Ether Cleavage Re-Investigated: Elucidating the Mechanism of BBr3- Facilitated Demethylation of Aryl Methyl Ethers

Boron tribromide is a versatile reagent utilized in diverse areas ranging from polymer chemistry to natural product synthesis.[1] Owing its high reactivity to the Lewis acidic boron center, BBr3 reactions include haloborylation,[2] boron–silicon exchange,[3] and rearrangement of 7,7-diphenylhydromorphone derivatives.[4] While there is no shortage in the diversity of BBr3-mediated reactions, many of the mechanisms for these transformations have not been fully elucidated. In this report we investigate the mechanism of ether cleavage by BBr3 [5–10] in anisole. Conceptually, demethylation of anisole is initiated by the formation of an ether adduct 1 followed by the loss of bromide. Free bromide nucleophilically attacks the methyl group of the cationic intermediate (2) cleaving the C–O bond and producing PhOBBr2, which undergoes hydrolysis upon aqueous work-up. While this pathway (Scheme 1) at first appears to be viable, we calculated that the formation of 2 and bromide in dichloromethane is thermodynamically inaccessible (ΔG = +38.9 kcal/mol). Recently, alternative mechanisms for ether cleavage were proposed by Sousa and Silva that involve unimolecular or bimolecular rate-determining steps that circumvent formation of bromide in solution (Scheme 2).[11] While a unimolecular process is kinetically favored for ethers containing one or more substituents (e.g. branched alkyl) that stabilize carbocation character in an SN1-like transition state, this barrier for demethylation of primary C atoms, like in the methyl group of anisole, lies too high on the potential energy surface to be accessible under reported reaction conditions. They found that a bimolecular process (Scheme 2, bottom) decreases the kinetic barrier for anisole demethylation significantly. During this reaction pathway, one of the bromides of the first ether adduct nucleophilically attacks the methyl group of the second ether adduct. This is analogous to an SN2 reaction with 180o attack of the methyl group by a bromide in the nucleophilic ether adduct. However, this bimolecular pathway produces two highly charged intermediates 2 and 3 that Sousa and Silva did not investigate. Their computational investigation stopped with the calculation of the initial kinetic barrier.[11] We speculate that these charged intermediates may undergo a similar bimolecular reaction to yield two equivalents of PhOBBr2 and MeBr. Moreover, if charged intermediates are formed then we believe an important set of mechanistic pathways may have been overlooked, namely, those where Lewis acidic BBr3 abstracts bromide from the ether complex to form BBr4 – in a mechanism related to the pathway introduced in Scheme 1

Effectiveness of oseltamivir prophylaxis in influenza outbreaks in residential aged care

Influenza outbreaks in Aged Care Facilities (ACFs) can lead to hospitalizations and deaths. Influenza can spread rapidly through ACFs if precautionary measures are not taken. Along with influenza vaccination and precautionary hygiene measures, Oseltamivir Prophylaxis (OP) may be effective in reducing the attack rate of influenza by preventing new cases. A cohort study was carried out to investigate the effectiveness of OP use during influenza outbreaks in ACFs located within South Western Sydney Local Health District from 1 January 2015 to 31 December 2018. The main outcome assessed was the rate of OP failure (new cases of influenza in patients treated with OP) among ACF residents. Subgroups and various predictors of OP failure were investigated including presence of a dementia ward, high care ward, and days to Public Health Unit (PHU) notification. The cohort consisted of 86 ACF outbreaks involving 10,064 residents. OP prevented 90% of influenza cases during influenza outbreaks [0.1 RR (95% confidence interval (CI): 0.08–0.12); P < 0.0001]. ACFs with dementia wards had a 44% (0.56 relative risk (RR) (95% CI: 0.34–0.93); P < 0.05) lower OP failure rate. ACFs with high level care had an 87% (0.13 RR (95% CI: 0.05–0.38); P < 0.05) lower OP failure rate. OP is highly effective in preventing new cases of influenza during outbreaks in ACFs, especially in ACFs with dementia or high care wards. Mandatory reporting of influenza outbreaks to PHUs would ensure that ACFs are supported throughout the outbreak, which will facilitate reductions in hospitalizations and mortality. © 2020 South Western Sydney Local Health District

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Interlaboratory Comparison of Extractable Organofluorine Measurements in Groundwater and Eel (Anguilla rostrata): Recommendations for Methods Standardization

