An engineered ultrahigh affinity bi-paratopic uPAR targeting agent confers enhanced tumor targeting.

Urokinase-type plasminogen activator receptor (uPAR) is overexpressed on tumor cells in multiple types of cancer and contributes to disease progression and metastasis. In this work, we engineered a novel bi-paratopic uPAR targeting agent by fusing the binding domains of two native uPAR ligands: uPA and vitronectin, with a flexible peptide linker. The linker length was optimized to facilitate simultaneous engagement of both domains to their adjacent epitopes on uPAR, resulting in a high affinity and avid binding interaction. Furthermore, the individual domains were affinity-matured using yeast surface display and directed evolution, resulting in a bi-paratopic protein with affinity in the picomolar to femtomolar range. This engineered uPAR targeting agent demonstrated significantly enhanced tumor localization in mouse tumor models compared to the native uPAR ligand and warrants further investigation as a diagnostic and therapeutic agent for cancer.

Characterizing a learning curve for robotic-assisted bronchoscopy: Analysis of skills acquisition in a high-volume academic center.

OBJECTIVE: Shape-sensing robotic-assisted bronchoscopy (ssRAB) is an emerging technology for the sampling of pulmonary lesions. We seek to characterize the ssRAB learning curve at an academic center. METHODS: SsRAB procedures performed by 9 proceduralists at a single institution were analyzed. Cumulative sum analyses were performed to examine diagnostic sampling and procedure time over each operator's first 50 cases, with the acceptable yield threshold set to 73%. RESULTS: During the study period, 442 patients underwent sampling of 551 lesions. Each operator sampled 61 (IQR, 60-63) lesions. Lesion size was 1.90 cm (IQR, 1.33-2.80). The median procedure time for single-target cases decreased from 62 minutes during the first 10 cases to 39 minutes after case 40 (P<0.001). The overall diagnostic yield was 72% (range, 58-83%). Six of 9 operators achieved proficiency over the study period. An aggregated cumulative sum analysis of those who achieved competency demonstrated a steep improvement between lesions 1 and 21 and crossing of the competency threshold by lesion 25. Temporal analysis of yield-related lesion characteristics demonstrated that at approximately lesion 20, more challenging lesions were increasingly targeted, as evidenced by smaller target size, higher rates of unfavorable radial endobronchial ultrasound views and a negative bronchus sign. CONCLUSIONS: Skills acquisition in ssRAB is variable. Approximately half of proceduralists become facile with the technology within 25 lesions. After the initial learning phase, operators increasingly target lesions with more challenging features. Overall, these findings can inform certification and competency standards and provide new users with expectations related to performance over time.

Pneumatosis Intestinalis Following Surgical Gastrostomy Tube Placement in a Patient With Glottic Squamous Cell Carcinoma: A Case Report.

Pneumatosis intestinalis (PI) is a rare medical and post-surgical sequela of multiple different etiologies which can be either benign or life-threatening. Various mechanisms have been proposed to explain the occurrence of PI; however, the pathophysiology is dependent on the suspected cause. The condition is largely categorized into two broad groups: idiopathic PI, which remains relatively uncommon, and secondary PI. The latter often surfaces as a result of a wide array of both gastrointestinal and non-gastrointestinal illnesses. These encompass vascular compromise, bowel mucosal disruption, gastrointestinal dysmotility, as well as infectious and immunological etiologies. Management ranges from conservative medical strategies to emergent surgical intervention. We present the first case to our knowledge of spontaneous PI developing within five days of a surgical gastrostomy tube (SGT) placement in a 79-year-old female with glottic squamous cell carcinoma which unfortunately proved fatal. The purpose of this case report is to highlight a rare fatal complication of a common surgical procedure and the necessity of initiating interdisciplinary management quickly to determine the best treatment course.

Lightning Pose: improved animal pose estimation via semi-supervised learning, Bayesian ensembling and cloud-native open-source tools.

