Biotransformation research advances - 2023 year in review.

This annual review marks the eighth in the series starting with Baillie et al. (2016) Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation. Its format is to highlight important aspects captured in synopsis followed by a commentary with relevant figure and references.

Bioactivation and reactivity research advances - 2023 year in review.

Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.

Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

A Kinetic Model for Assessing Potential Nitrosamine Carcinogenicity.

Understanding the potential carcinogenic potency of nitrosamines is necessary to setting acceptable intake limits. Nitrosamines and the components that can form them are commonly present in food, water, cosmetics, and tobacco. The recent observation of nitrosamines in pharmaceuticals highlighted the need for effective methods to determine acceptable intake limits. Herein, we describe two computational models that utilize properties based upon quantum mechanical calculations in conjunction with mechanistic insights and established data to determine the carcinogenic potency of a variety of common nitrosamines. These models can be applied to experimentally untested nitrosamines to aid in the establishment of acceptable intake limits.

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency.

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., ß-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure-activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.

Performance of pan-enteroscopy in children with intestinal failure due to short bowel syndrome: A single-center retrospective study.

OBJECTIVES: In pediatric patients with intestinal failure (IF) due to short bowel syndrome, we hypothesized that young children, those with shorter residual small bowel and those with congenital malrotation of the bowel would be more likely to undergo pan-enteroscopy. We aimed to determine the feasibility and diagnostic yield of pan-enteroscopy in this cohort. METHODS: We performed a single-center, retrospective study of pediatric patients with IF due to short bowel syndrome (SBS) who had undergone at least one GI endoscopic evaluation between January 1, 2018 and January 1, 2023. RESULTS: A pan-enteroscopy might have been possible in 381 of the 431 procedures (206 patients) reviewed. 44 (21%) patients underwent 54 pan-enteroscopies. Children with a residual bowel length <35 cm had higher odds of undergoing pan-enteroscopy (odds ratio [OR] 3.72, 95% confidence interval [CI] [1.32, 10.48], p = 0.01), as did patients with periprocedural glucagon-like peptide 2 (GLP-2) analog use (OR 4.30, 95% CI [1.24, 14.95], p = 0.02). Patients with diagnoses other than necrotizing enterocolitis (NEC) tended to be more likely to achieve a pan-enteroscopy (OR 2.73, 95% CI [0.95,7.88], p = 0.06). Evidence of gross and histopathologic abnormalities were found in 77.8% and 78% of the procedures, respectively. No complications were identified. CONCLUSION: In a large cohort of children with SBS, pan-enteroscopy was successfully performed in 14.2% of the procedures and microscopic abnormalities were common. Shorter residual bowel length, underlying diagnoses of non-NEC, and GLP-2 analog use were generally associated with successful pan-enteroscopy, independent of age and several other factors. These data suggest that pan-enteroscopy is feasible and of high-yield in a subset of patients with SBS.

Membrane shaping proteins, lipids, and cytoskeleton: Recipe for nascent lipid droplet formation.

Lipid droplets (LDs) are ubiquitous, neutral lipid storage organelles that act as hubs of metabolic processes. LDs are structurally unique with a hydrophobic core that mainly consists of neutral lipids, sterol esters, and triglycerides, enclosed within a phospholipid monolayer. Nascent LD formation begins with the accumulation of neutral lipids in the endoplasmic reticulum (ER) bilayer. The ER membrane proteins such as seipin, LDAF1, FIT, and MCTPs are reported to play an important role in the formation of nascent LDs. As the LDs grow, they unmix from the highly charged ER membrane to form mature LDs. LD biogenesis is an exciting, emerging research area, and herein, we discuss the recent progress in our understanding of the formation of eukaryotic nascent LDs. We focus on the role of ER membrane shaping proteins such as reticulons and reticulon-like proteins, membrane lipids, and cytoskeleton proteins such as septin in the formation of nascent LDs.

Characterization of Individuals With Hepatitis B Virus-Related Cirrhosis in a Large Integrated Health Care Organization, 2008-2019.

