Results of Low Distal Femur Periprosthetic Fractures

Objectives- To compare retrograde intramedullary nail (RIMN) and open reduction internal fixation (ORIF) in very distal periprosthetic distal femur fractures (PDFF) to determine if RIMN is an acceptable option for these fractures that are often considered too distal for IMN due to limited bone stock. Design- Retrospective comparative series Setting- Level One trauma center Patients- Patients treated with fracture fixation for a very distal PDFF, defined as the fracture extending to the anterior flange of the implant or distal. Fifty-six patients met inclusion criteria, with eight excluded for less than twelve months of follow-up. Intervention- Fracture fixation with RIMN or ORIF Main Outcome Measurements- The primary outcome was unplanned return to surgery. Secondary outcomes included fracture union, radiographic alignment, Visual Analog Score (VAS) and Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) and Pain Interference (PI). Results- Mean follow up was 27 months. Twelve patients were treated with ORIF and 36 with RIMN. Twenty-one fractures were at the flange and 27 extended distal to the flange. There were no differences between fixation methods with respect to reoperation, deep infection, nonunion, malunion, VAS pain score, and PROMIS PI score. Mean PROMIS PF score was higher in the RIMN group compared to ORIF. There were five reoperations in the RIMN group (14%) and three in the ORIF group (25%). Conclusion- This is the largest series, to our knowledge, of a subset of very distal PDFFs. The results suggest that RIMN may be an acceptable treatment option for these very difficult fractures

Co-evolution of massive black holes and their host galaxies at high redshift: discrepancies from six cosmological simulations and the key role of JWST

The James Webb Space Telescope will have the power to characterize high-redshift quasars at z>6 with an unprecedented depth and spatial resolution. While the brightest quasars at such redshift (i.e., with bolometric luminosity L_bol> 10^46 erg/s) provide us with key information on the most extreme objects in the Universe, measuring the black hole (BH) mass and Eddington ratios of fainter quasars with L_bol= 10^45-10^46 erg/s opens a path to understand the build-up of more normal BHs at z>6. In this paper, we show that the Illustris, TNG100, TNG300, Horizon-AGN, EAGLE, and SIMBA large-scale cosmological simulations do not agree on whether BHs at z>4 are overmassive or undermassive at fixed galaxy stellar mass with respect to the M_BH-M_star scaling relation at z=0 (BH mass offsets). Our conclusions are unchanged when using the local scaling relation produced by each simulation or empirical relations. We find that the BH mass offsets of the simulated faint quasar population at z>4, unlike those of bright quasars, represent the BH mass offsets of the entire BH population, for all the simulations. Thus, a population of faint quasars with L_bol= 10^45-10^46 erg/s observed by JWST can provide key constraints on the assembly of BHs at high redshift. Moreover, this will help constraining the high-redshift regime of cosmological simulations, including BH seeding, early growth, and co-evolution with the host galaxies. Our results also motivate the need for simulations of larger cosmological volumes down to z=6, with the same diversity of sub-grid physics, in order to gain statistics on the most extreme objects at high redshift.Comment: published in MNRAS, 19 pages, 8 figures, key figures: Fig. 3, Fig.5, and Fig.

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10‾⁴⁹), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.This work was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.S. and L.V.W. (MC_PC_12010). This research has been conducted using the UK Biobank Resource under application 648. This article presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. This research used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details can be found in the Supplementary Note

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Irregularität der hinteren Hornhautoberfläche nach Femtosekundenlaser-assistierter versus Mikrokeratom-assistierter Descemet stripping automated endothelial keratoplasty (DSAEK)

