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Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease with a key role in regulating plasma low-density lipoprotein (LDL) concentration. Since its discovery via parallel molecular biology and clinical genetics studies in 2003, work to characterize PCSK9 has shed new light on the life-cycle of the low-density lipoprotein receptor and the molecular basis of familial hypercholesterolaemia. These discoveries have also led to the advent of the PCSK9 inhibitors, a new generation of low-density lipoprotein cholesterol (LDL-C) lowering drugs. Clinical trials have shown these agents to be both safe and capable of unprecedented reductions in LDL-C, and it is hoped they may herald a new era of cardiovascular disease prevention. As such, the still evolving PCSK9 story serves as a particularly successful example of translational medicine. This review provides a summary of the principal PCSK9 research findings, which underpin our current understanding of its function and clinical relevance.

IntroductionChildhood malnutrition is widespread in low-income and middle-income countries (LMICs) and increases the frequency and severity of infections such as pneumonia. We aimed to identify studies investigating pneumonia deaths in malnourished children and estimate mortality risk by malnutrition severity.MethodsWe conducted a systematic review of MEDLINE, EMBASE and Global Health databases to identify relevant studies. We used a network meta-analysis to derive ORs of death from pneumonia for moderately and severely underweight children using low weight-for-age, the most reported measure of malnutrition. We compared meta-estimates of studies conducted before and after 2000 to assess changes in mortality risk over time. We estimated the prevalence of underweight hospitalised children from hospital-based cohort studies and calculated the population attributable fraction of in-hospital pneumonia deaths from being underweight using our results.ResultsOur network meta-analysis included 33 544 underweight children from 23 studies. The estimated OR of death from pneumonia was 2.0 (95% CI 1.6 to 2.6) and 4.6 (95% CI 3.7 to 5.9) for children moderately and severely underweight, respectively. The OR of death from pneumonia for those severely underweight was 5.3 (95% CI 3.9 to 7.4) pre-2000 and remained high post-2000 at 4.1 (95% CI 3.0 to 6.0). Prevalence of underweight children hospitalised with pneumonia varied (median 40.2%, range 19.6–66.3) but was high across many LMIC settings. We estimated a median 18.3% (range 10.8–34.6) and 40.9% (range 14.7–69.9) of in-hospital pneumonia deaths were attributable to being moderately and severely underweight, respectively.ConclusionsThe risk of death from childhood pneumonia dramatically increases with malnutrition severity. This risk has remained high in recent years with an estimated over half of in-hospital pneumonia deaths attributable to child malnutrition. Prevention and treatment of all child malnutrition must be prioritised to maintain progress on reducing pneumonia deaths.

Objectives: This protocol outlines a systematic review methodology, aiming to assess the recent evidence-base for the impact of testing strategies and approaches on access to testing, testing coverage, and linkage to care for populations at risk for specific curable sexually transmitted infections (STIs) (chlamydia, gonorrhoea, syphilis, trichomoniasis, and Mycoplasma genitalium infections). Data sources: These include MEDLINE, Embase, PsycINFO, Global Health, Cochrane Database, Epistemonikos, CINAHL Plus, and Web of Science Core Collection. Review methods: Papers reporting primary data from 1 January 2012 onwards will be included. Titles, abstracts, and full texts will be reviewed for inclusion, and data will be extracted using a pre-specified and piloted data extraction form, by two independent reviewers. Experts in the field will be contacted and interviewed for further information about ongoing or unpublished studies. A narrative synthesis of the findings will be conducted. Discussion: Outcomes of this study will inform policy makers, national and international programme coordinators, public health and clinical experts, and civil society organisations involved in STI prevention and control in EU/EEA countries and elsewhere. The review will provide a direction for future researchers and programmers seeking to improve STI testing services among key populations at high risk for STIs. Systematic review registration: In accordance with guidelines outlined in the PRISMA-P methodology, this protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 30 January 2019: CRD42019118261.

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The degree of synchronized fluctuations in neocortical network activity can vary widely during alertness. One influential idea that has emerged over the past few decades is that perceptual decisions are more accurate when the state of population activity is desynchronized. This suggests that optimal task performance may occur during a particular cortical state – the desynchronized state. Here we show that, contrary to this view, cortical state can both facilitate and suppress perceptual performance in a task-dependent manner. We performed electrical recordings from surface-implanted grid electrodes in the temporal lobe while human subjects completed two perceptual tasks. We found that when local population activity is in a synchronized state, network and perceptual performance are enhanced in a detection task and impaired in a discrimination task, but these modulatory effects are reversed when population activity is desynchronized. These findings indicate that the brain has adapted to take advantage of endogenous fluctuations in cortical state to selectively enhance different modes of sensory processing during perception in a state-dependent manner.