Implications of the 2022 lung function update and GLI global reference equations among patients with interstitial lung disease.

BACKGROUND: Lung function testing remains a cornerstone in the assessment and management of interstitial lung disease (ILD) patients. The clinical implications of the Global Lung function Initiative (GLI) reference equations and the updated interpretation strategies remain uncertain. METHODS: Adult patients with ILD with baseline forced vital capacity (FVC) were included from the Australasian ILD registry and the National Healthcare Group ILD registry, Singapore.The European Coal and Steel Community and Miller reference equations were compared with the GLI reference equations to assess (a) differences in lung function percent predicted values; (b) ILD risk prediction models and (c) eligibility for ILD clinical trial enrolment. RESULTS: Among 2219 patients with ILD, 1712 (77.2%) were white individuals. Idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD and unclassifiable ILD predominated.Median FVC was 2.60 (2.01-3.36) L, forced expiratory volume in 1 s was 2.09 (1.67-2.66) L and diffusing capacity of the lungs for carbon monoxide (DLCO) was 13.60 (10.16-17.60) mL/min/mm Hg. When applying the GLI reference equations, the mean FVC percentage predicted was 8.8% lower (87.7% vs 78.9%, p<0.01) while the mean DLCO percentage predicted was 4.9% higher (58.5% vs 63.4%, p<0.01). There was a decrease in 19 IPF and 119 non-IPF patients who qualified for the nintedanib clinical trials when the GLI reference equations were applied. Risk prediction models performed similarly in predicting mortality using both reference equations. CONCLUSION: Applying the GLI reference equations in patients with ILD leads to higher DLCO percentage predicted values and smaller lung volume percentage predicted values. While applying the GLI reference equations did not impact on prognostication, fewer patients met the clinical trial criteria for antifibrotic agents.

[Vertebroplasty for chronic back pain due to osteoporotic vertebral compression fractures]. / Chronische rugpijn na osteoporotische wervelinzakking.

OBJECTIVE: Evidence regarding percutaneous vertebroplasty (PV) for chronic painful osteoporotic vertebral compression fractures (OVCFs) remains limited. To compare pain relief, quality of life, and disability between PV and active control (anesthetic infiltration) interventions for chronic OVCF. DESIGN: Randomized controlled trial. METHODS: This prospective randomized clinical trial was conducted between May 2013 and June 2019 in participants with pain due to OVCF lasting longer than 3 months with bone marrow edema present at MRI. Study participants were randomly assigned to undergo PV (n = 40) or active control intervention (n = 40). The primary outcome was pain severity, assessed with the visual analog scale (VAS) (range, 0-10) during 12 months after treatment. Secondary outcomes included Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) score (range, 0-100) and Roland Morris Disability Questionnaire (RMDQ) score (range, 0-100). Outcomes were analyzed according to a longitudinal multilevel model used to test the difference between groups in change from baseline across follow-up. RESULTS: The mean age of the 80 participants (54 women) was 69 years ± 10 (SD) in the PV group and 71 years ± 10 in the active control group. VAS score was 7.6 (95% CI: 7.0, 8.2) in the PV group and 7.3 (95% CI: 6.9, 7.8) in the active control group at baseline (P = .47) and 3.9 (95% CI: 3.1, 4.8) and 5.1 (95% CI: 4.3, 6.0), respectively, at month 12 (P = .045). At month 12, the group difference from baseline was 1.3 (95% CI: 0.1, 2.6; P = .02) for VAS, 5.2 (95% CI: 0.9, 9.4; P = .02) for QUALEFFO, and 7.1 (95% CI: -3.3, 17.5; P = .18) for RMDQ, favoring the PV group. CONCLUSION: In the treatment of pain caused by chronic OVCFs, PV is more effective for pain relief and quality of life improvement than anesthetic injection alone, with similar improvement for disability between the groups.

Determinants of Prognosis in Head and Neck Cutaneous Squamous Cell Carcinoma With Nodal Metastases.

