Resolving a sticky situation: A case report of mechanical thrombectomy of Histoacryl emboli in the right atrium and inferior vena cava.

A 68-year-old male with liver cirrhosis presented with dizziness and dyspnea two days after endoscopic Histoacryl occlusion of gastric varicses. Imaging revealed a large endovascular embolization of Histoacryl glue, spanning from porto-caval collaterals via the inferior vena cava to the right atrium, partially occluding right atrial inflow. This case report describes the successful removal of this large net-like mass of Histoacryl glue using thrombectomy devices from the inferior vena cava and the right atrium. Postprocedure imaging showed near-complete clearance with residual fragments in the superior mesenteric vein and small emboli in the pulmonary arteries. The patient was discharged in stable condition. Histoacryl glue can cause severe complications if embolized. This case highlights the potential of advanced thrombectomy devices for managing embolic complications from endovascular treatments.

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus.

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.

Post-insufflation diaphragm contractions in patients receiving various modes of mechanical ventilation.

BACKGROUND: During mechanical ventilation, post-insufflation diaphragm contractions (PIDCs) are non-physiologic and could be injurious. PIDCs could be frequent during reverse-triggering, where diaphragm contractions follow the ventilator rhythm. Whether PIDCs happens with different modes of assisted ventilation is unknown. In mechanically ventilated patients with hypoxemic respiratory failure, we aimed to examine whether PIDCs are associated with ventilator settings, patients' characteristics or both. METHODS: One-hour recordings of diaphragm electromyography (EAdi), airway pressure and flow were collected once per day for up to five days from intubation until full recovery of diaphragm activity or death. Each breath was classified as mandatory (without-reverse-triggering), reverse-triggering, or patient triggered. Reverse triggering was further subclassified according to EAdi timing relative to ventilator cycle or reverse triggering leading to breath-stacking. EAdi timing (onset, offset), peak and neural inspiratory time (Tineuro) were measured breath-by-breath and compared to the ventilator expiratory time. A multivariable logistic regression model was used to investigate factors independently associated with PIDCs, including EAdi timing, amplitude, Tineuro, ventilator settings and APACHE II. RESULTS: Forty-seven patients (median[25%-75%IQR] age: 63[52-77] years, BMI: 24.9[22.9-33.7] kg/m2, 49% male, APACHE II: 21[19-28]) contributed 2 ± 1 recordings each, totaling 183,962 breaths. PIDCs occurred in 74% of reverse-triggering, 27% of pressure support breaths, 21% of assist-control breaths, 5% of Neurally Adjusted Ventilatory Assist (NAVA) breaths. PIDCs were associated with higher EAdi peak (odds ratio [OR][95%CI] 1.01[1.01;1.01], longer Tineuro (OR 37.59[34.50;40.98]), shorter ventilator inspiratory time (OR 0.27[0.24;0.30]), high peak inspiratory flow (OR 0.22[0.20;0.26]), and small tidal volumes (OR 0.31[0.25;0.37]) (all P ≤ 0.008). NAVA was associated with absence of PIDCs (OR 0.03[0.02;0.03]; P < 0.001). Reverse triggering was characterized by lower EAdi peak than breaths triggered under pressure support and associated with small tidal volume and shorter set inspiratory time than breaths triggered under assist-control (all P < 0.05). Reverse triggering leading to breath stacking was characterized by higher peak EAdi and longer Tineuro and associated with small tidal volumes compared to all other reverse-triggering phenotypes (all P < 0.05). CONCLUSIONS: In critically ill mechanically ventilated patients, PIDCs and reverse triggering phenotypes were associated with potentially modifiable factors, including ventilator settings. Proportional modes like NAVA represent a solution abolishing PIDCs.

Electronically configurable microscopic metasheet robots.

Shape morphing is vital to locomotion in microscopic organisms but has been challenging to achieve in sub-millimetre robots. By overcoming obstacles associated with miniaturization, we demonstrate microscopic electronically configurable morphing metasheet robots. These metabots expand locally using a kirigami structure spanning five decades in length, from 10 nm electrochemically actuated hinges to 100 µm splaying panels making up the ~1 mm robot. The panels are organized into unit cells that can expand and contract by 40% within 100 ms. These units are tiled to create metasheets with over 200 hinges and independent electronically actuating regions that enable the robot to switch between multiple target geometries with distinct curvature distributions. By electronically actuating independent regions with prescribed phase delays, we generate locomotory gaits. These results advance a metamaterial paradigm for microscopic, continuum, compliant, programmable robots and pave the way to a broad spectrum of applications, including reconfigurable micromachines, tunable optical metasurfaces and miniaturized biomedical devices.

