The structures and reactivity of NHC-supported copper(i) triphenylgermyls.

Deprotonation of triphenyl germane with NHC-supported copper alkoxides afforded four novel (NHC)CuGePh3 complexes. Of these, (IPr)CuGePh3 (IPr = :C{N(2,6-iPr2C6H3)CH}2) was selected for further investigation. Analysis by EDA-NOCV indicates it to be a germyl nucleophile and its σ-bond metathesis reaction with a range of p-block halides confirmed it to be a convenient source of [Ph3Ge]-. The Cu-Ge bond of (IPr)CuGePh3 underwent π-bond insertions with tBuNCS, CS2, and PhNCO to furnish a series of germyl substituted carboxylate derivatives, (IPr)CuXC(Y)GePh3 (X = S, NPh; Y = S, NtBu, O), which were structurally characterised. (IPr)CuGePh3 inserted phenyl acetylene, providing both the Markovnikov and anti-Markovnikov products. The (NHC)CuGePh3 compounds were validated as catalytic intermediates; addition of 10 mol% of NHC-copper(i) alkoxide to a mixture of triphenyl germane and a tin(iv) alkoxide resulted in a tin/germanium cross coupling with concomitant formation of alcohol. Moreover, a catalytic hydrogermylation of Michael acceptors was developed with Ph3GeH adding to 7 activated alkenes in good conversions and yields in the presence of 10 mol% of NHC-copper(i) alkoxide. In all cases, this reaction provided the ß-germylated substrate implicating nucleophilicity at germanium.

Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance.

Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the in vitro and in vivo behavior of ADCs. Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures via a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation. In vitro, the ADCs prepared showed broadly similar potency (range: 16-34 pM) and were comparable to Adcetris® (16 pM). In vivo, the cyclodextrin containing ADCs showed greater efficacy than Adcetris® and the most efficacious variant (incorporating a 3'-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced in vivo efficacy compared to Adcetris®, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures.

Multispecialty multidisciplinary input into comorbidities along with treatment optimisation in heart failure reduces hospitalisation and clinic attendance.

AIMS: Heart failure (HF) is associated with comorbidities which independently influence treatment response and outcomes. This retrospective observational study (January 2020-June 2021) analysed the impact of monthly HF multispecialty multidisciplinary team (MDT) meetings to address management of HF comorbidities and thereby on provision, cost of care and HF outcomes. METHODS: Patients acted as their own controls, with outcomes compared for equal periods (for each patient) pre (HF MDT) versus post-MDT (multispecialty) meeting. The multispecialty MDT comprised HF cardiologists (primary, secondary, tertiary care), HF nurses, nephrologist, endocrinologist, palliative care, chest physician, pharmacist, clinical pharmacologist and geriatrician. Outcome measures were (1) all-cause hospitalisations, (2) outpatient clinic attendances and (3) cost. RESULTS: 334 patients (mean age 72.5±11 years) were discussed virtually through MDT meetings and follow-up duration was 13.9±4 months. Mean age-adjusted Charlson Comorbidity Index was 7.6±2.1 and Rockwood Frailty Score 5.5±1.6. Multispecialty interventions included optimising diabetes therapy (haemoglobin A1c-HbA1c pre-MDT 68±11 mmol/mol vs post-MDT 61±9 mmol/mol; p<0.001), deprescribing to reduce anticholinergic burden (pre-MDT 1.85±0.4 vs 1.5±0.3 post-MDT; p<0.001), initiation of renin-angiotensin aldosterone system inhibitors in HF with reduced ejection fraction (HFrEF) with advanced chronic kidney disease (9% pre vs 71% post-MDT; p<0.001). Other interventions included potassium binders, treatment of anaemia, falls assessment, management of chest conditions, day-case ascitic, pleural drains and palliative support. Total cost of funding monthly multispecialty meetings was £32 400 and resultant 64 clinic appointments cost £9600. The post-MDT study period was associated with reduction in 481 clinic appointments (cost saving £72150) and reduced all-cause hospitalisations (pre-MDT 1.1±0.4 vs 0.6±0.1 post-MDT; p<0.001), reduction of 1586 hospital bed-days and cost savings of £634 400. Total cost saving to the healthcare system was £664 550. CONCLUSION: HF multispecialty virtual MDT model provides integrated, holistic care across all healthcare tiers for management of HF and associated comorbidities. This approach is associated with reduced clinic attendances and all-cause hospitalisations, leading to significant cost savings.

