Large-scale application of free energy perturbation calculations for antibody design.

Alchemical free energy perturbation (FEP) is a rigorous and powerful technique to calculate the free energy difference between distinct chemical systems. Here we report our implementation of automated large-scale FEP calculations, using the Amber software package, to facilitate antibody design and evaluation. In combination with Hamiltonian replica exchange, our FEP simulations aim to predict the effect of mutations on both the binding affinity and the structural stability. Importantly, we incorporate multiple strategies to faithfully estimate the statistical uncertainties in the FEP results. As a case study, we apply our protocols to systematically evaluate variants of the m396 antibody for their conformational stability and their binding affinity to the spike proteins of SARS-CoV-1 and SARS-CoV-2. By properly adjusting relevant parameters, the particle collapse problems in the FEP simulations are avoided. Furthermore, large statistical errors in a small fraction of the FEP calculations are effectively reduced by extending the sampling, such that acceptable statistical uncertainties are achieved for the vast majority of the cases with a modest total computational cost. Finally, our predicted conformational stability for the m396 variants is qualitatively consistent with the experimentally measured melting temperatures. Our work thus demonstrates the applicability of FEP in computational antibody design.

Accelerators for Classical Molecular Dynamics Simulations of Biomolecules.

Atomistic Molecular Dynamics (MD) simulations provide researchers the ability to model biomolecular structures such as proteins and their interactions with drug-like small molecules with greater spatiotemporal resolution than is otherwise possible using experimental methods. MD simulations are notoriously expensive computational endeavors that have traditionally required massive investment in specialized hardware to access biologically relevant spatiotemporal scales. Our goal is to summarize the fundamental algorithms that are employed in the literature to then highlight the challenges that have affected accelerator implementations in practice. We consider three broad categories of accelerators: Graphics Processing Units (GPUs), Field-Programmable Gate Arrays (FPGAs), and Application Specific Integrated Circuits (ASICs). These categories are comparatively studied to facilitate discussion of their relative trade-offs and to gain context for the current state of the art. We conclude by providing insights into the potential of emerging hardware platforms and algorithms for MD.

Regenerative treatments to enhance orthopedic surgical outcome.

In orthopedic surgery there has been a never-ending quest to improve surgical outcome and the patient's experience. Progression has been marked by the refinement of surgical techniques and instruments and later by enhanced diagnostic imaging capability, specifically magnetic resonance. Over time implant optimization was achieved, along with the development of innovative minimally invasive arthroscopic technical skills to leverage new versions of classic procedures and implants to improve short-term patient morbidity and initial, mid-term, and long-term patient outcomes. The use of regenerative and/or biological adjuncts to aid the healing process has followed in the drive for continual improvement, and major breakthroughs in basic science have significantly unraveled the mechanisms of key healing and regenerative pathways. A wide spectrum of primary and complementary regenerative treatments is becoming increasingly available, including blood-derived preparations, growth factors, bone marrow preparations, and stem cells. This is a new era in the application of biologically active material, and it is transforming clinical practice by providing effective supportive treatments either at the time of the index procedure or during the postoperative period. Regenerative treatments are currently in active use to enhance many areas of orthopedic surgery in an attempt to improve success and outcome. In this review we provide a comprehensive overview of the peer-reviewed evidence-based literature, highlighting the clinical outcomes in humans both with preclinical data and human clinical trials involving regenerative preparations within the areas of rotator cuff, meniscus, ligament, and articular cartilage surgical repair.

Correlation of the SLAP lesion with lesions of the medial sheath of the biceps tendon and intra-articular subscapularis tendon.

