The Careful Return of Sports Medicine Procedures in the United States During COVID-19: Comparison of Utilization, Patient Demographics, and Complications.

OBJECTIVES: Sports medicine procedures encompass some of the highest-volume elective surgeries performed annually. Elective surgery was suspended because of the severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic; therefore, the purpose was to compare temporal trends in procedural volume, patient demographics, and postoperative complications of elective sports medicine procedures in 2019 and 2020. METHODS: Using a multicenter, nationwide sample, a retrospective query of the 2019 to 2020 American College of Surgeon's National Surgery Quality Improvement Program database was conducted for all patients undergoing common elective sports medicine procedures. Temporal trends in utilization, demographics, and 30-day complications were compared pre-COVID (2019 and 2020Q1) with post-COVID (2020Q2-Q4). Linear regression was used to evaluate changes in procedural volume over time. A significance threshold of P < 0.05 was used. RESULTS: A total of 48,803 patients underwent elective surgery in 2019 (n = 27,883) and 2020 (n = 20,920), a 25.0% decline. Procedural utilization declined by 42.5% in 2020Q2 and never returned to prepandemic baseline in 2020Q3-Q4. The percentage decline in case volume from 2019 to 2020Q2 was greatest for meniscectomy (47.6%), rotator cuff repair (42.7%), labral repair (41.6%), biceps tenodesis (41.3%), and anterior cruciate ligament reconstruction (38.5%). Total complication rates were similar in 2019 (1.31%) versus 2020 (1.51%; P = 0.072). The 30-day readmission (0.74% versus 0.67%; P = 0.374), reoperation (0.35% versus 0.35%; P = 0.963), and mortality (0.01% versus 0.01%; P = 0.657) rates were similar between calendar years. CONCLUSIONS: Sports medicine procedures declined during the second quarter of 2020. Despite pandemic restrictions, patients who did undergo surgery did not experience increased complications. The present study may be used by surgeons, hospitals, and subspecialty societies to support the careful utilization of elective surgery during COVID-19. LEVEL OF EVIDENCE: III, prognostic study.

How does sleep apnea impact outcomes following primary total hip arthroplasty for femoral neck fractures: a matched-control analysis.

BACKGROUND: Cross-sectional studies have demonstrated that the prevalence of sleep apnea (SA) to be increasing within the United States. While studies have shown the association of SA and its association on complications following elective orthopedic procedures, well-powered studies investigating its impact in a traumatic setting are limited. The purpose of this study was to determine whether SA patients undergoing primary total hip arthroplasty (THA) for femoral neck fractures have higher rates of: (1) hospital lengths of stay (LOS); (2) readmissions; (3) complications; and (4) healthcare expenditures. METHODS: The 100% Medicare Standard Analytical Files was queried from 2005 to 2014 for patients who sustained femoral neck fractures and were treated with primary THA. The study group consisted of patients with concomitant diagnoses of SA, whereas patients without SA served as controls. Study group patients were matched to controls in a 1:5 ratio by age, sex, and various comorbid conditions. Demographics of the cohorts were compared using Pearson's chi-squared analyses, and multivariate logistic regression analyses were used to calculate the odds (OR) of the effects of SA on postoperative outcomes. A p value less than 0.006 was considered to be statistically significant. RESULTS: The final query yielded 24,936 patients within the study (n = 4166) and control (n = 20,770) cohorts. SA patients had significantly longer in-hospital LOS (6 vs. 5 days, p < 0.0001) but similar readmission rates (24.12 vs. 20.50%; OR: 1.03, p = 0.476). SA patients had significantly higher frequency and odds of developing medical complications (72.66 vs. 43.85%; OR: 1.57, p < 0.0001), and higher healthcare costs ($22,743.79 vs. $21,572.89, p < 0.0001). CONCLUSION: SA is associated with longer in-hospital LOS, higher rates of complications and healthcare expenditures. This study is vital as it can allow orthopaedists to educate patients with SA on the potential complications which may occur following their procedure. LEVEL OF EVIDENCE: III.

