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A sequential explanatory mixed methods study was conducted to determine special education teachers' (SETs) pandemic experiences in the U.S. state of Georgia. We distributed a survey, held focus groups, and analyzed both data for complementarity. We found that SETs experienced challenges, benefits, and concerns when they returned to their classrooms. Although they reported feeling professionally supported during remote learning, they described difficulties and worries about meeting the individualized needs of students with disabilities. Special educators' increased workload and stress likely impacted attrition and student learning outcomes. Based on these pandemic-related experiences, we provided five recommendations for researchers, administrators, and policymakers to address the SET shortage and prepare for future school closures.

Menarche can be a difficult transition for young people. With appropriate education, youth can feel more positively about the menstrual experience. Since many elementary teachers are not equipped with menstrual health knowledge, the education falls to the school nurse. However, it is unknown if school nurses feel comfortable communicating about menstruation with young people. The purpose of this study was to explore school nurses' perceptions regarding menstrual health education in elementary schools (grades K-5). An online mixed-methods survey was established using Qualtrics. Through snowball sampling, 30 elementary school nurses responded. Using the Integrated Behavioral Model (IBM) as a framework, a deductive semantic thematic analysis was used to identify themes for each question. Data suggested that elementary school nurses would participate in professional development regarding menstrual health and hygiene. School health nurses are receiving limited knowledge/skills surrounding pedagogy and are not familiar with cultural differences when it comes to menstrual health.

Background: Quantitative thresholds are helpful to define an abnormal DaT SPECT in patients with suspected nigrostriatal degenerative diseases (NSDD). The optimal DaTQUANT threshold for diagnostic accuracy of DaT SPECT across combined movement and cognitive disorder populations has been previously described. Methods: We established optimal DaTQUANT thresholds that enhance the discrimination between dementia with Lewy bodies (DLB) and non-DLB dementia types, as well as between Parkinsonian syndromes (PS) and conditions not characterized by nigrostriatal degeneration (non-PS). Results: Data from a total of 303 patients were used in this retrospective analysis. Posterior putamen of the more affected hemisphere (MAH) was shown to be an accurate single-variable predictor for both DLB and PS and was comparable to the most accurate multi-variable models. Conclusions: Automated quantification with DaTQUANT can accurately aid in the differentiation of DLB from non-DLB dementias and PS from non-PS. Optimal thresholds for assisting a diagnosis of DLB are striatal binding ratio (SBR) ≤ 0.65, z-score ≤ −2.36, and a percent deviation ≤ −0.54 for the posterior putamen of the MAH. Optimal posterior putamen thresholds for assisting a diagnosis of PS are SBR ≤ 0.92, z-score ≤ −1.53, and a percent deviation ≤ −0.33, which are similar to our previously reported posterior putamen threshold values using a blended patient pool from multiple study populations.

Purpose More than 1,500,000 adolescents in the United States report using emergency services for the majority of their medical needs. Although the American Council for Graduate Medical Education offers some guidance on the inclusion of pediatric topics in an emergency medicine (EM) residency curriculum, it does not specifically address adolescent-related competencies. We aimed to develop a consensus on which adolescent health topics are most important to cover in a didactic curriculum for EM residents. Methods Physicians from multiple specialties, such as EM, pediatric EM, and adolescent medicine, were invited as panelists in a modified Delphi process. In round 1, the panelists were asked to determine which competencies in adolescent medicine are most important for a graduating EM resident to master. In round 2, they were asked to specify the competencies that should be included in an EM residency didactic curriculum. In round 3, they prioritized the most critical competencies for curriculum inclusion. Results Consensus was reached on a total of 26 topics that were found crucial to be included in a didactic curriculum for EM residents. Of these, the panel prioritized the following: (1) “manage a patient presenting after reported sexual assault,” (2) “accurately diagnose ovarian torsion,” and (3) “manage a patient presenting for symptoms of sexually transmitted infection.” Conclusion The modified Delphi process yielded recommendations to guide the development of an adolescent medicine curriculum for EM residents. Sexual and reproductive healthcare issues were identified as the most important topics.

