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Measurable residual disease (MRD) surveillance in acute myeloid leukemia (AML) may identify patients destined for relapse and thus provide the option of pre-emptive therapy to improve their outcome. Whilst flow cytometric MRD (Flow-MRD) can be applied to high-risk AML/ myelodysplasia patients, its diagnostic performance for detecting impending relapse is unknown. We evaluated this in a cohort comprising 136 true positives (bone marrows preceding relapse by a median of 2.45 months) and 155 true negatives (bone marrows during sustained remission). At an optimal Flow-MRD threshold of 0.040%, clinical sensitivity and specificity for relapse was 74% and 87% respectively (51% and 98% for Flow-MRD ≥ 0.1%) by ‘different-from-normal’ analysis. Median relapse kinetics were 0.78 log10/month but significantly higher at 0.92 log10/month for FLT3-mutated AML. Computational (unsupervised) Flow-MRD (C-Flow-MRD) generated optimal MRD thresholds of 0.036% and 0.082% with equivalent clinical sensitivity to standard analysis. C-Flow-MRD-identified aberrancies in HLADRlow or CD34+CD38low (LSC-type) subpopulations contributed the greatest clinical accuracy (56% sensitivity, 90% specificity) and notably, by longitudinal profiling expanded rapidly within blasts in > 40% of 86 paired MRD and relapse samples. In conclusion, flow MRD surveillance can detect MRD relapse in high risk AML and its evaluation may be enhanced by computational analysis.

Innovations in complementary metal-oxide semiconductor (CMOS) single-photon avalanche diode (SPAD) technology has featured in the development of next-generation instruments for point-based time-resolved fluorescence spectroscopy (TRFS). These instruments provide hundreds of spectral channels, allowing the collection of fluorescence intensity and fluorescence lifetime information over a broad spectral range at a high spectral and temporal resolution. We present Multichannel Fluorescence Lifetime Estimation, MuFLE, an efficient computational approach to exploit the unique multi-channel spectroscopy data with an emphasis on simultaneous estimation of the emission spectra, and the respective spectral fluorescence lifetimes. In addition, we show that this approach can estimate the individual spectral characteristics of fluorophores from a mixed sample.

Background: Colorectal liver metastases (CRLM) occur in roughly half of patients with colorectal cancer. Minimally invasive surgery (MIS) has become an increasingly acceptable and utilized technique for resection in these patients, but there is a lack of specific guidelines on the use of MIS hepatectomy in this setting. A multidisciplinary expert panel was convened to develop evidence-based recommendations regarding the decision between MIS and open techniques for the resection of CRLM. Methods: Systematic review was conducted for two key questions (KQ) regarding the use of MIS versus open surgery for the resection of isolated liver metastases from colon and rectal cancer. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Additionally, the panel developed recommendations for future research. Results: The panel addressed two KQs, which pertained to staged or simultaneous resection of resectable colon or rectal metastases. The panel made conditional recommendations for the use of MIS hepatectomy for both staged and simultaneous resection when deemed safe, feasible, and oncologically effective by the surgeon based on the individual patient characteristics. These recommendations were based on low and very low certainty of evidence. Conclusions: These evidence-based recommendations should provide guidance regarding surgical decision-making in the treatment of CRLM and highlight the importance of individual considerations of each case. Pursuing the identified research needs may help further refine the evidence and improve future versions of guidelines for the use of MIS techniques in the treatment of CRLM.

