Publications by authors named "John Casey"

93 Publications

Pancreas Utilisation Rates in the UK - an 11-year Analysis.

Transpl Int 2021 Apr 1. Epub 2021 Apr 1.

Edinburgh Transplant Centre, Scottish Pancreas Transplant Unit, Edinburgh, UK.

Background: Utilisation of pancreases for transplantation remains inferior to that of other organs. Herein we analysed UK pancreas discards to identify the reasons for the low utilisation rates.

Methods: Data on all pancreases offered first for solid organ transplantation between 1st January 2005 and 31st December 2015 were extracted from the UK Transplant Registry. The number of organs discarded, reasons and the time point of discard were analysed. A centre specific comparison was also undertaken.

Results: 7367 pancreases were offered first for solid organ transplantation. 35% were Donors after circulatory death (DCD). 3668 (49.7%) organs were not retrieved. Of the 3699 pancreases retrieved, 38% were initially accepted but subsequently discarded. 2145 (29%) grafts offered were transplanted as simultaneous pancreas-kidney or solitary pancreas. 1177 (55%) were transplanted on the first offer whilst the remaining 968 were transplanted after a median of 3 offers. 52% DBD pancreases were accepted and transplanted on the first offer compared with 68% DCD grafts. There were significant differences in discard rates between centres (30-80% for DBD and 3-78% for DCD, p<0.001).

Conclusions: A significant number of solid pancreases are discarded. Better graft assessment at retrieval could minimise unnecessary organ travel and discards. Closer links with islet programs may allow for better utilisation of discarded grafts.
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http://dx.doi.org/10.1111/tri.13876DOI Listing
April 2021

A Modern "Nightstick Fracture" Induced by Contemporary Ballistics During the George Floyd Protests.

Cureus 2021 Feb 24;13(2):e13530. Epub 2021 Feb 24.

Emergency Medicine, OhioHealth Doctors Hospital, Columbus, USA.

A 28-year-old male presented to the emergency department with an isolated ulnar shaft fracture secondary to a ballistic injury with a wooden pellet gun. This injury is also known as a "nightstick fracture," which is a common eponym in orthopedic surgery used to describe a fracture of the ulnar shaft. The eponym gained its title for the injury commonly seen when in a defensive position while being attacked with a wooden club. It is widely accepted that this infamous injury was popularized in the 1960s as a sequela of the many race-related riots across the United States. This case details how the nightstick fracture is still prevalent as a result of political protesting today, despite modern-day methods of non-lethal riot control.
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http://dx.doi.org/10.7759/cureus.13530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996478PMC
February 2021

Hepatitis delta virus-like circular RNAs from diverse metazoans encode conserved hammerhead ribozymes.

Virus Evol 2021 Jan 18;7(1):veab016. Epub 2021 Feb 18.

IBMCP (CSIC-UPV), C/Ingeniero Fausto Elio s/n, Valencia 46022, Spain.

Human hepatitis delta virus (HDV) is a unique infectious agent whose genome is composed of a small circular RNA. Recent data, however, have reported the existence of highly divergent HDV-like circRNAs in the transcriptomes of diverse vertebrate and invertebrate species. The HDV-like genomes described in amniotes such as birds and reptiles encode self-cleaving RNA motifs or ribozymes similar to the ones present in the human HDV, whereas no catalytic RNA domains have been reported for the HDV-like genomes detected in metagenomic data from some amphibians, fish, and invertebrates. Herein, we describe the self-cleaving motifs of the HDV-like genomes reported in newts and fish, which belong to the characteristic class of HDV ribozymes. Surprisingly, HDV-like genomes from a toad and a termite show conserved type III hammerhead ribozymes, which belong to an unrelated class of catalytic RNAs characteristic of plant genomes and plant subviral circRNAs, such as some viral satellites and viroids. Sequence analyses revealed the presence of similar HDV-like hammerhead ribozymes encoded in two termite genomes, but also in the genomes of several dipteran species. transcriptions confirmed the cleaving activity for these motifs, with moderate rates of self-cleavage. These data indicate that all described HDV-like agents contain self-cleaving motifs from either the HDV or the hammerhead class. Autocatalytic ribozymes in HDV-like genomes could be regarded as interchangeable domains and may have arisen from cellular transcriptomes, although we still cannot rule out some other evolutionary explanations.
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http://dx.doi.org/10.1093/ve/veab016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936874PMC
January 2021

Characterization of the Meal-Stimulated Incretin Response and Relationship With Structural Brain Outcomes in Aging and Alzheimer's Disease.

Front Neurosci 2020 30;14:608862. Epub 2020 Nov 30.

Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States.

Background: Individuals with Alzheimer's Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear.

Methods: Here, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; = 32) and AD ( = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging.

Results: The meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions.

Conclusion: Our findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.
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http://dx.doi.org/10.3389/fnins.2020.608862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734152PMC
November 2020

Molecular targeting of vulnerable RNA sequences in SARS CoV-2: identifying clinical feasibility.

Gene Ther 2020 Nov 12. Epub 2020 Nov 12.

Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington, DC, 20057, USA.

