Search

PURPOSE: Tethered cord syndrome (TCS) is characterized by abnormal attachment of the spinal cord neural elements to surrounding tissues. The most common symptoms include pain, motor or sensory dysfunction, and urologic deficits. Although TCS is common in children, there is a significant heterogeneity in outcomes reporting. We systematically reviewed surgical indications and postoperative outcomes to assess the need for a grading/classification system. METHODS: PubMed and EMBASE searches identified pediatric TCS literature published between 1950 and 2023. Studies reporting surgical interventions, ≥ 6-month follow-up, and ≥ 5 patients were included. RESULTS: Fifty-five studies representing 3798 patients were included. The most commonly reported non-urologic symptoms were nonspecific lower-extremity motor disturbances (36.4% of studies), lower-extremity/back pain (32.7%), nonspecific lower-extremity sensory disturbances (29.1%), gait abnormalities (29.1%), and nonspecific bowel dysfunction/fecal incontinence (25.5%). Urologic symptoms were most commonly reported as nonspecific complaints (40.0%). After detethering surgery, retethering was the most widely reported non-urologic outcome (40.0%), followed by other nonspecific findings: motor deficits (32.7%), lower-extremity/back/perianal pain (18.2%), gait/ambulation function (18.2%), sensory deficits (12.7%), and bowel deficits/fecal incontinence (12.7%). Commonly reported urologic outcomes included nonspecific bladder/urinary deficits (27.3%), bladder capacity (20.0%), bladder compliance (18.2%), urinary incontinence/enuresis/neurogenic bladder (18.2%), and nonspecific urodynamics/urodynamics score change (16.4%). CONCLUSION: TCS surgical literature is highly variable regarding surgical indications and reporting of postsurgical outcomes. The lack of common data elements and consistent quantitative measures inhibits higher-level analysis. The development and validation of a standardized outcomes measurement tool-ideally encompassing both patient-reported outcome and objective measures-would significantly benefit future TCS research and surgical management.

Adiposis dolorosa (Dercum disease) is a rare condition characterized by diffuse and recurring painful lipomas on the trunk and extremities. Patients are typically middle-aged females with an elevated BMI presenting with chronic pain. Physical examination reveals soft subcutaneous nodules and masses, tender to palpation. The associated pain significantly impacts quality of life and requires therapeutic intervention. The most common treatment option is surgical excision. Alternative options should be considered for patients with numerous lipomas where surgical management is not practical or is not desired. Deoxycholic acid injections are a viable alternative non-surgical technique. We present a case of a 55-year-old woman who presented with a history of Dercum disease and worsening pain associated with multiple lipomas. The patient desired a non-surgical intervention. She was subsequently treated with three rounds of deoxycholic acid injections with reduction in pain and improved mobility. Intralesional deoxycholic acid injections are a safe and effective nonsurgical alternative for patients with multiple lipomas.

INTRODUCTION: The fibrous posterior atlanto-occipital membrane (PAOM) at the craniocervical junction is typically removed during decompression surgery for Chiari malformation type I (CM-I); however, its importance and ultrastructural architecture have not been investigated in children. We hypothesized that there are structural differences in the PAOM of patients with CM-I and those without. METHODS: In this prospective study, blinded pathological analysis was performed on PAOM specimens from children who had surgery for CM-I and children who had surgery for posterior fossa tumors (controls). Clinical and radiographic data were collected. Statistical analysis included comparisons between the CM-I and control cohorts and correlations with imaging measures. RESULTS: A total of 35 children (mean age at surgery 10.7 years; 94.3% white) with viable specimens for evaluation were enrolled: 24 with CM-I and 11 controls. There were no statistical demographic differences between the two cohorts. Four children had a family history of CM-I and five had a syndromic condition. The cohorts had similar measurements of tonsillar descent, syringomyelia, basion to C2, and condylar-to-C2 vertical axis (all p>0.05). The clival-axial angle was lower in patients with CM-I (138.1 vs. 149.3 degrees, p = 0.016). Morphologically, the PAOM demonstrated statistically higher proportions of disorganized architecture in patients with CM-I (75.0% vs. 36.4%, p = 0.012). There were no differences in PAOM fat, elastin, or collagen percentages overall and no differences in imaging or ultrastructural findings between male and female patients. Posterior fossa volume was lower in children with CM-I (163,234 mm3 vs. 218,305 mm3, p

