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Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, currently the standard of care for this disease and the related plasma cell disorder multiple myeloma, due to upregulation of pro-apoptotic Noxa and its inhibitory binding to MCL-1. BCL-2 inhibitors sensitize clonal plasma cells to multiple front-line therapies including bortezomib, dexamethasone and lenalidomide. Strikingly, in mice bearing AL amyloidosis cell line xenografts, single agent treatment with the BCL-2 inhibitor ABT-199 (venetoclax) produces deeper remissions than bortezomib and triples median survival. Mass spectrometry-based proteomic analysis reveals rewiring of signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapies. These findings provide a roadmap for the use of BH3 mimetics to exploit endogenous and induced apoptotic vulnerabilities in AL amyloidosis., (© 2022. The Author(s).)

Adverse events affecting Black patients, including skin hyperpigmentation, may be overlooked using existing clinical trial data on lenalidomide. The objective of this systematic review is to characterize the representation of Black participants and rate of skin hyperpigmentation in clinical trials. In this systematic review and pooled analysis of 21 clinical trials comprising 4539 participants, the proportion of Black participants in trials (6.9%, n = 315) was significantly less than the multiple myeloma population (p < 0.001). The rate of skin hyperpigmentation (0.066%, n = 3) and all skin changes (6.4%, n = 291) was significantly less compared to a 40.8% incidence in a recent retrospective study (p. <0.001). Among participants undergoing treatment with lenalidomide for multiple myeloma, Black patients were underrepresented and the adverse event of skin hyperpigmentation was underreported. Fair representation of Black patients in clinical trials is needed to better describe this adverse event and other events that may be underreported., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor used for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Clinical and operational barriers may exist that warrant bridging or switching from thrombopoietin receptor agonists (TPO-RAs), such as volatility or unpredictability of platelets, adverse events, and quality of life or patient preference. While fostamatinib demonstrated durable platelet responses, the safety and efficacy in combination, bridging, and/or switching with TPO-RAs is not well documented. The objective of this article is to provide guidance from real-world case studies for a safe and effective strategy for the transitioning of patients from TPO-RAs to fostamatinib, with some degree of overlap between the two agents. Currently, the evidence does not exist to guide the safe and effective use of combination therapy or transition between therapies in ITP. This case series highlights the importance to further understand the complexities of managing this disease, as well as successfully combining, bridging, and/or switching patients over to fostamatinib without the need for rescue therapy or increase in adverse events. The need for real-world evidence that guides providers on the safety and efficacy of short- and long-term combination therapy of fostamatinib and TPO-RAs is crucial. The rationale for combination therapy is to target different pathways, platelet destruction, and production without added toxicities. Additionally, gradual tapering off of TPO-RAs may provide a more favorable clinical outcome when switching to fostamatinib. The need for additional data is necessary to provide clinicians with guidance when managing patients with ITP., Competing Interests: Dr. Hughes, Dr. Toste, Mr. Nelson, and Ms. Escalon have participated on an advisory board for Rigel Pharmaceuticals. Mr. Shah has served on the speakers bureau for Rigel Pharmaceuticals., (© 2021 Harborside™.)

The case of a 40-year-old man who sustained a medial malleolar fracture with extension of the fracture into the tibial plafond is discussed. Before surgery, the physical examination revealed an Achilles tendon rupture. Surgical treatment to repair the bone and tendon injury was performed. Achilles tendon rupture is not an uncommon injury, but it is rarely associated with a fracture. When a fracture is present, the Achilles tendon injury can be overlooked, which may result in a delay of treatment or residual morbidity.

This article reports the cases of what we believe to be the youngest patients with traumatic meniscal tears treated by repair. The 2 cases were treated with different meniscal repair techniques. A review of the literature regarding traumatic meniscal tears in children is provided.

