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Abstract The mechanisms underlying transthyretin‐related amyloidosis in vivo remain unclear. The abundance of the 49–127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49–127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49–127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non‐amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano‐enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49–127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis‐mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied.

Carrier-protein-dependent metabolic pathways biosynthesize fatty acids, polyketides, and non-ribosomal peptides, producing metabolites with important pharmaceutical, environmental, and industrial properties. Recent findings demonstrate that these pathways rely on selective communication mechanisms involving protein-protein interactions (PPIs) that guide enzyme reactivity and timing. While rational design of these PPIs could enable pathway design and modification, this goal remains a challenge due to the complex nature of protein interfaces. Computational methods offer an encouraging avenue, though many score functions fail to predict experimental observables, leading to low success rates. Here, we improve upon the Rosetta score function, leveraging experimental data through iterative rounds of computational prediction and mutagenesis, to design a hybrid fatty acid-non-ribosomal peptide initiation pathway. By increasing the weight of the electrostatic score term, the computational protocol proved to be more predictive, requiring fewer rounds of iteration to identify mutants with high in vitro activity. This allowed efficient design of new PPIs between a non-ribosomal peptide synthetase adenylation domain, PltF, and a fatty acid synthase acyl carrier protein, AcpP, as validated by activity and structural studies. This method provides a promising platform for customized pathway design, establishing a standard for carrier-protein-dependent pathway engineering through PPI optimization.

Erythropoietin (EPO) acts through the dimeric erythropoietin receptor to stimulate proliferation, survival, differentiation and enucleation of erythroid progenitor cells. We undertook two complimentary approaches to find EPO-dependent pSTAT5 target genes in murine erythroid cells: RNA-seq of newly transcribed (4sU-labelled) RNA, and ChIP-seq for pSTAT5 30 minutes after EPO stimulation. We found 302 pSTAT5-occupied sites: ~15% of these reside in promoters while the rest reside within intronic enhancers or intergenic regions, some >100kb from the nearest TSS. The majority of pSTAT5 peaks contain a central palindromic GAS element, TTCYXRGAA. There was significant enrichment for GATA motifs and CACCC-box motifs within the neighbourhood of pSTAT5-bound peaks, and GATA1 and/or KLF1 co-occupancy at many sites. Using 4sU-RNA-seq we determined the EPO-induced transcriptome and validated differentially expressed genes using dynamic CAGE data and qRT-PCR. We identified known direct pSTAT5 target genes such as Bcl2l1, Pim1 and Cish, and many new targets likely to be involved in driving erythroid cell differentiation including those involved in mRNA splicing (Rbm25), epigenetic regulation (Suv420h2), and EpoR turnover (Clint1/EpsinR). Some of these new EpoR-JAK2-pSTAT5 target genes could be used as biomarkers for monitoring disease activity in polycythaemia vera, and for monitoring responses to JAK inhibitors.

Supplementary feeding of garden birds generally has benefits for both bird populations and human wellbeing. Birds have excellent colour vision, and show preferences for food items of particular colours, but research into colour preferences associated with artificial feeders is limited to hummingbirds. Here, we investigated the colour preferences of common UK garden birds foraging at seed-dispensing artificial feeders containing identical food. We presented birds simultaneously with an array of eight differently coloured feeders, and recorded the number of visits made to each colour over 370 30-minute observation periods in the winter of 2014/15. In addition, we surveyed visitors to a garden centre and science festival to determine the colour preferences of likely purchasers of seed feeders. Our results suggest that silver and green feeders were visited by higher numbers of individuals of several common garden bird species, while red and yellow feeders received fewer visits. In contrast, people preferred red, yellow, blue and green feeders. We suggest that green feeders may be simultaneously marketable and attractive to foraging birds.

