Histone deacetylase-3 regulates the expression of the amyloid precursor protein and its inhibition promotes neuroregenerative pathways in Alzheimer's disease models.

HDAC3 inhibition has been shown to improve memory and reduce amyloid-ß (Aß) in Alzheimer's disease (AD) models, but the underlying mechanisms are unclear. We investigated the molecular effects of HDAC3 inhibition on AD pathology, using in vitro and ex vivo models of AD, based on our finding that HDAC3 expression is increased in AD brains. For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild-type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1-10 µM) for 24 h. Treatment with RGFP966 or HDAC3 knockdown in N2a cells was associated with an increase on amyloid precursor protein (APP) and mRNA expressions, without alterations in Aß42 secretion. In vitro chromatin immunoprecipitation analysis revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCSs from 5XFAD mice incubated with 1 µM RGFP966, without changes in Aß. In addition, HDAC3 inhibition resulted in a reduction of activated Iba-1-positive microglia and astrocytes in 5XFAD slices, which was not observed in OBCSs from wild-type mice. mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes.

Capturing Data on Antimicrobial Resistance Patterns and Trends in Use in Regions of Asia (CAPTURA).

BACKGROUND: In 2015, the UK government established the Fleming Fund with the aim to address critical gaps in surveillance of antimicrobial resistance (AMR) in low- and middle-income countries in Asia and Africa. Among a large portfolio of grants, the Capturing Data on Antimicrobial Resistance Patterns and Trends in Use in Regions of Asia (CAPTURA) project was awarded with the specific objective of expanding the volume of historical data on AMR, consumption (AMC), and use (AMU) in the human healthcare sector across 12 countries in South and Southeast Asia. METHODS: Starting in early 2019, the CAPTURA consortium began working with local governments and >100 relevant data-holding facilities across the region to identify, assess for quality, prioritize, and subsequently retrieve data on AMR, AMC, and AMU. Relevant and shared data were collated and analyzed to provide local overviews for national stakeholders as well as regional context, wherever possible. RESULTS: From the vast information resource generated on current surveillance capacity and data availability, the project has highlighted gaps and areas for quality improvement and supported comprehensive capacity-building activities to optimize local data-collection and -management practices. CONCLUSIONS: The project has paved the way for expansion of surveillance networks to include both the academic and private sector in several countries and has actively engaged in discussions to promote data sharing at the local, national, and regional levels. This paper describes the overarching approach to, and emerging lessons from, the CAPTURA project, and how it contributes to other ongoing efforts to strengthen national AMR surveillance in the region and globally.

Methodological Approach to Identify and Expand the Volume of Antimicrobial Resistance (AMR) Data in the Human Health Sector in Low- and Middle-Income Countries in Asia: Implications for Local and Regional AMR Surveillance Systems Strengthening.

Antimicrobial resistance (AMR) is a multifaceted global health problem disproportionately affecting low- and middle-income countries (LMICs). The Capturing data on Antimicrobial resistance Patterns and Trends in Use in Regions of Asia (CAPTURA) project was tasked to expand the volume of AMR and antimicrobial use data in Asia. The CAPTURA project used 2 data-collection streams: facility data and project metadata. Project metadata constituted information collected to map out data sources and assess data quality, while facility data referred to the retrospective data collected from healthcare facilities. A down-selection process, labelled "the funnel approach" by the project, was adopted to use the project metadata in prioritizing and selecting laboratories for retrospective AMR data collection. Moreover, the metadata served as a guide for understanding the AMR data once they were collected. The findings from CAPTURA's metadata add to the current discourse on the limitation of AMR data in LMICs. There is generally a low volume of AMR data generated as there is a lack of microbiology laboratories with sufficient antimicrobial susceptibility testing capacity. Many laboratories in Asia are still capturing data on paper, resulting in scattered or unused data not readily accessible or shareable for analyses. There is also a lack of clinical and epidemiological data captured, impeding interpretation and in-depth understanding of the AMR data. CAPTURA's experience in Asia suggests that there is a wide spectrum of capacity and capability of microbiology laboratories within a country and region. As local AMR surveillance is a crucial instrument to inform context-specific measures to combat AMR, it is important to understand and assess current capacity-building needs while implementing activities to enhance surveillance systems.

Pilot study of lung cancer screening for survivors of Hodgkin lymphoma.

