CP-Net: Instance-aware part segmentation network for biological cell parsing.

Instance segmentation of biological cells is important in medical image analysis for identifying and segmenting individual cells, and quantitative measurement of subcellular structures requires further cell-level subcellular part segmentation. Subcellular structure measurements are critical for cell phenotyping and quality analysis. For these purposes, instance-aware part segmentation network is first introduced to distinguish individual cells and segment subcellular structures for each detected cell. This approach is demonstrated on human sperm cells since the World Health Organization has established quantitative standards for sperm quality assessment. Specifically, a novel Cell Parsing Net (CP-Net) is proposed for accurate instance-level cell parsing. An attention-based feature fusion module is designed to alleviate contour misalignments for cells with an irregular shape by using instance masks as spatial cues instead of as strict constraints to differentiate various instances. A coarse-to-fine segmentation module is developed to effectively segment tiny subcellular structures within a cell through hierarchical segmentation from whole to part instead of directly segmenting each cell part. Moreover, a sperm parsing dataset is built including 320 annotated sperm images with five semantic subcellular part labels. Extensive experiments on the collected dataset demonstrate that the proposed CP-Net outperforms state-of-the-art instance-aware part segmentation networks.

Factors Associated with and Impact of Open Conversion in Laparoscopic and Robotic Minor Liver Resections: An International Multicenter Study of 10,541 Patients.

INTRODUCTION: Despite the increasing widespread adoption and experience in minimally invasive liver resections (MILR), open conversion occurs not uncommonly even with minor resections and as been reported to be associated with inferior outcomes. We aimed to identify risk factors for and outcomes of open conversion in patients undergoing minor hepatectomies. We also studied the impact of approach (laparoscopic or robotic) on outcomes. METHODS: This is a post-hoc analysis of 20,019 patients who underwent RLR and LLR across 50 international centers between 2004-2020. Risk factors for and perioperative outcomes of open conversion were analysed. Multivariate and propensity score-matched analysis were performed to control for confounding factors. RESULTS: Finally, 10,541 patients undergoing either laparoscopic (LLR; 89.1%) or robotic (RLR; 10.9%) minor liver resections (wedge resections, segmentectomies) were included. Multivariate analysis identified LLR, earlier period of MILR, malignant pathology, cirrhosis, portal hypertension, previous abdominal surgery, larger tumor size, and posterosuperior location as significant independent predictors of open conversion. The most common reason for conversion was technical issues (44.7%), followed by bleeding (27.2%), and oncological reasons (22.3%). After propensity score matching (PSM) of baseline characteristics, patients requiring open conversion had poorer outcomes compared with successful MILR cases as evidenced by longer operative times, more blood loss, higher requirement for perioperative transfusion, longer duration of hospitalization and higher morbidity, reoperation, and 90-day mortality rates. CONCLUSIONS: Multiple risk factors were associated with conversion of MILR even for minor hepatectomies, and open conversion was associated with significantly poorer perioperative outcomes.

A digital twin model incorporating generalized metabolic fluxes to identify and predict chronic kidney disease in type 2 diabetes mellitus.

We have developed a digital twin-based CKD identification and prediction model that leverages generalized metabolic fluxes (GMF) for patients with Type 2 Diabetes Mellitus (T2DM). GMF digital twins utilized basic clinical and physiological biomarkers as inputs for identification and prediction of CKD. We employed four diverse multi-ethnic cohorts (n = 7072): a Singaporean cohort (EVAS, n = 289) and a North American cohort (NHANES, n = 1044) for baseline CKD identification, and two multi-center Singaporean cohorts (CDMD, n = 2119 and SDR, n = 3627) for 3-year CKD prediction and risk stratification. We subsequently conducted a comprehensive study utilizing a single dataset to evaluate the clinical utility of GMF for CKD prediction. The GMF-based identification model performed strongly, achieving an AUC between 0.80 and 0.82. In prediction, the GMF generated with complete parameters attained high performance with an AUC of 0.86, while with incomplete parameters, it achieved an AUC of 0.75. The GMF-based prediction model utilizing complete inputs is the standard implementation of our algorithm: HealthVector Diabetes®. We have established the GMF digital twin-based model as a robust clinical tool capable of predicting and stratifying the risk of future CKD within a 3-year time horizon. We report the correlation of GMF with basic input parameters, their ability to differentiate between future health states and medication status at baseline, and their capability to quantify CKD progression rates. This holistic methodology provides insights into patients' health states and CKD progression rates based on GMF metabolic profile differences, enabling personalized care plans.

