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.

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.

Robotic, laparoscopic and open surgery for gallbladder cancer: a systematic review and network meta-analysis.

INTRODUCTION: Minimally invasive oncological resections have become increasingly widespread in the surgical management of cancers. However, the role of minimally invasive surgery (MIS) for gallbladder cancer (GBC) remains unclear. We aim to perform a systematic review and network meta-analysis of existing literature to evaluate the safety and feasibility of laparoscopic and robotic surgery in the management of GBC compared to open surgery (OS) by comparing outcomes. METHODS: A literature search of the PubMed/MEDLINE (2000 to December 2021) and EMBASE (2000 to December 2021) databases was conducted. The primary outcome studied was overall survival, and secondary outcomes studied were postoperative morbidity, severe complications, incidence of bile leak, length of hospital stay, operation time, R0 resection rate, local recurrence and lymph node yield. RESULTS: Thirty-two full-text articles met the eligibility criteria and were included in the final analysis with a total of 5883 patients undergoing either OS or MIS (laparoscopic or robotic) for GBC. 1- and 2-stage meta-analyses did not reveal any significant differences between OS, laparoscopic and robotic surgery in terms of overall survival, R0 resection, lymph node harvest, local recurrence and post-operative complications. Patients who underwent OS had significantly longer hospitalization stay and intra-operative blood loss compared to those who underwent laparoscopic or robotic surgery. Network meta-analysis did not reveal any significant differences between post-operative and survival outcomes of laparoscopic vs robotic surgery groups. CONCLUSION: This network meta-analysis suggests that both laparoscopic and robotic surgery are safe and effective approaches in the surgical management of GBC, with post-operative and survival outcomes comparable to OS. An MIS approach may also lead to shorter hospitalization stay, less intraoperative blood loss and post-operative complications compared to OS. There was no obvious benefit of either MIS approach (laparoscopic versus robotic) over the other.

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.

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.

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.

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.

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.

Systematic Review and Meta-Analysis of the Outcomes After Hepatic Artery Reconstruction in Pediatric Liver Transplantation Using a Microscope Versus Surgical Loupe.

BACKGROUND: To review the impact of the operating microscope (OM) for reconstruction of the hepatic artery (HA) by comparing the outcomes with standard loupe reconstruction (SL) in pediatric liver transplantation (LT). METHODS: Studies comparing the application of OM and SL for the reconstruction of the HA in primary pediatric LT were included from a systematic search of MEDLINE, Cochrane Library and EMBASE from inception to June 2022. Re-transplantation, dual grafts and auxiliary transplants were excluded. Primary outcome was the rate of HA thrombosis (HAT). Secondary outcomes were graft loss and mortality. RESULTS: There were 1261 liver recipients from 9 included studies published until June 2022. There were 484 patients in the OM group and 777 patients in the SL group. HAT incidence with OM was significantly lower with OR = 0.18 (95% CI: 0.07-0.48). The 1-year graft survival was significantly better in the OM group with OR = 2.77 (95% CI: 1.13-6.80). 1-year overall mortality was also significantly lower with OM with OR = 0.39 (0.18-0.86). The use of OM did not significantly impact the incidence of HAT in the living donor liver transplant subgroup. Differences in time for hepatic HA reconstruction, total operating time and length of hospital stay did not reach statistical significance. CONCLUSION: The use of OM has reduced the risk of HAT, graft loss and mortality in pediatric liver transplantation. Adoption of microsurgical principles in general may have contributed to the improved outcomes with SL reconstruction of HA in pediatric LT.

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.

