras-NIH 3T3 cells, which suggested that alternative autophagy plays a critical role in Ras-NIH 3T3 cells. In contrast, reactive oxygen species (ROS) production in Ras-NIH 3T3 cells was higher than that in NIH 3T3 cells during long-term culture. Moreover, NIH 3T3 cells exhibited a continual decrease in mitochondrial mass, whereas Ras-NIH 3T3 cells maintained high mitochondrial mass. Immunofluorescence analysis of mitochondrial membrane marker proteins and mitochondrial membrane potential (MMP) also demonstrated a temporal pattern of changes similar to those of mitochondrial mass. This finding could be attributed to the relatively higher level of alternative autophagy in Ras-NIH 3T3 cells facilitating the removal of damaged mitochondria. Paclitaxel treatment in Ras-NIH 3T3 cells induced an increase in canonical autophagy rates along with suppression of alternative autophagy. Ras-NIH 3T3 cells showed high sensitivity to paclitaxel at the early stage of culture, but as cell confluence increased, resistance to paclitaxel increased, showing a similar level of cell viability to the vehicle control group. The study findings suggest that alternative autophagy is more important than canonical autophagy for maintaining cell survival in response to an unfavorable environment, such as during high cell confluence and exposure to anticancer agents.

Exploring and Analyzing the Systemic Delivery Barriers for Nanoparticles.

Most nanomedicines require efficient in vivo delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. We reviewed nanoparticle design and biological modulation strategies to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, we studied the preclinical literature from 2011-2021 and analyzed nanoparticle blood circulation and organ biodistribution data. Our findings revealed that nanoparticle surface chemistry affected the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improved the blood area under the curve by ~418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.

A restatement of the natural science evidence base concerning grassland management, grazing livestock and soil carbon storage.

Approximately a third of all annual greenhouse gas emissions globally are directly or indirectly associated with the food system, and over a half of these are linked to livestock production. In temperate oceanic regions, such as the UK, most meat and dairy is produced in extensive systems based on pasture. There is much interest in the extent to which such grassland may be able to sequester and store more carbon to partially or completely mitigate other greenhouse gas emissions in the system. However, answering this question is difficult due to context-specificity and a complex and sometimes inconsistent evidence base. This paper describes a project that set out to summarize the natural science evidence base relevant to grassland management, grazing livestock and soil carbon storage potential in as policy-neutral terms as possible. It is based on expert appraisal of a systematically assembled evidence base, followed by a wide stakeholders engagement. A series of evidence statements (in the appendix of this paper) are listed and categorized according to the nature of the underlying information, and an annotated bibliography is provided in the electronic supplementary material.

Association of Patient-Reported Social Needs with Emergency Department Visits and Hospitalizations Among Federally Qualified Health Center Patients.

BACKGROUND: Health care systems are increasingly screening for unmet social needs. The association between patient-reported social needs and health care utilization is not well understood. OBJECTIVE: To investigate the association between patient-reported social needs, measured by the Protocol for Responding to and Assessing Patients' Assets, Risks, and Experiences (PRAPARE), and inpatient and emergency department (ED) utilization. DESIGN: This cohort study analyzed merged 2017-2019 electronic health record (EHR) data across multiple health systems. PARTICIPANTS: Adult patients from a federally qualified health center (FQHC) in central North Carolina who completed PRAPARE as part of a primary care visit with behavioral health services. MAIN MEASURES: The count of up to 12 unmet social needs, aggregated as 0, 1, 2, or 3 + . Outcomes include the probability of an ED visit and hospitalization 12 months after PRAPARE assessment, modeled by logistic regressions controlling for age, sex, race, ethnicity, comorbidity burden, being uninsured, and prior utilization in the past 12 months. KEY RESULTS: The study population consisted of 1924 adults (38.7% male, 50.1% Black, 36.3% Hispanic, 55.9% unemployed, 68.2% of patients reported 1 + needs). Those with more needs were younger, more likely to be unemployed, and experienced greater comorbidity burden. 35.3% of patients had ED visit(s) and 36.3% had hospitalization(s) 1 year after PRAPARE assessment. In adjusted analysis, having 3 + needs was associated with a percentage point increase in the predicted probability of hospitalization (average marginal effect 0.06, SE 0.03, p < 0.05) compared with having 0 needs. Similarly, having 2 needs (0.07, SE 0.03, p < 0.05) or 3 + needs (0.06, SE 0.03, p < 0.05) was associated with increased probability of ED visits compared to 0 needs. CONCLUSIONS: Patient-reported social needs were common and associated with health care utilization patterns. Future research should identify interventions to address unmet social needs to improve health and avoid potentially preventable escalating medical intervention.

