Intrathecal Drug Delivery System in Prepontine Cistern for Patients with Intractable Craniofacial Cancer Pain: A Multicenter Retrospective Study.

BACKGROUND: Patients with craniofacial cancer frequently suffer from severe pain. The traditional intrathecal, oral, or intravenous analgesics could only provide insufficient pain relief with many side effects. Thus, a more effective analgesia approach is required. This study aimed to investigate the safety and efficacy of placing the catheter of an intrathecal morphine pump in the prepontine cistern for the treatment of craniofacial cancer pain. METHODS: We performed a retrospective study of patients with primary or metastatic craniofacial cancer pain who received the catheter placement of an intrathecal morphine pump into the prepontine cistern in eleven medical centers from September 2019 to December 2023. Friedman test and pairwise signed-rank test were used to evaluate the difference in numeric rating scale (NRS) scores, the number of breakthrough pain episodes, dose of intrathecal morphine, and dose of systemic morphine equivalents (oral, patch, intravenous) from preoperative period to postoperative days 1, 7, and 30. P values were corrected for multiple comparisons using Bonferroni test. RESULTS: The study included 33 patients. The median (interquartile range [IQR]) of NRS scores at days 1, 7, and 30 postimplant were 2.0 (1.0-3.5), 2.0 (1.0-2.0), and 1.0 (1.0-2.0), respectively, which was significantly lower than that before surgery (median, 8.0; IQR, 7.0-10.0; all P < .001). Compared to baseline number/d of breakthrough pain episodes (median, 6.0; IQR, 4.5-10.0), there was a progressive decrease in the number/d of breakthrough pain episodes at day 1, day 7, and day 30 postimplant, and the median (IQR) were 1.0 (0.0-3.0), 2.0 (0.0-3.0), and 0.0 (0.0-1.2), respectively (all P < .001). Approximately 78.8% and 96.7% of patients reported pain relief >50% at days 1 and 30 postimplant, respectively. Compared with that at day 1 postimplant, the proportion of patients with a pain relief rate >75% at day 30 postimplant also increased with continued intrathecal treatment. Compared to the dose of baseline systemic morphine equivalents (median, 228 mg.d-1; IQR, 120-408 mg.d-1), the dose of systemic morphine equivalents reduced significantly from 0(0-120) mg.d-1 at day 1 postimplant (P = .001), to 0 (0-0) mg.d-1 at days 7 and 30 postimplant (both P < .001). Few patients reported perioperative adverse events, including nausea, constipation, hypotension, urinary retention, dry mouth, headache, and sedation. No severe adverse events occurred. CONCLUSIONS: Placing the catheter tip of an intrathecal morphine pump into the prepontine cistern could effectively relieve refractory craniofacial cancer pain with an extremely low total morphine dose requirement and few adverse events. This procedure could be considered in patients with severe refractory craniofacial cancer pain.

Sex and Age-Specific Analysis of Basketball-Related Shoulder Dislocations in the United States: A National Injury Data Review.

HYPOTHESIS/PURPOSE: Basketball-related shoulder dislocations frequently present to emergency departments (EDs) in the US. This study aimed to identify the primary mechanisms, distributions, and trends of these injuries. METHODS: All data was extracted from the National Electronic Injury Surveillance System (NEISS), a public database representing approximately 100 US EDs. NEISS was queried for all basketball-related injuries and shoulder dislocations from January 1, 2013 to December 31, 2022. Clinical narratives were used to assign injury mechanisms and the presence of player contact. RESULTS: Between 2013 and 2022, 52,417 basketball-related shoulder dislocations were reported. 30.9% of all basketball-related shoulder injuries were dislocations, and 30.5% of all joint dislocations occurred at the shoulder. Basketball-related shoulder dislocations decreased significantly from 2013-2022 (p<.001). From 2019 to 2020, a 31.0% decrease was identified. The most common mechanism of shoulder dislocation was falling (36.9%). Males accounted for 92.5% of all shoulder dislocations. However, females were significantly more likely than males to dislocate their shoulders from player contact (15.5% of female dislocations v. 10.0% of male dislocations, p<.001). Only 0.2% of all dislocations resulted in hospitalization. 10.4% of dislocations resulted from contact with another player. Compared to other age groups, young adults (43.3%) and adolescents (42.7%) presented with the majority of shoulder dislocations. Children were more likely to dislocate their shoulder from sustaining a direct blow (25.5%), while all other age groups were more likely to have fallen. Children were also the most likely to sustain a dislocation involving player contact (23.9%). CONCLUSION: Basketball-related shoulder dislocations decreased significantly from 2013 to 2022. Females and children were significantly more likely to present with a dislocation by sustaining player contact. Across all demographics, teaching athletes how to break their falls safely may decrease rates of dislocation by minimizing impacts on a posteriorly outstretched arm.

