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IMPORTANCE: Data describing the early additional protection afforded by the recently recommended BNT162b2 XBB vaccine (Pfizer-BioNTech; 2023-2024 formulation) are limited. OBJECTIVE: To estimate the association between receipt of the BNT162b2 XBB vaccine and medically attended COVID-19 outcomes among US adults 18 years and older. DESIGN, SETTING, AND PARTICIPANTS: This test-negative case-control study was performed to estimate the effectiveness of the BNT162b2 XBB vaccine against COVID-19–associated hospitalization and emergency department (ED) or urgent care (UC) encounters among adults in the Kaiser Permanente Southern California health system between October 10, 2023, and December 10, 2023. Cases were those presenting with an acute respiratory illness and who had a positive SARS-CoV-2 polymerase chain reaction test; controls had an acute respiratory illness but tested negative for SARS-CoV-2. EXPOSURE: The primary exposure was receipt of the BNT162b2 XBB vaccine compared with not receiving an XBB vaccine of any kind, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. Receipt of prior (non-XBB) versions of COVID-19 vaccines was also compared with being unvaccinated to estimate remaining protection from older vaccines. MAIN OUTCOMES AND MEASURES: Analyses for cases and controls were conducted separately for COVID-19 hospital admissions and ED/UC encounters. Adjusted odds ratios and 95% CIs were estimated from multivariable logistic regression models that were adjusted for patient demographic and clinical characteristics. Estimation of vaccine effectiveness was calculated as 1 − odds ratio × 100%. RESULTS: Among 2854 cases and 15 345 controls (median [IQR] age, 56 [37-72] years; 10 658 [58.6%] female), adjusted estimation of effectiveness of the BNT162b2 XBB vaccine received a median of 34 days prior vs not having received an XBB vaccine of any kind was 62% (95% CI, 32%-79%) against COVID-19 hospitalization and 58% (95% CI, 48%-67%) for ED/UC visits. Compared with being unvaccinated, those who had received only older versions of COVID-19 vaccines did not show statistically significant reduced risk of COVID-19 outcomes, including hospital admission. CONCLUSIONS AND RELEVANCE: Findings of this case-control study reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines given that (1) the BNT162b2 XBB vaccine provided statistically significant additional protection against a range of COVID-19 outcomes and (2) older versions of COVID-19 vaccines offered little, if any, long-term protection, including against hospital admission, regardless of the number or type of prior doses received.

Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection.

Purpose: The incidence of acute myocardial infarctions (AMI) shows circadian variation typically peaking during morning hours with a decline at night. However, this variation does not occur in patients with diabetes mellitus (DM). The night’s decline of AMI may be partially explained by melatonin-related platelet inhibition. Whether this effect is absent in diabetic patients is unknown. The aim was to study the effect of melatonin on in-vitro platelet aggregation in healthy individuals and patients with type 2 DM. Methods: Platelet aggregation was measured in blood samples from healthy individuals (n= 15) and type 2 DM patients (n= 15) using multiple electrode aggregometry. Adenosine diphosphate (ADP), arachidonic acid (ASPI) and thrombin (TRAP) were used as agonists. Aggregability for each subject was tested after adding melatonin in two concentrations. Results: In healthy individuals, melatonin inhibited platelet aggregation in both higher (10–5 M) and lower concentrations (10–9 M) induced by ADP, ASPI, and TRAP (p< 0.001, p= 0.002, p= 0.029, respectively). In DM patients, melatonin did not affect platelet aggregation in both concentrations induced by ADP, ASPI, and TRAP. Melatonin decreased platelet aggregation induced by ADP, ASPI, and TRAP significantly more in healthy individuals compared to patients with DM. (p= 0.005, p= 0.045 and p= 0.048, respectively). Conclusion: Platelet aggregation was inhibited by melatonin in healthy individuals. In-vitroantiplatelet effect of melatonin in type 2 DM patients is significantly attenuated.