Weight-change across parities and/or current BMI may influence maternal and fetal morbidity and requires to be differentiated to better inform weight-management guidance.Direction, pattern and magnitude of weight-change across three consecutive parities and thereby two inter-pregnancy periods was described in 5079 women. The association between inter-pregnancy weight-change versus current BMI and adverse maternal events, SGA-birth and preterm delivery at second and third pregnancy were investigated by logistic regression.More women gained weight across the defined childbearing period than lost it, with ~35% of normal and overweight women gaining sufficient weight to move up a BMI-category. Nine patterns of weight-change were defined across two inter-pregnancy periods and 50% of women remained weight-stable throughout (within 2BMI units/period). Women who were overweight/obese at first pregnancy had higher risk of substantial weight-gain and loss (>10kg) during each of two inter-pregnancy periods. Inter-pregnancy weight-gain (> 2BMI units) between first and second pregnancy increased the risk of maternal morbidity (1or more event of hypertensive disease, caesarean-section, thromboembolism) at second pregnancy, while weight-loss (>2BMI units) increased the risk of SGA-birth. Similarly, increased risk of maternal morbidity at the third pregnancy was influenced by weight-gain during both inter-pregnancy periods but not by current BMI-category. Both weight-gain between first and second pregnancy, and being overweight/obese by third pregnancy protected the fetus against SGA-birth whereas weight-loss between second and third pregnancy doubled the SGA risk.Half the women studied exhibited significant weight-fluctuations. This influenced their risk of maternal morbidity and SGA-birth at second and third pregnancy.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). The clinical and neurochemical features of LRRK2-linked PD are similar to idiopathic disease although neuropathology is somewhat heterogeneous. Dominant mutations in LRRK2 precipitate neurodegeneration through a toxic gain-of-function mechanism which can be modeled in transgenic mice overexpressing human LRRK2 variants. A number of LRRK2 transgenic mouse models have been developed that display abnormalities in dopaminergic neurotransmission and alterations in tau metabolism yet without consistently inducing dopaminergic neurodegeneration. To directly explore the impact of mutant LRRK2 on the nigrostriatal dopaminergic pathway, we developed conditional transgenic mice that selectively express human R1441C LRRK2 in dopaminergic neurons from the endogenous murine ROSA26 promoter. The expression of R1441C LRRK2 does not induce the degeneration of substantia nigra dopaminergic neurons or striatal dopamine deficits in mice up to 2 years of age, and fails to precipitate abnormal protein inclusions containing alpha-synuclein, tau, ubiquitin or autophagy markers (LC3 and p62). Furthermore, mice expressing R1441C LRRK2 exhibit normal motor activity and olfactory function with increasing age. Intriguingly, the expression of R1441C LRRK2 induces age-dependent abnormalities of the nuclear envelope in nigral dopaminergic neurons including reduced nuclear circularity and increased invaginations of the nuclear envelope. In addition, R1441C LRRK2 mice display increased neurite complexity of cultured midbrain dopaminergic neurons. Collectively, these novel R1441C LRRK2 conditional transgenic mice reveal altered dopaminergic neuronal morphology with advancing age, and provide a useful tool for exploring the pathogenic mechanisms underlying the R1441C LRRK2 mutation in PD.

"Tell me about your research." How does one begin to convey the importance of our life's work--our research? Enter stage right, Research-based Theatre, an innovative, arts-based methodology that takes research data and brings it to life, by showing, rather than telling. In this article, we tell the story of how Research-based Theatre first came to be, and why it is especially well suited to the contemporary challenge of showcasing diverse and marginalized voices. We also share a short scene that illustrates the methodology in practice. We conclude by offering ways Research-based Theatre can be a meaningful approach for pedagogy and community-engaged initiatives.

