Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Influence of Additives on the Reversible Oxygen Reduction Reaction/Oxygen Evolution Reaction in the Mg2+ -Containing Ionic Liquid N-Butyl-N-Methylpyrrolidinium Bis(Trifluoromethanesulfonyl)imide.

The influence of different additives on the oxygen reduction reaction/oxygen evolution reaction (ORR/OER) in magnesium-containing N-butyl-N-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide ([BMP][TFSI]) on a glassy carbon electrode was investigated to gain a better understanding of the electrochemical processes in Mg-air batteries. 18-Crown-6 was used as a complexing agent for Mg ions to hinder the passivation caused by their reaction with ORR products such as superoxide and peroxide anions. Furthermore, borane dimethylamine complex (NBH) was used as a potential water-removing agent to inhibit electrode passivation by reacting with trace impurities of water. The electrochemical processes were characterized by differential electrochemical mass spectrometry to monitor the consumed and evolved O2 in the ORR/OER and determine the number of transferred electrons. Crown ether and NBH efficiently masked Mg2+ . A stochiometric excess of crown ether resulted in reduced formation of a passivation layer, whereas at too high concentrations the reversibility of the ORR/OER was diminished.

The effectiveness and safety of introducing condom-catheter uterine balloon tamponade for postpartum haemorrhage at secondary level hospitals in Uganda, Egypt and Senegal: a stepped wedge, cluster-randomised trial.

OBJECTIVE: To assess the effectiveness of introducing condom-catheter uterine balloon tamponade (UBT) for postpartum haemorrhage (PPH) management in low- and middle-income settings. DESIGN: Stepped wedge, cluster-randomised trial. SETTING: Eighteen secondary-level hospitals in Uganda, Egypt and Senegal. POPULATION: Women with vaginal delivery from October 2016 to March 2018. METHODS: Use of condom-catheter UBT for PPH management was introduced using a half-day training and provision of pre-packaged UBT kits. Hospitals were randomised to when UBT was introduced. The incident rate (IR) of study outcomes was compared in the control (i.e. before UBT) and intervention (i.e. after UBT) periods. Mixed effects regression models accounted for clustering (random effect) and time period (fixed effect). MAIN OUTCOME MEASURES: Combined IR of PPH-related invasive surgery and/or maternal death. RESULTS: There were 28 183 and 31 928 deliveries in the control and intervention periods, respectively. UBT was used for 9/1357 and 55/1037 women diagnosed with PPH in control and intervention periods, respectively. PPH-related surgery or maternal death occurred in 19 women in the control period (IR = 6.7/10 000 deliveries) and 37 in the intervention period (IR = 11.6/10 000 deliveries). The adjusted IR ratio was 4.08 (95% confidence interval 1.07-15.58). Secondary outcomes, including rates of transfer and blood transfusion, were similar in the trial periods. CONCLUSIONS: Introduction of condom-catheter UBT in these settings did not improve maternal outcomes and was associated with an increase in the combined incidence of PPH-related surgery and maternal death. The lack of demonstrated benefit of UBT introduction with respect to severe outcomes warrants reflection on its role. TWEETABLE ABSTRACT: Stepped wedge trial shows UBT introduction does not reduce the combined incidence of PPH-related surgery or death.

High-precision measurement of the electron spin g factor of trapped atomic nitrogen in the endohedral fullerene N@C60.

The electronic g factor carries highly useful information about the electronic structure of a paramagnetic species, such as spin-orbit coupling and dia- or paramagnetic (de-)shielding due to local fields of surrounding electron pairs. However, in many cases, a near "spin-only" case is observed, in particular for light elements, necessitating accurate and precise measurement of the g factors. Such measurement is typically impeded by a "chicken and egg situation": internal or external reference standards are used for relative comparison of electron paramagnetic resonance (EPR) Larmor frequencies. However, the g factor of the standard itself usually is subject to a significant uncertainty which directly limits the precision and/or accuracy of the sought after sample g factor. Here, we apply an EPR reference-free approach for determining the g factor of atomic nitrogen trapped within the endohedral fullerene C60:N@C60 in its polycrystalline state by measuring the 1H NMR resonance frequency of dispersing toluene at room temperature. We found a value of g=2.00204(4) with a finally reached relative precision of ∼20 ppm. This accurate measurement allows us to directly compare the electronic properties of N@C60 to those found in atomic nitrogen in the gas phase or trapped in other solid matrices at liquid helium temperature. We conclude that spin-orbit coupling in N@C60 at room temperature is very similar in magnitude and of same sign as found in other inert solid matrices and that interactions between the quartet spin system and the C60 molecular orbitals are thus negligible.

