Total Hip Arthroplasty in Patients Who Have Marfan Syndrome: Adverse Events and 5-Year Revision Rates.

BACKGROUND: Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. METHODS: Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. RESULTS: Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P = .001), cardiac events (OR: 4.5, P = .034), pneumonia (OR: 3.5, P < .001), and urinary tract infections (OR: 5.2, P < .001). There was no significant difference in 5-year rates of revision. CONCLUSIONS: Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population.

Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A Randomized, Double-Blind, Placebo Controlled Study.

PURPOSE: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction. MATERIALS AND METHODS: This randomized, double-blind, placebo controlled, 12-week study (4-week run-in and 8-week treatment) randomized 145 men to placebo, 147 to avanafil 100 mg and 148 to avanafil 200 mg on demand. The primary efficacy variable was the per subject proportion of sexual attempts during the treatment period in which subjects achieved erection sufficient for vaginal penetration within approximately 15 minutes after dosing as measured by a stopwatch. The attempt had to enable successful completion of sexual intercourse according to SEP question 3. RESULTS: Significantly greater mean per subject percentages of successful intercourse attempts within approximately 15 minutes after dosing were observed for avanafil 100 mg (mean 25.9%, LS mean ± SE 24.7% ± 2.9%) and 200 mg (mean 29.1%, LS mean 28.2% ± 2.9%) vs placebo (mean 14.9%, LS mean 13.8% ± 2.9%, p = 0.001 and <0.001, respectively). After treatment we noted a statistically significant difference between avanafil and placebo in the average per subject proportion of successful intercourse attempts according to SEP question 3 as early as 10 minutes in the 200 mg group and 12 minutes in the 100 mg group. Treatment emergent adverse events included headache, upper respiratory tract infection and nasal congestion, and most such events were mild or moderate in severity. CONCLUSIONS: Avanafil was efficacious within approximately 15 minutes of dosing compared to placebo. A statistically significant treatment difference in the percentage of successful sexual attempts was demonstrated as early as 10 minutes after treatment.

Three-Dimensional Printed Total Talus Replacement with a Concurrent Total Ankle Arthroplasty as a Personalized Approach for Advanced Ankle Osteoarthritis A Case Repor.

Ankle arthritis is becoming more common and can be pain-ful and debilitating. As the disease progresses, degenera-tive cystic changes may be found in the distal fibula, distal tibia, and talus. After failure of non-operative modalities, arthrodesis is often considered the surgical intervention of choice, but this leaves the patient with reduced range of motion, altered gait, and can negatively impact adjacent joints of the foot. Total ankle arthroplasty has been found to be an effective surgical option for ankle arthritis but is contraindicated in patients with talar collapse. When this is the case, a more personalized approach for preserving ankle motion is necessary. We present the case of a 65-year-old male with severe right ankle arthritis and talar collapse treated with a custom three-dimensionally printed talus and concurrent total ankle replacement with 2-year follow-up.

A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy.

PURPOSE: We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy. MATERIALS AND METHODS: This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy. Patients were randomized to 100 or 200 mg avanafil or placebo (taken 30 minutes before sexual activity) for 12 weeks. Primary end points included successful vaginal insertion (Sexual Encounter Profile [SEP] question 2), successful intercourse (SEP3) and change in score on the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire. RESULTS: A total of 298 patients were randomized and 84.6% completed the study. At baseline 16.1% were age 65 years or older and 71.5% had severe erectile dysfunction (mean overall IIEF-EF domain score 9.2). After 12 weeks there were significantly greater increases in SEP2 and SEP3 and change in mean IIEF-EF domain score with 100 and 200 mg avanafil vs placebo (p <0.01). Following dosing with avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p <0.01). Avanafil was generally well tolerated. No serious adverse events were reported and fewer than 2% of patients discontinued the study due to an adverse event. CONCLUSIONS: Avanafil in 100 and 200 mg doses was effective and well tolerated in improving erectile function after prostatectomy. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels.

