Development and validation of multivariable predictive models for recurrence and mortality following nonoperative management of sigmoid volvulus.

AIM: Sigmoid volvulus is a challenging condition, and deciding between elective surgery or expectant management can be complex. The aim of this study was to develop a tool for predicting the risk of recurrent sigmoid volvulus and all-cause mortality within 1 year following initial nonoperative management. METHOD: This is a retrospective cohort study using Medicare claims data from 2016 to 2018 of beneficiaries admitted urgently/emergently for volvulus, undergoing colonic decompression and discharged alive without surgery (excluding those discharged to hospice). The primary outcomes were recurrent sigmoid volvulus and all-cause mortality within 1 year. Proportional hazards models and logistic regression were employed to identify risk factors and develop prediction equations, which were subsequently validated. RESULTS: Among the 2078 patients managed nonoperatively, 36.1% experienced recurrent sigmoid volvulus and 28.6% died within 1 year. The prediction model for recurrence integrated age, sex, race, palliative care consultations and four comorbidities, achieving area under the curve values of 0.63 in both the training and testing samples. The model for mortality incorporated age, palliative care consultations and nine comorbidities, with area under the curve values of 0.76 in the training and 0.70 in the testing sample. CONCLUSION: This study provides a straightforward predictive tool that utilizes easily accessible data to estimate individualized risks of recurrent sigmoid volvulus and all-cause mortality for older adults initially managed nonoperatively. The tool can assist clinicians and patients in making informed decisions about such risks. While the accuracy of the calculator was validated, further confirmation through external validation and prospective studies would enhance its clinical utility.

Occurrence of glycidyl esters in infant formula products on the Canadian market between 2015 and 2019.

Glycidyl fatty acid esters (GEs) are processing contaminants formed during refining steps of vegetable oils. 'In vivo' hydrolysis of GEs releases potentially carcinogenic and genotoxic glycidol (2,3-epoxy-1-propanol). Occurrence of GEs in vegetable oils used for infant formula manufacturing may pose a potential health concern for formula-fed infants. Refined oils are commonly used as the main fat ingredient in formula manufacturing. For this study, different infant formula products (powders, concentrates and ready-to-feed formula products) were purchased and analysed in 2015 (35 samples) and 2019 (33 samples). Seven individual GEs were analysed by LC-MS/MS via direct approach by stable isotope dilution analysis, and total bound glycidol concentrations were calculated. Concentrations of bound glycidol in reconstituted formula reached maxima of 40.3 ng/g in the 2015 samples and 31.5 ng/g in the samples collected in 2019, with respective means of 8.7 ng/g and 6.7 ng/g. The analysed bound glycidol concentrations are comparable with concentration ranges from other studies, but are higher than observed in studies from the European market. Temporal trend data show a reduction of bound glycidol concentrations in 2019. GE concentrations were compared across different manufacturers.

Occurrence of 2- and 3-monochloropropanediol esters (MCPDE) in infant formula products on the Canadian market between 2015 and 2019.