Covid-19 (SARS CoV-2) has become a deadly, world-wide pandemic. Although most who are infected survive, complications from the virus can be pronounced and long-lasting. To date, of all the respiratory viruses including influenza and coronaviruses, only influenza has had a drug (i.e., Tamiflu) specifically targeted to treat and prevent infection. As a result, additional agents that specifically target viral production and are clinically feasible are needed to alleviate respiratory viral infections. The idea of using a miRNA/siRNA molecular approach for treating various diseases was postulated over a decade ago; however, only within the past few years has it become feasible. One technological advancement has been the molecular linkage of lipophilic moieties to mi/siRNAs in order to bypass the need for enveloping these inhibitory RNAs in lipid-based transfection reagents, which could irritate the airway if inhaled. Here we show that siRNAs and miRNAs inhibit SARS CoV-2 spike protein production in a dose-dependent manner in both HEK293 cells and a primary human airway tracheal cell line. We also show that this inhibition is equally robust using a clinically relevant siRNA that does not need to be prepped with a transfection reagent.
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http://dx.doi.org/10.1038/s41434-020-00210-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659899PMC
November 2020

A Case of Phlegmasia Cerulea Dolens.

Cureus 2020 Sep 1;12(9):e10187. Epub 2020 Sep 1.

Emergency Medicine, OhioHealth Doctors Hospital, Columbus, USA.

Phlegmasia cerulea dolens (PCD) is a rare presenting condition that carries a high mortality and morbidity risk. It is a cannot miss diagnosis with potentially deadly sequelae, and we highlight the importance of a thorough physical examination and initiation of empiric treatment to help prevent such.
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http://dx.doi.org/10.7759/cureus.10187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529486PMC
September 2020

Murine hepatocytes do not support persistence of Hepatitis D virus mono-infection in vivo.

Liver Int 2021 02 15;41(2):410-419. Epub 2020 Oct 15.

German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems site, Borstel, Germany.

Backgrounds & Aims: As a result of the limited availability of in vivo models for hepatitis D virus (HDV), treatment options for HDV chronically infected patients are still scant. The discovery of sodium taurocholate cotransporting polypeptide (NTCP) as HDV entry receptor has enabled the development of new infection models.

Aim: To comparatively assess the efficacy and persistence of HDV mono-infection in murine and human hepatocytes in vivo.

Methods: Mice with humanized NTCP (hNTCP mice) were generated by editing amino acid residues 84-87 of murine NTCP in C57BL/6J mice. HDV infection was assessed in hNTCP mice and in immune deficient uPA/SCID/beige (USB) mice, whose livers were reconstituted with human or murine (hNTCP ) hepatocytes. Livers were analysed between 5 and 42 days post-HDV inoculation by qRT-PCR, immunofluorescence and RNA in situ hybridization (ISH).

Results: hNTCP mice could be infected with HDV genotype 1 or 3. ISH analysis demonstrated the presence of antigenomic HDV RNA positive murine hepatocytes with both genotypes, proving initiation of HDV replication. Strikingly, murine hepatocytes cleared HDV within 21 days both in immunocompetent hNTCP mice and in immunodeficient USB mice xenografted with murine hepatocytes. In contrast, HDV infection remained stable for at least 42 days in human hepatocytes. Intrinsic innate responses were not enhanced in any of the HDV mono-infected cells and livers.

Conclusion: These findings suggest that in addition to NTCP, further species-specific factors limit HDV infection efficacy and persistence in murine hepatocytes. Identifying such species barriers may be crucial to develop novel potential therapeutic targets of HDV.
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http://dx.doi.org/10.1111/liv.14677DOI Listing
February 2021

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function.

Am J Transplant 2021 03 19;21(3):1027-1038. Epub 2020 Sep 19.

Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10 cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.
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http://dx.doi.org/10.1111/ajt.16285DOI Listing
March 2021

A steady-state model of microbial acclimation to substrate limitation.

PLoS Comput Biol 2020 08 26;16(8):e1008140. Epub 2020 Aug 26.

Department of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

Microbes acclimate to changes in substrate availability by altering the number of transporters on the cell surface, however there is some disagreement on just how. We revisit the physics of substrate uptake and consider the steady-state scenario whereby cells have acclimated to maximize fitness. Flux balance analysis of a stoichiometric model of Escherichia coli was used in conjunction with quantitative proteomics data and molecular modeling of membrane transporters to reconcile these opposing views. An emergent feature of the proposed model is a critical substrate concentration S*, which delineates two rate limits. At concentrations above S*, transporter abundance can be regulated to maintain uptake rates as demanded by maximal growth rates, whereas below S*, uptake rates are strictly diffusion limited. In certain scenarios, the proposed model can take on a qualitatively different shape from the familiar hyperbolic kinetics curves, instead resembling the long-forgotten Blackman kinetics.
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http://dx.doi.org/10.1371/journal.pcbi.1008140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478835PMC
August 2020

Pancreas-derived mesenchymal stromal cells share immune response-modulating and angiogenic potential with bone marrow mesenchymal stromal cells and can be grown to therapeutic scale under Good Manufacturing Practice conditions.

Cytotherapy 2020 12 20;22(12):762-771. Epub 2020 Aug 20.