Contemporary pose estimation methods enable precise measurements of behavior via supervised deep learning with hand-labeled video frames. Although effective in many cases, the supervised approach requires extensive labeling and often produces outputs that are unreliable for downstream analyses. Here, we introduce 'Lightning Pose', an efficient pose estimation package with three algorithmic contributions. First, in addition to training on a few labeled video frames, we use many unlabeled videos and penalize the network whenever its predictions violate motion continuity, multiple-view geometry and posture plausibility (semi-supervised learning). Second, we introduce a network architecture that resolves occlusions by predicting pose on any given frame using surrounding unlabeled frames. Third, we refine the pose predictions post hoc by combining ensembling and Kalman smoothing. Together, these components render pose trajectories more accurate and scientifically usable. We released a cloud application that allows users to label data, train networks and process new videos directly from the browser.

Effects of Akt Activator SC79 on Human M0 Macrophage Phagocytosis and Cytokine Production.

Akt is an important kinase in metabolism. Akt also phosphorylates and activates endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS, respectively) expressed in M0 (unpolarized) macrophages. We showed that e/nNOS NO production downstream of bitter taste receptors enhances macrophage phagocytosis. In airway epithelial cells, we also showed that the activation of Akt by a small molecule (SC79) enhances NO production and increases levels of nuclear Nrf2, which reduces IL-8 transcription during concomitant stimulation with Toll-like receptor (TLR) 5 agonist flagellin. We hypothesized that SC79's production of NO in macrophages might likewise enhance phagocytosis and reduce the transcription of some pro-inflammatory cytokines. Using live cell imaging of fluorescent biosensors and indicator dyes, we found that SC79 induces Akt activation, NO production, and downstream cGMP production in primary human M0 macrophages. This was accompanied by a reduction in IL-6, IL-8, and IL-12 production during concomitant stimulation with bacterial lipopolysaccharide, an agonist of pattern recognition receptors including TLR4. Pharmacological inhibitors suggested that this effect was dependent on Akt and Nrf2. Together, these data suggest that several macrophage immune pathways are regulated by SC79 via Akt. A small-molecule Akt activator may be useful in some infection settings, warranting future in vivo studies.

An Adaptive Telephone Coaching Intervention for Patients in an Online Weight Loss Program: A Randomized Clinical Trial.

Importance: Weight loss (WL) during the first month of a behavioral program is associated with longer-term WL. Testing of translatable and adaptive obesity programs is needed. Objective: To compare brief, extended, and no telephone coaching for individuals with suboptimal response (ie, 1-month WL <4%) within an online WL program. Design, Setting, and Participants: This randomized clinical trial with enrollment between March 2019 and April 2022 (data collection completed May 2023) was conducted at an academic research center in the US. Eligible participants included adults aged 18 to 70 years with daily access to internet and a body mass index between 25 and 45. Interventions: All participants received an automated online WL program (4 months) and WL maintenance program (8 months), consisting of video lessons, self-monitoring, and personalized feedback. Participants were randomized, such that individuals with suboptimal response received either brief telephone coaching (3 calls during weeks 5-8), extended telephone coaching (12 calls during weeks 5-16), or no coaching (control). Coaching included education, problem solving, and goal setting, and promoted engagement with the online program. Main Outcomes and Measures: The primary outcomes were percent weight change and proportion of participants achieving 5% or greater WL at 4 and 12 months. A priori hypotheses for WL were that WL for extended coaching would be greater than for brief coaching, and both extended and brief coaching would be greater than no coaching (control). A longitudinal mixed-effects model with participant-specific intercept was used to examine intervention effects on percent WL at 4 and 12 months. Secondary analyses focused on program engagement and cost/kilogram of WL. Results: The study included a total of 437 participants who reported WL at 1 month (mean [SD] age, 50.8 [11.4] years; mean [SD] BMI, 34.6 [5.0]; 305 female [69.8%] and 132 male [30.2%]) with 148 randomized to extended coaching, 143 assigned to brief coaching, and 146 assigned to the control group. Of all participants, 346 (79.2%) were considered to have a suboptimal response. WL at 4 months was significantly greater in the extended coaching group (mean [SD] WL, -7.0% [5.1%]) and brief coaching group (mean [SD] WL, -6.2% [4.7%]) vs the control group (mean [SD] WL, -4.5% [4.7%]) (P < .001). Similarly, the proportion of participants achieving 5% or greater WL at 4 months was greater in the extended coaching group (89 participants [65.9%]) and brief coaching group (77 participants [58.5%]) vs control group (46 participants [36.5%]) (P < .001). At 12 months, a similar pattern was observed for achievement of 5% WL or greater (extended coaching, 63 participants [48.1%]; brief coaching, 58 participants [45.9%]; control, 38 participants [32.8%]; P = .03). Percent WL at 12 months was significantly higher in extended coaching vs control (mean [SD] WL for extended coaching, -5.5% [6.7%]; mean [SD] WL for control, -3.9% [7.4%]; P = .03) but not for brief coaching (mean [SD] WL, -4.9% [6.1%]).Both the brief and extended coaching groups watched more lessons and self-monitored on more days compared with the control group. The cost per additional kilogram of WL, beyond that of the control group, was $50.09 for brief coaching and $92.65 for extended coaching. Conclusions and Relevance: In this randomized clinical trial testing an adaptive intervention, the provision of coaching for individuals with suboptimal response improved WL and was cost-effective; further testing in clinical settings (eg, health care systems) is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT03867981.