Hodgkin lymphoma (HL) treatment increases the risk of lung cancer. Most HL survivors are not eligible for lung cancer screening (LCS) programmes developed for the general population, and the utility of these programmes has not been tested in HL survivors. We ran a LCS pilot in HL survivors to describe screening uptake, participant characteristics, impact of a decision aid and screen findings. HL survivors treated ≥5 years ago with mustine/procarbazine and/or thoracic radiation, were identified from a follow-up database and invited to participate. Participants underwent a low-dose CT (LDCT) reported using protocols validated for the general population. Two hundred and eighteen individuals were invited, 123 were eligible, 102 were screened (58% response rate): 58% female, median age 52 years, median 22 years since HL treatment. 91.4% were deemed to have made an informed decision; participation was not influenced by age, gender, years since treatment or deprivation. Only 3/35 ever-smokers met criteria for LCS through the programme aimed at the general population. Baseline LDCT results were: 90 (88.2%) negative, 10 (9.8%) indeterminate, 2 (2.0%) positive. Two 3-month surveillance scans were positive. Of 4 positive scans, 2 patients were diagnosed with small-cell lung cancer; 1 underwent curative surgery. Coronary artery calcification was detected in 36.3%, and clinically significant incidental findings in 2.9%. LDCT protocols validated in ever-smokers can detect asymptomatic early-stage lung cancers in HL survivors. This finding, together with screening uptake and low false positive rates, supports further research to implement LCS for HL survivors.

Renal safety of critical care sedation with sevoflurane: a systematic review and meta-analysis.

Volatile anesthetic agents are increasingly widely used for critical care sedation. There are concerns that sevoflurane presents a risk of renal injury when used in this role. RCTs comparing the use of critical care sevoflurane sedation with any control in humans were systematically identified using MEDLINE, Cochrane CENTRAL, web of Science, and CINAHL (until May 2022), if they presented comparative data on renal function or serum inorganic fluoride levels. Pooled SMDs (95% CI) were calculated where possible after assessment of quality with GRADE and risk of bias with ROB-2. Eight studies analyzing 793 patients were included. The median duration of use of critical care sevoflurane sedation was 4.8 [IQR 3.5-9.2] hours; however, most trials also included a period of prior intraoperative use. No significant difference was found in serum creatinine at 1 day (SMD 0.05, 95% CI - 0.12 to 0.21), 48 h (SMD = - 0.04; 95% Cl - 0.25 to 0.17), 72 h (SMD = - 0.15; 95% CI - 0.45 to 0.15), and at discharge (SMD = - 0.1; 95% CI - 0.3 to 0.13) between the sevoflurane group and the control groups. Creatinine clearance was measured in two studies at 48 h with no significant difference (SMD = - 0.13; 95% Cl - 0.38 to 0.11). Levels of serum inorganic fluoride were significantly elevated in patients where sevoflurane was used. Sevoflurane was not associated with renal failure when used for critical care sedation of fewer than 72-h duration, despite the elevation of serum fluoride. Longer-term studies are currently inadequate, including in patients with compromised renal function, to further evaluate the role of sevoflurane in this setting.Trial registration PROSPERO (CRD42022333099).

Rapid Genomic Characterization and Global Surveillance of Klebsiella Using Pathogenwatch.

BACKGROUND: Klebsiella species, including the notable pathogen K. pneumoniae, are increasingly associated with antimicrobial resistance (AMR). Genome-based surveillance can inform interventions aimed at controlling AMR. However, its widespread implementation requires tools to streamline bioinformatic analyses and public health reporting. METHODS: We developed the web application Pathogenwatch, which implements analytics tailored to Klebsiella species for integration and visualization of genomic and epidemiological data. We populated Pathogenwatch with 16 537 public Klebsiella genomes to enable contextualization of user genomes. We demonstrated its features with 1636 genomes from 4 low- and middle-income countries (LMICs) participating in the NIHR Global Health Research Unit (GHRU) on AMR. RESULTS: Using Pathogenwatch, we found that GHRU genomes were dominated by a small number of epidemic drug-resistant clones of K. pneumoniae. However, differences in their distribution were observed (eg, ST258/512 dominated in Colombia, ST231 in India, ST307 in Nigeria, ST147 in the Philippines). Phylogenetic analyses including public genomes for contextualization enabled retrospective monitoring of their spread. In particular, we identified hospital outbreaks, detected introductions from abroad, and uncovered clonal expansions associated with resistance and virulence genes. Assessment of loci encoding O-antigens and capsule in K. pneumoniae, which represent possible vaccine candidates, showed that 3 O-types (O1-O3) represented 88.9% of all genomes, whereas capsule types were much more diverse. CONCLUSIONS: Pathogenwatch provides a free, accessible platform for real-time analysis of Klebsiella genomes to aid surveillance at local, national, and global levels. We have improved representation of genomes from GHRU participant countries, further facilitating ongoing surveillance.