Tissues, Cells and Advanced Therapeutics, The Jack Copland Centre, Scottish National Blood Transfusion Service, Edinburgh, UK; Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK. Electronic address:

Background Aims: Mesenchymal stromal cells (MSCs) isolated from various tissues are under investigation as cellular therapeutics in a wide range of diseases. It is appreciated that the basic biological functions of MSCs vary depending on tissue source. However, in-depth comparative analyses between MSCs isolated from different tissue sources under Good Manufacturing Practice (GMP) conditions are lacking. Human clinical-grade low-purity islet (LPI) fractions are generated as a byproduct of islet isolation for transplantation. MSC isolates were derived from LPI fractions with the aim of performing a systematic, standardized comparative analysis of these cells with clinically relevant bone marrow-derived MSCs (BM MSCs).

Methods: MSC isolates were derived from LPI fractions and expanded in platelet lysate-supplemented medium or in commercially available xenogeneic-free medium. Doubling rate, phenotype, differentiation potential, gene expression, protein production and immunomodulatory capacity of LPIs were compared with those of BM MSCs.

Results: MSCs can be readily derived in vitro from non-transplanted fractions resulting from islet cell processing (i.e., LPI MSCs). LPI MSCs grow stably in serum-free or platelet lysate-supplemented media and demonstrate in vitro self-renewal, as measured by colony-forming unit assay. LPI MSCs express patterns of chemokines and pro-regenerative factors similar to those of BM MSCs and, importantly, are equally able to attract immune cells in vitro and in vivo and suppress T-cell proliferation in vitro. Additionally, LPI MSCs can be expanded to therapeutically relevant doses at low passage under GMP conditions.

Conclusions: LPI MSCs represent an alternative source of GMP MSCs with functions comparable to BM MSCs.
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http://dx.doi.org/10.1016/j.jcyt.2020.07.010DOI Listing
December 2020

Characterization of pre-transplant psychosocial burden in an integrated national islet transplant program.

Islets 2020 03 20;12(2):21-31. Epub 2020 Aug 20.

School of Psychology, Deakin University , Geelong, Australia.

The psychological burden experienced by people with diabetes prior to islet transplantation is recognized but has not been studied comprehensively, especially in relation to glycemia. Therefore, we conducted a rigorous pre-operative psychosocial profile of UK islet transplant recipients, and compared groups with higher/lower HbA1 c to test the null hypothesis that pre-transplant hypoglycemia awareness and psychosocial burden would not be related to baseline HbA1 c in this high-risk cohort. Pre-transplant, recipients (n = 44) completed validated hypoglycemia awareness questionnaires and generic/diabetes-specific measures of psychological traits and states. Scores were compared in groups, dichotomized by HbA1 c (≤8% versus >8%). Participants were aged (mean±SD) 53 ± 10 years; 64% were women; with HbA1 c 8.3 ± 1.7%. Median rate of severe hypoglycemia over the preceding 12 months was 13 events/person-year and 90% had impaired awareness of hypoglycemia (Gold/Clarke score ≥4). Participants had elevated fear of hypoglycemia (HFS-II Worry), impaired diabetes-specific quality of life (DQoL) and low generic health status (SF-36; EQ-5D). One quarter reported scores indicating likely anxiety/depression (HAD). Dispositional optimism (LOT-R) and generalized self-efficacy (GSE) were within published 'norms.' Despite negative perceptions of diabetes (including low personal control), participants were confident that islet transplantation would help (BIPQ). Hypoglycemia awareness and psychosocial profile were comparable in lower (n = 24) and higher (n = 20) HbA1 c groups. Islet transplant candidates report sub-optimal generic psychological states (anxiety/depressive symptoms), health status and diabetes-specific psychological states (fear of hypoglycemia, diabetes-specific quality of life). While their generic psychological traits (optimism, self-efficacy) are comparable with the general population, they are highly optimistic about forthcoming transplant. HbA1 c is not a proxy measure of psychosocial burden, which requires the use of validated questionnaires to systematically identify those who may benefit most from psychological assessment and support.
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http://dx.doi.org/10.1080/19382014.2020.1736740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527016PMC
March 2020

SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: A national cohort study.

Am J Transplant 2020 11 16;20(11):3008-3018. Epub 2020 Sep 16.

Medical Director, NHS Blood and Transplant, Bristol, UK.

Patients waitlisted for and recipients of solid organ transplants (SOT) are perceived to have a higher risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and death; however, definitive epidemiological evidence is lacking. In a comprehensive national cohort study enabled by linkage of the UK transplant registry and Public Health England and NHS Digital Tracing services, we examined the incidence of laboratory-confirmed SARS-CoV-2 infection and subsequent mortality in patients on the active waiting list for a deceased donor SOT and recipients with a functioning SOT as of February 1, 2020 with follow-up to May 20, 2020. Univariate and multivariable techniques were used to compare differences between groups and to control for case-mix. One hundred ninety-seven (3.8%) of the 5184 waitlisted patients and 597 (1.3%) of the 46 789 SOT recipients tested positive for SARS-CoV-2. Mortality after testing positive for SARS-CoV-2 was 10.2% (20/197) for waitlisted patients and 25.8% (154/597) for SOT recipients. Increasing recipient age was the only variable independently associated with death after positive SARS-CoV-2 test. Of the 1004 transplants performed in 2020, 41 (4.1%) recipients have tested positive for SARS-CoV-2 with 8 (0.8%) deaths reported by May 20. These data provide evidence to support decisions on the risks and benefits of SOT during the coronavirus disease 2019 pandemic.
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http://dx.doi.org/10.1111/ajt.16247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436919PMC
November 2020

Collective effects of age, sex, genotype, and cognitive status on fitness outcomes.

