Structural and molecular basis of choline uptake into the brain by FLVCR2.

Choline is an essential nutrient that the human body needs in vast quantities for cell membrane synthesis, epigenetic modification and neurotransmission. The brain has a particularly high demand for choline, but how it enters the brain remains unknown1-3. The major facilitator superfamily transporter FLVCR1 (also known as MFSD7B or SLC49A1) was recently determined to be a choline transporter but is not highly expressed at the blood-brain barrier, whereas the related protein FLVCR2 (also known as MFSD7C or SLC49A2) is expressed in endothelial cells at the blood-brain barrier4-7. Previous studies have shown that mutations in human Flvcr2 cause cerebral vascular abnormalities, hydrocephalus and embryonic lethality, but the physiological role of FLVCR2 is unknown4,5. Here we demonstrate both in vivo and in vitro that FLVCR2 is a BBB choline transporter and is responsible for the majority of choline uptake into the brain. We also determine the structures of choline-bound FLVCR2 in both inward-facing and outward-facing states using cryo-electron microscopy. These results reveal how the brain obtains choline and provide molecular-level insights into how FLVCR2 binds choline in an aromatic cage and mediates its uptake. Our work could provide a novel framework for the targeted delivery of therapeutic agents into the brain.

Local and dynamic regulation of neuronal glycolysis in vivo.

Energy metabolism supports neuronal function. While it is well established that changes in energy metabolism underpin brain plasticity and function, less is known about how individual neurons modulate their metabolic states to meet varying energy demands. This is because most approaches used to examine metabolism in living organisms lack the resolution to visualize energy metabolism within individual circuits, cells, or subcellular regions. Here, we adapted a biosensor for glycolysis, HYlight, for use in Caenorhabditis elegans to image dynamic changes in glycolysis within individual neurons and in vivo. We determined that neurons cell-autonomously perform glycolysis and modulate glycolytic states upon energy stress. By examining glycolysis in specific neurons, we documented a neuronal energy landscape comprising three general observations: 1) glycolytic states in neurons are diverse across individual cell types; 2) for a given condition, glycolytic states within individual neurons are reproducible across animals; and 3) for varying conditions of energy stress, glycolytic states are plastic and adapt to energy demands. Through genetic analyses, we uncovered roles for regulatory enzymes and mitochondrial localization in the cellular and subcellular dynamic regulation of glycolysis. Our study demonstrates the use of a single-cell glycolytic biosensor to examine how energy metabolism is distributed across cells and coupled to dynamic states of neuronal function and uncovers unique relationships between neuronal identities and metabolic landscapes in vivo.

Lung Disease and Social Justice: Chronic Obstructive Pulmonary Disease as a Manifestation of Structural Violence.

Lung health, the development of lung disease, and how well a person with lung disease is able to live all depend on a wide range of societal factors. These systemic factors that adversely affect people and cause injustice can be thought of as "structural violence." To make the causal processes relating to chronic obstructive pulmonary disease (COPD) more apparent, and the responsibility to interrupt or alleviate them clearer, we have developed a taxonomy to describe this. It contains five domains: 1) avoidable lung harms (processes impacting lung development, processes that disadvantage lung health in particular groups across the life course), 2) diagnostic delay (healthcare factors; norms and attitudes that mean COPD is not diagnosed in a timely way, denying people with COPD effective treatment), 3) inadequate COPD care (ways in which the provision of care for people with COPD falls short of what is needed to ensure they are able to enjoy the best possible health, considered as healthcare resource allocation and norms and attitudes influencing clinical practice), 4) low status of COPD (ways COPD as a condition and people with COPD are held in less regard and considered less of a priority than other comparable health problems), and 5) lack of support (factors that make living with COPD more difficult than it should be, i.e., socioenvironmental factors and factors that promote social isolation). This model has relevance for policymakers, healthcare professionals, and the public as an educational resource to change clinical practices and priorities and stimulate advocacy and activism with the goal of the elimination of COPD.

Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes.

OBJECTIVE: Phase II trials suggest glucagon-like peptide-1 receptor (GLP1) agonists resolve metabolic dysfunction-associated steatohepatitis but do not affect fibrosis regression. We aimed to determine the long-term causal effect of GLP1 agonists on the risk of major adverse liver outcomes (MALO) in patients with any chronic liver disease and type 2 diabetes. DESIGN: We used observational data from Swedish healthcare registers 2010-2020 to emulate a target trial of GLP1 agonists in eligible patients with chronic liver disease and type 2 diabetes. We used an inverse-probability weighted marginal structural model to compare parametric estimates of 10-year MALO risk (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or MALO-related death) in initiators of GLP1 agonists with non-initiators. We randomly sampled 5% of the non-initiators to increase computational efficiency. RESULTS: GLP1 agonist initiators had a 10-year risk of MALO at 13.3% (42/1026) vs 14.6% in non-initiators (1079/15 633) in intention-to-treat analysis (risk ratio (RR)=0.91, 95% CI=0.50 to 1.32). The corresponding 10-year per-protocol risk estimates were 7.4% (22/1026) and 14.4% (1079/15 633), respectively (RR=0.51, 95% CI=0.14 to 0.88). The per-protocol risk estimates at 6 years were 5.4% (21/1026) vs 9.0% (933/15 633) (RR=0.60, 95% CI=0.29 to 0.90) and at 8 years 7.2% (22/1026) vs 11.7% (1036/15 633) (RR=0.61, 95% CI=0.21 to 1.01). CONCLUSION: In patients with chronic liver disease and type 2 diabetes who adhered to therapy over time, GLP1 agonists may result in lower risk of MALO. This suggests that GLP1 agonists are promising agents to reduce risk of chronic liver disease progression in patients with concurrent type 2 diabetes, although this needs to be corroborated in randomised trials.

Identifying target populations to align with decision makers' needs.

Randomized trials estimate the average treatment effect within individuals that are eligible, invited and agree to enroll. However, decision makers often require evidence that extends beyond the trial's enrolled population to inform policy or actions for their specific target population. Each decision maker has distinct target populations, the composition of which may not often align with that of the trial population. As researchers, we should identify a decision maker for whom we aim to generate evidence early in the research process. We can then specify a target population of their interest and determine if a policy or action can be informed using results from a trial alone, or if additional complementary real-world data and analysis are required. In this commentary, we outline five key groupings of decision makers: policymakers, payers, purchasers, providers, and patients. We then specify relevant target populations for decision makers interested in the effectiveness of beta-blockers following a myocardial infarction with preserved ejection fraction. Finally, we summarize the scenarios in which results from a randomized trial may or may not apply to these target populations and suggest relevant analytic approaches that can generate evidence to better align with a decision makers' needs.

Association of time spent on social media with youth cigarette smoking and e-cigarette use in the UK: a national longitudinal study.

BACKGROUND: Social media may influence children and young people's health behaviour, including cigarette and e-cigarette use. METHODS: We analysed data from participants aged 10-25 years in the UK Household Longitudinal Study 2015-2021. The amount of social media use reported on a normal weekday was related to current cigarette smoking and e-cigarette use. Generalised estimating equation (GEE) logistic regression models investigated associations of social media use with cigarette smoking and e-cigarette use. Models controlled for possible confounders including age, sex, country of UK, ethnicity, household income and use of cigarette/e-cigarettes by others within the home. RESULTS: Among 10 808 participants with 27 962 observations, current cigarette smoking was reported by 8.6% of participants for at least one time point, and current e-cigarette use by 2.5% of participants. In adjusted GEE models, more frequent use of social media was associated with greater odds of current cigarette smoking. This was particularly apparent at higher levels of use (eg, adjusted odds ratio (AOR) 3.60, 95% CI 2.61 to 4.96 for ≥7 hours/day vs none). Associations were similar for e-cigarettes (AOR 2.73, 95% CI 1.40 to 5.29 for ≥7 hours/day social media use vs none). There was evidence of dose-response in associations between time spent on social media and both cigarette and e-cigarette use (both p<0.001). Analyses stratified by sex and household income found similar associations for cigarettes; however, for e-cigarettes associations were concentrated among males and those from higher household income groups. CONCLUSIONS: Social media use is associated with increased risk of cigarette smoking and e-cigarette use. There is a need for greater research on this issue as well as potential policy responses.