New type of tin(IV) complex based turn-on fluorescent chemosensor for fluoride ion recognition: elucidating the effect of molecular structure on sensing property.

A novel type of chemosensor based on tin(IV) complexes incorporating hydroxyquinoline derivatives has been designed and investigated for selectively detecting fluoride ions. Sn(meq)2Cl2 (meq = 2-methyl-8-quinolinol) (complex 1) exhibits a significant enhancement in luminescence upon the introduction of fluoride ions. This enhancement greatly surpasses that observed with Snq2Cl2 and Sn(dmqo)2Cl2 (q = 8-hydroxyquinnoline; dmqo = 5,7-dimethyl-8-quinolinol). Furthermore, complex 1 displays excellent sensitivity and selectivity for fluoride detection in comparison to halides and other anions. As a result, complex 1 serves as an outstanding turn-on fluorescent chemosensor, effectively sensing fluoride ions. The Benesi-Hilderbrand method and Job's plot confirmed that complex 1 associates with F- in a 1 : 2 binding stoichiometry. Also, complex 1 exhibited a large binding constant (pKb = 10.4 M-2) and a low detection limit (100 nM). To gain a deeper insight into the photophysical properties and the underlying mechanism governing the formation of the tin(IV) fluoride complex via halide exchange, we successfully synthesized partially fluorinated Sn(meq)2F0.67Cl1.33 (2) and fully fluorinated Sn(meq)2F2 (3), all of which were characterized through computational studies, thereby elucidating their photophysical properties. DFT studies reveal that converting Sn(meq)2Cl2 to Sn(meq)2F2, an endergonic process, leads to greater stability due to reducing steric hindrance about the metal center. Furthermore, the fluorinated complex significantly increases dipole moment, resulting in high affinity toward the F- ion.

Impact of neoadjuvant chemotherapy on short-term outcomes after simple and complex minimally invasive minor hepatectomy for colorectal liver metastases: A propensity-score matched and coarsened exact matched study.

BACKGROUND: In the last three decades, minimally invasive liver resection has been replacing conventional open approach in liver surgery. More recently, developments in neoadjuvant chemotherapy have led to increased multidisciplinary management of colorectal liver metastases with both medical and surgical treatment modalities. However, the impact of neoadjuvant chemotherapy on the surgical outcomes of minimally invasive liver resections remains poorly understood. METHODS: A multicenter, international, database of 4998 minimally invasive minor hepatectomy for colorectal liver metastases was used to compare surgical outcomes in patients who received neoadjuvant chemotherapy with surgery alone. To correct for baseline imbalance, propensity score matching, coarsened exact matching and inverse probability treatment weighting were performed. RESULTS: 2546 patients met the inclusion criteria. After propensity score matching there were 759 patients in both groups and 383 patients in both groups after coarsened exact matching. Baseline characteristics were equal after both matching strategies. Neoadjuvant chemotherapy was not associated with statistically significant worse surgical outcomes of minimally invasive minor hepatectomy. CONCLUSION: Neoadjuvant chemotherapy had no statistically significant impact on short-term surgical outcomes after simple and complex minimally invasive minor hepatectomy for colorectal liver metastases.

Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia.

Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.

The novel LESS (low-cost entrainment syringe system) O2 blender for use in modified bubble CPAP circuits: a clinical study of safety.