Alzheimers Dement (Amst) 2020 13;12(1):e12058. Epub 2020 Jul 13.

Department of Medicine University of Wisconsin-Madison Madison Wisconsin USA.

Introduction: Individuals with Alzheimer's disease (AD) broadly exhibit lower cardiorespiratory fitness (CRF) compared to cognitively healthy older adults. Other factors, such as increasing age and female sex, are also known to track with lower CRF levels. However, it is unclear how these factors together with AD diagnosis and genetic risk (apolipoprotein e4 ; ) collectively affect CRF.

Methods: Our primary objective was to characterize the collective relationship of age, sex, carrier status , and cognitive status (nondemented or AD) with two commonly reported CRF outcomes, VO max and oxygen uptake efficiency slope (OUES). To interrogate the unique and combined effect of age, sex, , and cognitive status on CRF, we pooled multiple datasets and tested several statistical models allowing all possible interactions.

Results: AD diagnosis was consistently associated with lower maximal CRF, which declined with increasing age. was also associated with lower maximal CRF (VO), but only in male subjects. Submaximal CRF (OUES) was lower in carriers of both sexes, although this difference converged in male subjects with advancing age.

Discussion: This multi-cohort analysis (n = 304) suggests that carrier status and sex are important considerations for studies that evaluate maximal and submaximal CRF.
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http://dx.doi.org/10.1002/dad2.12058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364859PMC
July 2020

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience.

Br J Haematol 2021 Mar 16;192(6):1049-1053. Epub 2020 Jul 16.

Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
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http://dx.doi.org/10.1111/bjh.16946DOI Listing
March 2021

Donor insulin use predicts beta-cell function after islet transplantation.

Diabetes Obes Metab 2020 10 14;22(10):1874-1879. Epub 2020 Jun 14.

Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

Insulin is routinely used to manage hyperglycaemia in organ donors and during the peri-transplant period in islet transplant recipients. However, it is unknown whether donor insulin use (DIU) predicts beta-cell dysfunction after islet transplantation. We reviewed data from the UK Transplant Registry and the UK Islet Transplant Consortium; all first-time transplants during 2008-2016 were included. Linear regression models determined associations between DIU, median and coefficient of variation (CV) peri-transplant glucose levels and 3-month islet graft function. In 91 islet cell transplant recipients, DIU was associated with lower islet function assessed by BETA-2 scores (β [SE] -3.5 [1.5], P = .02), higher 3-month post-transplant HbA1c levels (5.4 [2.6] mmol/mol, P = .04) and lower fasting C-peptide levels (-107.9 [46.1] pmol/l, P = .02). Glucose at 10 512 time points was recorded during the first 5 days peri-transplant: the median (IQR) daily glucose level was 7.9 (7.0-8.9) mmol/L and glucose CV was 28% (21%-35%). Neither median glucose levels nor glucose CV predicted outcomes post-transplantation. Data on DIU predicts beta-cell dysfunction 3 months after islet transplantation and could help improve donor selection and transplant outcomes.
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http://dx.doi.org/10.1111/dom.14088DOI Listing
October 2020

A 14-year retrospective analysis of indications and outcomes of autologous haemopoietic stem cell transplantation in regional Queensland: a single-centre experience.

Intern Med J 2020 02;50(2):214-221

Icon Group, Brisbane, Queensland, Australia.

Background: The Townsville Hospital is a tertiary hospital in North Queensland with one of the largest regional transplant centres in Australia, performing primarily autologous haemopoietic stem cell transplants (HSCT) for various haematological malignancies.

Aims: This single-centre, retrospective, observational study aims to describe the activity and outcomes of autologous HSCT at The Townsville Hospital between 2003 and 2017 to verify safety standards.

Methods: Patient-level data were collected, including demographics, frequency and indication for transplant, conditioning, current clinical status and cause of death. Key outcomes included overall survival, non-relapse mortality, incidence of therapy-related neoplasm and causes of death. Progression-free survival in the multiple myeloma (MM) subgroup was also assessed.

Results: There were 319 autologous HSCT in 286 patients, with a median age of 58 years (range 14-71 years); 62% of patients were male. Indications for transplantation were: MM 53.7%, non-Hodgkin lymphoma 29.4%, Hodgkin lymphoma 5.0% and other 11.9%. Causes of death were: disease progression/relapse (65.2%), second malignancy (17.0%), infection (9.8%) and other (8.0%). Non-relapse mortality was 1.2% (95% confidence interval 0.4-3.0) and 3.2% (1.7-5.7) at 100 days and 1 year, respectively, post-HSCT. Overall survival at 2 years was 81.0% (73.8-86.4) for MM and 69.6% (58.8-78.1) for non-Hodgkin lymphoma. The median progression-free survival in the MM cohort was 3.3 years.