No Difference in Short-Term Surgical Outcomes from Semaglutide Treatment for Type 2 Diabetes Mellitus after Cervical Decompression and Fusion: A Propensity Score-Matched Analysis.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To evaluate the impact of semaglutide treatment for Type 2 Diabetes Mellitus (T2DM) on the risk of short-term (<6 months) postoperative complications in patients undergoing primary cervical spine decompression and fusion (CSDF). SUMMARY OF BACKGROUND DATA: Semaglutide, a GLP-1 receptor agonist, is gaining popularity as a weekly injectable medication for the treatment of T2DM and obesity. Existing research indicates that higher levels of HbA1c and obesity are linked to fewer positive results after undergoing spine surgery, particularly cervical decompression and fusion. Nevertheless, there is a scarcity of publications evaluating the influence of semaglutide therapy on surgical complications, including surgical site infection, wound complications, and reoperation within 6 months, which were aggregated into a composite measure. METHODS: The PearlDiver Database was queried from January 2010 to December 2021 for patients with a primary diagnosis of T2DM who underwent CSDF for degenerative pathology. Patients with semaglutide treatment within 6 months before index surgery were propensity score-matched to patients without the treatment, employing age, gender, and Charlson comorbidity index (CCI) as matching covariates. A multivariate regression model was used to investigate the impact of semaglutide treatment on postoperative surgical complications. RESULTS: The propensity score-matched cohort included 596 patients (semaglutide cohort: 298, control cohort: 298). There were no statistically significant differences between cohorts in the composite measure of postoperative surgical complications following index CSDF (OR 1.26, 95% CI 0.83-1.93, P=0.331). Similarly, both 30-day (OR 0.83, 95% CI 0.49-1.42, P=0.589) and 90-day readmission rate (OR 0.89, 95% CI 0.56-1.42, P=0.724) were similar between both cohorts. CONCLUSION: This study suggests that in patients with T2DM, semaglutide treatment is not associated with higher rates of short-term adverse events after CSDF. The effect of semaglutide use on long-term outcomes remains unknown.

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.

Dexmedetomidine directly binds to and inhibits Toll-like receptor 4.

BACKGROUND: While a number of anesthetics has been shown potentially associated with neurotoxicity in the developing brain, dexmedetomidine, a drug that was rather recently introduced into the perioperative setting, is considered beneficial from neurological wellbeing. However, the underlying mechanism of how dexmedetomidine affects brain health remains to be determined. Based on our recent study, we hypothesized that dexmedetomidine would directly bind to and inhibit Toll-like receptor 4 (TLR4), a critical receptor largely expressed in microglia and responsible for neurological insult. METHODS: We used TLR4 reporter assays to test if dexmedetomidine attenuates TLR4 activation. Furthermore, a direct binding of dexmedetomidine on TLR4 was tested using photoactivatable medetomidine. Lastly, the effect of dexmedetomidine on ketamine (anesthetic)-induced neurotoxicity was tested in rat pups (P7). RESULTS: We showed that dexmedetomidine attenuated TLR4 activation using reporter assay (IC50 = 5.8 µg/mL). Photoactivatable dexmedetomidine delineated its direct binding sites on TLR4. We also showed that dexmedetomidine attenuated microglia activation both in vitro and in vivo. DISCUSSION: We proposed a novel mechanism of dexmedetomidine-mediated neuroprotection.

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.

Open source approaches for pediatric global health technologies.

Access to medical technologies is a critical component of universal access to care; however, the advancement of technologies for children has historically lagged behind those for adults. The small market size, anatomic and physiologic variability, and legal and ethical implications pose unique barriers to developing and commercialising paediatric biomedical innovations. These challenges are magnified in low-resource settings (LRS), which often lack appropriate regulatory oversight, support for service contracts, and supply chain capacity. The COVID-19 pandemic exposed shortcomings in the traditional industry model for medical technologies, while also catalysing open-source approaches to technology development and dissemination. Open-source pathways - where products are freely licenced to be distributed and modified - addressed key shortages in critical equipment. Relatedly, we argue that open-source approaches can accelerate paediatric global health technology development. Open-source approaches can be tailored to clinical challenges independent of economic factors, embrace low-cost manufacturing techniques, and can be highly customisable. Furthermore, diverse stakeholders, including families and patients, are empowered to participate in collaborative communities of practice. How to regulate the development, manufacture, and distribution of open-source technologies remains an ongoing area of exploration. The need for democratised innovation must be carefully balanced against the imperatives of safety and quality for paediatric-specific solutions. This can be achieved, in part, through close coordination between national regulatory agencies and decentralised networks where products can be peer-reviewed and tested. Altogether, there is significant potential for open source to advance more equitable and sustainable medical innovations for all children.