Background: Bubble continuous positive airway pressure (bCPAP) is used in resource-limited settings for children with respiratory distress. Low-cost modifications of bCPAP use 100% oxygen and may cause morbidity from oxygen toxicity. We sought to test a novel constructible low-cost entrainment syringe system (LESS) oxygen blender with low-cost modified bCPAP in a relevant clinical setting. Methods: We conducted a clinical trial evaluating safety of the LESS O2 blender among hospitalized children under five years old in rural Cambodia evaluating the rate of clinical failure within one hour of initiation of the LESS O2 blender and monitoring for any other blender-related complications. Findings: Thirty-two patients were included. The primary outcome (clinical failure) occurred in one patient (3.1%, 95% CI = 0.1-16.2%). Clinical failure was defined as intubation, death, transfer to another hospital, or two of the following: oxygen saturation <85% after 30 min of treatment; new signs of respiratory distress; or partial pressure of carbon dioxide ≥60 mmHg and pH <7.2 on a capillary blood gas. Secondary outcomes included average generated FiO2's with blender use, which were 59% and 52% when a 5 mm entrainment was used vs. a 10 mm entrainment port with 5-7 cm H2O of CPAP and 1-7 L/min (LPM) of flow; and adverse events including loss of CPAP bubbling (64% of all adverse events), frequency of repair or adjustment (44%), replacement (25%), and median time of respiratory support (44 h). Interpretation: Overall the LESS O2 blender was safe for clinical use. The design could be modified for improved performance including less repair needs and improved nasal interface, which requires modification for the blender to function more consistently.

Mechanistic Modeling of Intrathecal Chemotherapy Pharmacokinetics in the Human Central Nervous System.

PURPOSE: The pharmacokinetics of intrathecally administered antibody or small-molecule drugs in the human central nervous system (CNS) remains poorly understood. This study aimed to provide mechanistic and quantitative perspectives on the CNS pharmacokinetics of intrathecal chemotherapy, by using a physiologically based pharmacokinetic (PBPK) modeling approach. EXPERIMENTAL DESIGN: A novel CNS PBPK model platform was developed and verified, which accounted for the human CNS general anatomy and physiologic processes governing drug distribution and disposition. The model was used to predict CNS pharmacokinetics of antibody (trastuzumab) and small-molecule drugs (methotrexate, abemaciclib, tucatinib) following intraventricular injection or intraventricular 24-hour infusion, and to assess the key determinants of drug penetration into the deep brain parenchyma. RESULTS: Intraventricularly administered antibody and small-molecule drugs exhibited distinct temporal and spatial distribution and disposition in human CNS. Both antibody and small-molecule drugs achieved supratherapeutic or therapeutic concentrations in the cerebrospinal fluid (CSF) compartments and adjacent brain tissue. While intrathecal small-molecule drugs penetrated the deep brain parenchyma to a negligible extent, intrathecal antibodies may achieve therapeutic concentrations in the deep brain parenchyma. Intraventricular 24-hour infusion enabled prolonged CNS exposure to therapeutically relevant concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. CONCLUSIONS: CNS PBPK modeling, in line with available clinical efficacy data, confirms the therapeutic value of intrathecal chemotherapy with antibody or small-molecule drugs for treating neoplastic meningitis and warrants further clinical investigation of intrathecal antibody drugs to treat brain parenchyma tumors. Compared with intraventricular injection, intraventricular 24-hour infusion may mitigate neurotoxicity while retaining potential efficacy.

