Management of esophageal anastomotic leaks, a systematic review and network meta-analysis.

There is currently no consensus as to how to manage esophageal anastomotic leaks. Intervention with endoscopic vacuum-assisted closure (EVAC), stenting, reoperation, and conservative management have all been mooted as potential options. To conduct a systematic review and network meta-analysis (NMA) to evaluate the optimal management strategy for esophageal anastomotic leaks. A systematic review was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines with extension for NMA. NMA was performed using R packages and Shiny. In total, 12 retrospective studies were included, which included 511 patients. Of the 449 patients for whom data regarding sex was available, 371 (82.6%) were male, 78 (17.4%) were female. The average age of patients was 62.6 years (standard deviation 10.2). The stenting cohort included 245 (47.9%) patients. The EVAC cohort included 123 (24.1%) patients. The conservative cohort included 87 (17.0%) patients. The reoperation cohort included 56 (10.9%) patients. EVAC had a significantly decreased complication rate compared to stenting (odds ratio 0.23 95%, confidence interval [CI] 0.09;0.58). EVAC had a significantly lower mortality rate than stenting (odds ratio 0.43, 95% CI 0.21; 0.87). Reoperation was used in significantly larger leaks than stenting (mean difference 14.66, 95% CI 4.61;24.70). The growing use of EVAC as a first-line intervention in esophageal anastomotic leaks should continue given its proven effectiveness and significant reduction in both complication and mortality rates. Surgical management is often necessary for significantly larger leaks and will likely remain an effective option in uncontained leaks with systemic features.

Anomalous origin of the left circumflex coronary artery: is surgery required? A case report.

Background: Deviations from usual coronary artery anatomy are well documented. The left circumflex artery (LCx) arising from the pulmonary artery is an example of one such deviation which is rarely seen. We present the case of a 26-year-old male with this coronary artery distribution presenting with an episode of ventricular flutter with late gadolinium enhancement and pluri-morphological ventricular arrhythmias. Case summary: A 26-year-old male with a history of cardiac surgery presented to his local hospital with an episode of symptomatic broad-complex tachycardia (BCT). It failed to revert to sinus rhythm following intravenous beta-blockers and amiodarone and required external cardioversion. Subsequently, the patient developed a aspiration pneumonia requiring ICU admission, after which he was transferred to our institute for ongoing cardiac management. Cardiac computed tomography CTA and coronary angiography revealed that the LCx was found to originate from the pulmonary artery. He underwent insertion of a subcutaneous pacemaker and was subsequently discharged. Despite the potential for steal syndrome of viable coronary territories. Multidisciplinary team discussion determined him to be fit for conservative management and not for surgical correction of his anomalous coronary artery anatomy. Discussion: Aberrant coronary artery anatomy can lead to diverse outcomes for patients in terms of both morbidity and mortality. The need for surgery in these situations varies on a case-by-case basis and little research exists to guide decision-making for healthcare professionals. As such there is a need for further study both to guide treatment and to ensure high-quality outcomes for patients with this condition.

A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review.

BACKGROUND: Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It is typically molecularly characterised by a WWTR1::CAMTA1 gene fusion in approximately 90% of cases, or a YAP1::TFE3 gene fusion in approximately 10% of cases. EHE cases are typically refractory to therapies, and no anticancer agents are reimbursed for EHE in Australia. METHODS: We report a cohort of nine EHE cases with comprehensive histologic and molecular profiling from the Walter and Eliza Hall Institute of Medical Research Stafford Fox Rare Cancer Program (WEHI-SFRCP) collated via nation-wide referral to the Australian Rare Cancer (ARC) Portal. The diagnoses of EHE were confirmed by histopathological and immunohistochemical (IHC) examination. Molecular profiling was performed using the TruSight Oncology 500 assay, the TruSight RNA fusion panel, whole genome sequencing (WGS), or whole exome sequencing (WES). RESULTS: Molecular analysis of RNA, DNA or both was possible in seven of nine cases. The WWTR1::CAMTA1 fusion was identified in five cases. The YAP1::TFE3 fusion was identified in one case, demonstrating unique morphology compared to cases with the more common WWTR1::CAMTA1 fusion. All tumours expressed typical endothelial markers CD31, ERG, and CD34 and were negative for pan-cytokeratin. Cases with a WWTR1::CAMTA1 fusion displayed high expression of CAMTA1 and the single case with a YAP1::TFE3 fusion displayed high expression of TFE3. Survival was highly variable and unrelated to molecular profile. CONCLUSIONS: This cohort of EHE cases provides molecular and histopathological characterisation and matching clinical information that emphasises the molecular patterns and variable clinical outcomes and adds to our knowledge of this ultra-rare cancer. Such information from multiple studies will advance our understanding, potentially improving treatment options.

