Surgical Management of a Torn ACL and Bucket-Handle Meniscal Tear in the Pregnant Patient: A Case Report.

CASE: A 36-year-old, 7-month pregnant woman presented to the office with a locked knee and a displaced bucket-handle medial meniscus tear, in the setting of chronic anterior cruciate ligament (ACL) insufficiency. After thorough discussion with the patient and her husband, the obstetrician, and the anesthesiologist, the patient was treated with left knee ACL reconstruction and medial meniscus repair. CONCLUSION: With sufficient preoperative planning and coordinated multidisciplinary care among orthopaedic, anesthesiologist, and obstetric specialists, elective knee surgery can be performed safely in time-sensitive situations during pregnancy.

Proteogenomic characterization of primary colorectal cancer and metastatic progression identifies proteome-based subtypes and signatures.

Metastatic progression of colorectal adenocarcinoma (CRC) remains poorly understood and poses significant challenges for treatment. To overcome these challenges, we performed multiomics analyses of primary CRC and liver metastases. Genomic alterations, such as structural variants or copy number alterations, were enriched in oncogenes and tumor suppressor genes and increased in metastases. Unsupervised mass spectrometry-based proteomics of 135 primary and 123 metastatic CRCs uncovered distinct proteomic subtypes, three each for primary and metastatic CRCs, respectively. Integrated analyses revealed that hypoxia, stemness, and immune signatures characterize these 6 subtypes. Hypoxic CRC harbors high epithelial-to-mesenchymal transition features and metabolic adaptation. CRC with a stemness signature shows high oncogenic pathway activation and alternative telomere lengthening (ALT) phenotype, especially in metastatic lesions. Tumor microenvironment analysis shows immune evasion via modulation of major histocompatibility complex (MHC) class I/II and antigen processing pathways. This study characterizes both primary and metastatic CRCs and provides a large proteogenomics dataset of metastatic progression.

ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia.

While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear. ATM expression is enriched in microglia throughout cerebellar development and adulthood. Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we performed transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia, which revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may promote neurodegeneration in A-T.

Effects of a Perioperative Blood Flow Restriction Therapy Program on Early Quadriceps Strength and Patient-Reported Outcomes After Anterior Cruciate Ligament Reconstruction.

Background: Quadriceps muscle atrophy remains a limiting factor in returning to activity after anterior cruciate ligament reconstruction (ACLR). Blood flow restriction (BFR) therapy may accelerate quadriceps strengthening in the perioperative period. Purpose: To evaluate postoperative isometric quadriceps strength in patients who underwent ACLR with a perioperative BFR program. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Patients indicated for ACLR were randomized into 2 groups, BFR and control, at their initial clinic visit. All patients underwent 2 weeks of prehabilitation preoperatively, with the BFR group performing exercises with a pneumatic cuff set to 80% limb occlusion pressure placed over the proximal thigh. All patients also underwent a standardized postoperative 12-week physical therapy protocol, with the BFR group using pneumatic cuffs during exercise. Quadriceps strength was measured as peak and mean torque during seated leg extension and presented as quadriceps index (percentage vs healthy limb). Patient-reported outcomes (PROs), knee range of motion, and quadriceps circumference were also gathered at 6 weeks, 3 months, and 6 months postoperatively, and adverse effects were recorded. Results: Included were 46 patients, 22 in the BFR group (mean age, 25.4 ± 10.6 years) and 24 in the control group (mean age, 27.5 ± 12.0 years). At 6 weeks postoperatively, the BFR group demonstrated significantly greater strength compared with the controls (quadriceps index: 57% ± 24% vs 40% ± 18%; P = .029), and the BFR group had significantly better Patient-Reported Outcomes Measurement Information System-Physical Function (42.69 ± 5.64 vs 39.20 ± 5.51; P = .001) and International Knee Documentation Committee (58.22 ± 7.64 vs 47.05 ± 13.50; P = .011) scores. At 6 weeks postoperatively, controls demonstrated a significant drop in the peak torque generation of the operative versus nonoperative leg. There were no significant differences in strength or PROs at 3 or 6 months postoperatively. Three patients elected to drop out of the BFR group secondary to cuff intolerance during exercise; otherwise, no other severe adverse events were reported. Conclusion: Integrating BFR into perioperative physical therapy protocols led to improved strength and increased PROs at 6 weeks after ACLR. No differences in strength or PROs were found at 3 and 6 months between the 2 groups. Registration: NCT04374968 (ClinicalTrials.gov identifier).