XBB-related omicron sublineages have recently replaced BA.4/5 as the predominant omicron sublineages in the USA and other regions globally. Despite preliminary signs of immune evasion of XBB sublineages, few data exist describing the real-world effectiveness of bivalent COVID-19 vaccines, especially against XBB-related illness. We aimed to investigate the effectiveness of the Pfizer-–BioNTech BNT162b2 BA.4/5 bivalent vaccine against both BA.4/5-related and XBB-related disease in adults aged 18 years or older.

Executive functions like working memory, inhibitory control, and cognitive flexibility are a set of neurocognitive processes involved in reasoning, planning, and self-regulatory skills that allow goal-oriented behaviors. Mounting evidence supports the importance of these processes for educational success from early on. Executive functions can be improved by employing computerized activities. However, most of the evidence with gamified tasks comes from controlled studies in laboratory settings, while the efficiency of interventions deployed in real-world circumstances is scarce. Furthermore, the effectiveness of an intervention might be modulated by school socioeconomic status, but the evidence in this regard is still limited. The present study examined the efficiency of a short training program, aimed to stimulate executive functions, deployed in high- and low-socioeconomic school kindergarten classes. One hundred and thirty-six children (M = 5.30, SD = 0.36 years old) participated in a randomized, pre/post, controlled design. Data were analyzed with multilevel analysis. We found that all children that participated in the training group improved their working memory span and performance in a fluid intelligence task. Gains in inhibitory control and cognitive flexibility were observed only in children from low socioeconomic background schools. We also explored far-transfer effects on non-trained skills. We found no evidence of improved performance in a planning task, or classroom behaviors typically associated with executive functions. Our results show that it is possible to promote cognitive development in kindergarteners through video games played within classrooms of diverse sociocultural contexts.

The SARS-CoV-2 omicron (B.1.1.529 BA.1) lineage was first detected in November, 2021, and is associated with reduced vaccine effectiveness. By March, 2022, BA.1 had been replaced by sub-lineage BA.2 in the USA. As new variants evolve, vaccine performance must be continually assessed. We aimed to evaluate the effectiveness and durability of BNT162b2 (Pfizer–BioNTech) against hospital and emergency department admissions for BA.1 and BA.2.

The phenomenon through which vibrations are produced with frequencies related to the period of fingerprint ridges and the speed they slide across a surface is known as the fingerprint effect. Here, we use a simple bioinspired sensor with parallel, straight, fingerprint-like ridges and a single ferroelectric ceramic transducer to show that the fingerprint effect is orientation dependent and that, if the orientation is known, it can be used to estimate slip speed. Our results, obtained at sliding speeds of 15, 20, and 25 mm/s and orientations from 0° to 90°, clearly demonstrate this dependence. We then describe a simple algorithm for estimating slip speed in real time. Using experimental results as input, we use that algorithm to run simulations, using MATLAB software, of real-time slip speed estimation. From these simulations, we identify some tradeoffs in parameter selection for the slip speed estimation algorithm. Finally, the fingerprint effect is used for real-time slip speed estimation for feedback in a controlled slip experiment.

Immune stimulating agents like Toll-like receptor 7 (TLR7) agonists induce potent antitumor immunity but are limited in their therapeutic window due to off-target immune activation. Here, we developed a polymeric delivery platform that binds excess unpaired cysteines on tumor cell surfaces and debris to adjuvant tumor neoantigens as an in situvaccine. The metabolic and enzymatic dysregulation in the tumor microenvironment produces these exofacial free thiols, which can undergo efficient disulfide exchange with thiol-reactive pyridyl disulfide moieties upon intratumoral injection. These functional monomers are incorporated into a copolymer with pendant mannose groups and TLR7 agonists to target both antigen and adjuvant to antigen presenting cells. When tethered in the tumor, the polymeric glyco-adjuvant induces a robust antitumor response and prolongs survival of tumor-bearing mice, including in checkpoint-resistant B16F10 melanoma. The construct additionally reduces systemic toxicity associated with clinically relevant small molecule TLR7 agonists.

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Colon cancer, a potentially preventable and curable cancer, remains one of the leading causes of cancer-related death in the United States. In 2010 the researchers undertook a multifaceted initiative to reduce colon cancer mortality rates by 50% over 10 years.