2- and 3-monochloropropanediol esters (MCPDEs) are most commonly formed as process-induced contaminants during the refinement of vegetable oils used for food production. 'In vivo' hydrolysis of 3-MCPDEs releases the potential carcinogen 3-monochloropropanediol (3-MCPD). Levels of MCPDEs in infant formula are of particular concern, as refined oils are commonly used as main fat ingredients. For this study, infant formula samples (powders, liquid concentrates and ready-to-feed infant formula samples) from the Canadian market were purchased and analysed in 2015 (35 samples) and 2019 (33 samples). MCPDE concentrations (expressed as free MCPD equivalents) were examined through an indirect analytical approach, applying acid-catalysed ester cleavage and using cyclohexanone as derivatising agent. Labelled diesters were used as internal standards. 2015 Survey data were analysed by gas chromatography-mass spectrometry (GC-MS) in selected ion monitoring mode (SIM). 2019 Survey data were analysed with an updated method using GC-MS/MS in multiple reaction monitoring modes (MRM). In 2015, levels in reconstituted formula ranging from 3.7 ng/g to 111 ng/g for 3-MCPD and 2.2 ng/g to 56.2 ng/g for 2-MCPD were found. In 2019, levels ranging from 3.9 ng/g to 74.8 ng/g for 3-MCPD and 1.0 ng/g to 33.9 ng/g for 2-MCPD were found. A significantly reduced mean of combined MCPDEs was observed between 2015 and 2019 data (64.5 ng/g, standard deviation (SD) 8.6 ng/g in 2015 to 31.8 ng/g, SD 5.6 ng/g in 2019, p-value = 0.024). For the majority of manufacturers, the data comparison among brand products over time shows decreased levels of MCPDEs. Occurrence data of MCPDEs, including data from previously published surveys (2012/2013), were also compared and a temporal trend was established.

Assessing the Magnitude of Immunogenic Cell Death Following Chemotherapy and Irradiation Reveals a New Strategy to Treat Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) continues to have a dismal prognosis, in part, due to ineffective treatment strategies. The efficacy of some chemotherapies and especially radiotherapy is mediated partially by the immune system. Therefore, we hypothesized that profiling the immune response following chemotherapy and/or irradiation can be used as a readout for treatment efficacy but also to help identify optimal therapeutic schedules for PDAC. Using murine models of PDAC, we demonstrated that concurrent administration of stereotactic body radiotherapy (SBRT) and a modified dose of FOLFIRINOX (mFX) resulted in superior tumor control when compared with single or sequential treatment groups. Importantly, this combined treatment schedule enhanced the magnitude of immunogenic cell death, which in turn amplified tumor antigen presentation by dendritic cells and intratumoral CD8+ T-cell infiltration. Concurrent therapy also resulted in systemic immunity contributing to the control of established metastases. These findings provide a rationale for pursuing concurrent treatment schedules of SBRT with mFX in PDAC.

Stereotactic Body Radiation and Interleukin-12 Combination Therapy Eradicates Pancreatic Tumors by Repolarizing the Immune Microenvironment.

Over 80% of pancreatic ductal adenocarcinoma (PDA) patients are diagnosed with non-resectable late-stage disease that lacks effective neoadjuvant therapies. Stereotactic body radiation therapy (SBRT) has shown promise as an emerging neoadjuvant approach for treating PDA, and here, we report that its combination with local interleukin-12 (IL-12) microsphere (MS) immunotherapy results in marked tumor reduction and cures in multiple preclinical mouse models of PDA. Our findings demonstrate an increase of intratumoral interferon gamma (IFNγ) production following SBRT/IL-12 MS administration that initiates suppressor cell reprogramming and a subsequent increase in CD8 T cell activation. Furthermore, SBRT/IL-12 MS therapy results in the generation of systemic tumor immunity that is capable of eliminating established liver metastases, providing a rationale for follow-up studies in advanced metastatic disease.

An investigation of presence of 2- and 3-monochloropropanediol fatty acid esters in Canadian human milk samples.

Occurrence of 2- and 3-monochloropropanediol fatty acid esters (MCPDEs) in 199 human milk samples collected from Canadian women was examined in this study. MCPDEs were determined via indirect analytical approach by using acidic hydrolysis/transesterification and derivatization with cyclohexanone using a fluorinated sulfonic acid resin as a catalyst followed by GC-MS analysis. Analyses were done by a stable isotope dilution assay (SIDA) using 3-monochloropropanediol-d5 dipalmitate and 2-monochloropropanediol-d5 distearate as internal standards. In all samples 2-MCPD esters were not detected, at LOD = 1 ng/g for 2-MCPD equivalent. 3-MCPD esters were not detected, at LOD = 2 ng/g for 3-MCPD equivalent, in 193 samples. Six samples had the apparent concentration of 3-MCPD equivalent in the range of 2.0-5.1 ng/g, which was likely caused by accidental contamination during processing of samples. For selected samples, these findings were confirmed by direct analysis via LC-MS/MS analysis based on SIDA for 3-MCPD dipalmitate and 2-MCPD distearate. To our best knowledge, this is the first study to analyze human milk samples for 2-MCPD esters.