Cannabis Use is Associated With Higher Rates of Pseudarthrosis Following TLIF: A Multi-Institutional Matched-Cohort Study.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: To compare the rates of pseudarthrosis in patients undergoing 1 to 3 level transforaminal lumbar interbody fusion (TLIF) procedures between cannabis users and noncannabis users. SUMMARY OF BACKGROUND DATA: Recreational use of cannabis is common, though it remains poorly studied and legally ambiguous in the United States. Patients with back pain may turn to adjunctive use of cannabis to manage their pain. However, the implications of cannabis use on the achievement of bony fusion are not well-characterized. METHODS: Patients who underwent 1 to 3 level TLIF for degenerative disc disease or degenerative spondylolisthesis between 2010 and 2022 were identified using the PearlDiver Mariner all-claims insurance database. Cannabis users were identified with ICD 10 code F12.90. Patients undergoing surgery for nondegenerative pathologies such as tumors, trauma, or infection were excluded. 1:1 exact matching was performed using demographic factors, medical comorbidities, and surgical factors which were significantly associated with pseudarthrosis in a linear regression model. The primary outcome measure was development of pseudarthrosis within 24 months after 1 to 3 level TLIF. The secondary outcomes were the development of all-cause surgical complications as well as all-cause medical complications. RESULTS: A 1:1 exact matching resulted in two equal groups of 1593 patients who did or did not use cannabis and underwent 1 to 3 level TLIF. Patients who used cannabis were 80% more likely to experience pseudarthrosis compared with patients who do not [relative risk (RR): 1.816, 95% CI: 1.291-2.556, P <0.001]. Similarly, cannabis use was associated with significantly higher rates of all-cause surgical complications (RR: 2.350, 95% CI: 1.399-3.947, P =0.001) and all-cause medical complications (RR: 1.934, 95% CI: 1.516-2.467, P <0.001). CONCLUSION: After 1:1 exact matching to control for confounding variables, the findings of this study suggest that cannabis use is associated with higher rates of pseudarthrosis, as well as higher rates of all-cause surgical and all-cause medical complications. Further studies are needed to corroborate our findings.

Ehlers-Danlos Syndrome is Associated with Increased Rates of Adjacent Segment Disease Following TLIF: A Propensity Matched Study.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a collection of connective tissue disorders which are often associated with tissue laxity and disc degeneration. However, the implications of EDS on the risk of adjacent segment disease (ASD) after transforaminal lumbar interbody fusion (TLIF) are not well described. The objective of this study is to compare the rates of ASD among patients with EDS and those without EDS. METHODS: Patients who underwent 1-3 level TLIF for degenerative disc disease between 2010-2022 were identified using the PearlDiver Mariner all-claims insurance database. Patients with all types of EDS were included. Patients undergoing surgery for tumors, trauma, or infection were excluded. 1:1 propensity matching was performed using demographic factors, medical comorbidities, and surgical factors which were significantly associated with ASD in a linear regression model. The primary outcome measure was the development of ASD. The secondary outcomes were the development of pseudoarthrosis, medical complications, and surgical complications. RESULTS: Propensity matching resulted in 2 equal groups of 85 patients who did or did not have EDS and underwent 1-3 level TLIF. Patients without EDS were less likely to experience ASD (RR 0.18, 95% CI 0.09-0.35, P < 0.001). There was no significant difference between the 2 patient groups with regards to a diagnosis of pseudoarthrosis, and there was no significant difference for all-cause medical and surgical complications between the 2 patient groups. CONCLUSIONS: After propensity matching to control for confounding variables, the findings of this study suggest that EDS may be associated with an increased risk of ASD following TLIF. Future studies are needed to corroborate these findings.

One node among many: sevoflurane-induced hypnosis and the challenge of an integrative network-level view of anaesthetic action.

Building on their known ability to influence sleep and arousal, Li and colleagues show that modulating the activity of glutamatergic pedunculopontine tegmental neurones also alters sevoflurane-induced hypnosis. This finding adds support for the shared sleep-anaesthesia circuit hypothesis. However, the expanding recognition of many neuronal clusters capable of modulating anaesthetic hypnosis raises the question of how disparate and anatomically distant sites ultimately interact to coordinate global changes in the state of the brain. Understanding how these individual sites work in concert to disrupt cognition and behaviour is the next challenge for anaesthetic mechanisms research.

Impact of liver cirrhosis, severity of cirrhosis and portal hypertension on the difficulty of laparoscopic and robotic minor liver resections for primary liver malignancies in the anterolateral segments.

