Quadrivalent influenza nanoparticle vaccines induce broad protection.

Influenza vaccines that confer broad and durable protection against diverse viral strains would have a major effect on global health, as they would lessen the need for annual vaccine reformulation and immunization1. Here we show that computationally designed, two-component nanoparticle immunogens2 induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens contain 20 haemagglutinin glycoprotein trimers in an ordered array, and their assembly in vitro enables the precisely controlled co-display of multiple distinct haemagglutinin proteins in defined ratios. Nanoparticle immunogens that co-display the four haemagglutinins of licensed quadrivalent influenza vaccines elicited antibody responses in several animal models against vaccine-matched strains that were equivalent to or better than commercial quadrivalent influenza vaccines, and simultaneously induced broadly protective antibody responses to heterologous viruses by targeting the subdominant yet conserved haemagglutinin stem. The combination of potent receptor-blocking and cross-reactive stem-directed antibodies induced by the nanoparticle immunogens makes them attractive candidates for a supraseasonal influenza vaccine candidate with the potential to replace conventional seasonal vaccines3.

Transcriptional and Immune Landscape of Cardiac Sarcoidosis.

BACKGROUND: Cardiac involvement is an important determinant of mortality among sarcoidosis patients. Although granulomatous inflammation is a hallmark finding in cardiac sarcoidosis, the precise immune cell populations that comprise the granuloma remain unresolved. Furthermore, it is unclear how the cellular and transcriptomic landscape of cardiac sarcoidosis differs from other inflammatory heart diseases. METHODS: We leveraged spatial transcriptomics (GeoMx digital spatial profiler) and single-nucleus RNA sequencing to elucidate the cellular and transcriptional landscape of cardiac sarcoidosis. Using GeoMX digital spatial profiler technology, we compared the transcriptomal profile of CD68+ rich immune cell infiltrates in human cardiac sarcoidosis, giant cell myocarditis, and lymphocytic myocarditis. We performed single-nucleus RNA sequencing of human cardiac sarcoidosis to identify immune cell types and examined their transcriptomic landscape and regulation. Using multichannel immunofluorescence staining, we validated immune cell populations identified by single-nucleus RNA sequencing, determined their spatial relationship, and devised an immunostaining approach to distinguish cardiac sarcoidosis from other inflammatory heart diseases. RESULTS: Despite overlapping histological features, spatial transcriptomics identified transcriptional signatures and associated pathways that robustly differentiated cardiac sarcoidosis from giant cell myocarditis and lymphocytic myocarditis. Single-nucleus RNA sequencing revealed the presence of diverse populations of myeloid cells in cardiac sarcoidosis with distinct molecular features. We identified GPNMB (transmembrane glycoprotein NMB) as a novel marker of multinucleated giant cells and predicted that the MITF (microphthalmia-associated transcription factor) family of transcription factors regulated this cell type. We also detected additional macrophage populations in cardiac sarcoidosis including HLA-DR (human leukocyte antigen-DR)+ macrophages, SYTL3 (synaptotagmin-like protein 3)+ macrophages and CD163+ resident macrophages. HLA-DR+ macrophages were found immediately adjacent to GPMMB+ giant cells, a distinct feature compared with other inflammatory cardiac diseases. SYTL3+ macrophages were located scattered throughout the granuloma and CD163+ macrophages, CD1c+ dendritic cells, nonclassical monocytes, and T cells were located at the periphery and outside of the granuloma. Finally, we demonstrate mTOR (mammalian target of rapamycin) pathway activation is associated with proliferation and is selectively found in HLA-DR+ and SYLT3+ macrophages. CONCLUSIONS: In this study, we identified diverse populations of immune cells with distinct molecular signatures that comprise the sarcoid granuloma. These findings provide new insights into the pathology of cardiac sarcoidosis and highlight opportunities to improve diagnostic testing.

Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy.

BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.

Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA. Variant classification can play an important role in confirming the diagnosis of Pompe disease as well as in the identification of carriers. Furthermore, since the inclusion of Pompe disease on the Recommended Uniform Screening Panel (RUSP) for newborns in the USA in 2015, the addition of molecular genetic testing has become an important component in the interpretation of newborn screening results, particularly for asymptomatic individuals. To date, the LD VCEP has submitted classifications and supporting data on 243 GAA variants to public databases, specifically ClinVar and the ClinGen Evidence Repository. Here, we describe the ACMG/AMP criteria specification process for GAA, an update of the GAA-specific variant classification guidelines, and comparison of the ClinGen LD VCEP's GAA variant classifications with variant classifications submitted to ClinVar. The LD VCEP has added to the publicly available knowledge on the pathogenicity of variants in GAA by increasing the number of expert-curated GAA variants present in ClinVar, and aids in resolving conflicting classifications and variants of uncertain clinical significance.

A Lipid-Structured Model of Atherosclerotic Plaque Macrophages with Lipid-Dependent Kinetics.

Atherosclerotic plaques are fatty growths in artery walls that cause heart attacks and strokes. Plaque formation is driven by macrophages that are recruited to the artery wall. These cells consume and remove blood-derived lipids, such as modified low-density lipoprotein. Ineffective lipid removal, due to macrophage death and other factors, leads to the accumulation of lipid-loaded macrophages and formation of a necrotic lipid core. Experimental observations suggest that macrophage functionality varies with the extent of lipid loading. However, little is known about the influence of macrophage lipid loads on plaque fate. Extending work by Ford et al. (J Theor Biol 479:48-63, 2019) and Chambers et al. (A lipid-structured model of atherosclerosis with macrophage proliferation, 2022), we develop a plaque model where macrophages are structured by their ingested lipid load and behave in a lipid-dependent manner. The model considers several macrophage behaviours, including recruitment to and emigration from the artery wall; proliferation and apotosis; ingestion of plaque lipids; and secondary necrosis of apoptotic cells. We consider apoptosis, emigration and proliferation to be lipid-dependent and we model these effects using experimentally informed functions of the internalised lipid load. Our results demonstrate that lipid-dependent macrophage behaviour can substantially alter plaque fate by changing both the total quantity of lipid in the plaque and the distribution of lipid between the live cells, dead cells and necrotic core. The consequences of macrophage lipid-dependence are often unpredictable because lipid-dependent effects introduce subtle, nonlinear interactions between the modelled cell behaviours. These observations highlight the importance of mathematical modelling in unravelling the complexities of macrophage lipid accumulation during atherosclerotic plaque formation.

External validation of the Japanese difficulty score for laparoscopic hepatectomy in patients undergoing robotic-assisted hepatectomy.

INTRODUCTION: The Japanese difficulty score (JDS) categorizes laparoscopic hepatectomy into low, intermediate, and high complexity procedures, and correlates with operative and postoperative outcomes. We sought to perform a validation study to determine if the JDS correlates with operative and postoperative indicators of surgical complexity for patients undergoing robotic-assisted hepatectomy. METHODS: Retrospective review of 657 minimally invasive hepatectomy procedures was performed between January 2008 through March 2019. Outcomes included operative time, estimated blood loss (EBL), blood transfusion, complications, post-hepatectomy liver failure (PHLF), length of stay, 30-day readmission, and 30-day and 90-day mortality. Patients were grouped based on JDS defined as: low (< 4), intermediate (4-6), and high (7 +) complexity procedures. Statistical comparisons were analyzed by ANOVA or χ2 test. RESULTS: 241 of 657 patients underwent robotic-assisted resection. Of these patients, 137 were included in the analysis based on JDS: 25 low, 58 intermediate, and 54 high. High JDS was associated with more major resections (≥ 4 contiguous segments) versus minor resections (median JDS 8 vs. 5, P < 0.0001). High JDS was associated with significantly longer operative times, higher EBL, and more blood transfusions. High JDS was associated with higher rates of PHLF at 16.7%, compared with 5.2% intermediate and 0.0% low, (P = 0.018). Complication rates, 30-day readmissions, and mortality rates were similar between groups. Median LOS was longer in patients with high JDS compared with intermediate and low (4 days vs. 3 days vs. 2 days; P = 0.0005). DISCUSSION: Higher JDS was associated with multiple indicators of operative complexity, including greater extent of resection, increased operative time, EBL, blood transfusion, PHLF, and LOS. This validation study supports the ability of the JDS to categorize patients undergoing robotic-assisted hepatectomy by complexity.

