Machine Learning and Augmented Intelligence Enables Prognosis of Type 2 Diabetes Prior to Clinical Manifestation.

BACKGROUND: The global incidence of type 2 diabetes (T2D) persists at epidemic proportions. Early diagnosis and/or preventive efforts are critical to attenuate the multi-systemic clinical manifestation and consequent healthcare burden. Despite enormous strides in the understanding of pathophysiology and on-going therapeutic development, effectiveness and access are persistent limitations. Among the greatest challenges, the extensive research efforts have not promulgated reliable predictive biomarkers for early detection and risk assessment. The emerging fields of multi-omics combined with machine learning (ML) and augmented intelligence (AI) have profoundly impacted the capacity for predictive, preventive, and personalized medicine. OBJECTIVE: This paper explores the current challenges associated with the identification of predictive biomarkers for T2D and discusses potential actionable solutions for biomarker identification and validation. METHODS: The articles included were collected from PubMed queries. The selected topics of inquiry represented a wide range of themes in diabetes biomarker prediction and prognosis. RESULTS: The current criteria and cutoffs for T2D diagnosis are not optimal nor consider a myriad of contributing factors in terms of early detection. There is an opportunity to leverage AI and ML to significantly enhance the understanding of the underlying mechanisms of the disease and identify prognostic biomarkers. The innovative technologies being developed by GATC are expected to play a crucial role in this pursuit via algorithm training and validation, enabling comprehensive and in-depth analysis of complex biological systems. CONCLUSION: GATC is an emerging leader guiding the establishment of a systems approach towards research and predictive, personalized medicine. The integration of these technologies with clinical data can contribute to a more comprehensive understanding of T2D, paving the way for precision medicine approaches and improved patient outcomes.

Letter to the editor on "Antimicrobial compounds isolated from Tropaeolum tuberosum".

A bisphosphonate recently isolated from Tropaeolum tuberosum is almost certainly a contaminant and not a genuine natural product.

Exosomes; a Potential Source of Biomarkers, Therapy, and Cure for Type-1 Diabetes.

The scourge of type-1 diabetes (T1D) is the morbidity and mortality it and its complications cause at a younger age. This propels the constant search for better diagnostic, treatment, and management strategies, with the ultimate quest being a cure for T1D. Recently, the therapeutic potential of exosomes has generated a lot of interest. Among the characteristics of exosomes of particular interest are (a) their regenerative capacity, which depends on their "origin", and (b) their "content", which determines the cell communication and crosstalk they influence. Other functional capacities, including paracrine and endocrine homeostatic regulation, pathogenic response ability resulting in insulin secretory defects or ß-cell death under normal metabolic conditions, immunomodulation, and promotion of regeneration, have also garnered significant interest. Exosome "specificity" makes them suitable as biomarkers or predictors, and their "mobility" and "content" lend credence to drug delivery and therapeutic suitability. This review aims to highlight the functional capacities of exosomes and their established as well as novel contributions at various pathways in the onset and progression of T1D. The pathogenesis of T1D involves a complex crosstalk between insulin-secreting pancreatic ß-cells and immune cells, which is partially mediated by exosomes. We also examine the potential implications for type 2 diabetes (T2D), as the link in T2D has guided T1D exploration. The collective landscape presented is expected to help identify how a deeper understanding of exosomes (and their cargo) can provide a framework for actionable solutions to prevent, halt, or change the very course of T1D and its complications.

Clinical and oncological outcomes of pelvic exenteration surgery for anal squamous cell carcinoma.

AIM: Anal cancer incidence and mortality rates are rising in the United Kingdom (UK). Surgery is an important treatment modality for persistent or recurrent disease. There is a paucity of data on outcomes for patients undergoing pelvic exenteration for anal squamous cell carcinoma (SCC) for persistent or recurrent disease. The aim of this study was to investigate the outcomes for patients who were treated with pelvic exenteration for anal SCC from two high-volume, high-complexity pelvic exenteration units in the UK. METHOD: A retrospective review of prospectively maintained databases from 2011 to 2020 was undertaken. Primary endpoints included R0 resection rates, overall and disease-free survival at 2 and 5 years. RESULTS: From 2011 to 2020, 35 patients with anal SCC were selected for exenteration. An R0 resection was achieved in 26 patients (77%). Of the remaining patients, seven patients had an R1 resection and one had a R2 resection. One further patient was excluded from additional analysis as the disease was inoperable at the time of laparotomy. With a median follow-up of 19.5 months (interquartile range 7.9-53.5 months), overall survival was 50% (17/34). Patients with an R1/2 resection had a significantly poorer overall survival [0.27 (0.09-0.76), p = 0.021] than those patients in whom R0 resection was achieved. Disease-free survival was 38.2% (13/34) and an R1/R2 resection was associated with a significantly reduced disease-free survival [0.12 (0.04-0.36), p < 0.001]. CONCLUSION: Complete R0 resection for recurrent or persistent anal SCC is possible in the majority of patients and improves overall and disease-free survival compared with R1/R2 resection.

