Pediatric COVID-19 vaccination is effective in preventing COVID-19-related hospitalization, but duration of protection of the original monovalent vaccine during SARS-CoV-2 Omicron predominance merits ...evaluation, particularly given low coverage with updated COVID-19 vaccines. During December 19, 2021-October 29, 2023, the Overcoming COVID-19 Network evaluated vaccine effectiveness (VE) of ≥2 original monovalent COVID-19 mRNA vaccine doses against COVID-19-related hospitalization and critical illness among U.S. children and adolescents aged 5-18 years, using a case-control design. Too few children and adolescents received bivalent or updated monovalent vaccines to separately evaluate their effectiveness. Most case-patients (persons with a positive SARS-CoV-2 test result) were unvaccinated, despite the high frequency of reported underlying conditions associated with severe COVID-19. VE of the original monovalent vaccine against COVID-19-related hospitalizations was 52% (95% CI = 33%-66%) when the most recent dose was administered <120 days before hospitalization and 19% (95% CI = 2%-32%) if the interval was 120-364 days. VE of the original monovalent vaccine against COVID-19-related hospitalization was 31% (95% CI = 18%-43%) if the last dose was received any time within the previous year. VE against critical COVID-19-related illness, defined as receipt of noninvasive or invasive mechanical ventilation, vasoactive infusions, extracorporeal membrane oxygenation, and illness resulting in death, was 57% (95% CI = 21%-76%) when the most recent dose was received <120 days before hospitalization, 25% (95% CI = -9% to 49%) if it was received 120-364 days before hospitalization, and 38% (95% CI = 15%-55%) if the last dose was received any time within the previous year. VE was similar after excluding children and adolescents with documented immunocompromising conditions. Because of the low frequency of children who received updated COVID-19 vaccines and waning effectiveness of original monovalent doses, these data support CDC recommendations that all children and adolescents receive updated COVID-19 vaccines to protect against severe COVID-19.
Exploring the Continental Margin of Israel Coleman, Dwight F.; Austin, James A.; Ben-Avraham, Zvi
Oceanography (Washington, D.C.),
03/2011, Volume:
24, Issue:
1
Journal Article
Peer reviewed
Israel's continental margin is situated in the southeastern Mediterranean, bounded to the north and east by the Cypriot Arc and the continental margins of Syria and Lebanon, and to the south and west ...by the Palestinian Authority's Gaza Strip, the Egyptian margin, and Nile Fan (Figure 1). This margin consists of two prominent segments, separated by the Carmel Fault structure, an active left-lateral splay of the Dead Sea Transform (Figure 1, inset) that crosscuts central Israel and extends offshore to the northwest (Schattner and Ben-Avraham, 2007). These segments exhibit different crustal thicknesses and structure. The southern segment resembles a passive rifted margin, while the northern segment resembles a sheared margin with thinner crust and narrower, steeper margin slopes. The Nautilus expedition was conducted entirely in the southern segment, except for some exploration of Achziv Canyon. Large slump and slide features, notably, the Palmachim Disturbance, also characterize this margin, influenced in part by active salt tectonic processes (Ben-Avraham et al., 2006).
Toluene 4-monooxygenase (T4MO) catalyzes the hydroxylation of toluene to yield 96% p-cresol. This diiron enzyme complex was used to oxidize norcarane (bicyclo4.1.0heptane), 1,1-dimethylcyclopropane, ...and 1,1-diethylcyclopropane, substrate analogues that can undergo diagnostic reactions upon the production of transient radical or cationic intermediates. Norcarane closely matches the shape and volume of the natural substrate toluene. Reaction of isoforms of the hydroxylase component of T4MO (T4moH) with different regiospecificities for toluene hydroxylation (k(cat) approximately 1.9-2.3 s(-)(1) and coupling efficiency approximately 81-96%) revealed similar catalytic parameters for norcarane oxidation (k(cat) approximately 0.3-0.5 s(-)(1) and coupling efficiency approximately 72%). The products included variable amounts of the un-rearranged isomeric norcaranols and cyclohex-2-enyl methanol, a product attributed to rearrangement of a radical oxidation intermediate. A ring-expansion product derived from the norcaranyl C-2 cation, cyclohept-3-enol, was not produced by either the natural enzyme or any of the T4moH isoforms tested. Comparative studies of 1,1-dimethylcyclopropane and 1,1-diethylcyclopropane, diagnostic substrates with differences in size and with approximately 50-fold slower k(cat) values, gave products consistent with both radical rearrangement and cation ring expansion. Examination of the isotopic enrichment of the incorporated O-atoms for all products revealed high-fidelity incorporation of an O-atom from O(2) in the un-rearranged and radical-rearranged products, while the O-atom found in the cation ring-expansion products was predominantly obtained by reaction with H(2)O. The results show a divergence of radical and cation pathways for T4moH-mediated hydroxylation that can be dissected by diagnostic substrate probe rearrangements and by changes in the source of oxygen used for substrate oxygenation.
