Preemptive multimodal analgesia and post-operative pain outcomes in total hip and total knee arthroplasty.

BACKGROUND: Use of multimodal analgesia (MMA) prior to orthopedic surgery has been adopted by many practitioners as a strategy to minimize use of opioid medications. The purpose of this investigation was to quantify the effect of a preemptive three-drug regimen (acetaminophen, celecoxib, and gabapentin) in terms of post-operative opioid consumption and pain control in the field of total joint arthroplasty. METHODS: A retrospective chart review was conducted on 1691 patients who underwent total hip arthroplasty (THA) or total knee arthroplasty (TKA) and stratified by whether they received a preemptive three medication analgesic therapy (acetaminophen, celecoxib, and gabapentin) within 30 to 60 min prior to entering the operating room. Post-operative opioid consumption as well as subjectively reported patient pain scores were assessed throughout their hospital stay. RESULTS: A total of 1416 eligible patients were identified with 485 undergoing THA and 931 undergoing TKA. Statistically significant reductions in oral morphine equivalents were shown on post-operative day zero and two within the TKA cohort, and non-significant reductions were demonstrated in other intervals for both procedure types. Statistically significant reductions in patient reported pain scores were shown in nearly every time interval in both procedure types. CONCLUSION: The receipt of preemptive acetaminophen, celecoxib, and gabapentin 30-60 min prior to total joint arthroplasty demonstrated modest reductions in opioid requirements post-operatively. Patients receiving preemptive MMA reported lower pain scores throughout nearly every time interval during their admission after surgery. Further investigations are warranted regarding optimal preoperative medication therapies to promote adequate post-operative pain control-and ultimately diminished opioid consumption-in the setting of total joint arthroplasty.

Acute Common Peroneal Nerve Decompression After Total Knee Arthroplasty.

Common peroneal nerve palsy (CPNP) after total knee arthroplasty has a reported incidence of 0.3% to 4% and can lead to foot drop, equinovarus deformity, and marked disability if not resolved. Patients typically present in the early postoperative period with weakness or inability to dorsiflex the ankle and decreased sensation of the dorsum of the foot. The authors report their experience, technique, and outcomes of acute peroneal decompression within the first 90 days postoperatively for 5 patients with this unique complication. Preoperatively, all patients had valgus deformity with intact dorsiflexion and sensation of the foot. The diagnosis of CPNP was made on postoperative day 0 or 1 in all cases. After diagnosis, patients were offered acute peroneal decompression and returned to the operating room electively. The surgical technique for dissection, release, and decompression of the nerve is described. At an average follow-up of 12 weeks (range, 6-16 weeks), all patients showed return of motor and sensory function, as tested by ankle dorsiflexion and dorsal foot sensation, with average motor strength of 4.6 of 5.3. Acute decompression of acute CPNP after total knee arthroplasty is a prudent treatment option that provides good functional results and rapid recovery. [Orthopedics. 2021;44(4):e556-e562.].

Critical Elements of Community Engagement to Address Disparities and Related Social Determinants of Health: The Centers of Disease Control and Prevention Community Approaches to Reducing Sexually Transmitted Disease Initiative.

BACKGROUND: Community Approaches to Reducing Sexually Transmitted Disease (CARS), a unique initiative of the US Centers for Disease Control and Prevention, promotes the use of community engagement to increase sexually transmitted disease (STD) prevention, screening, and treatment and to address locally prioritized STD-related social determinants of health within communities experiencing STD disparities, including youth, persons of color, and sexual and gender minorities. We sought to identify elements of community engagement as applied within CARS. METHODS AND MATERIALS: Between 2011 and 2018, we collected and analyzed archival and in-depth interview data to identify and explore community engagement across 8 CARS sites. Five to 13 interview participants (mean, 7) at each site were interviewed annually. Participants included project staff and leadership, community members, and representatives from local community organizations (e.g., health departments; lesbian, gay, bisexual, transgender, and queer-serving organizations; faith organizations; businesses; and HIV-service organizations) and universities. Data were analyzed using constant comparison, an approach to grounded theory development. RESULTS: Twelve critical elements of community engagement emerged, including commitment to engagement, partner flexibility, talented and trusted leadership, participation of diverse sectors, establishment of vision and mission, open communication, reducing power differentials, working through conflict, identifying and leveraging resources, and building a shared history. CONCLUSIONS: This study expands the community engagement literature within STD prevention, screening, and treatment by elucidating some of the critical elements of the approach and provides guidance for practitioners, researchers, and their partners as they develop, implement, and evaluate strategies to reduce STD disparities.

