Incorporating the patient experience into clinical guidelines: recommendations for researchers and guideline developers

Focusing on a specific example from community care, this article argues that clinical guidelines will be better and more usable if they incorporate the findings of high-quality, qualitative research. We suggest the development and adoption of guidelines which take a holistic approach to the individual and their circumstances. These should take account of the best available evidence in terms of which treatments, devices or lifestyle changes are most effective in a particular instance, and how these are affected by the day-to-day life of patients. In so doing, clinical guidelines will become representative of the patient population to whom they relate and thus truly evidence based. We offer below one particular example of where the incorporation of qualitative evidence will improve the usability of clinical guidelines

Interventions for preventing delirium in older people in institutional long-term care

BACKGROUND: Delirium is a common and distressing mental disorder. It is often caused by a combination of stressor events in susceptible people, particularly older people living with frailty and dementia. Adults living in institutional long-term care (LTC) are at particularly high risk of delirium. An episode of delirium increases risks of admission to hospital, development or worsening of dementia and death. Multicomponent interventions can reduce the incidence of delirium by a third in the hospital setting. However, it is currently unclear whether interventions to prevent delirium in LTC are effective. This is an update of a Cochrane Review first published in 2014. OBJECTIVES: To assess the effectiveness of interventions for preventing delirium in older people in institutional long-term care settings. SEARCH METHODS: We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group (CDCIG) 's Specialised Register of dementia trials (dementia.cochrane.org/our-trials-register), to 27 February 2019. The search was sufficiently sensitive to identify all studies relating to delirium. We ran additional separate searches in the Cochrane Central Register of Controlled Trials (CENTRAL), major healthcare databases, trial registers and grey literature sources to ensure that the search was comprehensive. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-randomised controlled trials (cluster-RCTs) of single and multicomponent, non-pharmacological and pharmacological interventions for preventing delirium in older people (aged 65 years and over) in permanent LTC residence. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcomes were prevalence, incidence and severity of delirium; and mortality. Secondary outcomes included falls, hospital admissions and other adverse events; cognitive function; new diagnoses of dementia; activities of daily living; quality of life; and cost-related outcomes. We used risk ratios (RRs) as measures of treatment effect for dichotomous outcomes, hazard ratios (HR) for time-to-event outcomes and mean difference (MD) for continuous outcomes. For each outcome, we assessed the overall certainty of the evidence using GRADE methods. MAIN RESULTS: We included three trials with 3851 participants. All three were cluster-RCTs. Two of the trials were of complex, single-component, non-pharmacological interventions and one trial was a feasibility trial of a complex, multicomponent, non-pharmacological intervention. Risk of bias ratings were mixed across the three trials. Due to the heterogeneous nature of the interventions, we did not combine the results statistically, but produced a narrative summary.It was not possible to determine the effect of a hydration-based intervention on delirium incidence (RR 0.85, 95% confidence interval (CI) 0.18 to 4.00; 1 study, 98 participants; very low-certainty evidence downgraded for risk of bias and very serious imprecision). This study did not assess delirium prevalence, severity or mortality.The introduction of a computerised system to identify medications that may contribute to delirium risk and trigger a medication review was probably associated with a reduction in delirium incidence (12-month HR 0.42, CI 0.34 to 0.51; 1 study, 7311 participant-months; moderate-certainty evidence downgraded for risk of bias) but probably had little or no effect on mortality (HR 0.88, CI 0.66 to 1.17; 1 study, 9412 participant-months; moderate-certainty evidence downgraded for imprecision), hospital admissions (HR 0.89, CI 0.72 to 1.10; 1 study, 7599 participant-months; moderate-certainty evidence downgraded for imprecision) or falls (HR 1.03, CI 0.92 to 1.15; 1 study, 2275 participant-months; low-certainty evidence downgraded for imprecision and risk of bias). Delirium prevalence and severity were not assessed.In the enhanced educational intervention study, aimed at changing practice to address key delirium risk factors, it was not possible to determine the effect of the intervention on delirium incidence (RR 0.62, 95% CI 0.16 to 2.39; 1 study, 137 resident months; very low-certainty evidence downgraded for risk of bias and serious imprecision) or delirium prevalence (RR 0.57, 95% CI 0.15 to 2.19; 1 study, 160 participants; very low-certainty evidence downgraded for risk of bias and serious imprecision). There was probably little or no effect on mortality (RR 0.82, CI 0.50 to 1.34; 1 study, 215 participants; moderate-certainty evidence downgraded for imprecision). The intervention was probably associated with a reduction in hospital admissions (RR 0.67, CI 0.57 to 0.79; 1 study, 494 participants; moderate-certainty evidence downgraded due to indirectness). AUTHORS' CONCLUSIONS: Our review identified limited evidence on interventions for preventing delirium in older people in LTC. A software-based intervention to identify medications that could contribute to delirium risk and trigger a pharmacist-led medication review, probably reduces incidence of delirium in older people in institutional LTC. This is based on one large RCT in the US and may not be practical in other countries or settings which do not have comparable information technology services available in care homes. In the educational intervention aimed at identifying risk factors for delirium and developing bespoke solutions within care homes, it was not possible to determine the effect of the intervention on delirium incidence, prevalence or mortality. This evidence is based on a small feasibility trial. Our review identified three ongoing trials of multicomponent delirium prevention interventions. We identified no trials of pharmacological agents. Future trials of multicomponent non-pharmacological delirium prevention interventions for older people in LTC are needed to help inform the provision of evidence-based care for this vulnerable group

