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Abstract Background The widespread use of insecticide-treated nets (ITNs) has significantly contributed to the reduction in malaria cases and deaths observed across Africa. Unfortunately, this control strategy is threatened by the rapid spread of pyrethroid resistance in malaria vectors. Dual-active-ingredient insecticidal nets are now available to mitigate the impact of pyrethroid resistance. To facilitate evidence-based decisions regarding product selection in specific use settings, data are needed on the efficacy of these different nets against local mosquito populations. Methods Two experimental hut trials were performed in Za-Kpota, southern Benin in 2021 to evaluate the performance of Interceptor G2 (BASF), Royal Guard (Disease Control Technologies) and PermaNet 3.0 (Vestergaard Frandsen), all dual-active-ingredient bednets, in comparison to untreated or standard pyrethroid-treated bednets, against free-flying wild Anopheles gambiae mosquitoes. The performance of some of these next-generation nets was compared to the same type of nets that have been in use for up to 2 years. Mosquitoes collected in the huts were followed up after exposure to assess the sublethal effects of treatments on certain life-history traits. Results The predominant species in the study site was Anopheles gambiae sensu stricto (An. gambiae s.s.). Both Anopheles coluzzii and An. gambiae s.s. were resistant to pyrethroids (deltamethrin susceptibility was restored by piperonyl butoxide pre-exposure). In the experimental hut trials, the highest blood-feeding inhibition (5.56%) was recorded for the Royal Guard net, relative to the standard PermaNet 2.0 net (44.44% inhibition). The highest 72-h mortality rate (90.11%) was recorded for the Interceptor G2 net compared to the PermaNet 2.0 net (56.04%). After exposure, the risk of death of An. gambiae sensu lato (An. gambiae s.l.) was 6.5-fold higher with the Interceptor G2 net and 4.4-fold higher with the PermaNet 3.0 net compared to the respective untreated net. Lower mosquito mortality was recorded with an aged Interceptor G2 net compared to a new Interceptor G2 net. Oviposition rates were lower in mosquitoes collected from huts containing ITNs compared to those of untreated controls. None of the mosquitoes collected from huts equipped with Royal Guard nets laid any eggs. Conclusions The Royal Guard and Interceptor G2 nets showed a potential to significantly improve the control of malaria-transmitting vectors. However, the PermaNet 3.0 net remains effective in pyrethroid-resistant areas. Graphical Abstract

Abstract Background Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington). Findings Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend

Abstract Despite concern that climate change could increase the human risk to malaria in certain areas, the temperature dependency of malaria transmission is poorly characterized. Here, we use a mechanistic model fitted to experimental data to describe how Plasmodium falciparum infection of the African malaria vector, Anopheles gambiae, is modulated by temperature, including its influences on parasite establishment, conversion efficiency through parasite developmental stages, parasite development rate, and overall vector competence. We use these data, together with estimates of the survival of infected blood-fed mosquitoes, to explore the theoretical influence of temperature on transmission in four locations in Kenya, considering recent conditions and future climate change. Results provide insights into factors limiting transmission in cooler environments and indicate that increases in malaria transmission due to climate warming in areas like the Kenyan Highlands, might be less than previously predicted.

Abstract Sulfuryl fluoride (SO2F2) is a synthetic pesticide and a potent greenhouse gas that is accumulating in the global atmosphere. Rising emissions are a concern since SO2F2 has a relatively long atmospheric lifetime and a high global warming potential. The U.S. is thought to contribute substantially to global SO2F2 emissions, but there is a paucity of information on how emissions of SO2F2 are distributed across the U.S., and there is currently no inventory of SO2F2 emissions for the U.S. or individual states. Here we provide an atmospheric measurement-based estimate of U.S. SO2F2 emissions using high-precision SO2F2 measurements from the NOAA Global Greenhouse Gas Reference Network (GGGRN) and a geostatistical inverse model. We find that California has the largest SO2F2 emissions among all U.S. states, with the highest emissions from southern coastal California (Los Angeles, Orange, and San Diego counties). Outside of California, only very small and infrequent SO2F2 emissions are detected by our analysis of GGGRN data. We find that California emits 60-85% of U.S. SO2F2 emissions, at a rate of 0.26 ( ± 0.10) Gg yr−1. We estimate that emissions of SO2F2 from California are equal to 5.5–12% of global SO2F2 emissions.

Abstract Calcium carbonate (CaCO3) is abundant on Earth, is a major component of marine biominerals and thus of sedimentary and metamorphic rocks and it plays a major role in the global carbon cycle by storing atmospheric CO2 into solid biominerals. Six crystalline polymorphs of CaCO3 are known—3 anhydrous: calcite, aragonite, vaterite, and 3 hydrated: ikaite (CaCO3·6H2O), monohydrocalcite (CaCO3·1H2O, MHC), and calcium carbonate hemihydrate (CaCO3·½H2O, CCHH). CCHH was recently discovered and characterized, but exclusively as a synthetic material, not as a naturally occurring mineral. Here, analyzing 200 million spectra with Myriad Mapping (MM) of nanoscale mineral phases, we find CCHH and MHC, along with amorphous precursors, on freshly deposited coral skeleton and nacre surfaces, but not on sea urchin spines. Thus, biomineralization pathways are more complex and diverse than previously understood, opening new questions on isotopes and climate. Crystalline precursors are more accessible than amorphous ones to other spectroscopies and diffraction, in natural and bio-inspired materials.

Abstract Sensors based on spin qubits in 2D crystals offer the prospect of nanoscale proximities between sensor and source, which could provide access to otherwise inaccessible signals. For AC magnetometry, the sensitivity and frequency range are typically limited by the noise spectrum, which determines the qubit coherence time. We address this using phase modulated continuous concatenated dynamic decoupling, which extends the coherence time towards the T 1 limit at room temperature and enables tuneable narrowband AC magnetometry. Using an ensemble of negatively charged boron vacancies in hexagonal boron nitride, we detect out-of-plane AC fields in the range of ~ 10 − 150 MHz, and in-plane fields within ± 150 MHz of the electron spin resonance. We measure an AC magnetic field sensitivity of $$\sim 1\,\mu {{{\rm{T}}}}/\sqrt{{{{\rm{Hz}}}}}$$ ~ 1 μ T / Hz at ~ 2.5 GHz, for a sensor volume of ~ 0.1 μm3. This work establishes the viability of spin defects in 2D materials for high frequency magnetometry, with wide-ranging applications across science and technology.

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.

This review article (Ikhajiagbe et al., 2020) has been retracted at the request of the editors-in-chief and authors, following the identification of a similarity between a portion of this article and a previous work (Shen et al., 2011), which was not detected by anti-plagiarism software before publication. The first author apologizes to the editors and readers, as well as to the authors of the original work, for the unfortunate incidence of plagiarism and the unfortunate circumstances that occurred (Appendix 1).

BackgroundUnderstanding the relative contributions of SARS-CoV-2 infection-induced and vaccine-induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions.MethodsUsing a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population-level SARS-CoV-2 seroprevalence. EHR and survey data were incorporated to determine spike antibody positivity due to SARS-CoV-2 infection and COVID-19 vaccination. We used sampling and non-response weighting to create population-level estimates.ResultsWe enrolled 4,319 persons over six recruitment waves. SARS-CoV-2 spike antibody seroprevalence increased from 83.3% (CI 77.0-88.9) in May 2021 to 93.5% (CI 89.5-97.5) in April 2022. By April 2022, 68.5% (CI 61.9-74.3) of the population was seropositive from COVID-19 vaccination only, 13.9% (10.7-17.9) from COVID-19 vaccination and prior diagnosed SARS-CoV-2 infection, 8.2% (CI 4.5-14.5) from prior diagnosed SARS-CoV-2 infection only and 2.9% (CI 1.1-7.6) from prior undiagnosed SARS-CoV-2 infection only. We found high agreement (≥97%) between EHR and survey data for ascertaining COVID-19 vaccination and SARS-CoV-2 infection status.ConclusionsBy April 2022, 93.5% of persons had detectable SARS-CoV-2 spike antibody, predominantly from COVID-19 vaccination. In this highly vaccinated population and over 18 months into the pandemic, SARS-CoV-2 infection without COVID-19 vaccination was a small contributor to overall population-level seroprevalence.

Abstract Flexible printed cables and circuitry based on copper-polyimide materials are widely used in experiments looking for rare events due to their unique electrical and mechanical characteristics. However, past studies have found copper-polyimide flexible cables to contain 400-4700 pg 238U/g, 16-3700 pg 232Th/g, and 170-2100 ng natK/g, which can be a significant source of radioactive background for many current and next-generation ultralow background detectors. This study presents a comprehensive investigation into the fabrication process of copper-polyimide flexible cables and the development of custom low radioactivity cables for use in rare-event physics applications. A methodical step-by-step approach was developed and informed by ultrasensitive assay to determine the radiopurity in the starting materials and identify the contaminating production steps in the cable fabrication process. Radiopure material alternatives were identified, and cleaner production processes and treatments were developed to significantly reduce the imparted contamination. Through the newly developed radiopure fabrication process, fully-functioning cables were produced with radiocontaminant concentrations of 20-31 pg 238U/g, 12-13 pg 232Th/g, and 40-550 ng natK/g, which is significantly cleaner than cables from previous work and sufficiently radiopure for current and next-generation detectors. This approach, employing witness samples to investigate each step of the fabrication process, can hopefully serve as a template for investigating radiocontaminants in other material production processes.

ABSTRACT: Milk synthesis exhibits a daily rhythm that is modified by the timing of feed intake. However, it is unknown how specific nutrients entrain this daily rhythm. Amino acids have an important role in milk synthesis, and may have a role in entrainment of mammary circadian rhythms. The objective of this study was to determine the effects of intestinally absorbed protein on daily rhythms of milk and milk component synthesis and key plasma hormones and metabolites. Nine lactating Holstein cows were assigned to 1 of 3 treatment sequences in a 3 × 3 Latin square. Treatments included abomasal infusions of 500 g/d of sodium caseinate either continuously throughout the day (CON), for 8 h/d from 0900 to 1700 h (DAY), or for 8 h/d from 2100 to 0500 h (NGT). Cows were milked every 6 h during the final 8 d of each period. A 24-h rhythm was fit to data using cosine analysis and the amplitude and acrophase were determined. Night infusion of protein decreased the daily milk yield and milk protein yield by 8.2% and 9.2%, respectively. Milk fat yield was increased 5.5% by DAY and milk fat concentration was increased 8.8% by NGT. Milk yield exhibited a daily rhythm in all treatments, with NGT increasing the amplitude of the daily rhythm 33% compared with CON. Milk fat concentration fit a daily rhythm in CON and NGT, but not DAY, whereas milk protein concentration fit a daily rhythm in CON and DAY, but not NGT. Moreover, DAY abolished the daily rhythm of plasma glucose concentration, but induced rhythms of plasma insulin and nonesterified fatty acid concentrations. Results suggest that feeding increased protein levels during the early part of the day may increase milk fat yield and modify energy metabolism through increased daily variation in insulin-stimulated lipid release, but additional research focused on feeding multiple diets across the day is required.

Abstract The concept of truth is at the core of science, journalism, law, and many other pillars of modern society. Yet, given the imprecision of natural language, deciding what information should count as true is no easy task, even with access to the ground truth. How do people decide whether a given claim of fact qualifies as true or false? Across two studies (N = 1181; 16,248 observations), participants saw claims of fact alongside the ground truth about those claims. Participants classified each claim as true or false. Although participants knew precisely how accurate the claims were, participants classified claims as false more often when they judged the information source to be intending to deceive (versus inform) their audience, and classified claims as true more often when they judged the information source to be intending to provide an approximate (versus precise) account. These results suggest that, even if people have access to the same set of facts, they might disagree about the truth of claims if they attribute discrepant intentions to information sources. Such findings may shed light on the robust and persistent disagreements over claims of fact that have arisen in the “post-truth era”.

Purpose: This investigation provides a rigorous systematic review of the postoperative outcomes of patients with and without chronic hepatitis C who underwent total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods: We queried PubMed, Embase, Cochrane Database of Systematic Reviews, Scopus, Web of Science and the ‘gray’ literature, including supplemental materials, conference abstracts and proceedings as well as commentary published in various peer-reviewed journals from 1992 to present to evaluate studies that compared the postoperative outcomes of patients with and without chronic hepatitis C who underwent primary THA or TKA. This investigation was registered in the PROSPERO international prospective register of systematic reviews and follows the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. In our literature search, we identified 14 articles that met our inclusion criteria and were included in our fixed-effects meta-analysis. The postoperative outcomes analyzed included periprosthetic joint infection (PJI), aseptic revision, non-homebound discharge and inpatient mortality. Results: Our statistical analysis demonstrated a statistically significant increase in postoperative complications of patients with chronic hepatitis C who underwent primary THA or TKA including PJI (odds ratio (OR): 1.98, 95% CI: 1.86 – 2.10), aseptic revision (OR: 1.58, 95% CI: 1.50 – 1.67), non-homebound discharge (OR: 1.31, 95% CI: 1.28– 1.34) and inpatient mortality (OR: 9.37, 95% CI: 8.17 – 10.75). Conclusion: This meta-analysis demonstrated a statistically significant increase in adverse postoperative complications in patients with chronic hepatitis C who underwent primary THA or TKA compared to patients without chronic hepatitis C.

Implementation of negative pressure wound therapy (NPWT) as a standard of care has proven efficacious in reducing both the healing time and likelihood of nosocomial infection among pressure ulcers and traumatic, combat-related injuries. However, current formulations may not target or dramatically reduce bacterial biofilm burden following therapy. The purpose of this study was to determine the antibiofilm efficacy of an open-cell polyurethane (PU) foam (V.A.C.® Granufoam™) loaded with a first-in-class compound (CZ-01179) as the active release agent integrated via lyophilized hydrogel scaffolding. An ex vivo porcine excision wound model was designed to perform antibiofilm efficacy testing in the presence of NPWT. PU foam samples loaded with a 10.0% w/w formulation of CZ-01179 and 0.5% hyaluronic acid were prepared and tested against current standards of care: V.A.C.® Granufoam Silver™ and V.A.C.® Granufoam™. We observed statistically significant reduction of methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii biofilms with the CZ-01179 antibiofilm foam in comparison to current standard of care foams. These findings motivate further development of an antibiofilm PU foam loaded with CZ-01179.

Sepsis, an amplified immune response to systemic infection, is characterized by a transient cytokine storm followed by chronic immune dysfunction. Consequently, sepsis survivors are highly susceptible to newly introduced infections, suggesting sepsis can influence the function and composition of the naïve CD8 T cell pool and resulting pathogen-induced primary CD8 T cell responses. Here, we explored the extent to which sepsis induces phenotypic and functional changes within the naïve CD8 T cell pool. To interrogate this, the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis was used. In normal, non-septic mice, we show type-I interferon (IFN I)-mediated signaling plays an important role in driving the phenotypic and functional heterogeneity in the naïve CD8 T cell compartment leading to increased representation of Ly6C+ naïve CD8 T cells. In response to viral infection after sepsis resolution, naïve Ly6C+ CD8 T cells generated more primary effector and memory CD8 T cells with slower conversion to a central memory CD8 T cell phenotype (Tcm) than Ly6C- naïve CD8 T cells. Importantly, as a potent inducer of cytokine storm and IFN I production, sepsis leads to increased representation of Ly6C+ naïve CD8 T cells that maintained their heightened ability to respond (i.e., effector and memory CD8 T cell accumulation and cytokine production) to primary LCMV infection. Lastly, longitudinal analyses of peripheral blood samples obtained from septic patients revealed profound changes in CD8 T cell subset composition and frequency compared to healthy controls. Thus, sepsis has the capacity to alter the composition of naïve CD8 T cells, directly influencing primary CD8 T cell responses to newly introduced infections.

Background: Peroxisome proliferator-activated receptors (PPAR) α and γ genes play an important role in dyslipidaemia of T2DM. Aims: To estimate the frequency distribution of PPAR α and γ gene polymorphisms in South Indian T2DM patients with dyslipidaemia compared to healthy controls. Normative frequencies of SNPs were established and compared with data for 1000 genome populations. Methods: Eligible 382 cases and 336 age and sex-matched controls were enrolled. Six SNPs in PPARα [rs1800206 C>G (Leu162Val), rs4253778 G>C, rs135542 T>C] and PPARγ [rs3856806 (C>T), rs10865710 (C>G), rs1805192 C>G (Pro12Ala)] genes were selected for genotyping. Results: The allele and gene frequencies did not significantly differ between the diabetic dyslipidaemia cases and healthy controls. However, they were significantly different from that of 1000 genome populations except for rs1800206 C>G (Leu162Val) and rs1805192 C>G (Pro12Ala). Conclusion: The studied polymorphisms in PPARα and PPARγ genes are not associated with diabetic dyslipidaemia among South Indian patients.

Spin defects in 2D hBN are promising for magnetic field sensing but suffer from short spin coherence times. Here the authors extend the coherence time for an ensemble of spins in hBN to 4 microseconds by using a continuous microwave drive and demonstrate qubit control in a protected spin space.

Behavioral traits are often the first response to changing environmental conditions, including human induced rapid environmental change. For example, animals living in urban areas are often more aggressive than rural animals. This is especially evident in songbirds; males of several species display elevated aggression in urban habitats. Increased male aggression has been associated with reduced parental care, but the consequences of this trade-off for males, social partners, and offspring in the context of urbanization remains unclear. We explored the effects of increased urban male aggression on the life history traits, parental care, and offspring outcomes of song sparrows (Melospiza melodia). We predicted that urban males would reduce paternal investment and result in urban females providing greater nestling care or reduced fledging success in urban habitats compared to rural. Contrary to our prediction, aggressive urban males did not decrease care but visited the nest more often compared to rural males. Additionally, urban birds had higher nest and fledging success compared to rural, though this was largely due to higher nest predation in rural habitats. Our study is among the first to evaluate trade-offs associated with elevated aggression expressed by urban animals and adds to a growing body of evidence that urban habitats provide benefits to some species.

Continental-scale recycling of detrital zircon (DZ) grains and associated sediment across North American is not well understood. We trace a through line following the DZ proxy for the detritus originally sourced from Grenville and Appalachian orogens. This paper lays out an antecedent framework for one of the greatest sedimentation episodes of the Phanerozoic: the initial dispersal of Appalachian- and Grenville-age DZ grains to the western passive margin of Laurentia and the subsequent paleodrainage reorganization and sediment remobilization back to the east. The DZ U-Pb signature of the Appalachian-Ouachita orogenic system is dominated by Grenville (ca. 1250–950 Ma) and Appalachian (ca. 500–275 Ma) age groups and dominates the Phanerozoic record of North America. This study juxtaposes Pennsylvanian to modern DZ U-Pb data from across North America and demonstrates a persistent Appalachian signature, including a recycled Appalachian signature across Western North America. Lower Pennsylvanian deposits proximal to the Appalachian orogen are 50%–75% Appalachian- and Grenville-age DZ grains, representing the key component in the primary Appalachian signature. It remains unclear how the Appalachian signal was propagated to the west, but the Appalachian DZ signature was clearly present across the late Paleozoic passive margin of Laurentia and thus antecedent to potential DZ recycling throughout the Mesozoic and Cenozoic Eras. Triassic DZ samples document transcontinental fluvial systems that reached the western Laurentian margin, but subsequent Jurassic-Cretaceous samples indicate drainage reversal due to the rise of the Mesozoic Western Cordillera. A persistent Appalachian signature exists in these western-sourced, eastward-flowing systems—a phenomenon that continues to the present: samples are frequently composed of >40% Appalachian- and Grenville-age DZ. However, none of these systems are interpreted to be sourced by primary Appalachian or Grenville terranes, suggesting a recycled Appalachian signature. The persistent Appalachian signature, originally sourced by the linking of two orogenic terranes, continues to dominate the Phanerozoic record of much of North America to this day.

Accumulating evidence indicates that some COVID-19 survivors display reduced muscle mass, muscle strength, and aerobic capacity, which contribute to impairments in physical function that can persist for months after the acute phase of illness. Accordingly, strategies to restore muscle mass, muscle strength, and aerobic capacity following infection are critical to mitigate the long-term consequences of COVID-19. Blood flow restriction (BFR), which involves the application of mechanical compression to the limbs, presents a promising therapy that could be utilized throughout different phases of COVID-19 illness. Specifically, we hypothesize that: 1) use of passive BFR modalities can mitigate losses of muscle mass and muscle strength that occur during acute infection and 2) exercise with BFR can serve as an effective alternative to high-intensity exercise without BFR for regaining muscle mass, muscle strength, and aerobic capacity during convalescence. The various applications of BFR may also serve as a targeted therapy to address the underlying pathophysiology of COVID-19 and provide benefits to the musculoskeletal system as well as other organ systems affected by the disease. Consequently, we present a theoretical framework with which BFR could be implemented throughout the progression from acute illness to outpatient rehabilitation with the goal of improving short- and long-term outcomes in COVID-19 survivors. We envision that this paper will encourage discussion and consideration among researchers and clinicians of the potential therapeutic benefits of BFR to treat not only COVID-19 but similar pathologies and cases of acute critical illness.

The Drosophila polyadenosine RNA binding protein Nab2, which is orthologous to a human protein lost in a form of inherited intellectual disability, controls adult locomotion, axon projection, dendritic arborization, and memory through a largely undefined set of target RNAs. Here, we show a specific role for Nab2 in regulating splicing of ~150 exons/introns in the head transcriptome and focus on retention of a male-specific exon in the sex determination factor Sex-lethal (Sxl) that is enriched in female neurons. Previous studies have revealed that this splicing event is regulated in females by N6-methyladenosine (m6A) modification by the Mettl3 complex. At a molecular level, Nab2 associates with Sxl pre-mRNA in neurons and limits Sxl m6A methylation at specific sites. In parallel, reducing expression of the Mettl3, Mettl3 complex components, or the m6A reader Ythdc1 rescues mutant phenotypes in Nab2 flies. Overall, these data identify Nab2 as an inhibitor of m6A methylation and imply significant overlap between Nab2 and Mettl3 regulated RNAs in neuronal tissue.

Abstract Cryoneurolysis is an opioid-sparing therapy for long-lasting and reversible reduction of pain. We developed a nerve-selective method for cryoneurolysis by local injection of ice-slurry (− 5 to − 6 °C) that induced decrease in nocifensive response starting from about a week after treatment and lasting up to 8 weeks. In this study, we test the hypothesis that injection of colder slurry leads to faster onset of analgesia. Colder slurry (− 9ºC) was injected around the rat sciatic nerve to induce cryoneurolysis. Hematoxylin and Eosin (H&E) staining was used to examine histologic effects on surrounding tissues. Coherent anti-Stokes Raman scattering (CARS) microscopy was used to study effects on myelin sheaths. Functional tests were used to assess changes in sensory and motor function in the treated hind paw. No inflammation or scarring was detected in surrounding skin and muscle tissues at day 7 post slurry injection. Functional tests showed rapid onset reduction in mechanical pain sensitivity starting from day 1 and lasting up to day 98. CARS imaging demonstrated disintegration of myelin sheaths post treatment followed by complete recovery of nerve structure by day 140. In this study we showed that colder slurry (− 9 °C) produces more rapid onset and longer duration of analgesia, while remaining nerve-selective

Bracher et al. compare 15 forecasting models of COVID-19 cases and deaths in Germany and Poland between January and mid-April 2021. Many, though not all, models outperform a simple baseline model up to four weeks ahead, with ensemble methods showing very good relative performance.

Rare presentation of pediatric angiomatosis of the paranasal sinus and skull base presenting mimicking juvenile nasopharyngeal angiofibroma (JNA). This is a 16-year-old male who presented to the emergency room with acutely worsening headaches, decreased visual acuity, subjective diplopia on lateral gaze, and a skull base mass centered in the sphenoid cavity. Endoscopic biopsy at an outside facility was aborted due to profuse bleeding. Upon transfer to a tertiary care center, contrast MR demonstrated a heterogeneously and avidly enhancing vascular mass centered around the sphenoid and skull base originating from the internal maxillary artery with significant bilateral extension into the adjacent paranasal sinuses, sella, and cavernous sinus. History of presentation and imaging was suggestive of JNA. Patient underwent preoperative embolization followed by endoscopic endonasal transphenoidal resection with a skull base trained otolaryngologist and neurosurgeon. Final pathology confirmed angiomatosis. This is only the second reported case of paranasal sinus angiomatosis in the literature. Angiomatosis has a high rate of recurrence and failure of timely diagnosis can lead to requirement of repeated surgical intervention. Re-operations are associated with increased costs, patient dissatisfaction, and poorer surgical/clinical outcomes. Because angiomatosis can mimic JNA, hemangiomas, or other vascular tumors, it is essential to maintain a broad differential diagnosis that includes angiomatosis when evaluating sinonasal tumors.

IntroductionOver four billion people around the world rely on bread wheat (Triticum aestivum L.) as a major constituent of their diet. The changing climate, however, threatens the food security of these people, with periods of intense drought stress already causing widespread wheat yield losses. Much of the research into the wheat drought response has centred on the response to drought events later in development, during anthesis or grain filling. But as the timing of periods of drought stress become increasingly unpredictable, a more complete understanding of the response to drought during early development is also needed.MethodsHere, we utilized the YoGI landrace panel to identify 10,199 genes which were differentially expressed under early drought stress, before weighted gene co-expression network analysis (WGCNA) was used to construct a co-expression network and identify hub genes in modules particularly associated with the early drought response.ResultsOf these hub genes, two stood out as novel candidate master regulators of the early drought response – one as an activator (TaDHN4-D1; TraesCS5D02G379200) and the other as a repressor (uncharacterised gene; TraesCS3D02G361500).DiscussionAs well as appearing to coordinate the transcriptional early drought response, we propose that these hub genes may be able to regulate the physiological early drought response due to potential control over the expression of members of gene families well-known for their involvement in the drought response in many plant species, namely dehydrins and aquaporins, as well as other genes seemingly involved in key processes such as, stomatal opening, stomatal closing, stomatal morphogenesis and stress hormone signalling.

Acute Liver Failure (ALF) is a life-threatening illness characterized by the rapid onset of abnormal liver biochemistries, coagulopathy, and the development of hepatic encephalopathy. Extracorporeal bioengineered liver (BEL) grafts could offer a bridge therapy to transplant or recovery. The present study describes the manufacture of clinical scale BELs created from decellularized porcine-derived liver extracellular matrix seeded entirely with human cells: human umbilical vein endothelial cells (HUVECs) and primary human liver cells (PHLCs). Decellularized scaffolds seeded entirely with human cells were shown to adhere to stringent sterility and safety guidelines and demonstrated increased functionality when compared to grafts seeded with primary porcine liver cells (PPLCs). BELs with PHLCs were able to clear more ammonia than PPLCs and demonstrated lower perfusion pressures during patency testing. Additionally, to determine the full therapeutic potential of BELs seeded with PHLCs, longer culture periods were assessed to address the logistical constraints associated with manufacturing and transporting a product to a patient. The fully humanized BELs were able to retain their function after cold storage simulating a product transport period. Therefore, this study demonstrates the manufacture of bioengineered liver grafts and their potential in the clinical setting as a treatment for ALF.

Safely opening university campuses has been a major challenge during the COVID-19 pandemic. Here, the authors describe a program of public health measures employed at a university in the United States which, combined with other non-pharmaceutical interventions, allowed the university to stay open in fall 2020 with limited evidence of transmission.

Introduction Continued advancements in the treatments for neurological disease have helped interventionalists to refine approaches that offer improved surgical efficacy and patient outcomes. Carotid‐artery stenting (CAS) is a safe and effective alternative to carotid endarterectomy (CEA), that allows for revascularization of the internal carotid artery (ICA) in a minimally‐invasive manner. Traditionally, the mainstay for CAS has been through the femoral artery; however, patients with carotid‐artery disease (CAD) often have concomitant peripheral artery disease which confer increased risk of significant life‐threatening access‐site complications, such as retroperitoneal hematoma and limb ischemia. Given this, CAS via the radial artery has become increasingly popular. This study seeks to investigate the safety and feasibility of the transradial approach (TRA), in comparison to the traditional transfemoral approach (TFA), for carotid‐artery stenting. Methods The authors conducted a retrospective analysis of all adult patients (age >18) who underwent carotid‐artery stenting via TRA or TFA over a 4‐year study period (2018‐2021) across 4 different international academic centers. Important variables, such as patient demographics, comorbidities, procedural details, results, and complications were collected. Statistical analysis was performed to assess the strength of association and correlation for these variables. Results A total of 313 patients were enrolled during the study period. CAS via TFA was attempted in 251 patients and via TRA in 62 patients, respectively. Overall, CAS via TRA was found to be successful in 48/62 (76%) patients, and via TFA in 246/251 (98%) patients. Baseline demographics were similar for the two groups, with a female gender predilection, median age of 69, and hypertension and hyperlipidemia serving as the most common medical comorbidities. 14/62 (22.6%) patients who underwent TRA were converted to TFA. Spasm of the radial artery, kinking of the catheter and severe tortuosity of the vessels were the primary reasons for access site conversion. A total of five major access site‐related complications, including two deaths, and seven minor complications were noted in the TFA cohort. No serious access related complications were noted in the TRA group. In the multivariate‐analysis, after adjusting for age, hyperlipidemia, chronic heart failure, combination of stent plus angioplasty and fluoroscopy times, there was no statistically significant difference observed among the 2 groups in terms of procedural (OR: 0.31; CI: 0.36‐2.69; P = 0.29) and overall access site complications (OR: 0.17, CI: 0.02‐1.98, P = 0.16). Conclusions TRA seems to be a safe alternative approach for carotid stenting. In our cohort, no serious access site‐related complications were noted with TRA in comparison to the TFA group. Continued improvements in terms of patient selection, sample size, as well as advances in technique and technology will help to further refine TRA for CAS. Further studies and analysis will need to be performed to delineate the crucial variables that contribute to improved functional outcomes for these patients.

Abstract Brucellosis is an endemic bacterial zoonosis in Tanzania, and is among the most prioritized zoonotic diseases in the country. Brucellosis affects public health and livestock production in developing countries. Most human and livestock cases are not detected by the existing surveillance systems resulting in significant underestimation of the disease burden, and poor management of human cases by using nonspecific antibiotics may potentially contribute to antimicrobial resistance. To quantify the factors related to underreporting and those associated with the challenges in the diagnosis of brucellosis in Tanzania, search terms including “Brucella” “diagnosis” and “challenges” were used to query in Google search engine and publisher databases such as MEDLINE, PUBMED, NCBI, Springer, Hindawi, and Elsevier. The search parameters were limited to publications between 1995 and 2020. The searches returned 319 publications and grey articles which were screened and 57 were eligible for inclusion in this study. Four main areas were identified that cause underreporting of brucellosis and hinder brucellosis diagnosis: (1) inadequate knowledge of brucellosis among stakeholders in the livestock value chain, (2) limited diagnostic capacity for brucellosis due to unawareness of diagnostic tests and lack of epidemiological background of brucellosis among human and livestock health service workers (3) challenges associated with diagnostic tests, which include unreliable availability of diagnostic tests and unskilled workers, and (4) the uneven distribution of brucellosis surveillance studies in the country. This study suggests that there is a need for (1) training on public health education and brucellosis awareness among stakeholders in the livestock value chain; (2) providing scheduled continuing professional education with regard to brucellosis and other zoonotic diseases to health and livestock workers; (3) future brucellosis surveillance studies must focus on unrepresented regions; and (4) lastly, we recommend that the rose Bengal plate test (RBPT) and competitive enzyme-linked immunosorbent assay (cELISA) should be considered in brucellosis diagnostic schemes as a complementary tool to hasten the implementation of an ongoing national strategy for the prevention and control of brucellosis in humans and livestock in Tanzania. We suggest that these recommendations be considered for inclusion in the national strategy for brucellosis control in Tanzania. One Health Impact Statement Brucellosis is a disease caused by bacteria of genus Brucella and is transmitted from animals to humans. Humans get infected through ingestion of infected animal products but also through contact with bacteria via broken skin or inhalation of aerosolized bacteria particles during culture in the laboratory. Humans working with animals or animal products and laboratory personnel are at higher risk of infection. Tanzania has recently established a One-Health desk in the Prime Minister’s Office to address all matters related to One Health. However, the desk is in the infancy stage, more studies must be done to fill knowledge gaps so that working instruments became realistic. This review provides a synthesis of information that could be used by the One Health desk and other One Health stakeholders in the country on how to improve the existing brucellosis surveillance structures for improvement of One-Health service delivery in the country.

Abstract Objective The International League Against Epilepsy (ILAE) has revised the classification of epilepsies and seizures on several occasions since the original classification published in 1964. It is unclear if these changes have impacted the characterization of epilepsy, including the clinical validity of seizure semiology or epilepsy outcomes in resource‐poor areas. We aim to address this important knowledge gap. Methods We reviewed the clinical seizure semiology and etiological data of 483 persons with epilepsy identified from a population‐based survey in rural Kenya. The seizure semiology and etiological data were classified using the 1981 (for seizures) and 1989 (for epilepsy) ILAE criteria and then reclassified according to the ILAE‐2017 criteria. Logistic regression models adjusted for potential confounders were used to measure the associations between the seizure semiology and different clinical and electroencephalographic features of epilepsy. Results Focal (formerly localization‐related) and generalized epilepsies were lower in ILAE‐2017 (56% and 29%) than that of ILAE‐1989 (61% and 34%), P

Abstract Few germline genetic variants have been robustly linked with breast cancer outcomes. We conducted trans-ethnic meta genome-wide association study (GWAS) of overall survival (OS) in 3973 breast cancer patients from the Pathways Study, one of the largest prospective breast cancer survivor cohorts. A locus spanning the UACA gene, a key regulator of tumor suppressor Par-4, was associated with OS in patients taking Par-4 dependent chemotherapies, including anthracyclines and anti-HER2 therapy, at a genome-wide significance level ( $$P = 1.27 \times 10^{ - 9}$$ P = 1.27 × 1 0 − 9 ). This association was confirmed in meta-analysis across four independent prospective breast cancer cohorts (combined hazard ratio = 1.84, $$P = 1.28 \times 10^{ - 11}$$ P = 1.28 × 1 0 − 11 ). Transcriptome-wide association study revealed higher UACA gene expression was significantly associated with worse OS ( $$P = 4.68 \times 10^{ - 7}$$ P = 4.68 × 1 0 − 7 ). Our study identified the UACA locus as a genetic predictor of patient outcome following treatment with anthracyclines and/or anti-HER2 therapy, which may have clinical utility in formulating appropriate treatment strategies for breast cancer patients based on their genetic makeup.

Abstract Background Non-pharmaceutical interventions (NPIs) are a crucial suite of measures to prevent and control infectious disease outbreaks. Despite being particularly important for crisis-affected populations and those living in informal settlements, who typically reside in overcrowded and resource limited settings with inadequate access to healthcare, guidance on NPI implementation rarely takes the specific needs of such populations into account. We therefore conducted a systematic scoping review of the published evidence to describe the landscape of research and identify evidence gaps concerning the acceptability, feasibility, and effectiveness of NPIs among crisis-affected populations and informal settlements. Methods We systematically reviewed peer-reviewed articles published between 1970 and 2020 to collate available evidence on the feasibility, acceptability, and effectiveness of NPIs in crisis-affected populations and informal settlements. We performed quality assessments of each study using a standardised questionnaire. We analysed the data to produce descriptive summaries according to a number of categories: date of publication; geographical region of intervention; typology of crisis, shelter, modes of transmission, NPI, research design; study design; and study quality. Results Our review included 158 studies published in 85 peer-reviewed articles. Most research used low quality study designs. The acceptability, feasibility, and effectiveness of NPIs was highly context dependent. In general, simple and cost-effective interventions such as community-level environmental cleaning and provision of water, sanitation and hygiene services, and distribution of items for personal protection such as insecticide-treated nets, were both highly feasible and acceptable. Logistical, financial, and human resource constraints affected both the implementation and sustainability of measures. Community engagement emerged as a strong factor contributing to the effectiveness of NPIs. Conversely, measures that involve potential restriction on personal liberty such as case isolation and patient care and burial restrictions were found to be less acceptable, despite apparent effectiveness. Conclusions Overall, the evidence base was variable, with substantial knowledge gaps which varied between settings and pathogens. Based on the current landscape, robust evidence-based guidance is not possible, and a research agenda is urgently required that focusses on these specific vulnerable populations. Although implementation of NPIs presents unique practical challenges in these settings, it is critical that such an agenda is put in place, and that the lessons learned from historical and present experiences are documented to build a firm evidence base. Graphical Abstract

The DAMIC-M (DArk Matter In CCDs at Modane) experiment employs thick, fully depleted silicon charged-coupled devices (CCDs) to search for dark matter particles with a target exposure of 1 kg-year. A novel skipper readout implemented in the CCDs provides single electron resolution through multiple non-destructive measurements of the individual pixel charge, pushing the detection threshold to the eV-scale. DAMIC-M will advance by several orders of magnitude the exploration of the dark matter particle hypothesis, in particular of candidates pertaining to the so-called "hidden sector." A prototype, the Low Background Chamber (LBC), with 20g of low background Skipper CCDs, has been recently installed at Laboratoire Souterrain de Modane and is currently taking data. We will report the status of the DAMIC-M experiment and first results obtained with LBC commissioning data.

refellips is an open-source analysis package written in Python for modelling variable angle spectroscopic ellipsometry data. The software is designed to be used in Jupyter notebook environments or simple Python scripts, facilitating reproducible research. The modular design of refellips means users can implement simple models (e.g., slabs) or create their own complex mathematical optical models to describe an interface. refellips can read a range of file types from common ellipsometers and utilises the suite of local and global minimisers offered by the scipy package to fit data. refellips allows for the batch processing of large ellipsometry datasets, e.g., from the spatial mapping of surfaces or time-series experiments. Furthermore, as refellips is part of the refnx family, its operation (e.g., model creation) is almost identical to that used by refnx for neutron and X-ray reflectometry analyses, permitting simultaneous co-refinement of ellipsometry, neutron, and X-ray reflectometry data for the first time. This enables superior characterisation of complex interfaces in condensed matter films and oxide surfaces.

Abstract The importance of spatial and temporal environmental variation in shaping ecosystem dynamics is well appreciated, yet the ecological consequences of dynamic spatial variability, that is, the temporal patterning of spatial variation, remain unresolved. Here, we experimentally generate temporally fluctuating thermal environments that have either a negative, positive, or neutral relationship between the mean spatial environmental temperature and the degree of thermal spatial heterogeneity. We test the hypothesis that the timing of spatial variation relative to diel temperature cycles can meaningfully alter movement patterns and population dynamics, using the motile green algae Chlamydomonas reinhardtii. Our results indicate that C. reinhardtii individuals growing in environments with positive relationships between spatial variability and mean temperature show reduced population growth rates, more directed movement as indicated by a reduced turning angle, and decreased negative thermotaxis over time, relative to those growing in environments with a negative relationship between spatial variability and mean temperature. We additionally document substantial regional variation in the dynamics of natural spatial variability by collecting summer water temperature measurements from five ponds in the Mount Saint Helens watershed, WA, USA. Our results collectively suggest that the dynamics of spatial variation are an underappreciated but salient feature within the broader interwoven fabric of spatiotemporal variation.

Migraine is one of the most common pain disorders and causes disability in millions of people every year. Delta opioid receptors (DOR) have been identified as a novel therapeutic target for migraine and other headache disorders. DORs are present in both peripheral and central regions and it is unclear which receptor populations regulate migraine-associated effects. The aim of this study was to determine if DOR expressed in peripheral nociceptors regulates headache associated endpoints and the effect of delta agonists within these mouse models. We used a conditional knockout, in which DOR was selectively deleted from Nav1.8 expressing cells. Nav1.8-DOR mice and loxP control littermates were tested in models of chronic migraine-associated allodynia, opioid-induced hyperalgesia, migraine-associated negative affect, and aura. Nav1.8-DOR and loxP mice had comparable effect sizes in all of these models. The anti-allodynic effect of the DOR agonist, SNC80, was slightly diminished in the nitroglycerin model of migraine. Intriguingly, in the OIH model the peripheral effects of SNC80 were completely lost in Nav1.8-DOR mice while the cephalic effects remained intact. Regardless of genotype, SNC80 continued to inhibit conditioned place aversion associated with nitroglycerin and decreased cortical spreading depression events associated with migraine aura. These results suggest that DOR in Nav1.8-expressing nociceptors do not critically regulate the anti-migraine effects of delta agonist; and that brain-penetrant delta agonists would be a more effective drug development strategy.

Intercropping is an ancient agricultural management practice quickly re-gaining interest in mechanized agricultural systems. Mechanized management practices have led to a decreased biodiversity at the macro- and micro-fauna levels. These agricultural practices have also resulted in the degradation of soil and long-term inefficiencies in land, water, and nutrients. The inland Pacific Northwest (iPNW) of the United States of America is a wheat-dominated cropping system. The integration of winter and spring legumes and oilseeds has improved the biodiversity and nutrient-use efficiency of the cropping systems. This article examines the feasibility of pea-canola (peaola) intercropping in dryland production systems of the iPNW. In two site years, small plot peaola trials were established near Davenport, WA. Overall, the land equivalence ratio (LER) of peaola was found to be 1.46, showing an increase in efficiency of the system. Increasing the N fertilizer application rates did not affect peaola yield, indicating that peaola has low demand for N inputs. The effects of peaola on insects and bacterial diversity were examined on replicated large scale strip trials. Peaola was found to have significantly greater numbers of beneficial insects than the monoculture controls. There were no significant differences between the diversity of the soil bacterial communities found in peaola vs. pea and canola monocultures. However, we found that the strict core soil bacterial microbiome of peaola was larger than the monocultures and included core members from both the canola and pea soil microbiomes. In conclusion, the widespread adoption of peaola would likely increase the biodiversity and increase the land use efficiency of dryland production systems in the iPNW.

As Coronavirus Disease 2019 (COVID-19) hospitalization rates remain high, there is an urgent need to identify prognostic factors to improve patient outcomes. Existing prognostic models mostly consider the impact of biomarkers at presentation on the risk of a single patient outcome at a single follow up time. We collected data for 553 Polymerase Chain Reaction (PCR)-positive COVID-19 patients admitted to hospital whose eventual outcomes were known. The data collected for the patients included demographics, comorbidities and laboratory values taken at admission and throughout the course of hospitalization. We trained multivariate Markov prognostic models to identify high-risk patients at admission along with a dynamic measure of risk incorporating time-dependent changes in patients’ laboratory values. From the set of factors available upon admission, the Markov model determined that age >80 years, history of coronary artery disease and chronic obstructive pulmonary disease increased mortality risk. The lab values upon admission most associated with mortality included neutrophil percentage, red blood cells (RBC), red cell distribution width (RDW), protein levels, platelets count, albumin levels and mean corpuscular hemoglobin concentration (MCHC). Incorporating dynamic changes in lab values throughout hospitalization lead to dramatic gains in the predictive accuracy of the model and indicated a catalogue of variables for determining high-risk patients including eosinophil percentage, white blood cells (WBC), platelets, pCO2, RDW, large unstained cells (LUC) count, alkaline phosphatase and albumin. Our prognostic model highlights the nuance of determining risk for COVID-19 patients and indicates that, rather than a single variable, a range of factors (at different points in hospitalization) are needed for effective risk stratification.

Abstract Colorectal cancer (CRC) represents the third leading cause of death among cancer patients below the age of 50, necessitating improved treatment and prevention initiatives. A crude methanol extract from the wood pulp of Artocarpus heterophyllus was found to be the most bioactive among multiple others, and an enriched extract containing 84% (w/v) artocarpin (determined by HPLC–MS–DAD) was prepared. The enriched extract irreversibly inhibited the activity of human cytochrome P450 CYP2C9, an enzyme previously shown to be overexpressed in CRC models. In vitro evaluations on heterologously expressed microsomes, revealed irreversible inhibitory kinetics with an IC50 value of 0.46 µg/mL. Time- and concentration-dependent cytotoxicity was observed on human cancerous HCT116 cells with an IC50 value of 4.23 mg/L in 72 h. We then employed the azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-induced model in C57BL/6 mice, which revealed that the enriched extract suppressed tumor multiplicity, reduced the protein expression of proliferating cell nuclear antigen, and attenuated the gene expression of proinflammatory cytokines (Il-6 and Ifn-γ) and protumorigenic markers (Pcna, Axin2, Vegf, and Myc). The extract significantly (p = 0.03) attenuated (threefold) the gene expression of murine Cyp2c37, an enzyme homologous to the human CYP2C9 enzyme. These promising chemopreventive, cytotoxic, anticancer and anti-inflammatory responses, combined with an absence of toxicity, validate further evaluation of A. heterophyllus extract as a therapeutic agent.

Abstract Erosion degrades soils, reduces crop yields, and diminishes ecosystem services. The total amount of soil that has been eroded since the initiation of farming is unknown in most agricultural landscapes, which hinders assessment of soil erosion trends. In the Midwestern U.S., erosion has caused native prairie remnants to become perched above surrounding farmland, providing an opportunity to measure historical soil erosion rates. We use high‐resolution topographic surveys conducted across erosional escarpments at the boundary between 20 prairies and adjacent agricultural fields and show the median reduction in soil thickness ranges from 0.04 to 0.69 m, corresponding to erosion rates of 0.2–4.3 mm year−1, with a median value of 1.9 mm year−1. We used an association between the measured reduction in soil thickness and topographic curvature to predict regional soil erosion integrated since the beginning of farming to the present. We estimate a median historical erosion rate of 1.8 ± 1.2 mm year−1, which is nearly double the rate considered tolerable by the U.S. Department of Agriculture (USDA). Current soil loss predictions from the USDA National Resources Inventory (NRI) and the Daily Erosion Project (DEP) are lower than our historically averaged erosion rate by a factor of 3 and 8, respectively. We suggest that the NRI and the DEP underpredict soil loss rates because they do not include tillage erosion, a process shown to be important throughout the Midwestern U.S. Our findings indicate that further implementation of conservation practices is needed to reduce the high centennial‐averaged soil erosion rates that we measure to sustainable levels.

A large range of prognostic models for determining the risk of COVID-19 patient mortality exist, but these typically restrict the set of biomarkers considered to measurements available at patient admission. Additionally, many of these models are trained and tested on patient cohorts from a single hospital, raising questions about the generalisability of results. We used a Bayesian Markov model to analyse time series data of biomarker measurements taken throughout the duration of a COVID-19 patient's hospitalisation for n = 1540 patients from two hospitals in New York: State University of New York (SUNY) Downstate Health Sciences University and Maimonides Medical Center. Our main focus was to quantify the mortality risk associated with both static (e.g. demographic and patient history variables) and dynamic factors (e.g. changes in biomarkers) throughout hospitalisation, by so doing, to explain the observed patterns of mortality. By using our model to make predictions across the hospitals, we assessed how predictive factors generalised between the two cohorts. The individual dynamics of the measurements and their associated mortality risk were remarkably consistent across the hospitals. The model accuracy in predicting patient outcome (death or discharge) was 72.3% (predicting SUNY; posterior median accuracy) and 71.3% (predicting Maimonides) respectively. Model sensitivity was higher for detecting patients who would go on to be discharged (78.7%) versus those who died (61.8%). Our results indicate the utility of including dynamic clinical measurements when assessing patient mortality risk but also highlight the difficulty of identifying high risk patients.

Label-free surface-enhanced Raman spectroscopy is an emergent method for the detection and discrimination of biological analytes. Here, the authors describe SERS sensors with arrayed mildly-selective surface chemistries to give a fingerprint based on different interactions for analysing biological samples.

Los niveles de desinterés y desmotivación de gran parte del alumnado universitario representan uno de los retos más urgentes que debe afrontar el profesorado en la actualidad. En este sentido, cada vez son más los trabajos que evidencian el potencial de la “gamificación” a la hora de incrementar la motivación e implicación de los estudiantes en su proceso formativo. En estrecha relación con esto, las tecnologías digitales y, concretamente, el uso de dispositivos móviles supone un recurso de enorme significatividad para jóvenes y adolescentes. Por tanto, en este trabajo se describe la aplicación “$in TIME”, diseñada “ad hoc” con la intención de gestionar los diferentes elementos que conformaron un proyecto de “gamificación” basado en la película “In Time”. Este se implementó en la asignatura Fundamentos de la Educación Física (del segundo curso del grado en Ciencias de la Actividad Física y el Deporte, de la Universidad de Granada-España-). De igual modo, también se muestra la repercusión que tuvo en el alumnado participante, así como la valoración que hicieron de la misma. Todo ello permitirá a los docentes conocer un ejemplo real, que puede servir de ayuda e inspiración a la hora de diseñar sus futuros proyectos y, al mismo tiempo, contar con un nuevo aval del potencial de la “gamificación” en el ámbito educativo.

Summary: Circulating memory CD8 T cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 T cells (Tem) infiltrate the liver within 6 hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers. Recruitment requires CD8 T cell-intrinsic LFA-1 expression and the presence of liver phagocytes. Rapid Tem liver infiltration is distinct from recruitment to other non-lymphoid tissues in that it occurs both in the absence of liver tissue resident memory “sensing-and-alarm” function and ∼42 hours earlier than in lung infection by influenza virus. These data demonstrate relevance for Tem in protection against malaria and provide generalizable mechanistic insights germane to control of liver infections.

The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.

Madagascar experienced a major faunal turnover near the end of the first millenium CE that particularly affected terrestrial, large-bodied vertebrate species. Teasing apart the relative impacts of people and climate on this event requires a focus on regional records with good chronological control. These records may document coeval changes in rainfall, faunal composition, and human activities. Here we present new paleontological and paleoclimatological data from southwestern Madagascar, the driest part of the island today. We collected over 1500 subfossil bones from deposits at a coastal site called Antsirafaly and from both flooded and dry cave deposits at Tsimanampesotse National Park. We built a chronology of Late Holocene changes in faunal assemblages based on 65 radiocarbon-dated specimens and subfossil associations. We collected stalagmites primarily within Tsimanampesotse but also at two additional locations in southern Madagascar. These provided information regarding hydroclimate variability over the past 120,000 years. Prior research has supported a primary role for drought (rather than humans) in triggering faunal turnover at Tsimanampesotse. This is based on evidence of: (1) a large freshwater ecosystem west of what is now the hypersaline Lake Tsimanampesotse, which supported freshwater mollusks and waterfowl (including animals that could not survive on resources offered by the hypersaline lake today); (2) abundant now-extinct terrestrial vertebrates; (3) regional decline or disappearance of certain tree species; and (4) scant local human presence. Our new data allow us to document the hydroclimate of the subarid southwest during the Holocene, as well as shifts in faunal composition (including local extirpations, large-vertebrate population collapse, and the appearance of introduced species). These records affirm that climate alone cannot have produced the observed vertebrate turnover in the southwest. Human activity, including the introduction of cattle, as well as associated changes in habitat exploitation, also played an important role.