Social prescribing: Exploring general practitioners' and healthcare professionals' perceptions of, and engagement with, the NHS model.

Social prescribing (SP) has rapidly expanded over recent years. Previously a bottom-up, community-led phenomenon, SP is now a formal part of structured NHS policy and practice. This study was designed to ascertain how general practitioners and other primary healthcare professionals (HCPs) within one clinical commissioning group (CCG) perceive and engage with this new NHS model. The research comprised an online survey distributed to HCPs within a predominately rural, English CCG between June and August 2021. Qualitative data were gathered and analysed using reflexive thematic analysis. Positive portrayals of SP were found, although definitions and perceptions varied greatly. Many HCPs reported high levels of engagement with SP services; yet referral rates appeared to remain significantly lower than the previously estimated 20% of primary care attendees referred for social reasons. Moreover, 96% of HCPs reported signposting patients directly to community or external services, rather than referring them to SP. This signposting, which has been positioned as a model of SP, reflects engagement with SP in practice, which is likely to have pre-dated the introduction of the fuller NHS model. HCPs may be unaware that this could be classed as a social prescription, and this type of SP remains uncaptured within NHS statistics. These results indicate an underuse of the national system set up to deliver one particular model of SP, rather than that SP does not occur. Additionally, despite national guidance issued to accompany the NHS model, practices such as referral and feedback processes, and link worker presence within practices, were not uniform even within this single CCG. Nevertheless, understanding is increasing as SP becomes embedded within primary care. The lack of consistency in referrals between practices warrants further examination in terms of equity of service choices to patients, as does the very low self-reported referral rate to SP.

Language matters: representations of 'heart failure' in English discourse-a large-scale linguistic study.

AIMS: Heart failure (HF) has a lower public profile compared with other serious health conditions, notably cancer. This discourse analysis study investigates the extent to which HF is discussed in general contemporary English, UK parliamentary debates and the ways in which HF is framed in discussions, when compared with two other serious health conditions, cancer and dementia. METHODS: The Oxford English Corpus (OEC) of 21st century English-language texts (2 billion words) and the UK Hansard Reports of parliamentary debates from 1945 to early 2021 were used to investigate the relative frequencies, contexts and use of the terms 'heart failure', 'cancer' and 'dementia'. RESULTS: In the OEC, the term 'heart failure' occurs 4.26 times per million words (pmw), 'dementia' occurs 3.68 times pmw and 'cancer' occurs 81.96 times pmw. Cancer is talked about 19 times more often than HF and 22 times more often than dementia. These are disproportionately high in relation to actual incidence: annual cancer incidence is 1.8 times that of the other conditions; annual cancer mortality is two times that caused by coronary heart disease (including HF) or dementia.'Heart failure' is used much less than 'cancer' in UK parliamentary debates (House of Commons and House of Lords) between 1945 and early 2021, and less than 'dementia' from 1990 onwards. Moreover, HF is even mentioned much less than pot-holes in UK roads and pavements. In 2018, for example, 'pot-hole/s' were mentioned over 10 times pmw, 37 times more often than 'heart failure', mentioned 0.28 times pmw. Discussions of HF are comparatively technical and formulaic, lacking survivor narratives that occur in discussions of cancer. CONCLUSIONS: HF is underdiscussed in contemporary English compared with cancer and dementia and underdiscussed in UK parliamentary debates, even compared with the less-obviously life-threatening topic of pot-holes in roads and pavements.

Coenzyme Q10 to manage chronic heart failure with a reduced ejection fraction: a systematic review and economic evaluation.