A transdiagnostic approach to neurodiversity in a representative population sample: The N+ 4 model.

Background: The concept of neurodiversity draws upon scientific research, and lessons from practice and lived experience to suggest new ways of thinking about neurodevelopmental conditions. Among the formative observations are that characteristics associated with neurodevelopmental conditions are part of a "broader phenotype" of variation across the whole population, and that there appear to be "transdiagnostic" similarities as well as differences in these characteristics. These observations raise important questions that have implications for understanding diversity in neurodevelopmental conditions and in neurocognitive phenotypes across the whole population. Method: The present work examines broader phenotypes using seven widely used self-report assessments of traits associated with autism, ADHD, dyslexia, Developmental Coordination Disorder/dyspraxia, tic disorders/Tourette's, cortical hyperexcitability associated with subclinical epilepsy, and sensory sensitivities. A representative sample of 995 adults (aged 17-77) in the UK completed self-report measures of neurodiversity, wellbeing, generalized anxiety, and depression, and cognitive abilities (nonverbal intelligence and executive functioning). Results: We used confirmatory factor analysis to test whether variation and covariation was better characterized (1) by traditional diagnostic labels, or (2) transdiagnostically according to similarities in functions, behaviours, or phenomena. Results indicated that neurodiversity characteristics were best explained using a bifactor model with one general "N" factor and four condition-specific factors. Conclusion: This was the largest examination to date of the factor structure of broader phenotypes relevant to neurodevelopmental conditions. It provides critical benchmark data, and a framework approach for asking systematic questions about the structure of neurocognitive diversities seen in the whole population and in people with one or more diagnoses.

Microglia-targeted inhibition of miR-17 via mannose-coated lipid nanoparticles improves pathology and behavior in a mouse model of Alzheimer's disease.

Neuroinflammation and accumulation of Amyloid Beta (Aß) accompanied by deterioration of special memory are hallmarks of Alzheimer's disease (AD). Effective preventative and treatment options for AD are still needed. Microglia in AD brains are characterized by elevated levels of microRNA-17 (miR-17), which is accompanied by defective autophagy, Aß accumulation, and increased inflammatory cytokine production. However, the effect of targeting miR-17 on AD pathology and memory loss is not clear. To specifically inhibit miR-17 in microglia, we generated mannose-coated lipid nanoparticles (MLNPs) enclosing miR-17 antagomir (Anti-17 MLNPs), which are targeted to mannose receptors readily expressed on microglia. We used a 5XFAD mouse model (AD) that recapitulates many AD-related phenotypes observed in humans. Our results show that Anti-17 MLNPs, delivered to 5XFAD mice by intra-cisterna magna injection, specifically deliver Anti-17 to microglia. Anti-17 MLNPs downregulated miR-17 expression in microglia but not in neurons, astrocytes, and oligodendrocytes. Anti-17 MLNPs attenuated inflammation, improved autophagy, and reduced Aß burdens in the brains. Additionally, Anti-17 MLNPs reduced the deterioration in spatial memory and decreased anxiety-like behavior in 5XFAD mice. Therefore, targeting miR-17 using MLNPs is a viable strategy to prevent several AD pathologies. This selective targeting strategy delivers specific agents to microglia without the adverse off-target effects on other cell types. Additionally, this approach can be used to deliver other molecules to microglia and other immune cells in other organs.