Implementation fidelity of the 'Stay One Step Ahead' home safety intervention: a mixed-methods analysis.

OBJECTIVE: To assess implementation fidelity of the Stay One Step Ahead (SOSA), a complex intervention which was delivered by health visiting teams, children's centres, and family mentors and was aimed at preventing unintentional home injuries in children under 5 in disadvantaged communities. STUDY DESIGN: A mixed-methods evaluation of the implementation fidelity of the SOSA intervention. METHODS: A conceptual framework for implementation fidelity was used to triangulate data from questionnaires and semistructured interviews with parents and practitioners, observations of parent and practitioner contacts, and meeting documents. Quantitative data were analysed using logistic regression and descriptive statistics. Thematic analysis was used for qualitative data. RESULTS: Parents in intervention wards were more likely to receive home safety advice from a practitioner than those living in matched control wards. Monthly safety messages and family mentor home safety activities were delivered with greater fidelity than other intervention components. Content most frequently adapted included the home safety checklist used by health visiting teams, and safety weeks delivered at children's centres. CONCLUSION: Consistent with similarly complex interventions, SOSA was delivered with variable fidelity in a challenging environment. The findings add to the body of evidence on implementation fidelity of home injury prevention programmes, providing important information for future intervention development and delivery.

Cost-effectiveness of England's national 'Safe At Home' scheme for reducing hospital admissions for unintentional injury in children aged under 5.

BACKGROUND: Injuries in children aged under 5 years most commonly occur in the home and disproportionately affect those living in the most disadvantaged communities. The 'Safe at Home' (SAH) national home safety equipment scheme, which ran in England between 2009 and 2011, has been shown to reduce injury-related hospital admissions, but there is little evidence of cost-effectiveness. MATERIALS AND METHODS: Cost-effectiveness analysis from a health and local government perspective. Measures were the incremental cost-effectiveness ratio per hospital admission averted (ICER) and cost-offset ratio (COR), comparing SAH expenditure to savings in admission expenditure. The study period was split into three periods: T1 (years 0-2, implementation); T2 (years 3-4) and T3 (years 5-6). Analyses were conducted for T2 versus T1 and T3 versus T1. RESULTS: Total cost of SAH was £9 518 066. 202 223 hospital admissions in the children occurred during T1-3, costing £3 320 000. Comparing T3 to T1 SAH reduced admission expenditure by £924 per month per local authority and monthly admission rates by 0.5 per local authority per month compared with control areas. ICER per admission averted was £4209 for T3 versus T1, with a COR of £0.29, suggesting that 29p was returned in savings on admission expenditure for every pound spent on SAH. CONCLUSION: SAH was effective at reducing hospital admissions due to injury and did result in some cost recovery when taking into admissions only. Further analysis of its cost-effectiveness, including emergency healthcare, primary care attendances and wider societal costs, is likely to improve the return on investment further.

Effectiveness of systematically delivered evidence-based home safety promotion to improve child home safety practices: a controlled before-and-after study.

