A Randomized Clinical Trial Comparing Patellar Tendon, Hamstring Tendon, and Double-Bundle ACL Reconstructions: Patient-Reported and Clinical Outcomes at 5-Year Follow-up.

BACKGROUND: This randomized clinical trial evaluated the 5-year, disease-specific quality-of-life outcomes of patients treated for anterior cruciate ligament (ACL) deficiency with use of a patellar tendon, single-bundle quadruple-stranded hamstring, or double-bundle hamstring reconstruction. METHODS: Patients (n = 110 per group; 183 male; 14 to 50 years of age) were randomly allocated to anatomically positioned ACL reconstruction with use of a patellar tendon graft (patellar tendon group; mean age, 28.7 years), quadruple-stranded hamstring tendon construct (hamstring tendon group; mean age, 28.5 years), or double-bundle hamstring tendon construct (double-bundle group; mean age, 28.3 years). Computer-generated allocation with varied block randomization was performed intraoperatively. The 5-year primary outcome measure was the Anterior Cruciate Ligament-Quality of Life (ACL-QOL) score, and secondary outcome measures included the International Knee Documentation Committee (IKDC) subjective score and objective grades, pivot shift assessment, range of motion, kneeling pain, Tegner activity scale, Cincinnati Occupational Rating Scale, complete traumatic reruptures, partial traumatic tears, total traumatic reinjuries, and atraumatic graft failures. RESULTS: Three hundred and fifteen patients (95%) completed the 5-year follow-up (4 withdrawals, and 11 lost to follow-up). ACL-QOL scores increased significantly from baseline for all groups (p < 0.0001), but mean scores at 5 years did not differ among the groups (p = 0.548): mean (and standard deviation) of 82.5 ± 17.9 (95% confidence interval [CI], 79.0 to 86.0) for patellar tendon, 83.9 ± 18.2 (95% CI, 80.3 to 87.4) for hamstring tendon, and 81.1 ± 19.3 (95% CI, 77.4 to 84.8) for double-bundle. The proportions of patients at 5 years with a pivot shift grade of ≥2 (12% for patellar tendon, 16% for hamstring tendon, and 22% for double-bundle; p = 0.149) and with normal and nearly normal knees per IKDC grade (87%, 82%, and 75% for the 3 groups, respectively; p = 0.093) trended in favor of patellar tendon reconstruction. No differences were seen for the IKDC subjective scores, knee range of motion including passive extension deficits, the single leg hop test, Cincinnati Occupational Rating scores, and Tegner activity levels. Kneeling pain was more common with patellar tendon reconstruction (10% of patients compared with 4% for hamstring tendon and 2% for double-bundle; p = 0.029). For hamstring tendon and double-bundle reconstructions, there were trends toward more complete traumatic reruptures (4% for patellar tendon, 10% for hamstring tendon, and 10% for double-bundle; p = 0.145) and partial traumatic tears (0%, 5%, and 6%, respectively; p = 0.059), with significantly fewer combined traumatic reinjuries in the patellar tendon group (4 patients compared with 16 for hamstring tendon and 17 for double-bundle; p = 0.010). Atraumatic graft failure (pivot shift grade of ≥2) was found for 10% of the patients. CONCLUSIONS: At 5 years, we found no significant difference in the quality-of-life outcome among the patellar tendon, hamstring tendon, and double-bundle techniques for ACL reconstruction. Significantly more patients in the hamstring tendon and double-bundle groups experienced traumatic graft reinjury compared with the patellar tendon group. There was a trend toward a higher percentage with normal and nearly normal IKDC grades in the patellar tendon group compared with hamstring tendon and double-bundle groups. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Return to Sport-Specific Performance After Primary Anterior Cruciate Ligament Reconstruction: A Systematic Review.

