COVID-19 Vaccine Effectiveness and Digital Pandemic Surveillance in Germany (eCOV Study): Web Application-Based Prospective Observational Cohort Study.

BACKGROUND: The COVID-19 pandemic posed significant challenges to global health systems. Efficient public health responses required a rapid and secure collection of health data to improve the understanding of SARS-CoV-2 and examine the vaccine effectiveness (VE) and drug safety of the novel COVID-19 vaccines. OBJECTIVE: This study (COVID-19 study on vaccinated and unvaccinated subjects over 16 years; eCOV study) aims to (1) evaluate the real-world effectiveness of COVID-19 vaccines through a digital participatory surveillance tool and (2) assess the potential of self-reported data for monitoring key parameters of the COVID-19 pandemic in Germany. METHODS: Using a digital study web application, we collected self-reported data between May 1, 2021, and August 1, 2022, to assess VE, test positivity rates, COVID-19 incidence rates, and adverse events after COVID-19 vaccination. Our primary outcome measure was the VE of SARS-CoV-2 vaccines against laboratory-confirmed SARS-CoV-2 infection. The secondary outcome measures included VE against hospitalization and across different SARS-CoV-2 variants, adverse events after vaccination, and symptoms during infection. Logistic regression models adjusted for confounders were used to estimate VE 4 to 48 weeks after the primary vaccination series and after third-dose vaccination. Unvaccinated participants were compared with age- and gender-matched participants who had received 2 doses of BNT162b2 (Pfizer-BioNTech) and those who had received 3 doses of BNT162b2 and were not infected before the last vaccination. To assess the potential of self-reported digital data, the data were compared with official data from public health authorities. RESULTS: We enrolled 10,077 participants (aged ≥16 y) who contributed 44,786 tests and 5530 symptoms. In this young, primarily female, and digital-literate cohort, VE against infections of any severity waned from 91.2% (95% CI 70.4%-97.4%) at week 4 to 37.2% (95% CI 23.5%-48.5%) at week 48 after the second dose of BNT162b2. A third dose of BNT162b2 increased VE to 67.6% (95% CI 50.3%-78.8%) after 4 weeks. The low number of reported hospitalizations limited our ability to calculate VE against hospitalization. Adverse events after vaccination were consistent with previously published research. Seven-day incidences and test positivity rates reflected the course of the pandemic in Germany when compared with official numbers from the national infectious disease surveillance system. CONCLUSIONS: Our data indicate that COVID-19 vaccinations are safe and effective, and third-dose vaccinations partially restore protection against SARS-CoV-2 infection. The study showcased the successful use of a digital study web application for COVID-19 surveillance and continuous monitoring of VE in Germany, highlighting its potential to accelerate public health decision-making. Addressing biases in digital data collection is vital to ensure the accuracy and reliability of digital solutions as public health tools.

Constructing an Intent-to-Treat Score Index to Predict Survival Outcomes in Pediatric Liver Transplant Recipients.

BACKGROUND: Waitlist and posttransplant outcomes have been widely reported for pediatric liver transplantation. Yet, analyzing these metrics individually fails to provide a holistic perspective for patients and their families. Intent-to-treat (ITT) analysis fills this gap by studying the associations between waitlist outcomes, organ availability, and posttransplant outcomes. Our study aimed to construct a predictive index utilizing ITT analysis for pediatric liver transplant recipients (Pedi-ITT). METHODS: We performed a retrospective analysis utilizing de-identified data provided by the United Network for Organ Sharing (UNOS) from March 1, 2002, to December 31, 2021. We analyzed data for 12 926 pediatric recipients (age <18). We conducted a univariate and multivariable logistic regression to find the significant predictive factors affecting ITT survival. A scoring index was constructed to stratify outcome risk on the basis of the significant factors identified by regression analysis. RESULTS: Multivariable analysis found the following factors to be significantly associated with death on the waitlist or after transplant: gender, diagnosis, UNOS region, ascites, diabetes mellitus, age at the time of listing, serum sodium at the time of listing, total bilirubin at the time of listing, serum creatinine at the time of listing, INR at the time of listing, history of ventilator use, and history of re-transplantation. Using receiver operator characteristic analysis, the Pedi-ITT index had a c-statistic of 0.79 (95% confidence interval [CI]: 0.76-0.82). The c-statistics of the Model for End-Stage Liver Disease/Pediatric for End-Stage Liver Disease and pediatric version of the Survival Outcomes Following Liver Transplantation score indices were 0.74 (CI: 0.71-0.76) and 0.69 (CI: 0.66-0.72), respectively. CONCLUSIONS: The Pedi-ITT index provides an additional prognostic model with moderate predictive power to assess outcomes associated with pediatric liver transplantation. Further analysis should focus on increasing the predictive power of the index.

