Development of an adjustable patient-specific rigid guide to improve the accuracy of external ventricular catheter placement.

OBJECTIVE: The most common method for external ventricular drain (EVD) placement is the freehand approach, which has reported inaccuracy rates of 12.3%-44.9%, especially in the case of altered ventricular anatomy. Current assistive devices require added time or equipment or do not account for shifted ventricles. To improve the accuracy of emergent EVD placement in the setting of altered ventricular anatomy, the authors designed a patient-specific EVD (PS-EVD) guide. METHODS: The PS-EVD guide has a tripod base and a series of differently angled inserts that lock in place at multiple rotational positions, allowing for numerous insertion angles. For testing, the authors designed a 3D-printed phantom skull with a gelatin brain analog containing ventricles simulating normal and altered ventricular anatomy. Low-resolution CT scans of the phantom were used to calculate the insertion angle in relation to the standard perpendicular entry. The corresponding insert at the correct rotational position within the base unit was positioned over the entry point on the phantom, and the catheter was inserted. Accuracy was evaluated with repeat CT scans. RESULTS: With normal ventricular anatomy, as well as abnormally shifted ventricles, proper use of the PS-EVD guide led to accurate catheter insertion into the ventricle in trials, as confirmed on coronal and sagittal CT images, including cases in which a perpendicular trajectory, such as with the Ghajar guide, was insufficient. CONCLUSIONS: The PS-EVD guide allows consistent and accurate EVD placement in phantom skulls with both normal and altered ventricular anatomy. Further trials comparing this device to the freehand approach are required.

Bioreactor Technologies for Enhanced Organoid Culture.

An organoid is a 3D organization of cells that can recapitulate some of the structure and function of native tissue. Recent work has seen organoids gain prominence as a valuable model for studying tissue development, drug discovery, and potential clinical applications. The requirements for the successful culture of organoids in vitro differ significantly from those of traditional monolayer cell cultures. The generation and maturation of high-fidelity organoids entails developing and optimizing environmental conditions to provide the optimal cues for growth and 3D maturation, such as oxygenation, mechanical and fluidic activation, nutrition gradients, etc. To this end, we discuss the four main categories of bioreactors used for organoid culture: stirred bioreactors (SBR), microfluidic bioreactors (MFB), rotating wall vessels (RWV), and electrically stimulating (ES) bioreactors. We aim to lay out the state-of-the-art of both commercial and in-house developed bioreactor systems, their benefits to the culture of organoids derived from various cells and tissues, and the limitations of bioreactor technology, including sterilization, accessibility, and suitability and ease of use for long-term culture. Finally, we discuss future directions for improvements to existing bioreactor technology and how they may be used to enhance organoid culture for specific applications.

Adult Renal Transplantation in a Patient 28 Years after Heart Transplantation as a Neonate for Hypoplastic Left Heart Syndrome.

We present a case of kidney transplantation in a 28-year-old patient who received a heart transplant at 7 weeks of age due to hypoplastic left heart syndrome. The patient's renal insufficiency was the result of chronic immunosuppression and hypertension. The almost 28-year-old graft demonstrated very good function. This patient represents as one of the longest pediatric cardiac graft recipients living without any significant functional limitations.

Measurements of auto-antibodies to α-synuclein in the serum and cerebral spinal fluids of patients with Parkinson's disease.

Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto-antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared with HC, whereas serum levels were not significantly different. CSF auto-antibody levels did not associate with amyloid-ß1-42 , total tau, or phosphorylated tau. CSF auto-antibody levels correlated with performance on the Montreal Cognitive Assessment, even when controlled for CSF amyloidß1-42 . CSF hemoglobin levels, as a proxy for contamination of CSF by blood during lumbar puncture, did not influence these observations. Using recombinant α-synuclein with N- and C-terminal truncations, we found that CSF auto-antibodies target amino acids 100 through 120 of α-synuclein. We conclude that endogenous CSF auto-antibodies are significantly higher in PD patients as compared with HC, suggesting that they could indicate the presence of underlying synucleinopathy. These auto-antibodies associate with poor cognition, independently of CSF amyloidß1-42 , and target a select C-terminal region of α-synuclein. Read the Editorial Highlight for this article on page 433.

Updated guidelines on digital media use by children.

Given the speed at which mobile media has grown recently, the updated American Academy of Pediatrics guidelines for digital technology use by children are a welcome addition to the toolbox of pediatric healthcare providers. This article discusses the changes to the guidelines as well as other useful current research not specifically included in those guidelines.

Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease.

Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.