Conclusion: The Townsville Hospital transplant centre provides an important transplant service in regional Queensland, with outcomes comparable to national data. We reported a relatively high rate of second malignancy as a cause of death.
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http://dx.doi.org/10.1111/imj.14395DOI Listing
February 2020

Higher rate of kneeling after primary knee arthroplasty without patellar resurfacing at midterm review.

J Orthop 2020 Jul-Aug;20:204-206. Epub 2019 Nov 12.

Valley Orthopedic Surgery Residency, Doctors Medical Center, 1400 Florida Ave. Ste 201, Modesto, CA, 95350, USA.

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http://dx.doi.org/10.1016/j.jor.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997512PMC
November 2019

Characterising investments in EU fisheries and defining their desirability.

Fish Res 2020 Jan;221:105396

Lincoln International Business School, University of Lincoln, Lincoln, United Kingdom.

In most economic sectors, increases in capital (i.e., investments) are often considered virtuous, indicating confidence in the future and expected growth. In fisheries, however, investments are often harmful, as they may lead to increases in fleet capacity, which is not desirable considering the fully exploited or overexploited status of most fish stocks (natural capital), and the dissipation of the resource rent (overcapitalisation). In the EU, the number of fishing vessels have been decreasing for many years, but the fishing capacity is often claimed to have increased. In other words, there are less vessels, but the remaining ones have a higher fishing capacity. In this study, we analyse the evolution of the EU fishing industry's investments for the period 2008-2016, and whether these investments have been beneficial. Results show that despite the overall decrease in the number of vessels and their average value, investments in some fleets have increased. Moreover, investment decisions (i.e., whether to invest or disinvest) have been more accurate in recent years, leading to a better economic performance. However, results vary by the scale of the fishing activity (small-scale and large scale fleets) and sea basin (Northeast Atlantic Ocean and Mediterranean Sea).
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http://dx.doi.org/10.1016/j.fishres.2019.105396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853412PMC
January 2020

Administration of Naloxone by Prehospital Personnel: A Retrospective Analysis.

Cureus 2019 Sep 9;11(9):e5602. Epub 2019 Sep 9.

Emergency Medicine, OhioHealth Doctors Hospital, Columbus, USA.

Introduction Patient-specific discrepancies in prehospital naloxone administration have been documented. As the opioid epidemic continues to evolve, further evaluation of prehospital naloxone administration practices is needed. The objective of this study was to compare patients who received prehospital naloxone and received an emergency department (ED) diagnosis of opioid overdose with patients who received prehospital naloxone and received an alternative ED diagnosis.  Methods This was a retrospective, multicenter chart review of patients who received naloxone by prehospital personnel for suspected opioid overdose between October 1, 2016, and October 31, 2017. Patients were excluded if age was less than 18 years, naloxone was administered by non-emergency medical service (EMS) personnel, not transported, or if prehospital records could not be linked with ED records. Demographic information and several prehospital clinical findings, including unresponsiveness, apnea, and miosis, were compared between patients diagnosed with opioid overdoses versus an alternative ED diagnosis. Descriptive statistics were utilized. Results A total of 837 patients had complete data available and were included in the analysis. Overall, 402 (48%) of patients received an ED diagnosis of opioid overdose, and 435 (52%) of patients received an alternative ED diagnosis. Patients in the alternative diagnosis group were older, had less known drug use, were more likely to be admitted, and had lower incidences of apnea, unresponsiveness, and miosis. In the opioid overdose group, there was a higher proportion of previous drug use, apnea, unresponsiveness, and miosis in the EMS setting, whereas there was a higher proportion of previous overdose, previous suicide attempts, and neurological deficits in the ED setting. Conclusions In this retrospective review evaluating patients who received prehospital naloxone, several demographic and clinical differences were noted between the two groups. Further elucidation of the safety and efficacy of prehospital naloxone in alternative diagnoses is needed.
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http://dx.doi.org/10.7759/cureus.5602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822568PMC
September 2019

Oxylipin Profiling of Alzheimer's Disease in Nondiabetic and Type 2 Diabetic Elderly.

Metabolites 2019 Sep 5;9(9). Epub 2019 Sep 5.

Arkansas Children's Nutrition Center, Little Rock, AR 72205, USA.

