Encapsulation of iron(III) protoporphyrin IX and tetraphenylporphyrin in metal-organic frameworks for application as heterogeneous oxidation catalysts

Two MOFs, [H2N(CH3)2][Zn3(TATB2(HCOO)]·HN(CH3)2·DMF·6H2O (1) and ZnHKUST-1 (2) (TATB = 4,4′,4″-s-triazine-2,4,6-triyl-tribenzoate) were investigated as potential hosts to encapsulate Fe(III) protoporphyrin IX (ferrihaem = Fe(III)PPIX) and Fe(III) tetraphenylporphyrin (Fe(III)TPP). Methyl orange (MO) adsorption was used as an initial model for substrate uptake in MOFs 1 and 2. MOF 1 showed good adsorption of MO (10.3 ± 0.8 mg.g-1 ) which could undergo in situ protonation upon exposure to aqueous HCl vapour. By contrast MO uptake by 2 was much lower (2 ± 1 mg.g-1 ) and PXRD indicated structural instability on exposure to water was the likely cause. Two methods for Fe(III)PPIX incorporation into 1 were investigated: soaking and encapsulation. Encapsulation was verified by SEM-EDS and showed comparable concentrations of Fe(III)PPIX on exposed interior surfaces and on the original surface of fractured crystals. SEM EDS results were consistent with ICP-OES data on bulk material (1.2 ± 0.1 mass % Fe). PXRD data showed that the framework in 1 was unchanged after encapsulation of Fe(III)PPIX. MO adsorption (6 ± 1 mg.g1 ) by Fe(III)PPIX-1 confirmed there is space for substrate diffusion into the framework, while the UV-visible spectrum of solubilized crystals confirmed that Fe(III)PPIX retained its integrity. A solid-state UV-visible spectrum of Fe(III)PPIX-1 indicated that Fe(III)PPIX was not in a µ-oxo dimeric form. Although single-crystal XRD data did not allow for full refinement of the encapsulated Fe(III)PPIX molecule owing to disorder of the metalloporphyrin, the Fe atom and pyrrole N atoms were located, enabling rigid-body modelling of the porphine core. For comparison, Fe(III)PPIX was further encapsulated in 2, forming Fe(III)PPIX-2. Reaction ABSTRACT of 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulphonic acid (ABTS) with H2O2, catalysed by Fe(III)PPIX-1 and -2 showed that Fe(III)PPIX-1 is significantly more efficient than Fe(III)PPIX-2 and is superior to solid Fe(III)PPIX-Cl due to the faster initial rate of reaction as well as the greater conversion of ABTS to ABTS●+ . Both frameworks 1 and 2 were also investigated as potential hosts to encapsulate Fe(III) tetraphenylporphyrin (Fe(III)TPP). Attempts to encapsulate Fe(III)TPP into 1 were unsuccessful, but Fe(III)TPP was successfully encapsulated into 2, forming Fe(III)TPP-2. The framework was characterised by PXRD and SEM-EDS confirmed uniform distribution of Fe(III)TPP through the framework. The loading of Fe(III)TPP determined using ICP-OES (0.604 ± 0.008 Fe mass %) agreed well with SEM-EDS data. Single crystals of Fe(III)TPP-2 were obtained and structure determination showed that the Fe(III) porphyrin was positionally disordered over three positions. The instability of Fe(III)TPP-2 in the presence of H2O resulted in it being an inappropriate choice as an oxidation catalyst. The kinetics of ABTS oxidation by H2O2 catalysed by Fe(III)PPIX-1 were further investigated. The peroxidatic activity of this heterogeneous system conforms to a rate law identical to that observed in solution with no discernible influence of particle size, suggesting that the MOF system closely mimics the solution state. The proposed rate law indicates a reaction mechanism with two possible pathways, as suggested for the same reaction in solution. The major pathway describes the coordination of H2O2 to the Fe(III) centre and subsequent formation of a high valent intermediate, while the minor pathway describes the same process preceded by ABTS coordination to the Fe(III) centre forming a six-coordinate complex. The further application of Fe(III)PPIX-1 as an oxidation catalyst was probed by investigating the catalytic oxidation of hydroquinone, thymol, benzyl alcohol and phenyl ethanol by tert-butyl-hydroperoxide ( tBuOOH). Reactions were successful and showed t1/2 values that increase with increasing substrate molecular volume