INTRODUCTION: We performed this study in order to investigate the impact of liver cirrhosis (LC) on the difficulty of minimally invasive liver resection (MILR), focusing on minor resections in anterolateral (AL) segments for primary liver malignancies. METHODS: This was an international multicenter retrospective study of 3675 patients who underwent MILR across 60 centers from 2004 to 2021. RESULTS: 1312 (35.7%) patients had no cirrhosis, 2118 (57.9%) had Child A cirrhosis and 245 (6.7%) had Child B cirrhosis. After propensity score matching (PSM), patients in Child A cirrhosis group had higher rates of open conversion (p = 0.024), blood loss >500 mls (p = 0.001), blood transfusion (p < 0.001), postoperative morbidity (p = 0.004), and in-hospital mortality (p = 0.041). After coarsened exact matching (CEM), Child A cirrhotic patients had higher open conversion rate (p = 0.05), greater median blood loss (p = 0.014) and increased postoperative morbidity (p = 0.001). Compared to Child A cirrhosis, Child B cirrhosis group had longer postoperative stay (p = 0.001) and greater major morbidity (p = 0.012) after PSM, and higher blood transfusion rates (p = 0.002), longer postoperative stay (p < 0.001), and greater major morbidity (p = 0.006) after CEM. After PSM, patients with portal hypertension experienced higher rates of blood loss >500 mls (p = 0.003) and intraoperative blood transfusion (p = 0.025). CONCLUSION: The presence and severity of LC affect and compound the difficulty of MILR for minor resections in the AL segments. These factors should be considered for inclusion into future difficulty scoring systems for MILR.

Synthetic Interbody Devices and Traditional Bone Graft Are Associated With a Similar Rate of Surgical Complications After 1-2 Level Anterior Cervical Discectomy and Fusions.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To compare the rates of all-cause surgical complications of synthetic interbody devices versus allograft or autograft in patients undergoing 1-2 levels anterior cervical discectomy and fusion (ACDF) procedures. SUMMARY OF BACKGROUND DATA: Cervical degenerative disorders affect up to 60% of older adults in the United States. Both traditional allograft or autograft and synthetic interbody devices (polyetheretherketone or titanium) are used for decompression and arthrodesis, with increasing utilization of the latter. However, the differences in their postsurgical complication profiles are not well-characterized. PATIENTS AND METHODS: Patients who underwent 1-2 level ACDFs for cervical radiculopathy or myelopathy between 2010 and 2022 were identified using the PearlDiver Mariner all-claims insurance database. Patients undergoing surgery for nondegenerative pathologies, such as tumors, trauma, or infection, were excluded. 1:1 exact matching was performed based on factors that were significant predictors of all-cause surgical complications in a linear regression model. The primary outcome measure was the development of all-cause surgical complications after 1-2 level ACDFs. The secondary outcome was all-cause medical complications. RESULTS: 1:1 exact matching resulted in two equal groups of 11,430 patients who received treatment with synthetic interbody devices or allograft/autograft. No statistically significant difference in all-cause surgical complications was found between the synthetic cohort and the allograft or autograft cohort after 1-2 level ACDFs (Relative Risk: 0.86, 95% confidence interval: 0.730-1.014, P = 0.079). No significant differences were observed regarding any specific surgical complications except for pseudoarthrosis (Relative Risk: 0.73, 95% confidence interval: 0.554-0.974, P = 0.037), which was higher in the allograft/autograft cohort. CONCLUSION: After 1:1 exact matching to control for confounding variables, the findings of this study suggest that all-cause surgical complications are similar in patients undergoing ACDFs with synthetic interbody devices or allograft/autographs. However, the rate of pseudarthrosis appears to be higher in patients with allograft/autographs. Future prospective studies are needed to corroborate these findings.

Impact of Liver Cirrhosis, Severity of Cirrhosis, and Portal Hypertension on the Difficulty and Outcomes of Laparoscopic and Robotic Major Liver Resections for Primary Liver Malignancies.

