Use of Metadata-Driven Approaches for Data Harmonization in the Medical Domain: Scoping Review.

BACKGROUND: Multisite clinical studies are increasingly using real-world data to gain real-world evidence. However, due to the heterogeneity of source data, it is difficult to analyze such data in a unified way across clinics. Therefore, the implementation of Extract-Transform-Load (ETL) or Extract-Load-Transform (ELT) processes for harmonizing local health data is necessary, in order to guarantee the data quality for research. However, the development of such processes is time-consuming and unsustainable. A promising way to ease this is the generalization of ETL/ELT processes. OBJECTIVE: In this work, we investigate existing possibilities for the development of generic ETL/ELT processes. Particularly, we focus on approaches with low development complexity by using descriptive metadata and structural metadata. METHODS: We conducted a literature review following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We used 4 publication databases (ie, PubMed, IEEE Explore, Web of Science, and Biomed Center) to search for relevant publications from 2012 to 2022. The PRISMA flow was then visualized using an R-based tool (Evidence Synthesis Hackathon). All relevant contents of the publications were extracted into a spreadsheet for further analysis and visualization. RESULTS: Regarding the PRISMA guidelines, we included 33 publications in this literature review. All included publications were categorized into 7 different focus groups (ie, medicine, data warehouse, big data, industry, geoinformatics, archaeology, and military). Based on the extracted data, ontology-based and rule-based approaches were the 2 most used approaches in different thematic categories. Different approaches and tools were chosen to achieve different purposes within the use cases. CONCLUSIONS: Our literature review shows that using metadata-driven (MDD) approaches to develop an ETL/ELT process can serve different purposes in different thematic categories. The results show that it is promising to implement an ETL/ELT process by applying MDD approach to automate the data transformation from Fast Healthcare Interoperability Resources to Observational Medical Outcomes Partnership Common Data Model. However, the determining of an appropriate MDD approach and tool to implement such an ETL/ELT process remains a challenge. This is due to the lack of comprehensive insight into the characterizations of the MDD approaches presented in this study. Therefore, our next step is to evaluate the MDD approaches presented in this study and to determine the most appropriate MDD approaches and the way to integrate them into the ETL/ELT process. This could verify the ability of using MDD approaches to generalize the ETL process for harmonizing medical data.

Pharmacological Improvement of Cystic Fibrosis Transmembrane Conductance Regulator Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.

Rationale: Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. Objectives: To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Methods: Nasal swabs from 13 children with CF and at least one F508del allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Measurements and Main Results: Proportions of CFTR-positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Conclusions: Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.

Evaluation of Modeling Approaches for a Clinical Data Warehouse in a Highly Dynamic Environment.

The availability of clinical data for researchers is crucial for an improvement of healthcare and research. For this purpose, the integration, harmonization and standardization of healthcare-data from various sources in a clinical data warehouse (CDWH) is highly relevant. Our evaluation taking into account the general conditions and requirements of the project, led us to choose the Data Vault approach for the development of a clinical data warehouse at the University Hospital Dresden (UHD).

An integrated tumor, immune and microbiome atlas of colon cancer.

The lack of multi-omics cancer datasets with extensive follow-up information hinders the identification of accurate biomarkers of clinical outcome. In this cohort study, we performed comprehensive genomic analyses on fresh-frozen samples from 348 patients affected by primary colon cancer, encompassing RNA, whole-exome, deep T cell receptor and 16S bacterial rRNA gene sequencing on tumor and matched healthy colon tissue, complemented with tumor whole-genome sequencing for further microbiome characterization. A type 1 helper T cell, cytotoxic, gene expression signature, called Immunologic Constant of Rejection, captured the presence of clonally expanded, tumor-enriched T cell clones and outperformed conventional prognostic molecular biomarkers, such as the consensus molecular subtype and the microsatellite instability classifications. Quantification of genetic immunoediting, defined as a lower number of neoantigens than expected, further refined its prognostic value. We identified a microbiome signature, driven by Ruminococcus bromii, associated with a favorable outcome. By combining microbiome signature and Immunologic Constant of Rejection, we developed and validated a composite score (mICRoScore), which identifies a group of patients with excellent survival probability. The publicly available multi-omics dataset provides a resource for better understanding colon cancer biology that could facilitate the discovery of personalized therapeutic approaches.