Importance: The eighth edition tumor, node, metastasis (TNM) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) is a poor predictor of survival in patients with lymph node metastases, possibly due to the inclusion of extranodal extension (ENE). Objective: To identify the key determinants of prognosis in patients with nodal metastatic HNcSCC and analyze the association of ENE with TNM stage and investigate for prognostic heterogeneity in ENE-positive disease. Design, Setting, and Participants: This retrospective, multicenter cohort study was conducted at 4 Australian tertiary referral centers using prospectively collected data in patients treated between 1980 and 2017 with a median (IQR) follow-up of 3.2 (3.9) years. The study population included 1309 consecutive patients with HNcSCC that was metastatic to parotid and/or cervical nodes. After excluding cases with perioperative mortality, missing data, or follow-up, the final study population included 1151 patients. Exposure: Curative intent surgery ± adjuvant radiotherapy. Main Outcomes and Measures: Differences in locoregional control (LRC), disease-specific survival (DSS), and overall survival were determined using Cox regression analysis. Results: Among 1151 patients, 976 (84.8%) were male and 175 (15.2%) female, with a median age of 73.3 years (range, 18-100 years). On multivariable analysis, immunosuppression (hazard ratio [HR], 2.48; 95% CI, 1.64-3.74), perineural invasion (HR, 1.69; 95% CI, 1.25-2.30), ENE (HR, 1.53; 95% CI, 0.95-2.44), size (>3-6 cm vs ≤3 cm [HR, 1.41; 95% CI, 1.03-1.93]; >6 cm vs ≤3 cm [HR, 5.01; 95% CI, 2.98-8.42]), and number of nodal metastases (3-4 vs 1-2 [HR, 1.54; 95% CI, 1.01-2.34]; ≥5 vs 1-2 [HR, 2.86; 95% CI, 1.99-4.11]) were associated with DSS. Similar results were found for LRC and overall survival. More than 90% of the population was categorized as TNM stage IV, with 32% attributable to ENE. In the ENE-positive subset (n = 860), DSS ranged from 8% to 88% based on stratification using other clinicopathological factors. Conclusions and Relevance: The study results suggest that immunosuppression, perineural invasion, ENE, and size and number of nodal metastases are associated with reduced survival and LRC in HNcSCC with nodal metastases. The inclusion of ENE in HNcSCC staging needs to be reassessed, as it ascribes excessive importance to ENE and upstages most patients to TNM stage IV, despite many having a high chance of cure.

Decoding drivers of carbon flux attenuation in the oceanic biological pump.

The biological pump supplies carbon to the oceans' interior, driving long-term carbon sequestration and providing energy for deep-sea ecosystems1,2. Its efficiency is set by transformations of newly formed particles in the euphotic zone, followed by vertical flux attenuation via mesopelagic processes3. Depth attenuation of the particulate organic carbon (POC) flux is modulated by multiple processes involving zooplankton and/or microbes4,5. Nevertheless, it continues to be mainly parameterized using an empirically derived relationship, the 'Martin curve'6. The derived power-law exponent is the standard metric used to compare flux attenuation patterns across oceanic provinces7,8. Here we present in situ experimental findings from C-RESPIRE9, a dual particle interceptor and incubator deployed at multiple mesopelagic depths, measuring microbially mediated POC flux attenuation. We find that across six contrasting oceanic regimes, representing a 30-fold range in POC flux, degradation by particle-attached microbes comprised 7-29 per cent of flux attenuation, implying a more influential role for zooplankton in flux attenuation. Microbial remineralization, normalized to POC flux, ranged by 20-fold across sites and depths, with the lowest rates at high POC fluxes. Vertical trends, of up to threefold changes, were linked to strong temperature gradients at low-latitude sites. In contrast, temperature played a lesser role at mid- and high-latitude sites, where vertical trends may be set jointly by particle biochemistry, fragmentation and microbial ecophysiology. This deconstruction of the Martin curve reveals the underpinning mechanisms that drive microbially mediated POC flux attenuation across oceanic provinces.

Auto-expansion of in vivo HDAd-transduced hematopoietic stem cells by constitutive expression of tHMGA2.