BACKGROUND: Superior labral anterior to posterior (SLAP) lesions have been well described in the literature and are thought to be secondary to traction injuries to the biceps anchor and/or falls on the outstretched arm. The pulley has recently been described as a structure that aids in the prevention of biceps instability. The intra-articular subscapularis insertion (IASS) has been noted to contribute to the robust nature of the medial sheath. The purpose of the study was to determine a potential correlation of SLAP lesions and pulley lesions with/without IASS lesions, (hereafter referred to as medial sheath) as forces that can disrupt the biceps anchor and may also disrupt structures of the medial sheath or vice-versa. MATERIALS AND METHODS: Three hundred and sixteen consecutive shoulder arthroscopies performed by one surgeon were reviewed retrospectively. Operative reports and arthroscopic pictures were carefully reviewed with particular attention paid to the labral and pulley pathology. Selection bias was noted as the author had never operated primarily for a Type 1 SLAP lesion. Following, however, and as such, the exclusion criteria, was a Type 1 SLAP. RESULTS: There were a total of 30 SLAP lesions and a total of 126 medial sheath lesions. There were 13 patients who had both SLAP and medial sheath lesions. There were 17 patients who had a SLAP lesion without a medial sheath lesion. There were 96 medial sheath lesions without a SLAP. A comparison of rates between patients who had a medial sheath lesion with a SLAP and those who had a medial sheath lesion without a SLAP, for the 316 patients, and when tested with a Fisher exact test revealed that there was no statistical significance, P = 0.673. The prevalence of SLAP lesions in this population of 316 patients was 9.4%, Buford 1%, medial sheath lesions 39%, and SLAP and medial sheath lesions 4%. Interestingly, there were three Buford complexes, all associated with a SLAP and one Buford complex was associated with both a SLAP and a pulley. When looking at the rate for medial sheath lesions when restricted to patients with SLAP lesions, the medial sheath lesion rate was 43.3% (13/30; 95% confidence interval 19.6-66.9%). The medial sheath lesion rate for patients with SLAP lesions differs from a rate of zero and is statistically significant, with a P value <0.05. In other words, when a SLAP lesion is present there is a statistically significant rate of medial sheath lesions, a previously unpublished association. CONCLUSIONS: With a 43% association of the medial sheath lesion with SLAP lesions, the author postulates that forces that affect the biceps anchor may also damage the pulley system of the bicipital sheath and, as such, this anatomic structure should be evaluated, especially when SLAP lesions are present.

Arthroscopic bicipital sheath repair: two-year follow-up with pulley lesions.

PURPOSE: The purpose of this study was to evaluate arthroscopic repair in patients who had lesions of both the subscapularis insertion/medial head of the coracohumeral ligament and the lateral head of the coracohumeral ligament and supraspinatus tendon (a type 5 biceps subluxation/instability classification), and to determine if primary repair of the torn structures used to reconstruct the bicipital sheath was associated with a high biceps rupture rate. The null hypothesis, that there is no difference between preoperative and postoperative outcomes, was tested. TYPE OF STUDY: Prospective cohort. METHODS: Since 1995, the author has had 18 patients who had lesions that affected both the medial and lateral wall of the bicipital sheath. An adjunct was added if tendonitis was present with fraying, and the biceps tendon was debrided if the fraying consisted of 50% or less the width of the tendon. This was chosen arbitrarily. Greater than 50% fraying of the biceps tendon was treated with repair of the supraspinatus and subscapularis. The biceps tendon was treated with tenotomy or tenodesis in these cases and these patients were not included in this study. This article reports on the repair technique and results having a minimum of 2-year follow-up. RESULTS: There were 12 male patients (age range, 45 to 80 years; average, 62 years) and 6 female patients (age range, 50 to 85 years; average, 66 years). The dominant extremity was involved in 12 of the 16 extremities. Preoperative, ASES Index, Total Constant scores, Subjective Constant scores, Objective Constant scores, visual analog pain scales, and percent function were 31 +/- 19, 53 +/- 13, 12 +/- 8, 41 +/- 8, 7 +/- 3, and 42 +/- 17, respectively. Postoperative scores were 80 +/- 14, 77 +/- 10, 30 +/- 4, 47 +/- 7, 2 +/- 2, and 84 +/- 14, respectively. The null hypothesis was rejected at a level of P = .001, .001, .001, .05, .001, and .001, respectively. CONCLUSIONS: There was 1 biceps disruption in this cohort following repair, for an incidence rate of 6%. There were 2 patients, active tennis players, who had recurrence of biceps inflammation in the follow-up period with no evidence of biceps subluxation. The arthroscopic technique reported is a primary repair used to reconstruct the normal structures of the groove. This may explain why previous recommendations not to reconstruct the groove because of the high biceps disruption rate have been noted previously. This study did not deepen the groove, tubulize the biceps tendon, or close the rotator interval in nonanatomic fashion. This arthroscopic technique is technically feasible and can alleviate the symptoms of biceps tendon inflammation and/or subluxation in the majority of cases in this cohort. LEVEL OF EVIDENCE: Level IV, Case Series.

Arthroscopic repair of massive rotator cuff tears: a prospective cohort with 2- to 4-year follow-up.