Background: While surgical resection has a demonstrated utility for patients with colorectal liver metastases (CRLM), it is unclear whether minimally invasive surgery (MIS) or an open approach should be used. This review sought to assess the efficacy and safety of MIS versus open hepatectomy for isolated, resectable CRLM when performed separately from (Key Question (KQ) 1) or simultaneously with (KQ2) the resection of the primary tumor. Methods: PubMed, Embase, Google Scholar, Cochrane CENTRAL, International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov databases were searched to identify both randomized controlled trials (RCTs) and non-randomized comparative studies published during January 2000—September 2020. Two independent reviewers screened literature for eligibility, extracted data from included studies, and assessed internal validity using the Cochrane Risk of Bias 2.0 Tool and the Newcastle–Ottawa Scale. A random-effects meta-analysis was performed using risk ratios (RR) and mean differences (MD). Results: From 2304 publications, 35 studies were included for meta-analysis. For staged resections, three RCTs and 20 observational studies were included. Data from RCTs indicated MIS having similar disease-free survival (DFS) at 1-year (RR 1.03, 95%CI 0.70–1.50), overall survival (OS) at 5-years (RR 1.04, 95%CI 0.84–1.28), fewer complications of Clavien-Dindo Grade III (RR 0.62, 95%CI 0.38–1.00), and shorter hospital length of stay (LOS) (MD -6.6 days, 95%CI -10.2, -3.0). For simultaneous resections, 12 observational studies were included. There was no evidence of a difference between MIS and the open group for DFS-1-year, OS-5-year, complications, R0 resections, blood transfusions, along with lower blood loss (MD -177.35 mL, 95%CI -273.17, -81.53) and shorter LOS (MD -3.0 days, 95%CI -3.82, -2.17). Conclusions: Current evidence regarding the optimal approach for CRLM resection demonstrates similar oncologic outcomes between MIS and open techniques, however MIS hepatectomy had a shorter LOS, lower blood loss and complication rate, for both staged and simultaneous resections.

Background: Minimally invasive distal pancreatectomy (MIDP) is gaining popularity due to improved perioperative outcomes over open distal pancreatectomy (ODP). The purpose of this study is to compare outcomes of MIDP and ODP using patients within a nationwide cohort. Methods: The American College of Surgeons’ National Quality Improvement Program (2014–2018) was used to evaluate incidence of post-operative pancreatic fistula (POPF) as well as 30-day composite major morbidity for patients undergoing MIDP vs. ODP. Matching was performed with a Mahalanobis-distance model for demographic characteristics, preoperative risk factors, and benign versus malignant pathology. Outcomes were assessed via weighted multiple logistic regression. Results: A total of 3940 patients underwent distal pancreatectomy (1978 MIDP, 1962 ODP). After matching, 2985 patients were included (1978 MIDP, 1007 ODP). The rates of major morbidity (8.65% MIDP vs. 9.76% ODP, p= 0.37) were similar between groups. The MIDP group was found to have significantly decreased length of stay (5.6 vs. 7 days, p≤ 0.001), but greater rates (12.54% MIDP vs. 9.35% ODP, p= 0.02) of post-operative fistula. Conclusions: When matched for baseline patient characteristics, MIDP was associated with shorter length of hospitalization with similar rates of morbidity compared to ODP. However, MIDP was associated with significantly increased rates of POPF. Further studies are needed to investigate this difference in POPF rate, and determine how to optimize MIDP surgical technique to reduce this risk.

ABSTRACTIntroductionHER2 is a prevalent growth factor in a variety of malignancies, most prominently breast cancer. Over-expression has been correlated with the poorest overall survival and has been the target of successful therapies such as trastuzumab. AE37 is a novel, HER2-directed vaccine based on the AE36 hybrid peptide (aa776-790), which is derived from the intracellular portion of the HER2 protein, and the core portion of the MHC Class II invariant chain (the Ii-Key peptide). This hybrid peptide is given with GM-CSF immunoadjuvant as the AE37 vaccineAreas coveredThis article describes in detail the preclinical science leading to the creation of the AE37 vaccine and examines use of this agent in multiple clinical trials for breast and prostate cancer. The safety profile of AE37 is discussed and opinions on the potential of the vaccine in breast and prostate cancer patient subsets along with other malignancies, are offered.Expert opinionFuture trials utilizing the AE37 vaccine to treat other HER2-expressing malignancies are likely to see similar success, and this will be enhanced by combination immunotherapy. Ii-Key modification of other peptides of interest across oncology and virology could yield impressive results over the longer term.

The ability to understand the mental states of others – also known as Theory of Mind (ToM) – is critical for normal social interactions. We combine behavioural probes with structural and functional brain imaging to provide the first comprehensive analysis of ToM deficits following stroke using the Reading the Mind in the Eyes Test (RMET). First, fMRI was used to identify the functional brain network involved in a non-clinical cohort. Results indicated that, relative to a control task, the RMET increased activity in a widespread functional bilateral network comprising frontal and temporo-parietal areas. To investigate how damage to grey and white matter components of this network can lead to ToM impairment, parcel-based lesion-symptom mapping (PLSM), white-matter tract-wise statistical analysis (TSA) and disconnectome symptom mapping (DSM) were performed using structural images from 64 stroke patients. PLSM results revealed that low scores on the RMET were associated with damage centered around the right posterior frontal gyrus and insula. TSA and DSM results further revealed that low RMET scores were associated with damage to white-matter tracts connecting frontal and temporo-parietal components of the RMET functional network. Together, these findings suggest that making judgements about the mental states of others imposes demands on a large functional network that can easily be disrupted, both by damage to grey matter areas that form part of the network directly, or the white-matter pathways that connect them.

