Reference radiologic measurements for the assessment of tibial pilon fractures

Objectives: The management of pilon fractures is a challenge and the outcome depends on multiple factors, one of which is the quality of reduction. In the literature, there is no assessment of anatomical reduction in pilon fractures. We also lack standard radiological parameters in large patient groups to measure the reduction. The main aim of this analysis was to define normal standard radiological values and identify potential specific types of ankle joint morphology (morphotypes) that might deserve special attention intraoperatively. Methods: We analyzed data of 103 healthy contralateral ankles collected within an observational and prospective multicenter study about tibial pilon fractures. We divided the patients according to their height into two groups, measured 11 radiological parameters, and compared them with each other and the literature. In addition, using cluster analysis, we could identify three morphotypes. Results: There is a statistically significant difference between the two groups in the lengths of three parameters: Mortise width, medial clear space, and length of the lateral malleolus, but not in the angles. The three morphotypes differ only in body mass index and the length of the lateral malleolus. Conclusion: Reference values from the literature are insufficient to assess a reduction after open reduction and internal fixation of tibial pilon fractures because they depend on the height. This does not apply to angles because they are independent of height. For clinical practice, a radiological control of the contralateral healthy ankle gives the best information about the reduction quality and should always be done, especially in normal weight males.

Clinical Peculiarities in a Cohort of Patients with Wolfram Syndrome 1

Wolfram syndrome 1 is a rare, autosomal recessive, neurodegenerative, progressive disorder. Insulin-dependent, non-autoimmune diabetes mellitus and bilateral progressive optic atrophy are both sensitive and specific criteria for clinical diagnosis. The leading cause of death is central respiratory failure resulting from brainstem atrophy. We describe the clinical features of fourteen patients from seven different families followed in our Diabetes Center. The mean age at Wolfram syndrome 1 diagnosis was 12.4 years. Diabetes mellitus was the first clinical manifestation, in all patients. Sensorineural hearing impairment and central diabetes insipidus were present in 85.7% of patients. Other endocrine findings included hypogonadotropic hypogonadism (7.1%), hypergonadotropic hypogonadism (7.1%), and Hashimoto’s thyroiditis (21.4%). Neuropsychiatric disorders were detected in 35.7% of patients, and urogenital tract abnormalities were present in 21.4%. Finally, heart diseases were found in 14.2% of patients. Eight patients (57.1%) died at the mean age of 27.3 years. The most common cause of death was respiratory failure which occurred in six patients. The remaining two died due to end-stage renal failure and myocardial infarction. Our data are superimposable with those reported in the literature in terms of mean age of onset, the clinical course of the disease, and causes of death. The frequency of deafness and diabetes insipidus was higher in our patients. The incidence of urogenital diseases was lower although it led to the death of one patient. Long-term follow-up studies including large patient cohorts are necessary to establish potential genotype-phenotype correlation in order to personalize the most suitable clinical approach for each patient.

Novel Intraoperative Imaging of Gastric Tube Perfusion during Oncologic Esophagectomy—A Pilot Study Comparing Hyperspectral Imaging (HSI) and Fluorescence Imaging (FI) with Indocyanine Green (ICG)

Background: Novel intraoperative imaging techniques, namely, hyperspectral (HSI) and fluorescence imaging (FI), are promising with respect to reducing severe postoperative complications, thus increasing patient safety. Both tools have already been used to evaluate perfusion of the gastric conduit after esophagectomy and before anastomosis. To our knowledge, this is the first study evaluating both modalities simultaneously during esophagectomy. Methods: In our pilot study, 13 patients, who underwent Ivor Lewis esophagectomy and gastric conduit reconstruction, were analyzed prospectively. HSI and FI were recorded before establishing the anastomosis in order to determine its optimum position. Results: No anastomotic leak occurred during this pilot study. In five patients, the imaging methods resulted in a more peripheral adaptation of the anastomosis. There were no significant differences between the two imaging tools, and no adverse events due to the imaging methods or indocyanine green (ICG) injection occurred. Conclusions: Simultaneous intraoperative application of both modalities was feasible and not time consuming. They are complementary with regard to the ideal anastomotic position and may contribute to better surgical outcomes. The impact of their simultaneous application will be proven in consecutive prospective trials with a large patient cohort.