Treatment of an Infected Tibial Shaft Non-Union Using a Novel 3D-Printed Titanium Mesh Cage: A Case Report.

Treating large bone defects resulting from trauma, tumors, or infection can be challenging, as current methods such as external fixation with bone transport, bone grafting, or amputation often come with high costs, high failure rates, high requirements for follow-up, and potential complications. In this case report, we present the successful treatment of a complicated, infected tibial shaft non-union by using a personalized three-dimensional (3D)-printed titanium mesh cage. This case adds to the existing body of literature by demonstrating successful integration of bone into a titanium implant and a demonstration of immediate postoperative weight bearing in the setting of suboptimal operative and psychosocial conditions. Futhermore, this report highlights the flexibility of 3D-printing technology and its ability to allow for continued limb salvage, even after a planned bone transport procedure has been interrupted. The use of 3D-printed implants customized to the patient's specific needs offers a promising new avenue for treating complex tibial pathologies, and the technology's versatility and ability to be tailored to individual patients makes it a promising tool for addressing a wide range of bone defects.

Anterior Cervical Discectomy and Fusion Outcomes in Patients With and Without Bariatric Surgery-Weight Loss Does Make a Difference.

STUDY DESIGN: A retrospective comparative cohort study. OBJECTIVE: To compare outcomes of elective non-obese anterior cervical discectomy and fusion (ACDF) patients with those that underwent bariatric surgery (BS). SUMMARY OF BACKGROUND DATA: Morbid obesity (MO) has been associated with an increased risk of complications following procedures such as elective ACDF. While pre-emptive BS has been considered for those with MO (body mass index [BMI] ≥35 kg/m 2 ), the impact of this intervention on BMI and its resultant correlation with surgical outcomes remains limited. METHODS: The PearlDiver 2010-Q1 2020 MSpine database was used to identify patients undergoing elective isolated ACDF. Three sub-cohorts were defined as follows: (1) Non-obese controls without a history of BS, (2) patients with BS procedure within two years with a BMI <35 kg/m 2 (BS+MO-), and (3) patients with BS procedure within the two years with a BMI ≥35 kg/m 2 (BS+MO+). Univariate and multivariate regression analyses were performed to compare 90-day adverse event rates adjusting for age, sex, Elixhauser Comorbidity Index, and length of stay. Kaplan-Meier analysis was performed to assess five-year cervical reoperation rates. RESULTS: Of 160,166 elective ACDF patients, prior BS was identified for 479. Of these, 136 patients were BS+MO- and 343 were BS+MO+. On multivariate analysis, BS+MO- were not at increased odds of adverse events, but BS+MO+ were at greater odds of 90-day pulmonary embolism (odds ratio 3.28, P =0.043), wound dehiscence (5.02, P <0.001), hematomas (2.52, P =0.042), and overall minor adverse events (1.61, P =0.011) compared with controls. Five-year reoperation rates were not significantly different between the groups. CONCLUSION: Twenty-eight percent of those with BS before ACDF fell out of the categorization of MO. Among this group, the odds of adverse events were similar to non-obese patients. These findings suggest that the psychological preparation and BS alone are insufficient to reduce the risk of adverse events after ACDF. Weight reduction must be achieved as well, ideally moving patients out of the BMI range for morbid obesity.

The correlation of psoriasis and its treatment medications with lumbar discectomy postoperative infections.