Determination of Unnecessary Blood Transfusion by Comprehensive 15-Hospital Record Review.

BACKGROUND: Although unnecessary blood component transfusions are costly and pose substantial patient risks, the extent of unnecessary blood use in a community hospital setting has not been systematically measured. METHODS: A 15-hospital observational analysis was performed using comprehensive retrospective review. Approximately 100 encounters (x¯â€¯= 103.9, standard deviation [SD] ± 7.6) per hospital (6,696 total component transfusion events) were reviewed between 2012 and 2018. Review was performed by two medical directors. Findings were supported by blind intra- and inter-reviewer double review and blind external review by 10 independent reviewers. RESULTS: Patients received an average of 4.3 (± 1.3) units. Only 8.2% (± 6.7) of patient encounters did not receive unnecessary units. Fifty-five percent (54.6% ± 13.5) could have been managed without at least one component type, while 44.6% (± 14.9) could have been managed completely without transfusion. Forty-five percent (45.4% ± 17.0) of red blood cell, 54.9% (± 19.3) of plasma-cryoprecipitate, and 38.0% (± 15.6) of plateletpheresis encounters could likely have been managed without transfusion. Between 2,713 units (40.5%) and 3,306 units (49.4%) were likely unnecessary. In patients who could have been managed without transfusion of at least one component type, unnecessary blood use was associated with a 0.38 (± 0.11)-day increase in length of hospital stay for each additional unnecessary unit received (p < 0.001). CONCLUSION: Substantial unnecessary blood use was identified, all of which was unrecognized by hospitals prior to review. Unnecessary blood use was attributed to overreliance on laboratory transfusion criteria and failure to follow common blood management principles, which resulted in potential harm to patients and avoidable cost.

Synthesis of 1-Deoxymannojirimycin from d-Fructose using the Mitsunobu Reaction.

Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, N,O-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give 14. Acidic hydrolysis affords nitrone 15, which reduces quantitatively via catalytic hydrogenolysis to afford 1-DMJ (4) in 55% overall yield from d-fructose (cf. 37% for azide route and 29% for nosyl route).

Computational discoveries of reaction mechanisms: recent highlights and emerging challenges.

This review examines some of the notable advances and trends that have shaped the field of computational elucidation of organic reaction mechanisms over the last 10-15 years. It highlights the types of mechanistic problems that have recently become possible to study and summarizes the methodological developments that have permitted these new advances. Case studies are taken from three representative areas of organic chemistry-asymmetric catalysis, glycosylation reactions, and single electron transfer reactions-which illustrate themes common to the broader field. These include the trend towards modelling systems that are increasingly complex (both structurally and mechanistically), the growing appreciation of the mechanistic roles of non-covalent interactions, and the increasing ability to explore dynamical features of reaction mechanisms. Some interesting new challenges that have emerged in the field are identified.

Neurological outcome in adult out-of-hospital cardiac arrest - Not all doom and gloom!

AIMS: To describe neurological and functional outcomes among out-of-hospital cardiac arrest (OHCA) patients who survived to hospital discharge; to determine the association between neurological outcome at hospital discharge and 12-month survival. METHODS: Our cohort comprised adult OHCA patients (≥18 years) attended by St John WA (SJWA) paramedics in Perth, Western Australia (WA), who survived to hospital discharge, between 1st January 2004 and 31st December 2019. Neurological and functional status at hospital discharge (and before the arrest) was determined by medical record review using the five-point 'Cerebral Performance Category (CPC)' and 'Overall Performance Category (OPC)' scores. Adjusted multivariable logistic regression analysis was used to estimate the association of CPC score at hospital discharge with 12-month survival, adjusted for prognostic variables. RESULTS: Over the study period, SJWA attended 23,712 OHCAs. Resuscitation was attempted in 43.4% of cases (n = 10,299) with 2171 subsequent admissions, 99.4% (n = 2158) of these were admitted to a study hospital. Of the 1062 hospital survivors, 71.3% (n = 757) were CPC1 (highest category of neurological performance), 21.4% (n = 227) CPC2, 6.3% (n = 67) CPC3 and 1.0% (n = 11) CPC4. OPC scores followed a similar distribution. Of the 1,011 WA residents who survived to hospital discharge, 92.3% (n = 933) survived to 12-months. A CPC1-2 at hospital discharge was significantly associated with 12-month survival (adjusted odds ratio 3.28, 95% confidence interval 1.69-6.39). CONCLUSION: Whilst overall survival is low, most survivors of OHCA have a good neurological outcome at hospital discharge and are alive at 12-months.