Expression of epidermal stem cell markers in skin and adnexal malignancies.

BACKGROUND: Epidermal stem cells are multipotent cells that maintain the skin epidermis. Potential markers for stem cells have been identified in mammalian skin from mouse experiments; however, it is unclear if stem cells also contribute to tumour formation in human skin. OBJECTIVES: To investigate the expression of potential stem cell markers, such as leucine-rich repeat-containing G protein-coupled receptor (Lgr) 5, Lgr6, leucine-rich repeats and immunoglobulin-like domain protein 1 (Lrig1) and cytokeratin 15 (CK15) in basal cell carcinomas and tumours of the skin appendages. METHODS: We tested 45 human basal cell carcinomas (BCCs), including superficial, nodular, adenoid, infiltrating and sclerosing types, and 38 human tumours of skin appendages, including 13 sebaceous adenomas and carcinomas, 20 eccrine sweat gland tumours and five pilomatricomas, for the expression of hair follicle stem cell markers such as Lgr5, Lrig1, CK15, ß-catenin and SRY (sex determining region Y)-box 9 (SOX9), and compared these findings with those of healthy age-matched human epidermis. RESULTS: We detected the expression of stem cell markers in all tumours tested. Regarding Lgr5, Lrig1, CK15 and SOX9, expression seemed to be lower in more aggressive tumour types, such as in the most advanced parts of infiltrating BCC, in sebaceous carcinoma and late-stage porocarcinoma, compared with less aggressive superficial or nodular BCC or early-stage porocarcinoma and sebaceous gland tumours. In aggressive, sclerosing BCC, Lrig1 and Lgr5 were downregulated but CK15, SOX9 and nuclear ß-catenin were upregulated. CONCLUSIONS: Expression of potential stem cell markers of the epidermis and hair follicles was observed in skin tumours of appendages and BCCs. However, during tumour progression, many of these markers seemed to be downregulated.

A postpartum haemorrhage package with condom uterine balloon tamponade: a prospective multi-centre case series in Kenya, Sierra Leone, Senegal, and Nepal.

OBJECTIVE: To evaluate the effectiveness and safety of an ultra-low-cost uterine balloon tamponade package (ESM-UBT™) for facility-based management of uncontrolled postpartum haemorrhage (PPH) in Kenya, Sierra Leone, Senegal, and Nepal. DESIGN: Prospective multi-centre case series. SETTING: Facilities in resource-scarce areas of Kenya, Sierra Leone, Nepal, and Senegal. POPULATION: Women with uncontrolled postpartum haemorrhage in 307 facilities across the four countries. METHODS: A standardised ESM-UBT package was implemented in 307 facilities over 29 months (1 September 2012 to 1 February 2015). Data were collected via a multi-pronged approach including data card completion, chart reviews, and provider interviews. Beginning in August 2014, women who had previously undergone UBT placement were sought and queried regarding potential complications associated with UBT use. MAIN OUTCOME MEASURES: All-cause survival, survival from PPH, and post-UBT use complications (surgery, hospitalisation, antibiotics for pelvic infection) associated with UBT use. RESULTS: 201 UBTs were placed for uncontrolled vaginal haemorrhage refractory to all other interventions. In all, 38% (71/188) of women were either unconscious or confused at the time of UBT insertion. All-cause survival was 95% (190/201). However, 98% (160/163) of women survived uncontrolled PPH if delivery occurred at an ESM-UBT online facility. One (1/151) potential UBT-associated complication (postpartum endometritis) was identified and two improvised UBTs were placed in women with a ruptured uterus. CONCLUSIONS: These pilot data suggest that the ESM-UBT package is a clinically promising and safe method to arrest uncontrolled postpartum haemorrhage and save women's lives. The UBT was successfully placed by all levels of facility-based providers. Future studies are needed to further evaluate the effectiveness of ESM-UBT in low-resource settings. TWEETABLE ABSTRACT: Evidence for ESM-UBT as a clinically promising and safe method to arrest uncontrolled PPH and save women's lives.

Development of a community-based maternal, newborn and child emergency training package in South Sudan.

