Comprehensive evaluation of magnetic resonance imaging sequences for signal intensity based assessment of anterior cruciate ligament healing following surgical treatment.

Normalized signal intensity (SI) obtained from magnetic resonance imaging (MRI) has been used to track anterior cruciate ligament (ACL) postoperative remodeling. We aimed to assess the effect of MRI sequence (PD: proton density-weighted; T2: T2-weighted; CISS: constructive interference in steady state) on postoperative changes in healing ACLs/grafts. We hypothesized that CISS is better at detecting longitudinal SI and texture changes of the healing ACL/graft compared to the common clinical sequences (PD and T2). MR images of patients who underwent ACL surgery were evaluated and separated into groups based on surgical procedure (Bridge-Enhanced ACL Repair (BEAR; n = 50) versus ACL reconstruction (ACLR; n = 24)). CISS images showed decreasing SI across all timepoints in both the BEAR and ACLR groups (p < 0.01), PD and T2 images showed decreasing SI in the 6-to-12- and 12-to-24-month postoperative timeframes in the BEAR group (p < 0.02), and PD images additionally showed decreasing SI between 6- and 24-months postoperation in the ACLR group (p = 0.02). CISS images showed texture changes in both the BEAR and ACLR groups, showing increases in energy and decreases in entropy in the 6-to-12- and 6-to-24-month postoperative timeframes in the BEAR group (p < $\lt $ 0.04), and increases in energy, decreases in entropy, and increases in homogeneity between 6 and 24 months postoperation in the ACLR group (p < 0.04). PD images showed increases in energy and decreases in entropy between 6- and 24-months postoperation in the ACLR group (p < 0.008). Finally, CISS was estimated to require a smaller sample size than PD and T2 to detect SI differences related to postoperative remodeling.

Effect of stretching on inflammation in a subcutaneous carrageenan mouse model analyzed at single-cell resolution.

Understanding the factors that influence the biological response to inflammation is crucial, due to its involvement in physiological and pathological processes, including tissue repair/healing, cancer, infections, and autoimmune diseases. We have previously demonstrated that in vivo stretching can reduce inflammation and increase local pro-resolving lipid mediators in rats, suggesting a direct mechanical effect on inflammation resolution. Here we aimed to explore further the effects of stretching at the cellular/molecular level in a mouse subcutaneous carrageenan-inflammation model. Stretching for 10 min twice a day reduced inflammation, increased the production of pro-resolving mediator pathway intermediate 17-HDHA at 48 h postcarrageenan injection, and decreased both pro-resolving and pro-inflammatory mediators (e.g., PGE2 and PGD2 ) at 96 h. Single-cell RNA sequencing analysis of inflammatory lesions at 96 h showed that stretching increased the expression of both pro-inflammatory (Nos2) and pro-resolution (Arg1) genes in M1 and M2 macrophages at 96 h. An intercellular communication analysis predicted specific ligand-receptor interactions orchestrated by neutrophils and M2a macrophages, suggesting a continuous neutrophil presence recruiting immune cells such as activated macrophages to contain the antigen while promoting resolution and preserving tissue homeostasis.

Technology-Assisted Buprenorphine Treatment in Rural and Nonrural Settings: Two Randomized Clinical Trials.

Importance: Expansion of opioid use disorder treatment is needed, particularly in rural communities. Objective: To evaluate technology-assisted buprenorphine (TAB) efficacy (1) over a longer period than previously examined, (2) with the addition of overdose education, and (3) among individuals residing in rural communities. Design, Setting, and Participants: Two parallel, 24-week randomized clinical trials were conducted at the University of Vermont between February 1, 2018, and June 30, 2022. Participants were adults with untreated opioid use disorder from nonrural (trial 1) or rural (trial 2) communities. These trials are part of a programmatic effort to develop TAB protocols to improve treatment availability in underserved areas. Interventions: Within each trial, 50 participants were randomized to TAB or control conditions. Participants in the TAB group completed bimonthly visits to ingest medication and receive take-home doses via a computerized device. They received nightly calls via an interactive voice response (IVR) system, IVR-generated random call-backs, and iPad-delivered HIV, hepatitis C virus (HCV), and overdose education. Control participants received community resource guides and assistance with contacting resources. All participants received harm reduction supplies and completed monthly assessments. Main Outcomes and Measures: The primary outcome was biochemically verified illicit opioid abstinence across monthly assessments. Secondary outcomes included self-reported opioid use in both groups and abstinence at bimonthly and random call-back visits, treatment adherence, satisfaction, and changes in HIV, HCV, and overdose knowledge among TAB participants. Results: Fifty individuals (mean [SD] age, 40.6 [13.1] years; 28 [56.0%] male) participated in trial 1, and 50 (mean [SD] age, 40.3 [10.8] years; 30 [60.0%] male) participated in trial 2. Participants in the TAB group achieved significantly greater illicit opioid abstinence vs controls at all time points in both trial 1 (85.3% [128 of 150]; 95% CI, 70.7%-93.3%; vs 24.0% [36 of 150]; 95% CI, 13.6%-38.8%) and trial 2 (88.0% [132 of 150]; 95% CI, 72.1%-95.4%; vs 21.3% [32 of 150]; 95% CI, 11.4%-36.5%). High abstinence rates were also observed at TAB participants' bimonthly dosing visits (83.0% [95% CI, 67.0%-92.0%] for trial 1 and 88.0% [95% CI, 71.0%-95.0%] for trial 2). Treatment adherence was favorable and similar between trials (with rates of approximately 99% for buprenorphine administration, 93% for daily IVR calls, and 92% for random call-backs), and 183 of 187 urine samples (97.9%) tested negative for illicit opioids at random call-backs. iPad-delivered education was associated with significant and sustained increases in HIV, HCV, and overdose knowledge. Conclusions and Relevance: In these randomized clinical trials of TAB treatment, demonstration of efficacy was extended to a longer duration than previously examined and to patients residing in rural communities. Trial Registration: ClinicalTrials.gov Identifier: NCT03420313.