We developed an in vivo hematopoietic stem cell (HSC) gene therapy approach that does not require cell transplantation. To achieve therapeutically relevant numbers of corrected cells, we constructed HSC-tropic HDAd5/35++ vectors expressing a 3' UTR truncated HMGA2 gene and a GFP reporter gene. A SB100x transposase vector mediated random integration of the tHMGA2/GFP transgene cassette. HSCs in mice were mobilized by subcutaneous injections of G-CSF and AMD3100/Plerixafor and intravenously injected with the integrating tHMGA2/GFP vector. This resulted in a slow but progressive, competitive expansion of GFP+ PBMCs, reaching about 50% by week 44 with further expansion in secondary recipients. Expansion occurred at the level of HSCs as well as at the levels of myeloid, lymphoid, and erythroid progenitors within the bone marrow and spleen. Importantly, based on genome-wide integration site analyses, expansion was polyclonal, without any signs of clonal dominance. Whole-exome sequencing did not show significant differences in the genomic instability indices between tHGMGA2/GFP mice and untreated control mice. Auto-expansion by tHMGA2 was validated in humanized mice. This is the first demonstration that simple injections of mobilization drugs and HDAd vectors can trigger auto-expansion of in vivo transduced HSCs resulting in transgene-marking rates that, theoretically, are curative for hemoglobinopathies.

Siglec-7 and Siglec-9 expression in primary triple negative and oestrogen receptor positive breast cancer and in vitro signalling.

Objectives: PD-1/PD-L1 immune checkpoint blockade can be an effective treatment for advanced breast cancer patients. However, patients with oestrogen receptor positive (ER+) tumors often display only low lymphocyte infiltration, while a large part of triple negative (TN) breast tumors does not generate an effective immunotherapy response. Therefore, new treatment strategies have to be developed. Here, we investigate Siglec-7 and Siglec-9 as novel ITIM-bearing inhibitory immune checkpoint receptors similar to PD-1, but expressed on a broader range of immune cells. Methods: We assessed Siglec-7 and Siglec-9 (ligand) expression in TN and ER+ breast cancer tumors and their breast cancer cell line-induced signalling. Results: We report that Siglec-7 and Siglec-9 are highly expressed in TN tumors, and to a low extent in ER+ tumors. Siglec-7 was observed on myeloid cells, T cells, and NK cells and Siglec-9 preferentially on myeloid cells. Expression of sialoglycans, including Siglec-7 and Siglec-9 ligands, was observed in both TN and ER+ breast cancer tissue sections. Expression levels of Siglec-7 and Siglec-9 ligands were higher on in vitro cultured TN cell lines than ER+ cell lines. Importantly, by applying chimeric Siglec-7 reporter cells, we showed the induction of Siglec-7 signalling by multiple TN cell lines, but only by one ER+ cell line. Moreover, Siglec-7 signalling is directly related to Siglec-7 ligand expression levels of breast cancer cell lines. Conclusion: These data imply that immunotherapy targeting Siglec receptors may be particularly interesting for TN breast cancer patients not responding to current treatment strategies with tumors displaying high immune cell infiltration.

Ethnic Diversity and Distinctive Features of Familial Versus Multifactorial Chylomicronemia Syndrome: Insights From the UK FCS National Registry.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). METHODS: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. RESULTS: FCS was relatively common in non-Europeans and those with parental consanguinity (P<0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P=0.001), recurrent pancreatitis (92% versus 63%; P<0.001), unexplained abdominal pain (84% versus 52%; P<0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P<0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P<0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (P<0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (P=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS. CONCLUSIONS: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.

Bridged Treatment Comparisons: an Illustrative Application in HIV Treatment.

Comparisons of treatments, interventions, or exposures are of central interest in epidemiology, but direct comparisons are not always possible due to practical or ethical reasons. Here, we detail a fusion approach to compare treatments across studies. The motivating example entails comparing the risk of the composite outcome of death, AIDS, or greater than a 50% CD4 cell count decline in people with HIV when assigned triple versus mono antiretroviral therapy, using data from the AIDS Clinical Trial Group (ACTG) 175 (mono versus dual therapy) and ACTG 320 (dual versus triple therapy). We review a set of identification assumptions and estimate the risk difference using an inverse probability weighting estimator that leverages the shared trial arms (dual therapy). A fusion diagnostic based on comparing the shared arms is proposed that may indicate violation of the identification assumptions. Application of the data fusion estimator and diagnostic to the ACTG trials indicates triple therapy results in a reduction in risk compared to monotherapy in individuals with baseline CD4 counts between 50 and 300 cells/mm3. Bridged treatment comparisons address questions that none of the constituent data sources could address alone, but valid fusion-based inference requires careful consideration of the underlying assumptions.

Understanding hospital antimicrobial prescribing decisions and determinants of uptake of new local antimicrobial prescribing guidelines in Laos.