2- and 3-Monochloropropanediols in paper products and their transfer to foods.

The occurrence of 2- and 3-monochloropropanediol (MCPDs) in selected paper products sold on the Canadian market and the transfer of 3-MCPD from those products to beverages was probed. Products included coffee filters, tea bags, disposable paper hot beverage cups and milk packaged in paperboard containers. The occurrence MCPDs in coffee and tea filters on the German market was investigated as well. Furthermore, the presence of MCPDs in paper towels on the German market was also investigated. Analytes were determined by stable isotope dilution analysis GC-MS in SIM mode. 3-MCPD was detected in most paper products with levels ranging from a few nanograms in tea bags to a few micrograms in white coffee filters. Milk containers' paperboard contained 3-MCPD at about 500-1500 ng g(-1); however, 3-MCPD was detected in milk only in smaller containers, 237-500 ml (likely due to a lower volume/surface ratio) at levels of about 1 ng g(-1). Out of three disposable hot beverage paper cups tested (of 237-473 ml capacity), paperboard of two contained 3-MCPD at 632-792 ng g(-1), and 3-MCPD was detected in leachate from those paper cups at levels of about 16 ng per cup. 3-MCPD was detected in all paper towels at levels of 42-2466 ng g(-1). 2-MCPD was detected in many paper products (from Canadian and German sources) and in all the towels tested at levels varying from about 0.5-10% of that of 3-MCPD.

Stereoselective synthesis of 1,4-diols by a tandem allylboration-allenylboration sequence.

The reaction of mono- and dialdehydes with bis-borodienes (incorporating an allylboronate unit) has been studied. It was found that the initial allylboration reaction results in an allenylboronate, which has two stereogenic units: one of them has axial chirality and the other one is a stereogenic carbon center. This reaction proceeds with high diastereoselectivity. The allenylboronate formed in the allylboration reacts with an additional aldehyde with fair to high stereoselectivity depending on the aldehyde substrate. Aromatic dialdehydes react with bis-boro-butadienes creating three new stereocenters with usually high diastereoselectivity.

Borylation of propargylic substrates by bimetallic catalysis. Synthesis of allenyl, propargylic, and butadienyl Bpin derivatives.

Bimetallic Pd/Cu and Pd/Ag catalytic systems were used for borylation of propargylic alcohol derivatives. The substrate scope includes even terminal alkynes. The reactions proceed stererospecifically with formal SN2' pathways to give allenyl boronates. Opening of propargyl epoxides leads to 1,2-diborylated butadienes probably via en allenylboronate intermediate.

Trifluoromethylation of propargylic halides and trifluoroacetates using (Ph3P)3Cu(CF3) reagent.

A copper-mediated trifluoromethylation of propargylic halides and trifluoroacetates was performed with high allenyl or propargyl selectivity. The reaction proceeds smoothly with aliphatic and aromatic substituents bearing either electron-withdrawing or -supplying groups. Preliminary mechanistic results indicate an ionic mechanism involving nucleophilic transfer of the CF(3) group from the Cu complex to the propargylic substrate.

Palladium-catalyzed oxidative allylic C-H silylation.

Palladium-catalyzed allylic C-H silylation was performed with use of hexamethyldisilane as the silyl source. These C-H functionalization reactions occur only in the presence of hypervalent iodine reagents or other strong oxidants and proceed with excellent regioselectivity, providing the linear allylic isomer of the allylsilane products. In demonstrating the first oxidative allylic C-H silylation of alkenes, this study marks an important advance for the catalytic C-H functionalization method.