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Background:
Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukaemia (CMML) are haematological disorders that develop in haematopoietic stem or progenitor cells (HSPCs) and are ...characterised by ineffective haematopoiesis. 5'-Azacitidine (AZA), a DNA demethylating agent, is the primary drug for the treatment of high-risk MDS and CMML and response is associated with improved survival benefits. However, only half of treated patients will ever respond to AZA and the molecular basis for poor response is currently unknown. There are few alternative therapies for the non-responders. Additionally, AZA response is rarely sustained and a substantial fraction of responders will eventually relapse. The in vivo effect of AZA therapy on dysplastic cells in responders is unclear and there are no predictive markers for impending relapse in responders.
Methods:
To address these fundamental questions, we enrolled 18 high-risk MDS and CMML patients on a compassionate access program for AZA in Australia. Bone marrow was collected at seven different points - before treatment; through 6 cycles of treatment; and at up to two years after initiation - and we isolated high-purity CD34+ HSPCs (Figure A). 10 patients had a complete response while 8 were poorer responders. We performed RNA-seq to query the transcriptomes (and validated by Fluidigm-based PCR) and deduced the clonal evolution in the bone marrow in response to AZA therapy (by whole exome-sequencing, followed by targeted capture resequencing, and genotyping of individual CFU colonies). Our findings were validated in an independent cohort of 57 patients. We used flow cytometry to develop a clinically relevant prognostic assay for AZA resistance and developed a novel stromal co-culture based functional drug testing platform to rationally discover combinational drug therapies to overcome AZA resistance.
Results:
We hypothesised that primary AZA resistance would be driven by pre-existing molecular differences between responders and non-responders. Analysis of the pre-treatment RNA-seq data strikingly revealed the differential expression of 1148 genes between responders and non-responders (Figure B). Pathway analyses of these genes indicated that cell cycle and DNA damage response pathways were relatively up-regulated in responders compared to non-responders, indicating that HSPCs of non-responders are more quiescent compared to responders (Figure C). We validated these gene expression differences in independent patient cohorts from the U.K. and Sweden (n=57; 27 responders, 30 non-responders). We then adapted a flow cytometry based assay, amenable to prospective use in a clinical diagnostic setting, to directly detect the increased quiescence of CD34+ CD38+ haematopoietic progenitors in unsorted bone marrows of non-responders across all cohorts (Figure D). Finally, to reverse the quiescence of progenitor cells of non-responders, and make them more susceptive to AZA, we leveraged our RNA-seq discoveries to target pathways that were relatively up-regulated in non-responders. Using a stromal co-culture drug testing platform that we developed, we discovered that inhibiting integrin-linked signalling combinatorially with AZA improved the functionality of dysplastic cells (Figure E). Additionally, dysplastic cells were particularly sensitive to the inhibition of the mTOR pathway.
To trace the fate of dysplastic cells as patients undergo AZA therapy, and thereby understand the basis of eventual relapse in responders, we performed whole exome sequencing of all patients (Figure F). Using the mutations as "molecular barcodes", we deduced the clonal architecture in each individual and observed the clonal evolution that occurred in response to AZA treatment. Combined with genotyping of CFU colonies grown in vitro, we have discovered that clonal haematopoiesis originating from resistant multipotent cells bearing mutations persists even upon complete response and forms the basis for eventual relapse (Figure G).