Integrating Functional Imaging and Molecular Profiling for Optimal Treatment Selection in Neuroendocrine Neoplasms (NEN).

PURPOSE OF REVIEW: Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. RECENT FINDINGS: In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation.

Spatial Control of Substitutional Dopants in Hexagonal Monolayer WS2 : The Effect of Edge Termination.

The ability to control the density and spatial distribution of substitutional dopants in semiconductors is crucial for achieving desired physicochemical properties. Substitutional doping with adjustable doping levels has been previously demonstrated in 2D transition metal dichalcogenides (TMDs); however, the spatial control of dopant distribution remains an open field. In this work, edge termination is demonstrated as an important characteristic of 2D TMD monocrystals that affects the distribution of substitutional dopants. Particularly, in chemical vapor deposition (CVD)-grown monolayer WS2 , it is found that a higher density of transition metal dopants is always incorporated in sulfur-terminated domains when compared to tungsten-terminated domains. Two representative examples demonstrate this spatial distribution control, including hexagonal iron- and vanadium-doped WS2 monolayers. Density functional theory (DFT) calculations are further performed, indicating that the edge-dependent dopant distribution is due to a strong binding of tungsten atoms at tungsten-zigzag edges, resulting in the formation of open sites at sulfur-zigzag edges that enable preferential dopant incorporation. Based on these results, it is envisioned that edge termination in crystalline TMD monolayers can be utilized as a novel and effective knob for engineering the spatial distribution of substitutional dopants, leading to in-plane hetero-/multi-junctions that display fascinating electronic, optoelectronic, and magnetic properties.

Citrate-based fluorometric sensor for multi-halide sensing.

Halides play important roles in human health and environmental monitoring. However, different halides interfere with each other in current measurement methods. Simultaneous sensing of multiple halides in a fast and low-cost manner remains a challenge. Here, we report a fluorometric multi-halide sensing method by using a single citrate-based fluorophore, CA-Cys, on a custom-made portable device. The fluorescence emitted by CA-Cys is quenched due to the dynamic quenching of halide ions; the sensitivities vary from halide types and pH, providing the capability to obtain multiple Stern-Volmer equations at various pH values. The concentration of each halide can then be obtained by solving the resultant set of equations. A mM scale detection limit is demonstrated, which is suitable for halide wastewater monitoring. A proof-of-concept smartphone-based portable device is also fabricated and tested. The results from the fluorometer and portable device indicated that our multi-halide system is promising for real-world multi-halide sensing applications. This work represents a new direction in developing portable, low-cost, and simultaneous multi-halide sensing technologies.

The Military Treatment Facility COVID-19 Response in an Isolated Rural Environment: Challenges and Lessons Learned.

The coronavirus disease-2019 (COVID-19) pandemic remains an extraordinary event that continues to strain healthcare systems worldwide. Unlike the military treatment facilities (MTFs) in the USA, which have ready access to tertiary care facilities, those MTFs in foreign countries confront a host of challenges in meeting mission requirements. In this article, we discuss the MTFs' COVID-19 response in the rural environment of Bavaria, Germany. Relevant factors including regional and clinic response, force health protection, and contingency planning, which influenced the MTFs response, are identified. These factors are further analyzed from a "lessons learned" perspective, and recommendations to shape the future response to a pandemic are provided. This current crisis portends a future where pandemics may remain an omnipresent threat.

Nursing Leadership During COVID-19: Leading an Inpatient Response at a Regional Military Medical Center.