N083E (Alliance): long-term outcomes of patients treated in a pilot phase II study of docetaxel, carboplatin, trastuzumab, and lapatinib as adjuvant therapy for early-stage HER2-positive breast cancer.

BACKGROUND: The addition of lapatinib (L) to trastuzumab (T) was previously found to be synergistic in preclinical models and in the neoadjuvant setting. Prior to the results of the ALTTO trial, this study assessed the safety and feasibility of adding L to the standard adjuvant docetaxel, carboplatin, and trastuzumab (TCH) regimen in early-stage HER2-positive breast cancer (HER2+ BC). METHODS: In this single-arm, 2-stage, phase II study, patients with stages I-III HER2+ BC received TCH plus L at 1000 mg daily for a total of 12 months. The primary endpoint was the safety and tolerability, including the rate of diarrhea. Secondary endpoints included adverse event (AE) profile using the NCI CTCAE v3.0 and cardiac safety. RESULTS: Thirty eligible patients were enrolled. Median follow-up is 5.3 years. Diarrhea was the most common AE with 50% Grade (G)1/2 and 43% G3 diarrhea. However, it was responsive to dose reduction of L (750 mg) and institution of anti-diarrheal medications. Cardiovascular AE were infrequent and no patients experienced congestive heart failure while on treatment. CONCLUSION: TCHL was a tolerable regimen at a starting L dose of 750 mg PO daily when given concurrently with chemotherapy.

Anterior Capsular Reconstruction Using a Dermal Allograft for an Irreparable Subscapularis Tear After Shoulder Arthroplasty: A Case Report.

CASE: A 51-year-old man was noted to have an irreparable subscapularis tear after total shoulder arthroplasty (TSA). Owing to positive reported results with superior capsular reconstruction, his insufficiency was addressed with anterior capsular reconstruction with use of a dermal allograft. Two-year follow-up results demonstrate good functional outcomes, no recurrent instability, and excellent patient satisfaction. CONCLUSIONS: Anterior shoulder insufficiency after TSA can significantly alter glenohumeral function and is an important cause of patient morbidity. This novel technique exhibits a good outcome and provides an alternative to previous methods of repair.

Well-Leg Rhabdomyolysis After Prolonged Knee Arthroscopy: A Case Report.

CASE: We present the case of an obese patient who underwent combined arthroscopic and open multiligamentous knee reconstruction who, 3 months later, required revision arthroscopic anterior cruciate ligament and posterior cruciate ligament reconstruction with open lateral collateral ligament and posterolateral corner reconstruction lasting 6 hours 30 minutes. The patient developed rhabdomyolysis of the nonoperative leg after the revision procedure. Both procedures were performed in a hemilithotomy position with a commonly used leg positioner. CONCLUSIONS: Complications secondary to patient positioning are a source of unnecessary patient morbidity. Surgeons should be mindful of the nonoperative extremity, particularly during prolonged cases in obese patients. Prompt diagnosis and multidisciplinary treatment can lead to the resolution of symptoms without long-term sequelae.

Displaced Meniscus Tear in the Acute Postoperative Period After Total Hip Arthroplasty: A Case Report.

CASE: Total hip arthroplasty (THA) is a commonly performed surgery with well-known complications. Unreported in the literature is a displaced meniscus tear in the acute postoperative period. We present the case of a displaced meniscus tear acutely after THA and discuss our management of this unique problem. CONCLUSIONS: Displaced meniscus tears after THA pose unique challenges and should be considered in patients with knee pain after THA. Arthroscopic intervention occurred 8 weeks after THA to minimize prosthetic joint dislocation and loosening during arthroscopy.

Mid-term outcomes following primary semi-constrained total knee arthroplasty in patients less than 60 years old, a retrospective review.