The 5-Item Modified Frailty Index for Risk Stratification of Patients Undergoing Total Elbow Arthroplasty.

BACKGROUND: Frailty, quantified using the 5-item modified frailty index (mFI-5), has been shown to predict adverse outcomes in orthopaedic surgery. The utility in total elbow arthroplasty (TEA) patients is unclear. We evaluated if increasing frailty would correlate with worse postoperative outcomes. METHODS: A retrospective assessment of patients in the American College of Surgeons National Surgery Quality Improvement Program undergoing primary TEA was performed. The mFI-5 was calculated by assigning 1 point for each comorbidity (diabetes, hypertension, congestive heart failure, chronic obstructive pulmonary disease, and functionally dependent health status). Poisson regression was used to evaluate mFI-5 scores on complications, length of stay (LOS), and adverse discharge. A significance threshold was at P < .05. RESULTS: In total, 609 patients were included; 34.5% (n = 210) were not frail (mFI = 0), 44.0% (n = 268) were slightly frail (mFI = 1), and 21.5% (n = 131) were frail (mFI ≥ 2). As mFI score increased from 0 to ≥ 2, the following rates increased: any complication (9.0%-19.8%), major complication (11.0%-20.6%), cardiac complication (0.0%-2.3%), hematologic complication (3.3%-9.2%), adverse discharge (2.9%-22.9%), and LOS from 2.08 to 3.97 days (all P < .048). Following adjustment, Poisson regression demonstrated patients with a mFI ≥ 2 had increased risk of major complication (risk ratio [RR]: 2.13; P = .029), any complication (RR: 2.49; P = .032), Clavien-Dindo IV complication (RR: 5.53; P = .041), and adverse discharge (RR: 5.72; P < .001). CONCLUSIONS: Frailty is not only associated with longer hospitalizations, but more major complications and non-home discharge. The mFI-5 is a useful risk stratification that may assist in decision-making for TEA.

The effects of the COVID-19 pandemic on elective unicompartmental knee arthroplasty in the USA: further evidence that outpatient arthroplasty is safe and effective.

PURPOSE: In response to COVID-19, elective surgeries including unicompartmental knee arthroplasties (UKA) decreased. We aimed to quantify and compare temporal trends in utilization and complications in the calendar year 2019 (pre-pandemic) to 2020 in the USA. METHODS: The 2019 to 2020 ACS-NSQIP database was queried for patients undergoing elective UKA. Patients prior to COVID-19 (2019 and 2020 Q1) were compared to those after (2020 Q2-Q4). Case volumes, patient demographics, complications, and lengths of stay (LOS) were compared between years. Pearson's chi-square test was used to compare patient demographics. Linear regression was conducted to evaluate the change in case volumes. P values less than 0.05 were significant. RESULTS: In total, 3361 patients underwent UKA: 1880 in 2019 and 1481 in 2020. The number of outpatient UKAs increased (56.4% vs. 65.6%; p < 0.001). There was no significant difference in the volume of cases in 2019Q1 through 2020Q1 (p = 0.424). Case volumes fell by 60% in 2020Q2 compared with the average quarterly volume in 2019. Comparing 2019 to 2020, there was no significant difference in rates of total complications (2.1% vs. 2.2%; p = 0.843), minor complications (1.2% vs. 0.9%; p = 0.529), major complications (1.1% vs. 1.4%; p = 0.447), infection complications (1.0% vs. 0.8%; p = 0.652), wound complications (0.1% vs. 0.1%; p = 1.0), cardiac complications (0.0% vs. 0.1%; p = 0.111), pulmonary complications (0.1% vs. 0.2%; p = 0.473), hematology complications (0.1% vs. 0.1%; p = 1.0), renal complications (0.1% vs. 0.0%; p = 1.0), and Clavien-Dindo IV complications (0.1% vs. 0.4%; p = 0.177). CONCLUSION: UKA case volumes declined during the second quarter of 2020. A significant proportion of surgeries were transitioned outpatient, despite no change in complication rates.

