An earlier Cochrane review of dietary advice identified insufficient evidence to assess effects of reduced salt intake on mortality or cardiovascular events.
1. To assess the long term effects of ...interventions aimed at reducing dietary salt on mortality and cardiovascular morbidity.2. To investigate whether blood pressure reduction is an explanatory factor in any effect of such dietary interventions on mortality and cardiovascular outcomes.
The Cochrane Library (CENTRAL, Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effect (DARE)), MEDLINE, EMBASE, CINAHL and PsycInfo were searched through to October 2008. References of included studies and reviews were also checked. No language restrictions were applied.
Trials fulfilled the following criteria: (1) randomised with follow up of at least six-months, (2) intervention was reduced dietary salt (restricted salt dietary intervention or advice to reduce salt intake), (3) adults, (4) mortality or cardiovascular morbidity data was available. Two reviewers independently assessed whether studies met these criteria.
Data extraction and study validity were compiled by a single reviewer, and checked by a second. Authors were contacted where possible to obtain missing information. Events were extracted and relative risks (RRs) and 95% CIs calculated.
Seven studies (including 6,489 participants) met the inclusion criteria - three in normotensives (n=3518), two in hypertensives (n=758), one in a mixed population of normo- and hypertensives (n=1981) and one in heart failure (n=232) with end of trial follow-up of seven to 36 months and longest observational follow up (after trial end) to 12.7 yrs. Relative risks for all cause mortality in normotensives (end of trial RR 0.67, 95% CI: 0.40 to 1.12, 60 deaths; longest follow up RR 0.90, 95% CI: 0.58 to 1.40, 79 deaths) and hypertensives (end of trial RR 0.97, 95% CI: 0.83 to 1.13, 513 deaths; longest follow up RR 0.96, 95% CI; 0.83 to 1.11, 565 deaths) showed no strong evidence of any effect of salt reduction. Cardiovascular morbidity in people with normal blood pressure (longest follow-up RR 0.71, 95% CI: 0.42 to 1.20, 200 events) or raised blood pressure at baseline (end of trial RR 0.84, 95% CI: 0.57 to 1.23, 93 events) also showed no strong evidence of benefit. Salt restriction increased the risk of all-cause death in those with congestive heart failure (end of trial relative risk: 2.59, 95% 1.04 to 6.44, 21 deaths). We found no information on participants health-related quality of life.
Despite collating more event data than previous systematic reviews of randomised controlled trials (665 deaths in some 6,250 participants), there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or cardiovascular morbidity in normotensive or hypertensive populations. Further RCT evidence is needed to confirm whether restriction of sodium is harmful for people with heart failure. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small blood pressure reduction achieved.
Background
Although meta-analyses of randomized controlled trials (RCTs) of salt reduction report a reduction in the level of blood pressure (BP), the effect of reduced dietary salt on cardiovascular ...disease (CVD) events remains unclear.
Methods
We searched for RCTs with follow-up of at least 6 months that compared dietary salt reduction (restricted salt dietary intervention or advice to reduce salt intake) to control/no intervention in adults, and reported mortality or CVD morbidity data. Outcomes were pooled at end of trial or longest follow-up point.
Results
Seven studies were identified: three in normotensives, two in hypertensives, one in a mixed population of normo- and hypertensives and one in heart failure. Salt reduction was associated with reductions in urinary salt excretion of between 27 and 39mmol/24h and reductions in systolic BP between 1 and 4mmHg. Relative risks (RRs) for all-cause mortality in normotensives (longest follow-up-RR: 0.90, 95% confidence interval (CI): 0.58-1.40, 79 deaths) and hypertensives (longest follow-up RR 0.96, 0.83-1.11, 565 deaths) showed no strong evidence of any effect of salt reduction CVD morbidity in people with normal BP (longest follow-up: RR 0.71, 0.42-1.20, 200 events) and raised BP at baseline (end of trial: RR 0.84, 0.57-1.23, 93 events) also showed no strong evidence of benefit. Salt restriction increased the risk of all-cause mortality in those with heart failure (end of trial RR 2.59, 1.04-6.44, 21 deaths).We found no information on participant's health-related quality of life.
Conclusions
Despite collating more event data than previous systematic reviews of RCTs (665 deaths in some 6,250 participants) there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or CVD morbidity. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small BP reduction achieved.
A more detailed review has been published and will be updated in the Cochrane Database of Systematic Reviews Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S. Reduced dietary salt for the prevention of cardiovascular disease. Cochrane Database of Systematic Reviews (CDSR) 2011, Issue 7 (see www.thecochranelibrary.com for information). This is a version of a Cochrane review, which is available in The Cochrane Library. Cochrane systematic reviews are regularly updated to include new research, and in response to feedback from readers. The results of a Cochrane review can be interpreted differently, depending on people's perspectives and circumstances. Please consider the conclusions presented carefully. They are the opinions of review authors, and are not necessarily shared by The Cochrane Collaboration.
