Representation of Social Determinants of Health terminology in medical subject headings: impact of added terms.

OBJECTIVES: To enhance and evaluate the quality of PubMed search results for Social Determinants of Health (SDoH) through the addition of new SDoH terms to Medical Subject Headings (MeSH). MATERIALS AND METHODS: High priority SDoH terms and definitions were collated from authoritative sources, curated based on publication frequencies, and refined by subject matter experts. Descriptive analyses were used to investigate how PubMed search details and best match results were affected by the addition of SDoH concepts to MeSH. Three information retrieval metrics (Precision, Recall, and F measure) were used to quantitatively assess the accuracy of PubMed search results. Pre- and post-update documents were clustered into topic areas using a Natural Language Processing pipeline, and SDoH relevancy assessed. RESULTS: Addition of 35 SDoH terms to MeSH resulted in more accurate algorithmic translations of search terms and more reliable best match results. The Precision, Recall, and F measures of post-update results were significantly higher than those of pre-update results. The percentage of retrieved publications belonging to SDoH clusters was significantly greater in the post- than pre-update searches. DISCUSSION: This evaluation confirms that inclusion of new SDoH terms in MeSH can lead to qualitative and quantitative enhancements in PubMed search retrievals. It demonstrates the methodology for and impact of suggesting new terms for MeSH indexing. It provides a foundation for future efforts across behavioral and social science research (BSSR) domains. CONCLUSION: Improving the representation of BSSR terminology in MeSH can improve PubMed search results, thereby enhancing the ability of investigators and clinicians to build and utilize a cumulative BSSR knowledge base.

Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells.

The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells in vitro. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents.

Preventing Exertional Heat Stroke in Football: Time for a Paradigm Shift.

CONTEXT: Among American sports, football has the highest incidence of exertional heat stroke (EHS), despite decades of prevention strategies. Based on recent reports, 100% of high school and college EHS football fatalities occur during conditioning sessions. Linemen are the at-risk population, constituting 97% of football EHS deaths. Linemen heat up faster and cool down slower than other players. EVIDENCE ACQUISITION: Case series were identified from organized, supervised football at the youth, high school, and collegiate levels and compiled in the National Registry of Catastrophic Sports Injuries. Sources for event occurrence were media reports and newspaper clippings, autopsy reports, certificates of death, school-sponsored investigations, and published medical literature. Articles were identified through PubMed with search terms "football," "exertional heat stroke," and "prevention." STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: Football EHS is tied to (1) high-intensity drills and conditioning that is not specific to individual player positions, (2) physical exertion as punishment; (3) failure to modify physical activity for high heat and humidity, (4) failure to recognize early signs and symptoms of EHS, and (5) death when cooling is delayed. CONCLUSION: To prevent football EHS, (1) all training and conditioning should be position specific; (2) physical activity should be modified per the heat load; (3) understand that some players have a "do-or-die" mentality that supersedes their personal safety; (4) never use physical exertion as punishment; (5) eliminate conditioning tests, serial sprints, and any reckless drills that are inappropriate for linemen; and (6) consider air-conditioned venues for linemen during hot practices. To prevent EHS, train linemen based on game demands. STRENGTH-OF-RECOMMENDATION TAXONOMY: n/a.

Identification of Microbial Strains via 2D Cross-Correlation of LC-MS Data.

Mass spectrometry is commonly used in the identification of species present in microbial samples, but the high similarity in the peptide composition between strains of a single species has made analysis at the subspecies level challenging. Prior research in this area has employed methods such as Principal Component Analysis (PCA), the k-Nearest Neighbors' (kNN) algorithm, and Pearson correlation. Previously, 1D cross-correlation of mass spectra has been shown to be useful in the classification of small molecule compounds as well as in the identification of peptide sequences via the SEQUEST algorithm and its variants. While direct application of cross-correlation to mass spectral data has been shown to aid in the identification of many other types of compounds, this type of analysis has not been demonstrated in the literature for the purpose of LC-MS based identification of microbial strains. A method of identifying microbial strains is presented here that applies the principle of 2D cross-correlation to LC-MS data. For a set of N = 30 yeast isolate samples representing 5 yeast strains (K-97, S-33, T-58, US-05, WB-06), high-resolution LC-MS-Orbitrap data were collected. Reference spectra were then generated for each strain from the combined data of each sample of that strain. Sample strains were then predicted by computing the 2D cross-correlation of each sample against the reference spectra, followed by application of correction factors measuring the asymmetry of the 2D correlation functions.