Technical assessment of different extraction methods and transcriptome profiling of RNA isolated from small volumes of blood.

Transcriptome profiling of human whole blood is used to discover biomarkers of diseases and to assess phenotypic traits. Recently, finger-stick blood collection systems have allowed a less invasive and quicker collection of peripheral blood. Such non-invasive sampling of small volumes of blood offers practical advantages. The quality of gene expression data is strictly dependent on the steps used for the sample collection, extraction, preparation and sequencing. Here we have: (i) compared the manual and automated RNA extraction of small volumes of blood using the Tempus Spin RNA isolation kit and the MagMAX for Stabilized Blood RNA Isolation kit , respectively; and (ii) assessed the effect of TURBO DNA Free treatment on the transcriptomic data of RNA isolated from small volumes of blood. We have used the QuantSeq 3' FWD mRNA-Seq Library Prep kit to prepare RNA-seq libraries, which were sequenced on the Illumina NextSeq 500 system. The samples isolated manually displayed a higher variability in the transcriptomic data as compared to the other samples. The TURBO DNA Free treatment affected the RNA samples negatively, decreasing the RNA yield and reducing the quality and reproducibility of the transcriptomic data. We conclude that automated extraction systems should be preferred over manual extraction systems for data consistency, and that the TURBO DNA Free treatment should be avoided when working on RNA samples isolated manually from small volumes of blood.

Impact of COVID-19 lockdown on hospital admissions for epistaxis in Germany.

BACKGROUND: Reports of a decrease in hospital admissions during the coronavirus disease 2019 (COVID-19) lockdown period have raised concerns about delayed or missed diagnoses and treatments for non-COVID-19-related illnesses. AIM: To investigate the impact of the COVID-19 pandemic-induced lockdown and its end on hospital admissions of patients with epistaxis in Germany. METHODS: A retrospective analysis based on the national database of the Hospital Remuneration System was used to compare hospital admissions during defined time periods between 2019 and 2022 with the lockdown period as the reference period. This was done on a weekly basis before, during, and after the lockdown. An Interrupted Time Series was used as the analysis method. RESULTS: In our analysis, we included 26183 patients. The implementation of the lockdown led to a substantial reduction in the overall occurrence of epistaxis among patients (P < 0.05). This effect was most pronounced in the age group of 0-39 years, where the decrease was highly significant (P < 0.001). However, there was no change observed in patients aged 80 years and older (not significant). With the end of the lockdown period, the overall number of patients, especially in the youngest age group, increased abruptly and significantly (P < 0.01). CONCLUSION: During the lockdown period, there was a decrease in hospital admissions for younger patients with epistaxis, possibly due to the fear of COVID-19 exposure. We also conclude that the severity of epistaxis was not underestimated in the elderly during the pandemic.

High-temporal resolution profiling reveals distinct immune trajectories following the first and second doses of COVID-19 mRNA vaccines.

Knowledge of the mechanisms underpinning the development of protective immunity conferred by mRNA vaccines is fragmentary. Here, we investigated responses to coronavirus disease 2019 (COVID-19) mRNA vaccination via high-temporal resolution blood transcriptome profiling. The first vaccine dose elicited modest interferon and adaptive immune responses, which peaked on days 2 and 5, respectively. The second vaccine dose, in contrast, elicited sharp day 1 interferon, inflammation, and erythroid cell responses, followed by a day 5 plasmablast response. Both post-first and post-second dose interferon signatures were associated with the subsequent development of antibody responses. Yet, we observed distinct interferon response patterns after each of the doses that may reflect quantitative or qualitative differences in interferon induction. Distinct interferon response phenotypes were also observed in patients with COVID-19 and were associated with severity and differences in duration of intensive care. Together, this study also highlights the benefits of adopting high-frequency sampling protocols in profiling vaccine-elicited immune responses.

Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model.

Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart's contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These knockout zebrafish displayed significant morphological heart alterations related to a significant decrease in ventricular and atrial diameters at systolic and diastolic states at the larval stages. Immunofluorescence staining revealed significant hyperplasia in the mutant's total cardiac and ventricular cardiomyocytes. Although cardiac contractility was similar to the wild-type control, the ejection fraction was significantly increased in the mypbc3 mutants. At later stages of larval development, the mutants demonstrated an early cardiac phenotype of myocardium remodeling, concurrent cardiomyocyte hyperplasia, and increased ejection fraction as critical processes in HCM initiation to counteract the increased ventricular myocardial wall stress. The examination of zebrafish adults showed a thickened ventricular cardiac wall with reduced heart rate, swimming speed, and endurance ability in both the mypbc3 heterozygous and homozygous groups. Furthermore, heart transcriptome profiling showed a significant downregulation of the actin-filament-based process, indicating an impaired actin cytoskeleton organization as the main dysregulating factor associated with the early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model.

A 3D transcriptomics atlas of the mouse nose sheds light on the anatomical logic of smell.

The sense of smell helps us navigate the environment, but its molecular architecture and underlying logic remain understudied. The spatial location of odorant receptor genes (Olfrs) in the nose is thought to be independent of the structural diversity of the odorants they detect. Using spatial transcriptomics, we create a genome-wide 3D atlas of the mouse olfactory mucosa (OM). Topographic maps of genes differentially expressed in space reveal that both Olfrs and non-Olfrs are distributed in a continuous and overlapping fashion over at least five broad zones in the OM. The spatial locations of Olfrs correlate with the mucus solubility of the odorants they recognize, providing direct evidence for the chromatographic theory of olfaction. This resource resolves the molecular architecture of the mouse OM and will inform future studies on mechanisms underlying Olfr gene choice, axonal pathfinding, patterning of the nervous system, and basic logic for the peripheral representation of smell.

Choline Kinetics in Neonatal Liver, Brain and Lung-Lessons from a Rodent Model for Neonatal Care.

Choline requirements are high in the rapidly growing fetus and preterm infant, mainly serving phosphatidylcholine (PC) synthesis for parenchymal growth and one-carbon metabolism via betaine. However, choline metabolism in critical organs during rapid growth is poorly understood. Therefore, we investigated the kinetics of D9-choline and its metabolites in the liver, plasma, brain and lung in 14 d old rats. Animals were intraperitoneally injected with 50 mg/kg D9-choline chloride and sacrificed after 1.5 h, 6 h and 24 h. Liver, plasma, lungs, cerebrum and cerebellum were analyzed for D9-choline metabolites, using tandem mass spectrometry. In target organs, D9-PC and D9-betaine comprised 15.1 ± 1.3% and 9.9 ± 1.2% of applied D9-choline at 1.5 h. D9-PC peaked at 1.5 h in all organs, and decreased from 1.5-6 h in the liver and lung, but not in the brain. Whereas D9-labeled PC precursors were virtually absent beyond 6 h, D9-PC increased in the brain and lung from 6 h to 24 h (9- and 2.5-fold, respectively) at the expense of the liver, suggesting PC uptake from the liver via plasma rather than local synthesis. Kinetics of D9-PC sub-groups suggested preferential hepatic secretion of linoleoyl-PC and acyl remodeling in target organs. D9-betaine showed rapid turnover and served low-level endogenous (D3-)choline synthesis. In conclusion, in neonatal rats, exogenous choline is rapidly metabolized to PC by all organs. The liver supplies the brain and lung directly with PC, followed by organotypic acyl remodeling. A major fraction of choline is converted to betaine, feeding the one-carbon pool and this must be taken into account when calculating choline requirements.