Global neuro-oncology: what lies ahead for low- and middle-income countries?

Over the past few decades, the global healthcare community has achieved remarkable success in controlling many communicable diseases across various regions. However, non-communicable diseases now constitute a significant portion of disease morbidity and mortality, particularly in low- and middle-income countries (LMICs). Among these, cancer, in particular, is witnessing a notable increase in incidence in many LMICs. Among cancers, neurological tumours bear significant impact in terms of long-term disability, escalating costs of comprehensive multidisciplinary care, and often encounter resource-related and systemic delays in care leading to worse outcomes. This opinion paper discusses key concepts in developing global neuro-oncology care, with specific case examples from Pakistan to illustrate methods for improving care in these underserved regions. Additionally, it outlines strategic approaches and potential solutions to address these challenges, aiming to provide a roadmap for enhancing neuro-oncology care in LMICs.

Role of neurosurgeons In strengthening paediatric neuro-oncology In low- and middle-income countries: a narrative review with case examples.

Paediatric neuro-oncology in low- and middle-income countries (LMICs) accounts for a significant proportion of cancer-related mortalities in this age group. The current dearth of structured paediatric neurosurgery training programmes in LMICs requires multidisciplinary coordination; neurosurgeons play certain key roles, as discussed in this article, in ensuring safe and effective care for paediatric neuro-oncology patients. This document intends to elaborate through illustrative cases of the technical and structural nuances required by neurosurgeons in LMICs to provide appropriate surgical care.

Rethinking the residual approach: Leveraging machine learning to operationalize cognitive resilience in Alzheimer's disease.

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data.

Engineering a PbrR-Based Biosensor for Cell-Free Detection of Lead at the Legal Limit.

Industrialization and failing infrastructure have led to a growing number of irreversible health conditions resulting from chronic lead exposure. While state-of-the-art analytical chemistry methods provide accurate and sensitive detection of lead, they are too slow, expensive, and centralized to be accessible to many. Cell-free biosensors based on allosteric transcription factors (aTFs) can address the need for accessible, on-demand lead detection at the point of use. However, known aTFs, such as PbrR, are unable to detect lead at concentrations regulated by the Environmental Protection Agency (24-72 nM). Here, we develop a rapid cell-free platform for engineering aTF biosensors with improved sensitivity, selectivity, and dynamic range characteristics. We apply this platform to engineer PbrR mutants for a shift in limit of detection from 10 µM to 50 nM lead and demonstrate use of PbrR as a cell-free biosensor. We envision that our workflow could be applied to engineer any aTF.

Analysis of Brain Protein Stability Changes in a Mouse Model of Alzheimer's Disease.

The stability of proteins from rates of oxidation (SPROX), thermal proteome profiling (TPP), and limited proteolysis (LiP) techniques were used to profile the stability of ∼2500 proteins in hippocampus tissue cell lysates from 2- and 8-months-old wild-type (C57BL/6J; n = 7) and transgenic (5XFAD; n = 7) mice with five Alzheimer's disease (AD)-linked mutations. Approximately 200-500 protein hits with AD-related stability changes were detected by each technique at each age point. The hit overlap from technique to technique was low, and all of the techniques generated protein hits that were more numerous and largely different from those identified in protein expression level analyses, which were also performed here. The hit proteins identified by each technique were enriched in a number of the same pathways and biological processes, many with known connections to AD. The protein stability hits included 25 high-value conformation biomarkers with AD-related stability changes detected using at least 2 techniques at both age points. Also discovered were subunit- and age-specific AD-related stability changes in the proteasome, which had reduced function at both age points. The different folding stability profiles of the proteasome at the two age points are consistent with a different mechanism for proteasome dysfunction at the early and late stages of AD.

Validation of a whole slide image management system for metabolic-associated steatohepatitis for clinical trials.

