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.

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.

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.

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.

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.

[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.

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.

Memory: proline induces retrograde amnesia in chicks.

Intracerebral injection of L-proline, 1 minute after one-trial avoidance training of chicks, impaired memory 24 hours later. Chicks injected with proline 1 or 4 hours after training and controls injected with L-isoleucine at intervals after training, showed no impairment of memory 24 hours after training. The retrograde impairment of long-term memory induced by proline occurred without the convulsions or electrographic events usually associated with retrograde amnesic treatments.

Response to ethanol reduced by past thiamine deficiency.

Ethanol-induced intoxication and hypothermia were studied in rats approximately 7 months after severe thiamine deficiency, when treated rats appeared to have recovered their physical health. Previously induced thiamine deficiency without prior ethanol exposure significantly decreased the area under the curve plotted for the concentration of ethanol in blood and also decreased behavioral impairment and hypothermia due to ethanol exposure. Pathophysiologic changes resulting from thiamine deficiency may contribute to both the pharmacodynamic and pharmacokinetic tolerance to ethanol in chronic alcoholics.

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.

Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics.

BACKGROUND: We investigated the interrelationships of age at onset of excessive alcohol consumption, family history of alcoholism, psychiatric comorbidity, and cerebrospinal fluid monoamine metabolite concentrations in abstinent, treatment-seeking alcoholics. METHODS: We studied 131 recently abstinent alcoholics. Supervised abstinence was maintained on a research ward at the National Institutes of Health Clinical Center for a minimum of 3 weeks. All alcoholics received a low-monoamine diet for a minimum of 3 days before lumbar puncture. Lumbar punctures were performed in the morning after an overnight fast. Monamine metabolites and tryptophan in cerebrospinal fluid were quantified with liquid chromatography by means of electrochemical detection. Psychiatric diagnoses were established from blind-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews administered by a research social worker. Severity and age at onset of excessive alcohol consumption were documented with a structured lifetime drinking history questionnaire and with selected alcoholism screening questionnaires (CAGE and Michigan Alcoholism Screening Test). Family history of alcoholism was obtained from the probands. RESULTS: A majority of the treatment-seeking, primarily white male alcoholics had a lifetime history of psychiatric disorders other than alcoholism. None fulfilled criteria for antisocial personality disorder. Early-onset alcoholics (onset of excessive consumption before 25 years of age) had a more severe course of alcoholism and lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration than late-onset alcoholics. Patients who reported both parents to be alcoholics had particularly low mean cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan concentrations. CONCLUSION: Among treatment-seeking alcoholics, early age at onset is generally associated with a more severe course of alcoholism and lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.

Effective pharmacotherapy of alcoholic amnestic disorder with fluvoxamine. Preliminary findings.

Ten patients with alcoholic chronic organic brain disease were categorized as having alcohol amnestic disorder, or Korsakoff's psychosis (n = 6), dementia associated with alcoholism (n = 3), or compensated alcoholic liver disease (n = 1). All patients had severe deficits in memory for recently acquired information (episodic memory). Patients with alcohol dementia also showed global intellectual decline, including decreased performance on measures of semantic (knowledge) memory and reduction in levels of cerebrospinal fluid somatostatin. In a 4-week double-blind crossover design, the serotonin-uptake blocker fluvoxamine maleate (100 to 200 mg/d) was found to improve episodic memory in only the patients with alcohol amnestic disorder. These improvements in memory were significantly correlated with reductions in levels of cerebrospinal fluid 5-hydroxyindoleacetic acid, suggesting that facilitation of serotonergic neurotransmission may ameliorate the episodic memory failure in patients with alcohol amnestic disorder.

Hypothalamic-pituitary-adrenal axis functioning and cerebrospinal fluid corticotropin releasing hormone and corticotropin levels in alcoholics after recent and long-term abstinence.

We assessed the plasma corticotropin (adrenocorticotropic hormone) and cortisol responses to ovine corticotropin releasing hormone (oCRH) and the cerebrospinal fluid levels of CRH and corticotropin in alcoholics at various durations of abstinence and compared these variables with age-equivalent controls. Alcoholics who were tested at 1 week of abstinence (n = 11) demonstrated a significantly attenuated corticotropin response to oCRH compared with their response at 3 weeks of abstinence. Nine of these alcoholic patients demonstrated a significantly blunted corticotropin response at both 1 and 3 weeks of abstinence compared with controls (n = 15). A markedly exaggerated corticotropin response to oCRH, associated with tachycardia, was exhibited by 2 alcoholics at both 1 and 3 weeks of abstinence. Alcoholics who were abstinent greater than 3 weeks did not differ in their response to oCRH compared with controls. Controls demonstrated a significant inverse correlation between baseline cortisol levels and the cortisol response to oCRH. This correlation was not evident in any of the alcoholic groups, including those patients who were abstinent greater than 6 months. There was a positive correlation between cerebrospinal fluid concentrations of CRH and corticotropin in all patient groups. These findings indicated that alcoholics have significantly altered hypothalamic-pituitary-adrenal axis functioning up to 3 weeks following the cessation of drinking, with a more subtle impairment present for greater than 6 months following abstinence.