Topology-guided polar ordering of collective cell migration.

The ability of epithelial monolayers to self-organize into a dynamic polarized state, where cells migrate in a uniform direction, is essential for tissue regeneration, development, and tumor progression. However, the mechanisms governing long-range polar ordering of motility direction in biological tissues remain unclear. Here, we investigate the self-organizing behavior of quiescent epithelial monolayers that transit to a dynamic state with long-range polar order upon growth factor exposure. We demonstrate that the heightened self-propelled activity of monolayer cells leads to formation of vortex-antivortex pairs that undergo sequential annihilation, ultimately driving the spread of long-range polar order throughout the system. A computational model, which treats the monolayer as an active elastic solid, accurately replicates this behavior, and weakening of cell-to-cell interactions impedes vortex-antivortex annihilation and polar ordering. Our findings uncover a mechanism in epithelia, where elastic solid material characteristics, activated self-propulsion, and topology-mediated guidance converge to fuel a highly efficient polar self-ordering activity.

Feasibility Study on Menstrual Cycles With Fitbit Device (FEMFIT): Prospective Observational Cohort Study.

BACKGROUND: Despite its importance to women's reproductive health and its impact on women's daily lives, the menstrual cycle, its regulation, and its impact on health remain poorly understood. As conventional clinical trials rely on infrequent in-person assessments, digital studies with wearable devices enable the collection of longitudinal subjective and objective measures. OBJECTIVE: The study aims to explore the technical feasibility of collecting combined wearable and digital questionnaire data and its potential for gaining biological insights into the menstrual cycle. METHODS: This prospective observational cohort study was conducted online over 12 weeks. A total of 42 cisgender women were recruited by their local gynecologist in Berlin, Germany, and given a Fitbit Inspire 2 device and access to a study app with digital questionnaires. Statistical analysis included descriptive statistics on user behavior and retention, as well as a comparative analysis of symptoms from the digital questionnaires with metrics from the sensor devices at different phases of the menstrual cycle. RESULTS: The average time spent in the study was 63.3 (SD 33.0) days with 9 of the 42 individuals dropping out within 2 weeks of the start of the study. We collected partial data from 114 ovulatory cycles, encompassing 33 participants, and obtained complete data from a total of 50 cycles. Participants reported a total of 2468 symptoms in the daily questionnaires administered during the luteal phase and menses. Despite difficulties with data completeness, the combined questionnaire and sensor data collection was technically feasible and provided interesting biological insights. We observed an increased heart rate in the mid and end luteal phase compared with menses and participants with severe premenstrual syndrome walked substantially fewer steps (average daily steps 10,283, SD 6277) during the luteal phase and menses compared with participants with no or low premenstrual syndrome (mean 11,694, SD 6458). CONCLUSIONS: We demonstrate the feasibility of using an app-based approach to collect combined wearable device and questionnaire data on menstrual cycles. Dropouts in the early weeks of the study indicated that engagement efforts would need to be improved for larger studies. Despite the challenges of collecting wearable data on consecutive days, the data collected provided valuable biological insights, suggesting that the use of questionnaires in conjunction with wearable data may provide a more complete understanding of the menstrual cycle and its impact on daily life. The biological findings should motivate further research into understanding the relationship between the menstrual cycle and objective physiological measurements from sensor devices.