The coronavirus disease 2019 pandemic stressed healthcare systems worldwide and exposed major flaws in military and civilian healthcare systems. Landstuhl Regional Medical Center (LRMC) serves as the only military medical center for over 205,000 U.S. service members, beneficiaries, and coalition partners stationed throughout Europe, Africa, and the Middle East. The pandemic response required LRMC leaders to reconfigure services to meet pandemic concerns while providing lifesaving care to injured service members from combatant commands. The quickly evolving pandemic challenged leaders to ensure healthcare delivery amid constant change and imperfect information. While LRMC senior leaders developed a strategic pandemic response plan, a multidisciplinary team of nurses, doctors, and technicians collaborated to create an inpatient team to support the dual mission of coronavirus disease 2019 response and casualty care for the warfighter. In this manuscript, we discuss how a multidisciplinary clinical working group at a regional medical center prepared and responded to the pandemic, strategically planned patient care, and ensured support to combatant commands for ongoing forward military operations. Additionally, we share our experiences and lessons learned to inform other military facilities across the medical community and global healthcare systems.

Intraperitoneal vancomycin for peritoneal dialysis-associated peritonitis in children: Evaluation of loading dose guidelines.

BACKGROUND: Current pediatric International Society for Peritoneal Dialysis guidelines for initial treatment of peritoneal dialysis (PD)-associated peritonitis suggest either monotherapy with cefepime or double therapy with first-generation cephalosporin or glycopeptide and ceftazidime or aminoglycoside. When using vancomycin, the intraperitoneal (IP) recommended pediatric loading dosage is 1000 mg/L of dialysate. This is based on adult pharmacokinetic (PK) studies and roughly translates to the adult recommendation where 30 mg/kg in 2 L is approximately 1000 mg/L. However, since the dialysate volume in pediatric patients is normalized to body surface area and not weight, the current recommended dosing can result in high vancomycin exposure in children. Vancomycin can potentially cause adverse effects. We aimed to determine if the IP vancomycin dosing of 1000 mg/L was causing elevated vancomycin levels and to offer possible dosing recommendations based on PK modeling and simulation. METHODS: Retrospective review of pediatric patients who had been treated with IP vancomycin for PD-associated peritonitis. Vancomycin levels obtained for clinical monitoring were analyzed using NONMEM to generate population and individual (empiric Bayesian) estimates of vancomycin PK parameters and estimated peak levels. Predicted vancomycin peaks were also simulated from virtual pediatrics patients 3-70 kg following various dosing strategies. RESULTS: Six episodes of peritonitis in three patients were analyzed. In the two episodes treated with 1000 mg/L, the first vancomycin levels (h post) were 95.6 ug/mL (3) and 49 (33) and following 500 mg/L were 33.2 (11), 30.2 (11), 23.6 (24), and 22.1 (11). All patients were cured of their peritonitis without the need for catheter removal. Based on our population PK model, a 1000 mg/L IP vancomycin loading dose will typically result in peak > 50 mg/L in patients weighing <35 kg and >60 mg/L in patients <15 kg. Vancomycin levels will remain above 20 mg/L for over 2 days without additional vancomycin dosing. CONCLUSION: The data suggest that a loading dose of vancomycin 1000 mg/L leads to higher than desired vancomycin levels and should be lowered. A 500 mg/L loading dosing appears more appropriate and needs further study.

Organic redox-active crystalline layers for reagent-free electrochemical antibiotic susceptibility testing (ORACLE-AST).