The Effect of the Coronavirus Disease 2019 (COVID-19) Pandemic on Elective Cervical Spine Surgery Utilization and Complications in the United States: A Nationwide Temporal Trends Analysis.

OBJECTIVES: As a result of the coronavirus disease 2019 (COVID-19) pandemic, elective surgeries nationwide were suspended. The objective was to compare temporal trends in patient demographics, case volumes, and postoperative complications of patients undergoing elective cervical spine surgery from pre-COVID-19 (2019-2020 Q1) to post-COVID-19 (2020 Q2-Q4). METHODS: The 2019 to 2020 American College of Surgeon's National Surgery Quality Improvement Program database was queried for common elective cervical spine surgeries. Patients pre-COVID-19 (2019-2020 Q1) were compared with those undergoing surgery during post-COVID-19 (2020 Q2-Q4) protocols. Procedural use, patient demographics, and complications were compared. Linear regression was used to evaluate case volume changes over time. P values less than 0.05 were significant. RESULTS: In total, 31,013 patients underwent elective cervical spine surgery in 2019 (N = 16,316) and 2020 (N = 14,697); an overall 10% decline. Compared with the calendar year 2019 through 2020 Q1 mean, elective surgery volume decreased by 21.6% in 2020 Q2 and never returned to prepandemic baseline. The percentage decline in case volume from 2019 to 2020 Q1 to 2020 Q2 was greatest for anterior cervical discectomy and fusion (23.3%), followed by cervical decompression (23.4%), posterior cervical fusion (15.0%), and cervical disc arthroplasty and vertebral corpectomy (13.7%). Patients undergoing surgery in 2020 Q2-Q4 had overall greater comorbidity burden (American Society of Anesthesiologists grade 3 and 4) (P < 0.001). From 2019-2020 Q1 versus 2020 Q2-Q4, there was a significant increase in total complication (5.5% vs. 6.8%, P < 0.001), reoperation (1.9% vs. 2.2%, P = 0.048), and mortality (0.25% vs. 0.37%, P = 0.049) rates. CONCLUSIONS: Elective surgery declined drastically during the second quarter of 2020. Patients undergoing surgery during the pandemic had an overall greater comorbidity burden, resulting in increased total complication and mortality rates over the study period.

Resident and Fellow Participation Does Not Affect Short-Term Postoperative Complications After Distal Radius Fracture Fixation.

Background Complications after open reduction internal fixation (ORIF) for distal radius fractures (DRF) are well documented, but the impact of trainee involvement on postoperative outcomes has not been studied. Questions Does trainee involvement affect postoperative complication rates and length of hospital stay? Methods The American College of Surgeons National Surgical Quality Improvement Program was queried from 2006 to 2012 for patients undergoing DRF ORIF. A 1:1 propensity score matched resident/fellow involved cases to attending-only cases. Demographics, length of stay, and postoperative complications were compared between the two groups. Logistic regression was used to evaluate independent predictors of adverse events and to evaluate cases with and without trainee involvement. Results Overall, 3,003 patients underwent DRF ORIF from 2006 to 2012. After matching, 1,150 cases (50% with resident/fellow involvement) were included. The overall rate of adverse events was 4.4% (46/1,050). There were no significant differences in the short-term complication rate in trainee-involved (2.3%) versus attending-only cases (3.9%) ( p = 0.461). For ORIF of DRF, there were no significant differences, between attending-only cases and resident/fellow-involved cases, with regard to short-term major complications ( p = 0.720) or minor complications ( p = 0.374). Length of hospital stay was similar between cohorts (1.22 vs. 0.98 days) ( p = 0.723). On multivariate analysis, trainee involvement was not an independent predictor of minor, major, or any complication after DRF fixation after controlling for multiple independent factors (all p > 0.364). Discussion Trainee participation in DRF ORIF is not associated with increased risk of short-term (30 days) medical or surgical postoperative complications. Level of Evidence This is a Level IV case-control study.