The molecular mechanisms driving Plasmodium cell division.

Malaria, a vector borne disease, is a major global health and socioeconomic problem caused by the apicomplexan protozoan parasite Plasmodium. The parasite alternates between mosquito vector and vertebrate host, with meiosis in the mosquito and proliferative mitotic cell division in both hosts. In the canonical eukaryotic model, cell division is either by open or closed mitosis and karyokinesis is followed by cytokinesis; whereas in Plasmodium closed mitosis is not directly accompanied by concomitant cell division. Key molecular players and regulatory mechanisms of this process have been identified, but the pivotal role of certain protein complexes and the post-translational modifications that modulate their actions are still to be deciphered. Here, we discuss recent evidence for the function of known proteins in Plasmodium cell division and processes that are potential novel targets for therapeutic intervention. We also identify key questions to open new and exciting research to understand divergent Plasmodium cell division.

Malaria and other infections induce polyreactive antibodies that impact SARS-CoV-2 seropositivity estimations in endemic settings.

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence is used to estimate the proportion of individuals within a population previously infected, to track viral transmission, and to monitor naturally and vaccine-induced immune protection. However, in sub-Saharan African settings, antibodies induced by higher exposure to pathogens may increase unspecific seroreactivity to SARS-CoV-2 antigens, resulting in false positive responses. To investigate the level and type of unspecific seroreactivitiy to SARS-CoV-2 in Africa, we measured immunoglobulin G (IgG), IgA, and IgM to a broad panel of antigens from different pathogens by Luminex in 602 plasma samples from African and European subjects differing in coronavirus disease 2019, malaria, and other exposures. Seroreactivity to SARS-CoV-2 antigens was higher in prepandemic African than in European samples and positively correlated with antibodies against human coronaviruses, helminths, protozoa, and especially Plasmodium falciparum. African subjects presented higher levels of autoantibodies, a surrogate of polyreactivity, which correlated with P. falciparum and SARS-CoV-2 antibodies. Finally, we found an improved sensitivity in the IgG assay in African samples when using urea as a chaotropic agent. In conclusion, our data suggest that polyreactive antibodies induced mostly by malaria are important mediators of the unspecific anti-SARS-CoV-2 responses, and that the use of dissociating agents in immunoassays could be useful for more accurate estimates of SARS-CoV-2 seroprevalence in African settings.

High volume, low volume, or pills, which way should we go? a review of bowel preparation for colonoscopy.

PURPOSE OF REVIEW: Colorectal cancer (CRC) is the second leading cause of adult cancer-related deaths in the United States. Colonoscopy is the gold standard for CRC screening. Adequate bowel preparation prior to colonoscopy is essential for good visualization, which results in higher polyp detection rates and shorter procedural times. Achieving adequate preparation prior to colonoscopy is accomplished approximately 75% of the time. This review covers current recommendations and recent updates in bowel preparation for colonoscopy. RECENT FINDINGS: Split-dose bowel preparation is recommended, but recent studies show that same day, low-volume preparations are noninferior. Low-volume polyethylene glycol with electrolytes + ascorbic acid can achieve high-quality bowel preparation and 1-day, low-residue diets prior to colonoscopy, particularly prepackaged low-residue diets, can lead to better outcomes. Utilizing visual aids and artificial intelligence in the form of smartphone applications and quality prediction systems can also lead to higher rates of bowel preparation adequacy. SUMMARY: An individualized approach should be used to decide on the best preparation option for patients. Lower volume, same day preparations are available and lead to better patient tolerability and compliance, along with less stringent precolonoscopy diets. Smartphone applications and artificial intelligence will allow us to better educate and guide patients with regards to following preparation instructions.