ABSTRACT Spiroplasma bacteria are highly motile bacteria with no cell wall and a helical morphology. This clade includes many vertically transmitted insect endosymbionts, including Spiroplasma poulsonii, a natural endosymbiont of Drosophila melanogaster. S. poulsonii bacteria are mainly found in the hemolymph of infected female flies and exhibit efficient vertical transmission from mother to offspring. As is the case for many facultative endosymbionts, S. poulsonii can manipulate the reproduction of its host; in particular, S. poulsonii induces male killing in Drosophila melanogaster. Here, we analyze the morphology of S. poulsonii obtained from the hemolymph of infected Drosophila. This endosymbiont was not only found as long helical filaments, as previously described, but was also found in a Y-shaped form. The use of electron microscopy, immunogold staining of the FtsZ protein, and antibiotic treatment unambiguously linked the Y shape of S. poulsonii to cell division. Observation of the Y shape in another Spiroplasma, S. citri, and anecdotic observations from the literature suggest that cell division by longitudinal scission might be prevalent in the Spiroplasma clade. Our study is the first to report the Y-shape mode of cell division in an endosymbiotic bacterium and adds Spiroplasma to the so far limited group of bacteria known to utilize this cell division mode. IMPORTANCE Most bacteria rely on binary fission, which involves elongation of the bacteria and DNA replication, followed by splitting into two parts. Examples of bacteria with a Y-shape longitudinal scission remain scarce. Here, we report that Spiroplasma poulsonii, an endosymbiotic bacterium living inside the fruit fly Drosophila melanogaster, divide with the longitudinal mode of cell division. Observations of the Y shape in another Spiroplasma, S. citri, suggest that this mode of scission might be prevalent in the Spiroplasma clade. Spiroplasma bacteria are wall-less bacteria with a distinctive helical shape, and these bacteria are always associated with arthropods, notably insects. Our study raises the hypothesis that this mode of cell division by longitudinal scission could be linked to the symbiotic mode of life of these bacteria.

Women with specific adverse pregnancy outcomes in their first pregnancy may be receptive to inter-pregnancy weight management guidance aimed at preventing these complications reoccurring in subsequent pregnancies. Thus the association between inter-pregnancy weight change and the risk of recurrent pregnancy complications at the second pregnancy was investigated in a retrospective cohort study of 24,520 women with their first-ever and second consecutive deliveries in Aberdeen using logistic regression. Compared with women who were weight stable, weight loss (>2BMI units) between pregnancies was associated with an increased risk of recurrent small for gestational age (SGA) birth and elective Cesarean-section, and was protective against recurrent pre-eclampsia, placental oversize and large for gestational age (LGA) birth. Conversely weight gain (>2BMI units) between pregnancies increased the risk of recurrent gestational hypertension, placental oversize and LGA birth and was protective against recurrent low placental weight and SGA birth. The relationships between weight gain, and placental and birth weight extremes were evident only in women with a healthy weight at first pregnancy (BMI

It has been suggested that the research priorities of those funding and performing research in transplantation may differ from those of end service users such as patients, carers and healthcare professionals involved in day-to-day care. The Kidney Transplant Priority Setting Partnership (PSP) was established with the aim of involving all stakeholders in prioritising future research in the field.The PSP methodology is as outlined by the James Lind Alliance. An initial survey collected unanswered research questions from patients, carers and clinicians. Duplicate and out-of-scope topics were excluded and the existing literature searched to identify topics answered by current evidence. An interim prioritisation survey asked patients and professionals to score the importance of the remaining questions to create a ranked long-list. These were considered at a final consensus workshop using a modified nominal group technique to agree a final top ten.The initial survey identified 497 questions from 183 respondents, covering all aspects of transplantation from assessment through to long-term follow-up. These were grouped into 90 unanswered "indicative" questions. The interim prioritisation survey received 256 responses (34.8% patients/carers, 10.9% donors and 54.3% professionals), resulting in a ranked list of 25 questions that were considered during the final workshop. Participants agreed a top ten priorities for future research that included optimisation of immunosuppression (improved monitoring, choice of regimen, personalisation), prevention of sensitisation and transplanting the sensitised patient, management of antibody-mediated rejection, long-term risks to live donors, methods of organ preservation, induction of tolerance and bioengineering of organs. There was evidence that patient and carer involvement had a significant impact on shaping the final priorities.The final list of priorities relates to all stages of the transplant process, including access to transplantation, living donation, organ preservation, post-transplant care and management of the failing transplant. This list of priorities will provide an invaluable resource for researchers and funders to direct future activity.