CONTEXT: Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a risk factor for cirrhosis. The management of HBV-related cirrhosis is challenging, with guidelines recommending treatment initiation and regular monitoring for those affected. OBJECTIVE: Our study characterized Kaiser Permanente Southern California patients with HBV-related cirrhosis and assessed whether they received recommended laboratory testing and imaging monitoring. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: We identified KPSC members aged ≥18 years with CHB (defined by 2, consecutive positive hepatitis B surface antigens ≥6 months apart) from 2008 to 2019. Of these patients, we further identified patients with potential HBV-related cirrhosis through ICD-10 code diagnosis, adjudicated via chart review. MAIN OUTCOME MEASURES: Age, race/ethnicity, laboratory tests (eg, alanine aminotransferase [ALT]), and hepatocellular carcinoma (HCC) screening (based on standard screening recommendations via imaging) were described in those with HBV-related cirrhosis versus those without. RESULTS: Among patients with CHB, we identified 65 patients with HBV-related cirrhosis over ~8 years. Diabetes was the most common comorbidity and was approximately 3 times more prevalent among patients with cirrhosis compared to patients without cirrhosis (21.5% vs. 7.1%). Of the 65 patients with cirrhosis, 72.3% (N = 47) received treatment. Generally, we observed that liver function tests (eg, ALT) were completed frequently in this population, with patients completing a median of 10 (6, 16) tests/year. All patients with cirrhosis had ≥1 ALT completed over the study period, and almost all cirrhotic patients (N = 64; 98.5%) had ≥1 HBV DNA test. However, the proportion of yearly imaging visits completed varied across the study years, between 64.0% in 2012 and 87.5% in 2009; overall, 35% (N = 23) completed annual imaging. CONCLUSIONS: Our findings suggest that among patients with HBV-related cirrhosis, at the patient-level, completed imaging orders for HCC screening were sub-optimal. However, we observed adequate disease management practices through frequent liver function tests, linkage to specialty care, image ordering, and shared EHR between KPSC providers.

An objective comparative study of non-surgical cleansing techniques and cleanser types in bacterial burden management.

Cleansing is a vital component of effective wound hygiene and biofilm management, often accomplished through vigorous mechanical action or through soaking with moistened gauze. In the present study, a quantitative comparison of the effectiveness of different cleansing techniques and solutions in removing bacteria was conducted on 71 chronic wounds using bacterial fluorescence imaging as a real-time diagnostic for moderate to high bacterial loads. Vigorous gauze cleansing for 30 s proved most effective by reducing bacterial fluorescence by 33.99%, surpassing 10-min soaking in bacterial reduction (13.24%). Among different cleansers, no statistically significant differences in effectiveness were observed, but povidone-iodine showed the strongest trend towards bacterial reduction. Sub-analysis highlighted the superiority of antiseptic cleansers over saline and gentle soap (-33.30% vs. -1.80% bacterial reduction respectively). Five percent acetic acid was also shown to be more effective in removing specific bacterial strains (Pseudomonas aeruginosa). Findings from studies like this contribute to refining wound hygiene guidelines and clinical algorithms for bacterial and biofilm management.

Biotransformation research advances - 2022 year in review.

This annual review is the eighth of its kind since 2016 (Baillie et al. 2016, Khojasteh et al. 2017, Khojasteh et al. 2018, Khojasteh et al. 2019, Khojasteh et al. 2020, Khojasteh et al. 2021, Khojasteh et al. 2022). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation.

Bioactivation and reactivity research advances - 2022 year in review‡.

With the 50th year mark since the launch of Drug Metabolism and Disposition journal, the field of drug metabolism and bioactivation has advanced exponentially in the past decades (Guengerich 2023).This has, in a major part, been due to the continued advances across the whole spectrum of applied technologies in hardware, software, machine learning (ML), and artificial intelligence (AI). LC-MS platforms continue to evolve to support key applications in the field, and automation is also improving the accuracy, precision, and throughput of these supporting assays. In addition, sample generation and processing is being aided by increased diversity and quality of reagents and bio-matrices so that what is being analyzed is more relevant and translatable. The application of in silico platforms (applied software, ML, and AI) is also making great strides, and in tandem with the more traditional approaches mentioned previously, is significantly advancing our understanding of bioactivation pathways and how these play a role in toxicity. All of this continues to allow the area of bioactivation to evolve in parallel with associated fields to help bring novel or improved medicines to patients with urgent or unmet needs.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.