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

Objectives To (1) pilot a study of behavioural characterisation based on risk and time preferences in clinically well-characterised individuals, (2) assess the distribution of preferences in this population and (3) explore differences in preferences between individuals with ‘lifestyle-related’ (LS) and ‘non-lifestyle-related’ (NLS) cardiovascular diseases.Design Cross-sectional study with an economic online experiment to collect risk and time preferences, a detailed clinical characterisation and a sociodemographic and lifestyle survey. A definition of LS and NLS groups was developed.Setting Specialist outpatient clinics of the clinic for cardiology and pneumology of the University Hospital Düsseldorf and patients from a cardiology practice in Düsseldorf.Participants A total of 74 individuals with cardiovascular diseases.Outcomes Risk and time preferences.Results The implementation of the study process, including participant recruitment and data collection, ran smoothly. The medical checklist, the survey and the time preference instrument were well received. However, the conceptual understanding of the risk preference instrument resulted in inconsistent choices for many participants (47%). The remaining individuals were more risk averse (27%) than risk seeking (16%) and risk neutral (10%). Individuals in our sample were also more impatient (49%) than patient (42%). The participant classification showed that 65% belonged to the LS group, 19% to the NLS group and 16% could not be assigned (unclear allocation to lifestyle (ULS) group). Excluding the ULS group, we show that individuals in the LS group were more risk seeking, and unexpectedly, more patient than those in the NLS group.Conclusions The process of the pilot study and its results can be used as a basis for the design of the main study. The differences in risk and time preferences between the LS and NLS groups provide us with a novel hypothesis for unhealthy behaviours: individuals never give up a bad habit, they simply postpone the latter, which can be tested alongside other additional research questions.

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease’s pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which—upon effective drug delivery to their target cells—allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.

BackgroundIn vitro studies often use two-dimensional (2D) monolayers, but 3D cell organization, such as in spheroids, better mimics the complexity of solid tumors. To metastasize, cancer cells undergo the process of epithelial-to-mesenchymal transition (EMT) to become more invasive and pro-angiogenic, with expression of both epithelial and mesenchymal markers.AimsWe asked whether EMMPRIN/CD147 contributes to the formation of the 3D spheroid structure, and whether spheroids, which are often used to study proliferation and drug resistance, could better model the EMT process and the metastatic properties of cells, and improve our understanding of the role of EMMPRIN in them.MethodsWe used the parental mouse CT26 colon carcinoma (CT26-WT) cells, and infected them with a lentivirus vector to knock down EMMPRIN expression (CT26-KD cells), or with an empty lentivirus vector (CT26-NC) that served as a negative control. In some cases, we repeated the experiments with the 4T1 or LLC cell lines. We compared the magnitude of change between CT26-KD and CT26-WT/NC cells in different metastatic properties in cells seeded as monolayers or as spheroids formed by the scaffold-free liquid overlay method.ResultsWe show that reduced EMMPRIN expression changed the morphology of cells and their spatial organization in both 2D and 3D models. The 3D models more clearly demonstrated how reduced EMMPRIN expression inhibited proliferation and the angiogenic potential, while it enhanced drug resistance, invasiveness, and EMT status, and moreover it enhanced cell dormancy and prevented CT26-KD cells from forming metastatic-like lesions when seeded on basement membrane extract (BME). Most interestingly, this approach enabled us to identify that EMMPRIN and miR-146a-5p form a negative feedback loop, thus identifying a key mechanism for EMMPRIN activities. These results underline EMMPRIN role as a gatekeeper that prevents dormancy, and suggest that EMMPRIN links EMT characteristics to the process of spheroid formation.ConclusionsThus, 3D models can help identify mechanisms by which EMMPRIN facilitates tumor and metastasis progression, which might render EMMPRIN as a promising target for anti-metastatic tumor therapy.

BackgroundUnderstanding complex cardiac anatomy is essential for percutaneous left atrial appendage (LAA) closure. Conventional multi-slice computed tomography (MSCT) and transesophageal echocardiography (TEE) are now supported by advanced 3D printing and virtual reality (VR) techniques for three-dimensional visualization of volumetric data sets. This study aimed to investigate their added value for LAA closure procedures.MethodsTen patients scheduled for interventional LAA closure were evaluated with MSCT and TEE. Patient-specific 3D printings and VR models were fabricated based on MSCT data. Ten cardiologists then comparatively assessed LAA anatomy and its procedure relevant surrounding structures with all four imaging modalities and rated their procedural utility on a 5-point Likert scale questionnaire (from 1 = strongly agree to 5 = strongly disagree).ResultsDevice sizing was rated highest in MSCT (MSCT: 1.9 ± 0.8; TEE: 2.6 ± 0.9; 3D printing: 2.5 ± 1.0; VR: 2.5 ± 1.1; p