The gold standard for enrollment and endpoint assessment in metabolic dysfunction-associated steatosis clinical trials is histologic assessment of a liver biopsy performed on glass slides. However, obtaining the evaluations from several expert pathologists on glass is challenging, as shipping the slides around the country or around the world is time-consuming and comes with the hazards of slide breakage. This study demonstrated that pathologic assessment of disease activity in steatohepatitis, performed using digital images on the AISight whole slide image management system, yields results that are comparable to those obtained using glass slides. The accuracy of scoring for steatohepatitis (nonalcoholic fatty liver disease activity score ≥4 with ≥1 for each feature and absence of atypical features suggestive of other liver disease) performed on the system was evaluated against scoring conducted on glass slides. Both methods were assessed for overall percent agreement with a consensus "ground truth" score (defined as the median score of a panel of three pathologists' glass slides). Each case was also read by three different pathologists, once on glass and once digitally with a minimum 2-week washout period between the modalities. It was demonstrated that the average agreement across three pathologists of digital scoring with ground truth was noninferior to the average agreement of glass scoring with ground truth [noninferiority margin: -0.05; difference: -0.001; 95% CI: (-0.027, 0.026); and p < 0.0001]. For each pathologist, there was a similar average agreement of digital and glass reads with glass ground truth (pathologist A, 0.843 and 0.849; pathologist B, 0.633 and 0.605; and pathologist C, 0.755 and 0.780). Here, we demonstrate that the accuracy of digital reads for steatohepatitis using digital images is equivalent to glass reads in the context of a clinical trial for scoring using the Clinical Research Network scoring system.

Trends and Future Directions in Margin Analysis for Head and Neck Cancers.

Margin status in head and neck cancer has important prognostic implications. Currently, resection is based on manual palpation and gross visualization followed by intraoperative specimen or tumor bed-based margin analysis using frozen sections. While generally effective, this protocol has several limitations including margin sampling and close and positive margin re-localization. There is a lack of evidence on the association of use of frozen section analysis with improved survival in head and neck cancer. This article reviews novel technologies in head and neck margin analysis such as 3-dimensional scanning, augmented reality, molecular margins, optical imaging, spectroscopy, and artificial intelligence.

An Overview of Global Neurosurgery.

Until recently, surgery had been passed over in the domain of global health, historically being described as "the neglected stepchild of global health." Knowledge of the existing global disparities in neurosurgical care has led to neurosurgery capacity-building efforts especially in low-income and middle-income countries. While many global collaborative projects are currently undertaken with philanthropic support, sustainability and scalability are not likely without governmental adoption of neurosurgery-inclusive national surgical plans. Momentum grows for the global neurosurgery community to develop a global neurosurgery action plan outlining goals, a guiding framework, an execution plan, and indicators for monitoring and evaluation.

Continuous muscle pump activation by neuromuscular electrical stimulation of the common peroneal nerve in the treatment of patients with venous leg ulcers: A position paper.

The standard treatment for patients with confirmed Venous Leg Ulcers (VLUs) is compression therapy to improve the function of the calf muscle pump. There is a significant cohort of patients who are unable to tolerate optimal compression therapy or indeed any level of compression therapy. In addition, there is a cohort of patients who can tolerate compression whose ulcers show little or no evidence of healing. There is a need for ways to further improve calf muscle pump function and to improve venous ulcer healing in these patients. Published data were reviewed on the use of Muscle Pump Activation (MPA) using common peroneal nerve neuromuscular electrical stimulation (NMES) to improve calf muscle pump function. There is physiological evidence that MPA can improve calf muscle pump function and venous return in both control subjects and in patients with venous disease. The use of MPA has also been shown to improve venous flow volume and venous flow velocity on ultrasound scanning in patients with venous disease. MPA has been shown to improve microcirculation in the skin using Laser Doppler and laser Doppler Speckle Contrast Imaging, in both normal subjects as well as in patients with venous disease and VLU. A recent randomized controlled trial of MPA plus compression therapy compared with compression therapy alone, found significantly faster rates of healing with the use of MPA in addition to compression therapy. There are indications for the use of MPA as an adjunctive treatment to enhance calf muscle pump function in patients with VLU: who cannot tolerate compression therapy who can only tolerate suboptimal, low-level compression whose ulcer healing remains slow or stalled with optimal compression.