Bringing Barley Back: Analysis of Heritage Varieties for Use as Germplasm Sources to Improve Resistance against the Most Devastating, Contemporary Disease in Canada, Fusarium Head Blight (Fusarium graminearum).

Fusarium head blight (FHB), caused by Fusarium graminearum, is currently the most devastating disease for barley (Hordeum vulgare) in Canada. Associated mycotoxins can compromise grain quality, where deoxynivalenol (DON) is considered particularly damaging due to its frequency of detection. Breeding barley with a lower DON content is difficult, due to the poor adaptation and malt quality of resistance sources. A set of European-derived heritage varieties were screened in an FHB nursery in Charlottetown, PE, with selections tested at Brandon, MB, between 2018-2022. Genetic evaluation demonstrated a distinct clustering of Canadian varieties from the heritage set. At Brandon, 72% of the heritage varieties ranked lower for DON content than did the moderately resistant Canadian check 'AAC Goldman', but resistance was associated with later heading and taller stature. In contrast with Canadian modern malting variety 'AAC Synergy', general deficiencies were observed in yield, enzyme activity, and extract, along with higher protein content. Nonetheless, several resistant varieties were identified with reasonable a heading date and yield, including 'Chevallier Chile', 'Domen', 'Djugay', 'Hannchen', 'Heils Franken', 'Moravian Barley', 'Loosdorfer' with 'Golden Melon', 'Nutans Moskva', and 'Vellavia', these being some of the most promising varieties when malting quality characteristics were also considered. These heritage resources could be used as parents in breeding to develop FHB-resistant malting barley varieties.

Synthesis and characterisation of a nucleotide based pro-drug formulated with a peptide into a nano-chemotherapy for colorectal cancer.

Recent studies in colorectal cancer patients (CRC) have shown that increased resistance to thymidylate synthase (TS) inhibitors such as 5-fluorouracil (5-FU), reduce the efficacy of standard of care (SoC) treatment regimens. The nucleotide pool cleanser dUTPase is highly expressed in CRC and is an attractive target for potentiating anticancer activity of chemotherapy. The purpose of the current work was to investigate the activity of P1, P4-di(2',5'-dideoxy-5'-selenouridinyl)-tetraphosphate (P4-SedU2), a selenium-modified symmetrically capped dinucleoside with prodrug capabilities that is specifically activated by dUTPase. Using mechanochemistry, P4-SedU2 and the corresponding selenothymidine analogue P4-SeT2 were prepared with a yield of 19% and 30% respectively. The phosphate functionality facilitated complexation with the amphipathic cell-penetrating peptide RALA to produce nanoparticles (NPs). These NPs were designed to deliver P4-SedU2 intracellularly and thereby maximise in vivo activity. The NPs demonstrated effective anti-cancer activity and selectivity in the HCT116 CRC cell line, a cell line that overexpresses dUTPase; compared to HT29 CRC cells and NCTC-929 fibroblast cells which have reduced levels of dUTPase expression. In vivo studies in BALB/c SCID mice revealed no significant toxicity with respect to weight or organ histology. Pharmacokinetic analysis of blood serum showed that RALA facilitates effective delivery and rapid internalisation into surrounding tissues with NPs eliciting lower plasma Cmax than the equivalent injection of free P4-SedU2, translating the in vitro findings. Tumour growth delay studies have demonstrated significant inhibition of growth dynamics with the tumour doubling time extended by >2weeks. These studies demonstrate the functionality and action of a new pro-drug nucleotide for CRC.

Utilizing a Dual Human Transporter MDCKII-MDR1-BCRP Cell Line to Assess Efflux at the Blood Brain Barrier.