Demographic and Academic Characteristics of Orthopaedic Shoulder and Elbow Division Chiefs in the United States.

INTRODUCTION: Division Chiefs (DCs) and department leadership play an integral role within the service, and in the department as a whole. The goal of this study was to assess the demographics and academic characteristics of the leadership in orthopedic shoulder and elbow services across academic centers in the United States and comment on the diversity within these leadership positions. METHODS: Academic medical centers were identified using the FRIEDA database. DCs were identified using the hospitals' respective websites where data such as sex, race/ethnicity, academic rank, fellowship institution, and time since graduating fellowship. Scopus database was used to determine individual h-indices. RESULTS: Of 198 academic programs identified, 49 were found to have a DC of the orthopedic shoulder and elbow division. An additional 26 programs were noted to have a shoulder and elbow division, but were not found to have a DC of the division. These DCs were mostly White (n=43, 87.8%), with only 6 identified DCs with a different ethnicity. Forty-five of the DCs (91.8%) were male and 4 were female (8.2%). The average time out of fellowship was 20.7 years and the average h-index was 18.9. More than 20% of the DCs trained at Columbia's Neer shoulder and elbow Fellowship. Six DCs were current or past president of ASES and 5 DCs completed the ASES traveling fellowship. CONCLUSIONS: There is a paucity of available research on demographic and leadership characteristics in academic orthopedic shoulder and elbow. Shoulder and elbow DC had average h-index of 18.9 and 20% trained at one fellowship. There also opportunities for increased gender/racial/ethnic diversity among the leadership of shoulder and elbow divisions.

The Lack of Reporting Social Determinants of Health in Pediatric Orthopaedic Randomized Controlled Trials.

BACKGROUND: Social determinants of health (SDOHs) affect health outcomes outside the hospital, and understanding them can enhance postoperative outcomes in orthopaedic surgery patients. This study aimed to describe the prevalence of randomized controlled trials (RCTs) in pediatric orthopaedic journals reporting on the SDOHs of their patient cohorts. We hypothesize that many SDOHs will be underreported in RCTs investigating pediatric orthopaedic surgery. METHODS: Utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, the authors queried the PubMed database to examine SDOHs from 2 pediatric orthopaedic journals: Journal of Pediatric Orthopaedics and Journal of Pediatric Orthopaedics: Part B. The inclusion criteria incorporated RCTs published between 2005 and April 2024. The exclusion criteria included any articles that were not RCTs published in this period. RESULTS: One hundred thirteen articles met the search criteria, with 31 excluded because they did not fall from 2005 to 2024. Eighty-two were published from 2005 to 2024, but 6 RCTs were excluded, as 3 were non-RCTs, and 3 examined cadavers. Seventy-six RCTs were included for analysis, with 65 articles from the Journal of Pediatric Orthopaedics and 11 articles from the Journal of Pediatric Orthopaedics: Part B. Articles originated from 17 countries, with the United States producing 61.8% (47) of the included studies. Of all 76 included studies, 96.1% (73) reported age, 88.2% (67) reported sex/gender, 30.3% (23) reported BMI, 21.1% (16) reported race/ethnicity, 5.3% (4) reported educational level, 2.6% (2) reported stress, and 2.6% (2) reported insurance. Smoking status, socioeconomic status, income levels, and employment status were each reported by only 1 study. CONCLUSIONS: The RCTs examining pediatric orthopaedic surgery tend to scarcely report SDOHs. Future RCTs should expand beyond demographic characteristics such as age, race/ethnicity, sex/gender, and BMI and incorporate other relevant SDOHs. This will allow us to develop a more comprehensive understanding of health outcomes in the pediatric orthopaedic population. LEVEL OF EVIDENCE: I; Therapeutic Studies.