Allosteric inhibition of the T cell receptor by a designed membrane ligand.

The T cell receptor (TCR) is a complex molecular machine that directs the activation of T cells, allowing the immune system to fight pathogens and cancer cells. Despite decades of investigation, the molecular mechanism of TCR activation is still controversial. One of the leading activation hypotheses is the allosteric model. This model posits that binding of pMHC at the extracellular domain triggers a dynamic change in the transmembrane (TM) domain of the TCR subunits, which leads to signaling at the cytoplasmic side. We sought to test this hypothesis by creating a TM ligand for TCR. Previously we described a method to create a soluble peptide capable of inserting into membranes and binding to the TM domain of the receptor tyrosine kinase EphA2 (Alves et al., eLife, 2018). Here, we show that the approach is generalizable to complex membrane receptors, by designing a TM ligand for TCR. We observed that the designed peptide caused a reduction of Lck phosphorylation of TCR at the CD3ζ subunit in T cells. As a result, in the presence of this peptide inhibitor of TCR (PITCR), the proximal signaling cascade downstream of TCR activation was significantly dampened. Co-localization and co-immunoprecipitation in diisobutylene maleic acid (DIBMA) native nanodiscs confirmed that PITCR was able to bind to the TCR. AlphaFold-Multimer predicted that PITCR binds to the TM region of TCR, where it interacts with the two CD3ζ subunits. Our results additionally indicate that PITCR disrupts the allosteric changes in the compactness of the TM bundle that occur upon TCR activation, lending support to the allosteric TCR activation model. The TCR inhibition achieved by PITCR might be useful to treat inflammatory and autoimmune diseases and to prevent organ transplant rejection, as in these conditions aberrant activation of TCR contributes to disease.

Sequence-independent activity of a predicted long disordered segment of the human papillomavirus type 16 L2 capsid protein during virus entry.

The activity of proteins is thought to be invariably determined by their amino acid sequence or composition, but we show that a long segment of a viral protein can support infection independent of its sequence or composition. During virus entry, the papillomavirus L2 capsid protein protrudes through the endosome membrane into the cytoplasm to bind cellular factors such as retromer required for intracellular virus trafficking. Here, we show that an ~110 amino acid segment of L2 is predicted to be disordered and that large deletions in this segment abolish infectivity of HPV16 pseudoviruses by inhibiting cytoplasmic protrusion of L2, association with retromer, and proper virus trafficking. The activity of these mutants can be restored by insertion of protein segments with diverse sequences, compositions, and chemical properties, including scrambled amino acid sequences, a tandem array of a short sequence, and the intrinsically disordered region of an unrelated cellular protein. The infectivity of mutants with small in-frame deletions in this segment directly correlates with the size of the segment. These results indicate that the length of the disordered segment, not its sequence or composition, determines its activity during HPV16 pseudovirus infection. We propose that a minimal length of L2 is required for it to protrude far enough into the cytoplasm to bind cytoplasmic trafficking factors, but the sequence of this segment is largely irrelevant. Thus, protein segments can carry out complex biological functions such as Human papillomavirus pseudovirus infection in a sequence-independent manner. This finding has important implications for protein function and evolution.

Availability of Consumer Prices for Arthroscopic Meniscus Surgery.