Oxygenated lipids, called "oxylipins," serve a variety of important signaling roles within the cell. Oxylipins have been linked to inflammation and vascular function, and blood patterns have been shown to differ in type 2 diabetes (T2D). Because these factors (inflammation, vascular function, diabetes) are also associated with Alzheimer's disease (AD) risk, we set out to characterize the serum oxylipin profile in elderly and AD subjects to understand if there are shared patterns between AD and T2D. We obtained serum from 126 well-characterized, overnight-fasted elderly individuals who underwent a stringent cognitive evaluation and were determined to be cognitively healthy or AD. Because the oxylipin profile may also be influenced by T2D, we assessed nondiabetic and T2D subjects separately. Within nondiabetic individuals, cognitively healthy subjects had higher levels of the nitrolipid 10-nitrooleate (16.8% higher) compared to AD subjects. AD subjects had higher levels of all four dihydroxyeicosatrienoic acid (DiHETrE) species: 14,15-DiHETrE (18% higher), 11,12 DiHETrE (18% higher), 8,9-DiHETrE (23% higher), and 5,6-DiHETrE (15% higher). Within T2D participants, we observed elevations in 14,15-dihydroxyeicosa-5,8,11-trienoic acid (14,15-DiHETE; 66% higher), 17,18-dihydroxyeicosa-5,8,11,14-tetraenoic acid (17,18-DiHETE; 29% higher) and 17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid (17-HDoHE; 105% higher) and summed fatty acid diols (85% higher) in subjects with AD compared to cognitively healthy elderly, with no differences in the DiHETrE species between groups. Although these effects were no longer significant following stringent adjustment for multiple comparisons, the consistent effects on groups of molecules with similar physiological roles, as well as clear differences in the AD-related profiles within nondiabetic and T2D individuals, warrant further research into these molecules in the context of AD.
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http://dx.doi.org/10.3390/metabo9090177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780570PMC
September 2019

Kīlauea lava fuels phytoplankton bloom in the North Pacific Ocean.

Science 2019 09;365(6457):1040-1044

Department of Oceanography, Daniel K. Inouye Center for Microbial Oceanography: Research and Education (C-MORE), University of Hawai'i at Manoa, Honolulu, HI 96822, USA.

From June to August 2018, the eruption of Kīlauea volcano on the island of Hawai'i injected millions of cubic meters of molten lava into the nutrient-poor waters of the North Pacific Subtropical Gyre. The lava-impacted seawater was characterized by high concentrations of metals and nutrients that stimulated phytoplankton growth, resulting in an extensive plume of chlorophyll a that was detectable by satellite. Chemical and molecular evidence revealed that this biological response hinged on unexpectedly high concentrations of nitrate, despite the negligible quantities of nitrogen in basaltic lava. We hypothesize that the high nitrate was caused by buoyant plumes of nutrient-rich deep waters created by the substantial input of lava into the ocean. This large-scale ocean fertilization was therefore a unique perturbation event that revealed how marine ecosystems respond to exogenous inputs of nutrients.
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http://dx.doi.org/10.1126/science.aax4767DOI Listing
September 2019

A retrospective analysis of the prevalence and clinical outcomes of vitamin D deficiency in myeloma patients in tropical Australia.

Support Care Cancer 2020 Mar 21;28(3):1249-1254. Epub 2019 Jun 21.

Department of Haematology and Bone Marrow Transplantation, Townsville Hospital, 100 Angus Smith Drive, Douglas, Townsville, Queensland, 4814, Australia.

Purpose: The aim of this descriptive study was to assess the prevalence of vitamin D deficiency in patients on active therapy for multiple myeloma in a tropical climate. We also tested for the association of vitamin D status on clinical outcomes.

Methods: This was a single centre, observational study performed in Townsville, Australia, which has a sunlight heavy, tropical climate. Patients on active therapy for multiple myeloma underwent testing of serum 25-hydroxyvitamin D (25(OH)D). Information on disease stage, skeletal morbidity and symptoms of peripheral neuropathy were collected from medical records and self-reported patient questionnaires.

Results: A total of 41 patients were included. With a median disease duration of 38 months, 27% were found to be vitamin D deficient. Patients with vitamin D deficiency had a higher likelihood of peripheral neuropathy compared with their non-vitamin D counterparts (73% vs. 33%, P = 0.03). Although those with vitamin D deficiency had more skeletal morbidity, this was not statistically significant (73% vs 50%, P = 0.19). Reduced 25(OH) D was associated with a poor performance status (P = 0.003). There was no association between vitamin D status and stage of myeloma.

Conclusion: There is a relatively high prevalence of vitamin D deficiency in patients with myeloma in our study. This is despite a sunlight heavy, tropical climate. We report an association between vitamin D deficiency and peripheral neuropathy. Prospective interventional trials are required to further assess this.
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http://dx.doi.org/10.1007/s00520-019-04942-7DOI Listing
March 2020

Methylphosphonate Oxidation in Strain MIT9301 Supports Phosphate Acquisition, Formate Excretion, and Carbon Assimilation into Purines.

Appl Environ Microbiol 2019 07 17;85(13). Epub 2019 Jun 17.

Daniel K. Inouye Center for Microbial Oceanography: Research and Education, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA.