INTRODUCTION: Total knee arthroplasty (TKA) is a successful operation for osteoarthrosis. Typically, the knee can be balanced using posterior stabilized or cruciate retaining implants. However, in patients with severe deformity or ligamentous laxity, this cannot be obtained, and more constrained devices are needed. Semi-constrained implants, such as the Total Condylar III (TCIII) provide increased coronal stability. Outcomes in young (<60 years old) patients, following a primary semi-constrained TKA are not well reported in the literature. The purpose of this study was to evaluate patient reported outcomes, functional recovery, and implant survival in this population. METHODS: We performed a retrospective review of 21 patients, under the age of 60 years, that underwent primary semi-constrained TKA. Patient demographics, postoperative outcomes, patient satisfaction scores, and implant loosening were reported. RESULTS: At an average follow-up of 66 months, Knee Society Scores (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were 94.7 and 15.7, respectively. No difference in patient reported outcomes between 1 year and final follow-up were observed. Patient demographics such as age, BMI, and gender had no effect on functional outcomes. No cases of aseptic loosening were observed. Implant survivorship, patient satisfaction, and excellent or good results were reported in 100%, 85.7%, and 92%, respectively. CONCLUSION: In young patients, in which the knee cannot be effectively balanced with standard releases, the use of a semi-constrained TKA as a primary implant lead to positive patient reported outcomes and no evidence of loosening at mid-term follow-up.

Isolated Treatment of a Comminuted Capitate Fracture: A Case Report.

CASE: Comminuted fractures of the capitate, in the absence of associated carpal injuries, are exceedingly rare. Treatment of this complex injury is not well-documented in the literature. We describe the case of a comminuted capitate fracture that was successfully managed with Kirschner wire fixation. CONCLUSION: Based on this case and a review of the literature, management of a comminuted capitate fracture with Kirschner wire fixation can lead to successful treatment and positive patient outcomes.

Radiographic and Clinical Outcomes Following Robotic-Assisted Lateral Unicompartmental Knee Arthroplasty.

Much advancement has been made in the treatment of knee arthritis. A special area of interest has been the treatment of medial unicompartmental disease. However, patients with isolated lateral compartment arthritis represent a significant subset of the population. Lateral unicompartmental knee arthroplasty (UKA) is performed much less frequently than in the medial compartment and is known to be more technically demanding and less reproducible. Robotic-assisted arthroplasty provides a tool to improve component placement and reproducibility. The purpose of this study is to retrospectively review radiographic and clinical outcomes following robotic-assisted lateral UKA. We retrospectively reviewed 22 patients who underwent robotic-assisted lateral UKA by a single surgeon. Indications consisted of isolated lateral compartment arthritis with correctable valgus deformity and an intact anterior cruciate ligament. Eighteen patients met all inclusion criteria, resulting in 20 lateral UKA. Radiographic and clinical outcomes were evaluated and we found that robotic assistance during lateral UKA provided accurate and reproducible results. Native alignment of the tibia and femur were well maintained in the coronal and sagittal planes, and no overcorrection occurred. The standard deviation of tibial components was 1.8°, indicating strong accuracy and reproducibility. Operative times were increased, but this did not lead to intraoperative complications or slowed progression of postoperative rehabilitation. Robotic-assisted lateral UKA provides a tool for accurate and reproducible component placement with excellent short-term clinical outcomes.

Biomechanical Assessment of Torsional Stiffness in a Supracondylar Humerus Fracture Model.

BACKGROUND: We assessed the effect on the torsional stability by different pin diameters and varied pin configurations in a biomechanical supracondylar humerus fracture model. METHODS: After scanning a model of a pediatric humerus, the image was imported into software. Variable pin trajectories were planned. Acrylonitrile butadiene styrene plastic models were 3-dimensionally printed with predetermined pin trajectories. Models were osteotomized and potted with a polyurethane resin. Five-pin configurations were designed to test coronal and sagittal patterns of pin placement. Each included 3 lateral pins and a medial pin. Pin diameters of 1.6, 2.0, and 2.4 mm were tested in all configurations. Three models for each pin diameter/configuration were tested to ensure uniformity. Stability of the construct was tested to determine the torque needed to deflect the osteotomy 10 degrees in internal/external rotation. Each model was tested 3 times. RESULTS: In all models/configurations, the 2.4 mm pin diameter was statistically stiffer than 1.6 mm diameter pins; this lost statistical significance in certain patterns when comparing 2.0- and 2.4-mm pins. When comparing a divergent to a parallel configuration in the coronal plane, there was no significant difference in stability when pin diameter or number were controlled. The convergent pin configuration was, in general, the least stable pattern. Use of a medial pin conferred statistically significant stiffness throughout most models as demonstrated with pin deletion. Use of 2 pins was significantly less stiff than most 3-pin models. CONCLUSIONS: Larger pin diameters confer greater stiffness among all patterns. The use of 3 lateral and 1 medial pin was not statistically different than 2 lateral and 1 medial pin in our models. Both patterns were stiffer than 3 lateral pins only or other fewer pin constructs. The alignment of pins in the sagittal plane did not affect overall construct stiffness.