The duration of protection against the omicron (B.1.1.529) variant for current COVID-19 vaccines is not well characterised. Vaccine-specific estimates are especially needed. We aimed to evaluate the effectiveness and durability of two and three doses of the BNT162b2 (Pfizer–BioNTech) mRNA vaccine against hospital and emergency department admissions due to the delta (B.1.617.2) and omicron variants.

Concentration polarization is an effect of concentration boundary layers formation by solutions transported through a membrane. The paper was aimed at determining the osmotic membrane transport of a ternary solutions under concentration polarization conditions. Volume fluxes (Jvkr) in a system containing a Nephrophan® membrane set in a horizontal plane separating water and aqueous ammonia and/or H2SO4solutions were experimentally studied. The experimental results were used to evaluate the effects of concentration polarization, natural convection, and amplification of Jvkrusing defined coefficients. It was shown that for the homogenous solutions Jvkdepends on the concentration and composition of the solutions, whereas for concentration polarization conditions, Jvkradditionally depends on the configuration of the membrane system. Next, Jvkwas used to assess the production of entropy for the conditions of homogeneity of solutions (ΦSk), while Jvkrwas used to assess the production of entropy for concentration polarization conditions (ΦSkr). In addition, the diffusion–convective effects and the convection effect in the source of entropy were calculated. The concentration polarization coefficient ζirwas related to a modified concentration Rayleigh number, for example, the parameter controlling the transition from the non-convective (diffusive) to the convective state. The results show that the Rayleigh number acts as a switch between two states of the concentration field: a convective with a higher entropy production and a non-convective with a lower entropy production. Therefore, membrane transport under polarization concentration conditions leads to a decrease in the entropy production. Understanding the membrane transport properties and mechanism can be used for developing and improving membrane technologies and techniques useful in medicine and in water and wastewater treatment processes.

High-risk medication dispenses to patients with a prior fall or hip fracture represent a potentially dangerous disease-drug interaction among older adults. The research team quantified the prevalence, identified risk factors, and generated patient and provider insights into high-risk medication dispenses in a large, community-based integrated health system using a commonly used quality measure.

The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviourally relevant context, we generated humanised mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioural and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition, and sex. In humanised females carrying the CG- but not the AT-allele, ELA led to altered HPA axis functioning, exploratory behaviour, and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5in shaping the sex-specific outcome of ELA in adulthood.

While technology has dramatically changed medical practice, various aspects of mental health practice and diagnosis remain almost unchanged across decades. Here we argue that artificial intelligence — with its capacity to learn and infer from data the workings of the human mind — may rapidly change this scenario. However, this process will not happen without friction and will promote an explicit reflection of the overarching goals and foundational aspects of mental health. We suggest that the converse relation is also very likely to happen. The application of artificial intelligence to a field that relates to the foundations of what makes us human — our volition, our thoughts, our pains and pleasures — may shift artificial intelligence back to its earliest days, when it was mostly conceived of as a laboratory to explore the limits and possibilities of human intelligence.

There are many situations of excessive production of reactive oxygen species (ROS) such as radiation, ischemia/reperfusion (I/R), and inflammation. ROS contribute to and arises from numerous cellular pathologies, diseases, and aging. ROS can cause direct deleterious effects by damaging proteins, lipids, and nucleic acids as well as exert detrimental effects on several cell signaling pathways. However, ROS are important in many cellular functions. The injurious effect of excessive ROS can hypothetically be mitigated by exogenous antioxidants, but clinically this intervention is often not favorable. In contrast, molecular hydrogen provides a variety of advantages for mitigating oxidative stress due to its unique physical and chemical properties. H2may be superior to conventional antioxidants, since it can selectively reduce •OH radicals while preserving important ROS that are otherwise used for normal cellular signaling. Additionally, H2exerts many biological effects, including antioxidation, anti-inflammation, anti-apoptosis, and anti-shock. H2accomplishes these effects by indirectly regulating signal transduction and gene expression, each of which involves multiple signaling pathways and crosstalk. The Keap1-Nrf2-ARE signaling pathway, which can be activated by H2, plays a critical role in regulating cellular redox balance, metabolism, and inducing adaptive responses against cellular stress. H2also influences the crosstalk among the regulatory mechanisms of autophagy and apoptosis, which involve MAPKs, p53, Nrf2, NF-ΚB, p38 MAPK, mTOR, etc. The pleiotropic effects of molecular hydrogen on various proteins, molecules and signaling pathways can at least partly explain its almost universal pluripotent therapeutic potential.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