MicroRNA-330-5p Mediates the TDRG1-Regulated Myocardial Inflammation and Apoptosis after Myocardial Infarction by Inhibiting MAPK1.

Acute myocardial infarction (AMI) is a cardiovascular illness with the highest disability and mortality rates worldwide. This study aimed to estimate the mechanism of TDRG1 in myocardial damage.qRT-PCR was used to study the levels of TDRG1. After establishing hypoxia/reoxygenation (H/R) model, the inflammation was assessed by qRT-PCR, oxidation was detected by commercial kits, and apoptosis was estimated by qRT-PCR and flow cytometry. The luciferase intensity and RNA immunoprecipitation assay were detected for the identification of target relationship. The functional enrichment was unveiled by GO and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein interaction was conducted for screening key genes.The expression of TDRG1 was elevated and negatively correlated with miR-330-5p in the serum AMI patients. TDRG1/miR-330-5p axis regulated inflammation, oxidation, and viability and apoptosis of HL-1 cells induced by H/R. GO and KEGG analyses indicate that 76 overlapping targets of miR-330-5p were primarily involved in focal adhesion, calmodulin binding, and ErbB and Rap1 signaling pathways. MAPK1 was the top key gene and was a target gene of miR-330-5p.TDRG1/miR-330-5p axis could participate in the regulation of apoptosis and inflammation of H/R-induced cardiomyocytes.

Technique notes on the management of superior sagittal or transverse sinus during the falcotentorial meningioma surgery: a case report.

Background: Falcotentorial meningiomas (FM) are surgical challenges for protecting sinus, and the technique notes on the management of superior sagittal or transverse sinus are required for good results. Methods: We improved the technique notes on the management of superior sagittal or transverse sinus in three FM patients with signs of increased intracranial pressure or chronic headache. Results: All patients underwent surgeries in the prone position, and occipital/sup-occipital/sub-occipital craniotomy was performed. In one patient, the skull was removed traditionally with exposure of the confluence of sinuses, superior sagittal, and transverse sinus, while the longitudinal skull bridge was left to suspend the dura for protecting the superior sagittal sinus in one patient, and the transverse skull bridge was left to suspend the dura for protecting the transverse sinus in one patient. The dura was opened infratentorially or supratentorially to spare the sinus and then the "skull bridge" was suspended. The tumor was then removed completely without brain swelling or significant venous bleeding. Complete tumor resection was confirmed by early postoperative imaging, and all patients recovered well without postoperative morbidity. Conclusion: The authors recommend the "skull bridge" to suspend the dura for optimal control of the venous sinuses during FM surgery (less venous bleeding).

The Delayed Presentation and Diagnosis of Youth Wrestling Injuries: A 20-Year Analysis of National Injury Data.

INTRODUCTION: The nature of wrestling may lead athletes to mask injuries with the delayed presentations of youth wrestling-related injuries not being well characterized. METHODS: This descriptive epidemiological study queried the National Electronic Injury Surveillance System database to characterize delayed presentations of wrestling-related injuries in middle and high-school athletes. Data collection consisted of national estimates, demographics, and injury characteristics of patients with delayed (D) presentations (≥1 day) and same-day (S) presentations to US emergency departments after sustaining a wrestling-related injury during the scholastic wrestling season (December to February, 2000 to 2019). RESULTS: Of middle and high-school wrestlers presenting to US emergency departments, 5.6% (95% confidence interval [CI] 4.3% to 7.1%) reported delayed presentations for a total of 1,110 patients (CI, 591 to 1,630) annually. Most commonly (P < 0.001), injuries were sustained on Saturdays in both cohorts (D, 28.2%; CI, 22.4% to 34.8%; S, 29.6%; CI, 24.3% to 35.5%). Patients reporting delayed presentations were less likely to sustain fractures (D, 11.5%; CI, 8.3% to 15.6%; S, 18.9%; CI, 15.0% to 23.5%; P = 0.019) and injuries of the head/neck (D, 20.0%; CI, 16.5 to 24.1%; S, 26.2%; CI, 21.4% to 31.7%; P = 0.011). DISCUSSION: A substantial proportion of adolescent wrestlers report delayed presentations of injuries. This emphasizes the need for vigilance in detecting subtle signs of injury.