BACKGROUND CONTEXT: Psoriasis is a chronic, autoimmune disease of the skin that affects approximately 3% of the US adult population. Patients with psoriasis may be predisposed to spine surgical site infections (SSI) related to the condition and/or related medications following surgeries such as lumbar laminotomy/discectomy. PURPOSE: To assess the potential correlation of psoriasis and its related treatment medications on the risk of infection-related complications after lumbar laminotomy/discectomy. STUDY DESIGN: Retrospective case control, national administrative database study. PATIENT SAMPLE: Adult patients who underwent isolated single-level lumbar discectomy between 2010 and Q1 of 2021 were identified in the PearlDiver Mariner Ortho151 national administrative database (excluding those with concurrent diagnoses of fractures, neoplasms, or infections). OUTCOME MEASURES: Ninety-day postoperative rates of surgical site infection and sepsis. METHODS: Lumbar laminotomy/discectomy patients with versus without psoriasis were matched 1:4 based on age, sex, and Elixhauser Comorbidity Index. The risk of SSI and sepsis in the 90-day postoperative window between the cohorts were compared with multivariable analyses. Five-year reoperation rates were also compared with log rank test. The matched psoriasis cohort was further subdivided by psoriasis treatment regimens - no medication treatment (NT), topical therapies only (TT), topical therapies with oral systemic treatments (TT/OS), and topical therapies with biologics (TT/B). Multivariable logistic regression was used to assess the risk of SSI and sepsis within 90 days after lumbar laminotomy/discectomy for each treatment subgroup compared to patients without psoriasis. RESULTS: In total, 2,262 patients with psoriasis who underwent single-level lumbar laminotomy/discectomy were identified and matched by age, sex, and Elixhauser Comorbidity Index to 9,044 patients without psoriasis. Multivariable logistic regression showed that, compared to the patients without psoriasis, patients with psoriasis had a 1.795 times higher chance of developing SSI (odds ratio [OR]) (p<.001) and sepsis (OR: 1.743, p=.027) within 90 days of surgery. Having psoriasis did not significantly correlate with 5-year reoperation rates. Of those with psoriasis, NT subcohort had 1,038 patients, TT subcohort 571 patients, TT/OS subcohort 226 patients, and TT/B subcohort 140 patients. Based on multivariable analysis and compared to nonpsoriasis patients, those in the NT, TT, TT/OS were not at greater odds of postoperative SSI or sepsis. Conversely, those in the TT/B subcohort were at significantly greater odds of SSI (OR: 3.102, p=.019) and sepsis (OR: 6.367, p=.027). CONCLUSIONS: Of single-level lumbar laminotomy/discectomy patients with psoriasis, only those on topical therapies and biologics were at greater risk of postoperative SSI and sepsis. This subcohort warrants specific attention when undergoing lumbar laminotomy/discectomy and possibly holding such medications for a period prior to surgery may be warranted if possible.

Opioid Prescription Patterns 90 Days After Arthroscopic Rotator Cuff Repair: A 10-Year National Database Analysis.

Background: Arthroscopic rotator cuff repair (ARCR) is a common procedure that typically requires opioid prescription for postoperative pain management. Purpose: To investigate the current prescription patterns and factors influencing 90-day postoperative opioid prescription trends for opioid-naïve patients who underwent ARCR. Study Design: Case series; Level of evidence, 4. Methods: Opioid-naïve adult patients who underwent ARCR between January 2010 and September 2020 and had a record of opioid prescriptions during the 90-day postoperative period were identified in the PearlDiver Mariner91 national administrative database. Exclusions included patients with prior shoulder procedures, a history of chronic pain, and opioid prescription records dated earlier than 4 weeks before surgery. Covariates included age group, sex, Elixhauser Comorbidity Index, and prescriber specialty (orthopaedic or nonorthopaedic). The primary outcome-90-day postoperative morphine milligram equivalents (MMEs) prescribed per patient-was compared using univariate and multivariate regression analyses, and 90-day postoperative opioid prescription trends over the 10-year study period were analyzed with linear regression. Results: In total, 55,345 ARCR cases were identified. The mean ± SD amount prescribed within the first 90 days was 742.4 ± 256.5 MMEs, and the median was 487.5 MMEs. Multivariate linear regression analysis predicted higher 90-day postoperative MMEs for female patients and younger patients (P < .01 for both). From 2010 to 2020, there was a 66% decrease in mean MME prescribed per patient (▵ = 660.4 MME; P < .01), with a mean reduction of 55.1 MME per patient per year. In 2020, the mean 90-day postoperative amount prescribed was 341.1 MME, which is equivalent to 51 tablets of 5-mg oxycodone (Percocet). Conclusion: Female sex and younger age were predictors of more MME being prescribed after ARCR. While opioid prescriptions following ARCR have substantially decreased over the past decade, the amount prescribed warrants further attention.

Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. We therefore assessed the efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who were overweight and obese, with two or more risk factors. METHODS: In this 56-week phase 3 trial, we randomly assigned overweight or obese adults (aged 18-70 years), with a body-mass index of 27-45 kg/m(2) and two or more comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio in 93 centres in the USA. Drugs were administered orally. Patients were randomly assigned by use of a computer-generated algorithm that was implemented through an interactive voice response system, and were stratified by sex and diabetic status. Investigators, patients, and study sponsors were masked to treatment. Primary endpoints were the percentage change in bodyweight and the proportion of patients achieving at least 5% weight loss. Analysis was by intention to treat. This study is registered with Clinical Trials.gov, number NCT00553787. FINDINGS: Of 2487 patients, 994 were assigned to placebo, 498 to phentermine 7·5 mg plus topiramate 46·0 mg, and 995 to phentermine 15·0 mg plus topiramate 92·0 mg; 979, 488, and 981 patients, respectively, were analysed. At 56 weeks, change in bodyweight was -1·4 kg (least-squares mean -1·2%, 95% CI -1·8 to -0·7), -8·1 kg (-7·8%, -8·5 to -7·1; p<0·0001), and -10·2 kg (-9·8%, -10·4 to -9·3; p<0·0001) in the patients assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively. 204 (21%) patients achieved at least 5% weight loss with placebo, 303 (62%; odds ratio 6·3, 95% CI 4·9 to 8·0; p<0·0001) with phentermine 7·5 mg plus topiramate 46·0 mg, and 687 (70%; 9·0, 7·3 to 11·1; p<0·0001) with phentermine 15·0 mg plus topiramate 92·0 mg; for ≥10% weight loss, the corresponding numbers were 72 (7%), 182 (37%; 7·6, 5·6 to 10·2; p<0·0001), and 467 (48%; 11·7, 8·9 to 15·4; p<0·0001). The most common adverse events were dry mouth (24 [2%], 67 [13%], and 207 [21%] in the groups assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively), paraesthesia (20 [2%], 68 [14%], and 204 [21%], respectively), constipation (59 [6%], 75 [15%], and 173 [17%], respectively), insomnia (47 [5%], 29 [6%], and 102 [10%], respectively), dizziness (31 [3%], 36 [7%], 99 [10%], respectively), and dysgeusia (11 [1%], 37 [7%], and 103 [10%], respectively). 38 (4%) patients assigned to placebo, 19 (4%) to phentermine 7·5 mg plus topiramate 46·0 mg, and 73 (7%) to phentermine 15·0 mg plus topiramate 92·0 mg had depression-related adverse events; and 28 (3%), 24 (5%), and 77 (8%), respectively, had anxiety-related adverse events. INTERPRETATION: The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors. FUNDING: Vivus.

A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors have become standard treatment for erectile dysfunction (ED). AIM: To prospectively evaluate the safety and efficacy of avanafil, a novel PDE5 inhibitor, in men with mild to severe ED. METHODS: In this multicenter, double-blind, Phase 3 trial, 646 subjects were randomized to receive avanafil (50 mg, 100 mg, 200 mg) or placebo throughout a 12-week treatment period. Subjects were instructed to take study drug 30 minutes prior to initiation of sexual activity. At least a 12-hour separation time between doses was required; no restrictions were placed on food or alcohol intake. MAIN OUTCOME MEASURES: Improvement in erectile function (EF) was measured by Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3) and by the EF domain of the International Index of Erectile Function (IIEF) questionnaire. RESULTS: Mean change in percentage of successful sexual attempts (SEP2 and SEP3) and IIEF-EF domain score significantly favored all doses of avanafil over placebo (P ≤ 0.001). Secondary analyses demonstrated achievement of successful intercourse by subjects within 15 minutes of dosing. Of the 300 sexual attempts made during this interval, 64% to 71% were successful in avanafil-treated subjects compared with 27% in placebo-treated subjects. Successful intercourse was also demonstrated >6 hours post dosing, with 59% to 83% of the 80 sexual attempts successful in avanafil-treated subjects compared with 25% of placebo-treated subjects. The most commonly reported adverse events in subjects taking avanafil included headache, flushing, and nasal congestion; there were no drug-related serious adverse events. CONCLUSION: Following 12 weeks of avanafil treatment without food or alcohol restrictions, significant improvements in sexual function were observed with all 3 doses of avanafil compared with placebo. Successful intercourse was observed as early as 15 minutes and >6 hours after dosing in some subjects. Avanafil was generally well tolerated for the treatment of ED.

Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors are indicated for the treatment of erectile dysfunction (ED); however, they can also inhibit other PDE isozymes, affecting their target tissues (e.g., PDE1: heart; PDE6: retina; and PDE11: skeletal muscle), which in some cases can cause unwanted side effects and therapy discontinuation. Data from in vitro studies showed that avanafil, a PDE5 inhibitor for the treatment of ED, exhibited strong selectivity toward PDE5 and against all other PDE isozymes. AIM: To review the inhibitory effects of avanafil for PDE isozymes compared with those of sildenafil, tadalafil, and vardenafil and to discuss these results within the context of clinical trial safety observations. METHODS: Review of in vitro selectivity data for avanafil (published primary data from a peer-reviewed journal and scientific congress abstracts); PubMed search for pertinent publications on PDE5 inhibitor safety data; and review of published articles and abstracts from avanafil phase 1, 2, and 3 clinical trials. MAIN OUTCOME MEASURES: A low incidence of some PDE-related adverse events may be reflected by the high selectivity of avanafil against non-PDE5 isozymes. RESULTS: Avanafil is highly selective toward PDE5 and against all other PDE isozymes tested. Lower selectivity against PDE1, PDE6, and PDE11 is consistent with results from randomized, placebo-controlled, phase 3 trials in which musculoskeletal and hemodynamic adverse events were reported in <2% of patients and no color vision-related abnormalities were reported with avanafil doses up to 200 mg once daily. CONCLUSIONS: Data suggest that avanafil may confer a safety benefit, in terms of a lower incidence of specific adverse events, by virtue of its high specificity to PDE5 and its overall selectivity against other PDE isozymes.

Assessing the Quality of YouTube Videos on Adhesive Capsulitis.

Introduction  YouTube is the most popular video-based source of information on the Internet. It is accessed by over 1 billion users, which approximates to almost one-third of all Internet users. Orthopaedic video content published on YouTube is not screened and does not go through an editorial process, and most videos do not have information about authorship or appropriate references. Users who do not have the knowledge to assess the accuracy and reliability of the source may be misinformed about their medical condition. Previous studies have evaluated the quality of YouTube content for information in orthopaedics such as meniscus,kyphosis, and anterior cruciate ligament (ACL), but the quality of frozen shoulder videos on YouTube has not been investigated. The purpose of this study is to evaluate the quality and educational value of YouTube videos concerning adhesive capsulitis. Methods A YouTube search was performed using the term "frozen shoulder." Videos were excluded if they had no audio, were in a language other than English, or were longer than 10 minutes. A total of 70 videos were screened, and the first 50 videos that met the inclusion criteria were evaluated by three observers. Six video characteristics were extracted, and videos were categorized by source and content. Quality and educational value were assessed using the DISCERN (score range, 0-5), Global Quality score (GQS; score range, 0-4), and a Frozen Shoulder-Specific Score (FSSS; score range, 0-16). Results  The mean video duration was 242.46 ± 164.32 seconds. The mean number of views was 137,494 ± 262,756 and the total view count across 50 videos was 6,874,706. The mean DISCERN, GQS, and FSSS scores were 2.72 ± 0.85, 2.37 ± 0.895, and 4.42 ± 3.15, respectively. The video sources were primarily from non-physician healthcare professionals (32%), and most of the video content was focused on disease-specific information (50%). Significant between-group effects were observed for the DISCERN score and video source (P = .005), with videos from academic sources having the highest mean DISCERN score. DISCERN scores also differed significantly based on video content (P = .007), with disease content having the highest DISCERN score. Both GQS and FSSS scores differed significantly based on video content (both P < .001) but did not differ significantly based on the video source. Conclusions Information about frozen shoulder on YouTube is low quality and has limited educational value. Thus, providers for orthopaedic conditions should warn their patients and provide better alternatives for education.