AbstractAmphibian populations are threatened globally, and one of the hypotheses for these declines is climate change. Species distribution models are frequently used to predict changes in suitable habitat as a result of changing climates; however, these projections can be heavily influenced by choice of modeling approach. To evaluate global predictions for amphibians, we conducted a literature review of studies that utilize correlative species distribution models to project changes in climate suitability under various climate change scenarios. We paid particular attention to the use of model selection in choosing among candidate species distribution models (SDMs) so as to control for overparameterization of SDMs. In addition, we conducted a case study with three species of Slender Salamanders (Batrachoseps) to further investigate the impact of differences in modeling decisions on projected amphibian climate suitability. We found 83 studies (including the present case study) in which projections of future climate suitability were made for amphibian species. Of those studies, 36 included estimates of percent change in climate suitability and thus were included in our meta-analysis. These studies included projections for over 1000 species or species complexes, with the majority being Anurans (86%), and encompassed five continents with the most representation in South America, Europe, and North America. Across these studies, average projected change in climate suitability ranged from －70% to 167%, and these projected changes varied with dispersal assumptions representative concentration pathway (RCP) used, the projection year, and taxonomic order. Only three of the 36 studies reported the use of Akaike information criterion (AIC)-based model selection to choose a best-fit SDM. However, our case study demonstrated that predicted change in climate suitability varied whether the best-fit or default SDM was used for projections. Further, this result varied among species (ΔAIC = 0), suggesting that the impact of overparameterization differs across species. Our results illustrate that there is a pressing need to project climate suitability across more species and more geographic regions. In addition, we may need to revisit projections for previously investigated species to evaluate additional climate scenarios and whether overparameterization may have influenced projections. Our ability to accurately model future changes in climate suitability will be essential for successful conservation and management plans for amphibians.

Multiple regions, each with the same ambiguous chromatic neural representation, are resolved to have the identical perceived color more often than chance [Proc. Natl. Acad. Sci. USA93, 15508 (1996)PNASA60027-842410.1073/pnas.93.26.15508; J. Opt. Soc. Am. A35, B85 (2018)JOAOD60740-323210.1364/JOSAA.35.000B85]. This reveals that the regions are grouped, but it is unclear whether they are grouped because each one has the identical competing representations of the same stimuli (that is, the same chromaticities) or, alternatively, identical competing representations of the same colors one sees. The current study uses chromatic induction, as in Nat. Neurosci.6, 801 (2003)NANEFN1097-625610.1038/nn1099, to disentangle whether grouping depends on identical (though ambiguous) stimulus chromaticities or on perceived colors, by (1) inducing one chromaticity to appear in two different colors or (2) inducing two different chromaticities to appear in the same color. All stimuli were equiluminant gratings with chromatic inducing and test fields. Three observers were tested, first completing color matches to measure induced color-appearance shifts and second completing grouping measurements using interocular-switch rivalry, a method with rivalrous dichoptic images swapped between the eyes at 3.75 Hz [J. Vis.17, 9 (2017)1534-736210.1167/17.5.9]. Each of two separate areas, one above and one below fixation, had dichoptic rivalry. The two sets of regions had either identical or different chromaticities that could appear either as the same color or not. Observers reported their percepts when both areas above and below fixation were grouped by color or by chromaticity (or neither in an additional experimental condition). All conditions showed significant groupings for every observer, including when neither color nor chromaticity was identical in a “group.” Moreover, there was never a significant effect of chromaticity versus color for any observer. This is the result expected if neither color nor chromaticity must match between two regions in order for them to be grouped and suggests that, instead, some other feature drives grouping.