The LexA-RecA* structure reveals a cryptic lock-and-key mechanism for SOS activation.

The bacterial SOS response plays a key role in adaptation to DNA damage, including genomic stress caused by antibiotics. SOS induction begins when activated RecA*, an oligomeric nucleoprotein filament that forms on single-stranded DNA, binds to and stimulates autoproteolysis of the repressor LexA. Here, we present the structure of the complete Escherichia coli SOS signal complex, constituting full-length LexA bound to RecA*. We uncover an extensive interface unexpectedly including the LexA DNA-binding domain, providing a new molecular rationale for ordered SOS gene induction. We further find that the interface involves three RecA subunits, with a single residue in the central engaged subunit acting as a molecular key, inserting into an allosteric binding pocket to induce LexA cleavage. Given the pro-mutagenic nature of SOS activation, our structural and mechanistic insights provide a foundation for developing new therapeutics to slow the evolution of antibiotic resistance.

Technical guideline for intra-prepontine cisternal drug delivery via spinal puncture through subarachnoid catheterization. / ç»è„ŠæŸ±æ¤Žé—´éš™ç©¿åˆºè››ç½‘è†œä¸‹è ”è„‘æ¡¥å‰æ± ç½®ç®¡è¯ç‰©è¾“æ³¨æŠ€æœ¯åº”ç”¨æŒ‡å—.

OBJECTIVES: The distribution characteristics of intrathecal drugs and the limitation of current catheterization techniques make traditional intrathecal analgesic treatment nearly useless for refractory craniofacial pain, such as trigemina neuralgia. This technical guideline aims to promote the widespread and standardize the application of intra-prepontine cisternal drug delivery via spinal puncture and catheterization. METHODS: A modified Delphi approach was used to work for this guideline. On the issues related to the intra-prepontine cisternal targeted drug delivery technique, the working group consulted 10 experts from the field with 3 rounds of email feedback and 3 rounds of conference discussion. RESULTS: For the efficacy and safety of the intra-prepontine cisternal targeted drug delivery technique, a consensus was formed on 7 topics (with an agreement rate of more than 80%), including the principles of the technique, indications and contraindications, patient preparation, surgical specifications for intra-prepontine cisternal catheter placement, analgesic dosage coordination, analgesic management, and prevention and treatment of complications. CONCLUSIONS: Utilizing the intra-prepontine cisternal drug infusion system to manage refractory craniofacial pain could provide advantages in terms of minimally invasive, secure, and effective treatment. This application can not only alleviate the suffering of individuals experiencing the prolonged pain but also support the maintenance of quality of life and dignity in their final moments, justifiing its widespread dissemination and standardized adoption in domestic and international professional fields.

[Effect of Staphylococcal Nuclease and Tudor Domain Containing 1/SLC7A11 on the Occurrence and Development of Osteosarcoma by Inhibiting Ferroptosis].

