Effect of donor HSD17B13 genotype on patient survival after liver transplant: a retrospective cohort study.

Background: Several genetic variants are associated with chronic liver disease. The role of these variants in outcomes after liver transplantation (LT) is uncertain. The aim of this study was to determine if donor genotype at risk-associated variants in PNPLA3 (rs738409 C>G, p.I148M) and HSD17B13 (rs72613567 T>TA; rs80182459, p.A192Lfs∗8) influences post-LT survival. Methods: In this retrospective cohort study, data on 2346 adults who underwent first-time LT between January 1, 1999 and June 30, 2020 and who had donor DNA samples available at five large Transplant Immunology Laboratories in Texas, USA, were obtained from the United Network for Organ Sharing (UNOS). Duplicates, patients with insufficient donor DNA for genotyping, those who were <18 years of age at the time of transplant, had had a previous transplant or had missing genotype data were excluded. The primary outcomes were patient and graft survival after LT. The association between donor genotype and post-LT survival was examined using Kaplan-Meier method and multivariable-adjusted Cox proportional hazards models. Findings: Median age of LT recipients was 57 [interquartile range (IQR), 50-62] years; 837 (35.7%) were women; 1362 (58.1%) White, 713 (30.4%) Hispanic, 182 (7.8%) Black/African-American. Median follow-up time was 3.95 years. Post-LT survival was not affected by donor PNPLA3 genotype but was significantly reduced among recipients of livers with two HSD17B13 loss-of-function (LoF) variants compared to those receiving livers with no HSD17B13 LoF alleles (unadjusted one-year survival: 82.6% vs 93.9%, P < 0.0001; five-year survival: 73.1% vs 82.9%, P = 0.0017; adjusted hazard ratio [HR], 2.25; 95% CI, 1.61-3.15 after adjustment for recipient age, sex, and self-reported ethnicity). Excess mortality was restricted to those receiving steroid induction immunosuppression (crude 90-day post-LT mortality, 9.3% [95% CI, 1.9%-16.1%] vs 1.9% [95% CI, 0.9%-2.9%] in recipients of livers with two vs no HSD17B13 LoF alleles, P = 0.0012; age, sex, and ethnicity-adjusted HR, 2.85; 95% CI, 1.72-4.71, P < 0.0001). No reduction was seen among patients who did not receive steroid induction (90-day mortality 3.1% [95% CI, 0%-7.3%] vs 2% [95% CI, 0.9%-3.1%], P = 0.65; adjusted HR, 1.17; 95% CI, 0.66-2.08, P = 0.60). Interpretation: Donor HSD17B13 genotype adversely affects post-LT survival in patients receiving steroid induction. Additional studies are required to confirm this association. Funding: The National Institutes of Health and American Society of Transplant Surgeons Collaborative Scientist Grant.

Galantamine ameliorates hyperoxia-induced brain injury in neonatal mice.

Introduction: Prolonged oxygen therapy in preterm infants often leads to cognitive impairment. Hyperoxia leads to excess free radical production with subsequent neuroinflammation, astrogliosis, microgliosis and apoptosis. We hypothesized that Galantamine, an acetyl choline esterase inhibitor and an FDA approved treatment of Alzheimer's disease, will reduce hyperoxic brain injury in neonatal mice and will improve learning and memory. Methods: Mouse pups at postnatal day 1 (P1) were placed in a hyperoxia chamber (FiO2 95%) for 7 days. Pups were injected IP daily with Galantamine (5 mg/kg/dose) or saline for 7 days. Results: Hyperoxia caused significant neurodegeneration in cholinergic nuclei of the basal forebrain cholinergic system (BFCS), laterodorsal tegmental (LDT) nucleus and nucleus ambiguus (NA). Galantamine ameliorated this neuronal loss. Treated hyperoxic group showed a significant increase of choline acetyl transferase (ChAT) expression and a decrease of acetyl choline esterase activity, thus increasing acetyl choline levels in hyperoxia environment. Hyperoxia increased pro-inflammatory cytokines namely IL -1ß, IL-6 and TNF α, HMGB1, NF-κB activation. Galantamine showed its potent anti- inflammatory effect, by blunting cytokines surges among treated group. Treatment with Galantamine increased myelination while reducing apoptosis, microgliosis, astrogliosis and ROS production. Long term neurobehavioral outcomes at P60 showed improved locomotor activity, coordination, learning and memory, along with increased hippocampal volumes on MRI with Galantamine treated versus non treated hyperoxia group. Conclusion: Together our findings suggest a potential therapeutic role for Galantamine in attenuating hyperoxia-induced brain injury.