Spirometry performed as part of the Manchester community-based lung cancer screening programme detects a high prevalence of airflow obstruction in individuals without a prior diagnosis of COPD.

BACKGROUND: COPD is a major cause of morbidity and mortality in populations eligible for lung cancer screening. We investigated the role of spirometry in a community-based lung cancer screening programme. METHODS: Ever smokers, age 55-74, resident in three deprived areas of Manchester were invited to a 'Lung Health Check' (LHC) based in convenient community locations. Spirometry was incorporated into the LHCs alongside lung cancer risk estimation (Prostate, Lung, Colorectal and Ovarian Study Risk Prediction Model, 2012 version (PLCOM2012)), symptom assessment and smoking cessation advice. Those at high risk of lung cancer (PLCOM2012 ≥1.51%) were eligible for annual low-dose CT screening over two screening rounds. Airflow obstruction was defined as FEV1/FVC<0.7. Primary care databases were searched for any prior diagnosis of COPD. RESULTS: 99.4% (n=2525) of LHC attendees successfully performed spirometry; mean age was 64.1±5.5, 51% were women, 35% were current smokers. 37.4% (n=944) had airflow obstruction of which 49.7% (n=469) had no previous diagnosis of COPD. 53.3% of those without a prior diagnosis were symptomatic (n=250/469). After multivariate analysis, the detection of airflow obstruction without a prior COPD diagnosis was associated with male sex (adjOR 1.84, 95% CI 1.37 to 2.47; p<0.0001), younger age (p=0.015), lower smoking duration (p<0.0001), fewer cigarettes per day (p=0.035), higher FEV1/FVC ratio (<0.0001) and being asymptomatic (adjOR 4.19, 95% CI 2.95 to 5.95; p<0.0001). The likelihood of screen detected lung cancer was significantly greater in those with evidence of airflow obstruction who had a previous diagnosis of COPD (adjOR 2.80, 95% CI 1.60 to 8.42; p=0.002). CONCLUSIONS: Incorporating spirometry into a community-based targeted lung cancer screening programme is feasible and identifies a significant number of individuals with airflow obstruction who do not have a prior diagnosis of COPD.

Analysis of lung cancer risk model (PLCOM2012 and LLPv2) performance in a community-based lung cancer screening programme.

INTRODUCTION: Low-dose CT (LDCT) screening of high-risk smokers reduces lung cancer (LC) specific mortality. Determining screening eligibility using individualised risk may improve screening effectiveness and reduce harm. Here, we compare the performance of two risk prediction models (PLCOM2012 and Liverpool Lung Project model (LLPv2)) and National Lung Screening Trial (NLST) eligibility criteria in a community-based screening programme. METHODS: Ever-smokers aged 55-74, from deprived areas of Manchester, were invited to a Lung Health Check (LHC). Individuals at higher risk (PLCOM2012 score ≥1.51%) were offered annual LDCT screening over two rounds. LLPv2 score was calculated but not used for screening selection; ≥2.5% and ≥5% thresholds were used for analysis. RESULTS: PLCOM2012 ≥1.51% selected 56% (n=1429) of LHC attendees for screening. LLPv2 ≥2.5% also selected 56% (n=1430) whereas NLST (47%, n=1188) and LLPv2 ≥5% (33%, n=826) selected fewer. Over two screening rounds 62 individuals were diagnosed with LC; representing 87% (n=62/71) of 6-year incidence predicted by mean PLCOM2012 score (5.0%). 26% (n=16/62) of individuals with LC were not eligible for screening using LLPv2 ≥5%, 18% (n=11/62) with NLST criteria and 7% (n=5/62) with LLPv2 ≥2.5%. NLST eligible Manchester attendees had 2.5 times the LC detection rate than NLST participants after two annual screens (≈4.3% (n=51/1188) vs 1.7% (n=438/26 309); p<0.0001). Adverse measures of health, including airflow obstruction, respiratory symptoms and cardiovascular disease, were positively correlated with LC risk. Coronary artery calcification was predictive of LC (adjOR 2.50, 95% CI 1.11 to 5.64; p=0.028). CONCLUSION: Prospective comparisons of risk prediction tools are required to optimise screening selection in different settings. The PLCOM2012 model may underestimate risk in deprived UK populations; further research focused on model calibration is required.