ABSTRACT We are still largely reliant on pesticides for the suppression of arthropod pests which threaten human health and food production, but the recent rise of evolved resistance among important pest species has reduced pesticide efficacy. Despite this, our understanding of strategies that effectively limit the evolution of resistance remains weak. Male‐killing sex ratio distorting microbes (SRDMs), such as Wolbachia and Spiroplasma, are common among arthropod species. Previous theoretical work has suggested that they could limit adaptive potential in two ways: first, because by distorting sex ratios they reduce the effective population size, and second, because infected females produce no male offspring which restricts gene flow. Here we present the results of a novel experiment in which we test the extent by which these two mechanisms limit the adaptive response of arthropods to pesticide. Using a fully factorial design, we manipulated the adult sex ratio of laboratory populations of Drosophila melanogaster, both in the presence and absence of SRDMs, and exposed these populations to six generations of pesticide poisoning. This design allows the effects of SRDMs on sex ratio and their effects on gene flow to be estimated separately. After six generations, individuals from populations with even sex ratios displayed a higher resistance to pesticide relative to individuals from female‐biased populations. By contrast, we found no effect of the presence of SRDMs in host populations on pesticide resistance independent of sex ratio. In addition, males were more susceptible to pesticide than females—this was true of flies from both naïve and previously exposed populations. These findings provide the first empirical proof of concept that sex ratio distortion arising from SRDMs can limit adaptation to pesticides, but cast doubt on the theoretical effect of male‐killers limiting adaptation by disrupting gene flow.

The beneficial reuse and recovery of biosolids is an attractive option instead of disposal. However, odour emissions present significant challenges to land application of biosolids, increasing operational costs and reducing community acceptance. This study aimed to assess the influence of conveying and storage conditions in wastewater treatment plants on the sensory impact from biosolids. For sensory assessment, samples of anaerobically digested biosolids were collected after centrifuge and during storage out-loading. The emissions were extracted over 15 days using a dynamic flux chamber and sensory analysis conducted using an ODP coupled to a TD-GC-MS. Odour descriptors and intensities (from 1 – weak to 4 – strong) were evaluated by expert panellists, providing insights into the sensory aspects of odour emissions. The ODP results showed variations in the number of occurrences, intensity and modified frequency of odour events across the stages of wastewater solids processing and laboratory storage. Conveying could potentially impact the release of volatile compounds due to the mechanical agitation that can aerate and disturb the structure and surface of the biosolids. On the other hand, storage can accelerate biological and chemical processes as a result of the development of anaerobic conditions leading to subsequent odour generation. The interplay between wastewater treatment processes and odour emissions is complex and requires targeted strategies. The application of sensorial analysis contributes to valuable insights into understanding and managing odour emissions in wastewater treatment plants, offering potential avenues for optimizing operational parameters to benefit biosolids reuse initiatives. Keywords: Wastewater sludge; Anaerobic digestion; Biosolids; Beneficial reuse; Land application; Gaseous emissions; Sensory emissions; Sensory analysis; Odour detection port.

IntroductionInsomnia is associated with mild cognitive impairment, although the mechanisms of this impairment are not well-understood. Timing of slow-wave and rapid eye movement sleep may help explain cognitive impairments common in insomnia. This investigation aimed to determine whether cognitive changes following continuous theta-burst stimulation (cTBS) are attributable to active stimulation, polysomnographic parameters of sleep, or both.MethodData presented here are part of a pilot clinical trial aiming to treat insomnia by targeting a node in the default mode network using an inhibitory 40-s (cTBS). A double-blind counterbalanced sham-controlled crossover design was conducted. Participants (N = 20) served as their own controls on two separate in-laboratory visits—one with active cTBS and the other with sham cTBS. Each visit included cognitive assessments before and after stimulation and following a night of sleep in the lab monitored with polysomnography.ResultsSlow wave sleep duration influenced working memory in the active cTBS condition, with shorter duration predicting improvements in working memory post sleep (B = −0.003, p = 0.095). Onset latency to rapid eye movement sleep predicted subsequent working memory, regardless of treatment condition (B = −0.001, p = 0.040). Results suggest that changes in attention and processing speed were primarily due to slow wave sleep onset (B = −0.001, p = 0.017) and marginally predicted by slow wave sleep duration (B = 0.002, p = 0.081) and sleep efficiency (B = 0.006, p = 0.090).ConclusionsFindings emphasize the important role that timing of slow-wave and rapid eye movement sleep have on information processing. Future work using larger sample sizes and more stimulation sessions is needed to determine optimal interactions between timing and duration of slow wave and rapid eye movement throughout the sleep period.Clinical trial registrationThis study is registered on ClinicalTrials.gov (NCT04953559). https://clinicaltrials.gov/study/NCT04953559?locStr=Arizona&country=United%20States&state=Arizona&cond=insomnia&intr=tms%20&rank=1