Trends in Intra-Aortic Balloon Pump Use in Cardiogenic Shock After the SHOCK-II Trial.

Myocardial infarction complicated by cardiogenic shock (MI-CS) has a poor prognosis, even with early revascularization. Previously, intra-aortic balloon pump (IABP) use was thought to improve outcomes, but the IABP-SHOCK-II (Intra-aortic Balloon Pump in Cardiogenic Shock-II study) trial found no survival benefit. We aimed to determine the trends in IABP use in patients who underwent percutaneous intervention over time. Data were taken from patients in the Melbourne Interventional Group registry (2005 to 2018) with MI-CS who underwent percutaneous intervention. The primary outcome was the trend in IABP use over time. The secondary outcomes included 30-day mortality and major adverse cardiovascular and cerebrovascular events (MACCEs). Of the 1,110 patients with MI-CS, IABP was used in 478 patients (43%). IABP was used more in patients with left main/left anterior descending culprit lesions (62% vs 46%), lower ejection fraction (<35%; 18% vs 11%), and preprocedural inotrope use (81% vs 73%, all p <0.05). IABP use was associated with higher bleeding (18% vs 13%) and 30-day MACCE (58% vs 51%, both p <0.05). The rate of MI-CS per year increased over time; however, after 2012, there was a decrease in IABP use (p <0.001). IABP use was a predictor of 30-day MACCE (odds ratio 1.6, 95% confidence interval 1.18 to 2.29, p = 0.003). However, IABP was not associated with in-hospital, 30-day, or long-term mortality (45% vs 47%, p = 0.44; 46% vs 50%, p = 0.25; 60% vs 62%, p = 0.39). In conclusion, IABP was not associated with reduced short- or long-term mortality and was associated with increased short-term adverse events. IABP use is decreasing but is predominately used in sicker patients with greater myocardium at risk.

Cross-sectional survey of Australian and New Zealand clinical staff to explore attitudes regarding medication prescription and administration during neonatal emergencies.

AIM: To survey Australasian neonatal medical and nursing staff to determine confidence regarding medication use, prior experience with medication errors and common resources utilised in neonatal emergencies. METHODS: Data were collected through a cross-sectional online survey distributed to clinical staff affiliated with the Australian and New Zealand Neonatal Network. Information collected included: demographics, confidence in medication use, medication errors and resources used to assist with medication administration. Outcomes were compared between medical staff and nursing staff, and between clinical staff with differing levels of clinical experience (<5 years, 5-10 years and >10 years). RESULTS: Respondents (n = 133) were most confident in calculating medication doses (89%, n = 119), but least confident in prescribing medication (50%, n = 67). Nurses were more likely to be confident than doctors with respect to appropriately diluting and drawing up medication (88% nurses vs. 28% doctors, P < 0.0001), and administering intravenous medications to critically ill neonates (97% nurses vs. 82% doctors, P < 0.01). Over half of respondents reported being personally involved in a medication error in the last 12 months: 33% had been involved in an error related to delayed administration, 18% related to incorrect documentation and 17% related to an incorrect dose. Free-text responses highlighted issues relating to adrenaline (epinephrine) administration and difficulties with equipment (syringe drivers and/or infusion pumps). CONCLUSIONS: Medication errors in neonatal emergencies are common. Strategies to reduce such errors should be implemented in settings where neonates may require emergency care or resuscitation.