Spatiotemporal Forecasting of Opioid-Related Fatal Overdoses: Towards Best Practices for Modeling and Evaluation.

To inform public health interventions, researchers have developed models to forecast opioid-related overdose mortality. These efforts often have limited overlap in the models and datasets employed, presenting challenges to assessing progress in this field. Furthermore, common error-based performance metrics, such as root mean squared error (RMSE), cannot directly assess a key modeling purpose: the identification of priority areas for interventions. We recommend a new intervention-aware performance metric, Percentage of Best Possible Reach (%BPR). We compare metrics for many published models across two distinct geographic settings, Cook County, Illinois and Massachusetts, assuming the budget to intervene in 100 census tracts out of 1000s in each setting. The top-performing models based on RMSE recommend areas that do not always reach the most possible overdose events. In Massachusetts, the top models preferred by %BPR could have reached 18 additional fatal overdoses per year in 2020-2021 compared to models favored by RMSE. In Cook County, the different metrics select similar top-performing models, yet other models with similar RMSE can have significant variation in %BPR. We further find that simple models often perform as well as recently published ones. We release open code and data for others to build upon.

Constitutional mosaicism of pathogenic variants in SMARCB1 in a subset of patients with sporadic rhabdoid tumors.

BACKGROUND: Malignant rhabdoid tumors are aggressive malignancies predominantly affecting very young children. The characteristic genetic alteration is biallelic inactivation of SMARCB1. In approximately 30% of patients one SMARCB1 allele is constitutionally altered conferring a particularly unfavourable prognosis. Constitutional mosaicism for pathogenic SMARCB1 mutations has recently been reported in distinct cases of allegedly sporadic rhabdoid tumors. We aimed to systematically investigate the frequency and clinical impact of constitutional mosaicism in patients with sporadic rhabdoid tumors included in the EU-RHAB registry. METHODS: We selected 29 patients with rhabdoid tumors displaying at least one pathogenic small variant in SMARCB1 in the tumor DNA and absence of a germline mutation. We re-screened blood-derived patient and control DNA for the respective small variant by PCR with unique molecular identifiers and ultra-deep next generation sequencing. Clinical data in patients with and without mosaicism and 174 EU-RHAB controls were compared. RESULTS: Employing an ultra-deep sequencing approach, we detected tumor-associated SMARCB1 variants in blood-derived DNA in 9/29 patients. In 6/29 patients (21%), whose variant allele frequency (VAF) exceeded 2%, constitutional mosaicism was assumed whereas tumor DNA contamination was documented in 1/3 patients with VAF below 1%. No significant differences were observed between 6 mosaic-positive and 20 -negative patients regarding age at diagnosis, presence of metastases, event-free or overall survival. CONCLUSION: Constitutional mosaicism for pathogenic small SMARCB1 variants is recurrent in patients with allegedly sporadic rhabdoid tumors. The clinical implications of such variants need to be determined in larger, prospective cohorts also including detection of structural variants of SMARCB1.

Interrogation of a fluoropolymer dispersion manufactured with a non-fluorinated polymerization aid for targeted and non-targeted fluorinated residuals by liquid chromatography high resolution mass spectrometry.

Recent advances in fluoropolymer polymerization have focused on replacing perfluorinated polymerization aids (PAs) with hydrocarbon-based alternatives. Hydrocarbon PAs are vulnerable to fluorinated radicals during polymerization, leading to the creation of hundreds of process-specific polyfluorinated residuals. These residuals, which include low molecular weight extractable or leachable impurities, are challenging to detect at trace levels. This study investigates a polytetrafluoroethylene (PTFE) dispersion prepared with a hydrocarbon-based surfactant (DOSS) to measure these process-specific fluorinated residues. Liquid chromatography high resolution mass spectrometry is one of the few analytical methods that offers the sensitivity and selectivity required to detect these residuals in complex matrices at concentrations as low as parts per billion. The results indicate that using a hydrocarbon PA during emulsion polymerization produces numerous polyfluorinated residuals. These must be identified and monitored to develop effective abatement strategies, ensuring responsible fluoropolymer manufacturing.

Impact of regional SARS-CoV-2 proceedings on changes in diagnoses of pediatric malignancies in Bavaria during the COVID-19 pandemic.