OBJECTIVE: Evaluate the effectiveness of systematically delivered evidence-based home safety promotion for improving child home safety practices. DESIGN: Controlled before-and-after study. SETTING: Nine electoral wards in Nottingham, UK. PARTICIPANTS: 361 families with children aged 2-7 months at recruitment living in four intervention wards with high health, education and social need; and 401 in five matched control wards. INTERVENTION: Evidence-based home safety promotion delivered by health visiting teams, family mentors and children's centres including 24 monthly safety messages; home safety activity sessions; quarterly 'safety weeks'; home safety checklists. OUTCOMES: Primary: composite measure comprising having a working smoke alarm, storing poisons out of reach and having a stairgate. Secondary: other home safety practices; medically attended injuries. Parents completed questionnaires at 12 and 24 months after recruitment plus optional three monthly injury questionnaires. RESULTS: At 24 months there was no significant difference between groups in the primary outcome (55.8% vs 48.8%; OR 1.58, 95% CI 0.98 to 2.55) or medically attended injury rates (incidence rate ratio 0.89, 95% CI 0.51 to 1.56), but intervention families were more likely to store poisons safely (OR 1.81, 95% CI 1.06 to 3.07), have a fire escape plan (OR 1.81, 95% CI 1.06 to 3.08), use a fireguard or have no fire (OR 3.17, 95% CI 1.63 to 6.16) and perform more safety practices (ß 0.46, 95% CI 0.13 to 0.79). CONCLUSIONS: Systematic evidence-based home safety promotion in areas with substantial need increases adoption of some safety practices. Funders should consider commissioning evidence-based multicomponent child home safety interventions. TRIAL REGISTRATION NUMBER: ISRCTN31210493.

UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease 2023 UPDATE.

Large placebo-controlled trials have demonstrated kidney and cardiovascular clinical benefits of SGLT-2 inhibitors. Data from the EMPA-KIDNEY and DELIVER trials and associated meta-analyses triggered an update to the UK Kidney Association Clinical Practice Guideline on Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. We provide a summary of the full guideline and highlight the rationale for recent updates. The use of SGLT-2 inhibitors in people with specific medical conditions, including type 1 diabetes, kidney transplants, and people admitted to hospital with heart failure is also considered, along with Recommendations for future research and Recommendations for implementation. A full "lay" summary of the guidelines is provided as an appendix to ensure that these guidelines are accessible and understandable to people who are not medical professionals.

Newborn screening for neurodevelopmental diseases: Are we there yet?

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

A novel pathogenic variant in the corneodesmosin gene causing generalized inflammatory peeling skin syndrome with marked eosinophilia and trichorrhexis invaginata.

Generalized inflammatory peeling skin syndrome (PSS) is a rare autosomal recessive genodermatosis caused by loss-of-function disease-causing variants of the corneodesmosin gene (CDSN), resulting in excessive shedding of the superficial layers of the epidermis. We describe a case of generalized inflammatory PSS in an infant, presenting at day two of life with ichthyosiform erythroderma and superficial peeling of the skin. Hair microscopy showed trichorrhexis invaginata. Normal amounts of skin LEKT1, a product of SPINK5 on immunohistochemical staining excluded a diagnosis of Netherton syndrome. Genetic analysis revealed a homozygous novel complete CDSN deletion, estimated 4.6 kb in size, supporting the diagnosis of generalized inflammatory PSS.

DNA methylation from a Type I restriction modification system influences gene expression and virulence in Streptococcus pyogenes.

DNA methylation is pervasive across all domains of life. In bacteria, the presence of N6-methyladenosine (m6A) has been detected among diverse species, yet the contribution of m6A to the regulation of gene expression is unclear in many organisms. Here we investigated the impact of DNA methylation on gene expression and virulence within the human pathogen Streptococcus pyogenes, or Group A Streptococcus. Single Molecule Real-Time sequencing and subsequent methylation analysis identified 412 putative m6A sites throughout the 1.8 Mb genome. Deletion of the Restriction, Specificity, and Methylation gene subunits (ΔRSM strain) of a putative Type I restriction modification system lost all detectable m6A at the recognition sites and failed to prevent transformation with foreign-methylated DNA. RNA-sequencing identified 20 genes out of 1,895 predicted coding regions with significantly different gene expression. All of the differentially expressed genes were down regulated in the ΔRSM strain relative to the parent strain. Importantly, we found that the presence of m6A DNA modifications affected expression of Mga, a master transcriptional regulator for multiple virulence genes, surface adhesins, and immune-evasion factors in S. pyogenes. Using a murine subcutaneous infection model, mice infected with the ΔRSM strain exhibited an enhanced host immune response with larger skin lesions and increased levels of pro-inflammatory cytokines compared to mice infected with the parent or complemented mutant strains, suggesting alterations in m6A methylation influence virulence. Further, we found that the ΔRSM strain showed poor survival within human neutrophils and reduced adherence to human epithelial cells. These results demonstrate that, in addition to restriction of foreign DNA, gram-positive bacteria also use restriction modification systems to regulate the expression of gene networks important for virulence.