Prevalence of hepatitis B virus (HBV) and latent tuberculosis co-infection and risk of drug-induced liver injury across two large HBV cohorts in the United States.

The epidemiology of latent tuberculosis and hepatitis B virus (HBV-LTBI) co-infection among U.S. populations is not well studied. We aim to evaluate LTBI testing patterns and LTBI prevalence among two large U.S. cohorts of adults with chronic HBV (CHB). Adults with CHB in the Chronic Hepatitis Cohort Study (CHeCS) and Veterans Affairs national cohort were included in the analyses. Prevalence of HBV-LTBI co-infection was defined as the number of HBV patients with LTBI divided by the number of HBV patients in a cohort. Multivariable logistic regression evaluated odds of HBV-LTBI co-infection among CHB patients who underwent TB testing. Among 6019 CHB patients in the CHeCS cohort (44% female, 47% Asian), 9.1% were tested for TB, among whom 7.7% had HBV-LTBI co-infection. Among HBV-LTBI co-infected patient, only 16.7% (n = 7) received LTBI treatment, among whom 28.6% (n = 2) developed DILI. Among 12,928 CHB patients in the VA cohort (94% male, 42% African American, 39% non-Hispanic white), 14.7% were tested for TB, among whom 14.5% had HBV-LTBI. Among HBV-LTBI co-infected patient, 18.6% (n = 51) received LTBI treatment, among whom 3.9% (n = 3) developed DILI. Presence of cirrhosis, race/ethnicity, and country of birth were observed to be associated with odds of HBV-LTBI co-infection among CHB patients who received TB testing. In summary, among two large distinct U.S. cohorts of adults with CHB, testing for LTBI was infrequent despite relatively high prevalence of HBV-LTBI co-infection. Moreover, low rates of LTBI treatment were observed among those with HBV-LTBI co-infection.

Mitigating a Bioactivation Liability with an Azetidine-Based Inhibitor of Diacylglycerol Acyltransferase 2 (DGAT2) En Route to the Discovery of the Clinical Candidate Ervogastat.

We recently disclosed SAR studies on systemically acting, amide-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) that addressed metabolic liabilities with the liver-targeted DGAT2 inhibitor PF-06427878. Despite strategic placement of a nitrogen atom in the dialkoxyaromatic ring in PF-06427878 to evade oxidative O-dearylation, metabolic intrinsic clearance remained high due to extensive piperidine ring oxidation as exemplified with compound 1. Piperidine ring modifications through alternate N-linked heterocyclic ring/spacer combination led to azetidine 2 that demonstrated lower intrinsic clearance. However, 2 underwent a facile cytochrome P450 (CYP)-mediated α-carbon oxidation followed by azetidine ring scission, resulting in the formation of ketone (M2) and aldehyde (M6) as stable metabolites in NADPH-supplemented human liver microsomes. Inclusion of GSH or semicarbazide in microsomal incubations led to the formation of Cys-Gly-thiazolidine (M3), Cys-thiazolidine (M5), and semicarbazone (M7) conjugates, which were derived from reaction of the nucleophilic trapping agents with aldehyde M6. Metabolites M2 and M5 were biosynthesized from NADPH- and l-cysteine-fortified human liver microsomal incubations with 2, and proposed metabolite structures were verified using one- and two-dimensional NMR spectroscopy. Replacement of the azetidine substituent with a pyridine ring furnished 8, which mitigated the formation of the electrophilic aldehyde metabolite, and was a more potent DGAT2 inhibitor than 2. Further structural refinements in 8, specifically introducing amide bond substituents with greater metabolic stability, led to the discovery of PF-06865571 (ervogastat) that is currently in phase 2 clinical trials for the treatment of nonalcoholic steatohepatitis.

Pancreatitis-Associated Medication Use in Hospitalized Pediatric and Young Adult Patients With Acute Pancreatitis.