Real-Time SARS-CoV-2 Genotyping by High-Throughput Multiplex PCR Reveals the Epidemiology of the Variants of Concern in Qatar.

Complementing whole genome sequencing strategies with high-throughput multiplex RT-qPCR genotyping allows for more comprehensive and real-time tracking of SARS-CoV-2 variants of concern. During the second and third waves of COVID-19 in Qatar, PCR genotyping, combined with Sanger sequencing of un-typeable samples, was employed to describe the epidemiology of the Alpha, Beta and Delta variants. A total of 9792 nasopharyngeal PCR-positive samples collected between April-June 2021 were successfully genotyped, revealing the importation and transmission dynamics of these three variants in Qatar.

Global temperature modes shed light on the Holocene temperature conundrum.

Reconstructions of the global mean annual temperature evolution during the Holocene yield conflicting results. One temperature reconstruction shows global cooling during the late Holocene. The other reconstruction reveals global warming. Here we show that both a global warming mode and a cooling mode emerge when performing a spatio-temporal analysis of annual temperature variability during the Holocene using data from a transient climate model simulation. The warming mode is most pronounced in the tropics. The simulated cooling mode is determined by changes in the seasonal cycle of Arctic sea-ice that are forced by orbital variations and volcanic eruptions. The warming mode dominates in the mid-Holocene, whereas the cooling mode takes over in the late Holocene. The weighted sum of the two modes yields the simulated global temperature trend evolution. Our findings have strong implications for the interpretation of proxy data and the selection of proxy locations to compute global mean temperatures.

Combined Genome and Transcriptome (G&T) Sequencing of Single Cells.

The simultaneous examination of a single cell's genome and transcriptome presents scientists with a powerful tool to study genetic variability and its effect on gene expression. In this chapter, we describe the library generation method for combined genome and transcriptome sequencing (G&T-seq) originally described by Macaulay et al. (Nat Protoc 11(11):2081-2103, 2016; Nat Methods 12(6):519-522, 2015). This includes some alterations we made to improve robustness of this process for both the novice user and laboratories that want to deploy this method at scale. Using this method, genomic DNA and full-length mRNA from single cells are separated, amplified, and converted into Illumina sequencer-compatible sequencing libraries.

Surgical treatment of two adolescent athletes with dislocated avulsion fracture of the anterior superior iliac spine (ASIS).

INTRODUCTION: Avulsion fractures of the anterior superior iliac spine are rare. Therefore, evidence-based treatment guidelines do not exist. The therapeutic options are either conservative treatment or surgical intervention. The decision depends on grade of dislocation, age of the patient, and his sportive demands and competitive requirements. MATERIALS AND METHODS: We present the cases of two young athletes suffering from traumatic avulsion fractures of the anterior superior iliac spine. In both cases, the musculotendinous unit (sartorius muscle and tensor of the fascia lata) remained attached to the loose dislocated fragment. Both patients were treated by means of open reduction with a new surgical technique using suture anchors. RESULTS: Both patients were pain-free 4 weeks after surgery and had full range of motion. They were able to return to their preoperative sportive activity levels 10 weeks after surgery. No complications were reported at final follow-up 18 months postoperatively. CONCLUSION: Operative treatment of avulsion fracture of the ASIS using suture anchors shows excellent clinical outcome and a short convalescence period. The patients achieve their preinjury sportive levels within 3 months.

Meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures.