4D intravital imaging identifies platelets as the predominant cellular procoagulant surface in a mouse hemostasis model.

Interplay between platelets, coagulation factors, endothelial cells (ECs) and fibrinolytic factors is necessary for effective hemostatic plug formation. This study describes a four-dimensional (4D) imaging platform to visualize and quantify hemostatic plug components in mice with high spatiotemporal resolution. Fibrin accumulation following laser-induced vascular injury was observed at the platelet plug-EC interface, controlled by the antagonistic balance between fibrin generation and breakdown. We observed less fibrin accumulation in mice expressing low levels of tissue factor (TFlow) or F12-/- mice compared to controls, whereas increased fibrin accumulation, including on the vasculature adjacent to the platelet plug, was observed in plasminogen-deficient mice or wild-type mice treated with tranexamic acid (TXA). Phosphatidylserine (PS), a membrane lipid critical for the assembly of coagulation factors, was first detected at the platelet plug-EC interface, followed by exposure across the endothelium. Impaired PS exposure resulted in a significant reduction in fibrin accumulation in cyclophilin D-/- mice. Adoptive transfer studies demonstrated a key role for PS exposure on platelets, and to a lesser degree on ECs, in fibrin accumulation during hemostatic plug formation. Together, these studies suggest that (1) platelets are the functionally dominant procoagulant cellular surface, and (2) plasmin is critical for limiting fibrin accumulation at the site of a forming hemostatic plug.

Sustained antigen delivery improves germinal center reaction and increases antibody responses in neonatal mice.

Neonates and young infants are known to have limited responses to pediatric vaccines due to reduced germinal center formation. Extended vaccine antigen dosing was previously shown to expand germinal center formation and improve humoral responses in adult mice. We report that sustained antigen delivery through sequential dosing overcomes neonatal limitations to form germinal center reactions and improves humoral immunity. Thus, vaccine strategies that extend the release of vaccine antigens may reduce the number of doses, and time needed, to achieve protective immunity in neonates and young infants.

Determinants of radiation exposure during mobile cone-beam CT-guided robotic-assisted bronchoscopy.

BACKGROUND AND OBJECTIVE: Robotic-assisted bronchoscopy (RAB) is an emerging modality to sample pulmonary lesions. Cone-beam computed tomography (CBCT) can be incorporated into RAB. We investigated the magnitude and predictors of patient and staff radiation exposure during mobile CBCT-guided shape-sensing RAB. METHODS: Patient radiation dose was estimated by cumulative dose area product (cDAP) and cumulative reference air kerma (cRAK). Staff equivalent dose was calculated based on isokerma maps and a phantom simulation. Patient, lesion and procedure-related factors associated with higher radiation doses were identified by logistic regression models. RESULTS: A total of 198 RAB cases were included in the analysis. The median patient cDAP and cRAK were 10.86 Gy cm2 (IQR: 4.62-20.84) and 76.20 mGy (IQR: 38.96-148.38), respectively. Among staff members, the bronchoscopist was exposed to the highest median equivalent dose of 1.48 µSv (IQR: 0.85-2.69). Both patient and staff radiation doses increased with the number of CBCT spins and targeted lesions (p < 0.001 for all comparisons). Patient obesity, negative bronchus sign, lesion size <2.0 cm and inadequate sampling by on-site evaluation were associated with a higher patient dose, while patient obesity and inadequate sampling by on-site evaluation were associated with a higher bronchoscopist equivalent dose. CONCLUSION: The magnitude of patient and staff radiation exposure during CBCT-RAB is aligned with safety thresholds recommended by regulatory authorities. Factors associated with a higher radiation exposure during CBCT-RAB can be identified pre-operatively and solicit procedural optimization by reinforcing radiation protective measures. Future studies are needed to confirm these findings across multiple institutions and practices.