BACKGROUND: Physicians counseling athletes on the prognosis of sport-specific performance outcomes after anterior cruciate ligament reconstruction (ACLR) depend on the published literature. However, critical appraisal of the validity and biases in these studies is required to understand how ACLR affects an athlete's ability to return to sport, the athlete's sport-specific performance, and his or her ability to achieve preinjury levels of performance. PURPOSE: This review identifies the published prognostic studies evaluating sport-specific performance outcomes after ACLR. A risk of bias assessment and summaries of return to sport and career longevity results are provided for each included study. STUDY DESIGN: Systematic review. METHODS: Electronic databases (Ovid MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and PUBMED) were searched via a defined search strategy with no limits, to identify relevant studies for inclusion in the review. A priori defined eligibility criteria included studies measuring sport-specific performance within an athlete's sport, before and after primary ACLR. Reference lists of eligible studies were hand-searched for additional relevant studies. Data extraction was performed by use of a standardized spreadsheet. Each included study was assessed by use of 6 bias domains of the Quality in Prognosis Studies tool to critically appraise study participation, study attrition, prognostic factors, outcome measurement, confounders, and statistical analysis and reporting. Two authors independently performed each stage of the review and reached consensus through discussion. RESULTS: Fifteen pertinent prognostic studies evaluated sport-specific performance outcomes and/or return to play after ACLR for athletes participating in competitive soccer, football, ice hockey, basketball, Alpine ski, X-Games ski and snowboarding, and baseball. Twelve of these studies were considered to have a high level of bias. CONCLUSION: This review demonstrated that most high-performance or professional athletes returned to their preinjury level of sport after ACLR. The bulk of evidence suggests there was a measurable decrease in performance statistics, although this is highly sport-specific. A paucity of literature is available that addresses sport-specific performance in athletes after ACLR. This review has determined that the available literature is highly biased and must be read with caution. CLINICAL RELEVANCE: By better understanding the validity and biases in the published literature, physicians can provide more informed prognoses about return to sport-specific performance after ACLR while considering risk factors relevant to their patients. REGISTRATION: CRD42016046709 (International Prospective Register of Systematic Reviews, https://www.crd.york.ac.uk/prospero/ ).

The incidence of proximal deep vein thrombosis after elective hip arthroscopy: a prospective cohort study in low risk patients.

Prospectively assess the incidence of deep venous thrombosis (DVT) using Doppler Ultrasound, in patients receiving elective hip arthroscopy without pharmacologic/mechanical prophylaxis. One hundred and fifteen consecutive patients (mean 35.4 years, SD = 10.3) underwent elective hip arthroscopy. Patients with previous major risk factors for DVT were excluded. Signs/symptoms of DVT/pulmonary embolism were assessed at 2-week post-operatively. A bilateral whole leg Duplex color (Doppler) Ultrasonography was scheduled between 10- and 22-day post-op. The primary outcome was frequency of DVT. Secondary outcomes assessed surgical risk factors. One hundred and ten patients (mean = 34.3 years, SD = 10.1) did not get a DVT. Five patients (mean = 43.8 years, SD = 12.1) were diagnosed with a DVT, 2- to 22-day post-operatively. All DVT patients received arthroscopy in the supine position (n = 76), versus no patients in the lateral position (n = 39). Average traction time was 38 (SD = 4) and 61 (SD = 4) minutes for patients with and without a DVT, respectively. All other a priori defined risk factors were similar. Four out of five patients presented with symptoms of a DVT, confirmed by ultrasound. One patient was without symptoms/clinical findings. Four patients had a DVT restricted to the calf veins; one patient had involvement of the popliteal vein. No patients had proximal extension into the thigh or pelvis. No pulmonary emboli were suspected or occurred. The incidence of deep venous thromboembolism is 4.3%. The majority of patients had symptomatic and distal venous thromboembolic events. This study provides supportive evidence that routine prophylaxis and/or screening may not be necessary in low risk patients undergoing elective hip arthroscopy.

Electrothermal arthroscopic capsulorrhaphy: old technology, new evidence. A multicenter randomized clinical trial.

BACKGROUND: Radiofrequency technology for shoulder instability was rapidly adopted despite limited clinical evidence and a poor understanding of its indications. Reports of serious adverse events followed, leading to its abandonment. This paper presents findings from a multicenter randomized clinical trial evaluating the safety and efficacy of electrothermal arthroscopic capsulorrhaphy (ETAC) compared with open inferior capsular shift (ICS) and reviews the role of randomized trials in adopting new technology. METHODS: Patients (>14 years) diagnosed with multidirectional instability or multidirectional laxity with anteroinferior instability and failed nonoperative treatment were enrolled. Patients with bone lesions or labral, biceps anchor, or full-thickness rotator cuff tears were excluded intraoperatively. Outcomes included Western Ontario Shoulder Instability Index, function and recurrent instability at 2 years postoperatively, and surgical times. RESULTS: Fifty-four subjects (mean age, 23 years; 37 women) were randomized to ETAC (n = 28) or open ICS (n = 26). The groups were comparable at baseline, except for external rotation at the side. At 2 years postoperatively, there were no statistically or clinically significant differences between groups for the Western Ontario Shoulder Instability Index (P = .71), American Shoulder and Elbow Surgeons score (P = .43), Constant score (P = .43), and active range of motion. Recurrent instability was not statistically different (ETAC, 2; open, 4; P = .41). ETAC (23 minutes) was significantly shorter than open ICS (59 minutes) (P < .01) surgery. Three subjects (1 ETAC, 2 open) had stiff shoulders. CONCLUSIONS: At 2 years postoperatively, quality of life and functional outcomes between groups were not clinically different. ETAC had fewer complications and episodes of recurrence compared with open surgery. This evidence reinforces the need to critically evaluate new technology before widespread clinical use.