Co-culture of chondrocytes and stem cells: a review of head and neck cell lines for cartilage regeneration.

INTRODUCTION: Bioprinting, using "bio-inks" consisting of living cells, supporting structures and biological motifs to create customized constructs, is an emerging technique that aims to overcome the challenges of cartilaginous reconstruction of head and neck structures. Several living cell lines and culturing methods have been explored as bio-inks with varying efficacy. Co-culture of primary chondrocytes and stem cells (SCs) is one technique, well established for degenerative joint disease treatment, with potential for use in expanding chondrocyte populations for bio-inks. This study aims to evaluate the techniques for co-culture of primary chondrocytes and SCs for head and neck cartilage regeneration. METHODS: A literature review was performed through OVID/Web of Science/MEDLINE/BIOSIS Previews/Embase. Studies reporting on chondrocytes and SCs in conjunction with co-culture or cartilage regeneration were included. Studies not reporting on findings from chondrocytes/SCs of the head and neck were excluded. Extracted data included cell sources, co-culture ratios and histological, biochemical and clinical outcomes. RESULTS: 15 studies met inclusion criteria. Auricular cartilage was the most common chondrocyte source (n=10), then nasal septum (n=5), articular (n=1) and tracheal cartilage (n=1). Bone marrow was the most common SC source (n=9) then adipose tissue (n=7). Techniques varied, with co-culture ratios ranging from 1:1 to 1:10. All studies reported co-culture to be superior to SC mono-culture by all outcomes. Most studies reported superiority or equivalence of co-culture to chondrocyte mono-culture by all outcomes. When comparing clinical outcomes, co-culture constructs were equivalent to chondrocyte mono-culture in diameter, and equivalent or inferior in wet weight and height. CONCLUSION: Co-culture of primary chondrocytes and SCs is a promising technique for expanding chondrocyte populations, with at least equivalence to chondrocyte mono-culture and superior to SC mono-culture when seeded at the same chondrocyte densities. However, there remains a lack of consensus regarding the optimal cell sources and co-culture ratios.

Lean body mass in living kidney donors impacts postoperative renal function.

PURPOSE: A living donor kidney transplant is the optimal treatment for chronic renal impairment. Our objective is to assess if lean skeletal muscle mass and donor factors such as body mass index, hypertension, and age impact on renal function following donor nephrectomy. METHODS: Potential donors undergo CT angiography as part of their work-up in our institution. Using dedicated software (Horos®), standardized skeletal muscle area measured at the L3 vertebrae was calculated. When corrected for height, skeletal muscle index can be derived. Skeletal muscle mass index below predefined levels was classified as sarcopenic. The correlation of CT-derived skeletal muscle index and postoperative renal function at 12 months was assessed. Co-variables including donor gender, age, body mass index (BMI), and presence of pre-op hypertension were also assessed for their impact on postoperative renal function. RESULTS: 275 patients who underwent living donor nephrectomy over 10 years were included. Baseline pre-donation glomerular filtration rate (GFR) and renal function at one year post-op were similar between genders. 29% (n = 82) of patients met the criteria for CT-derived sarcopenia. Sarcopenic patients were more likely to have a higher GFR at one year post-op (69.3 vs 63.9 mL/min/1.73 m2, p < 0.001). The main factors impacting better renal function at one year were the presence of sarcopenia and younger age at donation. CONCLUSION: When selecting donors, this study highlights that patients with low skeletal mass are unlikely to underperform in terms of recovery of their renal function postoperatively at one year when compared to patients with normal muscle mass and should not be a barrier to kidney donation.