The 2019 US medical genetics workforce: a focus on clinical genetics.

PURPOSE: This study characterizes the US clinical genetics workforce to inform workforce planning and public policy development. METHODS: A 32-question survey was electronically distributed to American Board of Medical Genetics and Genomics board-certified/eligible diplomates in 2019. We conducted a descriptive analysis of responses from practicing clinical geneticists. RESULTS: Of the 491 clinical geneticists responding to the survey, a majority were female (59%) and White (79%), worked in academic medical centers (73%), and many engaged in telemedicine (33%). Clinical geneticists reported an average of 13 new and 10 follow-up patient visits per week. The average work week was 50 hours and the majority (58%) worked over half-time in clinical duties. Providers indicated that 39% of new emergency patients wait 3 days or more, and 39% of nonemergency patients wait over 3 months to be seen. Respondents were geographically concentrated in metropolitan areas and many reported unfilled clinical geneticist job vacancies at their institution of more than 3 years. CONCLUSION: With the rapid expansion of genomic medicine in the past decade, there is still a gap between genetics services needed and workforce capacity. A concerted effort is required to increase the number of clinical geneticists and enhance interdisciplinary teamwork to meet increasing patient needs.

Bacteriophages against Vibrio coralliilyticus and Vibrio tubiashii: Isolation, Characterization, and Remediation of Larval Oyster Mortalities.

Vibrio coralliilyticus and Vibrio tubiashii are pathogens responsible for high larval oyster mortality rates in shellfish hatcheries. Bacteriophage therapy was evaluated to determine its potential to remediate these mortalities. Sixteen phages against V. coralliilyticus and V. tubiashii were isolated and characterized from Hawaiian seawater. Fourteen isolates were members of the Myoviridae family, and two were members of the Siphoviridae In proof-of-principle trials, a cocktail of five phages reduced mortalities of larval Eastern oysters (Crassostrea virginica) and Pacific oysters (Crassostrea gigas) by up to 91% 6 days after challenge with lethal doses of V. coralliilyticus Larval survival depended on the oyster species, the quantities of phages and vibrios applied, and the species and strain of Vibrio A later-generation cocktail, designated VCP300, was formulated with three lytic phages subsequently named Vibrio phages vB_VcorM-GR7B, vB_VcorM-GR11A, and vB_VcorM-GR28A (abbreviated 7B, 11A, and 28A, respectively). Together, these three phages displayed host specificity toward eight V. coralliilyticus strains and a V. tubiashii strain. Larval C. gigas mortalities from V. coralliilyticus strains RE98 and OCN008 were significantly reduced by >90% (P < 0.0001) over 6 days with phage treatment compared to those of untreated controls. Genomic sequencing of phages 7B, 11A, and 28A revealed 207,758-, 194,800-, and 154,046-bp linear DNA genomes, respectively, with the latter showing 92% similarity to V. coralliilyticus phage YC, a strain from the Great Barrier Reef, Australia. Phage 7B and 11A genomes showed little similarity to phages in the NCBI database. This study demonstrates the promising potential for phage therapy to reduce larval oyster mortalities in oyster hatcheries.IMPORTANCE Shellfish hatcheries encounter episodic outbreaks of larval oyster mortalities, jeopardizing the economic stability of hatcheries and the commercial shellfish industry. Shellfish pathogens like Vibrio coralliilyticus and Vibrio tubiashii have been recognized as major contributors of larval oyster mortalities in U.S. East and West Coast hatcheries for many years. This study isolated, identified, and characterized bacteriophages against these Vibrio species and demonstrated their ability to reduce mortalities from V. coralliilyticus in larval Pacific oysters and from both V. coralliilyticus and V. tubiashii in larval Eastern oysters. Phage therapy offers a promising approach for stimulating hatchery production to ensure the well-being of hatcheries and the commercial oyster trade.