Supplemental Digital Content is available in the text.

There are an estimated 3.5 million Muslims in North America. During the holy month of Ramadan, healthy adult Muslims are to fast from predawn to after sunset. While there are exemptions for older and sick adults, many adults with diabetes fast during Ramadan. However, there are risks associated with fasting and specific management considerations for patients with diabetes. We evaluated provider practices and knowledge regarding the management of patients with diabetes who fast during Ramadan. A 15-question quality improvement survey based on a literature review and the American Diabetes Association guidelines was developed and offered to providers at the outpatient primary care and geriatric clinics at an inner-city hospital in New York City. Forty-five providers completed the survey. Most respondents did not ask their Muslim patients with diabetes if they were fasting during the previous Ramadan. Knowledge of fasting practices during Ramadan was variable, and most felt uncomfortable managing patients with diabetes during Ramadan. There is room for improvement in educating providers about specific cultural and medical issues regarding fasting for patients with diabetes during Ramadan.

Interest in the potential therapeutic efficacy of psilocybin and other psychedelic compounds has escalated significantly in recent years. To date, little is known regarding the biological activity of the psilocybin pathway intermediate, norbaeocystin, due to limitations around sourcing the phosphorylated tryptamine metabolite for in vivotesting. To address this limitation, we first developed a novel E. coliplatform for the rapid and scalable production of gram-scale amounts of norbaeocystin. Through this process we compare the genetic and fermentation optimization strategies to that of a similarly constructed and previously reported psilocybin producing strain, uncovering the need for reoptimization and balancing upon even minor genetic modifications to the production host. We then perform in vivomeasurements of head twitch response to both biosynthesized psilocybin and norbaeocystin using both a cell broth and water vehicle in Long-Evans rats. The data show a dose response to psilocybin while norbaeocystin does not elicit any pharmacological response, suggesting that norbaeocystin and its metabolites may not have a strong affinity for the serotonin 2A receptor. The findings presented here provide a mechanism to source norbaeocystin for future studies to evaluate its disease efficacy in animal models, both individually and in combination with psilocybin, and support the safety of cell broth as a drug delivery vehicle.

AbstractBackground:The home food environment influences children's eating behaviors and potentially affects overall diet quality. The aim of the present study was to evaluate the relationship between the home food environment and Hispanic children's diet quality.Methods:Hispanic children, 10–14 years of age (n=187), and their parents participated in this cross-sectional study. The Healthy Eating Index (HEI) was used to determine diet quality based on reported dietary intake obtained through a food frequency questionnaire administered to the children. Parents self-reported home food availability, familial eating habits, and their own habitual diet through a home environment survey.Results:The children's HEI total score was 59.4±8.8. Reported diets did not adhere to the dietary recommendations for total vegetables, greens and beans, whole grains, seafood and plant proteins, fatty acids, refined grains, sodium, solid fats, and added sugars. None of the participants had “good” scores (HEI, >80), 86% had scores that “need improvement” (HEI, 51–80), and 14% had “poor” scores (HEI, <50). Children with lower HEI scores had sugar-sweetened beverages available at home and participated in family meals while watching television more frequently, when compared with children with higher HEI scores.Conclusions:Home food availability, parental diet, and familial eating habits seem to play an important role in the diet quality of children. Interventions targeting family education on healthful dietary habits at home could have a positive impact on children's diet quality and overall health.