There is no single instrument that can sample quantitatively the complete spectrum of pelagic organisms, or even all the components of zooplankton. Mesh size is the main factor affecting species selectivity in the Continuous Plankton Recorder (CPR), implying a need to use multiple net systems to fully characterize a community. The spatial distribution of copepod communities in the water masses of the western and eastern sectors of Drake Passage were studied using, respectively, a CPR and a Pump Net onboard system. For this purpose, and assuming that copepod community size structures of each of the three water masses were similar in both the sectors studied, the possibility of complementing CPR results using a Pump-Net onboard system was evaluated. The latter system allows the estimation of absolute abundances and has the advantage of solving two problems associated with CPR, namely mesh clogging and low catching efficiency. The contribution of the nauplius forms and species accurately identified with both samplers was analyzed. Although Oithona similis dominated both communities, in the western sector small species made a greater contribution than Calanus simillimus, the opposite being true for the eastern sector. Nauplii and early copepodite stages of O. similis were missing from the CPR samples and represented between 69 and 79% of total copepod communities, whereas small calanoid copepods, C. simillimus copepodites and later stages of O. similis were inaccurately sampled by the CPR and represented between 14 and 18% of the copepod community. Hence, the Pump Net sampler is useful for complementing the semi-quantitative information of the CPR and for its calibration.Não há um único instrumento que possa efetuar uma amostragem quantitativa completa para o espectro de organismos pelágicos, ou mesmo, para todos os componentes do zooplâncton. O tamanho da malha é o principal fator que afeta a seletividade de espécies no Registro Contínuo de Plâncton (CPR). Neste trabalho, estudamos a distribuição espacial das comunidades da copépode nas massas de água registradas nos setores ocidentais e orientais da Passagem de Drake, usando um CPR e um equipamento de amostragem que consiste em uma bomba de sucção instalada a uma rede de malha de 20 µm, respectivamente. Para este fim, e supondo que o tamanho das estruturas da comunidade de Copépodes de cada uma das três massas de água são similares em ambos setores estudados, foi avaliada a possibilidade de complementar resultados obtidos com o uso de CPR usando à bordo o sistema de bomba de sucção-rede. Este sistema permite a avaliação da abundância absoluta e possui a vantagem de resolver dois problemas associados à CPR, que são o assoreamento da rede e a baixa eficiência de captura. A contribuição das formas nauplius e das espécies identificadas com os dois amostradores, foram analisadas. Embora Oithona similis dominasse ambas as comunidades no setor ocidental, pequenas espécies de calanóides apresentaram contribuição mais elevada do que Calanus simillimus, enquanto o inverso foi verdadeiro para o setor oriental. Nauplii e estágios iniciais de copepoditos de O. similis faltaram nas amostras de CPR e representaram entre 69-79% das comunidade total de copépode, enquanto as densidades de pequenos calanódes e copepoditos de C. simillimus e estágios posteriores do O. similis foram imprecisamente estimadas por meio de CPR e representaram entre 14 e 18% da comunidade copépodes. Portanto, o sistema de bomba de sucção-rede é útil para complementar informações semi-quantitativas de CPR e sua calibração.

"Southern Ocean Continuous Plankton Recorder (SO-CPR) Standards Workshop: SCAR Expert Group on CPR Research" was held at the National Institute of Polar Research (NIPR) on 22-26 November 2011. Twelve participants from four countries attended. The purposes of the workshop were to ensure that consistent and high standards of species identification, methodology, and data quality were being maintained amongst all participants and laboratories in the SO-CPR survey, and to discuss future contributions of the SO-CPR program to a global CPR network. The first three and a half days of the workshop were focused on assessing the accuracy and consistency of species identifications. We concluded that our species identifications and procedures are accurate and uniform, and that the SO-CPR database is of the highest possible standard. Certain taxonomic criteria developed at the workshop will be described in a new laboratory procedures manual. Four major gaps in the database (spatial, temporal, taxonomic, and data analysis gaps) were identified and discussed. Participants concurred that there should be more regular workshops to ensure that the high standards of the SO-CPR program are maintained.