Prolonged exposure therapy for PTSD in individuals with opioid use disorder: A randomized pilot study.

OBJECTIVE: Nearly all individuals with opioid use disorder (OUD) report lifetime trauma exposure and one-third meet diagnostic criteria for posttraumatic stress disorder (PTSD). Although prolonged exposure (PE) therapy is a first-line treatment for PTSD, little is known about the effects of PE in individuals with co-occurring OUD. Furthermore, its efficacy is commonly undermined by poor therapy attendance. This pilot study evaluated the feasibility and initial efficacy of a novel PE protocol for improving PE attendance and PTSD symptoms among buprenorphine- or methadone-maintained adults with PTSD. METHOD: Thirty participants with co-occurring PTSD and OUD were randomized to receive either: (a) continued medications for OUD (MOUD) treatment as usual (TAU), (b) Prolonged Exposure therapy (PE), or (c) PE with financial incentives delivered contingent upon PE session attendance (PE+). Primary outcomes included PE session attendance, PTSD symptom severity, and use of opioids other than prescribed MOUD. RESULTS: PE+ participants attended significantly more therapy sessions vs. PE (87% vs. 35%; p <.0001). PTSD symptom reductions were also significantly greater in the PE+ vs. TAU group (p =.046). Participants in the two PE conditions submitted significantly fewer urine samples that tested positive for opioids than TAU participants (0% vs. 22%; p =.007). CONCLUSIONS: These findings provide preliminary support for the efficacy of PE+ for improving PE attendance and PTSD symptoms without prompting opioid relapse in individuals with co-occurring PTSD and OUD. These promising results justify a larger scale randomized clinical trial to more rigorously evaluate this novel treatment approach.

Quantitative MRI Biomarkers to Predict Risk of Reinjury Within 2 Years After Bridge-Enhanced ACL Restoration.

BACKGROUND: Quantitative magnetic resonance imaging (qMRI) methods were developed to establish the integrity of healing anterior cruciate ligaments (ACLs) and grafts. Whether qMRI variables predict risk of reinjury is unknown. PURPOSE: To determine if qMRI measures at 6 to 9 months after bridge-enhanced ACL restoration (BEAR) can predict the risk of revision surgery within 2 years of the index procedure. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Originally, 124 patients underwent ACL restoration as part of the BEAR I, BEAR II, and BEAR III prospective trials and had consented to undergo an MRI of the surgical knee 6 to 9 months after surgery. Only 1 participant was lost to follow-up, and 4 did not undergo MRI, leaving a total of 119 patients for this study. qMRI techniques were used to determine the mean cross-sectional area; normalized signal intensity; and a qMRI-based predicted failure load, which was calculated using a prespecified equation based on cross-sectional area and normalized signal intensity. Patient-reported outcomes (International Knee Documentation Committee subjective score), clinical measures (hamstring strength, quadriceps strength, and side-to-side knee laxity), and functional outcomes (single-leg hop) were also measured at 6 to 9 months after surgery. Univariate and multivariable analyses were performed to determine the odds ratios (ORs) for revision surgery based on the qMRI and non-imaging variables. Patient age and medial posterior tibial slope values were included as covariates. RESULTS: In total, 119 patients (97%), with a median age of 17.6 years, underwent MRI between 6 and 9 months postoperatively. Sixteen of 119 patients (13%) required revision ACL surgery. In univariate analyses, higher International Knee Documentation Committee subjective score at 6 to 9 months postoperatively (OR = 1.66 per 10-point increase; P = .035) and lower qMRI-based predicted failure load (OR = 0.66 per 100-N increase; P = .014) were associated with increased risk of revision surgery. In the multivariable model, when adjusted for age and posterior tibial slope, the qMRI-based predicted failure load was the only significant predictor of revision surgery (OR = 0.71 per 100 N; P = .044). CONCLUSION: Quantitative MRI-based predicted failure load of the healing ACL was a significant predictor of the risk of revision within 2 years after BEAR surgery. The current findings highlight the potential utility of early qMRI in the postoperative management of patients undergoing the BEAR procedure.