Western diet consumption impairs memory function via dysregulated hippocampus acetylcholine signaling.

Western diet (WD) consumption during early life developmental periods is associated with impaired memory function, particularly for hippocampus (HPC)-dependent processes. We developed an early life WD rodent model associated with long-lasting HPC dysfunction to investigate the neurobiological mechanisms mediating these effects. Rats received either a cafeteria-style WD (ad libitum access to various high-fat/high-sugar foods; CAF) or standard healthy chow (CTL) during the juvenile and adolescent stages (postnatal days 26-56). Behavioral and metabolic assessments were performed both before and after a healthy diet intervention period beginning at early adulthood. Results revealed HPC-dependent contextual episodic memory impairments in CAF rats that persisted despite the healthy diet intervention. Given that dysregulated HPC acetylcholine (ACh) signaling is associated with memory impairments in humans and animal models, we examined protein markers of ACh tone in the dorsal HPC (HPCd) in CAF and CTL rats. Results revealed significantly lower protein levels of vesicular ACh transporter in the HPCd of CAF vs. CTL rats, indicating chronically reduced ACh tone. Using intensity-based ACh sensing fluorescent reporter (iAChSnFr) in vivo fiber photometry targeting the HPCd, we next revealed that ACh release during object-contextual novelty recognition was highly predictive of memory performance and was disrupted in CAF vs. CTL rats. Neuropharmacological results showed that alpha 7 nicotinic ACh receptor agonist infusion in the HPCd during training rescued memory deficits in CAF rats. Overall, these findings reveal a functional connection linking early life WD intake with long-lasting dysregulation of HPC ACh signaling, thereby identifying an underlying mechanism for WD-associated memory impairments.

Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

Considerations for first field trials of low-threshold gene drive for malaria vector control.

Sustainable reductions in African malaria transmission require innovative tools for mosquito control. One proposal involves the use of low-threshold gene drive in Anopheles vector species, where a 'causal pathway' would be initiated by (i) the release of a gene drive system in target mosquito vector species, leading to (ii) its transmission to subsequent generations, (iii) its increase in frequency and spread in target mosquito populations, (iv) its simultaneous propagation of a linked genetic trait aimed at reducing vectorial capacity for Plasmodium, and (v) reduced vectorial capacity for parasites in target mosquito populations as the gene drive system reaches fixation in target mosquito populations, causing (vi) decreased malaria incidence and prevalence. Here the scope, objectives, trial design elements, and approaches to monitoring for initial field releases of such gene dive systems are considered, informed by the successful implementation of field trials of biological control agents, as well as other vector control tools, including insecticides, Wolbachia, larvicides, and attractive-toxic sugar bait systems. Specific research questions to be addressed in initial gene drive field trials are identified, and adaptive trial design is explored as a potentially constructive and flexible approach to facilitate testing of the causal pathway. A fundamental question for decision-makers for the first field trials will be whether there should be a selective focus on earlier points of the pathway, such as genetic efficacy via measurement of the increase in frequency and spread of the gene drive system in target populations, or on wider interrogation of the entire pathway including entomological and epidemiological efficacy. How and when epidemiological efficacy will eventually be assessed will be an essential consideration before decisions on any field trial protocols are finalized and implemented, regardless of whether initial field trials focus exclusively on the measurement of genetic efficacy, or on broader aspects of the causal pathway. Statistical and modelling tools are currently under active development and will inform such decisions on initial trial design, locations, and endpoints. Collectively, the considerations here advance the realization of developer ambitions for the first field trials of low-threshold gene drive for malaria vector control within the next 5 years.

Counting the lifetime cost of obesity: Analysis based on national England data.