Risk Index Predicts Pediatric Heart Allograft Non-Utilization.

BACKGROUND: Children listed for heart transplantation face the highest waitlist mortality among all solid organ transplant patients (14%). Attempts at decreasing donor allograft non-utilization (41.5%) could potentially decrease waitlist mortality for pediatric heart transplant patients. Our aim was to quantify the non-utilization risk of pediatric donor heart allografts at the time of initial offering. METHODS: Using the United Network of Organ Sharing (UNOS) database, we retrospectively analyzed 8823 deceased donors (≤18 years old) data through univariable and multivariable analysis and logistic regression models. These factors were divided into a training (n = 5882) and validation set (n = 2941). Donor clinical characteristics and laboratory values were used to predict non-utilization of donor hearts. The multivariable analysis used factors that were significant from the univariable analysis (p-value < .05), and the pediatric non-utilization risk index (pDRSI) included significant factors from the multivariable analysis, producing an overall risk score for non-utilization. With these data, we created a non-utilization risk index to predict likelihood of donor allograft non-utilization. RESULTS: From the 24 potential factors that were identified from univariable analysis, 17 were significant predictors (p < .05) of pediatric heart non-utilization in the multivariable analysis. Low left ventricular ejection fraction (odds ratio (OR)-35.3), hepatitis C positive donor (OR-23.3), high left ventricular ejection fraction (OR-3.29), and hepatitis B positive donor (OR-3.27) were the most significant risk factors. The phDSRI has a C-statistic of 0.80 for the training set and 0.80 for the validation set. CONCLUSION: Using over 8000 donors, the phDSRI uses 17 significant risk factors to predict risk of pediatric heart donor allograft non-utilization.

Minimally Invasive Instrumentation of the Cervical Spine: Past, Present, and Future.

Posterior cervical instrumentation and fusion procedures are becoming more and more common with the aging population and rising numbers of multisegmental and revision procedures. The instrumentation of the cervical spine has so far been performed almost exclusively via open approaches. Over the past two decades, minimally invasive surgery (MIS) techniques have gained increasing popularity. To date, only a few attempts to instrument the cervical spine in a minimally invasive fashion have been reported. The following article, after a detailed review of the currently available literature, overviews MIS in dorsal cervical instrumentation and past, present and future techniques, and it discusses the current limitations. Nevertheless, and because of the multiple advantages of MIS instrumentation, a lot of work remains to be carried out to fully establish MIS procedures for posterior cervical instrumentation.

A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial-temporal regulation of histone arginine methylation in neurodevelopment.

BACKGROUND: Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency. RESULTS: We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial-temporal regulation of histone arginine methylation in specific brain regions. CONCLUSIONS: This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.

A Defect in Mitochondrial Complex III but Not in Complexes I or IV Causes Early ß-Cell Dysfunction and Hyperglycemia in Mice.

Mitochondrial metabolism and oxidative respiration are crucial for pancreatic ß-cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to ß-cell function is unknown. We generated ß-cell-specific, inducible OxPhos complex knock-out (KO) mouse models to investigate the effects of disrupting complex I, complex III, or complex IV on ß-cell function. Although all KO models had similar mitochondrial respiratory defects, complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted, depending on the complex targeted, supporting the unique roles of each complex in ß-cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from complex III KO, but not from complex I or IV KO mice, indicating that severe diabetic phenotype in the complex III-deficient mice is causing alterations in cellular redox status. The present study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes. ARTICLE HIGHLIGHTS: Mitochondrial metabolism is critical for ß-cell insulin secretion, and mitochondrial dysfunction is involved in type 2 diabetes pathogenesis. We determined whether individual oxidative phosphorylation complexes contribute uniquely to ß-cell function. Compared with loss of complex I and IV, loss of complex III resulted in severe in vivo hyperglycemia and altered ß-cell redox status. Loss of complex III altered cytosolic and mitochondrial Ca2+ signaling and increased expression of glycolytic enzymes. Individual complexes contribute differently to ß-cell function. This underscores the role of mitochondrial oxidative phosphorylation complex defects in diabetes pathogenesis.