BACKGROUND: Chronic heart failure is a debilitating condition that accounts for an annual NHS spend of £2.3B. Low levels of endogenous coenzyme Q10 may exacerbate chronic heart failure. Coenzyme Q10 supplements might improve symptoms and slow progression. As statins are thought to block the production of coenzyme Q10, supplementation might be particularly beneficial for patients taking statins. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of coenzyme Q10 in managing chronic heart failure with a reduced ejection fraction. METHODS: A systematic review that included randomised trials comparing coenzyme Q10 plus standard care with standard care alone in chronic heart failure. Trials restricted to chronic heart failure with a preserved ejection fraction were excluded. Databases including MEDLINE, EMBASE and CENTRAL were searched up to March 2020. Risk of bias was assessed using the Cochrane Risk of Bias tool (version 5.2). A planned individual participant data meta-analysis was not possible and meta-analyses were mostly based on aggregate data from publications. Potential effect modification was examined using meta-regression. A Markov model used treatment effects from the meta-analysis and baseline mortality and hospitalisation from an observational UK cohort. Costs were evaluated from an NHS and Personal Social Services perspective and expressed in Great British pounds at a 2019/20 price base. Outcomes were expressed in quality-adjusted life-years. Both costs and outcomes were discounted at a 3.5% annual rate. RESULTS: A total of 26 trials, comprising 2250 participants, were included in the systematic review. Many trials were reported poorly and were rated as having a high or unclear risk of bias in at least one domain. Meta-analysis suggested a possible benefit of coenzyme Q10 on all-cause mortality (seven trials, 1371 participants; relative risk 0.68, 95% confidence interval 0.45 to 1.03). The results for short-term functional outcomes were more modest or unclear. There was no indication of increased adverse events with coenzyme Q10. Meta-regression found no evidence of treatment interaction with statins. The base-case cost-effectiveness analysis produced incremental costs of £4878, incremental quality-adjusted life-years of 1.34 and an incremental cost-effectiveness ratio of £3650. Probabilistic sensitivity analyses showed that at thresholds of £20,000 and £30,000 per quality-adjusted life-year coenzyme Q10 had a high probability (95.2% and 95.8%, respectively) of being more cost-effective than standard care alone. Scenario analyses in which the population and other model assumptions were varied all found coenzyme Q10 to be cost-effective. The expected value of perfect information suggested that a new trial could be valuable. LIMITATIONS: For most outcomes, data were available from few trials and different trials contributed to different outcomes. There were concerns about risk of bias and whether or not the results from included trials were applicable to a typical UK population. A lack of individual participant data meant that planned detailed analyses of effect modifiers were not possible. CONCLUSIONS: Available evidence suggested that, if prescribed, coenzyme Q10 has the potential to be clinically effective and cost-effective for heart failure with a reduced ejection fraction. However, given important concerns about risk of bias, plausibility of effect sizes and applicability of the evidence base, establishing whether or not coenzyme Q10 is genuinely effective in a typical UK population is important, particularly as coenzyme Q10 has not been subject to the scrutiny of drug-licensing processes. Stronger evidence is needed before considering its prescription in the NHS. FUTURE WORK: A new independent, well-designed clinical trial of coenzyme Q10 in a typical UK heart failure with a reduced ejection fraction population may be warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018106189. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 4. See the NIHR Journals Library website for further project information.

People living with chronic heart failure suffer from shortness of breath, ankle swelling, tiredness, frequent stays in hospital and reduced quality of life and have shorter lives. The NHS spends over £2 billion each year managing chronic heart failure. Coenzyme Q10 is a vitamin-like substance made by the body that helps cells produce energy. Low levels of coenzyme Q10 in heart muscle may lead to, or exacerbate, chronic heart failure. Taking coenzyme Q10 supplements might improve symptoms or slow deterioration. To the best of our knowledge, we found all randomised clinical trials of coenzyme Q10 in patients with the type of chronic heart failure caused by muscle weakness (i.e. heart failure with reduced ejection fraction, where the heart's pumping function is weaker than normal). We asked the research groups responsible for these trials to provide the patient data that they had collected in their trials. Most research groups did not share their data and so we mainly used information from published trial reports. This limited our planned analyses. We found that taking coenzyme Q10 alongside usual treatment for heart failure with reduced ejection fraction potentially reduced deaths by approximately one-third and reduced readmission to hospital by around 40%. However, these results were uncertain. Side effects were not increased. We had some concerns about how reliable the data were, and it is not clear how well the results apply to UK patients. We also worked out what the benefits and costs to the NHS would be if coenzyme Q10 became available on prescription for patients with heart failure with reduced ejection fraction. Our model found that prescription could be worthwhile; however, a new trial is needed first to make sure that coenzyme Q10 improves outcomes for patients. A new trial would be particularly important because coenzyme Q10 has not been assessed in the same way as prescribed medicines. A new trial could make sure that there is better evidence about whether or not prescribing would be a good use of NHS resources.

Patient partnership in cardiovascular clinical trials.

Patients are ultimately the end-users of medical therapies and need to be actively integrated as contributors and decision-makers in the process of product development throughout product lifecycles. This is increasingly being recognized by patients, investigators, regulators, payers, sponsors, and medical journals. However, cardiovascular research remains behind other fields in terms of the extent of patient involvement and awareness of clinical trials in cardiovascular research. True patient partnerships in cardiovascular therapeutic development may permit more rapid recognition of unmet needs, ensure alignment of product development priorities with patient priorities, improve efficiency of trials (e.g. recruitment), and ensure outcomes of value to patients are being measured in trials (e.g. quality of life). This paper reviews ongoing initiatives and remaining opportunities to accomplish contributive patient involvement in cardiovascular clinical research.