Preoperative Risk Factors for Subsequent Ipsilateral ACL Revision Surgery After an ACL Restoration Procedure.

BACKGROUND: Anterior cruciate ligament (ACL) revision surgery is challenging for both patients and surgeons. Understanding the risk factors for failure after bridge-enhanced ACL restoration (BEAR) may help with patient selection for ACL restoration versus ACL reconstruction. PURPOSE: To identify the preoperative risk factors for ACL revision surgery within the first 2 years after BEAR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Data from the prospective BEAR I, II, and III trials were used to determine the preoperative risk factors for ACL revision surgery. All patients with a complete ACL tear (aged 13-47 years, depending on the trial), who met all other inclusion/exclusion criteria and underwent a primary BEAR procedure within 30 to 50 days from the injury (dependent on the trial), were included. Demographic data (age, sex, body mass index), baseline patient-reported outcomes (International Knee Documentation Committee [IKDC] subjective score, Marx activity score), preoperative imaging results (ACL stump length, notch size, tibial slope), and intraoperative findings (knee hyperextension, meniscal status) were evaluated to determine their contribution to the risk of ipsilateral ACL revision surgery. RESULTS: A total of 123 patients, with a median age of 17.6 years (interquartile range, 16-23 years), including 67 (54%) female patients, met study criteria. Overall, 18 (15%) patients required ACL revision surgery in the first 2 years after the BEAR procedure. On bivariate analyses, younger age (P = .011), having a contact injury at the time of the initial tear (P = .048), and increased medial tibial slope (MTS; P = .029) were associated with a higher risk of ipsilateral revision surgery. Multivariable logistic regression analyses identified 2 independent predictors of revision: patient age and MTS. The odds of ipsilateral revision surgery were decreased by 32% for each 1-year increase in age (odds ratio, 0.684 [95% CI, 0.517-0.905]; P = .008) and increased by 28% for each 1° increase in MTS (odds ratio, 1.280 [95% CI, 1.024-1.601]; P = .030). Sex, baseline IKDC or Marx score, knee hyperextension, and meniscal status were not significant predictors of revision. CONCLUSION: Younger age and higher MTS were predictors of ipsilateral ACL revision surgery after the BEAR procedure. Younger patients with higher tibial slopes should be aware of the increased risk for revision surgery when deciding to undergo ACL restoration.

Early MRI-based quantitative outcomes are associated with a positive functional performance trajectory from 6 to 24 months post-ACL surgery.

PURPOSE: Quantitative magnetic resonance imaging (qMRI) has been used to determine the failure properties of ACL grafts and native ACL repairs and/or restorations. How these properties relate to future clinical, functional, and patient-reported outcomes remain unknown. The study objective was to investigate the relationship between non-contemporaneous qMRI measures and traditional outcome measures following Bridge-Enhanced ACL Restoration (BEAR). It was hypothesized that qMRI parameters at 6 months would be associated with clinical, functional, and/or patient-reported outcomes at 6 months, 24 months, and changes from 6 to 24 months post-surgery. METHODS: Data of BEAR patients (n = 65) from a randomized control trial of BEAR versus ACL reconstruction (BEAR II Trial; NCT02664545) were utilized retrospectively for the present analysis. Images were acquired using the Constructive Interference in Steady State (CISS) sequence at 6 months post-surgery. Single-leg hop test ratios, arthrometric knee laxity values, and International Knee Documentation Committee (IKDC) subjective scores were determined at 6 and 24 months post-surgery. The associations between traditional outcomes and MRI measures of normalized signal intensity, mean cross-sectional area (CSA), volume, and estimated failure load of the healing ACL were evaluated based on bivariate correlations and multivariable regression analyses, which considered the potential effects of age, sex, and body mass index. RESULTS: CSA (r = 0.44, p = 0.01), volume (r = 0.44, p = 0.01), and estimated failure load (r = 0.48, p = 0.01) at 6 months were predictive of the change in single-leg hop ratio from 6 to 24 months in bivariate analysis. CSA (ßstandardized = 0.42, p = 0.01), volume (ßstandardized = 0.42, p = 0.01), and estimated failure load (ßstandardized = 0.48, p = 0.01) remained significant predictors when considering the demographic variables. No significant associations were observed between MRI variables and either knee laxity or IKDC when adjusting for demographic variables. Signal intensity was also not significant at any timepoint. CONCLUSION: The qMRI-based measures of CSA, volume, and estimated failure load were predictive of a positive functional outcome trajectory from 6 to 24 months post-surgery. These variables measured using qMRI at 6 months post-surgery could serve as prospective markers of the functional outcome trajectory from 6 to 24 months post-surgery, aiding in rehabilitation programming and return-to-sport decisions to improve surgical outcomes and reduce the risk of reinjury. LEVEL OF EVIDENCE: Level II.

Effects of Initial Graft Tension and Patient Sex on Knee Osteoarthritis Outcomes After ACL Reconstruction: A Randomized Controlled Clinical Trial With 10- to 12-Year Follow-up.