To facilitate the design of drugs readily able to cross the blood brain barrier (BBB), a Madin-Darby canine kidney (MDCK) cell line was established that over expresses both P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), the main human efflux transporters of the BBB. Proteomics analyses indicate BCRP is expressed at a higher level than Pgp in this cell line. This cell line shows good activity for both transporters [BCRP substrate dantrolene efflux ratio (ER) 16.3 ± 0.9, Pgp substrate quinidine ER 27.5 ± 1.2], and use of selective transporter inhibitors enables an assessment of the relative contributions to overall ERs. The MDCKII-MDR1-BCRP ER negatively correlates with rat unbound brain/unbound plasma ratio, Kpuu Highly brain penetrant compounds with rat Kpuu ≥ 0.3 show ERs ≤ 2 in the MDCKII-MDR1-BCRP assay while compounds predominantly excluded from the brain, Kpuu ≤ 0.05, demonstrate ERs ≥ 20. A subset of compounds with MDCKII-MDR1-BCRP ER < 2 and rat Kpuu < 0.3 were shown to be substrates of rat Pgp using a rat transfected cell line, MDCKII-rMdr1a. These compounds also showed ERs > 2 in the human National Institutes of Health (NIH) MDCKI-MDR1 (high Pgp expression) cell line, which suggests that they are weak human Pgp substrates. Characterization of 37 drugs targeting the central nervous system in the MDCKII-MDR1-BCRP efflux assay show 36 have ERs < 2. In drug discovery, use of the MDCKII-MDR1-BCRP in parallel with the NIH MDCKI-MDR1 cell line is useful for identification of compounds with high brain penetration. SIGNIFICANCE STATEMENT: A single cell line that includes both the major human efflux transporters of the blood brain barrier (MDCKII-MDR1-BCRP) has been established facilitating the rapid identification of efflux substrates and enabling the design of brain penetrant molecules. Efflux ratios using this cell line demonstrate a clear relationship with brain penetration as defined by rat brain Kpuu.

Interrogating Aptamer Chemical Space Through Modified Nucleotide Substitution Facilitated by Enzymatic DNA Synthesis.

Chemical modification of aptamers is an important step to improve their performance and stability in biological media. This can be performed either during their identification (mod-SELEX) or after the in vitro selection process (post-SELEX). In order to reduce the complexity and workload of the post-SELEX modification of aptamers, we have evaluated the possibility of improving a previously reported, chemically modified aptamer by combining enzymatic synthesis and nucleotides bearing bioisosteres of the parent cubane side-chains or substituted cubane moieties. This method lowers the synthetic burden often associated with post-SELEX approaches and allowed to identify one additional sequence that maintains binding to the PvLDH target protein, albeit with reduced specificity. In addition, while bioisosteres often improve the potency of small molecule drugs, this does not extend to chemically modified aptamers. Overall, this versatile method can be applied for the post-SELEX modification of other aptamers and functional nucleic acids.

Endogenic Phenolic Compounds of Barley as Potential Biomarkers Related to Grain Mycotoxin Production and Cultivar Selection.

Barley (Hordeum vulgare L.) is the fourth largest cereal crop in the world. One of the most devastating diseases in barley worldwide is Fusarium head blight (FHB) caused by Fusarium graminearum Schwabe. Several mycotoxins are produced by FHB infection, and deoxynivalenol (DON) is one of them responsible for the deterioration of grain quality. The current limited number of reliable molecular markers makes the development of FHB-resistant cultivars rather difficult and laborious. Moreover, there is a limited number of designed specific biomarkers that could distinguish the FHB resistance and mycotoxin accumulation in barley cultivars. This study investigated the phenolic compounds of ten different Canadian barley cultivars, grown in artificially FHB-infected and non-infected field trials. The enzyme-linked immunosorbent assay (ELISA) was used to assess the presence of DON in the harvested infected grains of each tested variety. High-performance liquid chromatography (HPLC) analysis was performed using both infected and non-infected samples. We identified differences among cultivars tested in non-infected samples through quantitative analysis of free and bound phenolic compounds. The resistant cultivars showed higher amounts of major bound phenolic compounds compared to the susceptible check CDC Bold. Additionally, the FHB-infected cultivars produced significantly higher amounts of sinapic acid (SIN) () and catechin (CAT) in the soluble free form of phenolics in barley compared to the non-infected subjects. This study suggests that phenolic compounds in barley could allow barley breeders to precisely identify and develop FHB-resistant barley germplasm and cultivars.