Supplemental Digital Content is available in the text.

PurposeDescribe an evidence-based process (EBP) to promote early skin-to-skin care (SSC) intervention and increase mother's-own-milk (MOM) feedings at discharge among extremely low birth weight (ELBW) infants.DesignThis EBP aimed to address the following clinical question: Among ELBW infants, does early SSC &#ξ2264;16 days of life (DOL), compared to SSC >16 DOL, result in more infants receiving MOM feedings at discharge?SampleA retrospective chart review of 199 ELBW infants.Main Outcome VariableEarly SSC intervention among ELBW infants and MOM at discharge.ResultsEarly SSC intervention increased from 46 to 73 percent among ELBW infants over the EBP period. Frequency of SSC intervention was associated with year of EBP and MOM at discharge (p= <.05). ELBW infants in the early SSC intervention group received more MOM at discharge.

Effective wildlife management requires an understanding of how individuals select environmental factors, although few studies assess how habitat selection may differ over time or between sexes. During the post‐breeding period (15 May to 1 Sep), we tracked 146 male American woodcock (Scolopax minor) in Rhode Island, USA, from 2010–2021 to assess how habitat selection varied over time, and 17 females and 51 males during the final 2 years of the study to document sex‐specific differences in habitat selection. Males generally had smaller home ranges (35.0 ± 10.7 [margin of error] ha) and preferred habitat mosaics that consisted of forested wetlands, young forest patches, areas of deciduous forest, moist soils with gentle slopes, and riparian corridors. We detected subtle differences between sexes in selection for wetland young forest, upland young forest, percent slope, distance to upland young forest, distance to streams, and distance to moist soils. During 2020–2021, females tended to have larger home ranges (78.7 ± 46.4 ha) than males (35.0 ± 10.7 ha) and more strongly selected sites closer to riparian corridors, while males selected areas that were closer to upland young forest with flatter slopes than the available surrounding landscape. Such sex‐specific differences in habitat selection may be related to males and females prospecting for potential breeding sites during this post‐breeding period for the following spring. We used the top‐ranked habitat selection models for males and females to produce a spatially explicit state‐wide map that identifies low‐to‐high likelihood of use areas that can be used to guide forest management decisions in southern New England to maximize benefits for American woodcock. We used a combination of long‐ and short‐term radio‐tracking datasets to understand male and female woodcock habitat selection. Males and females exhibited subtle differences in habitat selection, highlighting the importance of considering sex‐specific preferences when managing for species of conservation concern.

The only FDA-approved oral immunotherapy for a food allergy provides protection against accidental exposure to peanuts. However, this therapy often causes discomfort or side effects and requires long-term commitment. Better preventive and therapeutic solutions are urgently needed. We develop a tolerance-inducing vaccine technology that utilizes glycosylation-modified antigens to induce antigen-specific non-responsiveness. The glycosylation-modified antigens are administered intravenously (i.v.) or subcutaneously (s.c.) and traffic to the liver or lymph nodes, respectively, leading to preferential internalization by antigen-presenting cells, educating the immune system to respond in an innocuous way. In a mouse model of cow’s milk allergy, treatment with glycosylation-modified β-lactoglobulin (BLG) is effective in preventing the onset of allergy. In addition, s.c. administration of glycosylation-modified BLG shows superior safety and potential in treating existing allergies in combination with anti-CD20 co-therapy. This platform provides an antigen-specific immunomodulatory strategy to prevent and treat food allergies.

Immunogenic biologics trigger an anti-drug antibody (ADA) response in patients that reduces efficacy and increases adverse reactions. Our laboratory has shown that targeting protein antigen to the liver microenvironment can reduce antigen-specific T cell responses; herein, we present a strategy to increase delivery of otherwise immunogenic biologics to the liver via conjugation to a synthetic mannose polymer, p(Man). This delivery leads to reduced antigen-specific T follicular helper cell and B cell responses resulting in diminished ADA production, which is maintained throughout subsequent administrations of the native biologic. We find that p(Man)-antigen treatment impairs the ADA response against recombinant uricase, a highly immunogenic biologic, without a dependence on hapten immunodominance or control by T regulatory cells. We identify increased T cell receptor signaling and increased apoptosis and exhaustion in T cells as effects of p(Man)-antigen treatment via transcriptomic analyses. This modular platform may enhance tolerance to biologics, enabling long-term solutions for an ever-increasing healthcare problem.

AbstractAmphibian populations are threatened globally, and one of the hypotheses for these declines is climate change. Species distribution models are frequently used to predict changes in suitable habitat as a result of changing climates; however, these projections can be heavily influenced by choice of modeling approach. To evaluate global predictions for amphibians, we conducted a literature review of studies that utilize correlative species distribution models to project changes in climate suitability under various climate change scenarios. We paid particular attention to the use of model selection in choosing among candidate species distribution models (SDMs) so as to control for overparameterization of SDMs. In addition, we conducted a case study with three species of Slender Salamanders (Batrachoseps) to further investigate the impact of differences in modeling decisions on projected amphibian climate suitability. We found 83 studies (including the present case study) in which projections of future climate suitability were made for amphibian species. Of those studies, 36 included estimates of percent change in climate suitability and thus were included in our meta-analysis. These studies included projections for over 1000 species or species complexes, with the majority being Anurans (86), and encompassed five continents with the most representation in South America, Europe, and North America. Across these studies, average projected change in climate suitability ranged from −70 to 167, and these projected changes varied with dispersal assumptions representative concentration pathway (RCP) used, the projection year, and taxonomic order. Only three of the 36 studies reported the use of Akaike information criterion (AIC)-based model selection to choose a best-fit SDM. However, our case study demonstrated that predicted change in climate suitability varied whether the best-fit or default SDM was used for projections. Further, this result varied among species (ΔAIC 0), suggesting that the impact of overparameterization differs across species. Our results illustrate that there is a pressing need to project climate suitability across more species and more geographic regions. In addition, we may need to revisit projections for previously investigated species to evaluate additional climate scenarios and whether overparameterization may have influenced projections. Our ability to accurately model future changes in climate suitability will be essential for successful conservation and management plans for amphibians.

Two endothelial cell lines were selected as models to investigate an effect of incubation with cytokine tumour necrosis factor type a (TNF-a) using FT-IR imaging spectroscopy. Both cell lines are often used in laboratories, and are typical lung vascular endothelial cells (HMLVEC) and derived from the fusion of umbilical vein endothelial cells with lung adenocarcinoma cells (EA.hy926). This study was focused on alteration of spectral changes accompanying inflammation at the cellular level by applying two resolution systems of FT-IR microscopy. The standard approach, with a pixel size of ca. 5.5 µm2, determined the inflammatory state of the whole cell, while a high magnification resolution (pixel size of ca. 1.1 µm2) provided information at the sub-cellular level. Importantly, the analysis of IR spectra recorded with different modes produced similar results in overall and yielded to unambiguous classification of inflamed cells. Generally, the most significant changes in the cells under the influence of TNF-a are related with lipids - their composition and concentration; however segregation of cells into sub-cellular compartments provided an additional insight into proteins and nucleic acids related events. The observed spectral alterations are specific for the type of endothelial cell line.

Calprotectin, a metal ion-binding protein complex, plays a crucial role in the innate immune system and has gained prominence as a biomarker for various intestinal and systemic inflammatory and infectious diseases, including inflammatory bowel disease (IBD) and tuberculosis (TB). Current clinical testing methods rely on enzyme-linked immunosorbent assays (ELISAs), limiting accessibility and convenience. In this study, we introduce the Fab-Enabled Split-luciferase Calprotectin Assay (FESCA), a novel quantitative method for calprotectin measurement. FESCA utilizes two new fragment antigen binding proteins (Fabs), CP16 and CP17, that bind to different epitopes of the calprotectin complex. These Fabs are fused with split NanoLuc luciferase fragments, enabling the reconstitution of active luciferase upon binding to calprotectin either in solution or in varied immobilized assay formats. FESCA’s output luminescence can be measured with standard laboratory equipment as well as consumer-grade cell phone cameras. FESCA can detect physiologically relevant calprotectin levels across various sample types, including serum, plasma, and whole blood. Notably, FESCA can detect abnormally elevated native calprotectin from TB patients. In summary, FESCA presents a convenient, low-cost, and quantitative method for assessing calprotectin levels in various biological samples, with the potential to improve the diagnosis and monitoring of inflammatory diseases, especially in at-home or point-of-care settings.

•We present a novel immunotherapy platform for hematological cancers that exploits fundamental metabolic dysregulation of cancer cells.•Our multivalent, thiol-reactive chemistry covalently links immune adjuvants to free thiols on cancer cell debris induced by chemotherapy.

Timely follow-up of abnormal laboratory results is important for high-quality care. We sought to identify risk factors, facilitators, and barriers to timely follow-up of an abnormal estimated glomerular filtration rate (eGFR) for the diagnosis of chronic kidney disease.

American woodcock (Scolopax minor; woodcock) are monitored, in part, by counts of displaying male woodcock collected via the American Woodcock Singing Ground Survey (SGS), which suggests long‐term, range‐wide declines in woodcock populations. Data from the SGS have been used extensively to develop conservation plans, direct management actions, and understand causes of decline. To avoid bias, the SGS should be timed to avoid spring migration, and the distribution of survey routes should coincide with woodcock breeding distribution. Our objectives for this research were to evaluate SGS timing with the phenology of male woodcock migration, relate the spatial coverage of the SGS to male woodcock breeding distributions, and explore other sources of variation in woodcock migration timing. We marked 133 male woodcock captured throughout eastern North America with global positioning system (GPS) transmitters during 2019–2022, and compared the timing of their spring migration with the spatiotemporal stratification of the SGS. Most woodcock (74%) completed migration prior to the onset of the SGS. In the northernmost SGS zone, a greater percentage of males (34%) continued migration during the survey window; however, the influence of this mismatch is offset because SGS routes were run more frequently during the second half of the window. Young woodcock completing their first spring migration took 8.6 days longer to do so, on average, compared to adults, and so were more likely to migrate during the SGS window. We found little evidence that timing of migration varied among years. Existing SGS routes cover the majority of male woodcock post‐migratory breeding distribution, with 90% of male woodcock establishing final breeding sites within the spatial coverage of the SGS. Our results confirm the SGS includes some migrating males, with the proportion relative to resident breeding males increasing in more northern survey strata. Our data suggests these errors are unlikely to bias trend estimates at large scales (e.g., within woodcock management regions), but there may be potential for bias at more local scales (e.g., state or provincial population indices). American woodcock populations are monitored by roadside counts referred to as singing ground surveys (SGS). Using GPS tracking of male woodcock, we show that survey timing and locations are fairly consistent with migration phenology in the eastern portion of their range. At least 90% of male woodcock ended migration in regions with SGS coverage, and 85−90% of males complete migration before the start of SGS survey timing.

Butyrate is a key bacterial metabolite that plays an important and complex role in modulation of immunity and maintenance of epithelial barriers. Its translation to clinic is limited by poor bioavailability, pungent smell, and the need for high doses, and effective delivery strategies have yet to realize clinical potential. Here, a novel polymeric delivery platform for tunable and sustainable release of butyrate consisting of a methacrylamide backbone with butyryl ester or phenyl ester side chains as well as mannosyl side chains, which is also applicable to other therapeutically relevant metabolites is reported. This platform's utility in the treatment of non‐healing diabetic wounds is explored. This butyrate‐containing material modulated immune cell activation in vitro and induced striking changes in the milieu of soluble cytokine and chemokine signals present within the diabetic wound microenvironment in vivo. This novel therapy shows efficacy in the treatment of non‐healing wounds through the modulation of the soluble signals present within the wound, and importantly accommodates the critical temporal regulation associated with the wound healing process. Currently, the few therapies to address non‐healing wounds demonstrate limited efficacy. This novel platform is positioned to address this large unmet clinical need and improve the closure of otherwise non‐healing wounds. A novel delivery platform for the temporally controlled release of the microbial metabolite butyrate to accelerate the healing of chronic wounds is reported. Butyrate is implicated in the improvement of barrier function and is here employed to address the large clinical problem of non‐healing cutaneous wounds.