Nontraumatic Compartment Syndrome in a Patient with Protein S Deficiency: A Case Report.

CASE: Protein S deficiency, a hypercoagulable thrombophilia, often results in venous thromboembolism. Nontraumatic compartment syndrome in a patient with protein S deficiency has not been well publicized. Herein, we present a rare case of nontraumatic compartment syndrome of the hand and the thigh in a 48-year-old woman with a known history of protein S deficiency; emergency fasciotomies were needed. CONCLUSION: Based on our patient and a review of the current literature, we advocate for a heightened awareness of compartment syndrome in patients with protein S deficiency.

"Enjoy glass of wine before eating:" a randomized trial to test the orexigenic effects of this advice in advanced cancer patients.

BACKGROUND: Because the extant literature suggests wine increases appetite, this study sought to determine whether this effect could be observed in advanced cancer patients with appetite loss. METHODS: Advanced cancer patients with self-reported loss of appetite were randomly assigned to white wine with ≤15 % alcohol content twice a day for 3-4 weeks versus a nutritional supplement, such as Boost® or Ensure®. Patients assigned to wine were encouraged to also take a nutritional supplement, whereas patients assigned to the nutritional supplement arm were told to abstain completely from alcohol. Patient-reported outcomes were captured with a validated questionnaire to assess the primary endpoint of appetite improvement. RESULTS: A total of 141 patients (118 evaluable) were enrolled. Twenty-eight patients (48 %) in the wine arm reported an improvement in appetite at some point during the treatment period, whereas 22 patients (37 %) assigned to the nutritional supplement arm also reported improvement (p = 0.35). Other appetite-related questions and questionnaire items showed no statistically significant differences between treatment arms. In both arms, approximately 9 % of patients achieved weight stability (p = 0.98); median survival was not statistically different. Both interventions were well tolerated. CONCLUSION: As prescribed in this trial, wine does not improve appetite or weight in advanced cancer patients.

Estimating the Total Annual Direct Cost of Providing Sexually Transmitted Infection and HIV Testing and Counseling for Men Who Have Sex With Men in the United States.

BACKGROUND: The Centers for Disease Control and Prevention recommends annual sexually transmitted infection (STI) and HIV testing and counseling for men who have sex with men (MSM) in the United States. We estimated the annual total direct medical cost of providing recommended STI and HIV testing and counseling services for MSM in the United States. METHODS: We included costs for 9 STI (including anatomic site-specific) tests recommended by the Centers for Disease Control and Prevention (HIV, syphilis, gonorrhea, chlamydia, hepatitis B viral infection, and herpes simplex virus type 2), office visits, and counseling. We included nongenital tests for MSM with exposure at nongenital sites. All cost data were obtained from the 2012 MarketScan outpatient claims database. Men were defined as MSM if they had a male sex partner within the last 12 months, which was estimated at 2.9% (2.6%-3.2%) of the male population in a 2012 study. All costs were updated to 2014 US dollars. RESULTS: The estimated average costs were as follows: HIV ($18 [$9-$27]), hepatitis B viral infection ($23 [$12-$35]), syphilis ($8 [$4-$11]), gonorrhea and chlamydia ($45 [$22-$67]) per anatomic site), herpes simplex virus type 2 ($27 [$14-$41]), office visit ($100 [$50-$149]), and counseling ($29 [$15-$44]). We estimated that the total annual direct cost of a universal STI and HIV testing and counseling program was $1.1 billion ($473 million-$1.7 billion) for all MSM and $756 (range, $338-$1.2 billion) when excluding office visit cost. CONCLUSIONS: These estimates provide the potential costs associated with universal STI and HIV testing and counseling for MSM in the United States. This information may be useful in future cost and/or cost-effectiveness analyses that can be used to evaluate STI and HIV prevention efforts.

A randomized comparison of once weekly epoetin alfa to extended schedule epoetin or darbepoetin in chemotherapy-associated anemia.

Erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) increase hemoglobin (Hb) levels and reduce red blood cell (RBC) transfusion requirements in patients with cancer chemotherapy-associated anemia (CAA). Extended-interval ESA dosing (administration less than once weekly) is common with DA, but previous studies suggested that EA might also be administered less often than weekly. In this multicenter prospective trial, 239 CAA patients with Hb <10.5 g/dL were randomized to receive EA 40,000 U subcutaneously once weekly ("40K" arm), EA 80,000 U every 3 weeks ("80K"), EA 120,000 U every 3 weeks ("120K" arm), or DA 500 mcg every 3 weeks ("DA"), for 15 weeks. The primary endpoint was the proportion of patients achieving Hb ≥ 11.5 g/dL or increment of Hb > 2.0 g/dL from baseline without transfusion. Secondary endpoints included transfusion requirements, adverse events (AEs), and patient-reported outcomes (PROs). There were no significant differences between treatment arms in the proportion of patients achieving Hb response (68.9% for 40K, 61.7% for 80K, 65.5% for 120K, and 66.7% for DA; P > 0.41 for all comparisons) or requiring RBC transfusion, but the median Hb increment from baseline was higher in the 40K and DA arms compared to the two extended dosing EA arms, and Hb response was achieved soonest in the weekly EA arm. There were no differences in PROs or AEs. The FDA-approved schedules tested-weekly EA 40,000 U, and every 3 week DA 500 mcg-are reasonable standards for CAA therapy.

A phase I/II study of bortezomib in combination with paclitaxel, carboplatin, and concurrent thoracic radiation therapy for non-small-cell lung cancer: North Central Cancer Treatment Group (NCCTG)-N0321.

INTRODUCTION: Despite the advances in radiation techniques and chemotherapy, survival with current platinum-based chemotherapy and concomitant thoracic radiation remains dismal. Bortezomib, a proteasome inhibitor, modulates apoptosis and cell cycle through disruption of protein degradation. The combination of bortezomib and carboplatin/paclitaxel and concurrent radiation in unresectable stage III non-small-cell lung cancer was evaluated in this phase I/II study. METHODS: Patients with histologic or cytologic confirmed stage III nonmetastatic non-small-cell lung cancer who were candidates for radiation therapy were eligible. In the phase I portion, patients received escalating doses of bortezomib, paclitaxel, and carboplatin concomitantly with thoracic radiation (60 Gy/30 daily fractions) using a modified 3 + 3 design. The primary endpoint for the phase II portion was the 12-month survival rate (12MS). A one-stage design with an interim analysis yielded 81% power to detect a true 12MS of 75%, with a 0.09 level of significance if the true 12MS was 60% using a sample size of 60 patients. Secondary endpoints consisted of adverse events (AEs), overall survival, progression-free survival, and the confirmed response rate. RESULTS: Thirty-one patients enrolled during the phase I portion of the trial, of which four cancelled before receiving treatment, leaving 27 evaluable patients. Of these 27 patients, two dose-limiting toxicities were observed, one (grade 3 pneumonitis) at dose level 1 (bortezomib at 0.5 mg/m, paclitaxel at 150 mg/m, and carboplatin at area under the curve of 5) and one (grade 4 neutropenia lasting ≥8 days) at dose level 6 (bortezomib 1.2 mg/m, paclitaxel 175 mg/m, and carboplatin at area under the curve of 6). During the phase I portion, the most common grade 3 of 4 AEs were leukopenia (44%), neutropenia (37%), dyspnea (22%), and dysphagia (11%). Dose level 6 was declared to be the recommended phase II dose (RP2D) and the phase II portion of the study opened. After the first 26 evaluable patients were enrolled to the RP2D, a per protocol interim analysis occurred. Of these 26 patients, 23 (88%) survived at least 6 months (95% confidence interval [CI], 70-98%), which was enough to continue to full accrual per study design. However, due to slow accrual, the study was stopped after 27 evaluable patients were enrolled (6-phase I RP2D; 21-phase II). Of these 27 patients, the 12MS was 73% (95% CI, 58-92%), the median overall survival was 25.0 months (95% CI, 15.6-35.8), and the median progression-free survival was 8.4 months (95% CI, 4.1-10.5). The confirmed response rate was 26% (seven of 27; 95% CI, 11-46%), consisting of four partial responses and three complete responses. Grade 3+ and grade 4+ AEs occurred in 82% and 56% of patients, respectively. One patient experienced grade 5 pneumonitis that was possibly related to the treatment. Grade 3 and 4 hematological toxicities were observed in 82% and 56% patients, respectively. CONCLUSIONS: The addition of bortezomib to concurrent carboplatin/paclitaxel and radiation seemed to be feasible, although associated with increased hematological toxicities. A favorable median overall survival of 25 months suggests a potential benefit for this regimen.