Disparate Intent-to-Treat Outcomes for Pediatric Liver Transplantation Based on Indication.

Background: The impact of indication for pediatric liver transplantation on waitlist and post-transplant mortality outcomes is well known, but the impact on intent-to-treat outcomes has not been investigated. Intent-to-treat survival analysis is important in this study because it is more comprehensive, combining the transplant outcomes of waitlist mortality, post-transplant mortality, and transplant rate into a single metric to elucidate any disparities in outcomes based on indication. Methods: Cox regression was used to analyze factors impacting survival in 8,002 children listed for liver transplant in the UNOS database between 2006 and 2016. The Kaplan-Meier method and log-rank test were used to assess differences in waitlist, post-transplant, and intent-to-treat mortality among the top 5 indications of biliary atresia, acute hepatic necrosis, metabolic disorders, hepatoblastoma, and autoimmune cirrhosis. Results: When compared to the reference group of biliary atresia, multivariate analyses showed that every indication was associated with inferior intent-to-treat outcomes except for metabolic disorders. Hepatoblastoma (hazard ratio (HR): 3.73), autoimmune cirrhosis (HR: 1.86), and AHN (HR: 1.77) were associated with significantly increased intent-to-treat mortality. Hepatoblastoma was also associated with increased post-transplant mortality (HR: 3.77) and was the only indication significantly associated with increased waitlist mortality (HR: 6.43). Conclusion: Significant disparity exists across all indications with respect to an increased intent-to-treat mortality, along with an increased post-transplant and waitlist mortality, when compared to the biliary atresia reference group. If further studies validate these findings, a reexamination of the equitable distribution of allografts for transplant may be warranted as well as a focus on disparities in survival after transplant.

Depletion of the m1A writer TRMT6/TRMT61A reduces proliferation and resistance against cellular stress in bladder cancer.

Background: Bladder cancer (BLCA) is a common and deadly disease that results in a reduced quality of life for the patients and a significant economic burden on society. A better understanding of tumorigenesis is needed to improve clinical outcomes. Recent evidence places the RNA modification m1A and its regulatory proteins TRMT6/TRMT61A and ALKBH3 in BLCA pathogenesis. Methods: TRMT6/TRMT61A, ALKBH1, and ALKBH3 expression was examined in human BLCA cell lines and a normal urinary tract epithelium cell line through qRT-PCR and western blot analysis. Prestoblue Cell Viability Reagent, wound-healing assay, and live-cell imaging-based cell displacement analysis, were conducted to assess proliferation, migration, and displacement of this BLCA cell line panel. Cell survival was assessed after inducing cellular stress and activating the unfolded protein response (UPR) with tunicamycin. Moreover, siRNA-mediated gene silencing in two BLCA cell lines (5637 and HT1197) was conducted to investigate the biological roles of TRMT6/TRMT61A. Results: Heterogeneous morphology, proliferation, displacement, tunicamycin sensitivity, and expression levels of m1A regulators were observed among the panel of cell lines examined. In general, TRMT61A expression was increased in BLCA cell lines when compared to SV-HUC-1. Depletion of TRMT6/TRMT61A reduced proliferation capacity in both 5637 and HT1197 cell lines. The average cell displacement of 5637 was also reduced upon TRMT6/TRMT61A depletion. Interestingly, TRMT6/TRMT61A depletion decreased mRNA expression of targets associated with the ATF6-branch of the UPR in 5637 but not in HT1197. Moreover, cell survival after induction of cellular stress was compromised after TRMT6/TRMT61A knockdown in 5637 but not in HT1197 cells. Conclusion: The findings suggest that TRMT6/TRMT61A plays an oncogenic role in BLCA and is involved in desensitizing BLCA cells against cellular stress. Further investigation into the regulation of TRMT6/TRMT61A expression and its impact on cellular stress tolerance may provide insights for future BLCA treatment.

Participatory disease surveillance for a mass gathering - a prospective cohort study on COVID-19, Germany 2021.