Research on per- and polyfluoroalkyl substances (PFAS) frequently incorporates organofluorine measurements, particularly because they could support a class-based approach to regulation. However, standardized methods for organofluorine analysis in a broad suite of matrices are currently unavailable, including a method for extractable organofluorine (EOF) measured using combustion ion chromatography (CIC). Here, we report the results of an international interlaboratory comparison. Seven laboratories representing academia, government, and the private sector measured paired EOF and PFAS concentrations in groundwater and eel (Anguilla rostrata) from a site contaminated by aqueous film-forming foam. Among all laboratories, targeted PFAS could not explain all EOF in groundwater but accounted for most EOF in eel. EOF results from all laboratories for at least one replicate extract fell within one standard deviation of the interlaboratory mean for groundwater and five out of seven laboratories for eel. PFAS spike mixture recoveries for EOF measurements in groundwater and eel were close to the criterion (±30%) for standardized targeted PFAS methods. Instrumental operation of the CIC such as replicate sample injections was a major source of measurement uncertainty. Blank contamination and incomplete inorganic fluorine removal may introduce additional uncertainties. To elucidate the presence of unknown organofluorine using paired EOF and PFAS measurements, we recommend that analysts carefully consider confounding methodological uncertainties such as differences in precision between measurements, data processing steps such as blank subtraction and replicate analyses, and the relative recoveries of PFAS and other fluorine compounds.publishedVersio

Contributions and perspectives of Indigenous Peoples to the study of mercury in the Arctic

Arctic Indigenous Peoples are among the most exposed humans when it comes to foodborne mercury (Hg). In response, Hg monitoring and research have been on-going in the circumpolar Arctic since about 1991; this work has been mainly possible through the involvement of Arctic Indigenous Peoples. The present overview was initially conducted in the context of a broader assessment of Hg research organized by the Arctic Monitoring and Assessment Programme. This article provides examples of Indigenous Peoples' contributions to Hg monitoring and research in the Arctic, and discusses approaches that could be used, and improved upon, when carrying out future activities. Over 40 mercury projects conducted with/by Indigenous Peoples are identified for different circumpolar regions including the U.S., Canada, Greenland, Sweden, Finland, and Russia as well as instances where Indigenous Knowledge contributed to the understanding of Hg contamination in the Arctic. Perspectives and visions of future Hg research as well as recommendations are presented. The establishment of collaborative processes and partnership/co-production approaches with scientists and Indigenous Peoples, using good communication practices and transparency in research activities, are key to the success of research and monitoring activities in the Arctic. Sustainable funding for community-driven monitoring and research programs in Arctic countries would be beneficial and assist in developing more research/ monitoring capacity and would promote a more holistic approach to understanding Hg in the Arctic. These activities should be well connected to circumpolar/international initiatives to ensure broader availability of the information and uptake in policy development

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Social media as a platform for recruitment to a national survey during the COVID-19 pandemic: a feasibility analysis (Preprint)

BACKGROUND With the improved accessibility to social media globally, health researchers are capitalising on this method to recruit participants for research studies. This has particularly been the case during COVID-19, when traditional methods of recruitment have not been able to be used. Despite this, there is limited evidence on the feasibility of social media for recruiting a national sample. OBJECTIVE This paper describes the use of social media as a tool for recruiting a national sample of adults to an online survey during the COVID-19 pandemic. METHODS Between August – October 2020, participants were recruited through Facebook via two advertisement campaigns into an online survey exploring the relationship between social determinants of health and wellbeing of adults during the COVID-19 pandemic. Data were analysed using the Facebook metrics auto generated in the Facebook Ads Manager. RESULTS In total, 9594 people were reached nationally with the paid advertisement campaigns, resulting in 1211 online survey responses. The total cost of the advertisement campaign was $649.66, resulting in an overall cost per click of$0.25 AUD. CONCLUSIONS Facebook is a feasible and cost-effective method of recruiting participants into an online survey, enabling recruitment of population groups considered hard to reach or marginalised. Recruitment through Facebook facilitated diversity, with participants varying in socioeconomic status, geographical location, educational attainment and age. </sec

Social Support for Arab People with Chronic Conditions: A Scoping Review

Social support can play a crucial role in psycho-social well-being of people with chronic conditions. There is limited information about the experiences, barriers and sources of social support of Arab people affected by chronic conditions. The purpose of this review is to explore the experiences, barriers and sources of social support of Arab people affected by chronic conditions. A scoping review of the literature, based on Preferred Reporting Items for Scoping Reviews and Meta-Analyses (PRISMA) guidelines. Articles (n = 13) were identified for appraisal based on a group of inclusion and exclusion criteria. Eight articles were included in the final analysis. Three broad themes were identified: (a) Social support benefits—physical, emotional and financial benefits; (b) Source of social support—family and friends support, and (c) Support services utilization—cultural barrier, Arab migrants language and unfamiliarity with the health system barriers. Appropriate future support programs should be tailored based on Arab cultural beliefs and the inherent responsibility of the family together inside the Arab community.</jats:p