Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma.

BACKGROUND: Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. We aimed to study the impact of AURKA inhibitors on DNA damage and tumor cell death in combination with 131I-MIBG therapy in a pre-clinical model of high-risk neuroblastoma. RESULTS: Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels. CONCLUSION: The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models.

MYC phase separation selectively modulates the transcriptome.

Dysregulation and enhanced expression of MYC transcription factors (TFs) including MYC and MYCN contribute to the majority of human cancers. For example, MYCN is amplified up to several hundredfold in high-risk neuroblastoma. The resulting overexpression of N-myc aberrantly activates genes that are not activated at low N-myc levels and drives cell proliferation. Whether increasing N-myc levels simply mediates binding to lower-affinity binding sites in the genome or fundamentally changes the activation process remains unclear. One such activation mechanism that could become important above threshold levels of N-myc is the formation of aberrant transcriptional condensates through phase separation. Phase separation has recently been linked to transcriptional regulation, but the extent to which it contributes to gene activation remains an open question. Here we characterized the phase behavior of N-myc and showed that it can form dynamic condensates that have transcriptional hallmarks. We tested the role of phase separation in N-myc-regulated transcription by using a chemogenetic tool that allowed us to compare non-phase-separated and phase-separated conditions at equivalent N-myc levels, both of which showed a strong impact on gene expression compared to no N-myc expression. Interestingly, we discovered that only a small percentage (<3%) of N-myc-regulated genes is further modulated by phase separation but that these events include the activation of key oncogenes and the repression of tumor suppressors. Indeed, phase separation increases cell proliferation, corroborating the biological effects of the transcriptional changes. However, our results also show that >97% of N-myc-regulated genes are not affected by N-myc phase separation, demonstrating that soluble complexes of TFs with the transcriptional machinery are sufficient to activate transcription.

Fluid Dynamic Study of the Penn State Pediatric Total Artificial Heart.

Penn State University is developing a pediatric total artificial heart (TAH) as a bridge-to-transplant device that supports infants and small children with single ventricle anomalies or biventricular heart failure to address high waitlist mortality rates for pediatric patients with severe congenital heart disease (CHD). Two issues with mechanical circulatory support devices are thrombus formation and thromboembolic events. This in vitro study characterizes flow within Penn State's pediatric total artificial heart under physiological operating conditions. Particle image velocimetry (PIV) is used to quantify flow within the pump and to calculate wall shear rates (WSRs) along the internal pump surface to identify potential thrombogenic regions. Results show that the diastolic inflow jets produce sufficient wall shear rates to reduce thrombus deposition potential along the inlet side of the left and right pumps. The inlet jet transitions to rotational flow, which promotes wall washing along the apex of the pumps, prevents flow stasis, and aligns flow with the outlet valve prior to systolic ejection. However, inconsistent high wall shear rates near the pump apex cause increased thrombogenic potential. Strong systolic outflow jets produce high wall shear rates near the outlet valve to reduce thrombus deposition risk. The right pump, which has a modified outlet port angle to improve anatomical fit, produces lower wall shear rates and higher thrombus susceptibility potential (TSP) compared to the left pump. In summary, this study provides a fluid dynamic understanding of a new pediatric total artificial heart and indicates thrombus susceptibility is primarily confined to the apex, consistent with similar pulsatile heart pumps.

Development of the PSU Child Pump.

The Pennsylvania State University (PSU) Child Pump, a centrifugal continuous-flow ventricular assist device (cf-VAD), is being developed as a suitable long-term implantable device for pediatric heart failure patients between 10 and 35 kg, body surface area (BSA) of 0.5-1.2 m2, 1-11 years of age, and requiring a mean cardiac output of 1.0-3.5 L/min. In-vitro hydraulic and hemodynamic performances were evaluated on a custom mock circulatory loop with ovine blood. Normalized index of hemolysis (NIH) was evaluated under four conditions: 1) 8,300 rpm, 3.5 L/min, ΔP = 60 mm Hg, 2) 8,150 rpm, 5.1 L/min, ΔP = 20 mm Hg, 3) 8,400 rpm, 3.2 L/min, ΔP = 70 mm Hg, and 4) 9,850 rpm, 5.0 L/min, ΔP = 80 mm Hg, resulting in normalized index of hemolysis = 0.027 ± 0.013, 0.015 ± 0.006, 0.016 ± 0.008, and 0.026 ± 0.011 mg/dl, respectively. A mock fit study was conducted using a three-dimensional printed model of a 19 kg patient's thoracic cavity to compare the size of the PSU Child Pump to the HeartMate3 and the HVAD. Results indicate the PSU Child Pump will be a safer, appropriately sized device capable of providing the given patient cohort proper support while minimizing the risks of blood trauma as they wait for a transplant.