OBJECTIVE: To develop an evidence-based maternal, newborn and child emergency training package for community-based frontline health workers (FHWs) in post-conflict South Sudan. METHODS: In partnership with the new Republic of South Sudan, a multimodal needs assessment was conducted through purposive sampling, involving key informant interviews, focus group discussions, provider knowledge assessments and facility surveys. Data were analyzed using traditional qualitative techniques and compared with existing training programmes and curricula. These findings informed the development and implementation of the novel training approach. RESULTS: The needs assessment involved 33 FHWs, eight diverse health facilities in Eastern Equatoria, and stakeholders within 18 governmental and non-governmental organizations. Significant consensus emerged regarding the need for greater capacity among previously untrained FHWs. A maternal, newborn and child health training package was developed that included: (1) a participatory training course taught through a 'training of trainers' approach; (2) nine different pictorial action-based checklists covering basic management and referral of maternal, newborn and child emergencies; and (3) essential setting-appropriate equipment. CONCLUSION: A novel maternal, newborn and child survival package was developed for previously untrained and illiterate FHWs in South Sudan. It is hoped that this approach will build community-based capacity in resource-limited settings while greater capacity is being developed for facility-based deliveries by skilled birth attendants.

Uterine balloon tamponade for the treatment of postpartum haemorrhage in resource-poor settings: a systematic review.

BACKGROUND: Effective interventions addressing postpartum haemorrhage (PPH) are critically needed to reduce maternal mortality worldwide. Uterine balloon tamponade (UBT) has been shown to be an effective technique to treat PPH in developed countries, but has not been examined in resource-poor settings. OBJECTIVES: This literature review examines the effectiveness of UBT for the treatment and management of PPH in resource-poor settings. SEARCH STRATEGY: Publications were sought through searches of five electronic databases: Medline, Cochrane Reference Libraries, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Embase and Popline. SELECTION CRITERIA: Titles and abstracts were screened for eligibility by two independent reviewers. Each reviewer evaluated the full text of potentially eligible articles by defined inclusion criteria, including the presentation of empirical data and use of UBT in resource-poor settings to treat PPH. DATA COLLECTION AND ANALYSIS: Full text of all eligible publications was collected and systematically coded. MAIN RESULTS: The search identified 13 studies that met the inclusion criteria: six case reports or case series, five prospective studies and two retrospective studies for a total of 241 women. No randomised controlled trials were identified. The studies used various types of UBT, including condom catheter (n = 193), Foley catheter (n = 5) and Sengstaken-Blakemore oesophageal tube (n = 1). In these studies, primarily conducted in tertiary-care settings rather than lower-level health facilities, UBT successfully treated PPH in 234 out of 241 women. CONCLUSIONS: UBT is an effective treatment for PPH in resource-poor settings. Further study of UBT interventions is necessary to better understand the barriers to successful implementation and use in these settings.

[Chemotherapy-associated steatohepatitis in patients with colorectal cancer and surgery on hepatic metastasis: clinical validation of a histopathological scoring system and preoperative risk assessment]. / Chemotherapieassoziierte Leberveränderungen bei Patienten mit kolorektalem Karzinom und operativer Entfernung von Lebermetastasen: Evaluierung eines histopathologischen Scores und Erhebung präoperativer Risikofaktoren.

Colorectal cancer (CRC) can only be cured by complete resection of the tumour. Primarily unresectable metastases of the liver are treated by chemotherapy to achieve down-sizing of metastasis and curative resection. Chemotherapy can affect tumour-free healthy liver tissue and lead to histopathological and functional changes summarised as "chemotherapy-associated steatohepatitis" (CASH). We have evaluated a histopathological scoring system for CASH and searched for preoperative risk factors for the development of CASH. Liver alterations such as CASH were more pronounced when patients received chemotherapy, especially when treated with oxaliplatin. A higher BMI, male sex and elevated serum transaminases were risk factors for the development of CASH. Patients with a higher CASH score, reflecting more advanced changes in liver tissue, had a higher serum peak bilirubin level postoperatively. We did not find a higher morbidity or mortality in patients with a more severe liver damage measured by the CASH score.

Prolongation of the frequency-corrected QT dispersion following cerebral strokes with involvement of the insula of Reil.

Prolonged QT dispersion is a risk factor for cardiac arrhythmias and sudden death in patients with cardiac and peripheral artery diseases, but there is no study about prolonged QT dispersion in patients with ischaemic strokes. The insular cortex may play an important role in the genesis of cardiac arrhythmias and sudden death. In our study with 40 patients suffering from unilateral hemispheric ischaemic stroke, the QT dispersion was analysed and correlated to the location of the cerebral lesion. We found that in patients with involvement of the insular cortex, the QT dispersin is significantly longer than in those without insular involvement.

Buspirone treatment of alcoholism: age of onset, and cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid concentrations, but not medication treatment, predict return to drinking.

Disturbances in central nervous system serotonin (5-HT) have been implicated in the pathophysiology of alcoholism. To test the hypothesis that increasing 5-HT function could promote treatment compliance, we randomized patients who had completed a 5-week inpatient treatment program for alcoholism to receive either buspirone or placebo for 1 year. Ten of the 49 patients remained in the study for the entire year. The days to relapse did not differ significantly between patients receiving buspirone or placebo. Regardless of the medication, late-onset alcoholics had a longer time to relapse than early-onset alcoholics. Cerebrospinal fluid showed that patients with high concentrations of both the 5-HT metabolite, 5-hydroxyindoleacetic acid, and the dopamine metabolite, homovanillic acid, were more likely to relapse, compared with patients with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid.

Triazolam-induced changes in alcoholic thought processes.

This study was designed to examine and contrast cognitive effects (explicit memory and access to semantic knowledge) of the benzodiazepine Halcion (triazolam) in ten normal volunteers and ten cognitively un-impaired detoxified alcoholics. The two groups were indistinguishable from one another under placebo conditions on all measures of cognitive functioning. Under Halcion test conditions (0.375 mg p.o.), both groups were about equally impaired in their recall of to-be-remembered information. However, alcoholics, were more likely to recall information that they were not asked to remember (intrusion errors) on all measures of explicit remembering. Alcoholics also generated relatively uncommon (low frequency) responses from semantic memory, rather than common, categorically related associations in response to stimuli such as types of vegetables, flowers, and fruit following the administration of Halcion, but were not different from normal volunteers in the types of responses generated under placebo conditions. These findings suggest that a drug challenge that simulates many of the effects of acute alcohol administration induces alcoholics to think and remember differently (qualitatively) from normal volunteers.

Effects of moderate alcohol consumption on the central nervous system.

The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as "statistically" normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., approximately 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors--including gestational period, the periodicity of the mother's drinking, genetic factors, etc.--play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system.

Effect of alcoholism on the incidence of lactate-induced panic attacks.

BACKGROUND: Chronic alcohol use is associated with higher than expected rates of panic disorder. METHODS: To study the relationship between alcoholism and panic disorder, we administered the panicogenic agent, sodium lactate, to 26 alcoholics with either panic disorder or frequent panic attacks (ALCPAN), 20 nonalcoholics with panic disorder (PAN), 14 alcoholics without a history of panic attacks, and 14 healthy volunteers. RESULTS: PAN were significantly more likely to have a lactate-induced panic attack (65%) than ALCPAN (23%). ALCPAN who had the onset of panic attacks prior to alcoholism also had a reduced frequency of lactate-induced panic attacks (26.7%) compared to PAN. CONCLUSIONS: There is a reduced incidence of lactate-induced panic attacks in ALCPAN. This reduction does not appear to be explained by the relative onset of panic attacks to alcoholism. The role of excessive alcohol consumption in the decreased frequency of lactate-induced panic attacks seen in ALCPAN needs further study.

Serum ionized magnesium in chronic alcoholism: is it really decreased?

Chronic alcoholism is associated with a marked deficit in total magnesium (tMg). However, little is known about the status of the physiologically active form, ionized magnesium (iMg). We assessed serum iMg (measured with two ion-selective electrodes, AVL 988-4 and NOVA CRT) and tMg concentrations in chronic alcoholics at admission (n = 31) and after abstinence (n = 13) and compared these results with those for a control group (n = 40). At admission, the tMg and NOVA iMg concentrations in alcoholics (0.78 +/- 0.020 and 0.38 +/- 0.016 mmol/L, respectively) were significantly less (P <0.001) than in the controls (0.85 +/- 0.008 and 0.50 +/- 0.006 mmol/L). The AVL iMg results, however, did not differ significantly between the two groups: 0.53 +/- 0.013 vs 0.56 +/- 0.006 mmol/L, respectively (P >0.05). The mean iMg between the two analyzers differed significantly in both groups (P <0.001). After 3 weeks of abstinence, the alcoholics showed a significant increase in tMg (P <0.001) and in both NOVA and AVL iMg values (P <0.01 for each). tMg concentrations were positively correlated with the AVL iMg values in both alcoholics and controls but correlated positively with the NOVA iMg results only in the controls. Thus, the altered status of iMg is instrument-dependent, and the usefulness of the measurement in alcoholics is yet to be determined.