Abstract Background Several legacy and emerging per- and polyfluoroalkyl substances (PFAS) have been regulated around the world. There is growing concern over the proliferation of alternative PFAS, as well as PFAS precursors. Biomonitoring data for PFAS are critical for assessing exposure and human health risk. Methods We collected serum samples from 289 adult female participants in a 2018–2021 follow-up study of the Maternal-Infant Research on Environmental Chemicals (MIREC) Canadian pregnancy cohort. Samples were analyzed for 40 PFAS using ultra-performance liquid chromatography–tandem mass spectrometry. For those compounds with > 50% detection, as well as the sum of these compounds, we describe serum concentrations and patterns of exposure according to sociodemographic and obstetrical history characteristics. Results 17 out of 40 PFAS were detected in > 50% of samples with 7 of these detected in > 97% of samples. Median [95th percentile] concentrations (µg/L) were highest for PFOS (1.62 [4.56]), PFOA (0.69 [1.52]), PFNA (0.38 [0.81]), and PFHxS (0.33 [0.92]). Geometric mean concentrations of PFOA and PFHxS were approximately 2-fold lower among those with more children (≥ 3 vs. 1), greater number of children breastfed (≥ 3 vs. ≤ 1), longer lifetime duration of breastfeeding (> 4 years vs. ≤ 9 months), and shorter time since last pregnancy (≤ 4 years vs. > 8 years). We observed similar patterns for PFOS, PFHpS, and the sum of 17 PFAS, though the differences between groups were smaller. Concentrations of PFOA were higher among “White” participants, while concentrations of N-MeFOSE, N-EtFOSE, 7:3 FTCA, and 4:2 FTS were slightly higher among participants reporting a race or ethnicity other than “White”. Concentrations of legacy, alternative, and precursor PFAS were generally similar across levels of age, education, household income, body mass index, and menopausal status. Conclusions We report the first Canadian biomonitoring data for several alternative and precursor PFAS. Our findings suggest that exposure to PFAS, including several emerging alternatives, may be widespread. Our results are consistent with previous studies showing that pregnancy and breastfeeding are excretion pathways for PFAS.

Abstract Background Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured in blood cells, but little is known about the association between this peripheral epigenetic modification and brain serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and in-vivo brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals (N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals. Results We found no statistically significant association between peripheral DNA methylation and brain markers of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4 CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity. Conclusions We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation as biomarkers for environmental stress, depressive or anxiety symptoms.

Summary:. Fibrous dysplasia is a benign fibro-osseous process affecting the skeletal system, with resulting cystic and fibrous tissue expansion. Craniofacial fibrous dysplasia represents a small subset of monostotic disease, accounting for approximately 10%–25% of all such cases. Involvement of the frontal, temporal, and sphenoid bones has most commonly been described, with a limited number of reported cases citing disease isolated to the nasal bones. The case reported here is differentiated by the degree of expansion of the bilateral nasal bones and the required clinical management of the bony vault in the setting of gross nasal asymmetry.

Abstract Maternally‐inherited sex ratio distorting microbes (SRDMs) are common among arthropod species. Typically, these microbes cause female‐biased sex ratios in host broods, either by; killing male offspring, feminising male offspring, or inducing parthenogenesis. As a result, infected populations can experience drastic ecological and evolutionary change. The mechanism by which SRDMs operate is likely to alter their impact on host evolutionary ecology; despite this, the current literature is heavily biased towards a single mechanism of sex ratio distortion, male‐killing. Furthermore, amidst the growing concerns surrounding the loss of arthropod diversity, research into the impact of SRDMs on the viability of arthropod populations is generally lacking. In this study, using a theoretical approach, we model the epidemiology of an understudied mechanism of microbially‐induced sex ratio distortion—feminisation—to ask an understudied question—how do SRDMs impact extinction risk in a changing environment? We constructed an individual‐based model and measured host population extinction risk under various environmental and epidemiological scenarios. We also used our model to identify the precise mechanism modulating extinction. We find that the presence of feminisers increases host population extinction risk, an effect that is exacerbated in highly variable environments. We also identified transmission rate as the dominant epidemiological trait responsible for driving extinction. Finally, our model shows that sex ratio skew is the mechanism driving extinction. We highlight feminisers and, more broadly, SRDMs as important determinants of the resilience of arthropod populations to environmental change.