Utility of thromboelastography with platelet mapping (TEG-PM) for monitoring platelet transfusion in qualitative platelet disorders.

Patients with pathogenic variants in RASGRP2 (inherited platelet disorder (IPD)-18) have normal platelet counts but show impaired platelet aggregation due to diminished activation of αIIbß3 integrin. This defect results in moderate to severe bleeding episodes, especially following surgical procedures, which require patients to be transfused with platelets and/or pro-hemostatic agents. We recently demonstrated that the hemostatic efficacy of transfused platelets is limited by dysfunctional endogenous platelets in a mouse model of IPD-18 ( Rasgrp2 -/- mice), as dysfunctional platelets were recruited to the forming hemostatic plug but did not participate in clot contraction. Consequently, higher amounts of transfused platelets were required to outcompete these dysfunctional cells and to reverse bleeding. We here studied the usefulness of thromboelastography with platelet mapping (TEG-PM), a method to evaluate platelet-dependent clot contraction, for ex vivo monitoring of the hemostatic potential in Rasgrp2 -/- mice transfused with various amounts of wild-type (WT) platelets. Rasgrp2 -/- whole blood samples did not contract in TEG-PM, consistent with a critical role of this protein in αIIbß3 activation. Addition of WT platelets improved TEG parameters (K time, α-angle, MA) in a ratio dependent manner, consistent with our recent in vivo studies showing impaired hemostasis at a 5:1, but not at a 2:1 ratio of mutant to WT platelets. Interestingly, K and α values were identified as better predictors of transfusion efficacy than MA, the most platelet-dependent TEG parameter. In conclusion, this proof-of-concept study supports the use of TEG-PM to monitor platelet transfusion ratios and hemostatic potential in IPD-18 and potentially other platelet disorders.

Rapid molecular profiling utilising minimal quantities of endobronchial ultrasound-guided aspirates for the detection of Epidermal Growth Factor Receptor, KRAS, ALK, ROS1, RET, NTRK and MET gene alterations from patients with non-small-cell lung carcinomas on the Biocartis Idylla™ platform.

OBJECTIVES: Comprehensive molecular analysis for patients with non-small-cell lung carcinoma (NSCLC) is essential for managing modern targeted therapies. This study sought to establish the feasibility of utilising real-time PCR to perform rapid and comprehensive profiling on minimal amounts of endobronchial ultrasound-guided (EBUS) aspirates as a fast, tissue-sparing route of predictive profiling. METHODS: A volume of 500 µL of EBUS aspirate and fixative from patients with NSCLC was decanted, and 80 µL (<1% of total specimen received) was utilised for analysis. Biocartis Idylla™ cartridges for epidermal growth factor receptor (EGFR) mutations, KRAS mutations and a GeneFusion cartridge (ALK, ROS1, RET, NTRK1/2/3 rearrangements & MET 14 exon skipping) were analysed for each case to provide molecular data on the main clinically relevant targets as per UK guidelines. RESULTS: A total of 62 cases were included; all of which had successful DNA analysis (EGFR and KRAS cartridges). RNA analysis (GeneFusion cartridge) was successful for 42 of 51 (82%) with initial approach, with 11 of 11 (100%) achieving a successful result with modified protocol. In all, 23 KRAS mutations (37%), 5 EGFR mutations (8%) and 1 ROS fusion (2%) were identified. Average time from specimen receipt to molecular read-out was 5 h. CONCLUSION: Real-time PCR utilising the Idylla™ platform is rapid, utilises minimal amounts of tissue and provides accurate results. We propose this is a useful ancillary method to utilise alongside next-generation sequencing (NGS) in cases of urgent clinical requirement or EBUS aspirates with inadequate quantities of tissue for NGS.

Mechanical Ventilation in Older Adults With Dementia: Opportunities to Promote Goal-Concordant Care.