ALK upregulates POSTN and WNT signaling to drive neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma.

Background: Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. Here we explore whether AURKA inhibition potentiates a response to MIBG therapy. Results: Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels. Conclusion: The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models and is a promising clinical approach in high-risk neuroblastoma.

Phenytoin is associated with increased risk of osteoporosis and fragility fractures in adult epileptic patients.

INTRODUCTION: Osteoporotic fractures lead to significant decreases in the quality of life with increases in morbidity, mortality, and disability. Treatment with a variety of anti-epileptic drugs, such as phenytoin, has been understood to cause a decrease in bone mineral density. MATERIALS AND METHODS: Cohort A was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures that were also prescribed phenytoin. Cohort B was identified as patients that were 18-55 years old that had epilepsy and recurrent seizures but were not prescribed phenytoin or other anti-epileptic medications. Cohorts were matched for relevant confounding pathologies and demographic factors. Outcomes were evaluated from 1 day to 5 years after the indexed event. RESULTS: A total of 35,936 patients with epilepsy that were prescribed phenytoin were matched with 109,335 patients with epilepsy that were not prescribed phenytoin. Patients on phenytoin therapy were at significantly higher risk for osteoporosis without pathological fracture, fracture of metatarsal bone, fracture of shoulder and upper arm, fracture of distal radius, fracture of thoracic vertebra, fracture of cervical vertebra, fracture of lumbar vertebra, fracture of femoral head or neck, pertrochanteric fracture, femoral shaft fracture, and distal tibia fracture (all outcomes p < 0.001). CONCLUSION: Epileptic patients on phenytoin therapy that were 18-55 years old exhibited higher associated risk of osteoporosis and osteoporotic-fragility fractures of various regions. Patients that undergo phenytoin therapy for epilepsy treatment should be educated on the increased risk of bone fractures and have appropriate lifestyle and diet modifications.

Spinal Muscular Atrophy Type 1 Survival Without New Pharmacotherapies: Two Treatment Paradigms.

OBJECTIVES: The aims of the study are to present noninvasive respiratory management outcomes using continuous noninvasive ventilatory support and mechanical in-exsufflation from infancy for spinal muscular atrophy type 1 and to consider bearing on new medical therapies. DESIGN: Noninvasive ventilatory support was begun for consecutively referred symptomatic infants with spinal muscular atrophy type 1 from 1 to 10 mos of age. Intercurrent episodes of respiratory failure were managed by intubation then extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation despite failing ventilator weaning and extubation attempts. Intubations, tracheotomies, and survival were monitored. RESULTS: Of 153 patients with spinal muscular atrophy 1 consecutively referred since 1995, 37 became continuous noninvasive ventilatory support dependent, almost half before 10 yrs of age. Of the 37, 18 required continuous noninvasive ventilatory support for a mean 18.6 ± 3.3 yrs to a mean 25.3 (range, 18-30) yrs of age, dependent from as young as 4 mos of age with 0 to 40 ml of vital capacity. One of the 18 died from COVID-19 acute respiratory distress syndrome at age 24 after 23 yrs of continuous noninvasive ventilatory support. Extubation success rate of 85% per attempt (150/176) resulted in only one undergoing tracheotomy. CONCLUSIONS: Medical treatments begun during the first 6 wks of age convert spinal muscular atrophy 1 into spinal muscular atrophy 2 or 3 but cough flows remain inadequate to avoid many pneumonias that, once resolved by a treatment paradigm of extubation to continuous noninvasive ventilatory support and mechanical in-exsufflation, eliminates need to resort to tracheotomies.