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are characterized by progressive neurodegeneration resulting in widespread brain atrophy. Each form is assumed to be the consequence of some universal intracellular event; however, time course studies on the cerebral cortex of a sheep model of the CLN6 form revealed distinct regional neurodegeneration preceded by regional glial activation, spreading from quite localized foci. Previous neurological investigations have concentrated on obviously affected cortical functions. This study investigated the impact of ovine CLN6 NCL on a subcortical structure and function, the discrete gonadotrophin-releasing hormone (GnRH) secreting neurons of the hypothalamus, and the effect of changes in the neuroendocrine system on reproductive efficiency and embryonic development. The number of immunopositive GnRH neurons in the hypothalamus and median eminence of affected sheep was reduced by 80%, but the rest of the hypothalamus showed no changes or atrophy. This specific loss of neuron type was not accompanied by either microglial or astrocyte activation, which was absent from the hypothalamus and was not associated with cell-type-specific storage body accumulation. Ovarian responsiveness to follicle stimulating hormone, ovulation rates, sperm production, fertilization rates, embryonic development, and reproductive efficiency were sub-par but reproduction was still functional. This remains when the sheep are profoundly blind. We conclude that physiological functionality and connectivity, not genotype, determine neuron fate in CLN6 NCL.

IntroductionAvailable evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown.MethodsElectronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission.ResultsCurrent (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97).ConclusionsFormer but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers.ImplicationsPrior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited neurodegenerative diseases. Sheep affected with the CLN6 form provide a valuable model to investigate underlying disease mechanisms from preclinical stages. Excitatory neuron loss in these sheep is markedly regional, localized early reactive changes accurately predicting neuron loss and subsequent symptom development. This investigation of GABAergic interneuron loss revealed similar regional effects that correlate with symptoms.Loss of parvalbumin positive neurons from the affected cortex was apparent at four months and became profound by 19 months, as was somatostatin positive neuron loss to a lesser extent. Conversely calbindin and neuropeptide Y positive neurons were relatively preserved and calretinin staining temporarily increased. Staining of subcortical regions was more intense but subcortical architecture remained relatively intact. Discrete subcortical changes followed from cortical changes in interconnected regions. These data highlight cellular location and interconnectivity as the major determinants of neuron survival, rather than phenotype.

Batten disease (neuronal ceroid lipofuscinoses, NCLs) are a group of inherited childhood diseases that result in severe brain atrophy, blindness and seizures, leading to premature death. To date, eight different genes have been identified, each associated with a different form. Linkage analysis indicated a CLN5 form in a colony of affected New Zealand Borderdale sheep. Sequencing studies established the disease-causing mutation to be a substitution at a consensus splice site (c.571+1G>A), leading to the excision of exon 3 and a truncated putative protein. A molecular diagnostic test has been developed based on the excision of exon 3. Sequence alignments support the gene product being a soluble lysosomal protein. Western blotting of isolated storage bodies indicates the specific storage of subunit c of mitochondrial ATP synthase. This flock is being expanded as a large animal model for mechanistic studies and trial therapies.

Analysis of brain ultrastructure using electron microscopy typically relies on chemical fixation. However, this is known to cause significant tissue distortion including a reduction in the extracellular space. Cryo fixation is thought to give a truer representation of biological structures, and here we use rapid, high-pressure freezing on adult mouse neocortex to quantify the extent to which these two fixation methods differ in terms of their preservation of the different cellular compartments, and the arrangement of membranes at the synapse and around blood vessels. As well as preserving a physiological extracellular space, cryo fixation reveals larger numbers of docked synaptic vesicles, a smaller glial volume, and a less intimate glial coverage of synapses and blood vessels compared to chemical fixation. The ultrastructure of mouse neocortex therefore differs significantly comparing cryo and chemical fixation conditions.

The genus Mycetarotes is a fungus-growing ant (Formicidae: Myrmicinae: Attini) mostly recorded south of the Amazon: in southeastern Brazil, Paraguay, and northern Argentina. Here we report the first record of this genus in Colombia: M. parallelus (Emery, 1906). We collected the specimen using pitfall taps in oil palm plantations. The discovery of this species represents a significant range extension for this genus.

Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR–ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited neurodegenerative diseases characterized by gross brain atrophy, blindness, and intracellular accumulation of lysosome-derived storage bodies. A CLN6 form in sheep is studied as a large animal model of the human diseases. This study describes neuropathological changes in brains from presymptomatic affected sheep. Activated astrocytes and focal clusters of activated microglia were present in outer layers of occipital and somatosensory cortical regions as early as 12 days of age, together with activated perivascular macrophages. Astrocytic activation and progressive transformation of microglia to brain macrophages preceded neurodegeneration and spread to different cortical areas, most prominently in regions associated with clinical symptoms. In contrast, storage body accumulation was much more evenly spread across regions. These data support suggestions that neurodegeneration and storage body accumulation may be independent manifestations of CLN6 mutation and indicate that glial cell activation may be an important mediator in pathogenesis.

BackgroundThere is mixed evidence about the relations of current versus past cancer with severe COVID-19 outcomes and how they vary by patient and cancer characteristics.MethodsElectronic health record data of 104,590 adult hospitalized patients with COVID-19 were obtained from 21 United States health systems from February 2020 through September 2021. In-hospital mortality and ICU admission were predicted from current and past cancer diagnoses. Moderation by patient characteristics, vaccination status, cancer type, and year of the pandemic was examined.Results6.8% of the patients had current (n = 7,141) and 6.5% had past (n = 6,749) cancer diagnoses. Current cancer predicted both severe outcomes but past cancer did not; adjusted odds ratios (aOR) for mortality were 1.58 [95% confidence interval (CI), 1.46-1.70] and 1.04 (95% CI, 0.96-1.13), respectively. Mortality rates decreased over the pandemic but the incremental risk of current cancer persisted, with the increment being larger among younger vs. older patients. Prior COVID-19 vaccination reduced mortality generally and among those with current cancer (aOR, 0.69; 95% CI, 0.53-0.90).ConclusionsCurrent cancer, especially among younger patients, posed a substantially increased risk for death and ICU admission among patients with COVID-19; prior COVID-19 vaccination mitigated the risk associated with current cancer. Past history of cancer was not associated with higher risks for severe COVID-19 outcomes for most cancer types.ImpactThis study clarifies the characteristics that modify the risk associated with cancer on severe COVID-19 outcomes across the first 20 months of the COVID-19 pandemic. See related commentary by Egan et al., p. 3.

BackgroundThe Cancer Center Cessation Initiative (C3I) is a National Cancer Institute (NCI) Cancer Moonshot Program that supports NCI-designated cancer centers developing tobacco treatment programs for oncology patients who smoke. C3I-funded centers implement evidence-based programs that offer various smoking cessation treatment components (e.g., counseling, Quitline referrals, access to medications). While evaluation of implementation outcomes in C3I is guided by evaluation of reach and effectiveness (via RE-AIM), little is known about technical efficiency-i.e., how inputs (e.g., program costs, staff time) influence implementation outcomes (e.g., reach, effectiveness). This study demonstrates the application of data envelopment analysis (DEA) as an implementation science tool to evaluate technical efficiency of C3I programs and advance prioritization of implementation resources.MethodsDEA is a linear programming technique widely used in economics and engineering for assessing relative performance of production units. Using data from 16 C3I-funded centers reported in 2020, we applied input-oriented DEA to model technical efficiency (i.e., proportion of observed outcomes to benchmarked outcomes for given input levels). The primary models used the constant returns-to-scale specification and featured cost-per-participant, total full-time equivalent (FTE) effort, and tobacco treatment specialist effort as model inputs and reach and effectiveness (quit rates) as outcomes.ResultsIn the DEA model featuring cost-per-participant (input) and reach/effectiveness (outcomes), average constant returns-to-scale technical efficiency was 25.66 (SD = 24.56). When stratified by program characteristics, technical efficiency was higher among programs in cohort 1 (M = 29.15, SD = 28.65, n = 11) vs. cohort 2 (M = 17.99, SD = 10.16, n = 5), with point-of-care (M = 33.90, SD = 28.63, n = 9) vs. no point-of-care services (M = 15.59, SD = 14.31, n = 7), larger (M = 33.63, SD = 30.38, n = 8) vs. smaller center size (M = 17.70, SD = 15.00, n = 8), and higher (M = 29.65, SD = 30.99, n = 8) vs. lower smoking prevalence (M = 21.67, SD = 17.21, n = 8).ConclusionMost C3I programs assessed were technically inefficient relative to the most efficient center benchmark and may be improved by optimizing the use of inputs (e.g., cost-per-participant) relative to program outcomes (e.g., reach, effectiveness). This study demonstrates the appropriateness and feasibility of using DEA to evaluate the relative performance of evidence-based programs.