Natural history of asthma symptoms after epidemic thunderstorm asthma: a 3-year longitudinal study.

BACKGROUND: The world's most catastrophic epidemic thunderstorm asthma event (ETSA) affected Melbourne in 2016. Little is known about the natural history of individuals affected by such extreme events. OBJECTIVE: In this single center prospective 3-year longitudinal study, symptomatology and behaviors of individuals affected by ETSA were assessed. METHODS: Standardized telephone questionnaire was used to evaluate frequency of asthma symptoms, inhaled corticosteroid preventer use, asthma action plan ownership, and healthcare utilization. Questionnaires were administered at 12, 24, and 36 months after 2016 ETSA. Subgroup analyses of the 'current', 'past', 'possible,' and 'no asthma' subgroups were also conducted. RESULTS: Two hundred and eight, 164, and 112 completed questionnaires were analyzed in 2017, 2018, and 2019, respectively. Seventy to eighty five percent of respondents reported ongoing asthma symptoms in any given year, of which 20%-28% experienced weekly symptoms. Nearly 50% of respondents were prescribed preventers, with approximately 45% adherent at least 5 days a week. Less than 40% had an asthma action plan and 15%-20% sought urgent medical attention for asthma over the follow-up period. Among 106 individuals with 3 consecutive years of completed questionnaires, those with no prior doctor diagnosis of asthma were significantly more likely to be asymptomatic on follow-up than those with a prior doctor diagnosis of asthma (p = 0.02). Subgroup analyses suggest that large proportions of respondents with 'past' and 'no asthma' continue to remain symptomatic throughout the 36-month period. CONCLUSION: In individuals affected by ETSA, we found evidence of ongoing loss of asthma control in those with previously well controlled asthma, and the persistence of symptoms suggestive of asthma in those with no history or symptoms suggestive of prior asthma, even after 36 months from initial ETSA. Low rates of inhaler adherence and asthma action plan ownership may contribute to increased morbidity and mortality from future ETSA events. Further research is required to confirm these findings.

Persistent cloaca and caudal duplication in a monovular twin, a rare case report.

INTRODUCTION: A cloaca occurs when genitourinary tract and bowel converge into a common channel. We report a case of partial caudal duplication, persistent cloaca and vestigial appendage in a monovular female twin infant. PRESENTATION OF CASE: This is a monochorinonic-diamniotic twin born at 36 weeks with apgars of 9/9. She had a duplicated labia with two clitorises, and a partially formed accessory foot with 2 toes protruding from the right gluteal region. There was anal atresia and a punctate urethral opening in the right genitalia through which she voided spontaneously. X-ray of the accessory foot had rudimentary metatarsals and phalanges. There was left hydroureteronephrosis and a hydrocolpos causing severe mass effect. On the first day of life, she had exploratory laparotomy with a diverting colostomy and mucus fistula and drainage of hydrocolpos. At 6 months of age, she had removal of the accessory foot with flap closure of the perineal defect and vesicostomy. At 15 months of age she had laparotomy for repair of cloaca, excision of presacral pelvic mass and the duplicated vulva. DISCUSSION: Theories of etiology include failure of regression of Kovalevsky's canal (a communication that connects the amniotic and yolk sac), an incomplete form of twinning through iatrogenic damage to the zona pellucida or a failed triplet formation from a single embryo. CONCLUSION: Caudal duplication with persistent cloaca and vestigial appendage is a rare and complex malformation. Having a unified surgical and medical team to preserve quality of life and to treat complications is of key importance.

RGD inhibition of itgb1 ameliorates laminin-α2-deficient zebrafish fibre pathology.