The marine unicellular cyanobacterium is an abundant primary producer and widespread inhabitant of the photic layer in tropical and subtropical marine ecosystems, where the inorganic nutrients required for growth are limiting. In this study, we demonstrate that high-light strain MIT9301, an isolate from the phosphate-depleted subtropical North Atlantic Ocean, can oxidize methylphosphonate (MPn) and hydroxymethylphosphonate (HMPn), two phosphonate compounds present in marine dissolved organic matter, to obtain phosphorus. The oxidation of these phosphonates releases the methyl group as formate, which is both excreted and assimilated into purines in RNA and DNA. Genes encoding the predicted phosphonate oxidative pathway of MIT9301 were predominantly present in genomes from parts of the North Atlantic Ocean where phosphate availability is typically low, suggesting that phosphonate oxidation is an ecosystem-specific adaptation of some populations to cope with phosphate scarcity. Until recently, MPn was only known to be degraded in the environment by the bacterial carbon-phosphorus (CP) lyase pathway, a reaction that releases the greenhouse gas methane. The identification of a formate-yielding MPn oxidative pathway in the marine planctomycete (S. R. Gama, M. Vogt, T. Kalina, K. Hupp, et al., ACS Chem Biol 14:735-741, 2019, https://doi.org/10.1021/acschembio.9b00024) and the presence of this pathway in indicate that this compound can follow an alternative fate in the environment while providing a valuable source of P to organisms. In the ocean, where MPn is a major component of dissolved organic matter, the oxidation of MPn to formate by may direct the flow of this one-carbon compound to carbon dioxide or assimilation into biomass, thus limiting the production of methane.
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http://dx.doi.org/10.1128/AEM.00289-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581173PMC
July 2019

Hepatitis Delta Antigen Regulates mRNA and Antigenome RNA Levels during Hepatitis Delta Virus Replication.

J Virol 2019 04 3;93(8). Epub 2019 Apr 3.

Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA

Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of acute and chronic liver disease. HDV produces three processed RNAs that accumulate in infected cells: the circular genome; the circular antigenome, which serves as a replication intermediate; and lesser amounts of the mRNA, which encodes the sole viral protein, hepatitis delta antigen (HDAg). The HDV genome and antigenome RNAs form ribonucleoprotein complexes with HDAg. Although HDAg is required for HDV replication, it is not known how the relative amounts of HDAg and HDV RNA affect replication, or whether HDAg synthesis is regulated by the virus. Using a novel transfection system in which HDV replication is initiated using -synthesized circular HDV RNAs, HDV replication was found to depend strongly on the relative amounts of HDV RNA and HDAg. HDV controls these relative amounts via differential effects of HDAg on the production of HDV mRNA and antigenome RNA, both of which are synthesized from the genome RNA template. mRNA synthesis is favored at low HDAg levels but becomes saturated at high HDAg concentrations. Antigenome RNA accumulation increases linearly with HDAg and dominates at high HDAg levels. These results provide a conceptual model for how HDV antigenome RNA production and mRNA transcription are controlled from the earliest stage of infection onward and also demonstrate that, in this control, HDV behaves similarly to other negative-strand RNA viruses, even though there is no genetic similarity between them. Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of liver disease; approximately 15 million people are chronically infected worldwide. There are no licensed therapies available. HDV is not related to any known virus, and few details regarding its replication cycle are known. One key question is whether and how HDV regulates the relative amounts of viral RNA and protein in infected cells. Such regulation might be important because the HDV RNA and protein form complexes that are essential for HDV replication, and the proper stoichiometry of these complexes could be critical for their function. Our results show that the relative amounts of HDV RNA and protein in cells are indeed important for HDV replication and that the virus does control them. These observations indicate that further study of these regulatory mechanisms is required to better understand replication of this serious human pathogen.
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http://dx.doi.org/10.1128/JVI.01989-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450126PMC
April 2019

Purple Urine Bag Syndrome.

J Am Osteopath Assoc 2018 Oct;118(10):689

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http://dx.doi.org/10.7556/jaoa.2018.151DOI Listing
October 2018

Global seafood consumption footprint.

Ambio 2019 Feb 29;48(2):111-122. Epub 2018 May 29.

European Commission, Joint Research Centre (JRC). Unit D.02 Water and Marine Resources Unit, Sustainable Resources Directorate, Via E. Fermi 2749, 21027, Ispra, Italy.

To ensure food security and nutritional quality for a growing world population in the face of climate change, stagnant capture fisheries production, increasing aquaculture production and competition for natural resources, countries must be accountable for what they consume rather than what they produce. To investigate the sustainability of seafood consumption, we propose a methodology to examine the impact of seafood supply chains across national boundaries: the seafood consumption footprint. The seafood consumption footprint is expressed as the biomass of domestic and imported seafood production required to satisfy national seafood consumption, and is estimated using a multi-regional input output model. Thus, we reconstruct for the first time the global fish biomass flows in national supply chains to estimate consumption footprints at the global, country and sector levels (capture fisheries, aquaculture, distribution and processing, and reduction into fishmeal and fish oil) taking into account the biomass supply from beyond national borders.
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http://dx.doi.org/10.1007/s13280-018-1060-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346599PMC
February 2019

Rapid enhancement of chemical weathering recorded by extremely light seawater lithium isotopes at the Permian-Triassic boundary.

Proc Natl Acad Sci U S A 2018 04 26;115(15):3782-3787. Epub 2018 Mar 26.