Background: Antimicrobial use in Laos is among the highest in Southeast Asia. The first Lao comprehensive antimicrobial prescribing guidelines have been available since 2021. This study explored the determinants of antibiotic prescribing decisions and how the new prescribing guidelines were being used. Methods: In August 2022, in-depth interviews were conducted with 16 Lao prescribers from two hospitals. Participants were questioned about their prescribing behaviours, attitudes to guidelines, how they learned about the guidelines and factors influencing their uptake. The interviews were audio-recorded, transcribed, and translated into English. Thematic analysis of the transcripts was conducted. Results: Lao prescribers considered multiple factors before deciding to prescribe antibiotics to their patients. The most common factor was based on the clinical judgement of the prescribers. Lack of certain antibiotics and turnaround times of laboratory results were the main challenges to prescribing antibiotics appropriately. The majority of participants were satisfied with the guidelines, regarding them as comprehensive, simple and convenient. However, most participants admitted that they did not access the guidelines very often. The main reason was that they could remember the treatment recommendations because they treat similar diseases on a daily basis. Improving antibiotic knowledge was the most common recommendation in order to improve the appropriate use of antibiotics. Raising awareness of the guidelines and promoting their use should also be considered. In addition, heads of the wards, and policy and implementation leaders, should support, monitor and feedback their use to encourage all prescribers to follow the guidelines. Conclusions: Several factors contribute to enhancing appropriate antibiotic prescription. Key factors for improving antibiotic prescription include enhancing prescribers' clinical knowledge, ensuring access to essential antibiotics, and updating guidelines regularly. Health leaders must get involved to promote their use.

In Laos, antibiotic use is high compared to other Southeast Asian countries. In 2021, the first guidelines for prescribing antibiotics were introduced in Laos. This study aims to explore what influences doctors' decisions in prescribing antibiotics and how they used the new guidelines. In August 2022, we conducted in-depth interviews with 16 doctors in two Lao hospitals. We asked them how they decided which antibiotics to give, what they thought about the guidelines, how they found the guidelines and what could make them use the guidelines more. We recorded, transcribed, and translated the conversations. Then, we identified common themes and patterns. Before giving antibiotics, doctors in Laos considered many things. The most important thing was their own judgment based on their medical knowledge. Not having some antibiotics and waiting long time for the laboratory results were the main issues that made it challenging for doctors to prescribe antibiotics. Most interviewees liked the guidelines. They found the guidelines easy to understand and useful. Many of them said that they did not use the guidelines a lot. The main reason was that they remembered the treatment recommendations because they treat similar diseases every day. The most common suggestion to use antibiotics better was to learn and understand more about them. Also, leaders of hospital departments and those in charge of making rules should help, keep an eye on the use, and give feedback to make sure everyone who prescribes antibiotics uses the guidelines. To make sure doctors prescribe antibiotics better, they need to know and understand more about infectious diseases, have easy access to essential antibiotics, and regularly update the guidelines with support from the leaders.

Trimethylamine N-Oxide and Related Gut Microbe-Derived Metabolites and Incident Heart Failure Development in Community-Based Populations.

BACKGROUND: Growing evidence indicates that trimethylamine N-oxide, a gut microbial metabolite of dietary choline and carnitine, promotes both cardiovascular disease and chronic kidney disease risk. It remains unclear how circulating concentrations of trimethylamine N-oxide and its related dietary and gut microbe-derived metabolites (choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine) affect incident heart failure (HF). METHODS: We evaluated 11 768 participants from the Cardiovascular Health Study and the Multi-Ethnic Study of Atherosclerosis with serial measures of metabolites. Cox proportional hazard models were used to examine the associations between metabolites and incident HF, adjusted for cardiovascular disease risk factors. RESULTS: In all, 2102 cases of HF occurred over a median follow-up of 15.9 years. After adjusting for traditional risk factors, higher concentrations of trimethylamine N-oxide (hazard ratio, 1.15 [95% CI, 1.09-1.20]; P<0.001), choline (hazard ratio, 1.44 [95% CI, 1.26-1.64]; P<0.001), and crotonobetaine (hazard ratio, 1.24 [95% CI, 1.16-1.32]; P<0.001) were associated with increased risk for incident HF. After further adjustment for renal function (potential confounder or mediator), these associations did not reach Bonferroni-corrected statistical significance (P=0.01, 0.049, and 0.006, respectively). Betaine and carnitine were nominally associated with a higher incidence of HF (P<0.05). In exploratory analyses, results were similar for subtypes of HF based on left ventricular ejection fraction, and associations appeared generally stronger among Black and Hispanic/Latino versus White adults, although there were no interactions for any metabolites with race. CONCLUSIONS: In this pooled analysis of 2 well-phenotyped, diverse, community-based cohorts, circulating concentrations of gut microbe-derived metabolites such as trimethylamine N-oxide, choline, and crotonobetaine were independently associated with a higher risk of developing HF. REGISTRATION: URL: https://www.clinicaltrials.gov/; Unique identifiers: NCT00005133 and NCT00005487.