OBJECTIVE: The objective of this study is (1) to describe the prevalence of pancreatitis-associated medication (PAM) use at admission and discharge in pediatric and young adult patients hospitalized with acute pancreatitis (AP) and (2) to describe the prevalence of PAM use at admission in patients classified as having idiopathic AP. STUDY DESIGN: A single-center retrospective study of patients <21 years who were hospitalized with AP or acute recurrent pancreatitis from March 2015 to July 2017 was performed. Charts were reviewed for demographic data, etiology of pancreatitis, comorbidities, and use of PAMs at admission and discharge. PAMs were defined and scored based on an evidence-based classification system, with class I PAMs having strongest evidence for causation. Standard descriptive statistics were used to report prevalence data. RESULTS: Our cohort was comprised of 119 patients; 50% of patients were using a PAM at admission and 67% were taking a PAM at discharge, reflecting a significant change (P = 0.0009); 44% of patients classified as having idiopathic pancreatitis were taking a PAM on admission, reflecting a possibly missed role of medication in their presentation. Comorbidities significantly associated with PAM use included seizure disorder (P = 0.005) and oncologic disease (P = 0.005). The most commonly used class I PAMs were omeprazole, trimethoprim-sulfamethazole, valproic acid, and 6-mercaptopurine. The increase in prevalence of PAM use at discharge compared to admission was partially driven by addition of omeprazole to the outpatient medication regimen during the hospital stay (P = 0.07). CONCLUSION: Medications likely play an under-recognized role in pediatric AP. The practice of using proton pump inhibitors in management of AP warrants further study.

Species differences in plasma protein binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease inhibitor nirmatrelvir.

Plasma protein binding (PPB) studies on the SARS-CoV-2 main protease inhibitor nirmatrelvir revealed considerable species differences primarily in dog and rabbit, which prompted further investigations into the biochemical basis for these differences.The unbound fraction (fu) of nirmatrelvir in dog and rabbit plasma was concentration (2-200 µM)-dependent (dog fu,p 0.024-0.69, rabbit fu,p 0.010-0.82). Concentration (0.1-100 µM)-dependent binding in serum albumin (SA) (fu,SA 0.040-0.82) and alpha-1-acid glycoprotein (AAG) (fu,AAG 0.050-0.64) was observed in dogs. Nirmatrelvir showed minimal binding to rabbit SA (1-100 µM: fu,SA 0.70-0.79), while binding to rabbit AAG was concentration-dependent (0.1-100 µM: fu,AAG 0.024-0.66). In contrast, nirmatrelvir (2 µM) revealed minimal binding (fu,AAG 0.79-0.88) to AAG from rat and monkeys. Nirmatrelvir showed minimal-to-moderate binding to SA (1-100 µM; fu,SA 0.70-1.0) and AAG (0.1-100 µM; fu,AAG 0.48-0.58) from humans across tested concentrations.Nirmatrelvir molecular docking studies using published crystal structures and homology models of human and preclinical species SA and AAG were used to rationalise the species differences to plasma proteins. This suggested that species differences in PPB are primarily driven by molecular differences in albumin and AAG resulting in differences in binding affinity.

Platelet-Rich Plasma Injections for Shoulder Adhesive Capsulitis Are at Least Equivalent to Corticosteroid or Saline Solution Injections: A Systematic Review of Prospective Cohort Studies.

PURPOSE: To evaluate the role of platelet-rich plasma (PRP) for adhesive capsulitis (AC) as compared with other injectables. METHODS: A literature search of the PubMed and Embase online databases was performed to identify articles evaluating injection therapy for the treatment of AC. The inclusion criteria included prospective studies comparing PRP against alternative injectables with a minimum of 15 patients in each treatment arm and a minimum 12-week follow-up period. Pain scores, range of motion, and function scores were the primary outcomes assessed. RESULTS: Five articles comparing PRP with corticosteroid or saline solution injections met the inclusion criteria. A total of 157 patients were treated with PRP, with a follow-up duration ranging from 3 to 6 months. All 5 studies showed statistically significant improvements in pain scores, motion, and function scores in patients receiving PRP, corticosteroid, and saline solution injections. However, PRP was consistently superior on intergroup analyses in all but 1 study. In 4 studies, pain and function scores favored PRP over control at final follow-up (range in mean difference, -2.2 to 0.69 for visual analog scale pain score [n = 5] and -50.5 to -4.0 for Shoulder Pain and Disability Index score [n = 3]), whereas 3 studies found greater improvement in shoulder motion after PRP (range in mean difference, 0.7° to 34.3° for forward flexion and -2.3° to 20.4° for external rotation [n = 4]). One study found no significant difference between PRP and corticosteroid injections but noted that the results were comparable. CONCLUSIONS: According to a limited number of prospective studies, PRP injections for AC are at least equivalent to corticosteroid or saline solution injections and often lead to improved pain, motion, and functional outcomes at 3- to 6-month follow-up. Given the small number of studies, with design heterogeneity, there is insufficient evidence to routinely recommend PRP for AC. However, the results are promising and do support considering PRP as an adjunct treatment option for AC, especially for patients refractory and/or averse to corticosteroids or alternative treatment modalities. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.