CONTEXT: Recent studies show increasing use of mechanical ventilation among people living with dementia. There are concerns that this trend may not be driven by patient preferences. OBJECTIVES: To better understand decision-making regarding mechanical ventilation in people living with dementia. METHODS: This was an electronic health record-based retrospective cohort study of older adults with dementia (n = 295) hospitalized at one of two teaching hospitals between 2015 and 2019 who were supported with mechanical ventilation (n = 191) or died without mechanical ventilation (n = 104). Multivariable logistic regression was used to examine associations between patient characteristics and mechanical ventilation use. RESULTS: The median age was 78 years (IQR 71-86), 41% were female, 28% resided in a nursing home, and 58% had clinical markers of advanced dementia (dehydration, weight loss, mobility limitations, or pressure ulcers). Among patients supported with mechanical ventilation, 70% were intubated within 24 hours of presentation, including 31% intubated before hospital arrival. Younger age, higher illness acuity, and absence of a treatment-limiting Physician Orders for Life-Sustaining Treatment document were associated with mechanical ventilation use; nursing home residence and clinical markers of advanced dementia were not. Most patients (89%) had a documented goals of care discussion (GOCD) during hospitalization. CONCLUSION: Future efforts to promote goal-concordant care surrounding mechanical ventilation use for people living with dementia should involve identifying barriers to goal-concordant care in pre-hospital settings, assessing the timeliness of in-hospital GOCD, and developing strategies for in-the-moment crisis communication across settings.

A Prospective Study on Deep Inspiration Breath Hold Thoracic Radiation Therapy Guided by Bronchoscopically Implanted Electromagnetic Transponders.

BACKGROUND: Electromagnetic transponders bronchoscopically implanted near the tumor can be used to monitor deep inspiration breath hold (DIBH) for thoracic radiation therapy (RT). The feasibility and safety of this approach require further study. METHODS: We enrolled patients with primary lung cancer or lung metastases. Three transponders were implanted near the tumor, followed by simulation with DIBH, free breathing, and 4D-CT as backup. The initial gating window for treatment was ±5 mm; in a second cohort, the window was incrementally reduced to determine the smallest feasible gating window. The primary endpoint was feasibility, defined as completion of RT using transponder-guided DIBH. Patients were followed for assessment of transponder- and RT-related toxicity. RESULTS: We enrolled 48 patients (35 with primary lung cancer and 13 with lung metastases). The median distance of transponders to tumor was 1.6 cm (IQR 0.6-2.8 cm). RT delivery ranged from 3 to 35 fractions. Transponder-guided DIBH was feasible in all but two patients (96% feasible), where it failed because the distance between the transponders and the antenna was >19 cm. Among the remaining 46 patients, 6 were treated prone to keep the transponders within 19 cm of the antenna, and 40 were treated supine. The smallest feasible gating window was identified as ±3 mm. Thirty-nine (85%) patients completed one year of follow-up. Toxicities at least possibly related to transponders or the implantation procedure were grade 2 in six patients (six incidences, cough and hemoptysis), grade 3 in three patients (five incidences, cough, dyspnea, pneumonia, and supraventricular tachycardia), and grade 4 pneumonia in one patient (occurring a few days after implantation but recovered fully and completed RT). Toxicities at least possibly related to RT were grade 2 in 18 patients (41 incidences, most commonly cough, fatigue, and pneumonitis) and grade 3 in four patients (seven incidences, most commonly pneumonia), and no patients had grade 4 or higher toxicity. CONCLUSIONS: Bronchoscopically implanted electromagnetic transponder-guided DIBH lung RT is feasible and safe, allowing for precise tumor targeting and reduced normal tissue exposure. Transponder-antenna distance was the most common challenge due to a limited antenna range, which could sometimes be circumvented by prone positioning.

Can Ethanol Ablation Achieve Durable Control of Neck Nodal Recurrences in Adults With Stage I Papillary Thyroid Cancer?