The mucopolysaccharidoses (MPS) represent a group of inheritable, clinically heterogeneous lysosomal storage disorders, in which progressive accumulation of glycosaminoglycans (GAGs) can affect organs and tissues all over the body. The current paper discusses the skeletal X-ray and neuroimaging findings in MPS patients, and the imaging techniques that can be used for diagnosing and monitoring abnormalities in the skeleton and central nervous system. Most MPS types show a typical radiologic expression, called dysostosis multiplex, which manifests as malformations of the skeletal system involving bones in the skull, thorax, spine, pelvis, long bones, and hands. Abnormalities of the spine and GAG deposits in the meninges surrounding the spinal cord can result in spinal cord compression, which, if untreated, can lead to compressive myelopathy. Magnetic resonance imaging (MRI) is the most powerful imaging technique for detecting spinal cord compression, but also radiography and computed tomography are useful. GAG deposits in the brain and surrounding tissues can result in brain anomalies, i.e. white matter lesions, brain atrophy, and hydrocephalus, which can be detected using MRI. Skeletal X-ray and neuroimaging findings can play an important role in diagnosis, follow-up, surgical or medical planning, and assessment of treatment response in MPS patients. There is a need for standardized procedures in evaluating and monitoring neurologic complications in these patients.

Objectives:Pediatric obesity is a significant and increasing problem in Native‐American communities. The aim of this study was to determine whether parents and other caregivers from three Wisconsin tribes recognized overweight children. We also assessed caregiver attributes associated with levels of concern for risk of future overweight and chronic disease. Research Methods and Procedures:Data were obtained from child health screenings and caregiver surveys. Participants included 366 kindergarten‐through‐second grade child–caregiver dyads. Children's BMI percentiles were calculated and compared with caregiver responses. We assessed the relationships between predictors of caregiver concern for health risk factors and recognition of overweight. Results:Twenty‐six percent of children were overweight (≥95th percentile), and 19% were at risk for being overweight (≥85th to <95th percentile) using Centers for Disease Control standards. Caregivers recognized only 15.1% of overweight children. Factors predictive of child overweight recognition included a child BMI >99th percentile and grandmother as caregiver. Overall, caregivers were more concerned about diabetes and cardiovascular disease than obesity. Parents with diabetes and heart disease were more concerned than others about risk for these diseases; however, only diabetic parents made a connection between child weight status and future risk of obesity‐related disease. Child sex, child age, and parental education level were not significant predictors for caregiver recognition of an overweight child. Discussion:Most caregivers did not recognize overweight children or associate excess weight with increased risk of disease. When designing community interventions, it is crucial to incorporate caregivers’ attitudes and beliefs regarding childhood overweight and risk of future disease.

Measurement of 13C-labeled fatty acid oxidation is hindered by the need for acetate correction, measurement of the rate of CO2production in a controlled environment, and frequent collection of breath samples. The use of deuterium-labeled fatty acids may overcome these limitations. Herein, d31-palmitate was validated against [1-13C]palmitate during exercise. Thirteen subjects with body mass index of 22.9 ± 3 kg/m2and body fat of 19.6 ± 11% were subjected to 2 or 4 h of exercise at 25% maximum volume oxygen consumption (VO2max). The d31-palmitate and [1-13C] palmitate were given orally in a liquid meal at breakfast. The d3-acetate and [1-13C]acetate were given during another visit for acetate sequestration correction. Recovery of d31-palmitate in urine at 9 h after dose was compared with [1-13C] palmitate recovery in breath. Cumulative recovery of d31-palmitate was 10.6 ± 3% and that of [1-13C]palmitate was 5.6 ± 2%. The d3-acetate and [1-13C]acetate recoveries were 85 ± 4% and 54 ± 4%, respectively. When [1-13C]acetate recovery was used to correct 13C data, the average recovery differences were 0.4 ± 3%. Uncorrected d31-palmitate and acetate-corrected [1-13C]palmitate were well correlated (y = 0.96x + 0; P< 0.0001) when used to measure fatty acid oxidation during exercise.

Epizootic ulcerative syndrome (EUS) is one of the most destructive diseases of fresh and brackish water farmed and wild fish in the Asia–Pacific region. The in vitrogermination and growth of the propagules of the EUS pathogen, Aphanomyces invadans(=A. piscicida), were assessed in the presence of the head–kidney macrophages, serum, and serum heated to inactivate complement proteins, of three EUS-susceptible and one resistant fish species. The susceptible species were: striped snakehead (Channa striata), giant gourami (Osphronemus gouramy) and silver barb [Barbodes(=Puntius) gonionotus], and the resistant species was Nile tilapia (Oreochromis niloticus). Fish of all species were acclimatised to either low temperature (20°C±1·6) at which EUS is known to occur, or to high temperature (32°C±5·0) at which EUS does not occur, except for giant gouramis which were only studied at low temperature. The respiratory burst of the macrophages was assessed in the presence of A. invadansor the stimulant phorbol myristate acetate (PMA), and compared to that of controls. Anti- A. invadansantibody concentrations were assessed in all species except silver barbs. All assays were carried out at the same temperature, regardless of the temperature that the fish were kept at.