AIM: Obesity has a significant impact on all-cause mortality rate and overall health care resource use (HCRU). These outcomes are also strongly linked to age, sex and local deprivation of the population. We aimed to establish the lifetime costs of obesity by demographic group/geographic area using published mortality rates and HCRU use for integrated care boards (ICB) in England in the context of costs of therapeutic intervention. METHODS: Population and expected mortality rates by age, sex and deprivation were obtained from national data. Obesity class prevalence was taken from the health of the nation study. The published impact of obesity by age, group, sex and deprivation on mortality and HCRU were applied to estimate life years lost and lifetime HCRU [by sex, age band and body mass index (BMI) class for each ICB]. The year 2019 was chosen as the study basis data to avoid influences of COVID-19 pandemic on obesity rates with application of 2022/23 HCRU values. Outcomes including prevalence, deaths, life years lost, HCRU and lifetime HCRU were compared by age and sex groups across four BMI classes normal/underweight (BMI <25 kg/m2 ), overweight (25-29.9 kg/m2 ), obese class I and II (30-39.9 kg/m2 ), and obese class III (≥40), with benchmarking being set against all population being BMI <25 kg/m2 overall and by each of the 42 ICBs. We also associated future life with deaths to provide an estimate of 'future life years lost' occurring each year. RESULTS: Total population aged >16 years was 45.4 million (51% female). PREVALENCE: 13.7 million (28% of the total adult population) had a BMI ≥30 mg/m2 and BMI ≥40 kg/m2 were 1.50 million (12%) of these 1.0 million (68%) were female and of these 0.6 million 40% were women aged 16-49 years. In addition, 35% of those with a BMI ≥40 kg/m2 were in the top deprivation quintile (i.e. overall 20%). Mortality was based on expected deaths of 518K/year, and modelling suggested that if a BMI <25 kg/m2 was achieved in all individuals, the death rate would fall by 63K to 455K/year for the English population (12% reduction). For those with a BMI ≥40 kg/m2 the predicted reduction was 12K deaths (54% lower); while in those aged 16-49 years with a BMI ≥40 kg/m2 72% of deaths were linked to obesity. For future life years lost, we estimated 2.5 years were lost in people with BMI 30-39.9 kg/m2 6.7 years when BMI ≥40 kg/m2 . However, for those aged 16-49 years with a BMI ≥40 kg/m2 , 8.3 years were lost. HCRU, for weight reduction, the annual HCRU decrease from BMI ≥40 kg/m2 to BMI 30-39.9 kg/m2 was £342 per person and from BMI 30-39.9 to 25-29.9 kg/m2 the reduction was £316/person. However, lifetime costs were similar because of reduced life expectancy for obese individuals. In quality adjusted life years (QALY), overall, 791 689 future life years were lost (13.1% of all) in people with BMI ≥25 kg/m2 and were related to excess weight. When the NICE £30 000 per QALY value was applied to the estimated total 791 689 future life years lost then the potential QALY value reduction lost was equivalent to £24 billion/year or £522/person in the obese population. For morbidly obese men and women the potential QALY value lost was £2864/person/year. Regarding geography, across the 42 ICBs, we observed significant variation in the prevalence of BMI ≥40 (1.8%-4.3%), excess mortality (11.6%-15.4%) and HCRU linked to higher BMI (7.2%-8.8%). The areas with the greatest impact on HCRU were in the north-west, north-east and Midlands of England, while the south shows less impact. CONCLUSION: The expected increases in annual HCRU because of obesity, when considered over a lifetime, are being mitigated by the increased mortality of obese individuals. Our data suggest that simple short-term HCRU reduction brought about through BMI reduction will be insufficient to fund additional specialist weight reduction interventions. The HRCUs associated with BMI are not in most cases related to short-term health conditions. They are a cumulative result over a number of years, so for age 16-49 years reducing BMI from ≥40 to 30-39.9 kg/m2 might show an annual decrease in HCRU/person by £325/year for women and £80/year for men but this might not have immediately occurred within that year. For those aged >70 years reducing BMI from ≥40 to 30-39.9 kg/m2 might show an annual decrease in HCRU/person by £777/year for women and £796/year for men but also may not be manifest within that year. However, for the morbidly obese men and women, the potential QALY value lost was £2864 per person per year with the potential for these funds to be applied to intensive weight management programmes, including pharmacotherapy.