Effects of ethanol administration on parameters of immunocompetency in rats.

Ethanol administered to rats intragastrically in doses sufficient to cause dependency resulted in a rapid cell loss from the thymus and spleen. Cell loss from the peripheral blood was due primarily to a loss of lymphocytes, but a concomitant granulocytosis resulted in only small changes in the total leukocyte count. Lymphocyte proliferation to both T- and B-cell mitogens was severely compromised by ethanol treatment. The cell loss and functional lymphocyte impairment also occurred at half the ethanol dose required to induce dependency. Although cell numbers recovered relatively quickly after ethanol withdrawal, lymphocyte function, as measured by proliferation, recovered more slowly. Ethanol administration before or during immunization with sheep erythrocytes resulted in an impairment in the ability of animals to respond with a primary immune response to this antigen. These data suggest that ethanol given in quantities sufficient to produce dependence impairs in vitro and in vivo parameters of immunocompetency.

Clinical relationships between serum phosphorus and other blood chemistry values in alcoholics.

Hypophosphatemia was found in 11 of 434 (2.5%) male patients admitted to an alcohol treatment program and 21 of 69 (30.4%) male alcoholic patients admitted to the medical wards. In contrast, hyperphosphatemia was found in 43 of 434 (9.9%) treatment program alcoholics, and only one of 69 (1.4%) medical-ward alcoholics. Analysis of a sample of 57 nonalcoholic inpatients from the same hospital revealed one (1.8%) patient with hypophosphatemia and one (1.8%) patient with hyperphosphatemia. No relationship was found between phosphorus levels and magnesium, creatinine phosphokinase, RBCs, or hematocrit. A transient by significant (P less than .05) hypophosphatemia was found between the second and fifth days after admission in a subsample of 26 medical-ward alcoholics who had had a normal serum phosphate level on admission. It is suggested that phosphate levels of less than 1.1 mg/dL may predict impending hemolysis or rhabdomyolysis in the alcoholic.

Relationship between neuropsychological performance and alcohol consumption in alcoholics.

Cognitive performance in drug-free alcoholic patients (n = 95) within 7 days of their last drink was significantly predicted by chronic and recent drinking practices. Conceptually distinct cognitive functions were differentially influenced by various combinations of drinking variables. Consideration of curvilinear relationships enhanced the amount of variance explained, and it is suggested that certain patterns of consumption may accelerate the alcohol-induced decline of brain function.

Changes in neuropsychological performance during treatment for alcoholism.

A battery of 24 neuropsychological tests was administered to drug-free alcoholic inpatients (n = 91) within 7 days of their last drink and again 17 days later. Comparisons between this group and a nonalcoholic group of medical inpatients (n = 20) also given the same test battery twice indicated very little improvement due to abstinence (short-term improvement) in the alcoholics after controlling for practice effects. Similarly, when early postwithdrawal performance of the alcoholics was compared to an alcoholic control group (n = 32), which took the test battery only once 21 days after their last drink, little evidence for short-term recovery of cognitive functions was obtained. Insofar as decisions about the initiation of therapeutic treatments which rely on cognitive processes are based on neuropsychological performance, we conclude that such treatments may commence as soon as the clinical symptoms associated with acute withdrawal have subsided.

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.

Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism.

Central nervous system serotonin functions may differ between certain subgroups of alcoholics, patients with panic disorder, and healthy volunteers. To investigate these possibilities we administered the serotonin uptake inhibitor, clomipramine (12.5 mg, i.v.), to patients with alcohol dependence, patients with panic disorder with or without alcohol dependence, and healthy volunteers. Alcoholics did not differ from healthy volunteers in their neuroendocrine or behavioral responses. In contrast, patients with panic disorder exhibited marked dysphoric reactions and/or panic attacks following low-dose i.v. clomipramine, whereas their neuroendocrine responses were similar to the other two groups. Patients with panic disorder may have super-sensitive postsynaptic serotonin receptors in areas of their central nervous system, which are important for mood regulation.