Recently, there has been an increasing interest in the potential effect of dietary chromium on the health of fish, particularly with respect to their metabolism and growth. Information as to the role of this mineral on their immune response, is limited however, so the aim of this study was to assess the effects of dietary chromium yeast supplementation on the immune response of rainbow trout (Oncorhynchus mykiss).

Aphanomyces invadans, also referred toA. invaderisorA. piscicida, is the aetiological agent of epizootic ulcerative syndrome (EUS). Immune responses of rainbow trout (Oncorhynchus mykiss) against this fungus were examined, including both antibody and macrophage responses. The fish antibodies to the fungus, assessed by an enzyme-linked immunosorbent assay (ELISA) were generally non-specific, but sera from fish vaccinated withA. invadansreacted with bands at 55 and 40kDa by Western blot analysis. Macrophage activity was examinedin vitroby culturing rainbow trout head kidney macrophages with fungal spores. The macrophages were able to phagocytose sporesin vitroand, in some cases, hyphae were observed growing from germinated spores within the macrophage. When low concentrations of spores (1×102and 1×103spore ml−1) were cultured with macrophage monolayers, no germination of spores or growth of hyphae was observed. At concentrations of 1×104spore ml−1or higher, macrophages were unable to kill all the spores and fungal mycelium eventually overgrew the culture. Transmission electron microscopy (TEM) was used to examine the ultrastructural interaction between macrophages and the fungus. The possible role of rainbow trout as a model forA. invadansinfection in salmonids is also discussed.

The development of monoclonal antibody probes (MAbs) to bacterial and parasitic fish pathogens has provided useful tools for the rapid immuno-diagnosis and control of disease. Immunohistochemistry, IFAT and ELISA tests have been developed to detect a variety of infectious agents, including those causing bacterial kidney disease (Renibacterium salmoninarum), mycobacteriosis (Mycobacterium spp.) and proliferative kidney disease (PKX). MAb probes are also being utilised as specific markers to identify and map potential vaccine candidates for PKD. As well as illustrating the invaluable contribution which MAbs can make to the control of fish diseases, the results indicate the ephemeral nature of some antigens and the importance of pathogen culture conditions prior to the production of MAbs.

A primary intraperitoneal (IP) vaccination of extracellular products (ECP) from Mycobacteriumspp. (strains TB40, TB267, or Mycobacterium marinum) mixed with Freund's incomplete adjuvant and followed by a secondary IP injection at 8 weeks resulted in the elevation of both the nonspecific and the specific immune responses of rainbow trout Oncorhynchus mykiss. Increased nitroblue tetrazolium and phagocytosis activity were observed in these fish; peaks in activity occurred at weeks 2 and 6 after primary immunization with a third peak at week 10. Lysozyme activity, on the other hand, peaked at weeks 2 and 8 after primary immunization except in the TB40-immunized group. A third peak of lysozyme activity was observed at week 10 after primary immunization. The activity of the specific immune response was monitored by an enzyme-linked immunosorbent assay and Western blot. The results indicate that antibodies to the ECP of Mycobacteriumspp. were present in rainbow trout serum and that they reacted with major ECP antigens at 65 and 16 kDa (kilodaltons) as well as with some minor antigens at 48, 46, and 40 kDa.

Thirteen monoclonal antibodies (MAbs) were prepared against the extracellular product (ECP) of Mycobacteriumsp., strain TB267, isolated from chevron snakehead Channa striata, and five MAbs were prepared against the reference strain Mycobacterium chelonei. The reactivity of the MAbs was examined against seven different strains of mycobacteria by an enzyme-linked immunosorbent assay (ELISA), and Western blot analysis was used to establish the molecular weight of antigens recognized by the MAbs. Western blot analysis proved essential for the selection of the MAbs because some that did not react by ELISA were found to be positive in this assay. All MAbs recognized a 65-kilodalton (kDa) protein present in ECPs, whole cell sonicates, and lysate preparations of the mycobacteria examined, and the epitopes recognized by the MAbs were located on molecules susceptible to protease activity. The 65-kDa protein, one of the major protein constituents of the mycobacterial preparations, was found in periplasmic spaces and cell walls of the bacteria via immunogold staining with MAbs.