BACKGROUND: The initial graft tension applied during anterior cruciate ligament (ACL) graft fixation may promote posttraumatic osteoarthritis (PTOA). PURPOSE/HYPOTHESIS: This study sought to assess the effect of initial graft tension and patient sex on PTOA outcomes at 10 to 12 years after ACL reconstruction (ACLR). The hypothesis was that there would be no group- or sex-based differences in outcomes. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients were randomized to receive ACLR with a low or high initial graft tension. Outcomes were evaluated at 10 to 12 years postoperatively and compared with a matched, uninjured control group. Outcomes included clinical assessments (anteroposterior [AP] knee laxity measurement, International Knee Documentation Committee [IKDC] examination score), a functional assessment (single-leg hop for distance), patient-reported outcomes (Knee injury and Osteoarthritis Outcome Score [KOOS], 36-Item Short Form Health Survey, Tegner activity level, patient satisfaction), and PTOA imaging (Osteoarthritis Research Society International [OARSI] radiographic score and Whole-Organ Magnetic Resonance Imaging Score [WORMS]). Two-way mixed-model analyses of variance were used to evaluate differences in outcomes between tension groups and the control group and between female and male patients. RESULTS: Both tension groups scored worse than the control group for the IKDC examination (P≤ .021), KOOS (Pain, Activities of Daily Living, Sport/Recreation, and Quality of Life subscales) (P≤ .049), and WORMS difference score (P≤ .042). The low-tension group scored worse than the control group for KOOS Symptoms (P = .016) and the OARSI difference score (P = .015). The index limb had worse scores than the contralateral limb within the high-tension group for AP laxity (P = .030) and hop deficit (P = .011). This result was also observed within both tension groups for the WORMS (P≤ .050) and within the low-tension group for the OARSI score (P = .001). Male patients had higher Tegner scores (mean ± SE) relative to female patients (male, 5.49 ± 1.88; female, 4.45 ± 1.65) and worse OARSI difference scores (male, 1.89 ± 5.38; female, 0.244 ± 0.668) (P = .007 and .034, respectively). However, no significant differences were detected between tension groups for any of the outcomes measured. CONCLUSION: Overall, ACLR failed to prevent PTOA regardless of initial graft tension. However, male patients treated with a low initial graft tension may be at greater risk for PTOA. These results do not support the hypothesis of no sex differences in outcomes at 10 to 12 years after ACLR.

Quadruped Gait and Regulation of Apoptotic Factors in Tibiofemoral Joints following Intra-Articular rhPRG4 Injection in Prg4 Null Mice.

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome leads to diarthrodial joint arthropathy and is caused by the absence of lubricin (proteoglycan 4-PRG4), a surface-active mucinous glycoprotein responsible for lubricating articular cartilage. In this study, mice lacking the orthologous gene Prg4 served as a model that recapitulates the destructive arthrosis that involves biofouling of cartilage by serum proteins in lieu of Prg4. This study hypothesized that Prg4-deficient mice would demonstrate a quadruped gait change and decreased markers of mitochondrial dyscrasia, following intra-articular injection of both hindlimbs with recombinant human PRG4 (rhPRG4). Prg4-/- (N = 44) mice of both sexes were injected with rhPRG4 and gait alterations were studied at post-injection day 3 and 6, before joints were harvested for immunohistochemistry for caspase-3 activation. Increased stance and propulsion was shown at 3 days post-injection in male mice. There were significantly fewer caspase-3-positive chondrocytes in tibiofemoral cartilage from rhPRG4-injected mice. The mitochondrial gene Mt-tn, and myosin heavy (Myh7) and light chains (Myl2 and Myl3), known to play a cytoskeletal stabilizing role, were significantly upregulated in both sexes (RNA-Seq) following IA rhPRG4. Chondrocyte mitochondrial dyscrasias attributable to the arthrosis in CACP may be mitigated by IA rhPRG4. In a supporting in vitro crystal microbalance experiment, molecular fouling by albumin did not block the surface activity of rhPRG4.

Preliminary side effect profile, safety, and tolerability of hormonal contraception among women receiving opioid-agonist therapy.