Objective: Results of ethanol ablation (EA) for controlling neck nodal metastases (NNM) in adult patients with papillary thyroid carcinoma (APTC) beyond 6 months have rarely been reported. We now describe outcome results in controlling 71 NNM in 40 node-positive stage I APTC patients followed for 66 to 269 months. Methods: All 40 patients were managed with bilateral thyroidectomy and radioiodine therapy and followed with neck ultrasound (US) for >48 months after EA. Cumulative radioiodine doses ranged from 30 to 550 mCi; pre-EA 27 patients (67%) had 36 additional neck surgeries. Cytologic diagnosis of PTC in 71 NNM selected for EA was confirmed by US-guided biopsy. EA technique and follow-up protocol were as previously described. Results: The 40 patients had 1 to 4 NNM; 67/71 NNM (94%) received 2 to 4 ethanol injections (total median volume 0.8 cc). All ablated 71 NNM shrank (mean volume reduction of 93%); nodal hypervascularity was eliminated. Thirty-eight NNM (54%) with initial volumes of 12-1404 mm3 (median 164) disappeared on neck sonography. Thirty-three hypovascular foci from ablated NNM (pre-EA volume range 31-636 mm3; median 147) were still identifiable with volume reductions of 45% to 97% observed (median 81%). There were no complications and no postprocedure hoarseness. Final results were considered to be ideal or near ideal in 55% and satisfactory in 45%. There was no evidence of tumor regrowth after EA. Conclusion: Our results demonstrate that for patients with American Joint Committee on Cancer stage I APTC, who do not wish further surgery or radioiodine, and are uncomfortable with active surveillance, EA can achieve durable control of recurrent NNM.

Assessing corn recovery from early season nutrient stress under different soil moisture regimes.

Corn (Zea mays) biomass accumulation and nutrient uptake by the six-leaf collar (V6) growth stage are low, and therefore, synchronizing nutrient supply with crop demand could potentially minimize nutrient loss and improve nutrient use efficiency. Knowledge of corn's response to nutrient stress in the early growth stages could inform such nutrient management. Field studies were conducted to assess corn recovery from when no fertilizer application is made until the V6 growth stage, and thereafter, applying fertilizer rates as those in non-stressed conditions. The early season nutrient stress and non-stress conditions received the same amount of nutrients. As the availability of nutrients for plant uptake is largely dependent on soil moisture, corn recovery from the early season nutrient stress was assessed under different soil moisture regimes induced via irrigation scheduling at 50% and 80% field capacity under overhead and subsurface drip irrigation (SSDI) systems. Peanut (Arachis hypogaea) was the previous crop under all conditions, and the fields were under cereal rye (Secale cereale) cover crop prior to planting corn. At the V6 growth stage, the nutrient concentrations of the early season-stressed crops, except for copper, were above the minimum threshold of sufficiency ranges reported for corn. However, the crops showed poor growth, with biomass accumulation being reduced by over 50% compared to non-stressed crops. Also, the uptake of all nutrients was significantly lower under the early season nutrient stress conditions. The recovery of corn from the early season nutrient stress was low. Compared to non-stress conditions, the early season nutrient stress caused 1.58 Mg ha-1 to 3.4 Mg ha-1 yield reduction. The percent yield reduction under the SSDI system was 37.6-38.2% and that under the overhead irrigation system was 11.7-13%. The high yield reduction from the early season nutrient stress under the SSDI system was because of water stress conditions in the topsoil soil layer. The findings of the study suggest ample nutrient supply in the early season growth stage is critical for corn production, and thus, further studies are recommended to determine the optimum nutrient supply for corn at the initial growth stages.

Hepatic veno-occlusive disease complicated with extreme hyperammonaemia (920 µmol/L) treated with defibrotide, lactulose, rifampin and haemodialysis.

Hepatic veno-occlusive disease (VOD)/sinusoidal obstructive syndrome (SOS) is a severe complication that can occur following haematopoietic stem cell transplant (HSCT) with high-intensity conditioning chemotherapy regimens. Severe VOD/SOS, often characterised by multiorgan failure, is associated with a high mortality rate. This case report details the complex clinical course of a male patient in his mid-20s, recently diagnosed with B cell acute lymphoblastic leukaemia, who underwent allogeneic HSCT. Based on the 2023 European Society for Blood and Marrow Transplantation (EBMT) criteria, the patient developed very severe VOD/SOS, prompting immediate treatment with defibrotide. Unexpectedly, he developed profound hyperammonaemia exceeding 900 µmol/L, leading to encephalopathy and cerebral oedema. Despite aggressive interventions including defibrotide, lactulose, rifampin and haemodialysis, the patient passed away due to cerebral oedema and pulseless electrical activity arrest. We theorise the hyperammonaemia is disproportionate to his hepatic dysfunction and is possibly secondary to an acquired defect of the urea synthesis consistent with idiopathic hyperammonaemia, a rare complication in patients receiving intense conditioning chemotherapy.