Relative efficacy and safety of inhaled corticosteroids in patients with asthma: Systematic review and network meta-analysis.

BACKGROUND: Inhaled corticosteroids (ICSs) are recommended as first-line controller medications for persistent asthma. However, guidelines on the initial ICS doses, step-up and step-down algorithms, and when to switch to combination therapy vary. OBJECTIVE: To understand the ideal starting doses of ICS therapy based on current evidence and to systematically compare low, moderate, and high starting doses of ICSs as monotherapy and in combination with long-acting ß-agonists with respect to efficacy and safety. METHODS: MEDLINE, Embase, and Cochrane databases were searched for relevant English-language articles published from 1980 to November 17, 2018. Randomized controlled trials with adult, steroid-naive, ICS-free (for ≥4 weeks) patients with asthma and a duration of 4 weeks or longer with an ICS treatment arm (monotherapy or combination therapy) were included. Separate fixed-effects Bayesian network meta-analyses were conducted on the extracted data for peak expiratory flow, forced expiratory volume in 1 second, nighttime rescue medication use, nighttime symptom score, and study withdrawal because of an adverse event. RESULTS: A total of 31 randomized controlled trials were analyzed. All starting doses of ICSs were comparable with respect to nighttime rescue medication use, nighttime symptom score, change in forced expiratory volume in 1 second, and study withdrawal because of an adverse event. Significant improvement in morning peak expiratory flow was observed with high-dose ICSs and with low- and moderate-dose ICSs and long-acting ß-agonists than with low-dose ICSs. CONCLUSION: Overall, a high starting dose of ICSs had no additional clinical benefit in 3 of the 4 efficacy parameters compared with low or moderate ICS doses for controlling moderate to severe asthma but might have potential safety concerns.

Serious games for serious crises: reflections from an infectious disease outbreak matrix game.

BACKGROUND: While there is widespread recognition of global health failures when it comes to infectious disease outbreaks, there is little discussion on how policy-makers and global health organizations can learn to better prepare and respond. Serious games provide an underutilized tool to promote learning and innovation around global health crises. In order to explore the potential of Serious Games as a policy learning tool, Global Affairs Canada, in collaboration with the Department of National Defense and academic partners, developed and implemented a matrix game aimed at prompting critical reflection and gender-based analysis on infectious disease outbreak preparedness and response. This commentary, written by the core development team, reflects on the process and outcomes of the gaming exercise, which we believe will be of interest to others hoping to promote innovative thinking and learning around global health policy and crisis response, as well as the application of serious games more broadly. MAIN BODY: Participants reported, through discussions and a post-game survey, that they felt the game was reflective of real-world decision-making and priority-setting challenges during a crisis. They reflected on the challenges that emerge around global health co-operation and outbreak preparedness, particularly noting the importance of learning to work with private actors. While participants only sporadically applied gender-based analysis or considered the social determinants of health during the game, post-game discussions led to reflection on the ways in which equity concerns are put aside during a crisis scenario and on why this happens, offering critical learning opportunities. CONCLUSION: Matrix games provide opportunities for policy-makers and health professionals to experience the challenges of global health co-operation, test ideas and explore how biases, such as those around gender, influence policy-making and implementation. Due to their flexibility, adaptability and accessibility, serious games offer a potentially powerful learning tool for global health policy-makers and practitioners.

Second round results from the Manchester 'Lung Health Check' community-based targeted lung cancer screening pilot.

We report results from the second annual screening round (T1) of Manchester's 'Lung Health Check' pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.

Implementing lung cancer screening: baseline results from a community-based 'Lung Health Check' pilot in deprived areas of Manchester.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Development of algorithms for identifying fatal cardiovascular disease in Medicare claims.