The effect of combined oral contraceptives (COCs) on female sexuality has long been a matter of discussion, but placebo-controlled studies are lacking. Thus, the aim of the present study was to investigate if an oestradiol-containing COC influences sexual function.Investigator-initiated, randomised, double-blinded, placebo-controlled clinical trial where 202 healthy women were randomised to a combined oral contraceptive (1.5 mg oestradiol and 2.5 mg nomegestrol acetate) or placebo for three treatment cycles.Sexual function at baseline and during the last week of the final treatment cycle was evaluated by the McCoy Female Sexuality Questionnaire. Serum and hair testosterone levels were assessed at the same time points.Compared to placebo, COC use was associated with a small decrease in sexual interest (COC median change score: −2.0; interquartile range (IQR): −5.0 to 0.5 vs placebo: −1.0; IQR: −3.0 to 2.0, P= 0.019), which remained following adjustment for change in self-rated depressive symptoms (B= −0.80 ± 0.30, Wald = 7.08, P= 0.008). However, the proportion of women who reported a clinically relevant deterioration in sexual interest did not differ between COC or placebo users (COC 18 (22.2%) vs placebo 16 (17.8%), P= 0.47). Change in other measured aspects of sexual function as well as total score of sexual function did not differ between the two treatments.This study suggests that use of oestradiol-based COCs is associated with reduced sexual interest. However, the changes are minute, and probably not of clinical relevance.

Amphetamine is a common therapeutic agent for alleviating the core symptoms associated with attention-deficit hyperactivity disorder (ADHD) in children and adults. The current study used a translational model of attention, the five-choice serial reaction time (5-CSRT) procedure with rats, to examine the time-course effects of d-amphetamine. Effects of different dosages of d-amphetamine were related to drug–plasma concentrations, fashioned after comprehensive pharmacokinetic/pharmacodynamic assessments that have been employed in clinical investigations. We sought to determine whether acute drug–plasma concentrations that enhance performance in the 5-CSRT procedure are similar to those found to be therapeutic in patients diagnosed with ADHD. Results from the pharmacokinetic/pharmacodynamic assessment indicate that d-amphetamine plasma concentrations associated with improved performance on the 5-CSRT procedure overlap with those that have been reported to be therapeutic in clinical trials. The current findings suggest that the 5-CSRT procedure may be a useful preclinical model for predicting the utility of novel ADHD therapeutics and their effective concentrations.

Variability of response to treatment hinders successful management of rheumatoid arthritis (RA). Consequently, a clinical pharmacogenetics model for predicting response to methotrexate (CP-MTX) has been previously proposed that includes four clinical variables (disease activity, sex, the presence of rheumatoid factor and smoking status) and four SNPs (rs2236225, rs17602729, rs1127354, and rs2372536) in genes of the folate pathway. It showed good performance, but failed to attract attention, likely, in relation with lack of clear clinical benefit. Here, we have revised the value of the CP-MTX model directly addressing its clinical benefit by focusing on the expected benefit-cost of the predictions. In addition, our study included a much larger number of RA patients (n= 720) in MTX monotherapy than previous studies. Benefit of CP-MTX prediction was defined as the patients that would have received combination therapy as first treatment because they were correctly predicted as non-responders to MTX monotherapy. In contrast, cost of CP-MTX prediction was defined as the responder patients that were wrongly predicted as non-responders. Application of CP-MTX predictions to our patients showed a good benefit-cost relationship, with half of the 66.7% non-responders to MTX monotherapy rightly directed to alternative treatments (a benefit of 33.3%) at the cost of 8.5% wrongly predicted non-responders. These benefits-costs were consistent with reanalysis of the previously published studies. Therefore, predictions of CP-MTX showed a good benefit-cost relationship for informing MTX prescription.