Synthesis of New Triazolopyrazine Antimalarial Compounds.

A radical approach to late-stage functionalization using photoredox and Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC50 values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.

Arterial carbon dioxide tension has a non-linear association with survival after out-of-hospital cardiac arrest: A multicentre observational study.

PURPOSE: International guidelines recommend targeting normocapnia in mechanically ventilated out-of-hospital cardiac arrest (OHCA) survivors, but the optimal arterial carbon dioxide (PaCO2) target remains controversial. We hypothesised that the relationship between PaCO2 and survival is non-linear, and targeting an intermediate level of PaCO2 compared to a low or high PaCO2 in the first 24-h of ICU admission is associated with an improved survival to hospital discharge (STHD) and at 12-months. METHODS: We conducted a retrospective multi-centre cohort study of adults with non-traumatic OHCA requiring admission to one of four tertiary hospital intensive care units for mechanical ventilation. A four-knot restricted cubic spline function was used to allow non-linearity between the mean PaCO2 within the first 24 h of ICU admission after OHCA and survival, and optimal PaCO2 cut-points were identified from the spline curve to generate corresponding odds ratios. RESULTS: We analysed 3769 PaCO2 results within the first 24-h of ICU admission, from 493 patients. PaCO2 and survival had an inverted U-shape association; normocapnia was associated with significantly improved STHD compared to either hypocapnia (<35 mmHg) (adjusted odds ratio [aOR] 0.45, 95% confidence interval [CI] 0.24-0.83) or hypercapnia (>45 mmHg) (aOR 0.45, 95% CI 0.24-0.84). Of the twelve predictors assessed, PaCO2 was the third most important predictor, and explained >11% of the variability in survival. The survival benefits of normocapnia extended to 12-months. CONCLUSIONS: Normocapnia within the first 24-h of intensive care admission after OHCA was associated with an improved survival compared to patients with hypocapnia or hypercapnia.

Non-linear association between arterial oxygen tension and survival after out-of-hospital cardiac arrest: A multicentre observational study.

BACKGROUND: Studies to identify safe oxygenation targets after out-of-hospital cardiac arrest (OHCA) have often assumed a linear relationship between arterial oxygen tension (PaO2) and survival, or have dichotomised PaO2 at a supra-physiological level. We hypothesised that abnormalities in mean PaO2 (both high and low) would be associated with decreased survival after OHCA. METHODS: We conducted a retrospective multicentre cohort study of adult OHCA patients who received mechanical ventilation on admission to the intensive care unit (ICU). The potential non-linear relationship between the mean PaO2 within the first 24 -hs of ICU admission and survival to hospital discharge (STHD) was assessed by a four-knot restricted cubic spline function with adjustment for potential confounders. RESULTS: 3764 arterial blood gas results were available for 491 patients in the first 24-hs of ICU admission. The relationship between mean PaO2 over the first 24-hs and STHD was an inverted U-shape, with highest survival for those with a mean PaO2 between 100 and 180 mmHg (reference category) compared to a mean PaO2 of <100 mmHg (adjusted odds ratio [aOR] 0.50 95% confidence interval [CI] 0.30, 0.84), or >180 mmHg (aOR 0.41, 95% CI 0.18, 0.92). Mean PaO2 within 24 -hs was the third most important predictor and explained 9.1% of the variability in STHD. CONCLUSION: The mean PaO2 within the first 24-hs after admission for OHCA has a non-linear association with the highest STHD seen between 100 and 180 mmHg. Randomised controlled trials are now needed to validate the optimal oxygenation targets in mechanically ventilated OHCA patients.

Genome-Inspired Chemical Exploration of Marine Fungus Aspergillus fumigatus MF071.