Augmentation is a well-accepted and common component of coracoclavicular ligament repairs and reconstructions. The purpose of this study was to examine and compare the strength, stiffness, and mode of failure of the coracoclavicular ligament complex and four different augmentation techniques in cadaveric shoulders. There was no significant difference in the mean failure load between the intact ligament complex (724.9+/-230.9 N) and augmentations performed with braided polydioxanone (PDS) (676.7+/-115.4 N) or braided polyethylene placed through (986.1+/-391.1 N) or around (762.7+/-218.2 N) the clavicle. The mean failure load for augmentations using a 6.5-mm cancellous screw through the clavicle and into a single cortex of the coracoid (390.1+/-253.6 N) was significantly lower than that for the intact coracoclavicular ligaments. There was no difference in mean stiffness between the intact coracoclavicular ligament complex (115.9+/-36.2 N/mm) and the braided polyethylene augmentations placed through (99.8+/-22.2 N/mm) or around (90.0+/-25.5 N/mm) the clavicle. Polydioxanone augmentations were significantly less stiff (27.4+/-3.3 N/mm) than the intact complex, while screw augmentations were significantly stiffer (250.4+/-88.2 N/mm). There were no significant differences in strength or stiffness of braided polyethylene reconstructions placed around or through a drill hole in the clavicle.

We reviewed the results in 13 patients who underwent simultaneous allograft reconstruction of both the anterior and posterior cruciate ligaments after a knee dislocation (nine acute and four chronic injuries). Seven patients sustained related medial collateral ligament injuries and six patients had posterolateral complex injuries. Ligament reconstructions were performed using fresh-frozen Achilles or patellar tendon allografts. At follow-up evaluation (mean of 38 months), only one patient described the reconstructed knee as normal. Six patients had returned to unrestricted sports activities and four had returned to modified sports. The average extension loss was 3 degrees (range, 0 degree to 10 degrees) and average flexion loss was 5 degrees (range, 0 degree to 15 degrees). The KT-1000 arthrometer measurements at 133 N anterior-posterior tibial load showed a mean side-to-side difference of 4.5 mm (range, 0 to 10) at 20 degrees and 5.0 mm (range, 0 to 9) at 70 degrees. The mean Lysholm score was 88 (range, 42 to 100). International Knee Documentation Committee ratings were six nearly normal, five abnormal, and one grossly abnormal. Two patients required manipulations for knee stiffness. This study demonstrates that reconstruction of both cruciate ligaments can restore stability sufficient to allow sports activity in most patients with knee dislocations, but "normal" results are difficult to achieve.

Three cases of Staphylococcus epidermidis septic arthritis following inside-out arthroscopic meniscus repair within a 4-day period at the same facility are described. All three patients responded to surgical debridement and 4 to 6 weeks of intravenous antibiotics. In each instance, the meniscus and repair sutures were left intact; 12- to 38-month follow-up revealed no evidence of infection or meniscal symptoms. Epidemiological investigation implicated the meniscus repair cannulas as one of the few factors common to all three cases. Molecular typing of bacterial DNA revealed that two of the three isolated organisms showed identical pulsed-field gel electrophoretic patterns, implying a common source of inoculation. Experimental contamination of the cannulas revealed that only sterilization involving ultrasonification, lumen washing by water jet, and steam sterilization resulted in clean and sterile cannulas.

Glenohumeral translation and rotation were measured in 6 grossly normal, fresh frozen shoulder preparations while a manual load was applied to the humerus. The same tests (maximum elevation, total rotation, anterior/posterior (A/P) translation, and inferior translation) were repeated for each shoulder through 8 series: 1 with the shoulder intact, 1 with the shoulder vented, and 6 with progressively larger humeral head components after hemiarthroplasty. There was an inverse linear relation between humeral head component size and all 4 outcome variables. Replacing the native head with a component of equal diameter reduced elevation 20%, rotation 40%, A/P translation 50%, and inferior translation 60% in the vented shoulder. Replacing the native head with a component of equal effective volume decreased elevation 8%, rotation 20%, A/P translation 25%, and inferior translation 40% in the vented shoulder. Increasing humeral head component size decreased rotation, A/P translation, and inferior translation by similar percentages and elevation somewhat less. Humeral head component size is better described in terms of volume than in terms of diameter or offset.

This article characterizes chondral injuries and reviews the results of microfracture treatment in high-level competitive and recreational athletes. Thirty-eight high-level and 140 recreational athletes completed functional questionnaires preoperatively and yearly postoperatively, recording symptoms, function, and activity level. Second-look arthroscopy tapes were available in 26 high-level and 54 recreational athletes. The mean follow-up for the high-level athletes was 3.7 +/- 1.4 years. Chondral defects averaged 223 +/- 180 mm2. Lesion size and follow-up were not significantly different in the recreational group. Functional questionnaire responses demonstrated significant improvements from the time of microfracture to final follow-up. Improvement in function and symptoms was similar for the competitive and recreational athletes.