A randomized clinical trial comparing open and arthroscopic stabilization for recurrent traumatic anterior shoulder instability: two-year follow-up with disease-specific quality-of-life outcomes.

BACKGROUND: The literature comparing open and arthroscopic repair for glenohumeral instability is conflicting. We performed a prospective, expertise-based, randomized clinical trial to compare open shoulder stabilization with arthroscopic shoulder stabilization by measuring quality-of-life outcomes and recurrence rates at two years among patients treated for traumatic anterior shoulder instability. METHODS: Computer-generated, variable-block-size, concealed randomization allocated 196 patients to either the open-repair group (n = 98) or the arthroscopic-repair group (n = 98). An expertise-based randomization design was employed to avoid a differential bias in terms of physician experience. Outcomes were measured at baseline, at three and six months postoperatively, and at one and two years postoperatively with use of the Western Ontario Shoulder Instability Index (WOSI) and the American Shoulder and Elbow Surgeons (ASES) functional outcome scale. Recurrent instability was also analyzed. RESULTS: There were no significant differences in outcome scores at baseline. At two years, seventy-nine patients in the open group and eighty-three patients in the arthroscopic group were available for follow-up. There was no significant difference in mean WOSI scores between the groups; the mean WOSI score (and standard deviation) for the open group was 85.2 ± 20.4 (95% confidence interval [CI] = 80.5 to 89.8), and for the arthroscopic group, 81.9 ± 19.8 (95% CI = 77.4 to 86.4); p = 0.31. There was also no significant difference in mean ASES scores: 91.4 ± 12.7 (95% CI = 88.5 to 94.4) for the open group and 88.2 ± 15.9 (95% CI = 84.6 to 91.8) for the arthroscopic group; p = 0.17. Recurrence rates at two years were significantly different: 11% in the open group and 23% in the arthroscopic group (p = 0.05). Recurrent instability was more likely in patients with a preoperative Hill-Sachs lesion and in male patients who were twenty-five years old and younger. There was no significant difference in shoulder motion between the groups at two years. CONCLUSIONS: There was no difference between open and arthroscopic repair in terms of patient quality of life. Open repair resulted in a significantly lower risk of recurrence. Secondary outcome data from this trial suggest that open surgical repair may be recommended to reduce the risk of recurrent instability in younger male patients with a Hill-Sachs lesion.

Oligomerization transforms human APOBEC3G from an efficient enzyme to a slowly dissociating nucleic acid-binding protein.

The human APOBEC3 proteins are a family of DNA-editing enzymes that play an important role in the innate immune response against retroviruses and retrotransposons. APOBEC3G is a member of this family that inhibits HIV-1 replication in the absence of the viral infectivity factor Vif. Inhibition of HIV replication occurs by both deamination of viral single-stranded DNA and a deamination-independent mechanism. Efficient deamination requires rapid binding to and dissociation from ssDNA. However, a relatively slow dissociation rate is required for the proposed deaminase-independent roadblock mechanism in which APOBEC3G binds the viral template strand and blocks reverse transcriptase-catalysed DNA elongation. Here, we show that APOBEC3G initially binds ssDNA with rapid on-off rates and subsequently converts to a slowly dissociating mode. In contrast, an oligomerization-deficient APOBEC3G mutant did not exhibit a slow off rate. We propose that catalytically active monomers or dimers slowly oligomerize on the viral genome and inhibit reverse transcription.

Patellar tendon versus hamstring tendon autograft for anterior cruciate ligament rupture in adults.