Cobalt-Catalyzed Enantioselective Hydrogenation of Diaryl Ketones with Ferrocene-Based Secondary Phosphine Oxide Ligands.

A new class of cobalt catalytic system for asymmetric hydrogenation of ketones was herein reported, involving the development of novel ferrocene-based secondary phosphine oxide ligands. An unusual P-O bidentate coordination pattern with cobalt was confirmed by an X-ray diffraction study. The bichelating tetrahedral cobalt(II) complexes afforded high reactivities (up to 99% yield) and good to excellent enantioselectivities (up to 92% ee) in the AH of various ortho-substituted diaryl ketones. In addition, the diferrocenyl cobalt complex was characterized with intriguing UV-vis absorption and electrochemical properties.

Highly Selective Aptamer-Molecularly Imprinted Polymer Hybrids for Recognition of SARS-CoV-2 Spike Protein Variants.

Virus recognition has been driven to the forefront of molecular recognition research due to the COVID-19 pandemic. Development of highly sensitive recognition elements, both natural and synthetic is critical to facing such a global issue. However, as viruses mutate, it is possible for their recognition to wane through changes in the target substrate, which can lead to detection avoidance and increased false negatives. Likewise, the ability to detect specific variants is of great interest for clinical analysis of all viruses. Here, a hybrid aptamer-molecularly imprinted polymer (aptaMIP), that maintains selective recognition for the spike protein template across various mutations, while improving performance over individual aptamer or MIP components (which themselves demonstrate excellent performance). The aptaMIP exhibits an equilibrium dissociation constant of 1.61 nM toward its template which matches or exceeds published examples of imprinting of the spike protein. The work here demonstrates that "fixing" the aptamer within a polymeric scaffold increases its capability to selectivity recognize its original target and points toward a methodology that will allow variant selective molecular recognition with exceptional affinity.

A plug-and-play aptamer diagnostic platform based on linear dichroism spectroscopy.

A plug-and-play sandwich assay platform for the aptamer-based detection of molecular targets using linear dichroism (LD) spectroscopy as a read-out method has been demonstrated. A 21-mer DNA strand comprising the plug-and-play linker was bioconjugated onto the backbone of the filamentous bacteriophage M13, which gives a strong LD signal due to its ready alignment in linear flow. Extended DNA strands containing aptamer sequences that bind the protein thrombin, TBA and HD22, were then bound to the plug-and-play linker strand via complementary base pairing to generate aptamer-functionalised M13 bacteriophages. The secondary structure of the extended aptameric sequences required to bind to thrombin was checked using circular dichroism spectroscopy, with the binding confirmed using fluorescence anisotropy measurements. LD studies revealed that this sandwich sensor design is very effective at detecting thrombin down to pM levels, indicating the potential of this plug-and-play assay system as a new label-free homogenous detection system based on aptamer recognition.

A Biodegradable, Polymer-Supported Oxygen Atom Transfer Reagent.

Biodegradable polymers are desirable to mitigate the environmental impact of plastic waste in the environment. Over the past several decades, the development of organocatalytic ring-opening polymerization (OROP) has made the synthesis of many new types of biodegradable polymers possible. In this research article, the first example of an oxygen atom transfer reagent pendant on a biodegradable polymer backbone is reported. The monomers for the polycarbonate backbone are sourced from the biodegradable 2,2-bis(hydroxymethyl) propionic acid molecule, and an iodoaryl group is installed pendant to the cyclic monomer for post-polymerization modification into an iodosylaryl oxygen atom transfer reagent. The key I-O bond is characterized by XPS spectroscopy, and a test reaction to triphenylphosphine demonstrates the ability of the polymer to engage in an oxygen atom transfer reaction with a substrate.

Safety and performance of a novel implantable sensor in the inferior vena cava under acute and chronic intravascular volume modulation.