The Effect of COVID-19 on Elective Total Knee Arthroplasty Utilization, Patient Comorbidity Burden, and Complications in the United States: A Nationwide Analysis.

INTRODUCTION: Total knee arthroplasty (TKA) is one of the highest volume elective procedures done nationwide. Elective surgery was suspended because of the COVID-19 pandemic. The utilization trends, comparison of patient demographics, and postoperative outcomes in 2020 have yet to be evaluated substantially. We compared temporal trends in procedural volume, patient demographics, and postoperative complications of elective TKA in 2019 and 2020. METHODS: Using a multicenter, nationwide representative sample, a retrospective query of the 2019 to 2020 American College of Surgeon's National Surgery Quality Improvement Program database was conducted for patients undergoing elective TKA. Temporal trends in utilization, demographics, and length of stay were compared pre-COVID-19 (2019 to 2020Q1) with post-COVID-19 (2020Q2 to Q4). Postoperative outcomes were compared by calendar year (2019 versus 2020). Linear regression was used to evaluate changes in procedural volume over time. A significance threshold of P < 0.05 was used. RESULTS: A total of 121,415 patients underwent elective TKA in 2019 (N = 72,002) and 2020 (N = 49,413), a 31.4% decline. The proportion of hospital-defined "outpatient" TKAs in 2020 was significantly greater than that in 2019 (41.5% versus 25.5%; P < 0.001). Elective TKA utilization declined by 65.1% in 2020Q2 and never returned to prepandemic baseline in 2020Q3 to Q4. The average length of stay was shorter in 2020 (1.56 versus 1.87 days; P < 0.001). The proportion of same-day discharge increased each quarter from 2019Q1 to Q4 (6.2% to 8.6%) to 2020Q1 to Q4 (8.7% to 17.1%). Total complication rates were similar in 2019 (4.84%) versus 2020 (4.75%); P = 0.430. The 30-day mortality (0.08% versus 0.07%; P = 0.858), revision surgery (1.0% versus 1.0%; P = 0.940), and readmission (2.8% versus 2.6%; P = 0.053) rates were no different between 2019 and 2020. CONCLUSION: Elective TKA declined during the second quarter of 2020. A large proportion of surgeries were transitioned to outpatient with rates of same-day discharge increasing over the study period, despite no change in complication, mortality, and readmission rates. Patient outcomes were not compromised despite pandemic restrictions for elective surgery. LEVEL OF EVIDENCE: Level III.

The combined effect of policy changes and the covid-19 pandemic on the same day discharge and complications following total hip arthroplasty: a nationwide analysis.

INTRODUCTION: As a result of the SARS-CoV-2 (COVID-19) pandemic in 2020, elective surgeries, including total joint arthroplasty (TJA), were suspended nationwide. Concurrent removal of total hip arthroplasty (THA) from the Medicare inpatient-only list posed challenges to the delivery of quality patient care with low payor cost. Therefore, the objective of this study was to compare temporal trends in patient demographics, case volumes, length of stay, and complications following elective THA in the years 2019 to 2020 in the United States. METHODS: The 2019 to 2020 ACS-NSQIP database was queried for elective THA patients. Patients Pre-COVID (2019 and 2020Q1) were compared with post-COVID (2020Q2-Q4). THA utilization, demographics, 30-day complications, and length of stay (LOS) were compared between years. Linear regression evaluated changes in case volumes over time with significance threshold of P < 0.05. RESULTS: A total of 77,797 patients underwent elective THA in 2019 (n = 43,667) and 2020 (n = 34,130), resulting in a 24.5% decline. Outpatient THA increased in 2020 (35.6%) vs. 2019 (5.7%) (P < 0.001). There was no significant difference in the volume of cases in 2019Q1 through 2019Q4 (P = 0.984). Elective THA volumes declined by 68.8% in 2020Q2, returned to pre-pandemic baseline in 2020Q3, before leveling off at 81.5% of baseline in Q4. Average LOS was significantly shorter in 2020 (1.55 days) vs. 2019 (1.78 days) (P < 0.001) and the proportion of same day discharge (SDD) increased quarterly from 2019 to 2020. There was no significant difference in the total complication rates in 2019 (6.6%) vs. 2020 (6.6%) (P = 0.831). DISCUSSION: Elective THA precipitously declined during the second quarter of 2020. The combined effect of policy changes and the COVID-19 pandemic resulted in a seven-fold increase in the number of surgeries performed in the outpatient setting in 2020. Rates of SDD doubled over the study period, despite no change in complication rates.