BACKGROUND: Cause of death is often not available in administrative claims data. OBJECTIVE: To develop claims-based algorithms to identify deaths due to fatal cardiovascular disease (CVD; ie, fatal coronary heart disease [CHD] or stroke), CHD, and stroke. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) study data were linked with Medicare claims to develop the algorithms. Events adjudicated by REGARDS study investigators were used as the gold standard. Stepwise selection was used to choose predictors from Medicare data for inclusion in the algorithms. C-index, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to assess algorithm performance. Net reclassification index (NRI) was used to compare the algorithms with an approach of classifying all deaths within 28 days following hospitalization for myocardial infarction and stroke to be fatal CVD. RESULTS: Data from 2,685 REGARDS participants with linkage to Medicare, who died between 2003 and 2013, were analyzed. The C-index for discriminating fatal CVD from other causes of death was 0.87. Using a cut-point that provided the closest observed-to-predicted number of fatal CVD events, the sensitivity was 0.64, specificity 0.90, PPV 0.65, and NPV 0.90. The algorithms resulted in positive NRIs compared with using deaths within 28 days following hospitalization for myocardial infarction and stroke. Claims-based algorithms for discriminating fatal CHD and fatal stroke performed similarly to fatal CVD. CONCLUSION: The claims-based algorithms developed to discriminate fatal CVD events from other causes of death performed better than the method of using hospital discharge diagnosis codes.

Dynamic sentinel lymph node biopsy for penile cancer: a comparison between 1- and 2-day protocols.

OBJECTIVE: To determine the outcome of clinically negative node (cN0) patients with penile cancer undergoing dynamic sentinel node biopsy (DSNB), comparing the results of a 1- and 2-day protocol that can be used as a minimal invasive procedure for staging of penile cancer. PATIENTS AND METHODS: This is a retrospective analysis of 151 cN0 patients who underwent DSNB from 2008 to 2013 for newly diagnosed penile cancer. Data were analysed per groin and separated into groups according to the protocol followed. The comparison of the two protocols involved the number of nodes excised, γ-counts, false-negative rates (FNR), and complication rates (Clavien-Dindo grading system). RESULTS: In all, 280 groins from 151 patients underwent DSNB after a negative ultrasound ± fine-needle aspiration cytology. The 1-day protocol was performed in 65 groins and the 2-day protocol in 215. Statistically significantly more nodes were harvested with the 1-day protocol (1.92/groin) compared with the 2-day protocol (1.60/groin). The FNRs were 0%, 6.8% and 5.1%, for the 1-day protocol, 2-day protocol, and overall, respectively. Morbidity of the DSNB was 21.4% for all groins, and 26.2% and 20.1% for the 1-day and 2-day protocols, respectively. Most of the complications were of Clavien-Dindo Grade 1-2. CONCLUSIONS: DSNB is safe for staging patients with penile cancer. There is a trend towards a 1-day protocol having a lower FNR than a 2-day protocol, albeit at the expense of a slightly higher complication rate.

Early reduction in tumour [18F]fluorothymidine (FLT) uptake in patients with non-small cell lung cancer (NSCLC) treated with radiotherapy alone.

PURPOSE: Changes in tumour 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) uptake during concurrent chemo-radiotherapy in patients with non-small cell lung cancer (NSCLC) have been reported, at variable time points, in two pilot positron emission tomography (PET) studies. The aim of this study was to assess whether FLT changes occur early in response to radiotherapy (RT) without concurrent chemotherapy and whether such changes exceed test-retest variability. METHODS: Sixteen patients with NSCLC, scheduled to have radical RT, underwent FLT PET once/twice at baseline to assess reproducibility and/or after 5-11 RT fractions to evaluate response. Primary and nodal malignant lesions were manually delineated on CT and volume, mean and maximum standardized uptake values (SUV(mean) and SUV(max)) estimated. Analysis included descriptive statistics and parameter fitting to a mixed-effects model accounting for patients having different numbers of evaluable lesions. RESULTS: In all, 35 FLT PET scans from 7 patients with a total of 18 lesions and 12 patients with a total of 30 lesions were evaluated for reproducibility and response, respectively. SUV(mean) reproducibility in primary tumours (SD 8.9%) was better than SUV(max) reproducibility (SD 12.6%). In nodes, SUV(mean) and SUV(max) reproducibilities (SD 18.0 and 17.2%) were comparable but worse than for primary tumours. After 5-11 RT fractions, primary tumour SUV(mean) decreased significantly by 25% (p = 0.0001) in the absence of significant volumetric change, whereas metastatic nodes decreased in volume by 31% (p = 0.020) with a larger SUV(mean) decrease of 40% (p < 0.0001). Similar changes were found for SUV(max). CONCLUSION: Across this group of NSCLC patients, RT induced an early, significant decrease in lesion FLT uptake exceeding test-retest variability. This effect is variable between patients, appears distinct between primary and metastatic nodal lesions, and in primary tumours is lower than previously reported for concurrent chemo-RT at a similar time point. These results confirm the potential for FLT PET to report early on radiation response and to enhance the clinical development of novel drug-radiation combinations by providing an interpretable, early pharmacodynamic end point.