AIMS: The management of congestion is one of the key treatment targets in heart failure. Assessing congestion is, however, difficult. The purpose of this study was to investigate the safety and dynamic response of a novel, passive, inferior vena cava (IVC) sensor in a chronic ovine model. METHODS AND RESULTS: A total of 20 sheep divided into three groups were studied in acute and chronic in vivo settings. Group I and Group II included 14 sheep in total with 12 sheep receiving the sensor and two sheep receiving a control device (IVC filter). Group III included an additional six animals for studying responses to volume challenges via infusion of blood and saline solutions. Deployment was 100% successful with all devices implanted; performing as expected with no device-related complications and signals were received at all observations. At similar volume states no significant differences in IVC area normalized to absolute area range were measured (55 ± 17% on day 0 and 62 ± 12% on day 120, p = 0.51). Chronically, the sensors were completely integrated with a thin, reendothelialized neointima with no loss of sensitivity to infused volume. Normalized IVC area changed significantly from 25 ± 17% to 43 ± 11% (p = 0.007) with 300 ml infused. In contrast, right atrial pressure required 1200 ml of infused volume prior to a statistically significant change from 3.1 ± 2.6 mmHg to 7.5 ± 2.0 mmHg (p = 0.02). CONCLUSION: In conclusion, IVC area can be measured remotely in real-time using a safe, accurate, wireless, and chronic implantable sensor promising to detect congestion with higher sensitivity than filling pressures.

Risk of suicide after diagnosis of severe physical health conditions: A retrospective cohort study of 47 million people.

Background: The diagnosis of a severe physical health condition can cause psychological distress and lead to severe depression. The association between severe physical health conditions and the risk of suicide, and how the risk of suicide changes in the months following diagnosis, are not clear. Methods: We estimated whether a diagnosis of severe physical health conditions is associated with an increase in the risk of death by suicide using a dataset based on the 2011 Census linked to hospital records and death registration records covering 47,354,696 people alive on 1 January 2017 in England. Patients diagnosed with a low-survival cancer, chronic ischaemic heart disease, chronic obstructive pulmonary disease, or degenerative neurological condition were matched to individuals using socio-demographic characteristics from the Census. Using the Aalen-Johansen estimator, we estimated the cumulative incidence of death by suicide occurring between 1 January 2017 and 31 December 2021 (registered by 31 December 2021) in patients and matched controls, adjusted for other potential confounders using inverse probability weighting. Findings: Diagnosis of severe conditions was associated with an increased risk of dying by suicide. One year after diagnosis, the rate of suicide was 21.6 (95% confidence intervals: 14.9-28.4, number of events (N): 39) per 100,000 low-survival cancer patients compared to 9.5 (5.6-14.6, N:16) per 100,000 matched controls. For COPD patients, the one-year suicide rate was 22.4 (19.4-25.5, N:208) per 100,000 COPD patients (matched controls: 10.6, 8.3-13.0, N:85), for ischaemic heart disease 16.1 (14.1-18.2, N:225) per 100,000 patients (matched controls: 8.8, 7.1-10.4, N:128), for degenerative neurological conditions 114.5 (49.6-194.7, N:11) per 100,000 patients. The increase in risk was more pronounced in the first six months after diagnosis or first treatment. Interpretation: A diagnosis of severe physical illness is associated with higher suicide risk. The interaction of physical and mental illness emphasises the importance of collaborative physical and mental health care in these patients. Funding: The Office for National Statistics. KES is the Laing Galazka chair in palliative care at King's College London, funded by an endowment from Cicely Saunders International and the Kirby Laing Foundation.

Ferrocene as a potential electrochemical reporting surrogate of abasic sites in DNA.

Methods for the real-time monitoring of the substrate acceptance of modified nucleotides by DNA polymerases are in high demand. In a step towards this aim, we have incorporated ferrocene-based abasic nucleotides into DNA templates and evaluated their compatibility with enzymatic synthesis of unmodified and modified DNA. All canonical nucleotides can be incorporated opposite ferrocene sites with a strong preference for purines. DNA polymerases with lesion-bypass capacity such as Dpo4 allow DNA synthesis to be resumed beyond the site of incorporation. Modified purine nucleotides can readily be incorporated opposite ferrocene basic site analogs, while pyrimidine nucleotides decorated with simple side-chains are also readily tolerated. These findings open up directions for the design of electrochemical sensing devices for the monitoring of enzymatic synthesis of natural or modified DNA.

Increased shark bite survivability revealed by two centuries of Australian records.