The first deployment of a Continuous Plankton Recorder (CPR) on board the icebreaker Shirase was conducted during the 41st Japanese Antarctic Research Expedition (JARE) in 1999/2000 austral summer in the Indian sector of the Antarctic Ocean. The CPR was towed horizontally at approximately 10m depth while the Shirase was steaming at about 14 knots across the Polar Front (PF). Mean total abundance of zooplankton for horizontal five nautical mile sample units was 168.1(SD : ±117.18) individuals with the maximum of 456 individuals. Zooplanktons were counted for 34 categories of species/taxa. Copepods occupied more than 90% of the total abundance in numbers. Oithona spp. was the most dominant group among copepods, representing 59% of the total zooplankton. Other numerically important categories were small-sized calanoids (copepodites and adults; 18.4%), and copepodites of Calanoides acutus and Calanus simillimus (8.2%). Latitudinal change of zooplankton abundance coincided with increasing/decreasing tends of temperature and salinity. Two different zooplankton assemblages were identified by cluster analysis and these assemblages seem to be closely related to different water characteristics, such as the of PF and areas of cold water masses. CPR is considered to be an ideal tool for long term monitoring of surface zooplankton communities.

Bacterial polyketides are highly biologically active molecules that are frequently used as drugs, particularly as antibiotics and anticancer agents, thus the discovery of new polyketides is of major interest. Since the 1980s discovery of polyketides has slowed dramatically due in large part to the repeated rediscovery of known compounds. While recent scientific and technical advances have improved our ability to discover new polyketides, one key area has been under addressed, namely the distribution of polyketide-producing bacteria in the environment. Identifying environments where producing bacteria are abundant and diverse should improve our ability to discover (bioprospect) new polyketides. This review summarizes for the bioprospector the state-of-the-field in terrestrial microbial ecology. It provides insight into the scientific and technical challenges limiting the application of microbial ecology discoveries for bioprospecting and summarizes key developments in the field that will enable more effective bioprospecting. The major recent efforts by researchers to sample new environments for polyketide discovery is also reviewed and key emerging environments such as insect associated bacteria, desert soils, disease suppressive soils, and caves are highlighted. Finally strategies for taking and characterizing terrestrial samples to help maximize discovery efforts are proposed and the inclusion of non-actinomycetal bacteria in any terrestrial discovery strategy is recommended.

This is a case study of a female patient diagnosed with superficial spreading melanoma who decided to treat the lesion by the application of a preparation known as black salve. Persistence of the melanoma was documented five years later with subsequent evidence of metastatic spread to the regional lymph nodes, lungs, liver, subcutaneous tissues and musculature. A literature search has revealed one other case study of the use of black salve for the treatment of melanoma.

In animals carotenoids show biological activity unrelated to vitamin A that has been considered to arise directly from the behavior of the parent compound, particularly as an antioxidant. However, the very property that confers antioxidant activity on some carotenoids in plants also confers susceptibility to oxidative transformation. As an alternative, it has been suggested that carotenoid oxidative breakdown or metabolic products could be the actual agents of activity in animals. However, an important and neglected aspect of the behavior of the highly unsaturated carotenoids is their potential to undergo addition of oxygen to form copolymers. Recently we reported that spontaneous oxidation of ß-carotene transforms it into a product dominated by ß-carotene-oxygen copolymers. We now report that the polymeric product is biologically active. Results suggest an overall ability to prime innate immune function to more rapidly respond to subsequent microbial challenges. An underlying structural resemblance to sporopollenin, found in the outer shell of spores and pollen, may allow the polymer to modulate innate immune responses through interactions with the pattern recognition receptor system. Oxygen copolymer formation appears common to all carotenoids, is anticipated to be widespread, and the products may contribute to the health benefits of carotenoid-rich fruits and vegetables.