A digital pathology tool for quantification of color features in histologic specimens.

In preclinical research, histological analysis of tissue samples is often limited to qualitative or semiquantitative scoring assessments. The reliability of this analysis can be impaired by the subjectivity of these approaches, even when read by experienced pathologists. Furthermore, the laborious nature of manual image assessments often leads to the analysis being restricted to a relatively small number of images that may not accurately represent the whole sample. Thus, there is a clear need for automated image analysis tools that can provide robust and rapid quantification of histologic samples from paraffin-embedded or cryopreserved tissues. To address this need, we have developed a color image analysis algorithm (DigiPath) to quantify distinct color features in histologic sections. We demonstrate the utility of this tool across multiple types of tissue samples and pathologic features, and compare results from our program to other quantitative approaches such as color thresholding and hand tracing. We believe this tool will enable more thorough and reliable characterization of histological samples to facilitate better rigor and reproducibility in tissue-based analyses.

Development and Performance of a Web-Based Tool to Adjust Urine Toxicology Testing Frequency: Retrospective Study.

BACKGROUND: Several pain management guidelines recommend regular urine drug testing (UDT) in patients who are being treated with chronic opioid analgesic therapy (COAT) to monitor compliance and improve safety. Guidelines also recommend more frequent testing in patients who are at high risk of adverse events related to COAT; however, there is no consensus on how to identify high-risk patients or on the testing frequency that should be used. Using previously described clinical risk factors for UDT results that are inconsistent with the prescribed COAT, we developed a web-based tool to adjust drug testing frequency in patients treated with COAT. OBJECTIVE: The objective of this study was to evaluate a risk stratification tool, the UDT Randomizer, to adjust UDT frequency in patients treated with COAT. METHODS: Patients were stratified using an algorithm based on readily available clinical risk factors into categories of presumed low, moderate, high, and high+ risk of presenting with UDT results inconsistent with the prescribed COAT. The algorithm was integrated in a website to facilitate adoption across practice sites. To test the performance of this algorithm, we performed a retrospective analysis of patients treated with COAT between June 2016 and June 2017. The primary outcome was compliance with the prescribed COAT as defined by UDT results consistent with the prescribed COAT. RESULTS: 979 drug tests (867 UDT, 88.6%; 112 oral fluid testing, 11.4%) were performed in 320 patients. An inconsistent drug test result was registered in 76/979 tests (7.8%). The incidences of inconsistent test results across the risk tool categories were 7/160 (4.4%) in the low risk category, 32/349 (9.2%) in the moderate risk category, 28/338 (8.3%) in the high risk category, and 9/132 (6.8%) in the high+ risk category. Generalized estimating equation analysis demonstrated that the moderate risk (odds ratio (OR) 2.1, 95% CI 0.9-5.0; P=.10), high risk (OR 2.0, 95% CI 0.8-5.0; P=.14), and high risk+ (OR 2.0, 95% CI 0.7-5.6; P=.20) categories were associated with a nonsignificantly increased risk of inconsistency vs the low risk category. CONCLUSIONS: The developed tool stratified patients during individual visits into risk categories of presenting with drug testing results inconsistent with the prescribed COAT; the higher risk categories showed nonsignificantly higher risk compared to the low risk category. Further development of the tool with additional risk factors in a larger cohort may further clarify and enhance its performance.

Steady-state pharmacokinetics following application of a novel transdermal estradiol spray in healthy postmenopausal women.

This study was designed to evaluate the steady-state pharmacokinetics (PK) of estradiol and its metabolites, estrone and estrone sulfate, following application of a novel estradiol transdermal spray to healthy postmenopausal women. Participants were randomly assigned in parallel to receive 1-, 2-, or 3-spray doses (24 participants/dose level) of a 1.7% estradiol metered-dose transdermal spray (1.53 mg/spray) once daily for 14 days. Blood was collected predose on days 1 to 14 and over 7 days after the last dose. Serum concentrations for all 3 analytes reached steady state by day 7 or 8 and were still slightly above baseline on day 21. Estradiol, estrone, and estrone sulfate serum concentrations generally increased with increasing dose. Mean estradiol and estrone maximum serum concentration (C(max)) following 1, 2, or 3 sprays for 14 days were 36 and 50, 57 and 60, and 54 and 71 pg/mL, respectively. Estradiol time when maximum concentration occurred (t(max)) was 18 to 20 hours. The area under the serum concentration-time curve over 24 hours following the last dose of study drug (AUC(0-24 h)) on day 14 for the 1-, 2-, and 3-spray groups, respectively, was 471, 736, and 742 pg.h/mL for estradiol; 886, 1208, and 1367 pg x h/mL for estrone; and 16,501, 26,515, and 27,971 pg x h/mL for estrone sulfate. The metered-dose estradiol transdermal spray delivers estradiol at therapeutic levels and produces low serum estrone concentrations.

Low-dose estradiol spray to treat vasomotor symptoms: a randomized controlled trial.

OBJECTIVE: To investigate the safety and efficacy of a transdermal estradiol (E2) spray in women with postmenopausal vasomotor symptoms. METHOD: A randomized, double-blind, placebo-controlled, multicenter, parallel-group clinical trial was conducted. Postmenopausal women (N=454) with at least eight moderate-to-severe hot flushes per day applied daily, one, two, or three E2 (90 microliter spray contains 1.53 mg E2) or matching placebo sprays. The primary efficacy endpoints were mean change from baseline in frequency and severity of moderate-to-severe hot flushes at weeks 4 and 12. RESULTS: All three E2 groups showed a significant decrease in hot flushes at weeks 4 and 12 compared with their placebo groups (P<.010). The mean change in frequency at week 12 was eight fewer flushes per day for women in the E2 groups and between four and six fewer flushes for women in the placebo groups. Women in the three- and two-E2 spray groups demonstrated significant (P<.050) reductions in severity score at weeks 4 and 12; women in the one-spray group showed significant reductions at week 5. At week 12, the majority (74-85%) of women on E2 showed at least a 50% hot flush frequency reduction as compared with 46% in the placebo group. The systemic E2 delivery rates at week 12 were approximately 0.021 mg/d, 0.029 mg/d, and 0.040 mg/d for the one-, two-, and three-spray doses, respectively. Common adverse events were similar to those previously reported with other transdermal products. Treatment-related application site reaction rate was similar to placebo (1.3% compared with 1.8%). CONCLUSION: The three dose levels of E2 spray achieved efficacy at 0.021-0.040 mg/d delivery rates. The spray is a well-tolerated, new, convenient method of delivering low-dose E2 transdermally. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00122200. LEVEL OF EVIDENCE: I.

Continuing Anti-thrombotic Medication During Low-to-Intermediate Risk Spinal Procedures: A Retrospective Evaluation.