A pre-operative platelet transfusion algorithm for patients with cirrhosis and hepatocellular carcinoma undergoing laparoscopic microwave ablation.

BACKGROUND: Thrombocytopenia is a common finding in patients with chronic liver disease. It is associated with poor clinical outcomes due to increased risk of bleeding after even minor procedures. We sought to determine an algorithm for pre-operative platelet transfusion in patients with cirrhosis and hepatocellular carcinoma (HCC) undergoing laparoscopic microwave ablation (MIS-MWA). METHODS: A retrospective review identified all patients with cirrhosis and HCC who underwent MIS-MWA at a single tertiary institution between 2007 and 2019. Demographics, pre-operative and post-operative laboratory values, transfusion requirements, and bleeding events were collected. The analyzed outcome of bleeding risk included any transfusion received intra-operatively or a transfusion or surgical intervention post-operatively. Logistic regression models were created to predict bleeding risk and identify patients who would benefit from pre-operative transfusion. RESULTS: There were 433 patients with cirrhosis and HCC who underwent MIS-MWA identified; of these, 353 patients had complete laboratory values and were included. Bleeding risk was evaluated through bivariate analysis of statistically and clinically significant variables. The accuracy of both models was substantiated through bootstrap validation for 500 iterations (model 1: ROC 0.8684, Brier score 0.0238; model 2: ROC 0.8363, Brier score 0.0252). The first model captured patients with both thrombocytopenia and anemia: platelet count < 60 × 109 / L (OR 7.75, p 0.012, CI 1.58-38.06) and hemoglobin < 10 gm/dL (OR 5.76, p 0.032, CI 1.16-28.63). The second model captured patients with thrombocytopenia without anemia: platelet count < 30 × 109/L (OR 8.41, p 0.05, CI 0.96-73.50) and hemoglobin > 10 gm/dL (OR 0.16, p 0.026, CI 0.031-0.80). CONCLUSION: The prediction of patients with cirrhosis and HCC requiring pre-operative platelet transfusions may help to avoid bleeding complications after invasive procedures. This study needs to be prospectively validated and ultimately may be beneficial in assessment of novel therapies for platelet-based clinical treatment in liver disease.

Pathologic response translates to improved patient survival after locoregional treatment for hepatocellular carcinoma: the importance of minimally invasive microwave ablation.

BACKGROUND: Hepatectomy or transplantation can serve as curative treatment for early-stage hepatocellular carcinoma (HCC). Unfortunately, as progression remains a reality, locoregional therapies (LRT) for curative or bridging intent have become common. Efficacy on viability, outcomes, and accuracy of imaging should be defined to guide treatment. METHODS: Patients with HCC who underwent minimally invasive (MIS) microwave ablation (MWA), transarterial chemoembolization (TACE), or both (MIS-MWA-TACE) prior to hepatectomy or transplantation were identified. Tumor response and preoperative computed tomography (CT) accuracy were assessed and compared to pathology. Clinical and oncologic outcomes were compared between MIS-MWA, TACE, and MIS-MWA-TACE. RESULTS: Ninety-one patients, with tumors from all stages of the Barcelona Clinic Liver Cancer (BCLC) staging, were identified who underwent LRT prior to resection or transplant. Fourteen patients underwent MIS-MWA, 46 underwent TACE, and 31 underwent both neoadjuvantly. TACE population was older; otherwise, there were no differences in demographics. Fifty-seven percent of MIS-MWA patients had no viable tumor on pathology whereas only 13% of TACE patients and 29% of MIS-MWA-TACE patients had complete destruction (p = 0.004). The amount of remaining viable tumor in the explant was also significantly different between groups (MIS-MWA: 17.2%, TACE: 48.7%, MIS-MWA-TACE: 18.6%; p ≤ 0.0001). Compared with TACE, the MIS-MWA and MIS-MWA-TACE groups had significantly improved overall survival (MIS-MWA: 99.94 months, TACE: 75.35 months, MIS-MWA-TACE: 140 months; p = 0.017). This survival remained significant with stratification by tumor size. CT accuracy was found to be 50% sensitive and 86% specific for MIS-MWA. For TACE, CT had an 82% sensitivity and 33% specificity and for MIS-MWA-TACE, there was a 42% sensitivity and 78% specificity. CONCLUSION: The impact of locoregional treatments on tumor viability is distinct and superior with MIS-MWA alone and MIS-MWA-TACE offering significant advantage over TACE alone. The extent of this effect may be implicated in the improved overall survival.