PURPOSE: To prospectively evaluate the prevalence and characteristics of meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures and to test for possible relationships between associated meniscal lesions and patient demographics or injury characteristics. METHODS: A prospective multicenter study was conducted to arthroscopically assess the prevalence and characteristics of meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures between 04/2014 and 10/2015. Patient demographics and injury characteristics were assessed preoperatively. The presence of a meniscal injury was evaluated arthroscopically and characterized according to tear type and location (Cooper classification). Patients with and without meniscal injuries were compared with regard to sex, age, height, weight, BMI, type of injury, mechanism of injury, time to surgery, Tanner stage, sexual maturity (prepubescent vs. pubescent), and modified Meyers and McKeever classification. RESULTS: A total of 54 consecutive patients (65 % males, mean age: 12.5 ± 3.2 years) were enrolled. Meniscal injury were found in 20 patients (37 %). The lateral meniscus was involved in 18 patients (90 % of all meniscus injuries) and the medial meniscus in 2 patients (10 % of all meniscus injuries). The most common tear pattern was a longitudinal tear of the posterior horn of the lateral meniscus (30 % of all meniscus injuries) and the second most common tear was a root detachment of the anterior horn of the lateral meniscus (20 % of all meniscus injuries). Higher age, advanced Tanner stage, and pubescence were significantly associated with an accompanying meniscal injury. CONCLUSION: Meniscal injuries in children and adolescents undergoing surgical treatment for tibial eminence fractures must be expected in almost 40 %, with a higher prevalence with increasing age and sexual maturity. With regard to the clinical relevance, the results of the present study argue in favor for magnetic resonance imaging prior to surgery in every patient with a suspected tibial eminence fracture and for an arthroscopic approach to adequately diagnose and treat meniscal injuries. LEVEL OF EVIDENCE: II.

Novel technique for sternoclavicular joint reconstruction using a gracilis tendon autograft.

UNLABELLED: Surgical treatment of sternoclavicular joint instability can be challenging and carries the inherent risk of damaging vital structures if the posterior capsule is violated during surgery. In the current manuscript, a novel and easy technique for open reduction and tendon graft stabilization of the unstable sternoclavicular joint is presented. Analogous to other techniques, the graft is passed through drill holes in a figure-of-eight configuration. However, for this technique, the drill holes are placed in oblique direction from the anterior cortex towards the articular surface of the sternum, respectively the medial clavicle. By doing so, graft reconstruction is achieved without any need for retrosternal dissection and mobilization of the posterior capsule, thus minimizing the risk of severe intraoperative complications. LEVEL OF EVIDENCE: V.

Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling.

BACKGROUND: Colorectal cancer is the third most common malignancy in humans and novel therapeutic approaches are urgently needed. Autophagy is an evolutionarily highly conserved cellular process by which cells collect unnecessary organelles or misfolded proteins and subsequently degrade them in vesicular structures in order to refuel cells with energy. Dysregulation of the complex autophagy signaling network has been shown to contribute to the onset and progression of cancer in various models. The Bcl-2 family of proteins comprises central regulators of apoptosis signaling and has been linked to processes involved in autophagy. The antiapoptotic members of the Bcl-2 family of proteins have been identified as promising anticancer drug targets and small molecules inhibiting those proteins are in clinical trials. METHODS: Flow cytometry and colorimetric assays were used to assess cell growth and cell death. Long term 3D cell culture was used to assess autophagy in a tissue mimicking environment in vitro. RNA interference was applied to modulate autophagy signaling. Immunoblotting and q-RT PCR were used to investigate autophagy signaling. Immunohistochemistry and fluorescence microscopy were used to detect autophagosome formation and autophagy flux. RESULTS: This study demonstrates that autophagy inhibition by obatoclax induces cell death in colorectal cancer (CRC) cells in an autophagy prone environment. Here, we demonstrate that pan-Bcl-2 inhibition by obatoclax causes a striking, late stage inhibition of autophagy in CRC cells. In contrast, ABT-737, a Mcl-1 sparing Bcl-2 inhibitor, failed to interfere with autophagy signaling. Accumulation of p62 as well as Light Chain 3 (LC3) was observed in cells treated with obatoclax. Autophagy inhibition caused by obatoclax is further augmented in stressful conditions such as starvation. Furthermore, our data demonstrate that inhibition of autophagy caused by obatoclax is independent of the essential pro-autophagy proteins Beclin-1, Atg7 and Atg12. CONCLUSIONS: The objective of this study was to dissect the contribution of Bcl-2 proteins to autophagy in CRC cells and to explore the potential of Bcl-2 inhibitors for autophagy modulation. Collectively, our data argue for a Beclin-1 independent autophagy inhibition by obatoclax. Based on this study, we recommend the concept of autophagy inhibition as therapeutic strategy for CRC.

