Looking back to look forward: Surviving COVID-19 and the future of the NHS.

The COVID-19 pandemic affected healthcare systems worldwide, including the National Health Service (NHS). It drastically changed the practice and delivery of healthcare and laid bare longstanding structural flaws. It also brought a time of innovation and digitalisation and renewed appreciation of the role of public health. This paper offers a thematic summary of a debate held in December 2021 by the University of Edinburgh School of Medicine. It featured a multi-specialty panel of doctors and patient representative discussing the likely impact of the pandemic on the future of NHS. It serves as a reflection point on the pressures the NHS has faced since and their likely genesis at a time when the impact of the pandemic on staff risks being forgotten.

4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy.

The lead optimization of a series of potent azaindole IKK2 inhibitors is described. Optimization of the human whole blood activity and selectivity over IKK1 in parallel led to the discovery of 16, a potent and selective IKK2 inhibitor showing good efficacy in a rat model of neutrophil activation.

Predicting mortality and uptake of renal replacement therapy in patients with stage 4 chronic kidney disease.

BACKGROUND: Novel strategies are required to efficiently manage the increasing number of patients diagnosed with chronic kidney disease (CKD). We sought to identify factors predicting outcome in patients with stage 4 CKD and to determine whether low-risk patients could be managed in primary care. METHODS: We performed a two-centre, retrospective cohort study including 396 patients with stage 4 CKD referred to nephrology clinics from 1998 to 2002. We utilized electronic databases to determine the incidence of renal replacement therapy (RRT) and mortality and the rate of deterioration in estimated glomerular filtration rate (eGFR) to the year end 2005. RESULTS: This was an elderly cohort, with 71.7% of patients aged > or =65 years. The risk of surviving to require dialysis fell with increasing age (HR 0.44; 95% CI: 0.23-0.84 for those >74 years verses those <65 years), in part due to the slower rate of decline in renal function in older patients (median fall in eGFR was -2.25, -1.38 and -0.86 ml/ min/1.73 m(2)/year in those aged <65 years, 65-74 years and >74 years, respectively, P < 0.0001). Additional independent risk factors predicting RRT included: high baseline proteinuria (HR 6.26; 95% CI: 2.74-14.23 for >3 g/24 h versus <0.3 g/24 h), greater early decline in renal function (HR 3.86; 95% CI: 2.34-6.38 for > or =4 ml/min/1.73 m(2)/year versus <4 ml/min/1.73 m(2)/year), low baseline eGFR (HR 2.92; 95% CI: 1.61-5.30 for 15-19 versus 25-29 ml/min/1.73 m(2)) and low haemoglobin (HR 3.16; 95% CI: 1.64-6.08 for <10 versus >12 g/dl). The 98 (24.7%) patients discharged to primary care had more stable renal function than those remaining under nephrology care (median change in eGFR of +0.20 versus -1.88 ml/ min/1.73 m(2)/year, P = 0.0001). CONCLUSIONS: Most patients with stage 4 CKD, in particular the elderly, die without commencing RRT. Patients at low risk of progression can be identified and discharged safely to primary care with an active management plan.

4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors.

The synthesis and SAR of a novel series of IKK2 inhibitors are described. Modification around the hinge binding region of the 7-azaindole led to a series of potent and selective inhibitors with good cellular activity.

Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

Prospective management of end-stage renal failure within a conservative care programme.

Progression to end-stage renal disease (ESRD) is a major issue for heath care systems both clinically and financially. Given dialysis may not prolong life, and may indeed impair quality of life, alternative options for these patients such as conservative care are urgently needed. We appointed a dialysis charge nurse who had many years of experience of working with patients on dialysis to spearhead the newly set up Conservative Care Programme (CCP) in the Edinburgh Renal Unit. The rationale was to work as part of the renal multidisciplinary team to support patients and their families to make an informed shared decision whether to opt for dialysis or to follow the CCP. From the perspective of the patients, their families and carers we have received positive feedback since starting the CCP - thank you cards; phone calls both to the CCP Nurse Specialist and the renal unit affirming the positive experience patients had during the conservative management of their renal failure. Whilst continuing to provide the best quality of care to renal patients in NHS Lothian and Borders, the number of prevalent dialysis patients in our catchment area has fallen significantly over the last few years as demonstrated by Scottish Renal Registry data. These benefits are potentially applicable to other renal units across the UK.

Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.

A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.