OBJECTIVE(S): To characterize for the first time the side effect profile, safety, and tolerability of hormonal contraception among women receiving opioid-agonist therapy. STUDY DESIGN: We conducted a secondary analysis of data collected from participants in a three-arm randomized controlled trial (N = 138) aimed at increasing effective contraceptive use among women receiving opioid-agonist therapy. Participants in the 2 intervention conditions (n = 90) had free access to hormonal contraception at each of the 14 visits scheduled during the 6-month intervention. Contraceptive use and side effects were recorded at each visit; participants could change methods or discontinue use at any time. Verbatim side effects were classified using Medical Dictionary for Regulatory Activities (MedDRA) terminology. RESULTS: Of 67 participants reporting hormonal contraceptive use, 29 (43%) initiated implants, 14 (21%) intrauterine devices, 13 (19%) combined pills, 11 (16%) progestin-only pills, 10 (15%) injectables, 1 (2%) ring, and 1 (2%) patch; the average (±standard deviation) duration of use was 129 ± 55, 129 ± 60, 108 ± 62, 102 ± 61, 111 ± 31, 145, and 18 days, respectively. A total of 321 side effects were reported by 55 (82%) participants. Fifty (75%) participants reported menstrual cycle changes/uterine bleeding, followed by headaches (16, 24%), weight gain (15, 22%), and abdominal pain or nausea/vomiting (11, 16%). No serious side effects were reported. Twelve participants (18%) changed methods and 13 (19%) discontinued all hormonal contraceptive use. CONCLUSION(S): The hormonal contraceptive side effects reported by this small group of women receiving opioid-agonist therapy appear consistent with those reported by the general population, was generally well-tolerated, and did not raise safety concerns. IMPLICATIONS: These results provide important preliminary evidence that hormonal contraceptive use produces a familiar side effect profile and is well-tolerated by women receiving opioid-agonist therapy, although studies with larger samples followed over longer periods of time with appropriate comparison conditions are needed to fully assess tolerability and safety.

Psychological Readiness to Return to Sport at 6 Months Is Higher After Bridge-Enhanced ACL Restoration Than Autograft ACL Reconstruction: Results of a Prospective Randomized Clinical Trial.

BACKGROUND: Previous clinical studies have shown that psychological factors have significant effects on an athlete's readiness to return to sport after anterior cruciate ligament (ACL) reconstruction (ACLR). HYPOTHESIS: We hypothesized that patients who underwent bridge-enhanced ACL restoration (BEAR) would have higher levels of psychological readiness to return to sport compared with patients who underwent ACLR. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 100 patients (median age, 17 years; median preoperative Marx activity score, 16) with complete midsubstance ACL injuries were randomized to either the BEAR procedure (n = 65) or autograft ACLR (n = 35 [33 hamstring and 2 bone--patellar tendon-bone]) and underwent surgery within 45 days of injury. Objective, functional, and patient-reported outcomes, including the ACL--Return to Sport after Injury (ACL-RSI) scale, were assessed at 6, 12, and 24 months postoperatively. RESULTS: Patients who underwent the BEAR procedure had significantly higher ACL-RSI scores at 6 months compared with those who underwent ACLR (71.1 vs 58.2; P = .008); scores were similar at 12 and 24 months. Baseline factors independently predictive of higher ACL-RSI scores at 6 months were having a BEAR procedure and participating in level 1 sports prior to injury, explaining 15% of the variability in the scores. Regression analysis of baseline and 6-month outcomes as predictors indicated that the International Knee Documentation Committee (IKDC) score at 6 months explained 45% of the 6-month ACL-RSI variance. Subsequent analysis with IKDC excluded from the model indicated that decreased pain, increased hamstring and quadriceps strength in the surgical limb, and decreased side-to-side difference in anteroposterior knee laxity were significant predictors of a higher ACL-RSI score at 6 months, explaining 34% of the variability in scores. Higher ACL-RSI score at 6 months was associated with earlier clearance to return to sports. CONCLUSION: Patients who underwent the BEAR procedure had higher ACL-RSI scores at 6 months postoperatively. Better ACL-RSI scores at 6 months were related most strongly to higher IKDC scores at 6 months and were also associated with lower pain levels, better muscle recovery, and less knee laxity at 6 months. REGISTRATION: NCT02664545 (ClinicalTrials.gov identifier).

Earlier Resolution of Symptoms and Return of Function After Bridge-Enhanced Anterior Cruciate Ligament Repair As Compared With Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Bridge-enhanced anterior cruciate ligament repair (BEAR) has noninferior patient-reported outcomes when compared with autograft anterior cruciate ligament reconstruction (ACLR) at 2 years. However, the comparison of BEAR and autograft ACLR at earlier time points-including important outcomes such as resolution of knee pain and symptoms, recovery of strength, and return to sport-has not yet been reported. HYPOTHESIS: It was hypothesized that the BEAR group would have higher outcomes on the International Knee Documentation Committee and Knee injury and Osteoarthritis Outcome Score, as well as improved muscle strength, in the early postoperative period. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 100 patients aged 13 to 35 years with complete midsubstance anterior cruciate ligament injuries were randomized to receive a suture repair augmented with an extracellular matrix implant (n = 65) or an autograft ACLR (n = 35). Outcomes were assessed at time points up to 2 years postoperatively. Mixed-model repeated-measures analyses were used to compare BEAR and ACLR outcomes. Patients were unblinded after their 2-year visit. RESULTS: Repeated-measures testing revealed a significant effect of group on the International Knee Documentation Committee Subjective Score (P = .015), most pronounced at 6 months after surgery (BEAR = 86 points vs ACLR = 78 points; P = .001). There was a significant effect of group on the Knee injury and Osteoarthritis Outcome Score-Symptoms subscale scores (P = .010), largely attributed to the higher BEAR scores at the 1-year postoperative time point (88 vs 82; P = .009). The effect of group on hamstring strength was significant in the repeated-measures analysis (P < .001), as well as at all postoperative time points (P < .001 for all comparisons). At 1 year after surgery, approximately 88% of the patients in the BEAR group and 76% of the ACLR group had been cleared for return to sport (P = .261). CONCLUSION: Patients undergoing the BEAR procedure had earlier resolution of symptoms and increased satisfaction about their knee function, as well as improved resolution of hamstring muscle strength throughout the 2-year follow-up period. REGISTRATION: NCT02664545 (ClinicalTrials.gov identifier).