Magnetic Resonance Imaging Characteristics of Molecular Subgroups in Pediatric H3 K27M Mutant Diffuse Midline Glioma

Purpose Recent research identified histone H3 K27M mutations to be associated with a dismal prognosis in pediatric diffuse midline glioma (pDMG); however, data on detailed MRI characteristics with respect to H3 K27 mutation status and molecular subgroups (H3.1 and H3.3 K27M mutations) are limited. Methods Standardized magnetic resonance imaging (MRI) parameters and epidemiologic data of 68 pDMG patients (age <18 years) were retrospectively reviewed and compared in a) H3 K27M mutant versus H3 K27 wildtype (WT) tumors and b) H3.1 versus H3.3 K27M mutant tumors. Results Intracranial gliomas (n = 58) showed heterogeneous phenotypes with isointense to hyperintense signal in T2-weighted images and frequent contrast enhancement. Hemorrhage and necrosis may be present. Comparing H3 K27M mutant to WT tumors, there were significant differences in the following parameters: i) tumor localization (p = 0.001), ii) T2 signal intensity (p = 0.021), and iii) T1 signal homogeneity (p = 0.02). No significant imaging differences were found in any parameter between H3.1 and H3.3 K27M mutant tumors; however, H3.1 mutant tumors occurred at a younger age (p = 0.004). Considering spinal gliomas (n = 10) there were no significant imaging differences between the analyzed molecular groups. Conclusion With this study, we are the first to provide detailed MR imaging data on H3 K27M mutant pDMG with respect to molecular subgroup status in a large patient cohort. Our findings may support diagnosis and future targeted therapeutic trials of pDMG within the framework of the radiogenomics concept.

Within-subjects Effects of Standardized Prosthetic Socket Modifications on Physical Function and Patient-Reported Outcomes

• Background: Among the challenges of living with lower limb loss is the increased risk of long-term health problems that can be either attributed directly to the amputation surgery and/or prosthetic rehabilitation or indirectly to a disability-induced sedentary lifestyle. These problems are exacerbated by poorly fit prosthetic sockets. There is a knowledge gap regarding how the socket design affects in-socket mechanics, and how in-socket mechanics affect patient-reported comfort and function. The objectives of this study are: 1) to gain a better understanding of how in-socket mechanics of the residual limb in transfemoral amputees are related to patient-reported comfort and function, 2) to identify clinical tests that can streamline the socket design process, and 3) to evaluate the efficacy and cost of a novel, quantitatively informed socket optimization process.• Methods: Users of transfemoral prostheses will be asked to walk on a treadmill wearing their current socket plus 8 different check sockets with designed changes in different structural measurements that are likely to induce changes in residual limb motion, skin strain, and pressure distribution within the socket. Dynamic biplane radiography and pressure sensors will be used to measure in-socket residual limb mechanics. Patient-reported outcomes will also be collected after wearing each socket. The effects of in-socket mechanics on both physical function and patient-reported outcomes (aim 1) will be assessed using a generalized linear model. Partial correlation analysis will be used to examine the association between research grade measurements and readily available clinical measurements (aim 2). In order to compare the new quantitative design method to the Standard of Care, patient reported outcomes and cost will be compared between the two methods, utilizing the Wilcoxon Mann-Whitney non-parametric test (aim 3).• Discussion: Knowledge on how prosthetic socket modifications affect residual bone and skin biomechanics itself can be applied to devise future socket designs, and the methodology can be used to investigate and improve such designs, past and present. Apart from saving time and costs, this may result in better prosthetic socket fit for a large patient population, thus increasing their mobility, participation, and overall health-related quality of life. • Trial registration: clinicaltrials.gov: NCT05041998

DNA Repair Genes as Drug Candidates for Early Breast Cancer Onset in Latin America: A Systematic Review

The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC predisposition, progression, and therapy response, underscoring the need for further analyses on DNA repair genes. Public databases of large patient datasets such as METABRIC, TCGA, COSMIC, and cancer cell lines allow the identification of variants in DNA repair genes and possible precision drug candidates. This study aimed at identifying variants and drug candidates that may benefit Latin American (LA) YWBC. We analyzed pathogenic variants in 90 genes involved in DNA repair in public BC datasets from METABRIC, TCGA, COSMIC, CCLE, and COSMIC Cell Lines Project. Results showed that reported DNA repair germline variants in the LA dataset are underrepresented in large databases, in contrast to other populations. Additionally, only six gene repair variants in women under 50 years old from the study population were reported in BC cell lines. Therefore, there is a need for new approaches to study DNA repair variants reported in young women from LA.

Robotic versus Open Pancreatoduodenectomy for Pancreatic and Periampullary Tumors (PORTAL): a study protocol for a multicenter phase III non-inferiority randomized controlled trial