BACKGROUND: Reconstruction of the anterior cruciate ligament (ACL) commonly involves patellar tendon (PT) or hamstring tendon(s) (HT) autografts. There is no consensus with respect to the choice between these two grafts in ACL surgery. OBJECTIVES: This review compared the outcomes of ACL reconstruction using PT versus HT autografts in ACL deficient patients. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (April 2008), the Cochrane Central Register of Controlled Trials (2008, Issue 2), MEDLINE (1966 to April 10 2008), EMBASE (1980 to April 10 2008), conference proceedings and reference lists. No language restrictions were applied. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing outcomes (minimum two year follow-up) following ACL reconstruction using either PT or HT autografts in skeletally mature adults, irrespective of the number of bundles, fixation method or incision technique. DATA COLLECTION AND ANALYSIS: After independent study selection, the four authors independently assessed trial quality and risk of bias, and extracted data using pre-developed forms. Trial authors were contacted for additional data and information. Risk ratios with 95% confidence intervals were calculated for dichotomous outcomes, and mean differences and 95% confidence intervals for continuous outcomes. MAIN RESULTS: Nineteen trials providing outcome data for 1597 young to middle-aged adults were included. Many trials were at high risk of bias reflecting inadequate methods of randomization, lack of blinding and incomplete assessment of outcome.Pooled data for primary outcomes, reported in a minority of trials, showed no statistically significant differences between the two graft choices for functional assessment (single leg hop test), return to activity, Tegner and Lysholm scores, and subjective measures of outcome. There were also no differences found between the two interventions for re-rupture or International Knee Documentation Committee scores. There were inadequate long-term results, such as to assess the development of osteoarthritis.All tests (instrumental, Lachman, pivot shift) for static stability consistently showed that PT reconstruction resulted in a more statically stable knee compared with HT reconstruction. Conversely, patients experienced more anterior knee problems, especially with kneeling, after PT reconstruction. PT reconstructions resulted in a statistically significant loss of extension range of motion and a trend towards loss of knee extension strength. HT reconstructions demonstrated a trend towards loss of flexion range of motion and a statistically significant loss of knee flexion strength. The clinical importance of the above range of motion losses is unclear. AUTHORS' CONCLUSIONS: There is insufficient evidence to draw conclusions on differences between the two grafts for long-term functional outcome. While PT reconstructions are more likely to result in statically stable knees, they are also associated with more anterior knee problems.

HIV-1 Vif-mediated ubiquitination/degradation of APOBEC3G involves four critical lysine residues in its C-terminal domain.

During coevolution with the host, HIV-1 developed the ability to hijack the cellular ubiquitin/proteasome degradation pathway to counteract the antiviral activity of APOBEC3G (A3G), a host cytidine deaminase that can block HIV-1 replication. Abrogation of A3G function involves the HIV-1 Vif protein, which binds A3G and serves as an adapter molecule to recruit A3G to a Cullin5-based E3 ubiquitin ligase complex. Structure-guided mutagenesis of A3G focused on the 14 most surface-exposed Lys residues allowed us to identify four Lys residues (Lys-297, 301, 303, and 334) that are required for Vif-mediated A3G ubiquitination and degradation. Substitution of Arg for these residues confers Vif resistance and restores A3G's antiviral activity in the presence of Vif. In our model, the critical four Lys residues cluster at the C terminus, opposite to the known N-terminal Vif-interaction region in the protein. Thus, spatial constraints imposed by the E3 ligase complex may be an important determinant in Vif-dependent A3G ubiquitination.

A randomized clinical trial comparing open to arthroscopic acromioplasty with mini-open rotator cuff repair for full-thickness rotator cuff tears: disease-specific quality of life outcome at an average 2-year follow-up.

BACKGROUND: Rotator cuff tears affect patients' quality of life. The evolution toward less invasive operative techniques for rotator cuff repair requires appropriate comparisons with the standard open procedure, using validated outcomes in a randomized fashion. HYPOTHESIS: There is no difference in disease-specific quality of life outcomes at 2 years between an open surgical repair (open) versus an arthroscopic acromioplasty with mini-open (scope mini-open) repair for patients with full-thickness rotator cuff tears. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients with unremitting pain, failed nonoperative treatment, and imaging indicating full-thickness rotator cuff tears were included in the study. Massive irreparable cuff tears were excluded. Patients were assessed using the disease-specific Rotator Cuff-Quality of Life index, which produces a maximum score of 100, representing a high quality of life. Secondary shoulder-specific outcomes (American Shoulder and Elbow Society, Shoulder Rating Questionnaire, and Functional Shoulder Elevation Test) were also measured at baseline, 3 and 6 months, and 1 and 2 years. RESULTS: The mean Rotator Cuff-Quality of Life scores at an average follow-up of 28 months were not statistically different: open, 86.9 (95% confidence interval: 81.8-92.0); and scope mini-open, 87.2 (95% confidence interval: 80.6-93.8). At 3 months, the patients who underwent scope mini-open showed statistically significantly better outcomes (55.6 vs 71.3; P = .005). The baseline to 3-month difference in Rotator Cuff-Quality of Life scores between the scope mini-open and open groups was also statistically significant. CONCLUSION: Patient outcomes improved from baseline to all postoperative measurement intervals. There was no difference in outcome at 1 and 2 years after surgery between the scope mini-open and open procedures. The quality of life of patients undergoing the arthroscopic acromioplasty with mini-open rotator cuff repair improved statistically significantly and clinically at 3 months compared with the open group.

Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G.

APOBEC3G (A3G), a host protein that inhibits HIV-1 reverse transcription and replication in the absence of Vif, displays cytidine deaminase and single-stranded (ss) nucleic acid binding activities. HIV-1 nucleocapsid protein (NC) also binds nucleic acids and has a unique property, nucleic acid chaperone activity, which is crucial for efficient reverse transcription. Here we report the interplay between A3G, NC and reverse transcriptase (RT) and the effect of highly purified A3G on individual reactions that occur during reverse transcription. We find that A3G did not affect the kinetics of NC-mediated annealing reactions, nor did it inhibit RNase H cleavage. In sharp contrast, A3G significantly inhibited all RT-catalyzed DNA elongation reactions with or without NC. In the case of (-) strong-stop DNA synthesis, the inhibition was independent of A3G's catalytic activity. Fluorescence anisotropy and single molecule DNA stretching analyses indicated that NC has a higher nucleic acid binding affinity than A3G, but more importantly, displays faster association/disassociation kinetics. RT binds to ssDNA with a much lower affinity than either NC or A3G. These data support a novel mechanism for deaminase-independent inhibition of reverse transcription that is determined by critical differences in the nucleic acid binding properties of A3G, NC and RT.

Interaction between trichosanthin, a ribosome-inactivating protein, and the ribosomal stalk protein P2 by chemical shift perturbation and mutagenesis analyses.

Trichosanthin (TCS) is a type I ribosome-inactivating protein that inactivates ribosome by enzymatically depurinating the A(4324) at the alpha-sarcin/ricin loop of 28S rRNA. We have shown in this and previous studies that TCS interacts with human acidic ribosomal proteins P0, P1 and P2, which constitute the lateral stalk of eukaryotic ribosome. Deletion mutagenesis showed that TCS interacts with the C-terminal tail of P2, the sequences of which are conserved in P0, P1 and P2. The P2-binding site on TCS was mapped to the C-terminal domain by chemical shift perturbation experiments. Scanning charge-to-alanine mutagenesis has shown that K173, R174 and K177 in the C-terminal domain of TCS are involved in interacting with the P2, presumably through forming charge-charge interactions to the conserved DDD motif at the C-terminal tail of P2. A triple-alanine variant K173A/R174A/K177A of TCS, which fails to bind P2 and ribosomal stalk in vitro, was found to be 18-fold less active in inhibiting translation in rabbit reticulocyte lysate, suggesting that interaction with P-proteins is required for full activity of TCS. In an analogy to the role of stalk proteins in binding elongation factors, we propose that interaction with acidic ribosomal stalk proteins help TCS to locate its RNA substrate.

Structural basis for the interaction of [E160A-E189A]-trichosanthin with adenine.

Trichosanthin is a ribosome-inactivating protein that cleaves specifically the N-glycosidic bond of A-4324 of 28S rRNA. Trichosanthin and its variant [E160A-E189A]-trichosanthin were found to bind an adenine base with a K(d) value of approximately 0.2mM. To determine how this doubly mutated variant of trichosanthin interacts with adenine, the co-crystal structure of [E160A-E189A]-trichosanthin and adenine was resolved to 0.193nm which revealed that the active site conformation of the doubly mutated variant is isomorphous to wild-type trichosanthin. Water molecules were found at locations corresponding to the eliminated side chain of Glu-160 and Glu-189. On the other hand, the adenine base interacted with [E160A-E189A]-trichosanthin in a manner similar to that in wild-type trichosanthin. Our structural analysis illustrates that Glu-160 and Glu-189 in trichosanthin do not play an important role in maintaining the active site conformation and binding adenine, an essential step for substrate-enzyme interaction. On the other hand, removal of two glutamate residues changed a large patch of negatively charged surface to a positive charge, which may account for the destabilization of the oxocarbenium-like transition-state and the significant decrease in ribosome-inactivating activity in [E160A-E189A]-trichosanthin.