Gauge/Gravity Dynamics for Composite Higgs Models and the Top Mass.

We provide gauge/gravity dual descriptions of explicit realizations of the strong coupling sector of composite Higgs models using insights from nonconformal examples of the AdS/CFT correspondence. We calculate particle masses and pion decay constants for proposed Sp(4) and SU(4) gauge theories, where there is the best lattice data for comparison. Our results compare favorably to lattice studies and go beyond those due to a greater flexibility in choosing the fermion content. That content changes the running dynamics and its choice can lead to sizable changes in the bound state masses. We describe top partners by a dual fermionic field in the bulk. Including suitable higher dimension operators can ensure a top mass consistent with the standard model.

The impact of COVID-19 on the management of heart failure: a United Kingdom patient questionnaire study.

AIMS: The coronavirus disease 2019 (COVID-19) pandemic has created significant challenges to healthcare globally, necessitating rapid restructuring of service provision. This questionnaire survey was conducted amongst adult heart failure (HF) patients in the United Kingdom (UK), to understand the impact of COVID-19 upon HF services. METHODS AND RESULTS: The survey was conducted by the Pumping Marvellous Foundation, a UK HF patient charity. 'Survey Monkey' was used to disseminate the questionnaire in the Pumping Marvellous Foundation 's online patient group and in 10 UK hospitals (outpatient hospital and community HF clinics). There were 1050 responses collected (693/1050-66% women); 55% (579/1050) were aged over 60 years. Anxiety level was significantly higher regarding COVID-19 (mean 7 ± 2.5 on anxiety scale of 0 to 10) compared with anxiety regarding HF (6.1 ± 2.4; P < 0.001). Anxiety was higher amongst patients aged ≤60 years about HF (6.3 ± 2.2 vs. 5.9 ± 2.5 in those aged >60 years; P = 0.005) and COVID-19 (7.3 ± 2.3 vs. 6.7 ± 2.6 those aged >60 years; P < 0.001). Sixty-five per cent of respondents (686/1050) reported disruption to HF appointments (cancellation or postponement) during the lockdown period. Thirty-seven per cent reported disruption to medication prescription services, and Thirty-four per cent reported inability to access their HF teams promptly. Thirty-two per cent expressed reluctance to attend hospital (25% stated they would only attend hospital if there was no alternative, and 7% stated that they would not attend hospital at all). CONCLUSIONS: The COVID-19 pandemic has caused significant anxiety amongst HF patients regarding COVID-19 and HF. Cancellation or postponement of scheduled clinic appointments, investigations, procedures, prescription, and monitoring services were implicated as sources of anxiety.

Use of clinician-performed ultrasound in the assessment of safe umbilical venous catheter tip placement.

AIM: Safe tip placement of umbilical venous catheters (UVCs) in sick neonates is critical in minimising risk. We aimed to demonstrate the utility of clinician-performed ultrasound (CPU) in identifying UVCs that are placed within small intrahepatic portal vessels or within the heart despite the appearance of being well placed on X-ray. METHODS: This was a retrospective observational study of preterm and term neonates who had a UVC placed and the position assessed by X-ray and/or CPU according to the Royal Prince Alfred Hospital level 3 neonatal intensive care unit (NICU) guideline. Cases were identified by exporting the records of all admissions between 1 April 2015 and 30 June 2016 from the NICU's data collection database. Paper-based medical records, NICU's data collection database records and the ultrasound reporting system were reviewed to determine X-ray and CPU findings. RESULTS: A total of 157 neonates had 169 UVCs placed. CPU was performed in 77% (111). In 15 cases (14%), UVC placement on X-ray appeared appropriate based on estimated vertebral level; however, CPU demonstrated the line to be in an unsafe position (small intrahepatic portal vessel (3); right atrium (9); left atrium (3)). CONCLUSIONS: Assessment of safe UVC placement by estimations according to vertebral level on X-ray alone is inadequate. CPU offers confident localisation of the UVC tip and enables corrective manipulation of intracardiac or intrahepatic UVCs in real time. We recommend CPU as an adjunct to X-ray to ensure safe UVC placement.

"I don't go to Meetings": understanding farmer perspectives on bovine TB and biosecurity training.