PURPOSE: The goal of this study is to report on the complete arthroscopic repair of massive rotator cuff tears. TYPE OF STUDY: Prospective cohort study. METHODS: Between 1997 and 1999, 37 patients underwent complete arthroscopic repair of massive rotator cuff tears. The preoperative and postoperative outcomes of these 37 patients were analyzed using the constant score, American Shoulder and Elbow Society (ASES) index, visual analog pain scale (VAS), a single question of percent function compared with the opposite unaffected extremity, and a single question reflecting satisfaction (Would you undergo the surgery and the postoperative rehabilitation to achieve the result you have today?). The null hypothesis that was tested was that there was no difference between the preoperative and postoperative outcomes. The 37 patients were divided, by cohort design, into 2 groups; massive anterosuperior (AS; subscapularis, supraspinatus, and infraspinatus with or without the teres minor) and massive posterosuperior (PS; supraspinatus and infraspinatus, with or without the teres minor) tears. Additionally, the null hypothesis that there was no difference between outcomes for massive AS and massive PS subgroups was tested. RESULTS: There was no statistically significant difference between either subset of massive rotator cuff tears with respect to preoperative and postoperative outcomes. The null hypothesis was supported for between groups. All but 2 patients said that they would undergo surgery again to achieve the postoperative state. CONCLUSIONS: The arthroscopic repair of massive rotator cuff tears is effective for decreasing pain and improving the functional status of the shoulder for most patients. Complete coverage was achieved in 78% of the patients at the time of surgery. A subset of patients who did not have complete coverage or coverage at a second setting showed similar outcomes as those with full coverage. The patient satisfaction rate was 95%.

Arthroscopic repair of full-thickness supraspinatus tears (small-to-medium): A prospective study with 2- to 4-year follow-up.

PURPOSE: The objective of this study is to report on the complete arthroscopic repair of full-thickness tears of the supraspinatus. TYPE OF STUDY: Prospective cohort study. METHODS: Between 1995 and 1999, 139 full arthroscopic rotator cuff repairs were performed; 37 were repairs of full-thickness supraspinatus tears. Between 1997 and 1999, there were 24 patients who had a complete arthroscopic repair of supraspinatus tears. The preoperative and postoperative status of these patients was analyzed using the Constant score, American Shoulder and Elbow Society Index (ASES Index), a Visual Analog Pain Scale (VAS), a single question of percent function compared with the opposite unaffected extremity, and a single question reflecting satisfaction, "Would you undergo the surgery and the postoperative rehabilitation to achieve the result you have today?" There were 37 patients who had preoperative to postoperative VAS, percent function, postoperative acromiohumeral interval, and clinical rerupture incidences evaluated. The null hypothesis was tested and there was no difference between the preoperative to postoperative outcomes. Two groups were evaluated, those who had concomitant decompression and those who did not. RESULTS: The null hypothesis was not supported. The 4 scoring systems used for evaluation showed statistically significant improvement from preoperative to postoperative. There were no differences in outcome based upon sex or age as a variable. All patients would have surgery again to achieve their postoperative state. CONCLUSIONS: The arthroscopic repair of supraspinatus tears is effective for improving the functional status of the shoulder.

Arthroscopic repair of isolated subscapularis tears: A prospective cohort with 2- to 4-year follow-up.

PURPOSE: The goal of this study was to evaluate the outcomes of the arthroscopic repair of isolated subscapularis tears. Additionally, this study explores details of the clinical diagnosis, magnetic resonance arthrography findings, and surgical repair techniques. TYPE OF STUDY: A prospective cohort. METHODS: The preoperative and postoperative status of patients with isolated subscapularis tears were analyzed using the Constant Score, American Shoulder and Elbow Society Index (ASES Index), a visual analog pain scale (VAS), a single question of percent function compared with the opposite unaffected extremity, and a single question reflecting satisfaction: "Would you undergo the surgery and the postoperative rehabilitation to achieve the result you have today." RESULTS: There was a statistically significant difference for all outcome measures from preoperative to postoperative follow-up at 2 to 4 years, except for the objective Constant Score. There were no differences based on gender. Preoperative magnetic resonance arthrography aids in the confirmation of the subscapularis tear. CONCLUSIONS: The arthroscopic repair of the isolated subscapularis tear provides for reliable expectations of improvement in function, particularly the use of the arm behind the back, decreases in pain, decreases in biceps subluxation or instability, and the return of active normal internal rotation. Subjectively, magnetic resonance arthrography is better than magnetic resonance imaging for visualizing the subscapularis tear.

Arthroscopic repair of anterosuperior (supraspinatus/subscapularis) rotator cuff tears: a prospective cohort with 2- to 4-year follow-up. Classification of biceps subluxation/instability.