The COVID-19 pandemic affected daily life significantly and had massive consequences for healthcare systems with tremendous regional differences. This retrospective study aimed to investigate whether the pandemic and resulting societal changes impacted the diagnosis of pediatric malignancies in a distinct region. Pediatric cancer cases in Bavaria (2016-2021) and SARS-CoV-2 proceedings during the peak phase of the pandemic (2020-2021) were retrospectively analyzed. All new diagnoses of pediatric malignancies reported from cancer centers in Bavaria were included. Clinical data from pre-pandemic years was compared to diagnoses made during the pandemic. Official SARS-CoV-2 reports were received from the Bavarian Health and Food Safety Authority and data on regional pandemic measures were obtained from the Healthcare Data Platform. With this design, a comprehensive analysis of the pandemic proceedings was performed. We found significantly decreased incidence-rate ratios for pediatric cancer diagnosis during the early spring peak of SARS-CoV-2 as it was observed in May during the pandemic, followed by non-significantly increased metastatic cancer diagnosis two months later. Additionally, the time-to-diagnosis of pediatric malignancies was significantly prolonged during the pandemic, and outpatient contacts were significantly reduced, although the availability of consultations remained the same. From our findings, we may hypothesize that there have been effects on pediatric cancer diagnosis during the COVID-19 pandemic at vulnerable times. Interpretation of changes remains speculative with potential causes from behavior patterns, such as hesitation, concerns, and potential societal changes during phases of public restrictions, rather than overwhelmed medical capacities. Nevertheless, specific awareness is needed to protect this patient population during potential future pandemics.

Significance of an Early Repeat Troponin Measurement Upon Presentation to the Hospital for Acute Heart Failure.

BACKGROUND: Higher cardiac troponin is associated with worse outcomes in patients with acute heart failure. The significance of repeat measurements over hours remains unclear. We assessed whether a repeat measurement and the Δ between measurements of high-sensitivity cardiac troponin I (hs-cTnI) were associated with outcomes in hypervolemic patients with acute heart failure without acute coronary syndrome. METHODS AND RESULTS: We analyzed 582 individuals from AKINESIS (Acute Kidney Injury Neutrophil Gelatinase-Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) with hs-cTnI measured ≤12 hours from admission and repeated ≤6 hours thereafter. Associations between hs-cTnI levels and their Δ with short-term (death, intensive care unit admission, receipt of inotropes, or positive pressure ventilation during hospitalization) and long-term (death or heart failure readmission within 1 year) outcomes were assessed. The average age was 69±13 years, 62% were men, 65% were White, 46% had coronary artery disease, and 22% had chest pain. Median hs-cTnI levels were 27 (interquartile range [IQR], 13-62) ng/L initially and 28 (IQR, 14-68) ng/L subsequently, with a Δ of 0 [IQR, -2 to 4] ng/L over 3.4±1 hours. Only the second measurement was associated with short-term outcomes (odds ratio, 1.14 per 2-fold higher [95% CI, 1.02-1.28]). Both individual measurements and the Δ were associated with long-term outcomes (hazard ratios, 1.09, 1.12, and 1.16 for first, second, and Δ, respectively). Associated risk for the first and second measurements were not constant over the year but highest early after being measured and decreased over 1 year. CONCLUSIONS: Repeat measurements of hs-cTnI over hours can identify individuals with acute heart failure without acute coronary syndrome at risk for short- and long-term outcomes.

Human milk variation is shaped by maternal genetics and impacts the infant gut microbiome.

Human milk is a complex mix of nutritional and bioactive components that provide complete nourishment for the infant. However, we lack a systematic knowledge of the factors shaping milk composition and how milk variation influences infant health. Here, we characterize relationships between maternal genetics, milk gene expression, milk composition, and the infant fecal microbiome in up to 310 exclusively breastfeeding mother-infant pairs. We identified 482 genetic loci associated with milk gene expression unique to the lactating mammary gland and link these loci to breast cancer risk and human milk oligosaccharide concentration. Integrative analyses uncovered connections between milk gene expression and infant gut microbiome, including an association between the expression of inflammation-related genes with milk interleukin-6 (IL-6) concentration and the abundance of Bifidobacterium and Escherichia in the infant gut. Our results show how an improved understanding of the genetics and genomics of human milk connects lactation biology with maternal and infant health.