Abstract Granitic batholiths of the ∼500 Ma Ross Orogen in Antarctica are voluminous in scale, reflecting prolific magmatism along the active early Paleozoic convergent margin of Gondwana. New age and isotopic analysis of zircons from a large suite of Ross granitoids spanning >2,000 km along the orogen provide a wealth of geochronologic, tracer, and inheritance information, enabling us to investigate the pace of magmatism, along‐strike temporal and geochemical trends, magmatic sources, and tectonic modes of convergence. Because granitoids penetrate the crust of the earlier Neoproterozoic rift margin, they also provide insight into the age and composition of the largely ice‐covered East Antarctic craton. Zircon U‐Pb ages from these and other samples indicate that active Ross magmatism spanned 475–590 Ma, much longer than generally regarded. Most samples have heavy zircon δ18O values between 6.5 and 11.5‰ and initial εHf compositions between 0 and −15; their isotopic co‐variations are independent of age, as in other contemporary continental arcs, and reflect largely crustal melt sources. Samples near Shackleton Glacier have distinctly more mantle‐like isotope composition (i.e., radiogenic εHf and low δ18O) and separate two regions with distinctive isotopic properties and inheritance patterns—a more juvenile section of Mesoproterozoic crust underlying the southern TAM and an older, more evolved region of Paleoproterozoic and Archean crust in the central TAM. The isotopic discontinuity separating these regions indicates the presence of a cryptic crustal boundary of Grenvillian or younger age within the East Antarctic shield that may be traceable into the western Laurentian part of the Rodinia supercontinent.

Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.

BackgroundNoninvasive respiratory support modalities are common alternatives to mechanical ventilation in acute hypoxemic respiratory failure. However, studies historically compare noninvasive respiratory support to conventional oxygen rather than mechanical ventilation. In this study, we compared outcomes in patients with acute hypoxemic respiratory failure treated initially with noninvasive respiratory support to patients treated initially with invasive mechanical ventilation.MethodsThis is a retrospective observational cohort study between January 1, 2018 and December 31, 2019 at a large healthcare network in the United States. We used a validated phenotyping algorithm to classify adult patients (≥18 years) with eligible International Classification of Diseases codes into two cohorts: those treated initially with noninvasive respiratory support or those treated invasive mechanical ventilation only. The primary outcome was time-to-in-hospital death analyzed using an inverse probability of treatment weighted Cox model adjusted for potential confounders. Secondary outcomes included time-to-hospital discharge alive. A secondary analysis was conducted to examine potential differences between noninvasive positive pressure ventilation and nasal high flow.ResultsDuring the study period, 3177 patients met inclusion criteria (40% invasive mechanical ventilation, 60% noninvasive respiratory support). Initial noninvasive respiratory support was not associated with a decreased hazard of in-hospital death (HR: 0.65, 95% CI: 0.35-1.2), but was associated with an increased hazard of discharge alive (HR: 2.26, 95% CI: 1.92-2.67). In-hospital death varied between the nasal high flow (HR 3.27, 95% CI: 1.43-7.45) and noninvasive positive pressure ventilation (HR 0.52, 95% CI 0.25-1.07), but both were associated with increased likelihood of discharge alive (nasal high flow HR 2.12, 95 CI: 1.25-3.57; noninvasive positive pressure ventilation HR 2.29, 95% CI: 1.92-2.74).ConclusionsThese data show that noninvasive respiratory support is not associated with reduced hazards of in-hospital death but is associated with hospital discharge alive.

Abstract Brain serotonergic (5-HT) signaling is posited to modulate neural responses to emotional stimuli. Dysfunction in 5-HT signaling is implicated in major depressive disorder (MDD), a disorder associated with significant disturbances in emotion processing. In MDD, recent evidence points to altered 5-HT4 receptor (5-HT4R) levels, a promising target for antidepressant treatment. However, how these alterations influence neural processing of emotions in MDD remains poorly understood. This is the first study to examine the association between 5-HT4R binding and neural responses to emotions in patients with MDD and healthy controls. The study included one hundred and thirty-eight participants, comprising 88 outpatients with MDD from the NeuroPharm clinical trial (ClinicalTrials.gov identifier: NCT02869035) and 50 healthy controls. Participants underwent an [11C]SB207145 positron emission tomography (PET) scan to quantify 5-HT4R binding (BPND) and a functional magnetic resonance imaging (fMRI) scan during which they performed an emotional face matching task. We examined the association between regional 5-HT4R binding and corticolimbic responses to emotional faces using a linear latent variable model, including whether this association was moderated by depression status. We observed a positive correlation between 5-HT4R BPND and the corticolimbic response to emotional faces across participants (r = 0.20, p = 0.03). This association did not differ between groups (parameter estimate difference = 0.002, 95% CI = −0.008: 0.013, p = 0.72). Thus, in the largest PET/fMRI study of associations between serotonergic signaling and brain function, we found a positive association between 5-HT4R binding and neural responses to emotions that appear unaltered in MDD. Future clinical trials with novel pharmacological agents targeting 5-HT4R are needed to confirm whether they ameliorate emotion processing biases in MDD.