BACKGROUND: The current American Society of Regional Anesthesia (ASRA) guidelines recommend discontinuing anti-thrombotic therapy prior to any interventional spine procedures to decrease the incidence of bleeding complications. However, discontinuing anti-thrombotics may pose considerable danger in terms of cerebrovascular and cardiovascular events. Recent evidence suggests that some spinal interventions may still be performed safely with anti-thrombotics on board and some practitioners thus elect to continue certain anti-thrombotics for these procedures. OBJECTIVE: To assess the rate of adverse events in patients undergoing spine procedures that are currently classified by the ASRA guidelines as "low-to-intermediate bleeding risk," while being on continued anti-thrombotic therapy. STUDY DESIGN: Retrospective cohort study. SETTING: Interventional pain management practice. METHODS: A retrospective chart review was performed on patients who underwent low-to-intermediate risk spine procedures with variable anti-thrombotic medications continued throughout the course of treatment. RESULTS: Between October 2015 and May 2016, out of 2,204 patients who underwent low-to-intermediate risk spine procedures, we identified 490 patients on anti-thrombotic medications. These included aspirin (N = 275), P2Y12 inhibitors (N = 129), warfarin (N = 62), heparin (N = 10), factor Xa inhibitors (N = 55), and dipyridamole (N = 1). Forty-two patients were on multiple anti-thrombotics. Anti-thrombotics were continued throughout the procedure for 467 of 490 patients (88%). One bleeding complication (injection site bleeding) occurred in a patient that continued clopidogrel and aspirin during a lumbar radiofrequency ablation. We encountered no bleeding complications attributable to anti-thrombotics in the other 466 procedures in which anti-thrombotics were continued during lumbar (N = 260), thoracic (N = 18), and cervical (N = 40) medial branch injections, sacroiliac injections (N = 47), and during lumbar (N = 87) thoracic (N = 2), and cervical (N = 12) medial branch radiofrequency ablations. LIMITATIONS: The retrospective nature of the study and its reliance on electronic medical records are potential limitations. CONCLUSIONS: Continuing anti-thrombotic medication during medial branch and sacroiliac injections may be possible. KEY WORDS: Interventional pain management, thrombotic complications, hemostasis, anti-coagulation, bleeding complications.

Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene.

OBJECTIVE: Osteoporosis is a significant health problem in postmenopausal women. Consequently, new and effective therapies are being sought to preserve bone mass and prevent osteoporosis in this population of women. The objective of this study was to compare the effects of lasofoxifene with raloxifene and placebo on indices of bone health in postmenopausal women. DESIGN: A randomized, double-blind, placebo- and active treatment-controlled study of 2 years duration was conducted. Women included 410 postmenopausal women aged 47 to 74 years. The four treatment groups were: lasofoxifene 0.25 mg/day, or 1.0 mg/day, raloxifene 60 mg/day, or placebo daily. All women received daily calcium and vitamin D supplements. The primary endpoint was percent change from baseline to 2 years in lumbar spine bone mineral density (BMD) in all women having baseline and at least one follow-up bone density measurement. Total hip BMD, biochemical markers of bone turnover, low-density lipoprotein cholesterol, and safety were also evaluated in all women. RESULTS: Both doses of lasofoxifene significantly increased lumbar spine BMD compared with raloxifene (P < or = 0.05) and with placebo treatment (P < or = 0.05). Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 3.6% (1.9, 5.2) for lasofoxifene 0.25 mg/day, 3.9% (2.4, 5.5) for lasofoxifene 1.0 mg/day, and 1.7% (0.3, 3.0) for raloxifene. The two doses of lasofoxifene and raloxifene were equally effective at increasing total hip BMD. Lasofoxifene and raloxifene significantly reduced the levels of biochemical markers of bone turnover compared with placebo. In general, the effects of lasofoxifene were greater than the responses to raloxifene. At 2 years, lasofoxifene significantly (P < or = 0.05) reduced low-density lipoprotein cholesterol levels by 20.6% and 19.7% with 0.25 mg/day and 1 mg/day, respectively, compared with raloxifene (12.1%) and placebo (3.2%). Lasofoxifene and raloxifene had a similar adverse event profile with low rate of discontinuations due to adverse events. CONCLUSIONS: Lasofoxifene may be an effective and well-tolerated treatment option for the prevention of bone loss in postmenopausal women.

Orally-effective, long-acting sorbitol dehydrogenase inhibitors: synthesis, structure-activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines.

Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED(90) < or = 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED(90) values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day.