Mortality, Safety, and Effectiveness of Paclitaxel-Containing Balloons and Stents in the Femoropopliteal Artery: Systematic Review and Meta-Analysis of Randomized Controlled Trials since 2018.

PURPOSE: To provide an updated systematic review and meta-analysis of safety and effectiveness outcomes with paclitaxel-containing devices. MATERIALS AND METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) investigating paclitaxel-containing balloons or stents in the treatment of femoropopliteal disease was performed. Pooled risk ratio (RR) was calculated using the inverse-variance, random-effects model in the assessment of primary patency, all-cause mortality, target limb major amputation, target lesion revascularization (TLR), and thrombosis. RESULTS: In total, 19 RCTs were included comprising 4,284 participants. All-cause mortality rates did not differ significantly between the 2 arms at 12 months (RR, 1.06; 95% confidence interval [CI], 0.66-1.72; P = .80), 24 months (RR, 0.92; 95% CI, 0.56-1.50; P = .73), 36 months (RR, 1.21; 95% CI, 0.65-2.25; P = .55), or 48-60 months (RR, 0.95; 95% CI, 0.66-1.39; P = .81) after intervention. Primary patency was significantly higher at 12 months in the paclitaxel-containing arm: 80.92% (1,438/1,777) versus 57.48% (607/1,056) in the control arm (RR, 1.44; 95% CI, 1.30-1.59; P < .00001). CONCLUSIONS: The present study demonstrates no statistically significant difference in all-cause mortality, target limb major amputation, or thrombosis with paclitaxel drug-eluting therapy to the femoropopliteal region. Additionally, improved and durable patency rates with a statistically significantly lower risk of clinically driven TLR with paclitaxel drug-eluting therapy have been demonstrated.

Clinical genetics in breast cancer.

As genetic testing becomes increasingly more accessible and more applicable with a broader range of clinical implications, it may also become more challenging for breast cancer providers to remain up-to-date. This review outlines some of the current clinical guidelines and recent literature surrounding germline genetic testing, as well as genomic testing, in the screening, prevention, diagnosis, and treatment of breast cancer, while identifying potential areas of further research.

A Qualitative Systematic Review of Endovascular Management of Renal Artery Aneurysms.

PURPOSE: To perform a qualitative systematic review of endovascular management of renal artery aneurysms (RAAs). MATERIALS AND METHODS: A comprehensive electronic search of PubMed, MEDLINE, Embase, Google Scholar, and Cochrane databases from 2000 to 2022 was performed using the search terms "renal artery," "aneurysm," and "endovascular." Means of outcome measures were calculated with a primary end point focused on RAA-related mortality and rupture. Secondary end points included reintervention rate and renal infarction. RESULTS: Twenty-six, single-center, retrospective, observational studies were included. There were 454 RAAs treated in 427 patients using endovascular techniques. Mean age was 53.8 years, with a female predominance (62%). A variety of endovascular treatments of RAA were used with excellent technical success (96%), renal parenchymal preservation, and a low rate of moderate/severe adverse events (AEs). Primary coil embolization was the most commonly used technique (44.7%). There was an overall AE rate of 22.9%, of which 6.7% were moderate/severe and there was 0% periprocedural mortality. The most common AE was renal infarction (49 patients, 11.5%); however, renal function was preserved in 84% of patients. Nephrectomy rate was 0.4%. Computed tomography (CT) angiography was the most common imaging follow-up modality used in 72% of studies. Only 9 studies (34%) reported anticoagulant use. Although the risk of delayed aneurysm reperfusion warrants clinical and imaging surveillance, relatively few patients (3%) required reintervention in this cohort. CONCLUSIONS: Endovascular management of RAA is a technically feasible treatment option with low rates of AEs and reintervention. The present study highlights the techniques available for interventional radiologists, a need for standardization of AE reporting, anticoagulation therapy, and follow-up imaging.