Predictors of distant metastatic recurrence in head and neck cutaneous squamous cell carcinoma with lymph node metastases treated with curative intent: A multicenter study.

BACKGROUND: We aimed to identify predictors of distant metastatic recurrence (DMR) in patients with head and neck cutaneous squamous cell carcinoma (HNcSCC) with nodal metastases treated with curative intent. METHODS: Predictors of DMR were identified using Cox regression in a multicenter study of 1151 patients. RESULTS: The 5-year risk of DMR was 9.6%. On multivariate analysis, immunosuppression (HR 2.93; 95% CI: 1.70-5.05; p < 0.001), nodal size >6 cm [versus ≤3 cm (HR 2.77; 95% CI: 1.09-7.03; p = 0.032)], ≥5 nodal metastases [versus 1-2 (HR 2.79; 95% CI: 1.63-4.78; p < 0.001)], and bilateral disease (HR 3.11; 95% CI: 1.40-6.90; p = 0.005) predicted DMR. A DMR risk score was developed that stratified risk from 6.6% (no risk factors) to 100% (≥3 risk factors) (p < 0.001). CONCLUSIONS: The risk of DMR in nodal metastatic HNcSCC increases with immunosuppression, nodal size >6 cm, ≥5 nodal metastases, and bilateral disease. A simple DMR risk score estimated prior to treatment may be clinically useful.

Non-malarial febrile illness: a systematic review of published aetiological studies and case reports from China, 1980-2015.

BACKGROUND: Rapid point-of-care tests for malaria are now widely used in many countries to guide the initial clinical management of patients presenting with febrile illness. With China having recently achieved malaria elimination, better understanding regarding the identity and distribution of major non-malarial causes of febrile illnesses is of particular importance to inform evidence-based empirical treatment policy. METHODS: A systematic review of published literature was undertaken to characterise the spectrum of pathogens causing non-malaria febrile illness in China (1980-2015). Literature searches were conducted in English and Chinese languages in six databases: Ovid MEDLINE, Global Health, EMBASE, Web of Science™ - Chinese Science Citation Database SM, The China National Knowledge Infrastructure (CNKI), and WanFang Med Online. Selection criteria included reporting on an infection or infections with a confirmed diagnosis, defined as pathogens detected in or cultured from samples from normally sterile sites, or serological evidence of current or past infection. The number of published articles, reporting a given pathogen were presented, rather than incidence or prevalence of infection. RESULTS: A total of 57,181 records from 13 provinces of China where malaria used to be endemic were screened, of which 392 met selection criteria and were included in this review. The review includes 60 (15.3%) records published from 1980 to 2000, 211 (53.8%) from 2001 to 2010 and 121 (30.9%) from 2011 to 2015;. Of the 392 records, 166 (42.3%) were from the eastern region of China, 120 (30.6%) were from the south-west, 102 (26.0%) from south-central, and four (1.0%) were multi-regional studies. Bacterial infections were reported in 154 (39.3%) records, viral infections in 219 (55.9%), parasitic infections in four (1.0%), fungal infections in one (0.3%), and 14 (3.6%) publications reported more than one pathogen group. Participants of all ages were included in 136 (34.7%) studies, only adults in 75 (19.1%), only children in 17 (4.3%), only neonates in two (0.5%) and the age distribution was not specified in 162 (41.3%) records. The most commonly reported bacterial pathogens included Typhoidal Salmonella (n = 30), Orientia/ Rickettsia tsutsugamushi (n = 31), Coxiella burnetii (n = 17), Leptospira spp. (n = 15) and Brucella spp. (n = 15). The most commonly reported viral pathogens included Hantavirus/Hantaan virus (n = 89), dengue virus (DENV) (n = 76 including those with unknown serovars), Japanese encephalitis virus (n = 21), and measles virus (n = 15). The relative lack of data in the western region of the country, as well as in in neonates and children, represented major gaps in the understanding of the aetiology of fever in China. CONCLUSIONS: This review presents a landscape of non-malaria pathogens causing febrile illness in China over 36 years as the country progressed toward malaria elimination. These findings can inform guidelines for clinical management of fever cases and infection surveillance and prevention, and highlight the need to standardize operational and reporting protocols for better understanding of fever aetiology in the country.