Deficiency of muscle basement membrane (MBM) component laminin-α2 leads to muscular dystrophy congenital type 1A (MDC1A), a currently untreatable myopathy. Laminin--α2 has two main binding partners within the MBM, dystroglycan and integrin. Integrins coordinate both cell adhesion and signalling; however, there is little mechanistic insight into integrin's function at the MBM. In order to study integrin's role in basement membrane development and how this relates to the MBM's capacity to handle force, an itgß1.b-/- zebrafish line was created. Histological examination revealed increased extracellular matrix (ECM) deposition at the MBM in the itgß1.b-/- fish when compared with controls. Surprisingly, both laminin and collagen proteins were found to be increased in expression at the MBM of the itgß1.b-/- larvae when compared with controls. This increase in ECM components resulted in a decrease in myotomal elasticity as determined by novel passive force analyses. To determine if it was possible to control ECM deposition at the MBM by manipulating integrin activity, RGD peptide, a potent inhibitor of integrin-ß1, was injected into a zebrafish model of MDC1A. As postulated an increase in laminin and collagen was observed in the lama2-/- mutant MBM. Importantly, there was also an improvement in fibre stability at the MBM, judged by a reduction in fibre pathology. These results therefore show that blocking ITGß1 signalling increases ECM deposition at the MBM, a process that could be potentially exploited for treatment of MDC1A.

Ecology of sleeping: the microbial and arthropod associates of chimpanzee beds.

The indoor environment created by the construction of homes and other buildings is often considered to be uniquely different from other environments. It is composed of organisms that are less diverse than those of the outdoors and strongly sourced by, or dependent upon, human bodies. Yet, no one has ever compared the composition of species found in contemporary human homes to that of other structures built by mammals, including those of non-human primates. Here we consider the microbes and arthropods found in chimpanzee beds, relative to the surrounding environment (n = 41 and 15 beds, respectively). Based on the study of human homes, we hypothesized that the microbes found in chimpanzee beds would be less diverse than those on nearby branches and leaves and that their beds would be primarily composed of body-associated organisms. However, we found that differences between wet and dry seasons and elevation above sea level explained nearly all of the observed variation in microbial diversity and community structure. While we can identify the presence of a chimpanzee based on the assemblage of bacteria, the dominant signal is that of environmental microbes. We found just four ectoparasitic arthropod specimens, none of which appears to be specialized on chimpanzees or their structures. These results suggest that the life to which chimpanzees are exposed while in their beds is predominately the same as that of the surrounding environment.

A somitic contribution to the apical ectodermal ridge is essential for fin formation.

The transition from fins to limbs was an important terrestrial adaptation, but how this crucial evolutionary shift arose developmentally is unknown. Current models focus on the distinct roles of the apical ectodermal ridge (AER) and the signaling molecules that it secretes during limb and fin outgrowth. In contrast to the limb AER, the AER of the fin rapidly transitions into the apical fold and in the process shuts off AER-derived signals that stimulate proliferation of the precursors of the appendicular skeleton. The differing fates of the AER during fish and tetrapod development have led to the speculation that fin-fold formation was one of the evolutionary hurdles to the AER-dependent expansion of the fin mesenchyme required to generate the increased appendicular structure evident within limbs. Consequently, a heterochronic shift in the AER-to-apical-fold transition has been postulated to be crucial for limb evolution. The ability to test this model has been hampered by a lack of understanding of the mechanisms controlling apical fold induction. Here we show that invasion by cells of a newly identified somite-derived lineage into the AER in zebrafish regulates apical fold induction. Ablation of these cells inhibits apical fold formation, prolongs AER activity and increases the amount of fin bud mesenchyme, suggesting that these cells could provide the timing mechanism proposed in Thorogood's clock model of the fin-to-limb transition. We further demonstrate that apical-fold inducing cells are progressively lost during gnathostome evolution;the absence of such cells within the tetrapod limb suggests that their loss may have been a necessary prelude to the attainment of limb-like structures in Devonian sarcopterygian fish.

Population status of chimpanzees in the Masito-Ugalla Ecosystem, Tanzania.