The rotator cuff is the primary dynamic stabiliser of the glenohumeral joint and is placed under significant stress during overhead and contact sports. Mechanisms of injury include repetitive microtrauma, usually seen in the athlete involved in overhand sports, and macrotrauma associated with contact sports. Rotator cuff injury and dysfunction in the overhand athlete may be classified based on aetiology as primary impingement, primary tensile overload, and secondary impingement and tensile overload resulting from glenohumeral instability. A thorough history and physical examination are paramount in the evaluation, classification and treatment planning of the athlete with rotator cuff pathology. Imaging studies are a helpful adjunct to the history and physical. Athletes with primary impingement are usually middle aged or older and often have chronic shoulder pain and sometimes weakness associated with overhand sporting activities. Night pain is typical of full thickness rotator cuff tears. Impingement signs are positive and strength of elevation and external rotation are often limited. They usually respond to a nonoperative rehabilitation programme centred on decreasing inflammation, restoring range of motion and strengthening the rotator cuff and scapular stabilisers. Depending on the degree of cuff pathology, acromioplasty, debridement of partial cuff tears, and repair of full thickness tears are usually successful in those who fail a rehabilitation programme. Overhand athletes with cuff pathology secondary to subtle anterior instability are usually young and complain of pain and decreased throwing velocity. Instability may be so subtle that it is only detectable through a positive relocation test on examination. The majority of these athletes do not have a Bankart lesion on magnetic resonance imaging or arthroscopic examination. Arthroscopic examination usually demonstrates anterior capsular laxity (positive 'drive-through' sign), as well as superior-posterior labral and cuff injury typical of internal impingement. If rehabilitation alone is not successful, a capsulolabral repair followed by rehabilitation may allow the athlete to return to their previous level of competition. The athlete with an acute episode of macrotrauma to the shoulder resulting in cuff pathology usually presents with pain, limited active elevation and a positive 'shrug sign'. Arthroscopy and debridement of thickened, inflamed or scarred subacromial bursa with cuff repair or debridement as indicated is usually successful in those who do not respond to a rehabilitation programme.

In vivo dissociation of the Morse-taper of shoulder arthroplasty modular humeral components has been reported. The incidence of this complication appears to be approximately 1:1000. The objective of this study was to identify conditions that might affect the Morse-taper interface strength in humeral components. Mechanical tests were performed to load and dissociate humeral heads from the humeral stems (titanium). The effect of loading rate, load amplitude, and number of impactions was investigated. Dissociation force was measured after the taper was contaminated with water, oil, blood, and bone cement particles. The mean dissociation force after two impactions with a mallet was 2926 +/- 955 N. Dissociation force was linearly proportional to impaction force. Repetitive loading beyond two impactions did not significantly increase taper strength. Contamination of the taper with as little as 0.4 ml of fluid could prevent fixation of the taper.

Tendons are complex composite material composed primarily of water, collagen, proteolycans, and cells, designed to transmit tensile loads from muscle to bone. Although rotator cuff tendons differ in many ways from other tendons in the body, a knowledge of basic tendon structure and function is helpful in understanding rotator cuff tendon biology, injury, and repair. In addition to type I collagen, rotator cuff tendons contain small amounts of type III collagen, which play a role in healing and repair. In comparison with other tendons, the increased glycosaminoglycan and proteoglycan content seen in rotator cuff tendons may be adaptive, pathologic, or both. The etiology of rotator cuff pathology is probably related to trauma, aging, and degeneration. As our understanding of these processes increases, we will be able to develop and implement improved preventative and therapeutic interventions for rotator cuff pathology.

The causes and incidence of rotator cuff injuries in patients under the age of 40 has not been clearly established. The present study focuses on a group of 10 male contact athletes with rotator cuff injuries related to trauma sustained during football (ages from 24 to 36 years). Symptoms included pain and dysfunction in all 10 patients and a positive shrug sign in 8 of 10. The diagnoses for these patients were two isolated contusions, five partial-thickness tears, and three full-thickness tears. Surgery was performed on all patients after nonoperative treatment failed. Three partial-thickness tears were arthroscopically debrided. One full-thickness and two partial-thickness tears were repaired using the arthroscopically assisted miniarthrotomy technique. An open repair was performed in two patients. Two isolated rotator cuff contusions were arthroscopically debrided. The average followup was 21 months. Nine of 10 athletes returned to active participation in football, 7 of these at their preinjury levels. The diagnosis of rotator cuff injury should be considered in a contact athlete who has persistent shoulder pain, impingement signs, weakness, and a positive shrug sign. Arthroscopic debridement of the subacromial space followed by debridement or repair of rotator cuff tears, as clinically indicated, resulted in a marked improvement in function and rapid return to sport for these patients.