The purpose is to examine the availability of consumer pricing information for arthroscopic meniscal surgery in the United States. Secondary objectives were comparing the price of meniscal repair to meniscectomy and regional pricing differences. Orthopaedic sports medicine clinics were sorted by state and randomly selected from American Orthopaedic Society for Sports Medicine's online directory. Following standardized script, each clinic was called a maximum of three times to obtain pricing information for meniscal surgery. A total of 1,008 distinct orthopaedic sport medicine practices were contacted. Six (6%) clinics were able to provide complete bundle pricing, and 183 (18.2%) clinics were able to provide physician-only fees for either meniscectomy or meniscal repair. Physician-only fees and bundle pricing were significantly less for meniscal repairs as compared to meniscectomies. There were no geographic regional differences in pricing for physician-only fees. There is a paucity of information regarding price transparency for arthroscopic meniscal surgery. (Journal of Surgical Orthopaedic Advances 32(2):083-087, 2023).

Acute Exertional Bilateral Thigh Compartment Syndrome in a Patient with Rhabdomyolysis After Spin Class: A Case Report.

CASE: A healthy 24-year-old woman developed rhabdomyolysis and acute bilateral thigh compartment syndrome after 10 minutes of spin class. She was successfully managed with early recognition, aggressive fluid resuscitation, and prompt bilateral surgical decompressive fasciotomy. CONCLUSION: Rhabdomyolysis with acute compartment syndrome is a rare but devastating combination of conditions. A high suspicion for rhabdomyolysis and progression to acute compartment syndrome is warranted for any patient presenting with increasing pain even with a limited history of trauma or exertion. Early recognition and medical and surgical treatment are paramount to preventing permanent damage.

Patient factors influencing the choice of opioid versus non-opioid postoperative analgesia following common sports procedures: a prospective survey study.

Purpose: Despite established opioid-free protocols for postoperative analgesia after common orthopaedic sports procedures, many patients continue to request opioids postoperatively. The purpose of this study was to elucidate patient factors influencing preferences for opioid versus nonopioid postoperative analgesia. Methods: Patients (age >/ = 15) without a history of a documented chronic pain disorder who were scheduled for one of ten sports procedure types from August 2020 to May 2021 were eligible for inclusion. Patients were excluded if undergoing revision surgery, had concomitant injuries, had opioids use >3 months preoperatively, or unable to read English. Recruitment ended after 100 patients enrolled. At the patients' preoperative visit, patients were administered a written survey assessing pain medication preferences. Participants completed the Opioid Risk Tool survey, as well as Visual Analog Scale and Patient-Reported Outcome Measurement Information System surveys. Results: One hundred patients participated in the study. Forty-two patients preferred opioids versus 58 patients preferring nonopioid postoperative analgesia. Patients preferring opiates were more likely to have had previous surgery (90.2% vs. 69.6%, p = 0.023) with post-operative pain managed with opiates (87.5% vs 55.4%, p = 0.003), higher preoperative Visual Analog Scale score (6±3.5 vs. 3±2, p < 0.001), reported post-operative pain as a reason for opioids preference (88.1% vs 20.0%, p < 0.001), and were less concerned about addiction (4.8% vs. 45.5%, p < 0.001) and side effects (11.9% vs. 52.7%, p < 0.001). For every unit increase in Visual Analog Scale score, the odds of preferring opioid pain control increased 1.41 times. Conclusions: Patients with a history of prior surgery utilizing opioid pain control, higher Visual Analog Scale scores preoperatively, and concern for inadequately managed postoperative pain were more likely to prefer opioid pain control following common orthopaedic sports procedures. Patients may benefit from increased preoperative education about opioid risks and the role of multimodal pain management regimens.

Sequence independent activity of a predicted long disordered segment of the human papillomavirus L2 capsid protein during virus entry.