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

BACKGROUND: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy. METHODS: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments. RESULTS: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR. CONCLUSION: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals.

In the European Medicines Agency (EMA) "Guideline for Environmental Risk Assessment of Medicinal Products for Human Use," a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation ('B') potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

Rechallenges without desensitization following platinum-based chemotherapy reactions.

BACKGROUND: There is increasing interest in non-desensitization protocols as a potential way to reintroduce chemotherapy following hypersensitivity reactions (HSR). OBJECTIVE: To provide insight into the potential utility of non-desensitization reintroduction, particularly at institutions where allergy consultation may not be available. METHODS: For 70 patients with platinum HSR who underwent rechallenge with standard (≤2 hours), extended (1-bag, 1-step, 4-6 hours), or titrated (4-to-5-bag and -step, 6-7.5 hours) infusions between 1/2014 and 7/2019, demographics and clinical characteristics were reviewed and initial and breakthrough reactions (BTR) were graded using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Tolerance (no BTR) and completion (dose completed despite BTR) were compared using Fisher's exact test. RESULTS: Patients (mean [standard deviation] age 57 [13] years, initial HSR grade 2 [1]), were rechallenged with standard (n = 8), extended (n = 23), or titrated (n = 22) infusions after oxaliplatin HSR; and standard (n = 5) or titrated (n = 12) after carboplatin HSR. Tolerance and completion were higher for extended versus (vs) standard (tolerance-87%-vs-8%, p < 0.005; completion-96%-vs-38%, p < 0.005) and titrated versus standard (tolerance-76%-vs-8%, p < 0.005; completion-79%-vs-38%, p < 0.05) infusions. CONCLUSIONS: Extended and titrated infusions may increase reintroduction safety compared to standard infusions. Further investigation into extended infusions may provide a safe alternative to standard infusions in patients who may not have access to desensitization at their institution.

Corticosteroid Injections Administered Within 4 Weeks Prior to Hip Arthroscopy Are Associated With Higher Rates of Postoperative Infection.

PURPOSE: To evaluate the association between the timing of intra-articular hip corticosteroid injections and the risk of postoperative infection in patients undergoing hip arthroscopy. METHODS: The 2010-2021 PearlDiver M157 administrative claims database was queried for patients who underwent hip arthroscopy. Patients who received intra-articular corticosteroid injections within 12 weeks prior to arthroscopy were matched 1:1 to patients who did not receive such injections based on age, sex, and Elixhauser Comorbidity Index, as well as the presence of diabetes mellitus, hypertension, obesity, and tobacco use. Those with injections prior to arthroscopy were subdivided based on having received injections within 12 weeks prior to surgery. To verify that the corticosteroid injections and surgical procedures were conducted in the hip joint, Current Procedural Terminology codes were used. By use of Current Procedural Terminology and International Classification of Diseases (ninth revision and tenth revision) coding, postoperative surgical-site infection after corticosteroid injection was evaluated. The impact of the timing of preoperative corticosteroid injections on the incidence of postoperative infection was evaluated using multivariable logistic regression analysis. RESULTS: A total of 12,390 hip arthroscopy cases were identified, including 3,579 patients who received corticosteroid injections 0 to 4 weeks prior to surgery; 4,759, within 4 to 8 weeks prior to surgery; and 4,052, within 8 to 12 weeks prior to surgery. Compared with controls, patients who received corticosteroid injections within 0 to 4 weeks preoperatively had a significantly higher rate of surgical-site infection (odds ratio, 2.43; P = .0001). No significant differences in infection rates were observed at the later time intervals (4-8 weeks or 8-12 weeks). Furthermore, in comparison to controls, patients who received corticosteroid injections had a significantly higher rate of wound dehiscence (odds ratio, 1.84; P = .0007). CONCLUSIONS: Intra-articular corticosteroid injections within 4 weeks prior to hip arthroscopy were significantly associated with increased surgical-site infection rates after hip arthroscopy surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Autologous Matrix-Induced Chondrogenesis for the Treatment of Hip Acetabular Chondral Lesions Demonstrates Improved Outcomes: A Systematic Review.