Is Intraoperative Dexamethasone Utilization Associated With Increased Rates of Periprosthetic Joint Infection Following Total Joint Arthroplasty?

BACKGROUND: Intraoperative dexamethasone can reduce postoperative pain and nausea following total knee (TKA) and total hip arthroplasty (THA). To the best of our knowledge, no study to date has been adequately powered to detect the risk of periprosthetic joint infection (PJI) from early dexamethasone exposure. This study aimed to assess PJI rates and complications in patients undergoing primary elective TKA and THA who received intraoperative dexamethasone. METHODS: A national database was used to identify adults undergoing primary elective TKA and THA between 2015 and 2020. Patients who received intraoperative dexamethasone and those who did not were identified. The primary endpoint was 90-day risk of infectious complications. Secondary end points included thromboembolic, pulmonary, renal, and wound complications. Multivariate analyses were performed to assess the risk of all endpoints between cohorts. Between 2015 and 2020, 1,322,025 patients underwent primary elective TJA, of which 857,496 (64.1%) underwent TKA and 474,707 (35.9%) underwent TKA. RESULTS: In patients who underwent TKA, dexamethasone was associated with lower risk of PJI (adjusted odds ratio: 0.87, 95% CI: 0.82-0.93, P < .001) as well as other secondary endpoints such as pulmonary embolism, deep vein thrombosis, and acute kidney injury. In patients who underwent THA, dexamethasone was associated with a lower risk of PJI (adjusted odds ratio: 0.80, 95% CI: 0.73-0.86, P < .001) as well as other secondary endpoints such as pulmonary embolism, deep vein thrombosis, acute kidney injury, and pneumonia. CONCLUSION: Intraoperative dexamethasone was not associated with increased risk of infectious complications. The data presented here provide evidence in support of intraoperative dexamethasone utilization during primary TKA or THA.

Safety and Efficacy of Rivaroxaban in Primary Total Hip and Knee Arthroplasty.

BACKGROUND: An optimal venous thromboembolism prophylaxis agent should balance efficacy and safety. While rivaroxaban provides effective venous thromboembolism prophylaxis after total joint arthroplasty, it may be associated with higher rates of bleeding. This study aimed to compare the safety and efficacy of rivaroxaban to aspirin and enoxaparin. METHODS: A large national database was queried for patients who underwent elective primary total hip (THA) or total knee arthroplasty (TKA) from January 2015 through December 2020 who received rivaroxaban, aspirin, or enoxaparin. Multivariate analyses were performed to assess the 90-day risk of bleeding and thromboembolic complications. Among TKA patients identified, 86,721 (10.8%) received rivaroxaban, 408,038 (50.8%) received aspirin, and 108,377 (13.5%) received enoxaparin. Among THA patients, 42,469 (9.5%) received rivaroxaban, 242,876 (54.5%) received aspirin, and 59,727 (13.4%) received enoxaparin. RESULTS: After accounting for confounding factors, rivaroxaban was associated with increased risk of transfusion (TKA: adjusted odds ratio [aOR] = 2.58, P < .001; THA: aOR 1.64, P < .001), pulmonary embolism (TKA: aOR = 1.25, P = .007), and deep vein thrombosis (TKA: aOR = 1.13, P = .022) compared to aspirin. Compared to enoxaparin, rivaroxaban was associated with an increased risk of combined bleeding events (TKA: aOR = 1.07, P < .001, THA: aOR = 1.11, P < .001), but decreased risk of combined prothrombotic events (THA: aOR = 0.85, P = .036). CONCLUSION: Rivaroxaban chemoprophylaxis following TKA and THA was associated with an increased risk of bleeding and prothrombotic complications compared to aspirin and enoxaparin.