The papillomavirus L2 capsid protein protrudes through the endosome membrane into the cytoplasm during virus entry to bind cellular factors required for intracellular virus trafficking. Cytoplasmic protrusion of HPV16 L2, virus trafficking, and infectivity are inhibited by large deletions in an ∻110 amino acid segment of L2 that is predicted to be disordered. The activity of these mutants can be restored by inserting protein segments with diverse compositions and chemical properties into this region, including scrambled sequences, a tandem array of a short sequence, and the intrinsically disordered region of a cellular protein. The infectivity of mutants with small in-frame insertions and deletions in this segment directly correlates with the size of the segment. These results indicate that the length of the disordered segment, not its sequence or its composition, determines its activity during virus entry. Sequence independent but length dependent activity has important implications for protein function and evolution.

The impact of nonoperative hip and core injuries on National Football League athlete performance.

OBJECTIVES: Hip and core injuries are common in National Football League (NFL) athletes; however, the impact following injury remains unclear. The goal of this manuscript was to determine the impact of nonoperative hip and core injuries on return to play and performance. METHODS: NFL athletes who sustained a hip or core injury treated nonoperatively between 2010 and 2016 were identified. Offensive and defensive power ratings were calculated for each player's injury season and two seasons before and after to assess longitudinal impact. A matched control group without an identified hip and/or core injury was assembled for comparison. RESULTS: A total of 41 offensive and 71 defensive players with nonoperative hip or core injury were analyzed. All athletes returned to play; offensive and defensive players missed 4.0 ± 5.2 and 3.1 ± 2.6 games after injury, respectively. Offensive players played fewer cumulative career games returning from core injury versus hip (23.5 ± 20.6 vs 41.0 ± 26.4). Defensive players played fewer games (58.1 ± 41.1 versus 37.4 ± 27.1, p < 0.05) with lower defensive power rating (133.9 ± 128.5 versus 219.8 ± 212.2, p < 0.05) cumulatively after hip or core injury. Additionally, 2 years following injury, defensive players played fewer games compared to controls (9.5 ± 7.0 versus 10.9 ± 6.8, p < 0.05). Following hip injury specifically, NFL defenders played fewer games (39.8 ± 27.9 vs 61.9 ± 38.8; p < 0.05) and had a lower defensive power rating (145.9 ± 131.7 vs 239.0 ± 205.9; p < 0.05) compared to before injury. CONCLUSION: Overall, NFL players return to play following nonoperative hip and core injuries. Defensive players played in fewer games following hip or core injury compared to controls; offensive players were unaffected. Hip injuries have a greater impact on performance compared to core injuries in defensive athletes; offensive players played fewer games upon return from core injury.

Retrospective Review of Radiographic Imaging of Tibial Bony Stress Injuries in Adolescent Athletes With Positive MRI Findings: A Comparative Study.