Centrality to the metapopulation is more important for population genetic diversity than habitat area or fragmentation.

Drift and gene flow affect genetic diversity. Given that the strength of genetic drift increases as population size decreases, management activities have focused on increasing population size through preserving habitats to preserve genetic diversity. Few studies have empirically evaluated the impacts of drift and gene flow on genetic diversity. Kryptolebias marmoratus, henceforth 'rivulus', is a small killifish restricted to fragmented New World mangrove forests with gene flow primarily associated with ocean currents. Rivulus form distinct populations across patches, making them a well-suited system to test the extent to which habitat area, fragmentation and connectivity are associated with genetic diversity. Using over 1000 individuals genotyped at 32 microsatellite loci, high-resolution landcover data and oceanographic simulations with graph theory, we demonstrate that centrality (connectivity) to the metapopulation is more strongly associated with genetic diversity than habitat area or fragmentation. By comparing models with and without centrality standardized by the source population's genetic diversity, our results suggest that metapopulation centrality is critical to genetic diversity regardless of the diversity of adjacent populations. While we find evidence that habitat area and fragmentation are related to genetic diversity, centrality is always a significant predictor with a larger effect than any measure of habitat configuration.

Public transport use and mortality among older adults in England: A cohort study.

BACKGROUND: Most evidence on transport use and mortality has focused on the commute to work. This study aims to fill a gap by assessing relationships between public transport use and mortality among older adults. METHODS: Data come from a cohort of 10,186 individuals aged 50 or older who participated in the English Longitudinal Study of Ageing (ELSA), with survey data linked to mortality records over 16 years (2002-2018). We assessed a binary measure of public transport use and frequency of use from 'every day or nearly every day' to 'never'. Cox proportional-hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for associations between public transport use and mortality. Analyses were adjusted for a range of covariates including socio-demographic factors, chronic disease, and self-reported problems with daily living activities. RESULTS: Overall, 3371 participants (33.1%) died within the study period. Mortality was lower among public transport users (21.3%) compared with non-users (64.2%). Adjusted analyses found that users had 34% lower mortality than non-users (HR 0.66 (95% CI 0.61;0.71)). Adjusted analyses showed similar association sizes across frequencies of public transport use, with those using public transport every day or nearly every day having 41% lower mortality than never users (HR 0.59 (0.49;0.71)). Associations were similar among those with and without a longstanding illness. CONCLUSION: The use of public transport among older adults is linked to lower levels of mortality. Reductions in provision of public transport services could be detrimental to both transportation and population health.

Blood stored in EDTA tubes provides accurate peanut basophil activation test results for 48 hours.

BACKGROUND: The peanut basophil activation test (BAT) has demonstrated excellent diagnostic accuracy with heparinized blood, but its clinical utility is limited by the short stability of samples stored in this anticoagulant. OBJECTIVE: Using EDTA anticoagulated blood, these investigations determined if Peanut BAT sample stability can be extended to 2 days, the minimum stability requirement for diagnostic tests currently offered through American reference laboratories. METHODS: Peanut non-allergic control (NAC), peanut IgE sensitized (PS), and peanut allergic (PA) children aged 6 months through 17 years were recruited from members of Kaiser Permanente Southern California. EDTA anti-coagulated blood samples were collected from participants, shipped to a centralized laboratory, and stored at 4oC for peanut BAT testing 1 and 2 days later. RESULTS: Peanut BAT results for 23 unblinded participants were used to establish sample rejection and interpretation criteria that were subsequently validated in a prospective double-blind study involving 112 additional children (39-NAC, 36-PS, 37-PA). Of 105 blinded blood samples tested on each study day, 88 (84%) day-1 and 90 (86%) day-2 peanut BAT results were considered interpretable, with diagnostic accuracies of 95.5% and 94.4%, respectively. Moreover, all interpretable PA results were considered positive (100% sensitivity). CONCLUSION: Using EDTA anti-coagulated blood samples collected remotely, 1 and 2 days before testing, study results highlight the favorable diagnostic performance characteristics of the peanut BAT and provide further evidence that the test could be readily operationalized for clinical use by interested commercial reference laboratories.