Background Pancreatoduodenectomy is a complex and challenging procedure that requires meticulous tissue dissection and proficient suturing skills. Minimally invasive surgery with the utilization of robotic platforms has demonstrated advantages in perioperative patient outcomes in retrospective studies. The development of robotic pancreatoduodenectomy (RPD) in specific has progressed significantly, since first reported in 2003, and high-volume centers in pancreatic surgery are reporting large patient series with improved pain management and reduced length of stay. However, prospective studies to assess objectively the feasibility and safety of RPD compared to open pancreatoduodenectomy (OPD) are currently lacking. Methods/design The PORTAL trial is a multicenter randomized controlled, patient-blinded, parallel-group, phase III non-inferiority trial performed in seven high-volume centers for pancreatic and robotic surgery in China (> 20 RPD and > 100 OPD annually in each participating center). The trial is designed to enroll and randomly assign 244 patients with an indication for elective pancreatoduodenectomy for malignant periampullary and pancreatic lesions, as well as premalignant and symptomatic benign periampullary and pancreatic disease. The primary outcome is time to functional recovery postoperatively, measured in days. Secondary outcomes include postoperative morbidity and mortality, as well as perioperative costs. A sub-cohort of 128 patients with pancreatic adenocarcinoma (PDAC) will also be compared to assess the percentage of patients who undergo postoperative adjuvant chemotherapy within 8 weeks, in each arm. Secondary outcomes in this cohort will include patterns of disease recurrence, recurrence-free survival, and overall survival. Discussion The PORTAL trial is designed to assess the feasibility and safety of RPD compared to OPD, in terms of functional recovery as described previously. Additionally, this trial will explore whether RPD allows increased access to postoperative adjuvant chemotherapy, in a sub-cohort of patients with PDAC. Trial registration ClinicalTrials.govNCT04400357. Registered on May 22, 2020

Organisational determinants and consequences of diagnostic discrepancy in two large patient groups in the emergency departments: a national study of consecutive episodes between 2008 and 2016

Background Diagnostic discrepancy (DD) is a common phenomenon in healthcare, but little is known about its organisational determinants and consequences. Thus, the aim of the study was to evaluate this among selected emergency department (ED) patients. Method We conducted an observational study including all consecutive ED patients (hip fracture or erysipelas) in the Danish healthcare sector admitted between 2008 and 2016. DD was defined as a discrepancy between discharge and admission diagnoses. Episode and department statistics were retrieved from Danish registers. We conducted a survey among all 21 Danish EDs to gather information about organisational determinants. To estimate the results while adjusting for episode- and department-level heterogeneity, we used mixed effect models of ED organisational determinants and 30-day readmission, 30-day mortality and episode costs (2018-DKK) of DDs. Results DD was observed in 2308 (3.3%) of 69,928 hip fracture episodes and 3206 (8.5%) of 37,558 erysipelas episodes. The main organisational determinant of DD was senior physicians (nonspecific medical specialty) being employed at the ED (hip fracture: odds ratio (OR) 2.74, 95% confidence interval (CI) 2.15–3.51; erysipelas: OR 3.29, 95% CI 2.65–4.07). However, 24-h presence of senior physicians (nonspecific medical specialty) (hip fracture) and availability of external senior physicians (specific medical specialty) (both groups) were negatively associated with DD. DD was associated with increased 30-day readmission (hip fracture, mean 9.45% vs 13.76%, OR 1.46, 95% CI 1.28–1.66, p < 0.001) and episode costs (hip fracture, 61,681 DKK vs 109,860 DKK, log cost 0.58, 95% CI 0.53–0.63, p < 0.001; erysipelas, mean 20,818 DKK vs 56,329 DKK, log cost 0.97, 95% CI 0.92–1.02, p < 0.001) compared with episodes without DD. Conclusion DD was found to have a negative impact on two out of three study outcomes, and particular organisational characteristics seem to be associated with DD. Yet, the complexity of organisations and settings warrant further studies into these associations.

Recapitulation of patient-specific 3D chromatin conformation using machine learning and validation of identified enhancer-gene targets

Regulatory networks containing enhancer to gene edges define cellular state and their rewiring is a hallmark of cancer. While efforts, such as ENCODE, have revealed these networks for reference tissues and cell-lines by integrating multi-omics data, the same methods cannot be applied for large patient cohorts due to the constraints on generating ChIP-seq and three-dimensional data from limited material in patient biopsies. We trained a supervised machine learning model using genomic 3D signatures of physical enhancer-gene connections that can predict accurate connections using data from ATAC-seq and RNA-seq assays only, which can be easily generated from patient biopsies. Our method overcomes the major limitations of correlation-based approaches that cannot distinguish between distinct target genes of given enhancers in different samples, which is a hallmark of network rewiring in cancer. Our model achieved an AUROC (area under receiver operating characteristic curve) of 0.91 and, importantly, can distinguish between active regulatory elements with connections to target genes and poised elements with no connections to target genes. Our predicted regulatory elements are validated by multi-omics data, including histone modification marks from ENCODE, with an average specificity of 0.92. Application of our model on chromatin accessibility and transcriptomic data from 400 cancer patients across 22 cancer types revealed novel cancer-type and subtype-specific enhancer-gene connections for known cancer genes. In one example, we identified two enhancers that regulate the expression of ESR1 in only ER+ breast cancer (BRCA) samples but not in ER- samples. These enhancers are predicted to contribute to the high expression of ESR1 in 93% of ER+ BRCA samples. Functional validation using CRISPRi confirms that inhibition of these enhancers decreases the expression of ESR1 in ER+ samples.