Deep sequencing of HetR-bound DNA reveals novel HetR targets in Anabaena sp. strain PCC7120.

BACKGROUND: Anabaena (also Nostoc) sp. strain PCC7120, hereafter Anabaena, is a cyanobacterium that fixes atmospheric N2 in specialized cells called heterocysts. Heterocyst differentiation is regulated by a homodimeric transcription factor, HetR. HetR is expressed at a basal level in all cells but its expression increases in differentiating cells early after nitrogen deprivation. HetR is required for heterocyst development, and therefore nitrogen fixation and diazotrophic growth. Overexpression of HetR leads to multiple contiguous heterocysts (Mch phenotype). HetR binds in vitro to DNA fragments upstream of several genes upregulated in heterocysts, including hetZ, hetP, hepA, patS, pknE, and hetR itself. HetR binds an inverted repeat sequence upstream of a few of these genes; however, HetR binds to promoters that do not contain this sequence, such as the promoter regions for patS and pknE. RESULTS: We employed chromatin pull-down and deep sequencing (ChIP-seq) to globally identify HetR DNA targets in vivo at six hours after fixed-nitrogen deprivation. We identified novel DNA binding targets of tagged HetR-6xHis and defined a consensus HetR binding site from these HetR target sequences. Promoter-gfp reporter fusions were used to determine the spatiotemporal expression of four potential HetR-target genes. The promoter region for asr1469 was expressed transiently in differentiating heterocysts, alr3758 was upregulated in heterocysts, asl2028 was expressed in vegetative cells, and alr2242 was derepressed in vegetative cells of a hetR mutant strain. CONCLUSIONS: In addition to identifying known HetR target genes hetR and hetP, the ChIP-seq data were used to identify new potential HetR targets and to define a consensus HetR-binding site. The in vivo ChIP-seq analysis of HetR's regulon suggests a possible role for HetR in vegetative cells in addition to its role in heterocyst development. The potential HetR target genes identified in this study provide new subjects for future work on the role of HetR in gene regulation.

Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial.

PURPOSE: In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS: We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS: In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION: This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

Release factor one is nonessential in Escherichia coli.

Recoding a stop codon to an amino acid may afford orthogonal genetic systems for biosynthesizing new protein and organism properties. Although reassignment of stop codons has been found in extant organisms, a model organism is lacking to investigate the reassignment process and to direct code evolution. Complete reassignment of a stop codon is precluded by release factors (RFs), which recognize stop codons to terminate translation. Here we discovered that RF1 could be unconditionally knocked out from various Escherichia coli stains, demonstrating that the reportedly essential RF1 is generally dispensable for the E. coli species. The apparent essentiality of RF1 was found to be caused by the inefficiency of a mutant RF2 in terminating all UAA stop codons; a wild type RF2 was sufficient for RF1 knockout. The RF1-knockout strains were autonomous and unambiguously reassigned UAG to encode natural or unnatural amino acids (Uaas) at multiple sites, affording a previously unavailable model for studying code evolution and a unique host for exploiting Uaas to evolve new biological functions.