BACKGROUND: Mass gatherings (MGs) such as music festivals and sports events have been associated with a high risk of SARS-CoV-2 transmission. On-site research can foster knowledge of risk factors for infections and improve risk assessments and precautionary measures at future MGs. We tested a web-based participatory disease surveillance tool to detect COVID-19 infections at and after an outdoor MG by collecting self-reported COVID-19 symptoms and tests. METHODS: We conducted a digital prospective observational cohort study among fully immunized attendees of a sports festival that took place from September 2 to 5, 2021 in Saxony-Anhalt, Germany. Participants used our study app to report demographic data, COVID-19 tests, symptoms, and their contact behavior. This self-reported data was used to define probable and confirmed COVID-19 cases for the full "study period" (08/12/2021 - 10/31/2021) and within the 14-day "surveillance period" during and after the MG, with the highest likelihood of an MG-related COVID-19 outbreak (09/04/2021 - 09/17/2021). RESULTS: A total of 2,808 of 9,242 (30.4%) event attendees participated in the study. Within the study period, 776 individual symptoms and 5,255 COVID-19 tests were reported. During the 14-day surveillance period around and after the MG, seven probable and seven PCR-confirmed COVID-19 cases were detected. The confirmed cases translated to an estimated seven-day incidence of 125 per 100,000 participants (95% CI [67.7/100,000, 223/100,000]), which was comparable to the average age-matched incidence in Germany during this time. Overall, weekly numbers of COVID-19 cases were fluctuating over the study period, with another increase at the end of the study period. CONCLUSION: COVID-19 cases attributable to the mass gathering were comparable to the Germany-wide age-matched incidence, implicating that our active participatory disease surveillance tool was able to detect MG-related infections. Further studies are needed to evaluate and apply our participatory disease surveillance tool in other mass gathering settings.

Methylation differences in Alzheimer's disease neuropathologic change in the aged human brain.

Alzheimer's disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) is known to be associated with numerous DNA methylation changes in the human brain, but the oldest old (> 90 years) have so far been underrepresented in epigenetic studies of ADNC. Our study participants were individuals aged over 90 years (n = 47) from The 90+ Study. We analyzed DNA methylation from bulk samples in eight precisely dissected regions of the human brain: middle frontal gyrus, cingulate gyrus, entorhinal cortex, dentate gyrus, CA1, substantia nigra, locus coeruleus and cerebellar cortex. We deconvolved our bulk data into cell-type-specific (CTS) signals using computational methods. CTS methylation differences were analyzed across different levels of ADNC. The highest amount of ADNC related methylation differences was found in the dentate gyrus, a region that has so far been underrepresented in large scale multi-omic studies. In neurons of the dentate gyrus, DNA methylation significantly differed with increased burden of amyloid beta (Aß) plaques at 5897 promoter regions of protein-coding genes. Amongst these, higher Aß plaque burden was associated with promoter hypomethylation of the Presenilin enhancer 2 (PEN-2) gene, one of the rate limiting genes in the formation of gamma-secretase, a multicomponent complex that is responsible in part for the endoproteolytic cleavage of amyloid precursor protein into Aß peptides. In addition to novel ADNC related DNA methylation changes, we present the most detailed array-based methylation survey of the old aged human brain to date. Our open-sourced dataset can serve as a brain region reference panel for future studies and help advance research in aging and neurodegenerative diseases.

Transcriptional abnormalities in induced pluripotent stem cell-derived oligodendrocytes of individuals with primary progressive multiple sclerosis.

Multiple sclerosis (MS) is the most common neurological disorder in young adults and is classically defined as a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although MS affects millions of people worldwide, its underlying cause remains unknown making discovery of effective treatments challenging. Whether intrinsic or extrinsic factors contribute to MS initiation and progression is still unclear. This is especially true for primary progressive MS (PPMS), the rarest form of the disease, in which progressive and irreversible loss of neurological function is often observed in the absence of an overt immune-inflammatory response. To test the hypothesis that intrinsic dysfunction in oligodendrocytes (OLs), the primary targets of damage in MS, may contribute to PPMS etiopathology, we differentiated human induced pluripotent stem cell (hiPSC) lines derived from PPMS and healthy individuals into mature OLs to compare their transcriptional profile. PPMS derived OLs displayed hundreds of differentially expressed genes compared to control OLs, many associated with cell adhesion, apoptosis and inflammation, including the inflammasome component Nlrp2, which was highly upregulated. NLRP2 immunoreactivity in OLs was confirmed in post-mortem PPMS brain tissues, with higher expression than in control tissues. Altogether, our findings suggest that mature OLs in PPMS affected individuals carry intrinsic abnormalities that could contribute, at least in part, to the pathophysiology of this form of the disease.