Risk Factors Associated With Postoperative Cardiac Events Following Total Hip and Knee Arthroplasty.

BACKGROUND: This study investigated the prevalence of adverse cardiac events following a total joint arthroplasty and subsequently analyzed risk factors that may increase the likelihood of these events. METHODS: Data for this study were extracted from a large national database. Chi-squared analyses and multivariate modelings were performed to determine the risk factors associated with 30-day perioperative troponin elevation, myocardial infarction (MI), and heart failure. We identified 80,544 total hip arthroplasty (THA) patients and 112,531 total knee arthroplasty (TKA) patients and analyzed the following cardiac risk factors: diabetes, renal insufficiency, prior MI, hypertension, and cerebrovascular disease. RESULTS: There were 34% of THA patients and 52% of TKA patients who had at least one of the studied risk factors. At-risk THA patients had 2.2, 5.9, and 5.3 times the odds of troponin elevation, MI, and postoperative heart failure, respectively, within 1 month compared to the control group (P < .0001). The TKA group had 2.9, 5.3, and 5.9 times the odds of troponin elevation, MI, and postoperative heart failure within 1 month compared to the control group (P < .0001). For both procedures, prior MI had the highest odds of resulting in perioperative troponin elevation and MI. Renal insufficiency had the highest odds of resulting in perioperative heart failure. CONCLUSIONS: Risk stratification for postoperative complications in orthopedic surgery is important to minimize adverse outcomes. This study highlights the need for consideration of risk factors prior to joint arthroplasty surgery. LEVEL OF EVIDENCE: Level III, Prognostic.

Return to Play Rates Following Operative Ankle Fractures Differ Between High- and Low-Performing National Football League Athletes.

This study investigated predictive factors for return to play among National Football League athletes after operative treatment of ankle fractures and the impacts of these injuries on career longevity and player performance. Athletes who underwent surgery to repair ankle fractures from the 2013 to 2017 seasons were identified from injury reserve lists and press releases. Demographics and season metrics were collected before and after the injury. Statistical analysis assessed for differences in recorded variables between injured and uninjured players. Thirty-one players met study inclusion criteria. Twenty-two (71%) athletes successfully returned to play. Players who did not return showed no significant differences (P>.05) in position, age, body mass index, number of games or seasons played preinjury, or snaps per game the season prior to injury and had a significantly lower (42.6%, P=.013) preinjury season approximate value (SAV) compared with returning players. Returning athletes showed no significant differences (P>.05) in SAV or snaps per game compared with their preinjury season or with uninjured controls. A high preinjury SAV is associated with successful return to play. No difference in game time or performance metrics was detectable between returning players and uninjured controls, or between preinjury and postinjury seasons. [Orthopedics. 2024;47(1):22-27.].

Development and validation of a rabbit model of Pseudomonas aeruginosa non-ventilated pneumonia for preclinical drug development.

Background: New drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa, have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections. Methods: We report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression. Results: In a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO2 <60 mmHg, corresponding to a clinical cut-off when oxygen therapy would be required. When administered at 5 h post-infection, humanized dosing regimens of tobramycin and meropenem reduced mortality to 17-33%, compared to 100% for saline-treated rabbits (P<0.001 by log-rank tests). For meropenem which exhibits time-dependent bactericidal activity, rabbits treated with a humanized meropenem dosing regimen of 80 mg/kg q2h for 24 h achieved 100% T>MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved Cmax/MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had Cmax/MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects. Conclusion: The rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia.

An mRNA-based platform for the delivery of pathogen-specific IgA into mucosal secretions.

Colonization of the gut and airways by pathogenic bacteria can lead to local tissue destruction and life-threatening systemic infections, especially in immunologically compromised individuals. Here, we describe an mRNA-based platform enabling delivery of pathogen-specific immunoglobulin A (IgA) monoclonal antibodies into mucosal secretions. The platform consists of synthetic mRNA encoding IgA heavy, light, and joining (J) chains, packaged in lipid nanoparticles (LNPs) that express glycosylated, dimeric IgA with functional activity in vitro and in vivo. Importantly, mRNA-derived IgA had a significantly greater serum half-life and a more native glycosylation profile in mice than did a recombinantly produced IgA. Expression of an mRNA encoded Salmonella-specific IgA in mice resulted in intestinal localization and limited Peyer's patch invasion. The same mRNA-LNP technology was used to express a Pseudomonas-specific IgA that protected from a lung challenge. Leveraging the mRNA antibody technology as a means to intercept bacterial pathogens at mucosal surfaces opens up avenues for prophylactic and therapeutic interventions.