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Heterogeneous catalysis with encapsulated haem and other synthetic porphyrins: Harnessing the power of porphyrins for oxidation reactions

Encapsulated metalloporphyrins have been widely studied for their use as efficient heterogeneous catalysts, inspired by the known catalytic activity of porphyrins in haemoproteins. The oxidation of organic substrates by haemoproteins is one of the well-known roles of these proteins, in which the haem (ferriprotoporphyrin IX = FePPIX) cofactor is the centre of reactivity. While these porphyrins are highly efficient catalysts in the protein environment, once removed, they quickly lose their reactivity. It is for this reason that they have garnered much interest in the field of heterogeneous catalysis of oxidation reactions. This review details current research in the field, focusing on the application of encapsulated haem, and other synthetic metalloporphyrins, applied to oxidation reactions

Fe(III) Protoporphyrin IX Encapsulated in a Zinc Metal–Organic Framework Shows Dramatically Enhanced Peroxidatic Activity

Two MOFs, [H₂N­(CH₃)₂]­[Zn₃(TATB)₂­(HCOO)]·HN­(CH₃)₂·DMF·6H₂O (<b>1</b>) and Zn-HKUST-1 (<b>2</b>), were investigated as potential hosts to encapsulate Fe­(III) heme (Fe­(III) protoporphyrin IX = Fe­(III)­PPIX). Methyl orange (MO) adsorption was used as an initial model for substrate uptake. MOF <b>1</b> showed good adsorption of MO (10.3 ± 0.8 mg g^–1) which could undergo <i>in situ</i> protonation upon exposure to aqueous HCl vapor. By contrast, MO uptake by <b>2</b> was much lower (2 ± 1 mg g^–1), and PXRD indicated that structural instability on exposure to water was the likely cause. Two methods for Fe­(III)­PPIX-<b>1</b> preparation were investigated: soaking and encapsulation. Encapsulation was verified by SEM-EDS and showed comparable concentrations of Fe­(III)­PPIX on exposed interior surfaces and on the original surface of fractured crystals. SEM-EDS results were consistent with ICP-OES data on bulk material (1.2 ± 0.1 mass % Fe). PXRD data showed that the framework in <b>1</b> was unchanged after encapsulation of Fe­(III)­PPIX. MO adsorption (5.8 ± 1.2 mg g^–1) by Fe­(III)­PPIX-<b>1</b> confirmed there is space for substrate diffusion into the framework, while the UV–vis spectrum of solubilized crystals confirmed that Fe­(III)­PPIX retained its integrity. A solid-state UV–vis spectrum of Fe­(III)­PPIX-<b>1</b> indicated that Fe­(III)­PPIX was not in a μ-oxo dimeric form. Although single-crystal XRD data did not allow for full refinement of the encapsulated Fe­(III)­PPIX molecule owing to disorder of the metalloporphyrin, the Fe atom and pyrrole N atoms were located, enabling rigid-body modeling of the porphine core. Reaction of 2,2′-azino-bis­(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) with H₂O₂, catalyzed by Fe­(III)­PPIX-<b>1</b> and -<b>2</b>, showed that Fe­(III)­PPIX-<b>1</b> is significantly more efficient than Fe­(III)­PPIX-<b>2</b> and is superior to solid Fe­(III)­PPIX-Cl. Fe­(III)­PPIX-<b>1</b> was used to catalyze the oxidation of hydroquinone, thymol, benzyl alcohol, and phenyl ethanol by <i>tert</i>-butyl-hydroperoxide with <i>t</i>_1/2 values that increase with increasing substrate molecular volume