Effect of volatile anaesthetic agents on intracranial pressure, cerebrovascular flow and autoregulation: a protocol for a systematic review and meta-analysis.

INTRODUCTION: The use of volatile anaesthetic agents for the sedation of patients requiring critical care treatment offers several theoretical advantages over intravenous sedation, which may be of benefit in neurocritical care. However, there are concerns that they may increase intracranial pressure. The objective of this systematic review is to assess whether, and if so, to what extent volatile anaesthetic agents affect intracranial pressure, cerebral blood flow (CBF), cerebral oximetry and cerebrovascular autoregulation. If sufficient data exist, subgroup analyses will be conducted in traumatic brain injury and decompressive craniectomy patients. METHODS AND ANALYSIS: A database search of PubMed, Medline (including Medline plus), CINAHL (including CINAHL Plus), Embase databases and the Cochrane Central Controlled Trials Register without time limits will be conducted. The search results will be screened by title and abstract by two independent researchers on a rule-in basis against predetermined criteria-controlled studies in humans of contemporary fluorinated volatile anaesthetic agents against a control, which measures intracranial pressure, CBF, cerebral oximetry or cerebrovascular autoregulation. Articles responsive to screening will then be reviewed in full text by two independent researchers, requiring consensus or a tie-break by a third independent researcher. Reference lists and a non-generative AI tool will be examined for missed articles, with all identified articles being reviewed in full text by two independent researchers. The included articles will be assessed for risk of bias and will have data extracted by two independent researchers. If sufficient data exist, a meta-analysis will be performed; otherwise, a narrative description of outcomes will be performed. ETHICS AND DISSEMINATION: No ethics approval will be sought for this systematic review. This study has no explicit funding. The results of this study will be disseminated in a peer-reviewed journal, in a conference presentation and on PROSPERO. TRIAL REGISTRATION NUMBER: PROSPERO number CRD42023474587.

Calibrating Observational Health Record Data Against a Randomized Trial.

Importance: The conditions required for health record data sources to accurately assess treatment effectiveness remain unclear. Emulation of randomized clinical trials (RCTs) with health record data and subsequent calibration of the results can help elucidate this. Objective: To pilot an emulation of the KEYNOTE-189 RCT using a commercially available electronic health record (EHR) data source. Design, Setting, and Participants: This retrospective cohort study used an EHR database spanning from April 2007 to February 2023. Follow-up began on treatment initiation and proceeded until an outcome event, loss to follow-up, end of data, or end of study period (640 days). The population-based cohort was ascertained from EHRs provided by 52 health systems across the US. Eligibility criteria were defined as closely as possible to the benchmark RCT. Patients with non-small cell lung cancer initiating first-line treatment for metastatic disease were included. Patients with evidence of squamous non-small cell lung cancer, primary nonlung malignant neoplasms, or identified EGFR/ALK variations were excluded. Data were analyzed from June to October 2023. Exposures: Initiation of first-line pembrolizumab and chemotherapy and chemotherapy alone. Chemotherapy in both groups was defined as a combination of pemetrexed and platinum-based (carboplatin or cisplatin) therapy. Main Outcomes and Measures: Outcomes of interest were 12-month survival probability and mortality hazard ratio (HR). Results: A total of 1854 patients (mean [SD] age, 63.7 [9.6] years; 971 [52.4%] men) were eligible, including 589 patients who initiated pembrolizumab and chemotherapy and 1265 patients who initiated chemotherapy only. The cohort included 364 Black patients (19.6%) and 1445 White patients (77.9%). The 12-month survival probabilities were 0.60 (95% CI, 0.54-0.65) in the pembrolizumab group and 0.58 (95% CI, 0.55-0.62) in the chemotherapy-only group, compared with 0.69 (95% CI, 0.64-0.74) in the KEYNOTE-189 pembrolizumab group and 0.49 (95% CI, 0.42-0.56) in the KEYNOTE-189 chemotherapy-only group. The mortality HR was 0.95 (95% CI, 0.78-1.16), compared with 0.49 (95% CI, 0.38-0.64) in the KEYNOTE-189 RCT. Conclusions and Relevance: In this cohort study piloting an RCT emulation, results were incongruous with the benchmark trial. Differences in patient treatment and data capture between the RCT and EHR populations, confounding by indication, treatment crossover, and accuracy of captured diagnoses may explain these findings. Future feasibility assessments will require data sources to have important oncology-specific measures curated.