BACKGROUND: Minimally invasive liver resections (MILR) offer potential benefits such as reduced blood loss and morbidity compared with open liver resections. Several studies have suggested that the impact of cirrhosis differs according to the extent and complexity of resection. Our aim was to investigate the impact of cirrhosis on the difficulty and outcomes of MILR, focusing on major hepatectomies. METHODS: A total of 2534 patients undergoing minimally invasive major hepatectomies (MIMH) for primary malignancies across 58 centers worldwide were retrospectively reviewed. Propensity score (PSM) and coarsened exact matching (CEM) were used to compare patients with and without cirrhosis. RESULTS: A total of 1353 patients (53%) had no cirrhosis, 1065 (42%) had Child-Pugh A and 116 (4%) had Child-Pugh B cirrhosis. Matched comparison between non-cirrhotics vs Child-Pugh A cirrhosis demonstrated comparable blood loss. However, after PSM, postoperative morbidity and length of hospitalization was significantly greater in Child-Pugh A cirrhosis, but these were not statistically significant with CEM. Comparison between Child-Pugh A and Child-Pugh B cirrhosis demonstrated the latter had significantly higher transfusion rates and longer hospitalization after PSM, but not after CEM. Comparison of patients with cirrhosis of all grades with and without portal hypertension demonstrated no significant difference in all major perioperative outcomes after PSM and CEM. CONCLUSIONS: The presence and severity of cirrhosis affected the difficulty and impacted the outcomes of MIMH, resulting in higher blood transfusion rates, increased postoperative morbidity, and longer hospitalization in patients with more advanced cirrhosis. As such, future difficulty scoring systems for MIMH should incorporate liver cirrhosis and its severity as variables.

Correlation Between Rod Fracture and Shear Stress: A Novel Parameter.

BACKGROUND: We sought to assess the accuracy of a novel parameter proportional to the rod shear stress (RSS) in identifying patients at risk of rod fracture (RF) after surgery for correction of adult spinal deformity. METHODS: We performed a retrospective medical record review of patients aged ≥18 years treated for adult spinal deformity between 2004 and 2014 with ≥24 months of follow-up. The primary outcome was RFs identified radiographically. Patient weight (w), number of instrumented levels (N), and minimum rod diameter (d) were recorded and used to calculate the RSS parameter (RSS=Nwd2). Receiver operating characteristic curves were produced and the area under the curve (AUC ± 95% confidence interval [CI]) was calculated to compare this parameter's discriminative accuracy to that of its constituent variables. The sensitivity, specificity, and likelihood ratios (LRs) were calculated. RESULTS: A total of 28 RF-positive and 154 RF-negative patients were included. The average age was 59.2 ± 9.6 years, and 93.4% were women. The RSS parameter produced the greatest AUC (0.73 ± 0.11). At an RSS cutoff of 30.1, it achieved a sensitivity of 71.4% and specificity of 71.4% (LR, 2.5; 95% CI, 1.8-3.5). The number of instrumented levels produced the next-greatest AUC (0.65 ± 0.12), with a sensitivity of 78.6% and specificity of 50.0% at a cutoff of 15 (LR, 1.6; 95% CI, 1.2-2.0). CONCLUSIONS: The RSS is calculated using easily obtainable information and shows potential as a tool for predicting patient-specific risk of RF after spinal fusion. The number of instrumented levels also correlates strongly with the occurrence of RFs and is not significantly less accurate than the RSS. A larger sample size and prospective validation would be useful in determining with greater confidence which parameter is superior for predicting RFs after spinal fusion.

Pediatric Ventilator-Associated Events Before and After a Multicenter Quality Improvement Initiative.