Posttraumatic stress disorder in individuals seeking treatment for opioid use disorder in Vermont.

Posttraumatic stress disorder (PTSD) and opioid use disorder (OUD) may be associated with poor outcomes in rural areas where access to mental health services and opioid agonist treatment (OAT) is limited. This study examined the characteristics associated with a history of PTSD among a sample of individuals seeking buprenorphine treatment for OUD in Vermont, the second-most rural state in the US. Participants were 89 adults with OUD who participated in one of two ongoing randomized clinical trials examining the efficacy of an interim buprenorphine dosing protocol for reducing illicit opioid use during waitlist delays to OAT. Thirty-one percent of participants reported a history of PTSD. Those who did (PTSD+; n = 28) and did not (PTSD-; n = 61) report a history of PTSD were similar on sociodemographic and drug use characteristics. However, the PTSD+ group was less likely to have received prior OUD treatment compared to the PTSD- group (p = .02) despite being more likely to have a primary care physician (p = .009) and medical insurance (p = .002). PTSD+ individuals also reported greater mental health service utilization, more severe psychiatric, medical and drug use consequences, and greater pain severity and interference vs. PTSD- individuals (ps < 0.05). These findings indicate that a history of PTSD is prevalent and associated with worse outcomes among individuals seeking treatment for OUD in Vermont. Dissemination of screening measures and targeted interventions may help address the psychiatric and medical needs of rural individuals with OUD and a history of PTSD.

Sucrose subjective response and eating behaviors among individuals with opioid use disorder.

BACKGROUND: While opioid agonists represent the most efficacious treatment for opioid use disorder (OUD), they may enhance the reinforcing effects of sweets, placing individuals at risk for weight gain and associated consequences. We examined sucrose subjective response among adults receiving opioid agonist treatment vs. a comparison sample without OUD. METHODS: Forty adults with (OUD+) and 40 without OUD (OUD-) completed an intake battery of eating behaviors and body mass index. During two same-day sessions, participants sampled six experimenter-administered sucrose solutions (0, 0.10, 0.25, 0.50, 0.75, 1.0 M), each three times, under double-blind conditions and rated the pleasantness and intensity of each. RESULTS: OUD + participants presented with a higher prevalence of obesity and unhealthy eating behaviors vs. OUD- participants (p's < 0.05). They rated sucrose solutions as less pleasant than OUD- participants (p < 0.001), though this effect was limited to the three lowest concentrations (0, 0.10, 0.25M). There were no group differences on intensity ratings (p = 0.35). A change from baseline (placebo) analysis indicated a higher magnitude of change in pleasantness ratings and a lower magnitude of change in intensity ratings from 0M in OUD+ vs. OUD- (p's < 0.05). CONCLUSIONS: OUD+ participants exhibited a higher magnitude of change in pleasantness ratings from placebo vs. OUD-, which was largely driven by pronounced differences in perceived pleasantness of essentially unsweet solutions. OUD+ participants presented with a consistently more severe profile in regard to eating behaviors. These data highlight the risk factors experienced by OUD+ individuals that extend beyond drug-related risks and may inform future efforts to improve health outcomes.

Efficacy and Cost-Benefit of Onsite Contraceptive Services With and Without Incentives Among Women With Opioid Use Disorder at High Risk for Unintended Pregnancy: A Randomized Clinical Trial.