Clinical and radiological outcome 1-year after cervical total disc replacement using the Signus ROTAIO - Prosthesis.

INTRODUCTION: The instantaneous center of rotation (iCOR) of a motion segment has been shown to correlate with its total range of motion (ROM). Importantly, a correlation of the correct placement of cervical total disc replacement (cTDR) to preserve a physiological iCOR has been previously identified. However, changes of these parameters and the corresponding clinical relevance have hardly been analyzed. This study assesses the radiological and clinical correlation of iCOR and ROM following cTDR. MATERIALS/METHODS: A retrospective multi-center observational study was conducted and radiological as well as clinical parameters were evaluated preoperatively and 1 year after cTDR with an unconstrained device. Radiographic parameters including flexion/extension X-rays (flex/ex), ROM, iCOR and the implant position in anterior-posterior direction (IP ap), as well as corresponding clinical parameters [(Neck Disability Index (NDI) and the visual analogue scale (VAS)] were assessed. RESULTS: 57 index segments of 53 patients treated with cTDR were analyzed. Pre- and post-operative ROM showed no significant changes (8.0° vs. 10.9°; p > 0.05). Significant correlations between iCOR and IP (Pearson's R: 0.6; p < 0.01) as well as between ROM and IP ap (Pearson's R: - 0.3; p = 0.04) were identified. NDI and VAS improved significantly (p < 0.01). A significant correlation between NDI and IP ap after 12 months (Pearson's R: - 0.39; p < 0.01) was found. CONCLUSION: Implantation of the tested prosthesis maintains the ROM and results in a physiological iCOR. The exact position of the device correlates with the clinical outcome and emphasize the importance of implant design and precise implant positioning.

Minimally invasive versus open transforaminal lumbar interbody fusion: a prospective, controlled observational study of short-term outcome.

Instrumented stabilization with intersomatic fusion can be achieved by open (O-TLIF) or minimally invasive (MIS-TLIF) transforaminal surgical access. While less invasive techniques have been associated with reduced postoperative pain and disability, increased manipulation and insufficient decompression may contradict MIS techniques. In order to detect differences between both techniques in the short-term, a prospective, controlled study was conducted. Thirty-eight patients with isthmic or degenerative spondylolisthesis or degenerative disk disease were included in this prospective, controlled study (15 MIS-TLIF group vs. 23 O-TLIF group) after failed conservative treatment. Patients were examined preoperatively, on the first, third, and sixth postoperative day as well as after 2, 4, and 12 weeks postoperatively. Outcome parameters included blood loss, duration of surgery, pre- and postoperative pain (numeric rating scale [NRS], visual analog scale [VAS]), functionality (Timed Up and Go test [TUG]), disability (Oswestry Disability index [ODI]), and quality of life (EQ-5D). Intraoperative blood loss (IBL) as well as postoperative blood loss (PBL) was significantly higher in the O-TLIF group ([IBL O-TLIF 528 ml vs. MIS-TLIF 213 ml, p = 0.001], [PBL O-TLIF 322 ml vs. MIS-TLIF 30 ml, p = 0.004]). The O-TLIF cohort showed significantly less leg pain postoperatively compared to the MIS-TLIF group ([NRS leg 3rd postoperative day, p = 0.027], [VAS leg 12 weeks post-op, p = 0.02]). The MIS group showed a significantly better improvement in the overall ODI (40.8 ± 13 vs. 56.0 ± 16; p = 0.05). After 3 months in the short-term follow-up, the MIS procedure tends to have better results in terms of patient-reported quality of life. MIS-TLIF offers perioperative advantages but may carry the risk of increased nerve root manipulation with consecutive higher radicular pain, which may be related to the learning curve of the procedure.