Combined high rates of alternative breeding strategies unexpectedly found among populations of a solitary nesting raptor.

Social monogamy is the prevalent mating system in birds, but alternative strategies of extra-pair paternity (EPP) and conspecific brood parasitism (CBP) occur in many species. Raptors are virtually absent in discussions of broad taxonomic reviews regarding EPP and CBP likely because these strategies are mostly absent or at low frequency; CBP is unreported in solitary nesting raptors. In contrast, we found high frequencies of EPP (16%-31%) and CBP (15%-26%) nests among three populations of Cooper's Hawks (Accipiter cooperii) across the northern breeding range of this solitary nesting, socially monogamous species. EPP and CBP combined occurred in 42%-46% of all nests among populations and hence unexpectedly were nearly equivalent to proportions of genetically monogamous nests. Select covariates failed to predict presence of EPP and CBP in part because virtually all extra-pair adults were uncaught and likely were floaters. We found no support for the hypothesis that territorial females traded copulations for food to maximize energy intake for increased production. Our unique discoveries enhance knowledge of the extent and diversity of alternative breeding strategies among groups of avian and other animal species.

A narrative review of lifestyle management guidelines for metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) management guidelines have been published worldwide; we aimed to summarize, categorize and compare their lifestyle intervention recommendations. APPROACH RESULTS: We searched MASLD/nonalcoholic fatty liver disease (NAFLD) management guidelines published between 1 January 2013 and 31 June 2024 via databases including PubMed/MEDLINE, Cochrane, and CINAHL. In total, 35 qualifying guidelines were included in the final analysis. Guideline recommendations were categorized into five domains (i.e., weight reduction goals, physical activity, nutrition, alcohol, and tobacco smoking) and were ranked based on how frequently they appeared. A recommendation was defined as widely adopted if recommended in ≥24 (≥66.6%) of the guidelines. These included increase physical activity; reduce body weight by 7-10% to improve steatohepatitis and/or fibrosis; restrict caloric intake; undertake 150-300 or 75-150 minutes/week of moderate or vigorous-intensity physical activity, respectively; and decrease consumption of commercially produced fructose. The least mentioned topics, in ≤9 of the guidelines, evaluated environmental determinants of health, mental health, referring patients for psychological or cognitive behavioral therapy, using digital health interventions (DHIs), and assessing patients' social determinants of health. CONCLUSIONS: Most guidelines recommend weight reduction through physical activity and improving nutrition, as these have proven positive effects on health outcomes when sustained. However, gaps regarding mental health and the social and environmental determinants of MASLD were found. To optimize behavioral modifications and treatment, we recommend carrying out studies that will provide further evidence on social support, environmental factors, and mental health, and further exploring DHIs.

Using matrix assisted laser desorption ionisation mass spectrometry combined with machine learning for vaccine authenticity screening.

The global population is increasingly reliant on vaccines to maintain population health with billions of doses used annually in immunisation programmes. Substandard and falsified vaccines are becoming more prevalent, caused by both the degradation of authentic vaccines but also deliberately falsified vaccine products. These threaten public health, and the increase in vaccine falsification is now a major concern. There is currently no coordinated global infrastructure or screening methods to monitor vaccine supply chains. In this study, we developed and validated a matrix-assisted laser desorption/ionisation-mass spectrometry (MALDI-MS) workflow that used open-source machine learning and statistical analysis to distinguish authentic and falsified vaccines. We validated the method on two different MALDI-MS instruments used worldwide for clinical applications. Our results show that multivariate data modelling and diagnostic mass spectra can be used to distinguish authentic and falsified vaccines providing proof-of-concept that MALDI-MS can be used as a screening tool to monitor vaccine supply chains.

Beyond LDL-C: unravelling the residual atherosclerotic cardiovascular disease risk landscape-focus on hypertriglyceridaemia.

Aims: Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors. Findings: Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors. Implications: Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation.