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Abstract Background Efficient and scalable solutions are needed to identify patients who qualify for germline cancer genetic testing. We evaluated the clinical validity of a brief, patient-administered hereditary cancer risk assessment digital tool programmed to assess if patients meet criteria for germline genetic testing, based on personal and family history, and in line with national guidelines. Methods We applied the tool to cases seen in a nationwide telehealth genetic counseling practice. Validity of the tool was evaluated by comparing the tool’s assessment to that of the genetic counselor who saw the patient. Patients’ histories were extracted from genetic counselor-collected pedigrees and input into the tool by the research team to model how a patient would complete the tool. We also validated the tool’s assessment of which specific aspects of the personal and family history met criteria for genetic testing. Descriptive statistics were used. Results Of the 152 cases (80% female, mean age 52.3), 56% had a personal history of cancer and 66% met genetic testing criteria. The tool and genetic counselor agreed in 96% of cases. Most disagreements (4/6; 67%) occurred because the genetic counselor’s assessment relied on details the tool was not programmed to collect since patients typically don’t have access to the relevant information (pathology details, risk models). We also found complete agreement between the tool and research team on which specific aspects of the patient’s history met criteria for genetic testing. Conclusion We observed a high level of agreement with genetic counselor assessments, affirming the tool’s clinical validity in identifying individuals for hereditary cancer predisposition testing and its potential for increasing access to hereditary cancer risk assessment.

Abstract Background Mosquitoes in nature may acquire multiple bloodmeals (BMs) over the course of their lifetime; however, incorporation of frequent feeding behavior in laboratory vector competence studies is rarely done. We have previously shown that acquisition of a second non-infectious BM can enhance early dissemination of Zika virus (ZIKV), dengue virus, and chikungunya virus in Aedes aegypti and ZIKV in Aedes albopictus mosquitoes, yet it is unknown if other taxonomically-diverse virus-vector pairings show a similar trend under a sequential feeding regimen. Methods To test this, we evaluated the impact of a second noninfectious BM on the vector competence of Aedes aegypti and Anopheles quadrimaculatus for Mayaro virus, Culex quinquefasciatus for West Nile virus, Aedes triseriatus for La Crosse virus, and Aedes aegypti for Oropouche virus (OROV). Female mosquitoes were fed BMs containing these viruses and half of them were given a second noninfectious BM at 3 or 4-days post infection. Mosquitoes were harvested at various time points and assayed for virus infection in bodies and disseminated infection in legs by performing reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays. Results We found that a second noninfectious BM had no impact on midgut infection rates but increased virus dissemination for all but one of the virus-vector pairings- Ae. aegypti and OROV. Unlike the other arboviruses under consideration, which are strictly mosquito-borne, biting midges (Culicoides spp.) serve as the main vector of OROV and this virus rarely disseminated to the mosquito leg tissue in our study. Conclusions Taken together, our findings show that sequential blood feeding enhances virus dissemination across diverse arbovirus-vector pairings, representing three mosquito genera and virus families, but a second BM was insufficient to overcome a strong midgut virus escape barrier in a nonnatural virus–vector pairing. Graphical Abstract

Abstract Habitual short sleep durations are associated with several cardiovascular diseases. Experimental research generally supports these findings as metrics of arterial function are impaired after complete deprivation of sleep and after longer periods of partial sleep restriction. The acute influence of a single instance of partial sleep restriction (PSR), however, has not been defined. We evaluated arterial structure and function among 32 university‐aged participants on two occasions: once after normal habitual sleep (NS), and again the morning after an acute partial sleep restriction (PSR) intervention involving only 3 h of sleep for a single night. Endothelial function was measured using ultrasonography at the brachial artery via flow‐mediated dilatation (FMD), and a ramp peak oxygen uptake test was used to evaluate cardiorespiratory fitness. Blood samples were collected from a subset of participants to investigate the influence of circulatory factors on cellular mechanisms implicated in endothelial function. Sleep duration was lower after a night of PSR compared to NS (P 0.05). Ex vivo cell culture results aligned with in vivo data, showing that acute PSR does not alter intracellular processes involved in endothelial function. No differences in arterial structure or function were observed between NS and acute PSR in healthy and young participants, and cardiorespiratory fitness does not modulate the arterial response to acute sleep restriction.

The neutron-rich rare isotope 190W is discussed as a candidate for a prolate-oblate transitional nucleus with maximum γ-softness. The collectivity of this isotope is assessed for the first time by the measurement of the reduced E2 transition probability of its first 2+ state to the ground state. The experiment employed the FAst TIming Array (FATIMA), comprised of 36 LaBr3(Ce) scintillators, which was part of the DESPEC setup at GSI, Darmstadt. The 41+ and 21+ states of 190W were populated subsequently to the decay of its 127(12) μs isomeric Jπ=10− state. The mean lifetime of the 21+ state was determined to be τ=274(28) ps, which corresponds to a B(E2;21+→01+) value of 95(10) W.u. The results motivated a revision of previous calculations within an energy-density functional-based interacting boson model-2 approach, yielding E2 transition properties and spectroscopic quadrupole moments for tungsten isotopes. From comparison to theory, the new data suggest that 190W is at the transition from prolate to oblate structure along the W isotopic chain, which had previously been discussed as a nuclear shape-phase transition.

Abstract Background Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. Results We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ~ 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. The tumour tissues were characterised by a 5–10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. This effect was correlated with gene activity, differential DNA methylation and changes in local occupancy of linker histone variants H1.4 and H1X. Conclusions Our study offers a novel resource of high-resolution nucleosome maps in breast cancer patients and reports for the first time the effect of systematic decrease of NRL in paired tumour versus normal breast tissues from the same patient. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient diagnostics, stratification and monitoring.

Lateral patellar dislocations are the second most common type of traumatic knee injury, accounting for approximately 2-3% of cases, the most common being anterior cruciate ligament (ACL) injury. There are several well-documented anatomical risk factors predisposing to patellofemoral instability for example: patella alta, trochlear dysplasia, ligamentous laxity, and genu valgum. Co-existing medial collateral ligament injury in cases of patellar dislocations in the absence of ACL injury is uncommon and infrequently reported in the literature. The authors present a case of a 14-year-old boy presenting with a left knee injury while playing football who was diagnosed on magnetic resonance imaging (MRI) with a transient lateral patellar dislocation, high-grade medial patellofemoral ligament (MPFL) injury and a full thickness (grade III) injury to the distal medial collateral ligament.

Calcific tendinopathy in the gluteus medius is uncommon and sporadically reported. It may be asymptomatic or present with acute or chronic pain. Pain is usually isolated to the lateral hip overlying the gluteal muscles or greater trochanter. We present a rare case of gluteus medius calcific tendonitis as a cause of severe anterior hip pain. Given the atypical local and clinical presentation these can be often misdiagnosed as septic arthritis or fracture which may lead to overtreatment and even unnecessary surgery. This article will detail the clinical presentation, imaging findings, and clinical course following treatment. This will facilitate the clinician in making a timely diagnosis and establishing an effective treatment course.

Abstract The Amplified Luminescent Proximity Homogenous Assay-linked Immunosorbent Assay (AlphaLISA) is known for detecting various protein targets; however, its ability to detect nucleic acid sequences is not well established. Here, the capabilities of the AlphaLISA technology were expanded to include direct detection of DNA (aka: oligo-Alpha) and was applied to the detection of Listeria monocytogenes. Parameters were defined that allowed the newly developed oligo-Alpha to differentiate L. monocytogenes from other Listeria species through the use of only a single nucleotide polymorphism within the 16S rDNA region. Investigations into the applicability of this assay with different matrices demonstrated its utility in both milk and juice. One remarkable feature of the oligo-Alpha is that greater sensitivity could be achieved through the use of multiple acceptor oligos compared to only a single acceptor oligo, even when only a single donor oligo was employed. Additional acceptor oligos were easily incorporated into the assay and a tenfold change in the detection limit was readily achieved, with detection limits of 250 attomole of target being recorded. In summary, replacement of antibodies with oligonucleotides allows us to take advantage of genotypic difference(s), which both expands its repertoire of biological markers and furthers its use as a diagnostic tool.

Reduced transition probabilities have been extracted between excited, yrast states in the N=Z+2 nucleus 94Pd. The transitions of interest were observed following decays of the Iπ=14+, Ex=2129-keV isomeric state, which was populated following the projectile fragmentation of a 124Xe primary beam at the GSI Helmholtzzentrum für Schwerionenforschung accelerator facility as part of FAIR Phase-0. Experimental information regarding the reduced E2 transition strengths for the decays of the yrast 8+ and 6+ states was determined following isomer-delayed Eγ1−Eγ2−△T2,1 coincidence method, using the LaBr3(Ce)-based FATIMA fast-timing coincidence gamma-ray array, which allowed direct determination of lifetimes of states in 94Pd using the Generalized Centroid Difference (GCD) method. The experimental value for the half-life of the yrast 8+ state of 755(106) ps results in a reduced transition probability of B(E2:8→+6+) = 205−25+34 e2fm4, which enables a precise verification of shell-model calculations for this unique system, lying directly between the N=Z line and the N=50 neutron shell closure. The determined B(E2) value provides an insight into the purity of (g9/2)n configurations in competition with admixtures from excitations between the (lower) N=3pf and (higher) N=4gds orbitals for the first time. The results indicate weak collectivity expected for near-zero quadrupole deformation and an increasing importance of the T=0 proton-neutron interaction at N=48.

Abstract Background Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. Results Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. Conclusion Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691

Arboviruses can emerge rapidly and cause explosive epidemics of severe disease. Some of the most epidemiologically important arboviruses, including dengue virus (DENV), Zika virus (ZIKV), Chikungunya (CHIKV) and yellow fever virus (YFV), are transmitted by Aedes mosquitoes, most notably Aedes aegypti and Aedes albopictus. After a mosquito blood feeds on an infected host, virus enters the midgut and infects the midgut epithelium. The virus must then overcome a series of barriers before reaching the mosquito saliva and being transmitted to a new host. The virus must escape from the midgut (known as the midgut escape barrier; MEB), which is thought to be mediated by transient changes in the permeability of the midgut-surrounding basal lamina layer (BL) following blood feeding. Here, we present a mathematical model of the within-mosquito population dynamics of DENV (as a model system for mosquito-borne viruses more generally) that includes the interaction of the midgut and BL which can account for the MEB. Our results indicate a dose-dependency of midgut establishment of infection as well as rate of escape from the midgut: collectively, these suggest that the extrinsic incubation period (EIP)-the time taken for DENV virus to be transmissible after infection-is shortened when mosquitoes imbibe more virus. Additionally, our experimental data indicate that multiple blood feeding events, which more closely mimic mosquito-feeding behavior in the wild, can hasten the course of infections, and our model predicts that this effect is sensitive to the amount of virus imbibed. Our model indicates that mutations to the virus which impact its replication rate in the midgut could lead to even shorter EIPs when double-feeding occurs. Mechanistic models of within-vector viral infection dynamics provide a quantitative understanding of infection dynamics and could be used to evaluate novel interventions that target the mosquito stages of the infection.

Summary: Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic Olaparib treatment of LNCaP and C4-2B cell lines. Here, we found that IGFBP3 is highly expressed in acquired (OlapR) and intrinsic (Rv1) models of Olaparib resistance. We show that IGFBP3 expression promotes Olaparib resistance by enhancing DNA repair capacity through activation of EGFR and DNA-PKcs. IGFBP3 depletion enhances efficacy of Olaparib by promoting DNA damage accumulation and subsequently, cell death in resistant models. Mechanistically, we show that silencing IGFBP3 or EGFR expression reduces cell viability and resensitizes OlapR cells to Olaparib treatment. Inhibition of EGFR by Gefitinib suppressed growth of OlapR cells and improved Olaparib sensitivity, thereby phenocopying IGFBP3 inhibition. Collectively, our results highlight IGFBP3 and EGFR as critical mediators of Olaparib resistance.

Immunomagnetic separation (IMS) techniques employing superparamagnetic particles can successfully isolate various components from mixtures. However, their utility can be limited for large-volume samples, viscous samples, or those containing a high density of particulate matter because of the need to generate high field gradients for particle recovery. Therefore, a new class of immunomagnetic particles was devised utilizing a single, macroscopic Pyrex spinbar conjugated with biorecognition elements to address these limitations. Advantages include an inherent capacity for effective mixing, an almost instantaneous recovery of the spinbar that can be performed without expensive equipment and with no loss of magnetic particles during processing, and reduced transfer of sample matrix. As a result, spinbars can provide an effective means for IMS with large-volume assays composed of complex matrices.

Abstract Background Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD. Results: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment. Conclusions Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 .

Abstract Background Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12–17 year], nine children [6–11 year], and seven infants/early child [1–5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores. Results All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p

Foodborne pathogens are a significant cause of illness, and infection with Shiga toxin-producing Escherichia coli (STEC) may lead to life-threatening complications. The current methods to identify STEC in meat involve culture-based, molecular, and proteomic assays and take at least four days to complete. This time could be reduced by using long-read whole-genome sequencing to identify foodborne pathogens. Therefore, the goal of this project was to evaluate the use of long-read sequencing to detect STEC in ground beef. The objectives of the project included establishing optimal sequencing parameters, determining the limit of detection of all STEC virulence genes of interest in pure cultures and spiked ground beef, and evaluating selective sequencing to enhance STEC detection in ground beef. Sequencing libraries were run on the Oxford Nanopore Technologies’ MinION sequencer. Optimal sequencing output was obtained using the default parameters in MinKNOW, except for setting the minimum read length to 1 kb. All genes of interest (eae, stx1, stx2, fliC, wzx, wzy, and rrsC) were detected in DNA extracted from STEC pure cultures within 1 h of sequencing, and 30× coverage was obtained within 2 h. All virulence genes were confidently detected in STEC DNA quantities as low as 12.5 ng. In STEC-inoculated ground beef, software-controlled selective sequencing improved virulence gene detection; however, several virulence genes were not detected due to high bovine DNA concentrations in the samples. The growth enrichment of inoculated meat samples in mTSB resulted in a 100-fold increase in virulence gene detection as compared to the unenriched samples. The results of this project suggest that further development of long-read sequencing protocols may result in a faster, less labor-intensive method to detect STEC in ground beef.

The combination of laboratory and semifield experiments, paired with surveillance data, demonstrate the natural timeline for mosquito diapause, highlighting the importance of latitude and population genetics.

The Asian tiger mosquito (Aedes albopictus) arrived in the USA in the 1980’s and rapidly spread throughout eastern USA within a decade. The predicted northern edge of its overwintering distribution on the East Coast of the USA roughly falls across New York, Connecticut, and Massachusetts, where the species has been recorded as early as 2000. It is unclear whether Ae. albopictus populations have become established and survive the cold winters in these areas or are recolonized every year. We genotyped and analyzed populations of Ae. albopictus from the northeast USA using 15 microsatellite markers and compared them with other populations across the country and to representatives of the major global genetic clades to investigate their connectivity and stability. Founder effects or bottlenecks were rare at the northern range of the Ae. albopictus distribution in the northeastern USA, with populations displaying high levels of genetic diversity and connectivity along the East Coast. There is no evidence of population turnover in Connecticut during the course of three consecutive years, with consistent genetic structure throughout this period. Overall, these results support the presence of established populations of Ae. albopictus in New York, Connecticut, and Massachusetts, successfully overwintering and migrating in large numbers. Given the stability and interconnectedness of these populations, Ae. albopictus has the potential to continue to proliferate and expand its range northward under mean warming conditions of climate change. Efforts to control Ae. albopictus in these areas should thus focus on vector suppression rather than eradication strategies, as local populations have become firmly established and are expected to reemerge every summer.

Abstract Effectiveness of mosquito larvicide active ingredients (AI), such as Lysinibacillus sphaericus, varies between species, yet little is known regarding how differential effectiveness manifests in larval communities in applied settings. To examine how differential effectiveness of L. sphaericus influences larval community dynamics, we performed two experiments. We performed a field experiment in which containers were seeded with a standardized nutrient treatment, mosquitoes colonized the containers, and then containers received one of three L. sphaericus applications. We then performed competition assays between Culex pipiens and Aedes albopictus in low nutrient environments using multiple interspecific ratios and the presence/absence of a low dose of L. sphaericus. Field results demonstrated elimination of Culex spp. from treated containers while container breeding Aedes spp. proliferated across all treatments. Lysinibacillus sphaericus did not influence competition between Cx. pipiens and Ae. albopictus, and the L. sphaericus application eliminated Cx. pipiens in all treatment replicates while survival of Ae. albopictus was similar between treated and untreated containers across interspecific ratios. Lysinibacillus sphaericus is an effective AI for control of Culex spp. However, different AIs should be utilized in habitats containing non-Culex genera while a mix of AIs should be utilized where coexistence of multiple genera is expected or confirmed.

Patients with multiple myeloma (MM) who experience early relapse within 12 months of therapy initiation are considered functional high-risk and represent an unmet need, needing better therapies to improve outcomes. The final IKEMA (clinicaltrials gov. identifier: NCT03275285) progression-free survival (PFS) analysis confirmed the significant PFS improvement reported at interim analysis with isatuximab (Isa) plus carfilzomib and dexamethasone (Kd; Isa-Kd) versus Kd in patients with relapsed MM (updated median PFS: 35.7 vs. 19.2 months; hazard ratio [HR] =0.58, 95% confidence interval [CI]: 0.42- 0.79). This IKEMA subgroup analysis examined efficacy and safety of Isa-Kd versus Kd in patients who experienced early (n=61 [Isa-Kd], n=46 [Kd]) vs. late relapse (n=104 [Isa-Kd], n=72 [Kd]). As expected, more aggressive features in baseline characteristics were observed in early relapse patients. Consistent with IKEMA overall population results, median PFS (early relapse: 24.7 vs. 17.2 months, HR=0.662, 95% CI: 0.407-1.077; late relapse: 42.7 vs. 21.9 months, HR=0.542, 95% CI: 0.355- 0.826), minimal residual disease negativity (MRD−) (early relapse: 24.6% vs. 15.2%; late relapse: 37.5% vs. 16.7%), and MRD− complete response (≥CR) rates (early relapse: 18.0% vs. 10.9%; late relapse: 30.8% vs. 13.9%) were higher with Isa-Kd versus Kd, respectively, in both early and late relapse patients. Grade ≥3, serious treatment-emergent adverse events, and death rates were higher in the late relapse Isa-Kd arm. However, the numbers of deaths were low and treatment exposure was significantly longer in Isa-Kd versus Kd late relapse patients. These results support the addition of Isa to Kd as standardof- care therapy for relapsed and/or refractory MM regardless of relapse timing.

The role of entrance channel parameters such as Z²∕A, charge asymmetry αz, mass-asymmetry (ηA), charge product (Z1Z2), mean fissility Xm, Coulomb interaction parameter and (N-Z)-(N-Z) on compound nucleus formation of actinide nuclei using heavy ion fusion reactions were investigated. For the formation of compound nuclei, the considered atomic number range of the projectile varies between 5 ≤ Z ≤ 14 and the mass number lies between 10 ≤ 𝐴 ≤ 34. Similarly, the studied target atomic number varies between 78 ≤ Z ≤ 92 and the mass number range is 197 ≤ A ≤ 238. Among these entrance channel parameters, PCN is more systematic for (N-Z)(N+Z), Z²∕A and az. In addition to entrance channel parameters, the Ecm and Ebas also play a significant role in the prediction of PCN. The proposed empirical formulae are applicable to the compound nuclei from Fr to Sg. These findings are significant for the PCN prediction from Fr to Sg. [ABSTRACT FROM AUTHOR]

Abstract Background Item response theory (IRT) methods for addressing differential item functioning (DIF) can detect group differences in responses to individual items (e.g., bias). IRT and DIF-detection methods have been used increasingly often to identify bias in cognitive test performance by characteristics (DIF grouping variables) such as hearing impairment, race, and educational attainment. Previous analyses have not considered the effect of missing data on inferences, although levels of missing cognitive data can be substantial in epidemiologic studies. Methods We used data from Visit 6 (2016–2017) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 3,580) to explicate the effect of artificially imposed missing data patterns and imputation on DIF detection. Results When missing data was imposed among individuals in a specific DIF group but was unrelated to cognitive test performance, there was no systematic error. However, when missing data was related to cognitive test performance and DIF group membership, there was systematic error in DIF detection. Given this missing data pattern, the median DIF detection error associated with 10%, 30%, and 50% missingness was -0.03, -0.08, and -0.14 standard deviation (SD) units without imputation, but this decreased to -0.02, -0.04, and -0.08 SD units with multiple imputation. Conclusions Incorrect inferences in DIF testing have downstream consequences for the use of cognitive tests in research. It is therefore crucial to consider the effect and reasons behind missing data when evaluating bias in cognitive testing.

Abstract Background Arthropod-borne viruses (arboviruses) impose a major health and economic burden on human populations globally, with mosquitoes serving as important vectors. Measuring the ability of a mosquito population to transmit an arbovirus is important in terms of evaluating its public health risk. In the laboratory, a variety of methods are used to estimate arboviral transmission by mosquitoes, including indirect methods involving viral detection from mosquito saliva collected by forced salivation. The accuracy of indirect methods to estimate arbovirus transmission to live animal hosts has not been fully evaluated. Methods We compared three commonly used proxies of arboviral transmission, namely, the presence of virus in mosquito legs, in salivary glands (SG) and in saliva collected in capillary tubes using forced salivation, with direct transmission estimates from mosquitoes to suckling mice. We analyzed five vector-virus combinations, including Aedes aegypti infected with chikungunya virus, West Nile virus and Zika virus; Culex quinquefasciatus infected with West Nile virus; and Aedes triseriatus infected with La Crosse virus. Results Comparatively, the methods of detecting virus infection in mosquito legs and in SG were equally accurate in predicting transmission. Overall, the presence of virus in mosquito legs was a more accurate predictor of transmission than the commonly implemented viral detection method using forced salivation into a capillary tube, and was subject to less technical variation. Conclusions These results suggest that, in general, forced salivation methods tend to underestimate virus transmission, and they provide confidence in the use of mosquito leg screens to evaluate the transmission potential of a mosquito population. Graphical Abstract

The cerebellum is involved in higher-order cognitive functions, e.g., learning and memory, and is susceptible to age-related atrophy. Yet, the cerebellum's role in age-related cognitive decline remains largely unknown. We investigated cross-sectional and longitudinal associations between cerebellar volume and verbal learning and memory. Linear mixed effects models and partial correlations were used to examine the relationship between changes in cerebellum volumes (total cerebellum, cerebellum white matter [WM], cerebellum hemisphere gray matter [GM], and cerebellum vermis subregions) and changes in verbal learning and memory performance among 549 Baltimore Longitudinal Study of Aging participants (2,292 visits). All models were adjusted by baseline demographic characteristics (age, sex, race, education), and APOE e4 carrier status. In examining associations between change with change, we tested an additional model that included either hippocampal (HC), cuneus, or postcentral gyrus (PoCG) volumes to assess whether cerebellar volumes were uniquely associated with verbal learning and memory. Cross-sectionally, the association of baseline cerebellum GM and WM with baseline verbal learning and memory was age-dependent, with the oldest individuals showing the strongest association between volume and performance. Baseline volume was not significantly associated with change in learning and memory. However, analysis of associations between change in volumes and changes in verbal learning and memory showed that greater declines in verbal memory were associated with greater volume loss in cerebellum white matter, and preserved GM volume in cerebellum vermis lobules VI-VII. The association between decline in verbal memory and decline in cerebellar WM volume remained after adjustment for HC, cuneus, and PoCG volume. Our findings highlight that associations between cerebellum volume and verbal learning and memory are age-dependent and regionally specific.

Abstract INTRODUCTION Sensory impairment (SI) is linked to cognitive decline, but its association with early cognitive impairment (ECI) is unclear. METHODS Sensory functions (vision, hearing, vestibular function, proprioception, and olfaction) were measured between 2012 and 2018 in 414 Baltimore Longitudinal Study of Aging (BLSA) participants (age 74 ± 9 years; 55% women). ECI was defined as 1 standard deviation below age‐, sex‐, race‐, and education‐specific mean performance in Card Rotations or California Verbal Learning Test immediate recall. Log binomial models (cross‐sectional analysis) and Cox regression models (time‐to‐event analysis) were used to examine the association between SI and ECI. RESULTS Cross‐sectionally, participants with ≥3 SI had twice the prevalence of ECI (prevalence ratio = 2.10, p = 0.02). Longitudinally, there was no significant association between SI and incident ECI over up to 6 years of follow‐up. DISCUSSION SI is associated with higher prevalence, but not incident ECI. Future studies with large sample sizes need to further elucidate the relationship between SI and ECI. Highlights Sensory impairment is associated with high prevalence of early cognitive impairment Multisensory impairment may pose a strong risk of early changes in cognitive function Identifying multisensory impairment may help early detection of dementia

The remarkable potential of the carbon allotrope graphene and its derivatives in developing hybrid nanofluids has sparked considerable interest among researchers. These carbon nanoparticles offer excellent opportunities to blend with various metal or metal oxide nanoparticle binders to improve their material properties. This study focuses on investigating the synthesis, characterization, and thermophysical properties of silver- (Ag-) infused GO aqueous hybrid nanofluids with various weight percentages (0.025, 0.05, and 0.1 wt.%) using environmentally friendly reducing and stabilizing agents. Characterization of the hybrid nanofluids was performed using XRD, SEM, EDX, a UV-visible spectrometer, a particle size analyzer, and FTIR techniques. The thermal conductivity and viscosity of the GO-Ag hybrid nanofluids were experimentally determined in the temperature range of 293 K–333 K. Notably, the results indicated that the nanofluids with a concentration of 0.1 wt.% exhibited the most significant enhancement in thermal conductivity, with improvements of 15.22% at 293 K and 31.19% at 333 K compared to the base fluid. A mathematical model was developed based on the thermal conductivity experimental results using the response surface methodology (RSM). Overall, the results suggest that the silver nanoparticles-decorated aqueous graphene oxide hybrid nanofluid has promising potential as an innovative heat transfer fluid in various heat transfer applications.

BackgroundEstablished associations between hearing loss and cognitive decline were primarily defined by pure-tone audiometry, which reflects peripheral hearing ability. Speech-in-noise performance, which reflects central hearing ability, is more limited in prior literature. We examined the longitudinal associations of audiometric hearing and speech-in-noise performance with cognitive decline.MethodsWe studied 702 participants aged ≥60 years in the Baltimore Longitudinal Study of Aging 2012–2019. Global and domain-specific (language, memory, attention, executive function, visuospatial ability) cognitive performance were assessed by the cognitive assessment battery. Hearing thresholds at 0.5, 1, 2, and 4 kilohertz obtained from pure-tone audiometry were averaged to calculate better-ear pure-tone average (PTA) and participants were categorized as having hearing loss (>25 decibels hearing level [dB HL]) or normal hearing (≤25 dB HL). Speech-in-noise performance was assessed by the Quick Speech-in-Noise (QuickSIN) test, and participants were categorized as having below-median (worse) or above-median performance. Linear mixed effects models with random intercepts and slopes were used to assess baseline cognitive performance and cognitive decline by hearing status. Models adjusted for demographic, lifestyle and disease factors.ResultsParticipants with audiometric hearing loss showed similar baseline cognitive performance but faster decline in global cognitive function, language, executive function, and attention. Participants with below-median QuickSIN score showed worse baseline cognitive performance in all domains and faster decline in global cognitive function, language, memory, executive function and attention.ConclusionsAudiometric hearing might be targeted to delay cognitive decline. Speech-in-noise performance might be a novel marker and might be more sensitive to memory decline.

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare subtype of kidney cancer with no standard treatment options for the advanced disease. Here, the authors perform genomic and transcriptomic profiling of 63 untreated primary TFE3-tRCC tumours and reveal potential therapeutic targets.

Abstract Background Powassan virus (POWV; genus Flavivirus) is the sole North American member of the tick-borne encephalitis sero-complex and an increasing public health threat in the USA. Maintained in nature by Ixodes spp. ticks, POWV has also been isolated from species of other hard tick genera, yet it is unclear if these species can serve as vectors. Dermacentor variabilis and Amblyomma americanum share geographic and ecologic overlap with Ixodes spp. ticks and POWV transmission foci, raising the possibility that POWV could become established in these tick species and leading to range expansion and increased human risk. Therefore, we assessed the competency of Ixodes scapularis, D. variabilis and A. americanum for POWV lineage II (POWV II). Methods Larvae from all three species were co-infested on POWV-infected Balb/c mice. The engorged larvae were allowed to molt to nymphs and screened for the presence of POWV II RNA by reverse transcription-qPCR. Eight infected nymphs from each species were allowed to individually feed on a naïve mouse. Mice were screened for the presence of POWV II RNA to determine infection status. Results The results demonstrated that larvae from all three tick species were able to efficiently acquire POWV II via feeding on viremic mice, maintain infection through molting and successively transmit POWV to naïve mice at the nymphal stage at comparable rates across all three species. Conclusions Our findings reveal that non-Ixodes tick species can serve as competent vectors for POWV and highlight the potential role of these species in the ecology and epidemiology of POWV. Future studies examining the possible implications of these findings on POWV epidemiology and the adaptability of POWV in these new vectors are warranted. Graphical abstract

The detrimental effects of Huanglongbing (HLB) on citrus are well known and so is the need for effective methods to combat this disease. Solar thermotherapy (ST), one of the management methods to help alleviate some of the negative effects of HLB, is the process of heating trees to therapeutic temperatures by encompassing the tree within a plastic structure (Visqueen) to harness the sun's natural energy. ST was applied to mature ‘Valencia’ citrus trees in three locations. Tree vigor, yield, and Candidatus Liberibacter asiaticus (Las) titer in leaves were monitored for two consecutive seasons post ST treatment, while fruit and juice quality were evaluated at the end of the second season. ST promoted an increase in canopy density in most groves tested and did not have a significant effect on fruit quantity, despite the prolonged exposure of the trees to increased temperatures. Moreover, Las titer was reduced in both leaves and juice processed from affected trees post ST. With respect to fruit quality, the ratio of total soluble solids to titratable acidity was higher post ST compared to controls as was the sucrose content of the juice in most treated groves, whereas limonin was higher in juice from control trees. Principal components analysis of aroma volatiles showed significant differences between juice from treated versus control trees with volatiles imparting top-note and freshness to orange juice, such as acetaldehyde, hexanal, Z-3-hexenol and linalool, being higher in juice from treated trees. Taste panels confirmed that flavor differences existed, ultimately showing that ST resulted in improved juice flavor in well-managed groves. Although the effects of ST on the trees appear temporary, such outcomes emphasize its utility when used as part of an integrated management strategy for HLB-affected citrus, imparting beneficial horticultural responses with minimal to positive effects on subsequent juice flavor.

Once introduced to shallow aquatic ecosystems common carp (Cyprinus carpio) often degrade habitat, negatively impacting the native organisms that rely on these systems. Detrimental effects often observed following the introduction of carp include a reduction in water clarity as bottom sediments become disturbed and resuspended and phytoplankton blooms become more severe and frequent. This results in a reduction of submersed aquatic vegetation (SAV), the effects of which are felt across multiple trophic levels. We sought to limit large carp (>70 mm maximum body width) access to a culturally and biologically significant 18,500 ha freshwater coastal wetland located in Manitoba, Canada to restore pre-carp conditions which were characterized by clear water and abundant SAV. In winter 2012–2013, exclusion structures were built to limit access by large carp to Delta Marsh during the spring and summer. A monitoring program (2009–2018) compared marsh conditions before and after carp exclusion. Water clarity improved following carp exclusion, largely driven by a reduction of inorganic suspended solids (ISS) rather than phytoplankton biomass, indicating that maintaining clear water conditions might be supplemented by reductions in nutrient export from agricultural areas adjacent to the marsh. The decrease in ISS and phytoplankton varied spatially, with the greatest change observed in the westernmost area of the marsh which is more sheltered compared to the large open bays characterizing eastern areas of the marsh. SAV doubled in percent cover through the 6 years of monitoring post-carp exclusion and SAV cover and species richness in the marsh was comparable to what was present in the early 1970s when there was also partial carp exclusion. Similar to water clarity, the increase in SAV cover was most significant in sheltered areas of the marsh. Our results suggest that excluding large carp can improve water clarity, SAV cover, and SAV species richness in large freshwater wetlands, benefiting waterfowl and other species.

During 3 weeks in 2019, 4 human cases of Eastern equine encephalitis (EEE) were diagnosed at a single hospital in Connecticut, USA. The cases coincided with notable shifts in vector–host infection patterns in the northeastern United States and signified a striking change in EEE incidence. All 4 cases were geographically clustered, rapidly progressive, and neurologically devastating. Diagnostic tests conducted by a national commercial reference laboratory revealed initial granulocytic cerebrospinal fluid pleocytosis and false-negative antibody results. EEE virus infection was diagnosed only after patient samples were retested by the arbovirus laboratory of the Centers for Disease Control and Prevention in Fort Collins, Colorado, USA. The crucial diagnostic challenges, clinical findings, and epidemiologic patterns revealed in this outbreak can inform future public health and clinical practice.

The present work critically analyses the thermal characteristics of diverse molar (0.03, 0.06, and 0.09 M) Ag decorated GO hybrid nanofluids at constant 0.05 wt.%. The study broadly encompassed the synthesis, characterization, stability, thermophysical properties, reactivity, and contact angle measurements on copper substrates using varied molar Ag-GO hybrid nanofluids. The thermal impact of these hybrid nanofluids was evaluated across a temperature range of 293–333 K, encompassing thermal conductivity, specific heat, viscosity, surface tension, and density. The results illustrate that increasing the molarity of Ag over GO significantly influenced the thermal properties of the hybrid nanofluids. Notably, the most substantial improvements in thermal conductivity are observed at 333 K, reaching 30.12, 22.63, and 17.13% for 0.09, 0.06, and 0.03 M Ag-GO, respectively, compared to the base fluid. Furthermore, central composite design approach (CCD) was employed to establish correlations between the experimental and predicted thermal conductivity enhancement ratio (K-ratio) results. In conclusion, these studies underscore a promising insight that the optimizing of Ag molarity in GO hybrid nanofluids holds substantial potential for enhancing heat transfer performance across diverse heat transfer applications. [ABSTRACT FROM AUTHOR]

Etched-and-regrown GaN pn-diodes capable of high breakdown voltage (1610 V), low reverse current leakage (1 nA = 6 μA/cm2 at 1250 V), excellent forward characteristics (ideality factor 1.6), and low specific on-resistance (1.1 mΩ.cm2) were realized by mitigating plasma etch-related defects at the regrown interface. Epitaxial n-GaN layers grown by metal-organic chemical vapor deposition on free-standing GaN substrates were etched using inductively coupled plasma etching (ICP), and we demonstrate that a slow reactive ion etch (RIE) prior to p-GaN regrowth dramatically increases diode electrical performance compared to wet chemical surface treatments. Etched-and-regrown diodes without a junction termination extension (JTE) were characterized to compare diode performance using the post-ICP RIE method with prior studies of other post-ICP treatments. Then, etched-and-regrown diodes using the post-ICP RIE etch steps prior to regrowth were fabricated with a multi-step JTE to demonstrate kV-class operation.

Abstract Background La Crosse virus (LACV) (genus Orthobunyavirus, family Peribunyaviridae) is a mosquito-borne virus that causes pediatric encephalitis and accounts for 50–150 human cases annually in the USA. Human cases occur primarily in the Midwest and Appalachian regions whereas documented human cases occur very rarely in the northeastern USA. Methods Following detection of a LACV isolate from a field-collected mosquito in Connecticut during 2005, we evaluated the prevalence of LACV infection in local mosquito populations and genetically characterized virus isolates to determine whether the virus is maintained focally in this region. Results During 2018, we detected LACV in multiple species of mosquitoes, including those not previously associated with the virus. We also evaluated the phylogenetic relationship of LACV strains isolated from 2005–2018 in Connecticut and found that they formed a genetically homogeneous clade that was most similar to strains from New York State. Conclusion Our analysis argues for local isolation and long-term persistence of a genetically distinct lineage of LACV within this region. We highlight the need to determine more about the phenotypic behavior of these isolates, and whether this virus lineage poses a threat to public health.

Abstract Background Hearing loss, a highly prevalent sensory impairment affecting older adults, is a risk factor for cognition decline. However, there were very limited studies on this association in low-resource countries. This study aimed to assess the association between self-reported hearing loss and cognitive decline, and whether engagement in leisure activities moderated this association among older adults in China. Methods Data were obtained from two waves of the nationally representative survey of China Longitudinal Healthy Longevity Survey (CLHLS) between 2011/12–2014. Eight thousand eight hundred forty-four individuals aged 65 years old or above with a dichotomized measure of self-reported hearing status were included. Modified Mini-Mental Examination (MMSE) was used to measure global cognition. Fixed-effects models were used to estimate whether leisure activity engagement moderated the association of self-perceived hearing loss with global cognitive change in the overall sample and sex subsamples. Results Self-reported hearing loss was associated with cognitive impairment, with an odds ratio of 2.48 [1.22, 5.06]. Sex difference in the association of hearing loss and cognitive impairment was not found. Self-reported hearing loss was associated with cognitive decline, with 8% increase in risk compared with those with normal hearing. Frequent engagement in leisure activities moderated the association between hearing loss and cognitive decline for the whole and male samples. Conclusion Hearing loss was associated with cognitive decline, and leisure activities engagement moderated the association among males rather than females.

Summary: Plasmodium sporozoites invade hepatocytes and transform into liver stages within a parasitophorous vacuole (PV). The parasites then grow and replicate their genome to form exoerythrocytic merozoites that infect red blood cells. We report that the human malaria parasite Plasmodium falciparum (Pf) expresses a C-type ATP-binding cassette transporter, Pf ABCC2, which marks the transition from invasive sporozoite to intrahepatocytic early liver stage. Using a humanized mouse infection model, we show that Pf ABCC2 localizes to the parasite plasma membrane in early and mid-liver stage parasites but is not detectable in late liver stages. Pf abcc2— sporozoites invade hepatocytes, form a PV, and transform into liver stage trophozoites but cannot transition to exoerythrocytic schizogony and fail to transition to blood stage infection. Thus, Pf ABCC2 is an expression marker for early phases of parasite liver infection and plays an essential role in the successful initiation of liver stage replication.

BackgroundVideo and other technologies are reshaping the delivery of health care, yet barriers related to workflow and possible provider fatigue suggest that a thorough evaluation is needed for quality and process improvement. ObjectiveThis scoping review explored the relationship among technology, fatigue, and health care to improve the conditions for providers. MethodsA 6-stage scoping review of literature (from 10 databases) published from 2000 to 2020 that focused on technology, health care, and fatigue was conducted. Technologies included synchronous video, telephone, informatics systems, asynchronous wearable sensors, and mobile health devices for health care in 4 concept areas related to provider experience: behavioral, cognitive, emotional, and physical impact; workplace at the individual, clinic, hospital, and system or organizational levels; well-being, burnout, and stress; and perceptions regarding technology. Qualitative content, discourse, and framework analyses were used to thematically analyze data for developing a spectrum of health to risk of fatigue to manifestations of burnout. ResultsOf the 4221 potential literature references, 202 (4.79%) were duplicates, and our review of the titles and abstracts of 4019 (95.21%) found that 3837 (90.9%) were irrelevant. A full-text review of 182 studies revealed that 12 (6.6%) studies met all the criteria related to technology, health care, and fatigue, and these studied the behavioral, emotional, cognitive, and physical impact of workflow at the individual, hospital, and system or organizational levels. Video and electronic health record use has been associated with physical eye fatigue; neck pain; stress; tiredness; and behavioral impacts related to additional effort owing to barriers, trouble with engagement, emotional wear and tear and exhaustion, cognitive inattention, effort, expecting problems, multitasking and workload, and emotional experiences (eg, anger, irritability, stress, and concern about well-being). An additional 14 studies that evaluated behavioral, emotional, and cognitive impacts without focusing on fatigue found high user ratings on data quality, accuracy, and processing but low satisfaction with clerical tasks, the effort required in work, and interruptions costing time, resulting in more errors, stress, and frustration. Our qualitative analysis suggests a spectrum from health to risk and provides an outline of organizational approaches to human factors and technology in health care. Business, occupational health, human factors, and well-being literature have not studied technology fatigue and burnout; however, their findings help contextualize technology-based fatigue to suggest guidelines. Few studies were found to contextually evaluate differences according to health professions and practice contexts. ConclusionsHealth care systems need to evaluate the impact of technology in accordance with the Quadruple Aim to support providers’ well-being and prevent workload burden, fatigue, and burnout. Implementation and effectiveness approaches and a multilevel approach with objective measures for clinical, human factors, training, professional development, and administrative workflow are suggested. This requires institutional strategies and competencies to integrate health care quality, technology and well-being outcomes.

Abstract During an earthquake, work done to overcome fault friction is dissipated as heat. Coseismic temperature rise, critical for identifying and constraining the magnitude of past earthquakes, is difficult to accurately quantify. To address this issue, we compare two temperature‐sensitive geochemical systems, zircon (U‐Th)/He (ZHe) thermochronometry and thermal maturity of organic matter (biomarkers), which respond to short‐duration, high temperatures. Models of prior biomarker data from the Punchbowl fault (PF), CA, indicate coseismic temperatures of ∼465–1,065°C in the principal slip zone (PSZ; Savage & Polissar, 2019, https://doi.org/10.1029/2019gc008225) depending on prescribed thickness of the deforming zone. We resampled two PF sample sites and acquired high‐spatial resolution ZHe data (n = 45 individual analyses) from the PSZ and fault core gouge, together with adjacent crystalline basement and Punchbowl Formation rocks. Results define a positive ZHe date‐effective U (eU) trend from ∼10 to 60 Ma and ∼20–700 ppm eU with a plateau at ∼65 Ma at >700 ppm eU. This pattern suggests the PSZ and fault core gouge share a similar thermal history to material outside the PF. Individual apatite (U‐Th)/He dates (n = 5) from an undeformed Punchbowl Formation sample are ∼4 Ma for grains with ∼30–150 ppm eU, implying rapid cooling and exhumation at that time due to PF activity. Zircon damage‐diffusivity relationships inform a suite of numerical models that collectively bracket coseismic temperatures on the PF to