BACKGROUND: It is difficult to diagnose and grade bony stress injury (BSI) in the athletic adolescent population without advanced imaging. Radiographs are recommended as a first imaging modality, but have limited sensitivity and, even when findings are present, advanced imaging is often recommended. HYPOTHESIS: It was hypothesized that the significance of radiographs is underestimated for BSI in the adolescent with positive clinical examination and history findings. STUDY DESIGN: Case series. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 80 adolescent athletes with a history of shin pain underwent clinical examination by an orthopaedic surgeon. On the day of clinical examination, full-length bilateral tibial radiographs and magnetic resonance imaging (MRI) scans were obtained. MRI scans were reviewed using Fredericson grading for BSI. At the completion of the study, radiographic images were re-evaluated by 2 musculoskeletal (MSK) radiologists, blinded to MRI and clinical examination results, who reviewed the radiographs for evidence of BSI. Radiographic results were compared with clinical examination and MRI findings. Sensitivity, specificity, negative predictive value, and positive predictive value were calculated based on comparison with MRI. RESULTS: All radiographs were originally read as normal. Of the tibia studied, 80% (127 of 160) showed evidence of BSI on MRI. None of the original radiographs demonstrated a fracture line on initial review by the orthopaedic surgeons. Retrospective review by 2 MSK radiologists identified 27% of radiographs (34 of 127) with evidence of abnormality, which correlated with clinical examination and significant findings on MRI. Review of radiographs found evidence of new bone on 0 of 28 Fredericson grade 0, 0 of 19 Fredericson grade I, 11 of 80 (13.7%) Fredericson grade II, 18 of 28 (64%) Fredericson grade III, and 5 of 5 (100%) Fredericson grade IV. Sensitivity of radiographs showed evidence of new bone on 27% (34 of 127) of initial radiographs, with presence more common with greater degree of BSI, as 23 of 33 (70%) were higher-grade injuries (III of IV) of BSI. Specificity and positive predictive value were 100%, while negative predictive value was 17%. CONCLUSION: These findings highlight the importance of initial radiographs in identifying high-grade BSI. As radiographs are readily available in most office settings of sports medicine physicians, this information can influence the management of adolescent athletic BSI without the need to delay treatment to obtain an MRI. CLINICAL RELEVANCE: Adolescent athletes with radiographic evidence of BSI should be treated in a timely and more conservative manner, given the likelihood of higher-grade BSI. In addition, clinicians knowledgeable of the radiographic findings of high-grade BSI should feel more confident that a negative initial radiograph is not likely to be a high-grade BSI and can modify their treatment plans accordingly.

Personalized health risk assessment based on single-cell RNA sequencing analysis of a male with 45, X/48, XYYY karyotype.

Numeric sex chromosome abnormalities are commonly associated with an increased cancer risk. Here, we report a 14-year-old boy with a rare mosaic 45, X/48, XYYY karyotype presenting with subtle dysmorphic features and relative height deficiency, requiring growth hormone therapy. As only 12 postnatal cases have been described so far with very limited follow-up data, to assess the proband's long-term prognosis, including cancer risk, we performed high-throughput single-cell RNA sequencing (scRNA-seq) analysis. Although comprehensive cytogenetic analysis showed seemingly near perfect balance between 45, X and 48, XYYY cell populations, scRNA-seq revealed widespread differences in genotype distribution among immune cell fractions, specifically in monocytes, B- and T-cells. These results were confirmed at DNA level by digital-droplet PCR on flow-sorted immune cell types. Furthermore, deregulation of predominantly autosomal genes was observed, including TCL1A overexpression in 45, X B-lymphocytes and other known genes associated with hematological malignancies. Together with the standard hematological results, showing increased fractions of monocytes and CD4+/CD8+T lymphocytes ratio, long-term personalized hemato-oncological surveillance was recommended in the reported patient.

High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing.

The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation, and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population, and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor, and peripheral blood from 52 reportedly sporadic breast cancer patients. Targeted resequencing of 542 cancer-associated genes revealed subclonal somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3, and TSHR in the normal mammary gland at considerable allelic frequencies (9 × 10-2- 5.2 × 10-1), indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low-level subclonal (in 10-2-10-4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumorous mammary gland tissue of breast-conserving surgery patients.

An Automated Technique for the Measurement of Limb Occlusion Pressure During Blood Flow Restriction Therapy Is Equivalent to Previous Gold Standard.