HeartWare Left Ventricular Assist Device Exercise Hemodynamics With Speed Adjustment Based on Left Ventricular Filling Pressures.

Functional capacity remains limited in heart failure patients with left ventricular assist devices (LVADs) due to fixed pump speed and inability to offload the left ventricle adequately. We hypothesized that manually adjusting LVAD speed during exercise based on pulmonary capillary wedge pressures would increase total cardiac output and maximal oxygen consumption. Two participants with a HeartWare LVAD underwent an invasive ramp study at rest followed by an invasive cardiopulmonary stress test exercising in two randomized phases: fixed speed and adjusted speed. In the latter phase, speed was adjusted every 1 minute during exercise at ±20 rpm/1 mm Hg change from baseline pulmonary capillary wedge pressure. There was no difference in maximal oxygen consumption between the two phases, with a modest increase in total cardiac output during speed adjustment. Filling pressures were initially controlled during speed adjustment until speed was capped at 4,000 rpm, at which point filling pressures increased. Blood pressure was variable. The pressure across the head of the pump (ΔP) was higher with speed adjustment. Contrary to our hypothesis, LVAD speed adjustment during exercise did not improve total cardiac output and functional capacity. This variable response may be attributed to the native cardiac reserve and baroreceptor response; however, additional studies are needed.

The USP46 complex deubiquitylates LRP6 to promote Wnt/ß-catenin signaling.

The relative abundance of Wnt receptors plays a crucial role in controlling Wnt signaling in tissue homeostasis and human disease. While the ubiquitin ligases that ubiquitylate Wnt receptors are well-characterized, the deubiquitylase that reverses these reactions remains unclear. Herein, we identify USP46, UAF1, and WDR20 (USP46 complex) as positive regulators of Wnt signaling in cultured human cells. We find that the USP46 complex is similarly required for Wnt signaling in Xenopus and zebrafish embryos. We demonstrate that Wnt signaling promotes the association between the USP46 complex and cell surface Wnt coreceptor, LRP6. Knockdown of USP46 decreases steady-state levels of LRP6 and increases the level of ubiquitylated LRP6. In contrast, overexpression of the USP46 complex blocks ubiquitylation of LRP6 by the ubiquitin ligases RNF43 and ZNFR3. Size exclusion chromatography studies suggest that the size of the USP46 cytoplasmic complex increases upon Wnt stimulation. Finally, we show that USP46 is essential for Wnt-dependent intestinal organoid viability, likely via its role in LRP6 receptor homeostasis. We propose a model in which the USP46 complex increases the steady-state level of cell surface LRP6 and facilitates the assembly of LRP6 into signalosomes via a pruning mechanism that removes sterically hindering ubiquitin chains.

Estimating the effects of COVID-19 on essential health services utilization in Uganda and Bangladesh using data from routine health information systems.

Background: Since March 2020, the coronavirus disease 2019 (COVID-19) pandemic has been a major shock to health systems across the world. We examined national usage patterns for selected basic, essential health services, before and during the COVID-19 pandemic in Uganda and Bangladesh, to determine whether COVID-19 affected reporting of service utilization and the use of health services in each country. Methods: We used routine health information system data since January 2017 to analyze reporting and service utilization patterns for a variety of health services. Using time series models to replicate pre-COVID-19 trajectories over time we estimated what levels would have been observed if COVID-19 had not occurred during the pandemic months, starting in March 2020. The difference between the observed and predicted levels is the COVID-19 effect on health services. Results: The time trend models for Uganda and Bangladesh closely replicated the levels and trajectories of service utilization during the 38 months prior to the COVID-19 pandemic. Our results indicate that COVID-19 had severe effects across all services, particularly during the first months of the pandemic, but COVID-19 impacts on health services and subsequent recovery varied by service type. In general, recovery to expected levels was slow and incomplete across the most affected services. Conclusion: Our analytical approach based on national information system data could be very useful as a form of surveillance for health services disruptions from any cause leading to rapid responses from health service managers and policymakers.