Objective To investigate the effect of staphylococcal nuclease and tudor domain containing 1(SND1) on the biological function of osteosarcoma cells and decipher the mechanism of SND1 in regulating ferroptosis in osteosarcoma cells via SLC7A11. Methods Human osteoblasts hFOB1.19 and osteosarcoma cell lines Saos-2,U2OS,HOS,and 143B were cultured,in which the expression level of SND1 was determined.Small interfering RNA was employed to knock down the expression of SND1(si-SND1) in the osteosarcoma cell line HOS and 143B.The CCK8 assay kit,colony formation assay,and Transwell assay were employed to examine the effect of SND1 expression on the biological function of osteosarcoma cells.Furthermore,we altered the expression of SND1 and SLC7A11 in osteosarcoma cells to investigate the effect of SND1 on osteosarcoma ferroptosis via SLC7A11. Results The mRNA and protein levels of SND1 in Saos-2,U2OS,HOS,and 143B cells were higher than those in hFOB1.19 cells(all P<0.01).Compared with the control group,transfection with si-SND1 down-regulated the expression level of SND1 in HOS and 143B cells(all P<0.01),decreased the viability of HOS and 143B cells,reduced the number of colony formation,and inhibited cell invasion and migration(all P<0.001).The ferroptosis inducer Erastin promoted the apoptosis of HOS and 143B cells,while the ferroptosis inhibitor Ferrostatin-1 improved the viability of HOS and 143B cells(all P<0.001).After SND-1 knockdown,Erastin reduced the viability of HOS and 143B cells,while Ferrostatin-1 restored the cell viability(all P<0.001).After treatment with Erastin in the si-SND1 group,the levels of iron and malondialdehyde were elevated,and the level of glutathione was lowered(all P<0.001).The results of in vivo experiments showed that SND1 knockdown inhibited the mass of the transplanted tumor in 143B tumor-bearing nude mice(P<0.001).Knocking down the expression of SND1 resulted in down-regulated SLC7A11 expression(all P<0.001) and increased ferroptosis in HOS and 143B cells(P<0.001,P=0.020). Conclusions SND1 presents up-regulated expression in osteosarcoma cells.It may inhibit ferroptosis by up-regulating the expression of SLC7A11,thereby improving the viability of osteosarcoma cells.

Variability of MCID, SCB, and PASS Thresholds in Studies Assessing Patient-Reported Outcomes After Rotator Cuff Repair: A Systematic Review.

BACKGROUND: An increasing reliance on patient-reported outcomes has led to greater emphasis on minimal clinically important difference (MCID), substantial clinical benefit (SCB), and Patient Acceptable Symptom State (PASS) thresholds in assessing rotator cuff repairs. PURPOSE: To review the MCID, SCB, and PASS thresholds reported for patient-reported outcome measures (PROMs) after rotator cuff repair. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: The PubMed, Embase, Ovid, Cochrane, and Google Scholar databases were queried for full-text journal articles in English published between January 1, 2000, and May 31, 2022. Studies with MCID, SCB, and PASS thresholds reported for patients with rotator cuff repair and a minimum of 12 months of follow-up were included. Reported MCID, SCB, and PASS thresholds and associated calculation methods were extracted. RESULTS: There were 41 unique studies (6331 shoulders) that met the inclusion criteria. Of these, 37 (90%) reported MCID; 16 (39%), PASS; and 11 (27%), SCB values. The most common PROMs were the American Shoulder and Elbow Surgeons score and the Constant-Murley score. In total, 71% (29/41) of these studies referenced values in the literature, usually studies of patients undergoing rotator cuff repair (21/29). Twelve studies calculated MCID, SCB, or PASS thresholds using anchor-based approaches, whereas 6 studies also calculated thresholds using distribution-based methods. The use of MCID, SCB, and PASS in the rotator cuff repair literature is increasing, with half of the included studies published within the final 17 months of the studied period. CONCLUSION: Significant variability was seen in the reporting of MCID, SCB, and PASS threshold values after rotator cuff repair. Researchers should prioritize studies that report clinical outcome thresholds calculated using anchor-based methods and should critically review both the anchor question and its response choices. Standardization of MCID, SCB, and PASS values and calculation methods will allow for a more reliable assessment of PROMs in rotator cuff repair moving forward.

The clinical impact of plasma estrogen receptor-1 mutation in patients with metastatic breast cancer: A meta-analysis.

BACKGROUND: The relevance of the discovered plasma ESR1 mutations in positive metastatic breast cancer (BC) patients who had progressing disease after aromatase inhibitor (AI)-based therapy is still being debated. OBJECTIVES: We conducted this meta-analysis to explore the prognostic and predictive role of plasma ESR1 mutations in patients with progressive BC who have previously received AI therapy. MATERIAL AND METHODS: We searched for relevant studies in the PubMed, Embase and Cochrane Library databases to be included in the meta-analysis. This study was performed to compute combined hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the progression-free survival (PFS) rate and overall survival (OS) rate. Subgroup and sensitivity analyses were also performed. The heterogeneity between studies was evaluated using the I2 statistic. RESULTS: In this meta-analysis, a total of 1,844 patients with metastatic BC and positive for estrogen receptors (ERs) were enrolled from 8 articles. The analysis revealed that patients with circulating ESR1 mutations had significantly worse PFS (HR: 1.34; 95% CI: 1.17-1.55; p < 0.001) and OS (HR: 1.59; 95% CI: 1.31-1.92; p < 0.001) compared to wild-type ESR1 patients. Subgroup analysis showed that the types of plasma ESR1 mutations were associated with differences in the prognosis of metastatic BC. The D538G mutation showed a statistically significant lower PFS (p = 0.03), while the Y537S mutation was not significantly correlated with PFS (p = 0.354). CONCLUSION: According to the findings of this meta-analysis, the assessment for plasma ESR1 mutations may provide prognostic and clinical guidance regarding subsequent endocrine therapy decisions for ER-positive, metastatic BC patients who had received prior therapy with AIs.

The Statistical Fragility of Marrow Stimulation for Cartilage Defects of the Knee: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: Marrow stimulation is used to address knee cartilage defects. In this study, we used the fragility index (FI), reverse fragility index (rFI), and fragility quotient (FQ) to evaluate statistical fragility of outcomes reported in randomized controlled trials (RCTs) evaluating marrow stimulation. DESIGN: PubMed, Embase, and MEDLINE were queried for recent RCTs (January 1, 2010-September 5, 2023) assessing marrow stimulation for cartilage defects of the knee. The FI and rFI were calculated as the number of outcome event reversals required to alter statistical significance for significant and nonsignificant outcomes, respectively. The FQ was determined by dividing the FI by the study sample size. RESULTS: Across 155 total outcomes from 21 RCTs, the median FI was 3 (interquartile range [IQR], 2-5), with an associated median FQ of 0.067 (IQR, 0.033-0.010). Thirty-two outcomes were statistically significant, with a median FI of 2 (IQR, 1-3.25) and FQ of 0.050 (IQR, 0.025-0.069). Ten of the 32 (31.3%) outcomes reported as statistically significant had an FI of 1. In total, 123 outcomes were nonsignificant, with a median rFI of 3 (IQR, 2-5). Studies assessing stem cell augments were the most fragile, with a median FI of 2. In 55.5% of outcomes, the number of patients lost to follow-up was greater than or equal to the FI. CONCLUSION: Statistical findings in RCTs evaluating marrow stimulation for cartilage defects of the knee are statistically fragile. We recommend combined reporting of P-values with FI and FQ metrics to aid in the interpretation of clinical findings in comparative trials assessing cartilage restoration.

In Vivo Analysis of Acromioclavicular Kinematics and Distance During Multiplanar Humeral Elevation.

BACKGROUND: Knowledge of acromioclavicular (AC) joint kinematics and distance may provide insight into the biomechanical function and development of new treatment methods. However, accurate data on in vivo AC kinematics and distance between the clavicle and acromion remain unknown. PURPOSE/HYPOTHESIS: The purpose of this study was to investigate 3-dimensional AC kinematics and distance during arm elevation in abduction, scaption, and forward flexion in a healthy population. It was hypothesized that AC kinematics and distance would vary with the elevation angle and plane of the arm. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 19 shoulders of healthy participants were enrolled. AC kinematics and distance were investigated with a combined dual fluoroscopic imaging system and computed tomography. Rotation and translation of the AC joint were calculated. The AC distance was measured as the minimum distance between the medial border of the acromion and the articular surface of the distal clavicle (ASDC). The minimum distance point (MDP) ratio was defined as the length between the MDP and the posterior edge of the ASDC divided by the anterior-posterior length of the ASDC. AC kinematics and distance between different elevation planes and angles were compared. RESULTS: Progressive internal rotation, upward rotation, and posterior tilt of the AC joint were observed in all elevation planes. The scapula rotated more upward relative to the clavicle in abduction than in scaption (P = .002) and flexion (P = .005). The arm elevation angle significantly affected translation of the AC joint. The acromion translated more laterally and more posteriorly in scaption than in abduction (P < .001). The AC distance decreased from the initial position to 75° in all planes and was significantly greater in flexion (P < .001). The MDP ratio significantly increased with the elevation angle (P < .001). CONCLUSION: Progressive rotation and significant translation of the AC joint were observed in different elevation planes. The AC distance decreased with the elevation angle from the initial position to 75°. The minimum distance between the ASDC and the medial border of the acromion moved anteriorly as the shoulder elevation angle increased. CLINICAL RELEVANCE: These results could serve as benchmark data for future studies aiming to improve the surgical treatment of AC joint abnormalities to restore optimal function.