ABSTRACTWild animals are naturally infected with a range of viruses, some of which may be zoonotic. During the human COVID pandemic there was also the possibility of rodents acquiring SARS-CoV-2 from people, so-called reverse zoonoses. To investigate this, we sampled rats (Rattus norvegicus) and mice (Apodemus sylvaticus) from urban environments in 2020 during the human COVID-19 pandemic. We metagenomically sequenced lung and gut tissue and faeces for viruses, PCR screened for SARS-CoV-2, and serologically surveyed for anti-SARS-CoV-2 Spike antibodies. We describe the range of viruses that we found in these two rodent species. We found no molecular evidence of SARS-CoV-2 infection, though in rats we found lung antibody responses and evidence of neutralization ability that are consistent with rats being exposed to SARS-CoV-2 and/or exposed to other viruses that result in cross-reactive antibodies.

Summary:. Alveolar bone graft (ABG) surgery in cleft patients is technically challenging. The procedure requires design, dissection and release of soft tissue flaps to create a seal around the bone graft. In addition, visualization during the procedure is challenging within the confines of the cleft. These features make ABG surgery difficult to learn and teach, and it is, therefore, a suitable procedure for the use of a simulator. A high-fidelity cleft ABG simulator was developed using three-dimensional printing, polymer, and adhesive techniques. Simulated ABG surgery was performed by two expert cleft surgeons for a total of five simulation sessions to test the simulator’s features and the ability to perform the critical steps of an ABG. ABG surgery was successfully performed on the simulator. The simulations involved interacting with realistic dissection planes as well as multi-layered synthetic soft (periosteum, mucosa, gingiva, adipose tissue) and hard (teeth, bone) tissue. The simulator allowed performance of cleft marginal incisions, dissection, and elevation of a muco-gingival-periosteal flap, creation of nasal upturned and palatal downturned flaps, nasal and palatal side closure, insertion of simulated bone graft material, and advancement of the muco-gingival-periosteal flap for closure of the anterior wall of the cleft. The ABG simulator allowed performance of the critical steps of ABG surgery. This is the first ABG simulator developed, which incorporates the features necessary to practice the procedure from start to finish.

The Nearctic species of Saropogon Loew, 1847 north of Mexico are reviewed, with 19 species recognized and one described as new: Saropogon pyrodes sp. nov. from Arizona. This previously recognized new species has awaited description since its first collection in 1964. Only after a community scientist posted photographs taken in nature to an online database did its description become a priority. All species of Saropogon occurring in the Nearctic Region north of the Mexican border have been reexamined. Photographs and diagnoses of all species are provided with a distribution map of the included specimens studied. An updated key to the Nearctic species north of Mexico is provided. Finally, the need for a review of the diverse Mexican fauna is expressed.

Bull’s eye rot, caused by Phlyctema vagabunda, is an important postharvest rot of apples. A combination of laboratory and field trials were conducted to examine the relationship between infection and status of apple lenticels. Fruit were hydrated and then inoculated, and climatic factors were compared with inoculations and natural infections in the field. In laboratory trials it was shown that increased lenticel density and size led to more infections. Hydration distended lenticel diameter, and dehydration contracted lenticels. A strong relationship with wind run, leaf wetness and temperature were shown to be important for laboratory inoculations of monthly harvested fruit, natural infections in trap fruit experiments, and monthly field inoculations. It was hypothesised that high wind run (> c. 240 km/day) reduced fruit susceptibility by promoting lenticel closure, and when lenticels were open, temperature limited the formation of an infection stroma. If the stroma did not form, postharvest expression of disease was negligible. Leaf wetness over 28 days was also an important factor for infection, probably because of the effect on micro-crack formation and resealing of lenticels during maturation by components of the cuticle. From these results, pre-harvest application of compounds that close lenticels could provide some control of bull’s eye rot without the need for fungicides.

Summary: Background: Neurocognitive impairments are associated with poor clinical and employment outcomes in individuals with affective disorders. However, little is known about their associations with long-term clinical outcomes such as psychiatric hospitalizations, and with socio-demographic indicators other than employment. In the largest longitudinal study of neurocognition in affective disorders to date, we investigate the role of neurocognitive impairments on psychiatric hospitalizations and socio-demographic conditions. Methods: The study included 518 individuals with bipolar or major depressive disorder. Neurocognitive assessments covered executive function and verbal memory domains. Longitudinal data on psychiatric hospitalization and socio-demographic conditions (employment, cohabitation, and marital status) for up to 11 years were obtained using National population-based registers. The primary and secondary outcomes were psychiatric hospitalizations (n = 398) and worsening of socio-demographic conditions (n = 518), in the follow-up period since study inclusion, respectively. Cox regression models were used to examine the association of neurocognition with future psychiatric hospitalizations and the worsening of socio-demographic conditions. Findings: Clinically significant impairment in verbal memory (z-score ≤ −1; defined by the ISBD Cognition Task Force), but not in executive function, was associated with a higher risk of future hospitalization, when adjusted for age, sex, hospitalization in the year preceding inclusion, depression severity, diagnosis, and type of clinical trial (HR = 1.84, 95% CI:1.05–3.25, p = 0.034; n = 398). The results remained significant even after accounting for illness duration. Neurocognitive impairments were not associated with the worsening of socio-demographic conditions (p ≥ 0.17; n = 518). Interpretation: Promoting neurocognitive function, especially verbal memory, may mitigate the risk of future psychiatric hospitalization in individuals with affective disorders. Funding: Lundbeckfonden (R279-2018-1145).

Abstract Early detection of diseases such as COVID-19 could be a critical tool in reducing disease transmission by helping individuals recognize when they should self-isolate, seek testing, and obtain early medical intervention. Consumer wearable devices that continuously measure physiological metrics hold promise as tools for early illness detection. We gathered daily questionnaire data and physiological data using a consumer wearable (Oura Ring) from 63,153 participants, of whom 704 self-reported possible COVID-19 disease. We selected 73 of these 704 participants with reliable confirmation of COVID-19 by PCR testing and high-quality physiological data for algorithm training to identify onset of COVID-19 using machine learning classification. The algorithm identified COVID-19 an average of 2.75 days before participants sought diagnostic testing with a sensitivity of 82% and specificity of 63%. The receiving operating characteristic (ROC) area under the curve (AUC) was 0.819 (95% CI [0.809, 0.830]). Including continuous temperature yielded an AUC 4.9% higher than without this feature. For further validation, we obtained SARS CoV-2 antibody in a subset of participants and identified 10 additional participants who self-reported COVID-19 disease with antibody confirmation. The algorithm had an overall ROC AUC of 0.819 (95% CI [0.809, 0.830]), with a sensitivity of 90% and specificity of 80% in these additional participants. Finally, we observed substantial variation in accuracy based on age and biological sex. Findings highlight the importance of including temperature assessment, using continuous physiological features for alignment, and including diverse populations in algorithm development to optimize accuracy in COVID-19 detection from wearables.

A reverse Monte Carlo analysis of neutron and x-ray total scattering data from two ceria-zirconia samples of composition Ce0.75Zr0.25O2 is performed to analyze the distribution of cations and to examine the possibility of oxide-ion disorder. For the first material, heated in air under moderate conditions (800 °C), the structure is a single-phase solid-solution with the statistical distribution of cations, but a local tetragonal symmetry is found, consistent with the different coordination preferences of Ce and Zr. For the second material, heated under H2 at 1050 °C followed by reoxidation at 400 °C, the structure shows a considerable disorder, with evidence for oxygen interstitials (Frenkel-ion defects) and a non-statistical distribution of cations with significantly higher concentrations of like–like cation nearest neighbors, highlighting the existence of cation-rich nano-domains. The results highlight the dynamic nature of this solid-solution, with structural evolution upon thermal treatment, which is of relevance to understanding its stability under redox catalytic conditions in practical applications.