Rapid antibiotic susceptibility testing (AST) is critical in determining bacterial resistance or susceptibility to a particular antibiotic. Simple-to-use phenotype-based AST platforms can assist care-givers in timely prescription of the right antibiotic. Monitoring the change of bacterial viability by measuring electrochemical Faradaic current is a promising approach for rapid AST. However, the existing works require mixing redox-active reagents in the solution which can interfere with the antibiotics. In this paper, we developed a facile electrodeposition process for creating a redox-active crystalline layer (denoted as RZx) on pyrolytic graphite sheets (PGS), which was then utilized as the sensing layer for reagent-free electrochemical AST. To demonstrate the proof-of-principle, we tested the sensors with Escherichia coli (E. coli) K-12 treated with two antibiotics, ampicillin and kanamycin. While the sensors enable detection of bacterial metabolism mainly due to pH-sensitivity of RZx (∼ 53 mV/pH), secreted redox-active metabolites/compounds from whole cells are likely contributing to the signal as well. By monitoring the differential voltammetric signals, the sensors enable accurate prediction of the minimum inhibitory concentration (MIC) in 60 min (p < 0.03). The sensors are stable after 60 days storage in ambient conditions and enable analysis of microbial viability in complex solutions, as demonstrated in spiked milk and human whole blood.

Results of phase II trial of intensified neoadjuvant treatment with interdigitating radiotherapy and chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid in patients with locally advanced rectal cancer (PROARCT trial).

BACKGROUND AND PURPOSE: The chemotherapy exposure during chemoradiotherapy for rectal cancer is adequate for radiosensitization but suboptimal for treatment of distant micrometastasis. This study aimed to determine tolerability, dose intensity, response, and toxicity of a novel intensified neoadjuvant treatment approach. MATERIALS AND METHODS: Eligible patients were MRI-staged T3-4NxM0 rectal adenocarcinoma. Treatment consisted of FOLFOX chemotherapy given in weeks 1, 6, and 11 with pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fraction with oxaliplatin and 5-FU continuous infusion) given in weeks 3-5, and weeks 8-10. Surgery was performed 4-6 weeks later. The primary endpoint was tolerability defined as the percentage of patients who were able to complete the planned treatment course. Survival rates were estimated using the Kaplan-Meier method. RESULTS: Median age of the 40 patients was 61.5 years. Rectal MRI-stage was T3 in 88%. Overall, 95% completed the regimen. All patients received 50.4 Gy. Relative dose intensity (≥75%) was 92% and 98% for oxaliplatin and 5-FU, respectively. High grade toxicities included neutropenia (25% grade 3; 7.5% grade 4) and diarrhoea (10%). Pathologic CR rate was 20%. Median follow-up was 54 months. The 5-year overall survival, freedom from relapse, locoregional control, and freedom from distant metastasis of the cohort was 82%, 72%, 97% and 72%. CONCLUSIONS: Delivery of intensified neoadjuvant treatment with interdigitating chemotherapy and radiotherapy is feasible with no increase in acute perioperative complications. A larger prospective study is required to further evaluate the potential survival benefit of this design.

Discovery of PEGylated 6-Benzhydryl-4-amino-quinazolines as Peripherally Restricted CB1R Inverse Agonists.

The 6-benzhydryl-4-amino-quinolin-2-ones are peripherally restricted CB1 receptor inverse agonists (CB1RIAs) that have been reported to attenuate obesity and improve insulin sensitivity in the diet-induced obese (DIO) mouse model. However, chronic dosing of select compounds from the series showed time-dependent brain accumulation despite a low brain/plasma exposure ratio. To address this issue, a PEGylation approach was employed to identify a novel series of homodimeric 6-benzhydryl-4-amino-quinazoline-PEG conjugates with an extended half-life. The lead compound 18 engaged peripheral CB1Rs in a gastrointestinal (GI) tract motility study and demonstrated a high level of peripheral restriction in a chronic DIO mouse pharmacokinetic study.

Selective Synthesis of Bi2Te3/WS2 Heterostructures with Strong Interlayer Coupling.

The vertical integration of atomically thin-layered materials to create van der Waals heterostructures (vdWHs) has been proposed as a method to design nanostructures with emergent properties. In this work, epitaxial Bi2Te3/WS2 vdWHs are synthesized via a two-step vapor deposition process. It is calculated that the vdWH has an indirect band gap with a valence band edge that bridges the vdW gap, resulting in a quenched photoluminescence (PL) from the WS2 monolayer, reduced intensity of its resonance Raman vibrational peaks, improved vertical charge transport, and a decrease in the intensity of second harmonic generation (SHG). Furthermore, it is observed that induced defects strongly influence the nucleation and growth of vdWHs. By creating point defects in WS2 monolayers, it is shown that the growth of Bi2Te3 platelets can be patterned. This work offers important insights into the synthesis, defect engineering, and moiré engineering of an emerging class of two-dimensional (2D) heterostructures.