PURPOSE: To systematically investigate the outcomes of patients who underwent autologous matrix-induced chondrogenesis (AMIC) during hip arthroscopy for the treatment of acetabular chondral lesions due to femoroacetabular impingement syndrome. METHODS: PubMed and Cochrane were queried in June 2022 to conduct this systematic review using the following keywords: "femoroacetabular impingement," "arthroscopy," "microfracture," and "autologous matrix-induced chondrogenesis." Articles were included if they reported on patient-reported outcomes of AMIC during hip arthroscopy to treat chondral lesions of the hip. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Each study was queried for demographics, lesion classification, surgical treatment, patient-reported outcome scores, revision arthroscopy, and conversion to total hip arthroplasty (THA). A qualitative subanalysis was performed to compare patients undergoing AMIC to patients undergoing microfracture alone if included studies also assessed results of microfracture alone. RESULTS: Four studies met inclusion criteria and assessed 209 hips undergoing AMIC. The included studies consisted of 99 male and 110 female patients. Mean postoperative follow-up ranged from 1 to 8 years, and mean patient age ranged from 34.3 to 45 years. Three of the 4 included studies reported the modified Harris Hip Score, and all 3 of these studies reported statistically significant improvement in the modified Harris Hip Score at final follow-up (P < .001) with mean preoperative values ranging from 44.5 to 62.8 and mean postoperative values ranging from 78.8 to 95.8. Two of the 4 studies compared patients treated with AMIC to microfracture alone. In these 2 studies, the AMIC groups reported 0 patients converting to THA while the microfracture-alone groups reported a highly variable rate of conversion to THA (2%-32.6%). CONCLUSIONS: Patients who underwent hip arthroscopy and AMIC for the treatment of femoroacetabular impingement syndrome and acetabular chondral lesions demonstrated improved patient-reported outcomes and low rates of secondary surgeries at short-term follow-up. STUDY DESIGN: Level IV, systematic review of Level III and IV studies.

Osteochondral Allograft or Autograft Transplantation of the Femoral Head Leads to Improvement in Outcomes but Variable Survivorship: A Systematic Review.

PURPOSE: To review patient-reported outcomes (PROs) and survivorship in patients undergoing osteochondral autograft or allograft transplantation (OAT) of the femoral head. METHODS: PubMed, Cochrane Center for Register of Controlled Trials, and Scopus databases were searched in November 2022 with an updated search extending to December 2023 using criteria from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the following keywords: (hip OR femoral head) AND (mosaicplasty OR osteochondral allograft OR osteochondral autograft OR osteochondral lesion). Articles were included if they evaluated postoperative PROs in patients who underwent OAT of the femoral head and had a study size of 5 or more hips (n ≥ 5). Survivorship was defined as freedom from conversion to total hip arthroplasty. For PROs evaluated in 3 studies or more, forest plots were created and I2 was calculated. RESULTS: Twelve studies were included in this review, with a total of 156 hips and a mean follow-up time ranging between 16.8 and 222 months. In total, 104 (66.7%) hips were male while 52 (33.3%) were female. Age of patients ranged from 17.0 to 35.4 years, while body mass index ranged from 23.3 to 28.1. Eight studies reported on osteochondral autograft transplantation and 4 studies on osteochondral allograft transplantation. Three studies reported significant improvement in at least 1 PRO. Survivorship ranged from 61.5% to 96% at minimum 2-year follow-up and from 57.1% to 91% at minimum 5-year follow-up. At a follow-up of less than 5 years, osteochondral allograft transplantation studies showed 70% to 87.5% survivorship, while autograft varied from 61.54% to 96%. CONCLUSIONS: Patients with osteochondral lesions of the femoral head who underwent osteochondral autograft or allograft transplantation demonstrated improved PROs but variable survivorship rates. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.