PRDM6 promotes medulloblastoma by repressing chromatin accessibility and altering gene expression.

SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.

Cadaveric Prehospital Amputation: Which Reciprocating Saw Blade Offers the Most Efficient Amputation.

OBJECTIVE: Field amputations are a low-frequency, high-risk procedure. Many prehospital personnel utilize the reciprocating saw. This study compares the efficiency, speed, and degree of tissue damage of different reciprocating saw blades found commercially. METHODS: Amputations were performed on two human cadavers at different levels of the upper and lower extremities. Four different blades were used, each with a different teeth-per-inch (TPI) design. The amputations were timed, blade temperature was recorded, subjective operator effort was obtained, amount of splatter was evaluated, and an orthopedic physician evaluated the extent of tissue damage and operating room repair difficulty. RESULTS: The blade with fourteen TPI was superior in overall speed to complete the amputations at 1.07 seconds per one centimeter of tissue (SD = 0.49 seconds) and had the lowest fail rate (0/8 amputations). The three TPI, six TPI, and ten TPI blades all required a "rescue" technique and were slower. The blade with fourteen TPI caused the least amount of tissue damage and was deemed the easiest to repair. Secondary outcomes demonstrated the fourteen TPI blade had generated the least amount of heat and produced the least amount of splatter. All blades had a perceived effort of "easy" to complete the amputation. CONCLUSION: While all blades were able to achieve an amputation, the overall recommendation is use of a fourteen TPI blade. It did not require any rescue techniques, provided the most straightforward amputation to repair, had the least amount of biohazard splatter and temperature increase, and was the fastest blade overall.

Isolated medial patellofemoral reconstruction outcomes: A systematic review and meta-analysis.

BACKGROUND: Treatment of patellar instability remains up for debate, and a combination of tibial tubercle osteotomy and medial patellofemoral ligament reconstruction (MPFLr) of the medial patellofemoral ligament (MPFL) has become the mainstay treatment for recurrent lateral patellar dislocation. Due to limited small studies, there remains a variety of surgical techniques still being practiced. The use of MPFL reconstruction, in isolation, has demonstrated promise. PURPOSE: The purpose of this systematic review and meta-analysis is to investigate if isolated medial patellofemoral ligament reconstruction (iMPFLr) can safely and efficaciously restore knee stability and to present the patient demographics, surgical techniques, graft choices, clinical outcomes, and complications after iMPFLr for recurrent patellar dislocation (RPD). METHODS: A review of the current literature according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, yielded 299 abstracts. Twenty-seven articles met the inclusion/exclusion criteria accounting for 1200 patients. Data was pooled and analyzed focusing on patient demographics, graft type used, Kujala, International Knee Documentation Committee (IKDC), Lysholm, Tegner, and complications. RESULTS: Across all studies the weighted mean age was found to be an average of 24.5 years, BMI was 24.9 kg/m2, follow-up was 47.3 months, as 67% were female, TT-TG distance was 15.3 mm, and Caton Deschamps index 1.11. The pooled effect size difference of pre versus post assessment of Kujala was -2.8, IKDC was -4.5, Lysholm was -6.4, and Tegner was -0.74. The pooled complication rate was found to be 8% across all included studies. A subgroup analysis was also performed, specifically looking at how single bundle, double bundle, gracilis, semitendinosus and knee angle during fixation effect outcome data. CONCLUSION: This systematic review and meta-analysis demonstrates that isolated MPFL reconstruction is a safe and effective treatment for recurrent patellar dislocations. Given the efficacy of isolated MPFL reconstruction, future investigations should aim to uncover the exact TT-TG distance, trochlear dysplasia, and patella alta grade for selecting patients to undergo this procedure. Furthermore, more primary research needs to be conducted on this topic due to the overall lack of published data from randomized controlled studies and no broad standardization of outcome measurements. LEVEL OF EVIDENCE: (4) Systematic Review and Meta-Analysis.