Conclusions:
Our findings, across independent cohorts and relevant to both MDS and CMML, have immediate clinical utility not simply to prospectively identify AZA non-responders but also by suggesting combinatorial therapies that could improve response. Finally, elucidating the in vivo effects of AZA therapy lay the foundation for developing more durable treatments.
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Kulasekararaj:Alexion: Consultancy. Lynch:Celgene: Employment, Equity Ownership. Campbell:14M genomics: Other: Co-founder and consultant.
Reactant jetting in unstable detonation Sanderson, S.R.; Austin, J.M.; Liang, Z. ...
Progress in aerospace sciences,
02/2010, Volume:
46, Issue:
2
Journal Article
Peer reviewed
Open access
We note the common existence of a supersonic jet structure locally embedded within a surrounding transonic flow field in the hitherto unrelated phenomena of unstable gaseous detonation and ...hypervelocity blunt body shock wave interaction. Extending prior results that demonstrate the consequences of reduced endothermic reaction rate for the supersonic jet fluid in the blunt body case, we provide an explanation for observations of locally reduced OH PLIF signal in images of the keystone reaction zone structure of weakly unstable detonations. Modeling these flow features as exothermically reacting jets with similarly reduced reaction rates, we demonstrate a mechanism for jetting of bulk pockets of unreacted fluid with potentially differing kinetic pathways into the region behind the primary detonation front of strongly unstable mixtures. We examine the impact of mono-atomic and diatomic diluents on transverse structure. The results yield insight into the mechanisms of transition and characteristic features of both weakly and strongly unstable mixtures.
Coherent Phonon Heat Conduction in Superlattice Luckyanova, M; Garg, J; Esfarjani, Keivan ...
Science (American Association for the Advancement of Science),
11/2012, Volume:
338, Issue:
6109
Journal Article
Germ cell nuclear factor (GCNF), an orphan nuclear receptor, is essential for mouse embryogenesis. GCNF specifically binds to a DR0 response element via its DNA binding domain (DBD) in vitro and ...functions as a repressor of gene transcription. To further study the role of GCNF during embryogenesis, we have employed a Cre/loxP strategy and generated a line ofGCNF mutant mice (GCNFlox/lox) in which the 243-base pair DBD-encoding exon has been deleted in the germline. However, the ligand binding domain (LBD) of GCNF is still expressed at the mRNA and protein levels in theGCNFlox/lox mice.GCNFlox/lox mice die at 9.5–10.5 days postcoitum. The tailbuds of these mutant embryos protrude outside the yolk sac. Expression of Oct-4 in the somatic cells ofGCNFlox/lox embryos at 8.25 days postcoitum was not silenced as in the GCNF+/+ embryos. Therefore, GCNFlox/lox mice phenocopy theGCNF−/− mice. Our results indicate that the DBD is essential for the function of GCNF during early mouse embryogenesis, and that the LBD does not mediate any function independent of the DBD at this stage of embryonic development. Our results also suggest that GCNF is indeed a transcriptional factor that represses gene transcription mediated via its DBD.
Practical selection of antiemetics Flake, Zachary A; Scalley, Robert D; Bailey, Austin G
American family physician,
2004-Mar-01, Volume:
69, Issue:
5
Journal Article
Peer reviewed
An understanding of the pathophysiology of nausea and the mechanisms of antiemetics can help family physicians improve the cost-effectiveness and efficacy of therapy. Nausea and vomiting are mediated ...primarily by visceral stimulation through dopamine and serotonin, by vestibular and central nervous system causes through histamine and acetylcholine, and by chemoreceptor trigger zone stimulation through dopamine and serotonin. Treatment is directed at these pathways. Antihistamines and anticholinergic agents are most effective in patients with nausea resulting from vestibular and central nervous system causes. Dopamine antagonists block dopamine in the intestines and chemoreceptor trigger zone; indications for these agents are similar to those for serotonin antagonists. Serotonin antagonists block serotonin in the intestines and chemoreceptor trigger zone, and are most effective for treating gastrointestinal irritation and postoperative nausea and vomiting. Complementary and alternative therapies, such as ginger, acupressure, and vitamin B6, have variable effectiveness in the treatment of pregnancy-induced nausea.
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