Prospective benchmarking of an observational analysis in the SWEDEHEART registry against the REDUCE-AMI randomized trial.

Prospective benchmarking of an observational analysis against a randomized trial increases confidence in the benchmarking process as it relies exclusively on aligning the protocol of the trial and the observational analysis, while the trials findings are unavailable. The Randomized Evaluation of Decreased Usage of Betablockers After Myocardial Infarction (REDUCE-AMI, ClinicalTrials.gov ID: NCT03278509) trial started recruitment in September 2017 and results are expected in 2024. REDUCE-AMI aimed to estimate the effect of long-term use of beta blockers on the risk of death and myocardial following a myocardial infarction with preserved left ventricular systolic ejection fraction. We specified the protocol of a target trial as similar as possible to that of REDUCE-AMI, then emulated the target trial using observational data from Swedish healthcare registries. Had everyone followed the treatment strategy as specified in the target trial protocol, the observational analysis estimated a reduction in the 5-year risk of death or myocardial infarction of 0.8 percentage points for beta blockers compared with no beta blockers; effects ranging from an absolute reduction of 4.5 percentage points to an increase of 2.8 percentage points in the risk of death or myocardial infarction were compatible with our data under conventional statistical criteria. Once results of REDUCE-AMI are published, we will compare the results of our observational analysis against those from the trial. If this prospective benchmarking is successful, it supports the credibility of additional analyses using these observational data, which can rapidly deliver answers to questions that could not be answered by the initial trial. If benchmarking proves unsuccessful, we will conduct a "postmortem" analysis to identify the reasons for the discrepancy. Prospective benchmarking shifts the investigator focus away from an endeavour to use observational data to obtain similar results as a completed randomized trial, to a systematic attempt to align the design and analysis of the trial and the observational analysis.

Methylprednisolone dosing for pediatric critical asthma: a single-center cohort study.

OBJECTIVE: We aimed to characterize intravenous (IV) methylprednisolone (MP) dosing regimens and clinical outcomes for children hospitalized for critical asthma (CA). METHODS: A single-center, retrospective review was performed of children admitted to the pediatric intensive care unit (PICU) for CA between September 2015 and October 2019. Patients 5-to 17-year-olds, initiated on continuous nebulized albuterol, and prescribed at least one dose of IV MP were included. The primary outcome was to characterize PICU MP dosing. Cohorts were then compared by MP dosing: conservative-dose methylprednisolone (CDMP, ≤ 0.5 mg/kg/dose every 6 h) and standard-dose methylprednisolone (SDMP, > 0.5 mg/kg/dose every 6 h). Clinical efficacy endpoints were the duration of continuous nebulized albuterol and PICU length of stay (LOS). Safety endpoints included corticosteroid-related adverse events. RESULTS: Of 168 children studied, 50 (29.8%) were prescribed CDMP and 118 (70.2%) SDMP. The overall mean MP dose was 31.3 ± 19.6 mg (weight-adjusted: 0.77 ± 0.32 mg/kg/dose). Compared to those prescribed SDMP, those prescribed CDMP had a shorter median duration of continuous nebulized albuterol (12.8 [IQR: 10.5-20] versus 17.3 [IQR: 11.3-29.7] hours, p = 0.019) and median PICU LOS (0.9 [IQR: 0.7-1.4] versus 1.2 [IQR: 0.9-1.8] days, p = 0.012). No corticosteroid-related adverse events were observed. In adjusted models, weight-adjusted IV MP dose was not associated with PICU LOS or duration of continuous nebulized albuterol. CONCLUSIONS: Intravenous MP dosing for pediatric CA varied widely in our study sample. Prospective, controlled trials are required to validate our observations including clinical efficacy and safety endpoints.