Aspirin for Venous Thromboembolic Prophylaxis Following Total Hip and Total Knee Arthroplasty: An Analysis of Safety and Efficacy Accounting for Surgeon Selection Bias.

BACKGROUND: Aspirin may be effective at preventing venous thromboembolism following total knee arthroplasty (TKA) or total hip arthroplasty (THA). Current evidence is limited by bias as many surgeons who use aspirin prescribe for high-risk patients alternative chemoprophylactic agents. Therefore, this study aimed to evaluate the risk of pulmonary embolism (PE) and deep vein thrombosis (DVT) in patients who received aspirin and warfarin while accounting for surgeon selection bias. METHODS: A national database was queried for patients undergoing primary elective TKA or THA from 2015 to 2020. Patients whose surgeon used aspirin in >90% of their patients were compared to patients whose surgeon used warfarin in >90% of cases. Instrumental variable analyses were performed to assess for PE, DVT, and transfusion while accounting for selection bias. Among TKA patients, 26,657 (18.8%) were in the warfarin cohort and 115,005 (81.2%) were in the aspirin cohort. Among THA patients, 13,035 (17.7%) were in the warfarin cohort and 60,726 (82.3%) were in the aspirin cohort. RESULTS: Analyses were unable to identify a difference in the risk of PE (TKA: adjusted odds ratio [aOR]: 0.98, P = .659; THA: aOR = 0.93, P = .310) and DVT (TKA: aOR = 1.05, P = .188; THA: aOR = 0.96, P = .493) between the aspirin and warfarin cohorts. However, the aspirin cohort was associated with a lower risk of transfusion (TKA: aOR = 0.58, P < .001, THA: 0.84, P < .001). DISCUSSION: After accounting for surgeon selection bias, aspirin was as effective as warfarin at preventing PE and DVT following TKA and THA. Furthermore, aspirin was associated with a lower risk of transfusion compared to warfarin.

Does Prednisone Dose Affect Rates of Periprosthetic Joint Infection Following Primary Total Hip and Total Knee Arthroplasty?

BACKGROUND: Prednisone use is associated with higher rates of periprosthetic joint infection (PJI) following total joint arthroplasty (TJA). However, the relationship between prednisone dosage and infection risk is ill-defined. Therefore, this study aimed to assess the relationship between prednisone dosage and rates of PJI following TJA. METHODS: A national database was queried for all elective total hip (THA) and total knee arthroplasty (TKA) patients between 2015 and 2020. Patients who received oral prednisone following TJA were matched in a 1:2 ratio based on age and sex to patients who did not. Univariate and multivariate regression analyses were performed to assess the 90-day risk of infectious complications based on prednisone dosage as follows: 0 to 5, 6 to 10, 11 to 20, 21 to 30, and >30 milligrams. Overall, 1,322,043 patients underwent elective TJA (35.9% THA, 64.1% TKA). Of these, 14,585 (1.1%) received prednisone and were matched to 29,170 patients who did not. RESULTS: After controlling for confounders, TKA patients taking prednisone were at increased risk for sepsis (adjusted odds ratio [aOR] 2.76, P < .001), PJI (aOR 2.67, P < .001), and surgical site infection (aOR: 2.56, P = .035). THA patients taking prednisone were at increased risk for sepsis (aOR: 3.21, P < .001) and PJI (aOR: 1.73, P = .001). No dose-dependent relationship between prednisone and infectious complications was identified when TJA was assessed in aggregate. CONCLUSION: Patients receiving prednisone following TJA were at increased risk of PJI and sepsis. A dose-dependent relationship between prednisone and infectious complications was not identified. Arthroplasty surgeons should be aware of these risks and counsel TJA patients who receive prednisone therapy.