Importance: Rates of in utero opioid exposure continue to increase in the US. Nearly all of these pregnancies are unintended but there has been little intervention research addressing this growing and costly public health problem. Objective: To test the efficacy and cost-benefit of onsite contraceptive services with and without incentives to increase prescription contraceptive use among women with opioid use disorder (OUD) at high risk for unintended pregnancy compared with usual care. Design, Setting, and Participants: A randomized clinical trial of 138 women ages 20 to 44 years receiving medication for OUD who were at high risk for an unintended pregnancy at trial enrollment between May 2015 and September 2018. The final assessment was completed in September 2019. Data were analyzed from October 2019 to March 2021. Participants received contraceptive services at a clinic colocated with an opioid treatment program. Interventions: Participants were randomly assigned to receive 1 of 3 conditions: (1) usual care (ie, information about contraceptive methods and community health care facilities) (n = 48); (2) onsite contraceptive services adapted from the World Health Organization including 6 months of follow-up visits to assess method satisfaction (n = 48); or (3) those same onsite contraceptive services plus financial incentives for attending follow-up visits (n = 42). Main Outcomes and Measures: Verified prescription contraceptive use at 6 months with a cost-benefit analysis conducted from a societal perspective. Results: In this randomized clinical trial of 138 women (median age, 31 years [range, 20-44 years]), graded increases in verified prescription contraceptive use were seen in participants assigned to usual care (10.4%; 95% CI, 3.5%-22.7%) vs contraceptive services (29.2%; 95% CI, 17.0%-44.1%) vs contraceptive services plus incentives (54.8%; 95% CI, 38.7%-70.2%) at the 6-month end-of-treatment assessment (P < .001 for all comparisons). Those effects were sustained at the 12-month final assessment (usual care: 6.3%; 95% CI, 1.3%-17.2%; contraceptive services: 25.0%; 95% CI, 13.6%-39.6%; and contraceptive services plus incentives: 42.9%; 95% CI, 27.7%-59.0%; P < .001) and were associated with graded reductions in unintended pregnancy rates across the 12-month trial (usual care: 22.2%; 95% CI, 11.2%-37.1%; contraceptive services: 16.7%; 95% CI, 7.0%-31.4%; contraceptive services plus incentives: 4.9%; 95% CI, 0.6%-15.5%; P = .03). Each dollar invested yielded an estimated $5.59 (95% CI, $2.73-$7.91) in societal cost-benefits for contraceptive services vs usual care, $6.14 (95% CI, $3.57-$7.08) for contraceptive services plus incentives vs usual care and $6.96 (95% CI, $0.62-$10.09) for combining incentives with contraceptive services vs contraceptive services alone. Conclusions and Relevance: In this randomized clinical trial, outcomes with both onsite contraceptive service interventions exceeded those with usual care, but the most efficacious, cost-beneficial outcomes were achieved by combining contraceptive services with incentives. Colocating contraceptive services with opioid treatment programs offers an innovative, cost-effective strategy for preventing unintended pregnancy. Trial Registration: ClinicalTrials.gov Identifier: NCT02411357.

Impact of Current Pain Status on Low-Barrier Buprenorphine Treatment Response Among Patients with Opioid Use Disorder.

OBJECTIVE: Chronic non-cancer pain (CNCP) is prevalent among individuals with opioid use disorder (OUD). However, the impact of CNCP on buprenorphine treatment outcomes is largely unknown. In this secondary analysis, we examined treatment outcomes among individuals with and without CNCP who received a low-barrier buprenorphine maintenance regimen during waitlist delays to more comprehensive opioid treatment. METHODS: Participants were 28 adults with OUD who received 12 weeks of buprenorphine treatment involving bimonthly clinic visits, computerized medication dispensing, and phone-based monitoring. At intake and monthly follow-up assessments, participants completed the Brief Pain Inventory, Beck Anxiety Inventory, Beck Depression Inventory (BDI-II), Brief Symptom Inventory (BSI), Addiction Severity Index, and staff-observed urinalysis. RESULTS: Participants with CNCP (n = 10) achieved comparable rates of illicit opioid abstinence as those without CNCP (n = 18) at weeks 4 (90% vs 94%), 8 (80% vs 83%), and 12 (70% vs 67%) (P = 0.99). Study retention was also similar, with 90% and 83% of participants with and without CNCP completing the 12-week study, respectively (P = 0.99). Furthermore, individuals with CNCP demonstrated significant improvements on the BDI-II and Global Severity Index subscale of the BSI (P < 0.05). However, those with CNCP reported more severe medical problems and smaller reductions in legal problems relative to those without CNCP (P = 0.03). CONCLUSIONS: Despite research suggesting that chronic pain may influence OUD treatment outcomes, participants with and without CNCP achieved similar rates of treatment retention and significant reductions in illicit opioid use and psychiatric symptomatology during low-barrier buprenorphine treatment.

Within-subject evaluation of interim buprenorphine treatment during waitlist delays.

BACKGROUND: The effectiveness of opioid agonist treatment for opioid use disorder (OUD) is well established, and delays to treatment are still common, particularly in rural geographic areas. In a randomized 12-week pilot study, we demonstrated initial efficacy of a technology-assisted Interim Buprenorphine Treatment (IBT) vs. continued waitlist control (WLC) for reducing illicit opioid use and other risk behaviors during waitlist delays. Upon completion of that parent trial, WLC participants were given the opportunity to receive 12 weeks of IBT, permitting an additional within-subject examination of IBT effects. METHODS: Sixteen WLC participants crossed over to receive IBT, involving buprenorphine maintenance with bi-monthly visits, medication administration at home via a computerized device, daily monitoring calls using an Interactive Voice Response (IVR) phone system, and IVR-generated random call-backs. Biochemically-verified illicit opioid abstinence, changes in psychosocial functioning, and HIV + HCV knowledge were examined among participants originally randomized to the WLC phase and who subsequently crossed over to IBT (IBTc). RESULTS: Participants submitted a higher percentage of illicit opioid negative specimens at Weeks 4, 8, and 12 during IBT (75 %, 63 %, and 50 %) vs. WLC (0%, 0%, and 0%), respectively (p's<.01). Participants also demonstrated improvements in anxiety, depression, and HIV and HCV knowledge (p's<.01). Medication administration, daily IVR call and random call-back adherence and treatment satisfaction were also favorable. CONCLUSIONS: This within-subject evaluation provides additional support for interim buprenorphine's efficacy in reducing illicit opioid use and improving health outcomes during waitlist delays for more comprehensive treatment.