Walking for hypertension.

BACKGROUND: Increased physical activity has been recommended as an important lifestyle modification for the prevention and control of hypertension. Walking is a low-cost form of physical activity and one which most people can do. Studies testing the effect of walking on blood pressure have revealed inconsistent findings. OBJECTIVES: To determine the effect of walking as a physical activity intervention on blood pressure and heart rate. SEARCH METHODS: We searched the following databases up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL (2020, Issue 2), Ovid MEDLINE, Ovid Embase, CINAHL, PsycINFO, SPORTDiscus, PEDro, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the following Chinese databases up to May 2020: Index to Taiwan Periodical Literature System; National Digital Library of Theses and Dissertation in Taiwan; China National Knowledge Infrastructure (CNKI) Journals, Theses & Dissertations; and Wanfang Medical Online. We contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: Randomised controlled trials of participants, aged 16 years and over, which evaluated the effects of a walking intervention compared to non-intervention control on blood pressure and heart rate were included. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Where data were not available in the published reports, we contacted authors. Pooled results for blood pressure and heart rate were presented as mean differences (MDs) between groups with 95% confidence intervals (CIs). We undertook subgroup analyses for age and sex. We undertook sensitivity analyses to assess the effect of sample size on our findings. MAIN RESULTS: A total of 73 trials met our inclusion criteria. These 73 trials included 5763 participants and were undertaken in 22 countries. Participants were aged from 16 to 84 years and there were approximately 1.5 times as many females as males. The characteristics of walking interventions in the included studies were as follows: the majority of walking interventions was at home/community (n = 50) but supervised (n = 36 out of 47 reported the information of supervision); the average intervention length was 15 weeks, average walking time per week was 153 minutes and the majority of walking intensity was moderate. Many studies were at risk of selection bias and performance bias. Primary outcome We found moderate-certainty evidence suggesting that walking reduces systolic blood pressure (SBP) (MD -4.11 mmHg, 95% CI -5.22 to -3.01; 73 studies, n = 5060). We found moderate-certainty evidence suggesting that walking reduces SBP in participants aged 40 years and under (MD -4.41 mmHg, 95% CI -6.17 to -2.65; 14 studies, n = 491), and low-certainty evidence that walking reduces SBP in participants aged 41 to 60 years (MD -3.79 mmHg, 95% CI -5.64 to -1.94, P < 0.001; 35 studies, n = 1959), and those aged 60 years of over (MD -4.30 mmHg, 95% CI -6.17 to -2.44, 24 studies, n = 2610). We also found low certainty-evidence suggesting that walking reduces SBP in both females (MD -5.65 mmHg, 95% CI -7.89 to -3.41; 22 studies, n = 1149) and males (MD -4.64 mmHg, 95% CI -8.69 to -0.59; 6 studies, n = 203). Secondary outcomes We found low-certainty evidence suggesting that walking reduces diastolic blood pressure (DBP) (MD -1.79 mmHg, 95% CI -2.51 to -1.07; 69 studies, n = 4711) and heart rate (MD -2.76 beats per minute (bpm), 95% CI -4.57 to -0.95; 26 studies, n = 1747). We found moderate-certainty evidence suggesting that walking reduces DBP for participants aged 40 years and under (MD -3.01 mmHg, 95% CI -4.44 to -1.58; 14 studies, n = 491) and low-certainty evidence suggesting that walking reduces DBP for participants aged 41 to 60 years (MD -1.74 mmHg, 95% CI -2.95 to -0.52; 32 studies, n = 1730) and those aged 60 years and over (MD -1.33 mmHg, 95% CI -2.40 to -0.26; 23 studies, n = 2490). We found moderate-certainty evidence that suggests walking reduces DBP for males (MD -2.54 mmHg, 95% CI -4.84 to -0.24; 6 studies, n = 203) and low-certainty evidence that walking reduces DBP for females (MD -2.69 mmHg, 95% CI -4.16 to -1.23; 20 studies, n = 1000). Only 21 included studies reported adverse events. Of these 21 studies, 16 reported no adverse events, the remaining five studies reported eight adverse events, with knee injury being reported five times. AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that walking probably reduces SBP. Moderate- or low-certainty evidence suggests that walking may reduce SBP for all ages and both sexes. Low-certainty evidence suggests that walking may reduce DBP and heart rate. Moderate- and low-certainty evidence suggests walking may reduce DBP and heart rate for all ages and both sexes.

