Co-culture systems for the production of secondary metabolites: current and future prospects

Microorganisms are the great sources of Natural Products (NPs); these are imperative to their survival apart from conferring competitiveness amongst each other within their environmental niches. Primary and secondary metabolites are the two major classes of NPs that help in cell development, where antimicrobial activity is closely linked with secondary metabolites. To capitalize on the effects of secondary metabolites, co-culture methods have been often used to develop an artificial microbial community that promotes the action of these metabolites. Different analytical techniques will subsequently be employed based on the metabolite specificity and sensitivity to further enhance the metabolite induction. Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography (GC)-MS are commonly used for metabolite separation while Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) have been used as tools to elucidate the structure of compounds. This review intends to discuss current systems in use for co-culture in addition to its advantages, with discourse into the investigation of specific techniques in use for the detailed study of secondary metabolites. Further advancements and focus on co-culture technologies are required to fully realize the massive potential in synthetic biological systems

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

A case of Kawasaki Disease with concomitant leptospirosis

A 7-year-old Malay girl was admitted to our institution presenting with fever for 4 days that was persistently above 38°C, with a maximum temperature of 39.9°C. This was associated with a papular and pruritic rash over her chest and limbs for 4 days, as well as a tender right neck swelling for 3 days, diarrhea, and bitemporal headaches for 2 days. This was accompanied by early morning vomiting and nausea, but no blurring of vision or other neurological deficits. She also had red eyes and a dry cough that was not accompanied by coryzal symptoms for 1 day. She initially presented to a family physician and was given 3 days of oral azithromycin. However, her right neck swelling grew in size and redness over the last 2 days prior to admission. It was reported that she did not have contact with any sick persons. However, she had travelled to South India a month ago.Published versio

A Case of Kawasaki Disease With Concomitant Leptospirosis

A 7-year-old Malay girl was admitted to our institution presenting with fever for 4 days that was persistently above 38°C, with a maximum temperature of 39.9°C. This was associated with a papular and pruritic rash over her chest and limbs for 4 days, as well as a tender right neck swelling for 3 days, diarrhea, and bitemporal headaches for 2 days. This was accompanied by early morning vomiting and nausea, but no blurring of vision or other neurological deficits. She also had red eyes and a dry cough that was not accompanied by coryzal symptoms for 1 day. She initially presented to a family physician and was given 3 days of oral azithromycin. However, her right neck swelling grew in size and redness over the last 2 days prior to admission. It was reported that she did not have contact with any sick persons. However, she had travelled to South India a month ago.Published versio

Ethnicity-Specific Skeletal Muscle Transcriptional Signatures and Their Relevance to Insulin Resistance in Singapore

International audienceContext: Insulin resistance (IR) and obesity differ among ethnic groups in Singapore, with the Malays more obese yet less IR than Asian-Indians. However, the molecular basis underlying these differences is not clear.Objective: As the skeletal muscle (SM) is metabolically relevant to IR, we investigated molecular pathways in SM that are associated with ethnic differences in IR, obesity, and related traits.Design, setting, and main outcome measures: We integrated transcriptomic, genomic, and phenotypic analyses in 156 healthy subjects representing three major ethnicities in the Singapore Adult Metabolism Study.Patients: This study contains Chinese (n = 63), Malay (n = 51), and Asian-Indian (n = 42) men, aged 21 to 40 years, without systemic diseases.Results: We found remarkable diversity in the SM transcriptome among the three ethnicities, with >8000 differentially expressed genes (40% of all genes expressed in SM). Comparison with blood transcriptome from a separate Singaporean cohort showed that >95% of SM expression differences among ethnicities were unique to SM. We identified a network of 46 genes that were specifically downregulated in Malays, suggesting dysregulation of components of cellular respiration in SM of Malay individuals. We also report 28 differentially expressed gene clusters, four of which were also enriched for genes that were found in genome-wide association studies of metabolic traits and disease and correlated with variation in IR, obesity, and related traits.Conclusion: We identified extensive gene-expression changes in SM among the three Singaporean ethnicities and report specific genes and molecular pathways that might underpin and explain the differences in IR among these ethnic groups.Trial registration: ClinicalTrials.gov NCT00988819

Ethnicity-specific skeletal muscle transcriptional signatures and their relevance to insulin resistance in Singapore.

Context Insulin resistance (IR) and obesity differ among ethnic groups in Singapore, with the Malays more obese yet less IR than Asian-Indians. However, the molecular basis underlying these differences is not clear. Objective As the skeletal muscle (SM) is metabolically relevant to IR, we investigated molecular pathways in SM that are associated with ethnic differences in IR, obesity, and related traits. Design, Setting, and Main Outcome Measures We integrated transcriptomic, genomic, and phenotypic analyses in 156 healthy subjects representing three major ethnicities in the Singapore Adult Metabolism Study. Patients This study contains Chinese (n = 63), Malay (n = 51), and Asian-Indian (n = 42) men, aged 21 to 40 years, without systemic diseases. Results We found remarkable diversity in the SM transcriptome among the three ethnicities, with >8000 differentially expressed genes (40% of all genes expressed in SM). Comparison with blood transcriptome from a separate Singaporean cohort showed that >95% of SM expression differences among ethnicities were unique to SM. We identified a network of 46 genes that were specifically downregulated in Malays, suggesting dysregulation of components of cellular respiration in SM of Malay individuals. We also report 28 differentially expressed gene clusters, four of which were also enriched for genes that were found in genome-wide association studies of metabolic traits and disease and correlated with variation in IR, obesity, and related traits. Conclusion We identified extensive gene-expression changes in SM among the three Singaporean ethnicities and report specific genes and molecular pathways that might underpin and explain the differences in IR among these ethnic groups

Tumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression

10.1038/ncomms11702NATURE COMMUNICATIONS7

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding: the UCON randomised controlled trial and mechanism of action study

BackgroundHeavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown.ObjectivesTo determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women.DesignRandomised, open-label, parallel group, multicentre trial with embedded mechanistic study.SettingTen UK hospitals.ParticipantsWomen with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate.InterventionsThree 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure.Main trial outcome measuresPrimary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected.Mechanistic study outcomeCellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images.ResultsSample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use.Mechanistic study resultsUlipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow.LimitationsThe urgent safety measures and premature closure of recruitment impacted final sample size.ConclusionsWe found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity.Future workThere is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents.Study registrationThis trial is registered as ISRCTN 20426843