Solution blow-spun polyacrylonitrile–polyamide thin-film nanofibrous composite membrane for the removal of fermentation inhibitors

This study aims to develop a thin-film nanofibrous composite (TFNC) membrane for removing fermentation inhibitors from a hydrolysate solution. Such membrane was fabricated via interfacial polymerization of a polyamide thin-film layer on top of a solution blow-spun polyacrylonitrile nanofiber scaffold. The effects of pH (3.29, 4.29, 8.26) and pressure (4, 6.67, 9.33, 12 bar) on the membrane’s performance were investigated. The TFNC membrane had a high pure water permeability of 21.06 L/m2-h-bar and was able to deliver satisfactory rejection coefficients at pH 3.29 and pressure of 4 bar (glucose − 91.84%, xylose − 86.06%, hydroxymethylfurfural − 20.52%, furfural − 21.32%). Different pH settings resulted in similar permeate fluxes, but increasing the pH from acidic to basic reduced the rejection coefficients due to electrostatic repulsion. Increasing the pressure increased the permeate flux but decreased the rejection coefficients. The developed membrane showed remarkable permeability and effectively removed inhibitors, useful in biorefineries

Prevalence of Obesity-Related Disease in a Danish Population – The Results of an Algorithm-Based Screening Program

Claus B Juhl,1– 4 Else Marie Bladbjerg,3,5 Bibi Gram,3 Torben Knudsen,3,6 Mette Munk Lauridsen,3,6 Niels-Peter Brøchner Nygaard,1,3,7 Nina Drøjdahl Ryg,1,2,4 Lars Skadhauge,3,8 Anna-Marie Bloch Münster3,5 1Department of Endocrinology, University Hospital of Southern Denmark, Esbjerg, Denmark; 2Steno Diabetes Center Odense, University Hospital of Southern Denmark, Odense, Denmark; 3University of Southern Denmark, Department of Regional Health Research, Odense, Denmark; 4OPEN, Open Patient Data Explorative, Odense University Hospital, Odense, Denmark; 5Department of Clinical Biochemistry, University Hospital of Southern Denmark, Esbjerg, Denmark; 6Department of Gastroenterology, University Hospital of Southern Denmark, Esbjerg, Denmark; 7Department of Neurology, University Hospital of Southern Denmark, Esbjerg, Denmark; 8Department of Occupational Medicine, University Hospital of Southern Denmark, Esbjerg, DenmarkCorrespondence: Claus B Juhl, Department of Endocrinology, University Hospital Southern Denmark, Esbjerg, DK-6700, Denmark, Tel +45 6086 7172, Email [email protected]: The prevalence of obesity continues to rise. People with obesity are at increased risk of several diseases. We tested an algorithm-based screening program for people with a BMI above 30 kg/m2 and present data on the prevalence of previously undiagnosed obesity-related diseases.Patients and Methods: Seven hundred and sixty-nine persons with BMI > 30 kg/m2 and age 18– 60 years were screened for diabetes (assessed by glycosylated hemoglobin and oral glucose tolerance test at HbA1c 43– 48 mmol/mol), sleep apnea (screened by questionnaires and assessed by cardiorespiratory monitoring at indication of sleep disorder), liver steatosis or liver fibrosis (assessed by biochemistry and fibroscan) and arterial hypertension (assessed by both office and 24-hour blood pressure measurement). A reference group of people with a BMI of 18.5– 29.9 kg/m2 was established.Results: Of those referred, 73.0% were women. We identified new diabetes in 4.2%, prediabetes in 9.1%, moderate-to-severe sleep apnea in 25.1%, increased liver fat and increased liver stiffness in 68.1% and 17.4%, respectively, and hypertension or masked hypertension in 19.0%. The prevalence of diseases was much higher among men and increased with BMI. Except for hypertension, we found few participants with undiagnosed disease in the reference group.Conclusion: An algorithm-based screening program is feasible and reveals undiagnosed obesity-related disease in a large proportion of the participants. The disproportional referral pattern calls for a tailored approach aiming to include more men with obesity.Trial Registration: Inclusion of the non-obese group was approved by the Scientific Ethics Committee of The Region of Southern Denmark (project identification number: S-20210091), and the study was reported at clinicaltrials.gov (NCT05176132).Plain Language Summary: The number of people with obesity is going up, and they are at a higher risk for various diseases. We tested a screening program for people referred with a BMI over 30 kg/m2 and presented the prevalence of diseases related to obesity. We screened 769 people aged 18 to 60 years with a BMI over 30 kg/m2 for diabetes (biochemistry and glucose tolerance test), sleep apnea (both questionnaires and home monitoring), liver disease (biochemistry and liver scan) and high blood pressure (office and 24-hour readings). We also tested a reference group of people with BMI 18.5-30 kg/m2. Among those screened, 73.0% were women. We found new cases of diabetes in 4.2%, prediabetes in 9.1%, sleep apnea in 25.1%, increased liver fat in 68.1%, increased liver stiffness in 17.4%, and hypertension or masked hypertension in 19.0%. The diseases were more common in men and increased with both higher BMI and age. Except for hypertension, we found few cases in the reference groups. The screening program uncovered undiagnosed obesity-related diseases in a large group of individuals. The uneven distribution of referrals suggests we need a customized approach to include more men with obesity.Keywords: diabetes, pre-diabetes, sleep apnea, metabolic dysfunction-associated steatotic liver disease, hypertensio