The marine-derived fungus Aspergillus fumigatus MF071, isolated from sediment collected from the Bohai Sea, China, yielded two new compounds 19S,20-epoxy-18-oxotryprostatin A (1) and 20-hydroxy-18-oxotryprostatin A (2), in addition to 28 known compounds (3-30). The chemical structures were established on the basis of 1D, 2D NMR and HRESIMS spectroscopic data. This is the first report on NMR data of monomethylsulochrin-4-sulphate (4) and pseurotin H (10) as naturally occurring compounds. Compounds 15, 16, 20, 23, and 30 displayed weak antibacterial activity (minimum inhibitory concentration: 100 µg/mL). Compounds 18 and 19 exhibited strong activity against S. aureus (minimum inhibitory concentration: 6.25 and 3.13 µg/mL, respectively) and E. coli (minimum inhibitory concentration: 6.25 and 3.13 µg/mL, respectively). A genomic data analysis revealed the putative biosynthetic gene clusters ftm for fumitremorgins, pso for pseurotins, fga for fumigaclavines, and hel for helvolinic acid. These putative biosynthetic gene clusters fundamentally underpinned the enzymatic and mechanistic function study for the biosynthesis of these compounds. The current study reported two new compounds and biosynthetic gene clusters of fumitremorgins, pseurotins, fumigaclavines and helvolinic acid from Aspergillus fumigatus MF071.

The Effect of Clostridioides difficile Diagnostic Stewardship Interventions on the Diagnosis of Hospital-Onset Clostridioides difficile Infections.

BACKGROUND: Public reporting of Clostridioides difficile infection (CDI) using laboratory-identified events has led some institutions to revert from molecular-based tests to less sensitive testing modalities. At one academic medical center, researchers chose to use nucleic acid amplification test alone in CDI diagnosis with institutional protocols aimed at diagnostic stewardship. METHODS: A single-center, quasi-experimental study was conducted to introduce and analyze the effects of various diagnostic stewardship interventions. In April 2017 an order report was created to inform providers of patients' recent bowel movements, laxative use, and prior Clostridioides difficile (CD) testing (Intervention 1). In November 2017 nursing staff were empowered to not send nondiarrheal stools for testing (Intervention 2). In February 2019, an interruptive alert was implemented to prevent testing that was not indicated (Intervention 3). CD testing rates and healthcare facility-onset CDI (HO-CDI) rates were compared before and after the interventions using one-way analysis of variance (ANOVA). RESULTS: At baseline, testing for CD after 3 days of admission was performed at mean ± standard deviation of 15.9 ± 1.7 tests/1,000 patient-days. After Intervention 1, it decreased to 12.1 ± 1.1 tests. This further decreased to 10.6 ± 0.8 after Intervention 2 and to 8.1 ± 0.1 after Intervention 3 (p < 0.001). HO-CDI cases per 10,000 patient-days declined from 12.7 ± 1.4 cases at baseline to 10.7 ± 1.2 after Intervention 1, to 8.7 ± 2.4 after Intervention 2, and to 5.8 ± 0.2 after Intervention 3 (p = 0.03). CONCLUSION: A multidisciplinary approach optimizing electronic health record support tools and leveraging nursing education can reduce both testing and HO-CDI rates while using the most sensitive testing modality.

Mechanistic Aspects of Hydrosilane/Potassium tert-Butoxide (HSiR3/KO t Bu)-Mediated Reactions.

The hydrosilane/potassium tert-butoxide reagent system has attracted significant attention over the last 5 years since the discovery of its ability to silylate heteroarene C-H bonds. Numerous useful HSiR3/KO t Bu-mediated transformations are now known, including silylation of sp, sp2, and sp3 C-H bonds, reductive cleavage of C-O, C-S, and C-N bonds, reduction of polycyclic arenes, and hydrosilylation and polymerization of styrenes. This mini-review surveys the rich diversity of reaction mechanisms, both ionic and free radical and including hydride transfer, H atom transfer, and electron transfer, that have been uncovered during recent studies on the HSiR3/KO t Bu reagent system. Several mechanistic phenomena that remain to be explained are also highlighted.

Reaction of Papaverine with Baran DiversinatesTM.

The reaction of papaverine with a series of Baran DiversinatesTM is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C-H functionalization. Ten papaverine analogues (2-11), including seven new compounds, were synthesized. An unexpected radical-induced exchange reaction is reported where the dimethoxybenzyl group of papaverine was replaced by an alkyl group. This side reaction enabled the synthesis of additional novel fragments based on the isoquinoline scaffold, which is present in numerous natural products. Possible reasons for the poor yields in the DiversinateTM reactions with this particular scaffold are discussed.