More than 75 percent of Tanzania's chimpanzees live at low densities on land outside national parks. Chimpanzees are one of the key conservation targets in the region and long-term monitoring of these populations is essential for assessing the overall status of ecosystem health and the success of implemented conservation strategies. We aimed to assess change in chimpanzee density within the Masito-Ugalla Ecosystem (MUE) by comparing results of re-walking the same line transects in 2007 and 2014. We further used published remote sensing data derived from Landsat satellites to assess forest cover change within a 5 km buffer of these transects over that same period. We detected no statistically significant decline in chimpanzee density across the surveyed areas of MUE between 2007 and 2014, although the overall mean density of chimpanzees declined from 0.09 individuals/km(2) in 2007 to 0.05 individuals/km(2) in 2014. Whether this change is biologically meaningful cannot be determined due to small sample sizes and large, entirely overlapping error margins. It is therefore possible that the MUE chimpanzee population has been stable over this period and indeed in some areas (Issa Valley, Mkanga, Kamkulu) even showed an increase in chimpanzee density. Variation in chimpanzee habitat preference for ranging or nesting could explain variation in density at some of the survey sites between 2007 and 2014. We also found a relationship between increasing habitat loss and lower mean chimpanzee density. Future surveys will need to ensure a larger sample size, broader geographic effort, and random survey design, to more precisely determine trends in MUE chimpanzee density and population size over time.

Trace metals in the sponge Ircinia felix and sediments from North-Western Trinidad, West Indies.

The purpose of this study was to obtain data for trace metals in the sponge, Ircinia felix, and sediments found in coastal areas of north-western Trinidad, and to determine whether this sponge could be useful as a biomonitor for selected metals. Three sets of sediment and tissue samples were collected from four stations representing a range of anthropogenic input over a 12-month period. Samples were analyzed for Cd, Cr, Cu, Ni, Pb and Zn using flame and graphite furnace atomic absorption spectrometry. Extractable metal concentrations in sediments ranged from 0.01-0.28 µg g(-1)-cadmium, 0.02-16.2 µg g(-1)-chromium, 0.19-68.5 µg g(-1)-copper, <0.05-4.12 µg g(-1) -nickel, <0.03-37.0 µg g(-1) -lead and 4.08-148 µg g(-1)-zinc. Total metal concentrations in I. felix tissue (dry weight) ranged from 0.03-1.04 µg g(-1)-cadmium, 2.51-24.9 µg g(-1) -chromium, 15.2-49.9 µg g(-1)-copper, 6.30-53.9 µg g(-1) -nickel, 0.27-35.4 µg g(-1) -lead and 29.7-127 µg g(-1)- zinc. The results of the study suggest that I. felix could potentially have use as a biomonitor for Ni, Cd, Cu, and possibly Cr and Zn but may be less useful for monitoring Pb. Further work on temporal trends and intra-species variation of trace metals in the sponge is recommended.

Identification of novel pro-migratory, cancer-associated genes using quantitative, microscopy-based screening.

BACKGROUND: Cell migration is a highly complex process, regulated by multiple genes, signaling pathways and external stimuli. To discover genes or pharmacological agents that can modulate the migratory activity of cells, screening strategies that enable the monitoring of diverse migratory parameters in a large number of samples are necessary. METHODOLOGY: In the present study, we describe the development of a quantitative, high-throughput cell migration assay, based on a modified phagokinetic tracks (PKT) procedure, and apply it for identifying novel pro-migratory genes in a cancer-related gene library. In brief, cells are seeded on fibronectin-coated 96-well plates, covered with a monolayer of carboxylated latex beads. Motile cells clear the beads, located along their migratory paths, forming tracks that are visualized using an automated, transmitted-light screening microscope. The tracks are then segmented and characterized by multi-parametric, morphometric analysis, resolving a variety of morphological and kinetic features. CONCLUSIONS: In this screen we identified 4 novel genes derived from breast carcinoma related cDNA library, whose over-expression induces major alteration in the migration of the stationary MCF7 cells. This approach can serve for high throughput screening for novel ways to modulate cellular migration in pathological states such as tumor metastasis and invasion.