Factors Associated with Costly Hospital Care among Patients with Dementia and Acute Respiratory Failure.

Rationale: Understanding contributors to costly and potentially burdensome care for patients with dementia is of interest to healthcare systems and may facilitate efforts to promote goal-concordant care. Objective: To identify risk factors, in particular whether an early goals-of-care discussion (GOCD) took place, for high-cost hospitalization among patients with dementia and acute respiratory failure. Methods: We conducted an electronic health record-based retrospective cohort study of 298 adults with dementia hospitalized with respiratory failure (receiving ⩾48 h of mechanical ventilation) within an academic healthcare system. We collected demographic and clinical characteristics, including clinical markers of advanced dementia (weight loss, pressure ulcers, hypernatremia, mobility limitations) and intensive care unit (ICU) service (medical, surgical, neurologic). We ascertained whether a GOCD was documented within 48 hours of ICU admission. We used logistic regression to identify patient characteristics associated with high-cost hospitalization measured using the hospital system accounting database and defined as total cost in the top third of the sample (⩾$145,000). We examined a path model that included hospital length of stay as a final mediator between exposure variables and high-cost hospitalization. Results: Patients in the sample had a median age of 71 (IQR, 62-79) years. Approximately half (49%) were admitted to a medical ICU, 29% to a surgical ICU, and 22% to a neurologic ICU. More than half (59%) had a clinical indicator of advanced dementia. A minority (31%) had a GOCD documented within 48 hours of ICU admission; those who did had a 50% lower risk of a high-cost hospitalization (risk ratio, 0.50; 95% confidence interval, 0.2-0.8). Older age, limited English proficiency, and nursing home residence were associated with a lower likelihood of high-cost hospitalization, whereas greater comorbidity burden and admission to a surgical or neurologic ICU compared with a medical ICU were associated with a higher likelihood of high-cost hospitalization. Conclusions: Early GOCDs for patients with dementia and respiratory failure may promote high-value care by ensuring aggressive and costly life support interventions are aligned with patients' goals. Future work should focus on increasing early palliative care delivery for patients with dementia and respiratory failure, in particular in surgical and neurologic ICU settings.

Enhanced dissolution rates of glibenclamide through solid dispersions on microcrystalline cellulose and mannitol, combined with phosphatidylcholine.

OBJECTIVE: This study aimed to investigate the impact of physical solid dispersions of spray-dried glibenclamide (SG) on the surface of microcrystalline cellulose (MC) and mannitol (M) surfaces, as well as their combination with phosphatidylcholine (P), on enhancing the dissolution rate of glibenclamide (G). METHODS: Solid dispersions were prepared using varying proportions of 1:1, 1:4, and 1:10 for SG on the surface of MC (SGA) and M (SGM), and then combined with P, in a proportion of 1:4:0.02 using spray drying. The particle size, specific surface area, scanning electron microscopy (SEM), X-ray diffraction (XRD), and dissolution rate of SGA and SGM were characterized. RESULTS: SEM analysis revealed successful adhesion of SG onto the surface of the carrier surfaces. XRD showed reduced crystalline characteristic peaks for SGA, while SGM exhibited a sharp peaks pattern. Both SGA and SGM demonstrated higher dissolution rates compared to SG and G alone. Furthermore, the dissolution rates of the solid dispersions of SG, MC and P (SGAP), and SG, M, and P (SGMP) were sequentially higher than that of SGA and SGM. CONCLUSIONS: The study suggests that physical solid dispersions of SG on MC and M, along with their combination with P, can effectively enhance the dissolution rate of G. These findings may be valuable in developing of oral solid drug dosage forms utilizing SGA, SGM, SGAP, and SGMP.