The Munich Knee Questionnaire: Development and Validation of a New Patient-Reported Outcome Measurement Tool for Knee Disorders.

PURPOSE: To develop and validate an all-purpose patient-reported outcome questionnaire for a patient-based follow-up examination regarding knee disorders. METHODS: Each scale of the Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) score, Lysholm knee score, Western Ontario Meniscal Evaluation Tool (WOMET) score, and Tegner score was analyzed, and after matching of the general topics, the dedicated items underwent a fusion to the final Munich Knee Questionnaire (MKQ) item and a score comprising 33 items was created. In a prospective clinical study, we evaluated validity, reliability, and responsiveness in 152 physical active patients (75 women and 77 men; mean age, 47 years) with traumatic as well as degenerative knee disorders. RESULTS: Test-retest reliability was substantial, with intraclass correlation coefficients of at least 0.91. Construct validity and responsiveness were confirmed by correlation coefficients of 0.78 to 0.86 (P = .01) and 0.41 to 0.71, respectively. Correlation coefficients of the original scores (KOOS, IKDC, Lysholm, WOMET, and Tegner) and the scores calculated from the MKQ were between 0.80 and 0.91 (P = .01). CONCLUSIONS: The MKQ is a reliable and valid patient-reported outcome questionnaire for assessing knee function. It seems to enable the calculation of the original items of the KOOS, IKDC score, Lysholm knee score, WOMET score, and Tegner score. CLINICAL RELEVANCE: The MKQ facilitates the comparison of treatment results in knee disorders and allows the evaluation of treatment efficacy. Identified inadequate treatment concepts could be eliminated, leading to increased patient satisfaction and optimized quality of health care.

Influence of tibial rotation on tibial tunnel position measurements using lateral fluoroscopy in anterior cruciate ligament reconstruction.

PURPOSE: The purpose of the current study was to evaluate the influence of internal and external knee rotation on tibial tunnel position measurements in anterior cruciate ligament reconstruction using the Amis and Jakob line. METHODS: Anatomic double bundle ACL reconstruction was performed in seven cadaveric knees. Afterwards, the knees were CT scanned, and 3D CT models were established. Utilizing these models, strict lateral and radiographs with the knees in 5°, 10°, and 20° of internal as well as external rotation were established. Using these radiographs, the positions of the anteromedial (AM) and posterolateral (PL) tibial tunnels were measured using the Amis and Jacob line. The tunnel positions of the strict lateral were compared to the rotated radiographs. To assess the inter- and intraobserver reliability, two independent observers measured the tunnel positions, and one observer measured twice. RESULTS: Significant differences for the AM tunnel position were observed if more than 10° of external or 20° of internal rotation were applied. For the PL tunnel position, no significant differences were found between the strict lateral and the rotated radiographs. Inter- and intraobserver reliability was good. CONCLUSIONS: The accuracy of the Amis and Jakob line is dependent on the degree of knee rotation and the position of the measured tunnel. Therefore, when using the Amis and Jakob line to determine the tibial tunnel position during surgery, attention should be paid to rotational alignment of lateral radiographs. However, the maximum rotation tested in the present study (20°) showed only a difference in tunnel position of 3.3 % compared to optimal rotational alignment. Thus, in most cases, the effects of minor malrotation on tunnel position measurement should be of minimal clinical significance.