The resiliency of elective total shoulder arthroplasty case volumes in the United States during the COVID-19 pandemic: a nationwide temporal trends analysis.

BACKGROUND: Total shoulder arthroplasty (TSA) is one of the fastest growing procedures in terms of volume performed in hospitals in the United States. In 2020, elective surgery was suspended nationwide as a result of the SARS-CoV-2 (COVID-19) pandemic, and the use trends in the wake of the pandemic have yet to be evaluated substantially. Nationwide case volume reduction for TSA is unknown; therefore, the aim of this study is to compare patient demographics, complications, and temporal trends in case volume of elective TSA in the calendar year 2019 (prepandemic) to 2020 in the United States. METHODS: Using a multicenter, nationwide representative sample from 2019 to 2020, a retrospective query was conducted for all patients undergoing elective TSA. Patients undergoing surgery pre-COVID (2019 and 2020 Q1) were compared to those during COVID (2020 Q2-Q4). Temporal trends in case volumes were compared between time frames. TSA use, patient demographics, complications, and length of stay were compared between years. Linear regression was used to evaluate for changes in the case volume over the study period. A statistical significance threshold of P <.05 was used. RESULTS: In total, 9667 patients underwent elective TSA in 2019 (n = 5342) and 2020 (n = 4325). The proportion of patients who underwent outpatient TSA in 2020 was significantly greater than the year prior (20.6% vs. 13.9%; P < .001). Overall, elective TSA case volume declined by 19.0% from 2019 to 2020. There was no significant difference in the volume of cases in 2019 Q1 (n = 1401) through 2020 Q1 (n = 1296) (P = .216). However, elective TSA volumes declined by 54.6% in 2020 Q2. Elective TSA case volumes recovered to prepandemic baseline in 2020 Q3 and 2020 Q4. The average length of stay was comparable in 2020 vs. 2019 (1.29 vs. 1.32 days; P = .371), with the proportion of same-day discharge increasing per quarter from 2019 to 2020 (from 11.8% to 26.8% of annual cases). There was no significant difference in the total complication rates in 2019 (4.6%) vs. 2020 (4.9%) (P = .441). CONCLUSION: Using a nationwide sample, elective TSA precipitously declined during the second quarter of 2020. Patient demographics of those undergoing elective TSA in 2020 were similar in comorbidity burden. A large proportion of surgeries were transitioned to the outpatient setting, with rates of same-day discharge doubling over the study period despite no change in overall complication rates.

Comparison of patient-demographics, causes, and costs of 90-day readmissions following primary total shoulder arthroplasty for glenohumeral osteoarthritis.