ObjectiveExtremity venous aneurysms result in the risk of pulmonary embolism (PE) and chronic venous insufficiency. At present, owing to the rarity of these aneurysms, no consensus for their treatment has been established. The purpose of the present study was to review the presentation, natural history, and contemporary management of extremity venous aneurysms.MethodsWe performed a retrospective, multi-institutional review of all patients with extremity venous aneurysms treated from 2008 to 2018. A venous aneurysm was defined as saccular or fusiform with an aneurysm/vein ratio of >1.5.ResultsA total of 66 extremity aneurysms from 11 institutions were analyzed, 40 of which were in a popliteal location, 14 iliofemoral, and 12 in an upper extremity or a jugular location. The median follow-up was 27 months (range, 0-120 months). Of the 40 popliteal venous aneurysms, 8 (20%) had presented with deep vein thrombosis (DVT) or PE, 13 (33%) had presented with pain, and 19 had been discovered incidentally. The mean size of the popliteal venous aneurysms presenting with DVT or PE was larger than that of those presenting without thromboembolism (3.8 cm vs 2.5 cm; P = .003). Saccular aneurysm morphology in the lower extremity was associated with thromboembolism (30% vs 9%; P = .046) and fusiform aneurysm morphology with a thrombus burden >25% (45% vs 3%). Patients presenting with thromboembolism were more likely to have had a thrombus burden >25% in their lower extremity venous aneurysm compared with those who had presented without thromboembolism (70% vs 9%). Approximately half of all the patients underwent immediate intervention, and half were managed with observation or antithrombotic regimen. In the non-operative cohort, three patients subsequently developed a DVT. Eight patients in the medically managed cohort went on to require surgical intervention. Of the 12 upper extremity venous aneurysms, none had presented with DVT or PE, and only 2 (17%) had presented with pain. Of the 66 patients in the entire cohort, 41 underwent surgical intervention. The most common indication was the absolute aneurysm size. Nine patients had undergone surgery because of a DVT or PE, and 11 for pain or extremity swelling. The most common surgery was aneurysmorrhaphy in 21 patients (53%), followed by excision and ligation in 14 patients (35%). Five patients (12%) had undergone interposition bypass grafting. A postoperative hematoma requiring reintervention was the most common complication, occurring in three popliteal vein repairs and one iliofemoral vein repair. None of the patients, treated either surgically or medically, had reported post-thrombotic complications during the follow-up period.ConclusionsLarge lower extremity venous aneurysms and saccular aneurysms with thrombus >25% of the lumen are more likely to present with thromboembolic complications. Surgical intervention for lower extremity venous aneurysms is indicated to reduce the risk of venous thromboembolism (VTE) and the need for continued anticoagulation. Popliteal aneurysms >2.5 cm and all iliofemoral aneurysms should be considered for repair. Upper extremity aneurysms do not have a significant risk of VTE and warrant treatment primarily for symptoms other than VTE.

This document provides recommendations regarding the role of imaging in the staging and follow-up of esophageal cancer. For initial clinical staging, locoregional extent and nodal disease are typically assessed with esophagogastroduodenoscopy and esophageal ultrasound. FDG-PET/CT or CT of the chest and abdomen is usually appropriate for use in initial clinical staging as they provide additional information regarding distant nodal and metastatic disease. The detection of metastatic disease is critical in the initial evaluation of patients with esophageal cancer because it will direct patients to a treatment pathway centered on palliative radiation rather than surgery. For imaging during treatment, particularly neoadjuvant chemotherapy, FDG-PET/CT is usually appropriate, because some studies have found that it can provide information regarding primary lesion response, but more importantly it can be used to detect metastases that have developed since the induction of treatment. For patients who have completed treatment, FDG-PET/CT or CT of the chest and abdomen is usually appropriate for evaluating the presence and extent of metastases in patients with no suspected or known recurrence and in those with a suspected or known recurrence. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.