Prospective Multicenter Trial of Cervical Arthroplasty with the ROTAIO® Cervical Disc Prosthesis.

STUDY DESIGN: Clinical observational study. OBJECTIVE: The ROTAIO® cervical disc prosthesis is a novel unconstrained implant with a variable center of rotation aiming at physiological motion. The objective of this multicenter prospective trial was to evaluate clinical outcome and complications within 2 years. MATERIAL AND METHODS: 120 patients (72 females and 48 males with median age of 43.0 years [23-60 yrs] underwent ACDA (ROTAIO®, SIGNUS Medical, Alzenau, Germany) and were prospectively followed for 24 months. Preoperative complaints were mainly associated with radiculopathy (n = 104) or myelopathy (n=16). There were 108 monosegmental and 12 bisegmental procedures including 6 hybrid constructs. Clinical outcome was evaluated at 3, 12 and 24 months in 100%, 96% and 77% of the cohort by VAS, NDI, WL-26, Patient`s Satisfaction Index (PSI), SF-36, Nurick Score, mJOA, Composite Success Rate, complications, patient`s overall satisfaction and analgesics use. RESULTS: Highly significant clinical improvements were observed according to NDI and VAS (P < .0001 (arm); P < .001 (neck); P = .002 (head)) at all time points. Analgetic use could be reduced in 87.1 to 95.2%. Doctor`s visits have been reduced in 93.8% after 24 months. Patient`s overall satisfaction was high with 78.4 to 83.5% of patients. The composite success rate was 77.5% after 12 months and 76.9% after 24 months. There were no major complications in this series. Slight subsidence of the prosthesis was observed in 2 patients and 3 patients demonstrated fusion after 24 months. 2 patients developed symptomatic foraminal stenosis, so that implant removal and fusion was performed resulting in a revision rate of 1.7% in 2 years. CONCLUSION: The ROTAIO® cervical disc prosthesis is a safe and efficient treatment option for symptomatic degenerative disc disease demonstrating highly significant clinical improvement and high patient`s overall satisfaction with very low revision rates at 2 years.

Mechanical coupling of supracellular stress amplification and tissue fluidization during exit from quiescence.

Cellular quiescence is a state of reversible cell cycle arrest that is associated with tissue dormancy. Timely regulated entry into and exit from quiescence is important for processes such as tissue homeostasis, tissue repair, stem cell maintenance, developmental processes, and immunity. However, little is known about processes that control the mechanical adaption to cell behavior changes during the transition from quiescence to proliferation. Here, we show that quiescent human keratinocyte monolayers sustain an actinomyosin-based system that facilitates global cell sheet displacements upon serum-stimulated exit from quiescence. Mechanistically, exposure of quiescent cells to serum-borne mitogens leads to rapid amplification of preexisting contractile sites, leading to a burst in monolayer tension that subsequently drives large-scale displacements of otherwise motility-restricted monolayers. The stress level after quiescence exit correlates with the level of quiescence depth at the time of activation, and a critical stress magnitude must be reached to overcome the cell sheet displacement barrier. The study shows that static quiescent cell monolayers are mechanically poised for motility, and it identifies global stress amplification as a mechanism for overcoming motility restrictions in confined confluent cell monolayers.

Technical nuances and approach-related morbidity of anterolateral and posterolateral lumbar corpectomy approaches-a systematic review of the literature.