Introduction: Readmissions following orthopaedic surgery are associated with worse outcomes and increased healthcare costs. Studies investigating trends, causes, and costs of readmissions following primary total shoulder arthroplasty (TSA) for the indication of glenohumeral osteoarthritis (OA) are limited. The objective was to compare: 1) patient-demographics of those readmitted and not readmitted within 90-days following primary TSA for OA; 2) causes of readmissions and 3) associated costs. Methods: A retrospective query from 2005 to 2014 was performed using a nationwide administrative claims database. The study group consisted of patients readmitted within 90-days following primary TSA for glenohumeral OA, whereas patients not readmitted served as controls. Causes of readmission were stratified into the following groups: cardiovascular, hematological, endocrine, gastrointestinal (GI), musculoskeletal (MSK), neoplastic, neurological, pulmonary, infectious, renal, and miscellaneous causes. Patient demographics were compared, in addition to the frequency of the causes of readmissions, and their associated costs. Chi-square analyses compared demographics between groups. Analysis of variance was utilized to determine differences in 90-day costs for the causes of readmission. A p-value less than 0.001 was significant. Results: The overall 90-day readmission rate was 2.4% (3432/143,878). Patients readmitted following primary TSA were more likely to be over the age of 75, female, and higher prevalence of comorbid conditions, including psychiatric and medical conditions. Readmitted patients had a higher overall comorbidity burden per mean Elixhauser-Comorbidity Index (ECI) scores (10 vs. 7,p < .0001). The leading cause of readmissions were due to MSK (17.34%), cardiac (16.28%), infectious (16.26%), and gastrointestinal (11.64%) etiologies. There were differences in the mean 90-day costs of care for the various causes of readmissions, with the leading cost of readmissions being cardiac causes ($10,913.70) and MSK ($10,590.50) etiologies. Conclusion: Patients with greater comorbidities experienced increased incidence of readmission following TSA for glenohumeral OA. Cardiac and MSK etiologies were the primary cause of readmissions. Level of evidence: III.

How Did Coronavirus-19 Impact the Expenses for Medical Students Applying to an Orthopaedic Surgery Residency in 2020 to 2021?

BACKGROUND: Orthopaedic surgery is one of the most competitive specialties for residency applicants. For the 2021 residency match, the coronavirus-19 pandemic introduced complexity for programs and applicants because away rotations were limited and in-person interviews were cancelled. This may have changed the landscape in terms of expenses for candidates in important ways, but this topic has been insufficiently studied. QUESTIONS/PURPOSES: Given that in 2021, students did not attend away rotations and all interviews were held virtually, we asked (1) What were the financial savings associated with this change? (2) Was medical school geographic region associated with differences in expenses when applying to residency? METHODS: A retrospective, cross-sectional analysis of the 2020 and 2021 Texas Seeking Transparency in Application to Residency Dashboard database was performed. The data were derived from an online survey of a nationwide pool of applicants from 87% (123 of 141) of US allopathic medical schools upon conclusion of the match. The response percentage was 29% (521 of 1794). We believe this nationwide dataset represents the largest and most current data for this applicant group. Responses from applicants applying to orthopaedic surgery residency in the year before the COVID-19 pandemic application changes (2020) and during COVID-19 (2021) were queried and compared. After the orthopaedic surgery match, the database was evaluated for individual (application costs, away rotation expenses, and interview expenses) and total expenses for medical school seniors applying to orthopaedic surgery residency. Applicant characteristics were compared between application cycles. The 2020 to 2021 Texas Seeking Transparency in Application to Residency Dashboard database had 521 responses (n = 263 in 2020 and n = 258 in 2021) from applicants applying to orthopaedic surgery residency. Demographic and applicant characteristics were comparable between application cycles. Median expenses are reported with percentile distributions and geographic comparisons. A Mann-Whitney U test or Kruskal-Wallis H test was used to determine whether there were statistically significant differences in expenses between years and between medical school regions at a p value threshold of < 0.05. RESULTS: For all applicants, the median total expenses (USD 7250 versus USD 2250), application costs (USD 2250 versus USD 1750), away rotation expenses (USD 2750 versus USD 250), and interview expenses (USD 2250 versus USD 75) declined in 2021 compared with 2020 (all p < 0.001). The median total savings in expenses for all applicants in 2021 compared with 2020 was USD 5000. In 2021, median total expenses were lower in all geographic regions with the greatest savings from applicants in the West (USD 6000); in addition, the difference in median total expenses between the geographic region with the highest total expenses and the lowest total expenses was lower in the pandemic year than it was in the year prior (USD 1000 versus USD 1500; p < 0.001). In 2021, there were differences in total expenses between the Northeast (USD 1750), West (USD 1750), and Central (USD 2750) regions (p < 0.001). From 2020 to 2021, only application fees from Northeast applicants differed (USD 2250 versus USD 1250; p < 0.001). In 2020, interview expenses were not different between all regions (USD 2250 Northeast and West versus USD 2750 Central and South; p = 0.19); similarly in 2021, interview expenses were similar between all regions (USD 75 versus USD 75; p = 0.82). Finally, in 2020, Northeast (USD 3250) and Western (USD 3250) applicants spent more for away rotations than Southern (USD 2750) and Central (USD 2250) applicants (p = 0.01). In 2021, applicants from schools in the South (USD 250) and Central (USD 250) regions spent more than their counterparts (USD 0; p = 0.028). CONCLUSION: In the COVID-19 application cycle, the median expenditures of orthopaedic residency candidates were USD 5000 lower than they were in the previous year; the difference can be attributed to the use of virtual interviews and the lack of away rotations. There are geographic implications, with applicants from Western United States medical schools potentially saving the most. Despite the financial savings during the 2021 match, further study related to the long-term success of the current application process (both for applicants and programs) is needed. The recommendation in May 2020 by the AOA Council of Orthopaedic Residency Directors (CORD) to limit the number of applications submitted by candidates with USMLE Step 1 scores greater than 235 did not result in any considerable decline in applications submitted or expenses. A better understanding of how differences in these expenses may influence our specialty's ability to attract socioeconomically diverse candidates would be important, and we need to explore perceived and actual financial obstacles to obtaining this diversity in the application process. Finally, avenues should be explored by program directors and chairpersons to reduce the expenses of the traditional application process while maintaining recruitment of top candidates. LEVEL OF EVIDENCE: Level IV, economic analysis.

Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression.

We evaluated the clinical validity of a combinatorial pharmacogenomic test and single-gene Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines against patient outcomes and medication blood levels to assess their ability to inform prescribing in major depressive disorder (MDD). This is a secondary analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) randomized-controlled trial, which included patients with a diagnosis of MDD, and ≥1 prior medication failure. The ability to predict increased/decreased medication metabolism was validated against blood levels at screening (adjusted for age, sex, smoking status). The ability of predicted gene-drug interactions (pharmacogenomic test) or therapeutic recommendations (single-gene guidelines) to predict patient outcomes was validated against week 8 outcomes (17-item Hamilton Depression Rating Scale; symptom improvement, response, remission). Analyses were performed for patients taking any eligible medication (outcomes N=1,022, blood levels N=1,034) and the subset taking medications with single-gene guidelines (outcomes N=584, blood levels N=372). The combinatorial pharmacogenomic test was the only significant predictor of patient outcomes. Both the combinatorial pharmacogenomic test and single-gene guidelines were significant predictors of blood levels for all medications when evaluated separately; however, only the combinatorial pharmacogenomic test remained significant when both were included in the multivariate model. There were no substantial differences when all medications were evaluated or for the subset with single-gene guidelines. Overall, this evaluation of clinical validity demonstrates that the combinatorial pharmacogenomic test was a superior predictor of patient outcomes and medication blood levels when compared with guidelines based on individual genes.

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic®; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes.

The response of Escherichia coli to the alkylating agents chloroacetaldehyde and styrene oxide.