Purpose: To evaluate the efficacy of an automated pneumatic torniquet pump and its ability to automatically calculate the limb occlusion pressure (LOP), as compared with the manual Doppler ultrasound technique. Methods: Participants presenting to a Sports Medicine clinic were evaluated for study enrollment. Participants were fitted with a pneumatic tourniquet for the upper and lower extremity. LOP measurements were taken with a Doppler ultrasound or automated SmartCuffs PRO device in a randomized order. Results: Final analysis was performed on 96 limbs (48 upper extremities and 48 lower extremities). The study population had a mean age 37.1 ± 14.7 years old and a mean body mass index of 25.47 ± 3.80. The mean measured LOP pressure on the upper extremity with Doppler ultrasound was 174.0 ± 48.7 mm Hg with a range from 120 to 282 mm Hg, whereas the mean measured LOP by the automated pump was 184.0 ± 44.9 mm Hg with a range from 135 to 266 mm Hg. There was no statistically significant difference found between the Doppler LOP and the Smart Cuff upper extremity LOP (P = .29). When evaluating LOP pressure on the lower extremity the mean LOP found with the Doppler ultrasound was 195.0 ± 31.9 mm Hg with a range from 160 to 272 mm Hg, whereas the automated pump the mean LOP was 205.0 ± 27.1 mm Hg with a range from 168 to 278 mm Hg. There was no statistically significant difference found between the Doppler LOP and the automated pump lower extremity LOP (P = .09). Conclusions: No difference in the personalized LOP measurement was found when comparing an automated pump with the current gold standard of manual Doppler ultrasound. No patients companied of pain or discomfort during the LOP measurement. Level of Evidence: Level II, diagnostic: prospective cohort study.

Patellar Tendinopathy: Critical Analysis Review of Current Nonoperative Treatments.

¼: Patellar tendinopathy is an attritional injury of the patellar tendon that is frequently identified in jumping athletes. Through repetitive or explosive movements, considerable loads and high peak strains are generated across the patellar tendon. ¼: This leads to microinjury of tendon fibers, local mucoid degeneration, and loss of the fibrocartilaginous tissue that attaches tendon to bone. ¼: Management of patellar tendinopathy often begins with nonoperative modalities: progressive tendon loading and eccentric rehabilitative exercise programs are the most effective. While a variety of additional treatment modalities are available, the comparative efficacy of these supportive treatments is not well differentiated at this time. ¼: In this article, we analyze the existing literature regarding nonoperative treatment of patellar tendinopathy and provide additional insight on the effectiveness of current modalities.

Lower Extremity Injury After Return to Sports From Concussion: A Systematic Review.

BACKGROUND: Recent studies have suggested increased rates of lower extremity (LE) musculoskeletal injury after a diagnosed concussion, although significant heterogeneity exists. PURPOSE: To examine the current body of research and determine whether there is an increased risk for LE musculoskeletal injury after a concussion and to identify populations at an increased risk. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: A systematic review of current literature using MEDLINE and PubMed databases was performed. Keywords included concussion, athlete, lower extremity injury, and return to sport. Inclusion criteria required original research articles written in the English language examining the rate of LE injuries after a diagnosed concussion. RESULTS: A total of 13 studies involving 4349 athletes (88.1% male and 11.9% female; mean age, 19.8 years) met inclusion criteria. Athletes were classified as high school (46.1%), collegiate (17.0%), or professional (36.9%). Of the 13 studies, 4 demonstrated an increased risk of LE injury within 90 days of a diagnosed concussion (odds ratio [OR], 3.44; 95% CI, 2.99-4.42), and 6 revealed an elevated risk of injury within 1 year of concussion (OR, 1.85; 95% CI, 1.73-2.84). Increased risk was seen in professional (OR, 2.49; 95% CI, 2.40-2.72) and collegiate (OR, 2.00; 95% CI, 1.96-2.16) athletes compared with high school athletes (OR, 0.97; 95% CI, 0.89-1.05). A stepwise increase in risk of sustaining an LE injury was observed with multiple concussions, with increasing risk observed from ≥2 (OR, 2.29; 95% CI, 1.85-2.83) to ≥3 (OR, 2.86; 95% CI, 2.36-3.48) career concussions. CONCLUSION: An increased incidence of LE injuries was observed at 90 days and 1 year after the diagnosis of a concussion. Higher levels of competition, such as at the collegiate and professional levels, resulted in an increased risk of sustaining a subsequent LE injury after a diagnosed concussion. These results suggest an at-risk population who may benefit from injury prevention methods after a concussion. Future studies should focus on identifying which injuries are most common, during what time period athletes are most vulnerable, and methods to prevent injury after return to sports.