Die perforierende Keratoplastik wird seit 1905 bei Hornhauterkrankungen wie der bullösen Keratopathie und Fuchs’-Endothel-Dystrophie angewandt. In den letzten Jahren sind neue Operationstechniken wie die endotheliale Keratoplastik entwickelt worden. Dadurch sind Hornhauttransplantationen unter Erhaltung der vorderen Hornhautanteile möglich geworden. Damit haben sich die visuellen Ergebnisse verbessert und die Visus-Erholungszeiten verkürzt. Mittlerweile ist die DSAEK zur Mainstream-Therapie bei endothelialen Hornhauterkrankungen geworden. Wenngleich inzwischen eine neue sog. DMEK-Technik für eine isolierte endotheliale Transplantation ohne Stromafasern entwickelt worden ist und bessere visuelle Ergebnisse liefert, ist sie gegenwärtig aufgrund der technischen Komplexität den auf Hornhauttherapie spezialisierten Zentren vorbehalten, so dass die die DSAEK-Methode dominiert. Die verschiedenen Methoden zur Präparation der Spenderhornhaut für die EK werden diskutiert. In diesem Forschungsprojekt sollen zwei verschiedene Methoden der Transplantatpräparation für die EK untersucht werden. Zum einen die Femtosekundenlaser-assistierte intrasomale Schnittführung unter Verwendung eines gekrümmten Interfaces und zum anderen die Schnittführung mittels Mikrokeratom mit planarer Applanation. Die klinischen Visusergebnisse unter Verwendung des Mikrokeratoms scheinen besser zu sein, als die mit dem Femtosekundenlaser. Es wird vermutet, dass Irregularitäten der posterioren Hornhautoberfläche ein Faktor für die schlechtere Visusentwicklung bei Verwendung der Femtosekunden Laser sein können. Zur Erörterung dieser Fragestellung wurde bei 22 Patienten im Rahmen einer klinischen retrospektiven Studie nach einer DSAEK die Morphologie der inneren Oberfläche der Hornhauttransplantate und die bestkorrigierte Sehstärke untersucht. Acht von 22 Spenderhornhäuten wurden mit dem 200kHz VisuMax Femtosekundenlaser (Carl Zeiss Meditec AG, Jena Deutschland; Femtosekundenlaser Gruppe) präpariert, während 14 Transplantate mit dem Amadeus II Mikrokeratom (Ziemer Olphthalmic System AG, Port, Schweiz; Mikrokeratom Gruppe) bearbeitet wurden. Der postoperative bestkorrigierte Visus zeigte einen signifikanten Unterschied (p=0,038) zwischen den beiden Gruppen. Der Mittelwert des bestkorrigierten Visus der Femtosekundenlasergruppe ergab einen schlechteren Mittelwert 0,48 [0,2; 0,9] logMAR als der Mittelwert von 0,33 [0,1; 0,5] logMAR bei der Mikrokeratomgruppe. Zur Evaluation der Irregularität der endothelialen Hornhautmorphologie (RTVue; Optovue, Fremont, USA) wurde eine Regressionsanalyse (SPSS, IBM, Chicago, USA) mit einer idealen polynomischen Kurve 2. Grades durchgeführt, um die Wurzel des mittleren quadratischen Fehlers als Maßstab für die Unregelmäßigkeit der Oberfläche ermitteln zu können. Die Wurzel des quadratischen Fehlers betrug 9,9 [2,2] m in der Femtosekundenlasergruppe und 5,7 [2,2] m in der Mikrokeratom-Gruppe. Daraus resultierte ein hoch-signifikanter Irregularitätsunterschied mit p < 0,001. Bei der Fragestellung ob es einen Zusammenhang zwischen dem bestkorrigierten Visus und der Irregularität der hinteren Hornhautoberfläche gibt, zeigte sich ein positiver Zusammenhang der beiden Parameter mit einem Pearson-Korrelationswert von 0,438 (p=0,05). Somit zeigen unsere Ergebnisse, dass die Mikrokeratom assistierte Transplantatpräparation bei der DSAEK zu geringeren Fältelungen der Hornhautinnenfläche und folglich zur überlegenen Visus als bei der Femtosekundenlaser-Methode führt

Development of In Vitro Assays for Advancing Radioimmunotherapy against Brain Tumors

Glioblastoma (GBM) is the most common primary brain tumor. Due to high resistance to treatment, local invasion, and a high risk of recurrence, GBM patient prognoses are often dismal, with median survival around 15 months. The current standard of care is threefold: surgery, radiation therapy, and chemotherapy with temozolomide (TMZ). However, patient survival has only marginally improved. Radioimmunotherapy (RIT) is a fourth modality under clinical trials and aims at combining immunotherapeutic agents with radiotherapy. Here, we develop in vitro assays for the rapid evaluation of RIT strategies. Using a standard cell irradiator and an Electric Cell Impedance Sensor, we quantify cell migration following the combination of radiotherapy and chemotherapy with TMZ and RIT with durvalumab, a PD-L1 immune checkpoint inhibitor. We measure cell survival using a cloud-based clonogenic assay. Irradiated T98G and U87 GBM cells migrate significantly (p &lt; 0.05) more than untreated cells in the first 20&ndash;40 h post-treatment. Addition of TMZ increases migration rates for T98G at 20 Gy (p &lt; 0.01). Neither TMZ nor durvalumab significantly change cell survival in 21 days post-treatment. Interestingly, durvalumab abolishes the enhanced migration effect, indicating possible potency against local invasion. These results provide parameters for the rapid supplementary evaluation of RIT against brain tumors

The Virtual Vision of Neurosurgery: How Augmented Reality and Virtual Reality are Transforming the Neurosurgical Operating Room.

BACKGROUND: In this era of imagination and technological innovation, mixed reality systems such as virtual reality (VR) and augmented reality (AR) are contributing to a wide array of neurosurgical care, from the betterment of surgical planning and surgical comfort to even novel treatments and improved resident education. These systems can augment procedures that require high-level dexterity such as minimally invasive surgery, tumor excisions, as well as peripheral and neurovascular surgery. Herein, the authors will define and compare the technological features, indications, and characterized outcomes of VR and AR systems in the context of neurosurgery through a review of the literature to date. Moreover, this review will discuss the limitations of VR and AR while including an overview of the cost effectiveness of each of these systems. METHODS: An extensive review of published literature on augmented reality and virtual reality was performed utilizing PubMed, OVID Medline, and EMBASE journals from January 1, 2006 to April 2, 2022. Terms used for the search included augmented reality, spinal surgery, virtual reality, and neurosurgery. RESULTS: The search yielded full text English language-related articles regarding virtual and augmented reality application, limitations, and functional outcomes in neurosurgery. An initial set of 121 studies were screened and reviewed for content. There were 13 studies included that involved 162 patients, 550 screw placements, 58 phantom spines, and learning points from simulation training of 276 involved residents. CONCLUSION: This literature review examines recent research into virtual and augmented reality applications in neurosurgical care. The literature establishes there are technological features, indications, outcomes, limitations, and cost effectiveness differences between these systems. Based on ongoing and evolving applications of the VR and AR systems, their innovative potential they make available to the future of neurosurgical patient care makes clear the need for further studies to understand the nuances between their differing technological advances