The RNA-binding proteins Zfp36l1 and Zfp36l2 act redundantly in myogenesis.

BACKGROUND: Members of the ZFP36 family of RNA-binding proteins regulate gene expression post-transcriptionally by binding to AU-rich elements in the 3'UTR of mRNA and stimulating mRNA degradation. The proteins within this family target different transcripts in different tissues. In particular, ZFP36 targets myogenic transcripts and may have a role in adult muscle stem cell quiescence. Our study examined the requirement of ZFP36L1 and ZFP36L2 in adult muscle cell fate regulation. METHODS: We generated single and double conditional knockout mice in which Zfp36l1 and/or Zfp36l2 were deleted in Pax7-expressing cells. Immunostained muscle sections were used to analyse resting skeletal muscle, and a cardiotoxin-induced injury model was used to determine the regenerative capacity of muscle. RESULTS: We show that ZFP36L1 and ZFP36L2 proteins are expressed in satellite cells. Mice lacking the two proteins in Pax7-expressing cells have reduced body weight and have reduced skeletal muscle mass. Furthermore, the number of satellite cells is reduced in adult skeletal muscle and the capacity of this muscle to regenerate following muscle injury is diminished. CONCLUSION: ZFP36L1 and ZFP36L2 act redundantly in myogenesis. These findings add further intricacy to the regulation of the cell fate of Pax7-expressing cells in skeletal muscle by RNA-binding proteins

Mapping Rora expression in resting and activated CD4+ T cells.

The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells in general, but with an emphasis on Th2 cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment

A Novel Snf2 Protein Maintains trans-Generational Regulatory States Established by Paramutation in Maize

Paramutations represent heritable epigenetic alterations that cause departures from Mendelian inheritance. While the mechanism responsible is largely unknown, recent results in both mouse and maize suggest paramutations are correlated with RNA molecules capable of affecting changes in gene expression patterns. In maize, multiple required to maintain repression (rmr) loci stabilize these paramutant states. Here we show rmr1 encodes a novel Snf2 protein that affects both small RNA accumulation and cytosine methylation of a proximal transposon fragment at the Pl1-Rhoades allele. However, these cytosine methylation differences do not define the various epigenetic states associated with paramutations. Pedigree analyses also show RMR1 does not mediate the allelic interactions that typically establish paramutations. Strikingly, our mutant analyses show that Pl1-Rhoades RNA transcript levels are altered independently of transcription rates, implicating a post-transcriptional level of RMR1 action. These results suggest the RNA component of maize paramutation maintains small heterochromatic-like domains that can affect, via the activity of a Snf2 protein, the stability of nascent transcripts from adjacent genes by way of a cotranscriptional repression process. These findings highlight a mechanism by which alleles of endogenous loci can acquire novel expression patterns that are meiotically transmissible