DNA damage is ubiquitous and can arise from endogenous or exogenous sources. DNA-damaging alkylating agents are present in environmental toxicants as well as in cancer chemotherapy drugs and are a constant threat, which can lead to mutations or cell death. All organisms have multiple DNA repair and DNA damage tolerance pathways to resist the potentially negative effects of exposure to alkylating agents. In bacteria, many of the genes in these pathways are regulated as part of the SOS reponse or the adaptive response. In this work, we probed the cellular responses to the alkylating agents chloroacetaldehyde (CAA), which is a metabolite of 1,2-dichloroethane used to produce polyvinyl chloride, and styrene oxide (SO), a major metabolite of styrene used in the production of polystyrene and other polymers. Vinyl chloride and styrene are produced on an industrial scale of billions of kilograms annually and thus have a high potential for environmental exposure. To identify stress response genes in E. coli that are responsible for tolerance to the reactive metabolites CAA and SO, we used libraries of transcriptional reporters and gene deletion strains. In response to both alkylating agents, genes associated with several different stress pathways were upregulated, including protein, membrane, and oxidative stress, as well as DNA damage. E. coli strains lacking genes involved in base excision repair and nucleotide excision repair were sensitive to SO, whereas strains lacking recA and the SOS gene ybfE were sensitive to both alkylating agents tested. This work indicates the varied systems involved in cellular responses to alkylating agents, and highlights the specific DNA repair genes involved in the responses.

Synthesis and SAR of calcitonin gene-related peptide (CGRP) antagonists containing substituted aryl-piperazines and piperidines.

Calcitonin gene-related peptide (CGRP) is a potent neuropeptide implicated in the pathophysiology of migraine. In the course of seeking CGRP antagonists with improved oral bioavailability, metabolic stability, and pharmacokinetic properties, lower molecular weight, structurally simpler piperidine and piperazine analogs of BMS-694153 were prepared. Several were found to have nM binding affinity in vitro. The synthesis and SAR of these substituted piperidine and piperazine CGRP antagonists are discussed.

Successful use of right unilateral ECT for catatonia: a case series.

Catatonia is a neuropsychiatric syndrome involving motor signs in association with disorders of mood, behavior, or thought. Bitemporal electrode placement electroconvulsive therapy (ECT) is a proven effective treatment for catatonia, and this mode of ECT delivery is the preferred method of treatment in this condition. Studies in major depressive disorder have demonstrated that suprathreshold, nondominant (right) hemisphere, unilateral electrode placement ECT has fewer adverse effects, especially cognitive adverse effects, than bitemporal ECT. This case series describes the use of right unilateral (RUL) ECT in 5 patients with catatonia. Before ECT, all 5 patients in this series initially failed therapy with benzodiazepines and psychotropic medications. Each catatonic patient received a series of 8 to 12 RUL ECT in an every-other-day series. After ECT, 4 of the 5 patients had a full recovery from catatonia. One patient achieved only partial response to RUL ECT, and no additional benefit was obtained with bitemporal ECT. All patients in this case series tolerated RUL ECT without major adverse effects. This case series illustrates successful use of RUL ECT in patients with catatonia and adds to the early literature demonstrating its effective use in treating this complex condition.

Preparation of imidazoles as potent calcitonin gene-related peptide (CGRP) antagonists.

Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability.

90% hepatectomy with a porto-hepatic shunt in a canine model: a feasibility study.

BACKGROUND: We postulated that a surgical shunt between the portal and hepatic veins (portohepatic shunt) could improve the function and regeneration of the liver remnant after extensive hepatic resection. Using a canine model, we designed a survival study to test the feasibility of 90% hepatectomy with a portohepatic shunt. Of eight mixed-hound canines, it was necessary to sacrifice two animals for postmortem study of hepatic anatomy; we used the results to design a procedure for removing all of the liver except portions of two lobes. We tested this 90% hepatectomy procedure under general anesthesia in the remaining animals, with (N=3) or without (N=3) a portohepatic shunt. We monitored animals postoperatively with serial liver biochemical testing, and sacrificed on postoperative day 48. Assessment of liver regeneration was by weight after complete postmortem hepatectomy. Extended hepatectomy removed four complete lobes and portions of the right lateral and caudate lobes. For the portohepatic shunt, we anastomosed the left portal vein branch to the left hepatic vein branch. All procedures were performed successfully. One no-shunt animal expired on the second postoperative day. We thus confirmed the feasibility of 90% hepatectomy with portohepatic shunt in the canine model. If the efficacy of shunting is validated in a larger study population, it may increase the indications for extensive resection in patients with advanced hepatic malignancy.