Abstract For upland‐nesting ducks that rely on grassland and wetland habitats in landscapes characterized by human alteration and a strongly fluctuating climate, information on how landscape composition interacts with climate is needed to better understand the security of conservation investments and to inform adaptive management in a changing climate. We characterized spatial and temporal variation in a 10‐year study of nest survival of five species of upland‐nesting ducks at study areas across the Canadian Prairie Pothole Region. We assessed factors affecting nest survival across gradients of landscape composition, climate, and duck density. Habitat characteristics influenced nest survival at multiple scales spanning nest‐scale vegetation density to landscape‐scale perennial cover abundance, with the relative magnitude of spatial variation in nest survival greater than that of temporal variation in this study. An interaction between climate and landscape composition suggested that intact landscapes can moderate the effects of interannual variation in climate, reinforcing the importance of habitat conservation in a changing climate. Measured nest survival rates ranged from 4.7% to 40.5% and were high enough to sustain duck populations in only 31% of study areas, barring sustained climatic conditions suitable for elevating other breeding season vital rates, suggesting the need for continued investment in waterfowl conservation.

Sustainable small molecule Active Pharmaceutical Ingredient (API) manufacturing starts at the onset of route development by employing a Green-by-Design strategy. Reliable metrics are imperative for setting targets and measuring process improvements throughout the development cycle. This article reviews some of the many tools and methods established to analyze and assess the greenness and sustainability of a process, each of which highlights different aspects of process efficiency, waste formation or overall environmental impact reduction. Most calculations, such as process mass intensity (PMI), are mass-based and do not consider the types of raw materials used. In contrast, a full life cycle assessment (LCA) offers detailed information about the “cradle to grave” environmental impact of a manufacturing route and its specific resources, but the high data requirements and long timelines are not conducive for multiple processes or repeated assessments during process optimization. To address these challenges, we introduce a Streamlined PMI-LCA Tool, developed in collaboration with the ACS Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR), that combines PMI with a “cradle to gate” approach to include the environmental footprint of the synthesis’ raw materials. The frequent re-evaluation of a process continuously highlights areas for improvement and guides the prioritization of process development activities to effectively and rapidly achieve a Green-by-Design commercial synthetic route. The utility of this approach to Green-by-Design is demonstrated with the reduction of PMI for MK-7264 from 366 to 88 over the course of process development.

ObjectiveThe main objective of this study was to review the clinicopathologic characteristics and outcome of patients with oncocytic papillary thyroid carcinoma (PTC) and oncocytic poorly differentiated thyroid carcinoma (PDTC). The secondary objective was to evaluate the prevalence and outcomes of RAI use in this population.MethodsPatients with oncocytic PTC and PDTC who were treated at a quaternary cancer centre between 2002 and 2017 were retrospectively identified from an institutional database. All patients had an expert pathology review to ensure consistent reporting and definition. The cumulative incidence function was used to analyse locoregional failure (LRF) and distant metastasis (DM) rates. Univariable analysis (UVA) was used to assess clinical predictors of outcome.ResultsIn total, 263 patients were included (PTC [n=218], PDTC [n=45]) with a median follow up of 4.4 years (range: 0 = 26.7 years). Patients with oncocytic PTC had a 5/10-year incidence of LRF and DM, respectively, of 2.7%/5.6% and 3.4%/4.5%. On UVA, there was an increased risk of DM in PTC tumors with widely invasive growth (HR 17.1; p

Listeria monocytogenes is a regulated foodborne pathogen that is known to cause listeriosis, a disease associated with high mortality rates in humans. Olive leaf extract (OLE) has been shown to act as a plant antimicrobial and inhibit the growth of pathogens, such as L. monocytogenes, although its mode of action has not been defined. To help identify the cellular mechanisms important for conveying these beneficial traits, RNA-Seq was used to study the transcriptome of L. monocytogenes upon exposure to a sublethal level of OLE. Results obtained from cells cultured both with and without OLE at two different time points (3.5-h and 24-h) revealed 661 genes that were differentially expressed. Of the differentially expressed genes (DEGs) identified, transcription was altered for 171 genes in response to the 3.5-h OLE treatment while 490 genes were altered in response to the 24-h OLE treatment. These DEGs included but were not limited to genes encoding for signal transduction, ATP-binding cassette (ABC) transporters, and the phosphotransferase system. Interestingly, several virulence-related genes were downregulated including an ABC transporter permease previously shown to negatively regulate biofilm formation, genes involved in flagella assembly and binding/entry into host cells as well as those regulating acid resistance suggesting that OLE may decrease the virulence potential of L. monocytogenes. Furthermore, quantitative reverse-transcription PCR was used to validate the data obtained via RNA-Seq. Our study provides insight into the mode of action of OLE treatment against L. monocytogenes and may aid in identifying synergetic strategies to inhibit L. monocytogenes in food.

One of the most controversial elements of political tolerance concerns support for hate speech. We argue that there are two factors that can reduce tolerance for hate speech: 1) moral foundations and 2) party cues. U.S. citizens’ tolerance of hate speech will be reduced when it is framed as a violation of a specific moral foundation, opposed by a political party, or when the morality violation is utilized by party elites. Using two survey experiments, we manipulated the target of hate speech (i.e. Muslims or the American flag), whether the speech violated a moral foundation (i.e. harm or loyalty), and which political party supported or opposed the hate speech in question. For flag burning, moral frames and party cues on their own reduced U.S. citizens’ tolerance relative to a non-political control, while moral frames and party cues were successful in reducing tolerance of anti-Muslim speech compared to a free speech appeal. Partisans were generally responsive to cues from the in-party. We also found instances of moral repackaging, where morally incongruent appeals from the in-party reduced tolerance of flag burning among Democrats. Among Republicans, harm morality decreased tolerance of anti-Muslim speech when invoked by the in-party, but increased tolerance when used by the out-party – an indication of the power of party cues to repackage moral arguments and to trigger backlash. These results provide a better understanding of what factors can affect tolerance for hate speech, providing political leaders and social justice advocates with a roadmap to alleviate this problem.