PURPOSE: The purpose of this study was to evaluate the outcome of patients who underwent arthroscopic repair of anterosuperior rotator cuff tears. The null hypothesis, that there was no difference between preoperative scores and postoperative scores, was tested statistically. TYPE OF STUDY: A cohort study. METHODS: The preoperative and postoperative status of patients with anterosuperior rotator cuff tears was analyzed using the Constant score, American Shoulder and Elbow Society Index (ASES Index), a visual analog pain scale (VAS), a single question of percent function compared with the opposite unaffected extremity, and a single question reflecting satisfaction, "would you undergo the surgery and the postoperative rehabilitation to achieve the result you have today." There were also 2 groups compared: 1 that had a "tac" used for repair of the subscapularis tendon, and the other that used a "tie" technique for subscapularis repair. All supraspinatus tendon tears were complete and were repaired using a soft-tissue fixation device. RESULTS: There was a statistically significant difference for all outcome measures except for the objective Constant score of the tie group, P =.58. Follow-up was 2 to 4 years. There were no differences based on sex or type of fixation device used for repair of the subscapularis tendon. There were no reruptures, clinically. CONCLUSIONS: The arthroscopic repair of anterosuperior rotator cuff tears provides reliable expectation for improvement in function, decreases in pain, decreases in clinical findings of biceps subluxation and inflammation, improvement in shoulder scores, and the improvement of clinical findings of subscapularis insufficiency.

Using contrast-enhanced MR cholangiography with IV mangafodipir trisodium (Teslascan) to evaluate bile duct leaks after cholecystectomy: a prospective study of 11 patients.

OBJECTIVE: The purpose of our study was to determine whether contrast-enhanced MR cholangiography using IV mangafodipir trisodium can accurately detect the presence and location of bile duct leaks in patients who have undergone cholecystectomy. SUBJECTS AND METHODS: Our study group included 11 patients with suspected bile duct leaks after cholecystectomy. Axial single-shot fast spin-echo and gradient-echo images were acquired in all patients before and 1-2 hr after IV administration of mangafodipir trisodium. The contrast-enhanced MR cholangiograms were evaluated for image quality, degree of ductal or small bowel opacification, and the presence and location of bile duct leaks, strictures, and stones. MR cholangiograms were correlated with conventional contrast-enhanced cholangiograms obtained in all patients, including endoscopic retrograde cholangiography (n = 10) and percutaneous transhepatic cholangiography (n = 1). RESULTS: Excretion of mangafodipir trisodium was noted in the intrahepatic and extrahepatic bile ducts in all patients from 1 to 2 hr after IV administration. Bile ducts and fluid collections that contained excreted mangafodipir trisodium showed increased signal intensity on gradient-echo sequences and decreased signal intensity on single-shot fast spin-echo sequences. Conventional contrast-enhanced cholangiography showed the presence of bile duct leaks in six patients and the absence of bile duct leaks in five patients, with false-negative findings in one patient and false-positive findings in one patient for bile duct leak (sensitivity, 86%; specificity, 83%). CONCLUSION: Contrast-enhanced MR cholangiography with IV mangafodipir trisodium can successfully detect the presence and location of bile duct leaks in patients suspected of having such leaks after undergoing cholecystectomy. More research is necessary before acceptance of this examination as routine in the workup of these patients.

The graveyard shift: experience with a night float system.

The aim of this study is to describe the effects of a new night float system on the circadian rhythm and clinical judgment of our residents. In addition, the study looks at the residents' opinions of how to optimize the night float system in the future. All 20 of the radiology residents at our institution completed a questionnaire about the night float system after completing their night float coverage. The results of the questionnaire were then compiled and tabulated. It took our residents an average of 2.0 days to become acclimated to the night float and an average of 2.3 days to return to a normal daily routine after completing the night float. No residents perceived impairment in their clinical judgment while on the night float. However, 9 of the 20 residents (45%) stated that their clinical judgment was improved on the night float compared to that of a 24-hour call. Eighteen of 20 residents (90%) preferred the night float system to a 24-hour call system. On average, our residents believe that the optimal number of hours for a night float shift is 10.5 hours and the optimal numbers of days to do the night float consecutively is 6.8 days. In conclusion, a night float system can be a preferable means of evening coverage as it has a minimal effect on the circadian rhythm by allowing residents to become acclimated to working the night shift over the course of several days. The night float system also demonstrates no appreciable adverse effects on clinical judgment and may allow better clinical judgment than a 24-hour call system.

Ureterolithiasis: classical and atypical findings on unenhanced helical computed tomography.

Evaluation of patients with acute flank pain using helical computed tomography (CT) is a well-accepted, rapid, and safe procedure in the emergency setting. Various primary and secondary signs are described in the literature for evaluation of these patients. Our purpose is to demonstrate both the classical findings associated with ureteral calculi on unenhanced helical CT and atypical findings and potential pitfalls. We also provide readers with a systematic approach to interpreting unenhanced helical CT scans performed for acute flank pain.