Out of 78 patients identified who underwent mini-open cuff repair, 64 were interviewed and returned a detailed questionnaire and 47 returned for a physical examination. Their average age was 64 years (31 to 85 years); and the average follow-up was 29.2 months (range, 12 to 65 months). The average tear size was 8 cm2. Preoperatively, all patients complained of pain and weakness. Ninety-six percent of patients displayed positive impingement signs preoperatively compared with 16% postoperatively. Active elevation increased significantly (P < .05) from 129 degrees to 166 degrees. At the time of follow-up there was no significant difference between active elevation in the operative and contralateral shoulders (P > .05). Weakness was detectable by physical examination in 83% of patients initially, and in 22% at the time of the final examination. The average pain and function scores improved significantly. Eighty-nine percent were satisfied with the results of their surgery. Three patients required further surgery on their shoulder. We found no correlation between cuff tear size and final Hospital for Special Surgery shoulder score.

Over 50% of all knee injuries involve partial or complete tear of the anterior cruciate ligament. Surgical reconstruction of this ligament using an isometrically placed bone-patellar tendon-bone autograft is the current technique of choice; however, harvest of patellar tendon as a free graft can lead to increased morbidity. To address this issue, allogenic patellar tendon grafts have been introduced as alternatives to autogenic graft material. The purpose of this study was to examine effects of age and strain rate on tensile strength, modulus, and failure mode of bone-patellar tendon-bone allografts from a typical population of tissue donors. Eighty-two, fresh-frozen, bone-patellar tendon-bone allografts were harvested from 25 different donors, aged 17 to 54. Paired grafts from individual patellar tendons were assigned randomly to tensile testing at either 10% or 100% elongation per second. Tensile strength, modulus, and failure mode were not significantly different for tests conducted at these 2 strain rates. Correlations between tensile strength and age were not significant for tests conducted at either strain rate. Specimens tested at a strain rate of 100% per second exhibited weak but significant negative correlation between modulus and age, with modulus decreasing 25% over the age range examined.

The influence of functional electrical muscle stimulation (FES) on selected properties of vastus lateralis muscle fibres was studied in patients recovering from total knee arthroplasty for osteoarthritis. Prior to surgery, on the average, muscle biopsies from the vastus lateralis could be characterized as having a predominance of Type I fibres which were significantly larger in cross-sectional area than the Type II fibres in the same sample. Following surgery, muscle biopsies from a group of patients (n = 7) which received continuous passive motion and no FES, exhibited a marked increase in the proportion of Type II fibres along with a general atrophy of both the Type I and Type II fibres. Patients receiving passive motion and FES (n = 9) also showed an increase in the relative percentage of Type II fibres. Post-operatively, however, there was no significant reduction in fibre area in the stimulated muscles. These data suggest that FES was effective in attenuating the muscle atrophy associated with total knee arthroplasty but had no influence on those metabolic properties which were related to muscle fibre type classification criteria.

The muscle-fiber architecture of 29 muscles from six rabbits (Oryctolagus cuniculus) was measured in order to describe the muscular properties of this cursorial animal, which possesses several specific skeletal adaptations. Several muscles were placed into one of four functional groups: hamstrings, quadriceps, dorsiflexors, or plantarflexors, for statistical comparison of properties between groups. Antagonistic groups (i.e., hamstrings vs. quadriceps or dorsiflexors vs. plantarflexors) demonstrated significant differences in fiber length, fiber length/muscle length ratio, muscle mass, pinnation angle, and number of sarcomeres in series (P less than .02). Discriminant analysis permitted characterization of the "typical" muscle belonging to one of the four groups. The quadriceps were characterized by their large pinnation angles and low fiber length/mass ratios, suggesting a design for force production. Conversely, the hamstrings, with small pinnation angles, appeared to be designed to permit large excursions. Similar differences were observed between plantarflexors and dorsiflexors, which have architectural features that suit them for force production and excursion respectively. Although these differences were not absolute, they represented clear morphological distinctions that have functional consequences.