In 2016, a veterinary service company, XL Farmcare UK, was awarded a Defra contract to manage a series of on-farm demonstration workshops to raise biosecurity awareness. The workshops provided free training for cattle farmers in England on the practical measures that they could take to limit the threat of bovine tuberculosis (bTB). Despite communicating these events to farmers, the number who subsequently attended them was low and the company decided to conduct research to seek explanation. Farmers were interviewed at agricultural shows, their comments analysed and the frequency of words in use were measured to produce a set of common themes. This thematic analysis provides an illustrative rather than representative picture of farmer opinions yet holds significant explanatory value for understanding the apparent lack of engagement with biosecurity training. Broad-ranging farmer perspectives can be understood through a 'typology' of feelings about bTB, particularly expressions of blame, loss, confusion, ignorance, resignation and fear. The cumulative effect amounts to one of overwhelming negativity, explaining why so many farmers disengaged from training provision; a finding with relevance and value for the way training providers plan future communication methods in relation to biosecurity risk mitigation.

A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.

OBJECTIVE: To explore the efficacy and risks of oral paracetamol in later (>2 weeks old) treatment of patent ductus arteriosus (PDA). STUDY DESIGN: A multicentre double-blind placebo-controlled randomised pilot trial in three neonatal intensive care units in Australia. Infants born <33 weeks with haemodynamically significant PDA were treated with a 5-day course of oral paracetamol or placebo. Cardiac ultrasounds were used to document haemodynamic parameters. The primary outcome analysed was ductal closure by 48 h after treatment completion. Secondary outcomes included reduction in ductal diameter >25% and safety. RESULTS: Fifty-five infants were enrolled, of whom 27 received paracetamol and 28 placebo. Eighty percent had received previous non-steroidal anti-inflammatory drug. Mean postnatal age was 25 days. Four of the 27 ducts treated with paracetamol closed vs. 0/28 treated with placebo (p = 0.05). An additional 13/27 given  paracetamol vs. 7/28 given placebo showed significant constriction (p = 0.008). No adverse effects were observed . CONCLUSIONS: There was some evidence of increased closure with oral paracetamol at postnatal age >2 weeks; however, the overall efficacy was not high.

Correction: A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.

In the published version of this paper the author Yan Chen was missed out of the author list. This has now been corrected in the HTML and PDF versions of the paper.

The use of columns of the zeolite clinoptilolite in the remediation of aqueous nuclear waste streams.

Mud Hills clinoptilolite has been used in an effluent treatment plant (SIXEP) at the Sellafield nuclear reprocessing site. This material has been used to remove 134/137Cs and 90Sr successfully from effluents for 3 decades. Samples of the zeolite have been tested in column experiments to determine their ability to remove radioactive Cs+ and Sr2+ ions under increasing concentrations of competing ions, Ca2+, Mg2+, Na+ and K+. These ions caused increased elution of Cs+ and Sr2+. Ca2+, Mg2+ and K+ were more effective competitors than Na+. For Na+, it was found that if concentration was reduced, then column performance recovered rapidly.

Management of symptomatic degenerative low-grade lumbar spondylolisthesis.

Degenerative low-grade lumbar spondylolisthesis is the most common form of spondylolisthesis.The majority of patients are asymptomatic and do not require surgical intervention.Symptomatic patients present with a combination of lower back pain, radiculopathy and/or neurogenic claudication and may warrant surgery if non-operative measures fail.There is widespread controversy regarding the indications for surgery and appropriate treatment strategies for patients with this type of spondylolisthesis.This article provides a comprehensive evidence-based review of the available literature to support the management of degenerative low-grade spondylolisthesis. Cite this article: EFORT Open Rev 2018;3:620-631. DOI: 10.1302/2058-5241.3.180020.

Advancing care of residents in care homes.

There are more than twice as many people living in care homes in the UK than there are inpatients in NHS hospitals, yet there is much less research about how to provide the best care for these 416,000 residents.

There's more to staff recruitment than pay: NHS Improvement.

Retaining staff remains a major problem for the NHS. Over the past six years the proportion of nurses leaving the health service has risen by one quarter, to top 10% in 2016.

Roald Dahl charity funds network of specialist nurses.

As the author of some of the most famous children's books, Roald Dahl's impact on the lives of young people is obvious. But less well known is his legacy in terms of helping the sick and injured.

Updated perinatal palliative standards emphasise choice and bereavement support.

Ana Todorovic's baby, Nadia, died just before birth. Ana says she received excellent care and was told when 37 weeks pregnant that Nadia was not going to survive for long.