Infusing systems thinking activities in pre-college education (grades K-12) means updating precollege education so it includes a study of many systemic behavior patterns that are ubiquitous in the real world. Systems thinking tools include those using both paper and pencil and the computer and enhance learning in the classroom making it more student-centered, more active, and allowing students to analyze problems that have been heretofore beyond the scope of K-12 classrooms. Students in primary school have used behavior over time graphs to demonstrate dynamics described in story books, like the Lorax, and created stock-flow diagrams to describe what was needed to make a garden flourish. Middle school students have created larger stock-flow diagrams to study how composting helps to reduce pollution and have created small simulations to study population dynamics and the spread of epidemics. High school students have created/used numerous computer models to study systemic problems in mathematics, physical science, physics, biology, environmental science, global studies, and history. Some high schools developed modeling courses allowing students to create System Dynamics computer models to study problems of their choice, write technical papers explaining their models, and present their models and model results to an audience. This paper contains explanations of some of the systems thinking lessons that have been used with precollege students, some for just 5–6 years (especially the primary and middle school examples), others (especially the mathematics and system dynamics model courses for high school students) for decades.

Summary: Background: There is a paucity of studies evaluating perioperative systemic chemotherapy in conjunction with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colorectal cancer peritoneal metastases (CRCPM). The aim was to evaluate neoadjuvant and/or adjuvant systemic therapy in CRCPM. Methods: Patients with CRCPM from 39 treatment centres globally from January 1, 1991, to December 31, 2018, who underwent CRS+HIPEC were identified and stratified according to neoadjuvant/adjuvant use. Crude data analysis, propensity score matching (PSM) and Cox-proportional hazard modelling was performed. Findings: Of 2093 patients, 1613 were included in neoadjuvant crude evaluation with 708 in the PSM cohort (354 patients/arm). In the adjuvant evaluation, 1176 patients were included in the crude cohort with 778 in the PSM cohort (389 patients/arm). The median overall survival (OS) in the PSM cohort receiving no neoadjuvant vs neoadjuvant therapy was 37.0 months (95% CI: 32.6–42.7) vs 34.7 months (95% CI: 31.2–38.8, HR 1.08 95% CI: 0.88–1.32, p = 0.46). The median OS in the PSM cohort receiving no adjuvant therapy vs adjuvant therapy was 37.0 months (95% CI: 32.9–41.8) vs 45.7 months (95% CI: 38.8–56.2, HR 0.79 95% CI: 0.64–0.97, p = 0.022). Recurrence-free survival did not differ in the neoadjuvant evaluation but differed in the adjuvant evaluation – HR 1.04 (95% CI: 0.87–1.25, p = 0.66) and 0.83 (95% CI: 0.70–0.98, p = 0.03), respectively. Multivariable Cox-proportional hazard modelling in the crude cohorts showed hazard ratio 1.08 (95% CI: 0.92–1.26, p = 0.37) for administering neoadjuvant therapy and 0.86 (95% CI: 0.72–1.03, p = 0.095) for administering adjuvant therapy. Interpretation: Neoadjuvant therapy did not confer a benefit to patients undergoing CRS+HIPEC for CRCPM, whereas adjuvant therapy was associated with a benefit in this retrospective setting. Funding: None.

Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs. The anticancer HDAC inhibitor AR-42, as its racemate (rac-AR-42), and 36 analogues were investigated for in vitro activity against P. falciparum. Rac-AR-42 and selected compounds were assessed for cytotoxicity against human cells, histone hyperacetylation, human HDAC1 inhibition and oral activity in a murine malaria model. Rac-AR-42 was tested for ex vivo asexual and in vitro exoerythrocytic stage activity against P. berghei murine malaria parasites. Rac-AR-42 and 13 achiral analogues were potent inhibitors of asexual intraerythrocytic stage P. falciparum 3D7 growth in vitro (IC50 5–50 nM), with four of these compounds having >50-fold selectivity for P. falciparum versus human cells (selectivity index 56–118). Rac-AR-42 induced in situ hyperacetylation of P. falciparum histone H4, consistent with PfHDAC(s) inhibition. Furthermore, rac-AR-42 potently inhibited P. berghei infected erythrocyte growth ex vivo (IC50 40 nM) and P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). Oral administration of rac-AR-42 and two achiral analogues inhibited P. berghei growth in mice, with rac-AR-42 (50 mg/kg/day single dose for four days) curing all infections. These findings demonstrate curative properties for HDAC inhibitors in the oral treatment of experimental mouse malaria.