Evaluation of Graft Tensioning Effects in Anterior Cruciate Ligament Reconstruction between Hamstring and Bone-Patellar Tendon Bone Autografts.

This article investigates the clinical, functional, and radiographic outcomes in anterior cruciate ligament (ACL) reconstruction patients over 7 years to determine the effects of initial graft tension on outcomes when using patellar tendon (bone-tendon-bone [BTB]) and hamstring tendon (HS) autografts. Ninety patients, reconstructed with BTB or HS, were randomized using two initial graft tension protocols: (1) normal anteroposterior (AP) laxity ("low-tension"; n = 46) and (2) AP laxity overconstrained by 2 mm ("high-tension"; n = 44). Seventy-two patients had data available at 7 years, with 9 excluded for graft failure. Outcomes included the Knee Injury and Osteoarthritis Outcome Score, Short-Form-36 (SF-36), and Tegner activity scale. Clinical outcomes included KT-1000S and International Knee Documentation Committee examination score; and functional outcomes included 1-leg hop distance and peak knee extensor torque. Imaging outcomes included medial joint space width, Osteoarthritis Research Society International radiographic score, and Whole-Organ Magnetic Resonance Score. There were significantly improved outcomes in the high-tension compared with the low-tension HS group for SF-36 subset scores for bodily pain (p = 0.012), social functioning (p = 0.004), and mental health (p = 0.014) 84 months postsurgery. No significant differences in any outcome were found within the BTB groups. Tegner activity scores were also significantly higher for the high-tension HS group compared with the low-tension (6.0 vs. 3.8, p = 0.016). Patients with HS autografts placed in high tension had better outcomes relative to low tension for Tegner activity score and SF-36 subset scores for bodily pain, social functioning, and mental health. For this reason, we recommend that graft fixation be performed with the knee at 30-degree flexion ("high-tension" condition) when reconstructing the ACL with HS autograft.

Long-term outcomes of anterior cruciate ligament reconstruction surgery: 2020 OREF clinical research award paper.

ACL injuries place the knee at risk for post-traumatic osteoarthritis (PTOA) despite surgical anterior cruciate ligament (ACL) reconstruction. One parameter thought to affect PTOA risk is the initial graft tension. This randomized controlled trial (RCT) was designed to compare outcomes between two graft tensioning protocols that bracket the range commonly used. At 7 years postsurgery, we determined that most outcomes between the two tension groups were not significantly different, that they were inferior to an uninjured matched control group, and that PTOA was progressing in both groups relative to controls. The trial database was also leveraged to gain insight into mechanisms of PTOA following ACL injury. We determined that the inflammatory response at the time of injury undermines one of the joint's lubricating mechanisms. We learned that patients continue to protect their surgical knee 5 years postinjury compared to controls during a jump-pivot activity. We also established that presurgical knee function and mental health were correlated with symptomatic PTOA at 7 years, that there were specific anatomical factors associated with poor outcomes, and that there were no changes in outcomes due to tunnel widening in patients receiving hamstring tendon autografts. We also validated a magnetic resonance imaging technique to noninvasively assess graft strength. In conclusion, the RCT determined that initial graft tensioning does not have a major influence on 7-year outcomes. Therefore, surgeons can reconstruct the ACL using a graft tensioning protocol that is within the window of the two graft tensioning techniques evaluated in this RCT.

Neuromuscular function in anterior cruciate ligament reconstructed patients at long-term follow-up.

BACKGROUND: The permanence of neuromuscular adaptations following anterior cruciate ligament reconstruction is not known. The aim of this study was to compare bilateral muscle co-contraction indices, time to peak ground reaction force, and timing of muscle onset between anterior cruciate ligament reconstruction subjects 10-15 years post reconstruction with those of matched uninjured controls during a one-leg hop landing. METHODS: Nine healthy controls and 9 reconstruction subjects were recruited. Clinical and functional knee exams were administered. Lower limb co-contraction indices, time to peak ground reaction force, and muscle onset times were measured bilaterally. Differences in clinical and functional outcomes were assessed with unpaired t-tests, and mixed model repeated measures were used to examine effects of group, limb and interaction terms in electromyography measures. FINDINGS: 89% of control knees were clinically "normal", whereas only 33% of reconstructed knees were "normal". Anterior cruciate ligament-reconstructed subjects tended to achieve shorter functional hop distances but demonstrated symmetrical lower limb electromyography measures that were no different from those of controls' with the exception that biceps femoris activation was delayed bilaterally prior to ground contact but was greater during the injury risk phase of landing. INTERPRETATION: With the exception of hamstring activation, lower limb electromyography measures were largely similar between ligament-reconstructed and matched control subjects, which was in contrast to the clinical findings. This result brings into question the significance of neuromuscular function at this long-term follow-up but raises new questions regarding the role of symmetry and pre-injury risk.