Importance: Pediatric ventilator-associated events (PedVAEs, defined as a sustained worsening in oxygenation after a baseline period of stability or improvement) are useful for surveillance of complications from mechanical ventilation. It is unclear whether interventions to mitigate known risk factors can reduce PedVAE rates. Objective: To assess whether adherence to 1 or more test factors in a quality improvement bundle was associated with a reduction in PedVAE rates. Design, Setting, and Participants: This multicenter quality improvement study obtained data from 2017 to 2020 for patients who were mechanically ventilated and cared for in neonatal, pediatric, and cardiac intensive care units (ICUs). These ICUs were located in 95 hospitals participating in the Children's Hospitals' Solutions for Patient Safety (SPS) network in North America. Data analyses were performed between September 2021 and April 2023. Intervention: A quality improvement bundle consisted of 3 test factors: multidisciplinary apparent cause analysis, daily discussion of extubation readiness, and daily discussion of fluid balance goals. This bundle was distributed to a subgroup of hospitals that volunteered to participate in a collaborative PedVAE prevention initiative under the SPS network guidance in July 2018. Main Outcomes and Measures: Each SPS network hospital submitted monthly PedVAE rates from January 1, 2017, to May 31, 2020, and test factor data were submitted from July 1, 2018, to May 31, 2020. Analyses focused on hospitals that reliably submitted PedVAE rate data, defined as outcomes data submission through May 31, 2020, for at least 80% of the baseline and postbaseline periods. Results: Of the 95 hospitals in the SPS network that reported PedVAE data, 21 were grouped in the Pioneer cohort and 74 in the non-Pioneer cohort. Only 12 hospitals (57%) from the 21 Pioneer hospitals and 33 (45%) from the 74 non-Pioneer hospitals were considered to be reliable reporters of outcome data. Among the 12 hospitals, the PedVAE rate decreased from 1.9 to 1.4 events per 1000 ventilator days (absolute rate difference, -0.6; 95% CI, -0.5 to -0.7; P < .001). No significant change in the PedVAE rate was seen among the 33 hospitals that reliably submitted PedVAE rates but did not implement the bundle. Of the 12 hospitals, 3 that reliably performed daily discussion of extubation readiness had a decrease in PedVAE rate from 2.6 to 1.2 events per 1000 ventilator days (absolute rate difference, -1.4; 95% CI, -1.0 to -1.7; P < .001), whereas the other 9 hospitals that did not implement this discussion did not have a decrease. Conclusions and Relevance: This study found that a multicenter quality improvement intervention targeting PedVAE risk factors was associated with a substantial reduction in the rate of PedVAEs in hospital ICUs. The findings suggest that ICU teams seeking to reduce PedVAEs incorporate daily discussion of extubation readiness during morning rounds.

Cryo-electron tomography reveals the structural diversity of cardiac proteins in their cellular context.

Cardiovascular diseases are a leading cause of death worldwide, but our understanding of the underlying mechanisms is limited, in part because of the complexity of the cellular machinery that controls the heart muscle contraction cycle. Cryogenic electron tomography (cryo-ET) provides a way to visualize diverse cellular machinery while preserving contextual information like subcellular localization and transient complex formation, but this approach has not been widely applied to the study of heart muscle cells (cardiomyocytes). Here, we deploy a platform for studying cardiovascular disease by combining cryo-ET with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). After developing a cryo-ET workflow for visualizing macromolecules in hiPSC-CMs, we reconstructed sub-nanometer resolution structures of the human thin filament, a central component of the contractile machinery. We also visualized a previously unobserved organization of a regulatory complex that connects muscle contraction to calcium signaling (the troponin complex), highlighting the value of our approach for interrogating the structures of cardiac proteins in their cellular context.

Functional imaging studies of acute administration of classic psychedelics, ketamine, and MDMA: Methodological limitations and convergent results.