The perceived and real threat of shark bites have significant direct health and indirect economic impacts. Here we assess the changing odds of surviving an unprovoked shark bite using 200 years of Australian records. Bite survivability rates for bull (Carcharhinus leucas), tiger (Galeocerdo cuvier) and white (Carcharodon carcharias) sharks were assessed relative to environmental and anthropogenic factors. Survivability of unprovoked bull, tiger and white shark bites were 62, 75 and 53% respectively. Bull shark survivability increased over time between 1807 and 2018. Survivability decreased for both tiger and white sharks when the person was doing an in water activity, such as swimming or diving. Not unsurprisingly, a watercraft for protection/floatation increased survivability to 92% from 30%, and 88% from 45%, for tiger and white sharks respectively. We speculate that survival may be related to time between injury and treatment, indicating the importance of rapid and appropriate medical care. Understanding the predictors of unprovoked bites, as well as survivability (year and water activity), may be useful for developing strategies that reduce the number of serious or fatal human-shark interactions without impacting sharks and other marine wildlife.

Implications of Crop Rotation and Fungicide on Fusarium and Mycotoxin Spectra in Manitoba Barley, 2017-2019.

Fusarium head blight (FHB) is one of the most important diseases of barley in Manitoba province (western Canada), and other major barley producing regions of the world. Little is known about the Fusarium species and mycotoxin spectra associated with FHB of barley in Manitoba. Hence, barley grain samples were collected from 149 commercial fields from 2017 to 2019, along with information on respective cropping history, and analyzed with respect to Fusarium species spectra, abundance, chemotype composition, and mycotoxin profiles. Fusarium poae was the predominant Fusarium species associated with FHB of barley in Manitoba, followed by F. graminearum, and F. sporotrichioides; F. equiseti and F. avenaceum were also detected but at low levels. F. poae strains with the nivalenol (NIV) chemotype and F. graminearum strains with 3-acetyl deoxynivalenol (3-ADON) and 15-acetyl deoxynivalenol (15-ADON) chemotypes were commonly detected in the barley grain samples. Nivalenol (597.7, 219.1, and 412.4 µg kg-1) and deoxynivalenol (DON) (264.7, 56.7, and 65.3 µg kg-1) were the two most prevalent mycotoxins contaminating Manitoba barley in 2017, 2018 and 2019, respectively. A substantially higher DON content was detected in grain samples from barley fields with cereals as a preceding crop compared to canola and flax. Furthermore, F. poae proved less sensitive to four triazole fungicides (metconazole, prothioconazole+tebuconazole, tebuconazole, and prothioconazole) than F. graminearum. Findings from this research will assist barley producers with improved understanding of FHB threat levels and optimizing practices for the best management of FHB in barley.

A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that an organometallic nucleoside analogue, the ferronucleoside 1-(S,Rp), is cytotoxic in a panel of PDAC cell lines including gemcitabine-resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA replication, S-phase cell cycle arrest and stalling of DNA-replication forks, which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53-deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine-resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.

Maternal morbidity and mortality in pregnant/postpartum women with suspected HELLP syndrome identifiable as probable thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome by high LDH to AST ratio.

OBJECTIVE: To describe findings in 8 women initially diagnosed as presumptive HELLP Syndrome, eventually confirmed as TTP/aHUS as distinguished by elevated calculated LDH:AST ratio > 22:1. METHODS: All medicolegal files of patients evaluated between 1986 and 2015 with presumptive HELLP syndrome but later determined to have TTP/aHUS had LDH:AST ratios evaluated throughout care. RESULTS: Fifty-eight pregnant/postpartum women presented with a diagnosis of presumptive HELLP syndrome. In the final analysis, 8 women had TTP/aHUS characterized by severe thrombocytopenia (<20 000/µl) at admission, rare epigastric pain, and the consistent demonstration of a very high calculated total LDH to AST ratio. This calculation greatly exceeded 22:1 with TTP/aHUS (mean = 32:1) versus 2:1 with HELLP and could be consistently demonstrated throughout care. Six of 8 women with TTP/aHUS died. CONCLUSION: Correctly distinguishing between HELLP syndrome versus an imitator disorder continues to challenge obstetric specialists. This medicolegal data supplements prior findings supporting the concept of the LDH:AST ratio as a useful screening tool for clinicians to differentiate TTP/aHUS apart from HELLP syndrome in order to facilitate earlier hematology consultation, patient referral to tertiary care and emergent hemotherapy for these mothers.