Statement of problem: A working knowledge of the analytical capacities of contemporary registration methods is essential for prosthetic treatment; however, there is a paucity of studies which coherently investigate the capabilities and limitations of the various diagnostic procedures utilized for prosthetic occlusion. Purpose: The present prospective clinical study aimed to evaluate the similarities and differences among contemporary registration methods through comparative analysis. Material and methods: The habitual static occlusion of 19 healthy individuals (14 women; mean age ± standard deviation, 30.8 ± 4.8 years) was analyzed 3 times a day, using shimstock foil, occlusal foil, wax registration, silicone registration, and computerized registration. The procedures were repeated after 14 days. Statistical analyses included all registrations referencing the first measurement point to assess the mean values of antagonistic contacts and the differences between these measurements. Pearson's and Kendall's correlation analyses were performed as part of the coherent mixed logistic regression model, and marginal probabilities were calculated using the registration technique and repeated measurements. Results: Strong correlations were found among the various registration techniques. The largest effect sizes were observed among the wax, silicone, occlusion foil, and computerized registrations (r = 0.95, P

Background. Medication-related osteonecrosis of the jaw (MRONJ) is a rare, serious, and debilitating disease of unknown cause that can be associated with significant health-related quality of life (HRQOL) impairment. Hematological disease is characterized by a nonhealing exposed jawbone in patients with a history of antiresorptive or antiangiogenic agent use without radiation exposure to the head or neck. Patients and Materials and Methods. This prospective study over the period from May 2020 to December 2021 included a representative sample consisting of 27 patients with at least stage 2 MRONJ lesions who underwent surgical rehabilitation via oral and maxillofacial surgery at the University Medical Center Göttingen, Germany. Quality of life data were collected over a 6-month postoperative period using the Health-Related QOL (SF-12) and Oral Health-Related QOL (OHIP-14) questionnaires. Results. A total of 27 patients considered in the study had a total of 42 MRONJ lesions, corresponding to a mean of 1.56 necroses per patient. MRONJ lesions were downstaged in 85% of the patients. HRQOL was evaluated with the SF-12 questionnaire. Significant improvements were found in six of the eight categories (General Health (p

The solution structure, stability, and dynamics of a broadly-acting antiviral ACE2-IgG-Fc fusion protein are determined. Small chemical compounds binding to ACE2 can be used to drastically increase the thermal stability of the ACE2 domain.

Abstract Aims Absolute treatment effects—i.e. numbers needed to treat (NNTs)—of novel antidiabetic drugs for cardiovascular outcomes have not been comprehensively evaluated. We aimed to perform a meta‐analysis of digitalized individual patient outcomes to display and compare absolute treatment effects. Methods and results Individual patient time‐to‐event information from Kaplan–Meier plots of cardiovascular mortality (CM) and/or hospitalization for heart failure (HHF) endpoints from cardiovascular outcome trials (CVOTs) evaluating dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide‐1 (GLP‐1) receptor agonists, and sodium glucose transporter 2 (SGLT2) inhibitors vs. placebo were digitalized using WebPlotDigitizer 4.2 and the R code of Guyot et al.; Weibull regression models were generated, validated, and used to estimate NNT for individual trials; random‐effects meta‐analysis generated Meta‐NNT with 95% confidence intervals. Sixteen CVOTs reported time‐to‐event information (14 in primary diabetes and 2 in primary heart failure populations). Thirteen studies including 96 860 patients were meta‐analysed for CM: At the median follow‐up of 30 months, Meta‐NNTs were 178 (64 to ∞ to −223) for DPP‐4 inhibitors, 261 (158 to 745) for GLP‐1 receptor agonists, and 118 (68 to 435) for SGLT2 inhibitors. Ten studies including 96 128 patients were meta‐analysed for HHF: At the median follow‐up of 29 months, estimated Meta‐NNTs were −644 (229 to ∞ to −134) for DPP‐4 inhibitors, 441 (184 to ∞ to −1100) for GLP‐1 receptor agonists, and 126 (91 to 208) for SGLT2 inhibitors. SGLT2 inhibitors were especially effective for HHF in primary heart failure populations [Meta‐NNT 25 (19 to 39)] vs. primary diabetes populations [Meta‐NNT 233 (167 to 385)] at 16 months of follow‐up. Conclusions We found only modest treatment benefits of GLP‐1 receptor agonists and SGLT2 inhibitors for CM and HHF in primary type 2 diabetes mellitus populations. In primary heart failure populations, SGLT2 inhibitor benefits were substantial and comparable in efficacy to established heart failure medication.

Global introduction of m6dA into human DNA in HEK293 cells reduces their viability and directly alters their gene expression.