Point-of-care ultrasonography-An essential skill for medical graduates?

The recent proliferation of point-of-care ultrasonography (POCUS) in the clinical practice of many medical specialties has exposed persistent barriers to education, training and standardisation. Specialist training curriculums are already overwhelming, having grossly insufficient time available for the specialist trainees and for the small number of available trainers alike to incorporate POCUS into postgraduate education. The logical solution to overcome these barriers could be to incorporate basic POCUS education and training into the undergraduate university curriculums, introducing longitudinal integration with other relevant medical sciences. The Australasian Society of Ultrasound in Medicine already has well-established educational programmes in POCUS with standardised assessment of competency, which could potentially offer the basis for symbiosis with the Australian and New Zealand medical schools.

Cardiovascular Burden of Narcolepsy Disease (CV-BOND): a real-world evidence study.

STUDY OBJECTIVES: Narcolepsy is associated with cardiovascular risk factors; however, the risk of new-onset cardiovascular events in this population is unknown. This real-world study evaluated the excess risk of new-onset cardiovascular events in U.S. adults with narcolepsy. METHODS: A retrospective cohort study using IBM MarketScan administrative claims data (2014-2019) was conducted. A narcolepsy cohort, comprising adults (≥18 years) with at least two outpatient claims containing a narcolepsy diagnosis, of which at least one was non-diagnostic, was matched to a non-narcolepsy control cohort (1:3) based on cohort entry date, age, sex, geographic region, and insurance type. The relative risk of new-onset cardiovascular events was estimated using a multivariable Cox proportional hazards model to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The narcolepsy and matched non-narcolepsy control cohorts included 12 816 and 38 441 individuals, respectively. At baseline, cohort demographics were generally similar; however, patients with narcolepsy had more comorbidities. In adjusted analyses, the risk of new-onset cardiovascular events was higher in the narcolepsy cohort compared with the control cohort: any stroke (HR [95% CI], 1.71 [1.24, 2.34]); heart failure (1.35 [1.03, 1.76]); ischemic stroke (1.67 [1.19, 2.34]); major adverse cardiac event (1.45 [1.20, 1.74]); grouped instances of stroke, atrial fibrillation, or edema (1.48 [1.25, 1.74]); and cardiovascular disease (1.30 [1.08, 1.56]). CONCLUSION: Individuals with narcolepsy are at increased risk of new-onset cardiovascular events compared with individuals without narcolepsy. Physicians should consider cardiovascular risk in patients with narcolepsy when weighing treatment options.

Optical control of ultrafast structural dynamics in a fluorescent protein.

The photoisomerization reaction of a fluorescent protein chromophore occurs on the ultrafast timescale. The structural dynamics that result from femtosecond optical excitation have contributions from vibrational and electronic processes and from reaction dynamics that involve the crossing through a conical intersection. The creation and progression of the ultrafast structural dynamics strongly depends on optical and molecular parameters. When using X-ray crystallography as a probe of ultrafast dynamics, the origin of the observed nuclear motions is not known. Now, high-resolution pump-probe X-ray crystallography reveals complex sub-ångström, ultrafast motions and hydrogen-bonding rearrangements in the active site of a fluorescent protein. However, we demonstrate that the measured motions are not part of the photoisomerization reaction but instead arise from impulsively driven coherent vibrational processes in the electronic ground state. A coherent-control experiment using a two-colour and two-pulse optical excitation strongly amplifies the X-ray crystallographic difference density, while it fully depletes the photoisomerization process. A coherent control mechanism was tested and confirmed the wave packets assignment.