Randomized Controlled Trials Comparing Bone-Patellar Tendon-Bone Versus Hamstring Tendon Autografts in Anterior Cruciate Ligament Reconstruction Surgery Are Statistically Fragile: A Systematic Review.

PURPOSE: To assess the statistical fragility of recently published randomized controlled trials (RCTs) comparing the use of hamstring tendon autograft with bone-patellar tendon-bone autograft for anterior cruciate ligament (ACL) reconstruction. METHODS: The PubMed, Embase, and MEDLINE databases were queried for RCTs published since 2010 comparing autograft type (bone-patellar tendon-bone vs hamstring tendon) in ACL reconstruction surgery. The fragility index (FI) and reverse FI (rFI) were determined for significant and nonsignificant outcomes, respectively, as the number of outcome reversals required to change statistical significance. The fragility quotient (FQ) and reverse FQ, representing fragility as a proportion of the study population, were calculated by dividing the FI and rFI, respectively, by the sample size. RESULTS: We identified 19 RCTs reporting 55 total dichotomous outcomes. The median FI of the 55 total outcomes was 5 (interquartile range [IQR], 4-7), meaning a median of 5 outcome event reversals would alter the outcomes' significance. Five outcomes were reported as statistically significant with a median FI of 4 (IQR, 2-6), meaning a median of 4 outcome event reversals would change outcomes to be nonsignificant. Fifty outcomes were reported as nonsignificant with a median rFI of 5 (IQR, 4-7), meaning a median of 5 outcome event reversals would change outcomes to be significant. The FQ and reverse FQ for significant and nonsignificant outcomes were 0.025 (IQR, 0.018-0.045) and 0.082 (IQR, 0.041-0.106), respectively. For 61.8% of outcomes, patients lost to follow-up exceeded the corresponding FI or rFI. CONCLUSIONS: There is substantial statistical fragility in recent RCTs on autograft choice in ACL reconstruction surgery given that altering a few outcome events is sufficient to reverse study findings. For over half of outcomes, maintaining patients lost to follow-up may have been sufficient to reverse study conclusions. CLINICAL RELEVANCE: We recommend co-reporting FIs and P values to provide a more comprehensive representation of a study's conclusions when conducting an RCT.

Academic and Demographic Characteristics of Pediatric Orthopaedic Division Chiefs in the United States.

INTRODUCTION: Division Chiefs (DCs) and department leadership play an integral role within the service. The goal of this study is to assess the demographics and scholarly work of the leadership in pediatric orthopaedics services across the United States and comment on the role of diversity within leadership positions. METHODS: Academic medical centers and pediatric hospitals were identified using the Electronic Residency Application Service website, the Pediatric Orthopaedic Society of North America website, and the Children's Hospital Association website. Leadership was identified using the hospitals' respective websites where data such as sex, race/ethnicity, fellowship institution, time since graduating fellowship, and academic rank were collected. Scopus database was used to determine h-indices and PubMed was used to determine the number of publications. RESULTS: Of 196 academic centers and 223 pediatric hospitals identified, 98 had a designated DC of the pediatric orthopaedics division. The majority of the DCs were male (85.7%), and leadership positions at hospitals with academic affiliations had a higher proportion of female DCs than nonacademic centers ( P =0.0317). DCs were mostly white (83.7%), followed by Asian (12.2%), and African American (2.0%). The average time since fellowship was 21.1 years and the average h-index was 15.7. The average age of the DCs was 56.8 years old. Of those in academic settings, 48.5% held the rank of professor. The fellowship programs that trained the most DCs were Boston Children's Hospital (16.3%) and Texas Scottish Rite for Children (14.3%). DISCUSSION: There is a paucity of available research on leadership characteristics in pediatric orthopaedic surgery. While progress has been made, there is still a lack of diversity that exists among leadership in pediatric orthopaedics, both within the academic setting as well as the private sector. The position of DC is held predominately by white males with a rank of either professor or no academic association. Intentional efforts are needed to continue to increase diversity in leadership positions within pediatric orthopaedic programs in the United States. LEVEL OF EVIDENCE: IV.