American Journal of Hypertension, advance online publication 6 July 2011; doi:10.1038/ajh.2011.115
ObjectivesRecruiting to randomised trials is often challenging particularly when the intervention arms are markedly different. The Mesothelioma and Radical Surgery 2 randomised controlled trial (RCT) ...compared standard chemotherapy with or without (extended) pleurectomy decortication surgery for malignant pleural mesothelioma. Anticipating recruitment difficulties, a QuinteT Recruitment Intervention was embedded in the main trial phase to unearth and address barriers. The trial achieved recruitment to target with a 4-month COVID-19 pandemic-related extension. This paper presents the key recruitment challenges, and the strategies delivered to optimise recruitment and informed consent.DesignA multifaceted, flexible, mixed-method approach to investigate recruitment obstacles drawing on data from staff/patient interviews, audio recorded study recruitment consultations and screening logs. Key findings were translated into strategies targeting identified issues. Data collection, analysis, feedback and strategy implementation continued cyclically throughout the recruitment period.SettingSecondary thoracic cancer care.ResultsRespiratory physicians, oncologists, surgeons and nursing specialists supported the trial, but recruitment challenges were evident. The study had to fit within a framework of a thoracic cancer service considered overstretched where patients encountered multiple healthcare professionals and treatment views, all of which challenged recruitment. Clinician treatment biases, shaped in part by the wider clinical and research context alongside experience, adversely impacted several aspects of the recruitment process by restricting referrals for study consideration, impacting eligibility decisions, affecting the neutrality in which the study and treatment was presented and shaping patient treatment expectations and preferences. Individual and group recruiter feedback and training raised awareness of key equipoise issues, offered support and shared good practice to safeguard informed consent and optimise recruitment.ConclusionsWith bespoke support to overcome identified issues, recruitment to a challenging RCT of surgery versus no surgery in a thoracic cancer setting with a complex recruitment pathway and multiple health professional involvement is possible.Trial registration numberISRCTN ISRCTN44351742, Clinical Trials.gov NCT02040272.
There is an urgent need to populate the antimalarial clinical portfolio with new candidates because of resistance against frontline antimalarials. To discover new antimalarial chemotypes, we ...performed a high-throughput screen of the Janssen Jumpstarter library against the Plasmodium falciparum asexual blood-stage parasite and identified the 2,3-dihydroquinazolinone-3-carboxamide scaffold. We defined the SAR and found that 8-substitution on the tricyclic ring system and 3-substitution of the exocyclic arene produced analogues with potent activity against asexual parasites equivalent to clinically used antimalarials. Resistance selection and profiling against drug-resistant parasite strains revealed that this antimalarial chemotype targets PfATP4. Dihydroquinazolinone analogues were shown to disrupt parasite Na+ homeostasis and affect parasite pH, exhibited a fast-to-moderate rate of asexual kill, and blocked gametogenesis, consistent with the phenotype of clinically used PfATP4 inhibitors. Finally, we observed that optimized frontrunner analogue WJM-921 demonstrates oral efficacy in a mouse model of malaria.
Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the ...P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7′-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.
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•HT screens against P. falciparum identified the pyrazolopyridine hit chemotype.•Optimization led to analogs with potent antiparasitic activity and high solubility.•The transporter ABCI3 mediates resistance.•Analogs are slow-acting and show delayed efficacy in a malaria mouse model.
To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets ...PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound S-WJM992, were shown to inhibit PfATP4-associated Na+-ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, S-WJM992 showed appreciable efficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.
Plasmepsin X (PMX) is an aspartyl protease that processes proteins essential for Plasmodium parasites to invade and egress from host erythrocytes during the symptomatic asexual stage of malaria. PMX ...substrates possess a conserved cleavage region denoted by the consensus motif, SFhE (h=hydrophobic amino acid). Peptidomimetics reflecting the P3‐P1 positions of the consensus motif were designed and showed potent and selective inhibition of PMX. It was established that PMX prefers Phe in the P1 position, di‐substitution at the β‐carbon of the P2 moiety and a hydrophobic P3 group which was supported by modelling of the peptidomimetics in complex with PMX. The peptidomimetics were shown to arrest asexual P. falciparum parasites at the schizont stage by impairing PMX substrate processing. Overall, the peptidomimetics described will assist in further understanding PMX substrate specificity and have the potential to act as a template for future antimalarial design.
Substrate mimicry: Substrate peptidomimetics were designed and showed potent inhibition of plasmepsin X (PMX). The peptidomimetics block PMX ligand processing, arrest asexual parasites at the schizont stage and potently kill P. falciparum parasites. The peptidomimetics will further assist in the understanding of PMX selectivity and in the development of PMX targeted antimalarials.
BackgroundLong COVID is a rapidly evolving global health crisis requiring interdisciplinary support strategies that incorporate the lived experience of patients. Currently, there is a paucity of ...research documenting the day-to-day experiences of patients living with Long COVID.ObjectiveTo explore the lived experience of Long COVID patients.Study designLongitudinal, observation study.SettingAn inductive, data-driven, qualitative approach was used to evaluate hand-written diaries obtained from individuals who had been referred to a Derbyshire Long COVID clinic.Participants12 participants (11 females, age 49±10 years, 11 Caucasians) were recruited. Participants were included if they had a previous confirmed or suspected COVID-19 infection with ongoing recovery, >18 years old, understood the study requirements and provided informed consent.MethodParticipants were directed to complete self-report diaries over 16 weeks. Responses were transcribed verbatim and analysed using thematic analysis.ResultsThree key themes were highlighted: (1) understanding who helps patients manage symptoms, (2) daily activities and the impact on quality of life and health status and (3) the effect of turbulent and episodic symptom profiles on personal identity and recovery.ConclusionsThe novel challenges presented by Long COVID are complex with varying inter-related factors that are broadly impacting functional status and quality of life. Support mechanisms must incorporate the lived experiences and foster true collaborations between health professionals, patients and researchers to improve patient outcomes.Trial registration numberNCT04649957.
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