Continuous Flow Chiral Amine Racemization Applied to Continuously Recirculating Dynamic Diastereomeric Crystallizations

A new, dynamic diastereomeric crystallization method has been developed, in which the mother liquors are continuously separated, racemized over a fixed-bed catalyst, and recirculated to the crystallizer in a resolution–racemization–recycle (R3) process. Separating the racemization from crystallization overcomes problems of using catalysts in situ, that suffer conflicting sets of conditions, inhibition, and separation. Continuous racemization has been achieved through the covalent attachment of [IrCp*I2]2 SCRAM catalyst to Wang resin solid support to give a fixed-bed catalyst. One tertiary and a variety of secondary optically enriched amines have been racemized efficiently, with residence times compatible with the crystallization (2.25–30 min). The catalyst demonstrates lower turnover (TOF) than the homogeneous analogue but with reuse shows a long lifetime (e.g., 40 recycles, 190 h) giving acceptable turnover number (TON) (up to 4907). The slow release of methylamine during racemization of N-methyl amines was found to inactivate the catalyst, which could be partially reactivated using hydroiodic acid. Dynamic crystallization is achieved in the R3 process through the continual removal of the more soluble diastereomer and supply of the less soluble one. The solubility of the diastereomers was determined, and the difference correlates to the rate of resolution but is also affected by the rates of racemization, crystal growth, and dissolution. A variety of cyclic and acyclic amine salts were resolved using mandelic acid (MA) and ditoluoyl tartaric acid (DTTA) with higher resolvability (S = yield × d.e.) than the simple diastereomeric crystallization alone. Comparing resolvabilities, resolutions were 1.6–44 times more effective with the R3 process than batch, though one case was worse. Further investigation of this revealed an unusual thermodynamic switching behavior: rac-N-methylphenethylamine was initially resolved as an (S,S)-bis-alkylammonium tartrate crystal but over time became the equivalent (R,S) salt. Thermal, mixing, concentration, stoichiometry, and seeding conditions were all found to affect the onset of the switching behavior which is only associated with difunctional resolving reagents

Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial

BACKGROUND: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiotherapy versus pelvic radiotherapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). PATIENTS AND METHODS: 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiotherapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiotherapy alone. Toxicity was graded using CTCAE v3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28-subscales and compared to normative-data. An as-treated analysis was performed. RESULTS: Median follow up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiotherapy versus 46 (24%) who had received radiotherapy (p=0.008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, p=0.18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiotherapy in 6% (vs 0% after radiotherapy, p<0.001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, p<0.001 at 3 years; 24% vs 9%, p=0.002 at 5 years). Until 3 years, more patients who had chemoradiotherapy reported limb weakness (21% vs 5%, p<0.001) and lower physical (79 vs 87, p<0.001) and role functioning (78 vs 88, p<0.001) scores. Both treatment groups reported similar long-term global health/QOL scores, which were better than those of the normative-population. CONCLUSION: This study shows a long-lasting, clinically relevant, negative impact of chemoradiotherapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer

Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

This is the final version. Available on open access from Elsevier via the DOI in this recordData sharing: Data can be shared with qualifying researchers who submit a proposal with a valuable research question as assessed by a committee formed from the Trial Management Group, including senior statistical and clinical representation. A contract should be signed. Requests should be directed to [email protected] Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications. Methods In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580. Findings The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI −0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI −1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19. Interpretation Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK.UK Research and InnovationUK Department of Health and Social Car

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial

This is the final version. Available on open access from Elsevier via the DOI in this recordData sharing; Data can be shared with qualifying researchers who submit a proposal with a valuable research question as assessed by a committee formed from the trial management group, including senior statistical and clinical representation. A contract should be signed.Background A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. Methods PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 μg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. Findings The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI –0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). Interpretation Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications.National Institute for Health Research (NIHR)Wellcome Trus

Platform Randomised trial of INterventions against COVID-19 in older peoPLE (PRINCIPLE): protocol for a randomised, controlled, open-label, adaptive platform, trial of community treatment of COVID-19 syndromic illness in people at higher risk

Introduction: There is an urgent need to idenfy treatments for COVID-19 that reduce illness duration and hospital admission in those at higher risk of a longer illness course and complications. Methods and analysis: The Platform Randomised trial of INterventions against COVID-19 In older peoPLE trial is an open-label, multiarm, prospective, adaptive platform, randomised clinical trial to evaluate potential treatments for COVID-19 in the community. A master protocol governs the addition of new interventions as they become available, as well as the inclusion and cessation of existing intervention arms via frequent interim analyses. The first three interventions are hydroxychloroquine, azithromycin and doxycycline. Eligible participants must be symptomatic in the community with possible or confirmed COVID-19 that started in the preceding 14 days and either (1) aged 65 years and over or (2) aged 50–64 years with comorbidities. Recruitment is through general practice, health service helplines, COVID-19 ‘hot hubs’ and directly through the trial website. Participants are randomised to receive either usual care or a study drug plus usual care, and outcomes are collected via daily online symptom diary for 28 days from randomisation. The research team contacts participants and/or their study partner following days 7, 14 and 28 if the online diary is not completed. The trial has two coprimary endpoints: time to first self-report of feeling recovered from possible COVID-19 and hospital admission or death from possible COVID-19 infection, both within 28 days from randomisation. Prespecified interim analyses assess efficacy or futility of interventions and to modify randomisation probabilities that allocate more participants to interventions with better outcomes

One size fits all? High frequency trading, tick size changes and the implications for exchanges: market quality and market structure considerations

This paper offers a systematic review of the empirical literature on the implications of tick size changes for exchanges. Our focus is twofold: first, we are concerned with the market quality implications of a change in the minimum tick size. Second, we are interested in the implications of changes in the minimum tick size on market structure. We show that there is a large body of empirical literature that documents a decrease in transaction costs following a decrease in the minimum tick size. However, even though market liquidity increases, the incentive to provide market making activities decreases. We document a strong link between the minimum tick size regulations and the recent increase in high frequency trading activity. A smaller tick enhances the price discovery process. However, the question of how multiple tick size regimes affect market liquidity in a fragmented market remains to be answered. Finally, we identify topics for future research; we discuss the empirical literature on the minimum trade unit and the recent calls for a minimum resting time for quotes