Foundations of Translational Ecology

Ecologists who specialize in translational ecology (TE) seek to link ecological knowledge to decision making by integrating ecological science with the full complement of social dimensions that underlie today\u27s complex environmental issues. TE is motivated by a search for outcomes that directly serve the needs of natural resource managers and decision makers. This objective distinguishes it from both basic and applied ecological research and, as a practice, it deliberately extends research beyond theory or opportunistic applications. TE is uniquely positioned to address complex issues through interdisciplinary team approaches and integrated scientist–practitioner partnerships. The creativity and context-specific knowledge of resource managers, practitioners, and decision makers inform and enrich the scientific process and help shape use-driven, actionable science. Moreover, addressing research questions that arise from on-the-ground management issues – as opposed to the top-down or expert-oriented perspectives of traditional science – can foster the high levels of trust and commitment that are critical for long-term, sustained engagement between partners

Continuing versus stopping prestroke antihypertensive therapy in acute intracerebral hemorrhage: a subgroup analysis of the efficacy of nitric oxide in stroke trial

Background and purpose: More than 50% of patients with acute intracerebral haemorrhage (ICH) are taking antihypertensive drugs before ictus. Although antihypertensive therapy should be given long term for secondary prevention, whether to continue or stop such treatment during the acute phase of ICH remains unclear, a question that was addressed in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. Methods: ENOS was an international multicenter, prospective, randomized, blinded endpoint trial. Among 629 patients with ICH and systolic blood pressure between 140 and 220 mmHg, 246 patients who were taking antihypertensive drugs were assigned to continue (n = 119) or to stop (n = 127) taking drugs temporarily for 7 days. The primary outcome was the modified Rankin Score at 90 days. Secondary outcomes included death, length of stay in hospital, discharge destination, activities of daily living, mood, cognition, and quality of life. Results: Blood pressure level (baseline 171/92 mmHg) fell in both groups but was significantly lower at 7 days in those patients assigned to continue antihypertensive drugs (difference 9.4/3.5 mmHg, P < .01). At 90 days, the primary outcome did not differ between the groups; the adjusted common odds ratio (OR) for worse outcome with continue versus stop drugs was .92 (95% confidence interval, .45- 1.89; P = .83). There was no difference between the treatment groups for any secondary outcome measure, or rates of death or serious adverse events. Conclusions: Among patients with acute ICH, immediate continuation of antihypertensive drugs during the first week did not reduce death or major disability in comparison to stopping treatment temporarily

Diversity of Pol IV Function Is Defined by Mutations at the Maize rmr7 Locus

Mutations affecting the heritable maintenance of epigenetic states in maize identify multiple small RNA biogenesis factors including NRPD1, the largest subunit of the presumed maize Pol IV holoenzyme. Here we show that mutations defining the required to maintain repression7 locus identify a second RNA polymerase subunit related to Arabidopsis NRPD2a, the sole second largest subunit shared between Arabidopsis Pol IV and Pol V. A phylogenetic analysis shows that, in contrast to representative eudicots, grasses have retained duplicate loci capable of producing functional NRPD2-like proteins, which is indicative of increased RNA polymerase diversity in grasses relative to eudicots. Together with comparisons of rmr7 mutant plant phenotypes and their effects on the maintenance of epigenetic states with parallel analyses of NRPD1 defects, our results imply that maize utilizes multiple functional NRPD2-like proteins. Despite the observation that RMR7/NRPD2, like NRPD1, is required for the accumulation of most siRNAs, our data indicate that different Pol IV isoforms play distinct roles in the maintenance of meiotically-heritable epigenetic information in the grasses