RAF1 rearrangements are common in pancreatic acinar cell carcinomas.

There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.

Quantum Ensembles of Silicon Nanoparticles: Discrimination of Static and Dynamic Photoluminescence Quenching Processes.

Porous silicon photoluminescence is characterized by a broad emission band that displays unusually long (tens to hundreds of micro-seconds), wavelength-dependent emissive lifetimes. The photoluminescence is associated with quantum confinement of excitons in silicon nanocrystallites contained within the porous matrix, and the broad emission spectrum derives from the wide distribution of nanocrystallite sizes in the material. The longer emissive lifetimes in the ensemble of quantum-confined emitters correspond to the larger nanocrystallites, with their longer wavelengths of emission. The quenching of this photoluminescence by aromatic, redox-active molecules aminochrome (AMC), dopamine, adrenochrome, sodium anthraquinone-2-sulfonate, benzyl viologen dichloride, methyl viologen dichloride hydrate, and ethyl viologen dibromide is studied, and dynamic and static quenching mechanisms are distinguished by the emission lifetime analysis. Because of the dependence of the emission lifetime on emission wavelength from the silicon nanocrystallite ensemble, a pronounced blue shift is observed in the steady-state emission spectrum upon exposure to dynamic-type quenchers. Conversely, static-type quenching systems show uniform quenching across all emission wavelengths. Thus, the difference between static and dynamic quenching mechanisms is readily distinguished by ratiometric photoluminescence spectroscopy. The application of this concept to imaging of AMC, the oxidized form of the neurotransmitter dopamine that is of interest for its role in neurodegenerative diseases, is demonstrated. It is found that static electron acceptors result in no ratiometric contrast, while AMC shows a strong contrast, allowing ready visualization in a 2-D imaging experiment.

6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB1) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity.

A novel series of 6-benzhydryl-4-amino-quinolin-2-ones was discovered as cannabinoid type 1 receptor (CB1R) inverse agonists based on the high-throughput screening hit, compound 1a. Structure-activity relationships were studied to improve in vitro/in vivo pharmacology and restrict distribution to the peripheral circulation. We adopted several strategies such as increasing topological polar surface area, incorporating discrete polyethylene glycol side chains, and targeting P-glycoprotein (P-gp) to minimize access to the brain. Compound 6a is a P-gp substrate and a potent and highly selective CB1R inverse agonist, demonstrating excellent in vivo metabolic stability and a low brain to plasma ratio. However, brain receptor occupancy studies showed that compound 6a may accumulate in brain with repeat dosing. This was evidenced by compound 6a inhibiting food intake and inducing weight loss in diet-induced obese mice. Thus, a strategy based on P-gp efflux may not be adequate for peripheral restriction of the disclosed quinolinone series.

Design, synthesis and biological evaluation of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as potent and orally active SGLT dual inhibitors.

A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50 = 43 nM for SGLT1 and IC50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg.

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors.

Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors are described. Compound 19 showed high inhibitory potency at SGLT1 (IC50 = 45 nM), and excellent potency at SGLT2 (IC50 = 1 nM). It also displayed excellent PK profiles in mice, rats, dogs and monkeys (F = 78-107%). In SD rats, compound 19 treatments significantly reduced blood glucose levels in a dose-dependent manner. In ZDF rats, compound 19 displayed anti-hyperglycemic effect up to 24 h. Therefore, compound 19 may serve as valuable pharmacological tool, and potential use as a treatment for metabolic syndrome.

Discovery of N-arylpyrroles as agonists of GPR120 for the treatment of type II diabetes.

The discovery of a novel series of N-arylpyrroles as agonists of GPR120 (FFAR4) is discussed. One lead compound is a potent GPR120 agonist, has good selectivity for related receptor GPR40 (FFAR1), has acceptable PK properties, and is active in 2 models of Type 2 Diabetes in mice.