Vitamin K Prescribing Trends Among Critically Ill Children Hospitalized for Sepsis: A Multicenter Observational Cohort Study.

Objective: Vitamin K (VK) is commonly prescribed for pediatric sepsis-induced coagulopathy without trial-derived evidence to support its use for this indication. The purpose of this study was to characterize national prescribing trends for VK in this population. Patients and Methods: This is a multicenter retrospective cohort study using the Pediatric Health Information System registry including children 0 to 17 years of age hospitalized for sepsis in the pediatric intensive care unit from January 2016 through December 2022. The primary outcome was overall, annual, and center-specific VK prescribing rates. Descriptive data included demographics, length of stay, and rates of VK deficiency, hepatic insufficiency, red blood cell (RBC) transfusion, venous thromboembolism (VTE), and mortality. VK prescribing trends were assessed using Joinpoint regression. Descriptive statistics employed included Wilcoxon rank-sum, student's t, and chi-square tests. Results: Of the 31 221 encounters studied, 4539 (14.6%) were prescribed VK (median center-specific rate: 14.2%; interquartile range [IQR]: 8.8-21%) with a linear annual trend decreasing from 17.3% in 2016 to 13.3% in 2022 (-0.6%/year, r2 = .661). Those prescribed VK had greater rates of hepatic dysfunction (20.5% vs 3.1%), RBC transfusion (26.5% vs 11.2%), VTE (12.5% vs 4.6%), mortality (17.1% vs 4.4%), and median length of stay (16 [IQR: 8-33] vs 8 [4-15] days) (all P < .001). VK deficiency was diagnosed in 0.2% of encounters. Conclusions: In this multicenter retrospective cohort, VK prescribing was common among critically ill children diagnosed with sepsis. Phased trials are needed to demonstrate clinical efficacy and safety for VK in this population.

Association between the implementation of standardised tobacco packaging legislation and illicit tobacco and cross-border purchasing in England: a time-series analysis between 2012 and 2020.

BACKGROUND: In May 2016, the UK announced standardising packaging legislation for tobacco products. There was a 12-month transition period with both branded and standardised packs on the market until May 2017. The aim of this study was to investigate whether the implementation of standardised packaging in England was associated with changes in illicit tobacco and cross-border purchasing. METHODS: We used Smoking Toolkit Study data covering the time period from 2012 to 2020. We ran time-series analysis using Autoregressive Integrated Moving Average with Exogenous Variable models to investigate the monthly changes in illicit tobacco and cross-border purchasing in England. The model was adjusted for other tobacco control policies implemented during the relevant time period and tobacco pricing. We used May 2017 as an implementation point and run sensitivity analysis using July 2016 and February 2017 as alternative implementation points given phased introduction of the policy. RESULTS: The average prevalence of illicit tobacco and cross-border purchasing in the past 6 months was 14.4%. The implementation of standardised tobacco packaging legislation was associated with a monthly decline in illicit tobacco and cross-border purchases after May 2017 by 0.16% per month (beta=-0.158, 95% CI -0.270 to -0.046). The results were robust to considering different implementation points for the policy (July 2016: beta=-0.109, 95% CI -0.213 to -0.005; February 2017: beta=-0.141, 95% CI -0.245 to -0.036). CONCLUSIONS: In contrast to the tobacco industry's argument that the legislation would lead to an increase in the illicit tobacco and cross-border market, this study demonstrates that the implementation of the policy is associated with a decline in illicit tobacco and cross-border purchases in England.