Proteins Need Extra Attention: Improving the Predictive Power of Protein Language Models on Mutational Datasets with Hint Tokens.

In this computational study, we introduce "hint token learning," a novel machine learning approach designed to enhance protein language modeling. This method effectively addresses the unique challenges of protein mutational datasets, characterized by highly similar inputs that may differ by only a single token. Our research highlights the superiority of hint token learning over traditional fine-tuning methods through three distinct case studies. We first developed a highly accurate free energy of folding model using the largest protein stability dataset to date. Then, we applied hint token learning to predict a biophysical attribute, the brightness of green fluorescent protein mutants. In our third case, hint token learning was utilized to assess the impact of mutations on RecA bioactivity. These diverse applications collectively demonstrate the potential of hint token learning for improving protein language modeling across general and specific mutational datasets. To facilitate broader use, we have integrated our protein language models into the HuggingFace ecosystem for downstream, mutational fine-tuning tasks.

SaLT&PepPr is an interface-predicting language model for designing peptide-guided protein degraders.

Protein-protein interactions (PPIs) are critical for biological processes and predicting the sites of these interactions is useful for both computational and experimental applications. We present a Structure-agnostic Language Transformer and Peptide Prioritization (SaLT&PepPr) pipeline to predict interaction interfaces from a protein sequence alone for the subsequent generation of peptidic binding motifs. Our model fine-tunes the ESM-2 protein language model (pLM) with a per-position prediction task to identify PPI sites using data from the PDB, and prioritizes motifs which are most likely to be involved within inter-chain binding. By only using amino acid sequence as input, our model is competitive with structural homology-based methods, but exhibits reduced performance compared with deep learning models that input both structural and sequence features. Inspired by our previous results using co-crystals to engineer target-binding "guide" peptides, we curate PPI databases to identify partners for subsequent peptide derivation. Fusing guide peptides to an E3 ubiquitin ligase domain, we demonstrate degradation of endogenous ß-catenin, 4E-BP2, and TRIM8, and highlight the nanomolar binding affinity, low off-targeting propensity, and function-altering capability of our best-performing degraders in cancer cells. In total, our study suggests that prioritizing binders from natural interactions via pLMs can enable programmable protein targeting and modulation.

Statistical Fragility of Randomized Controlled Trials Evaluating Platelet-Rich Plasma Use for Knee Osteoarthritis: A Systematic Review.

Background: Numerous studies have been published on the use of platelet-rich plasma (PRP) for knee osteoarthritis (OA), with conflicting results. Purpose: To determine the fragility index (FI) and fragility quotient (FQ) of randomized controlled trials (RCTs) that evaluated the use of PRP to treat knee OA. Study Design: Systematic review. Methods: RCTs evaluating the efficacy of PRP injections for knee OA from 2000 to 2020 were included for analysis according to PRISMA guidelines. The FI was determined by calculating the number of outcome event reversals required to change the statistical significance. The associated FQ was determined by dividing the FI by the sample size. Results: Our initial search resulted in 41,149 studies, of which 8 RCTs (678 patients, 72 outcome events) were included in the analysis. One study failed to report PRP formulation details, whereas 87.5% of studies reported using either leukocyte-rich or leukocyte-poor PRP. The platelet concentration was reported in 25% of the included trials. The overall FI of the 72 outcome events was 8.5. Accounting for sample size, the associated FQ was determined to be 0.14, suggesting that the reversal of 14% of outcome events was required to change outcome significance. There were 51 statistically significant outcomes, of which the FI and FQ were 12 and 0.164, respectively. Conclusion: Comprehensive fragility analysis suggested that the published literature evaluating the efficacy of PRP use for knee OA may lack statistical stability. We recommend the reporting of both an FI and FQ in addition to P value analysis to provide a clear and thorough understanding of the statistical integrity of studies reporting on PRP use for knee OA.