Chinese Academy of Sciences Key Laboratory of Crust-Mantle Materials and Environments, School of Earth and Space Sciences, University of Science and Technology of China, Hefei 230026, China;

Lithium (Li) isotope analyses of sedimentary rocks from the Meishan section in South China reveal extremely light seawater Li isotopic signatures at the Permian-Triassic boundary (PTB), which coincide with the most severe mass extinction in the history of animal life. Using a dynamic seawater lithium box model, we show that the light seawater Li isotopic signatures can be best explained by a significant influx of riverine [Li] with light δLi to the ocean realm. The seawater Li isotope excursion started ≥300 Ky before and persisted up to the main extinction event, which is consistent with the eruption time of the Siberian Traps. The eruption of the Siberian Traps exposed an enormous amount of fresh basalt and triggered CO release, rapid global warming, and acid rains, which in turn led to a rapid enhancement of continental weathering. The enhanced continental weathering delivered excessive nutrients to the oceans that could lead to marine eutrophication, anoxia, acidification, and ecological perturbation, ultimately resulting in the end-Permian mass extinction.
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http://dx.doi.org/10.1073/pnas.1711862115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899431PMC
April 2018

Curated Collections for Educators: Five Key Papers on Evaluating Digital Scholarship.

Cureus 2018 Jan 3;10(1):e2021. Epub 2018 Jan 3.

Department of Emergency Medicine, Rush University Medical Center.

Traditionally, scholarship that was recognized for promotion and tenure consisted of clinical research, bench research, and grant funding. Recent trends have allowed for differing approaches to scholarship, including digital publication. As increasing numbers of trainees and faculty turn to online educational resources, it is imperative to critically evaluate these resources. This article summarizes five key papers that address the appraisal of digital scholarship and describes their relevance to junior clinician educators and faculty developers. In May 2017, the Academic Life in Emergency Medicine Faculty Incubator program focused on the topic of digital scholarship, providing and discussing papers relevant to the topic. We augmented this list of papers with further suggestions by guest experts and by an open call via Twitter for other important papers. Through this process, we created a list of 38 papers in total on the topic of evaluating digital scholarship. In order to determine which of these papers best describe how to evaluate digital scholarship, the authorship group assessed the papers using a modified Delphi approach to build consensus. In this paper we present the five most highly rated papers from our process about evaluating digital scholarship. We summarize each paper and discuss its specific relevance to junior faculty members and to faculty developers. These papers provide a framework for assessing the quality of digital scholarship, so that junior faculty can recommend high-quality educational resources to their trainees. These papers help guide educators on how to produce high quality digital scholarship and maximize recognition and credit in respect to receiving promotion and tenure.
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http://dx.doi.org/10.7759/cureus.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837232PMC
January 2018

Light-Enhanced Microbial Organic Carbon Yield.

Front Microbiol 2017 16;8:2157. Epub 2017 Nov 16.

Center for Microbial Oceanography, School of Ocean and Earth Science and Technology, University of Hawaii at Manoa, Honolulu, HI, United States.

Molecular evidence for proteorhodopsin- and bacteriochlorophyll-based photoheterotrophy is widespread in oligotrophic marine microbial community metagenomes, and has been implicated in light-enhanced growth rates, substrate uptake rates, and anapleurotic carbon fixation, thus complicating the web of interactions within the 'microbial loop.' We quantified photoheterotrophic metabolism of the oxidized organic acid glycolate, a fast-turnover and exclusively phytoplankton-derived substrate at an oligotrophic site in the subtropical North Pacific Ocean. As expected, concentration-dependent changes in uptake rates were observed over the diel cycle, with maxima occurring at midday. Although no light-enhanced substrate uptake rates were observed, samples exposed to light altered the balance between assimilation and respiration, resulting in an approximately four-fold increase in glycolate-specific assimilation efficiency. Energy demand for such a metabolic adjustment was linearly related to light, consistent with photoheterotrophy.
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http://dx.doi.org/10.3389/fmicb.2017.02157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715323PMC
November 2017

Coordinated regulation of growth, activity and transcription in natural populations of the unicellular nitrogen-fixing cyanobacterium Crocosphaera.

Nat Microbiol 2017 Jul 31;2:17118. Epub 2017 Jul 31.

Daniel K. Inouye Center for Microbial Oceanography: Research and Education, Department of Oceanography, University of Hawaii, Honolulu, Hawaii 96822, USA.

The temporal dynamics of phytoplankton growth and activity have large impacts on fluxes of matter and energy, yet obtaining in situ metabolic measurements of sufficient resolution for even dominant microorganisms remains a considerable challenge. We performed Lagrangian diel sampling with synoptic measurements of population abundances, dinitrogen (N) fixation, mortality, productivity, export and transcription in a bloom of Crocosphaera over eight days in the North Pacific Subtropical Gyre (NPSG). Quantitative transcriptomic analyses revealed clear diel oscillations in transcript abundances for 34% of Crocosphaera genes identified, reflecting a systematic progression of gene expression in diverse metabolic pathways. Significant time-lagged correspondence was evident between nifH transcript abundance and maximal N fixation, as well as sepF transcript abundance and cell division, demonstrating the utility of transcriptomics to predict the occurrence and timing of physiological and biogeochemical processes in natural populations. Indirect estimates of carbon fixation by Crocosphaera were equivalent to 11% of net community production, suggesting that under bloom conditions this diazotroph has a considerable impact on the wider carbon cycle. Our cross-scale synthesis of molecular, population and community-wide data underscores the tightly coordinated in situ metabolism of the keystone N-fixing cyanobacterium Crocosphaera, as well as the broader ecosystem-wide implications of its activities.
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http://dx.doi.org/10.1038/nmicrobiol.2017.118DOI Listing
July 2017