PURPOSE: Approaches for lumbar corpectomies can be roughly categorized into anterolateral (AL) and posterolateral (PL) approaches. It remains controversial to date whether one approach is superior to the other, and no comparative studies exist for the two approaches for lumbar corpectomies. METHODS: A systematic review of the literature was performed through a MEDLINE/PubMed search. Studies and case reports describing technique plus outcomes and possible complications were included. Thereafter, estimated blood loss (EBL), length of operation (LOO), utilized implants, neurological outcomes, complication rates, and reoperation rates were analyzed. RESULTS: A total of 64 articles reporting on 702 patients including 513 AL and 189 PL corpectomies were included in this paper. All patients in the PL group were instrumented via the same approach used for corpectomy, while in the AL group the majority (68.3%) of authors described the use of an additional approach for instrumentation. The EBL was higher in the AL group (1393 ± 1341 ml vs. 982 ± 567 ml). The LOO also was higher in the AL group (317 ± 178 min vs. 258 ± 93 min). The complication rate (20.5% vs. 29.1%, p = 0.048) and the revision rate (3.1% vs. 9.5%, p = 0.004) were higher in the PL group. Neurological improvement rates were 43.8% (AL) vs. 39.2% (PL), and deterioration was only noted in the AL group (6.0%), while 50.2% (AL) and 60.8% (PL) showed no change from initial presentation to the last follow-up. CONCLUSION: While neurological outcomes of both approaches are comparable, the results of the present review demonstrated lower complication and revision rates in anterolateral corpectomies. Nevertheless, individual patient characteristics must be considered in decision-making.

Hypereosinophilic syndrome presenting as coagulopathy.

BACKGROUND: Hypereosinophilic syndrome (HES) is an extremely uncommon group of disorders. It rarely presents with coagulopathy without cardiac involvement. CASE PRESENTATION: A 33-year-old previously healthy male with no history of atopic disease presented with abdominal pain, hematochezia, peripheral eosinophilia as high as 10,000 eos/µL, right and left portal vein, mesenteric, and splenic vein thrombi with ischemic colitis resulting in hemicolectomy and small bowel resection. Despite an extensive workup for primary and secondary etiologies of hypereosinophilia by hematology/oncology, infectious disease, rheumatology and allergy/immunology, no other clear causes were identified, and the patient was diagnosed with idiopathic HES. His eosinophilia was successfully treated with high-dose oral corticosteroids (OCS) and subsequently transitioned to anti-IL-5-receptor therapy with benralizumab. He has continued this treatment for over a year with no recurrence of eosinophilia or thrombosis while on benralizumab. CONCLUSION: In patients with an unexplained coagulopathy and eosinophilia, eosinophilic disorders such as HES should be considered. Corticosteroid-sparing agents, such as benralizumab show promise for successfully treating these patients.

A scoring system for the preoperative evaluation of prognosis in spinal infection: the MSI-20 score.

BACKGROUND CONTEXT: Spinal infection (SI) is a life-threatening condition and its treatment remains challenging. Recent studies have supported early and aggressive surgery, but mortality still reaches 5% to 10% and it remains unclear, if an aggressive surgical strategy also applies for severely sick patients. PURPOSE: The aim of this analysis was to generate an assessment score to predict mortality of SI in order to facilitate decision-making. STUDY DESIGN: Retrospective risk factor analysis. PATIENT SAMPLE: Two hundred fifty-two patients were retrospectively analyzed. OUTCOME MEASURES: Physiologic measures, functional measures. METHODS: Diagnosis was based on clinical presentation, imaging findings and inflammatory markers. Factors associated with mortality were identified by multivariate analysis, weighted according to their relative risk ratio (RR) and included in the novel assessment score. RESULTS: Eight parameters were included: (1) BMI, (2) ASA score, (3) presence of sepsis, (4) age-adjusted Charlson Comorbidity Index, (5) presence and degree of renal failure, (6) presence of hepatopathy, (7) neurological deficits and (8) CRP levels at diagnosis. Each parameter was assigned a certain range of points, resulting in a maximum total score of 20. The mortality in spinal infection (MSI-20) score - indicating poorer status with higher values - was obtained for each patient and correlated with mortality. CONCLUSION: An MSI-20 score of 11 or more points seems to identify the small group of patients being "too sick to undergo surgery," while early surgery can be recommended in the remainder (MSI-20 ≤10). Our results need to be confirmed in prospective studies, but may give guidance for indicating surgery even in rather sick and comorbid patients.