Functional magnetic resonance imaging (fMRI) is increasingly used to non-invasively study the acute impact of psychedelics on the human brain. While fMRI is a promising tool for measuring brain function in response to psychedelics, it also has known methodological challenges. We conducted a systematic review of fMRI studies examining acute responses to experimentally administered psychedelics in order to identify convergent findings and characterize heterogeneity in the literature. We reviewed 91 full-text papers; these studies were notable for substantial heterogeneity in design, task, dosage, drug timing, and statistical approach. Data recycling was common, with 51 unique samples across 91 studies. Fifty-seven studies (54%) did not meet contemporary standards for Type I error correction or control of motion artifact. Psilocybin and LSD were consistently reported to moderate the connectivity architecture of the sensorimotor-association cortical axis. Studies also consistently reported that ketamine administration increased activation in the dorsomedial prefrontal cortex. Moving forward, use of best practices such as pre-registration, standardized image processing and statistical testing, and data sharing will be important in this rapidly developing field.

Identification of multivariable microRNA and clinical biomarker panels to predict imatinib response in chronic myeloid leukemia at diagnosis.

Imatinib Mesylate (imatinib) was once hailed as the magic bullet for chronic myeloid leukemia (CML) and remains a front-line therapy for CML to this day alongside other tyrosine kinase inhibitors (TKIs). However, TKI treatments are rarely curative and patients are often required to receive life-long treatment or otherwise risk relapse. Thus, there is a growing interest in identifying biomarkers in patients which can predict TKI response upon diagnosis. In this study, we analyze clinical data and differentially expressed miRNAs in CD34+ CML cells from 80 patients at diagnosis who were later classified as imatinib-responders or imatinib-nonresponders. A Cox Proportional Hazard (CoxPH) analysis identified 16 miRNAs that were associated with imatinib nonresponse and differentially expressed in these patients. We also trained a machine learning model with different combinations of the 16 miRNAs with and without clinical parameters and identified a panel with high predictive performance based on area-under-curve values of receiver-operating-characteristic and precision-recall curves. Interestingly, the multivariable panel consisting of both miRNAs and clinical features performed better than either miRNA or clinical panels alone. Thus, our findings may inform future studies on predictive biomarkers and serve as a tool to develop more optimized treatment plans for CML patients in the clinic.

No Difference in Surgical Outcomes between Stand-Alone Devices and Anterior Plating for 1-2 level Anterior Cervical Discectomy and Fusion: A 1:1 Exact Matched Analysis.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: Compare rates of all-cause surgical and medical complications between zero-profile (stand-alone) implants versus any graft type with anterior plate in patients undergoing 1-2 level anterior cervical discectomy and fusion (ACDF) for treatment of degenerative cervical myeloradiculopathy. SUMMARY OF BACKGROUND DATA: Degenerative cervical myeloradiculopathy is increasingly prevalent in older adults. ACDF is a common surgical procedure for decompression of neural structures and stabilization and has been shown to have excellent outcomes. While ACDFs performed with a graft and plate has been the gold standard, more recently, zero-profile implants were developed to decrease implant related complications, such as severe postoperative dysphagia. However, there is a paucity of papers comparing the surgical and medical complications profile of zero-profile (stand-alone) implants to grafts with plating systems. METHODS: Data was extracted from the PearlDiver Mariner Database using CPT codes to classify patients into 1-level, 2-levels, and total 1-2 level ACDFs. Patients undergoing surgery for non-degenerative pathologies such as tumors, trauma, or infection were excluded. RESULTS: 1:1 exact matching created two equal groups of 7,284 patients that underwent 1-2 level ACDF with either grafting with a plate or zero-profile (standalone) implant. There were no statistically significant difference in all-cause surgical complications, pseudarthrosis rate, dysphagia or need for revision surgery between both cohorts (RR 0.99, 95% CI 0.80-1.21, P = 0.95). Additionally, all-cause medical complications were similar between both cohorts (RR 1.07, 95% CI 0.862-1.330, P = 0.573) or any specific surgical or medical complication included in this study. CONCLUSION: After 1:1 exact matching, the results of this study suggest that zero-profile (stand-alone) implants have similar outcomes compared to grafts with plating systems, with no observed differences in all-cause surgical or medical complications profile.