The technical aspects of ex vivo hepatectomy with autotransplantation: a systematic review and meta-analysis.

PURPOSE: Ex vivo hepatectomy is the incorporation of liver transplant techniques in the non-transplant setting, providing opportunity for locally advanced tumors found conventionally unresectable. Because the procedure is rare and reports in the literature are limited, we sought to perform a systematic review and meta-analysis investigating technical variations of ex vivo hepatectomies. METHODS: In the literature, there is a split in those performing the procedure between venovenous bypass (VVB) and temporary portacaval shunts (PCS). Of the 253 articles identified on the topic of ex vivo resection, 37 had sufficient data to be included in our review. RESULTS: The majority of these procedures were performed for hepatic alveolar echinococcosis (69%) followed by primary and secondary hepatic malignancies. In 18 series, VVB was used, and in 18, a temporary PCS was performed. Comparing these two groups, intraoperative variables and morbidity were not statistically different, with a cumulative trend in favor of PCS. Ninety-day mortality was significantly lower in the PCS group compared to the VVB group (p=0.03). CONCLUSION: In order to better elucidate these differences between technical approaches, a registry and consensus statement are needed.

Current trends in vena cava reconstructive techniques with major liver resection: a systematic review.

PURPOSE: Historically, invasion of the inferior vena cava (IVC) represented advanced and often unresectable hepatic disease. With surgical and anesthetic innovations, IVC resection and reconstruction have become feasible in selected patients. This review assesses technical variations in reconstructive techniques and post-operative management. METHODS: A comprehensive literature search was performed according to PRISMA. Inclusion criteria were (i) peer-reviewed articles in English; (ii) at least three cases; (iii) hepatic IVC resection and reconstruction (January 2015-March 2020). Primary outcomes were reconstructive technique, anti-thrombotic regimen, post-operative IVC patency, and infection. Secondary outcomes included post-operative complications and malignant disease survival. RESULTS: Fourteen articles were included allowing for investigation of 351 individual patients. Analysis demonstrated significant heterogeneity in surgical reconstructive technique, anti-thrombotic management, and post-operative monitoring of patency. There was increased utilization of ex vivo approaches and decreased use of venovenous bypass compared with previously published reviews. CONCLUSION: This review of literature published between 2015 and 2020 reveals persistent heterogeneity of hepatic IVC reconstructive techniques and peri-operative management. Increased utilization of ex vivo approaches and decreased use of venovenous bypass point towards improved operative techniques, peri-operative management, and anesthesia. In order to gain evidence for consensus on management, a registry would be beneficial.