Evaluation of Parkinsonian Syndromes (PS) with Ioflupane iodine-123 dopamine transporter single photon emission computed tomography (DaT-SPECT), in conjunction with history and clinical examination, aids in diagnosis. FDA-approved, semi-quantitative software, DaTQUANTTM (GE Healthcare, Chicago, IL, USA) is available to assist in interpretation. This study aims to evaluate the optimal variables and thresholds of DaTQUANT to yield the optimal diagnostic accuracy. It is a retrospective review with three different patient populations. DaT-SPECT images from all three study groups were evaluated using DaTQUANTTM software, and both single and multi-variable logistic regression were used to model PS status. The optimal models were chosen via accuracy, sensitivity, and specificity, then evaluated on the other study groups. Among single variable models, the posterior putamen yielded the highest accuracy (84% to 95%), while balancing sensitivity and specificity. Multi-variable models did not substantially improve the accuracy. When the optimal single variable models for each group were used to evaluate the remaining two groups, comparable results were achieved. In typical utilization of DaT-SPECT for differentiation between nigrostriatal degenerative disease (NSDD) and non-NSDD, the posterior putamen was the single variable that yielded the highest accuracy across three different patient populations. The posterior putamen’s recommended thresholds for DaTQUANT are SBR ≤ 1.0, z-score of ≤−1.8 and percent deviation ≤ −0.34.

E. coli MukBEF is an SMC complex that plays key roles in chromosome organization-segregation. Here the authors show that the interaction between MukBEF and the Acyl Carrier Protein (AcpP) is essential for MukBEF activity in vitro (ATPase) and in vivo.

Abstract Ulotaront (SEP‐363856) is a trace amine–associated receptor 1 agonist with 5‐HT1A agonist activity in phase III development for the treatment of schizophrenia. The efficacy of ulotaront is not mediated by blockade of D2 or 5‐HT2A receptors. The aim of this study was to evaluate the population pharmacokinetics (PopPKs) of ulotaront in adult subjects using pooled data from seven phase I studies, one phase II acute study, and one 6‐month extension study. Single and multiple (up to 7 days) oral doses (5–150 mg/day) were studied in both healthy adult subjects (with intensive serial plasma sampling) and adult patients with schizophrenia (some with intensive and some with sparse plasma sampling). Ulotaront was well‐absorbed and exhibited dose‐proportionality in doses ranging from 10 to 100 mg, in mean maximum concentration, area under the concentration‐time curve, and minimum concentration. Moderate interindividual variability was observed in concentration‐time profiles. The estimated median time to maximal concentration was 2.8 h and the median effective half‐life was 7 h, corresponding to an exposure accumulation ratio of 1.10 at steady‐state with daily dosing. There was no indication of time‐dependent changes in PKs after up to 12 weeks of daily dose administration. No clinically meaningful effects on ulotaront PK parameters were observed based on race, age, sex, formulation (capsule or tablet), or clinical status (healthy volunteer vs. patient with schizophrenia); body weight was the only meaningful covariate.

Background: Psilocin, the neuroactive metabolite of psilocybin, is a serotonergic psychedelic that induces an acute altered state of consciousness, evokes lasting changes in mood and personality in healthy individuals, and has potential as an antidepressant treatment. Examining the acute effects of psilocin on resting-state time-varying functional connectivity implicates network-level connectivity motifs that may underlie acute and lasting behavioral and clinical effects. Aim: Evaluate the association between resting-state time-varying functional connectivity (tvFC) characteristics and plasma psilocin level (PPL) and subjective drug intensity (SDI) before and right after intake of a psychedelic dose of psilocybin in healthy humans. Methods: Fifteen healthy individuals completed the study. Before and at multiple time points after psilocybin intake, we acquired 10-minute resting-state blood-oxygen-level-dependent functional magnetic resonance imaging scans. Leading Eigenvector Dynamics Analysis (LEiDA) and diametrical clustering were applied to estimate discrete, sequentially active brain states. We evaluated associations between the fractional occurrence of brain states during a scan session and PPL and SDI using linear mixed-effects models. We examined associations between brain state dwell time and PPL and SDI using frailty Cox proportional hazards survival analysis. Results: Fractional occurrences for two brain states characterized by lateral frontoparietal and medial fronto-parietal-cingulate coherence were statistically significantly negatively associated with PPL and SDI. Dwell time for these brain states was negatively associated with SDI and, to a lesser extent, PPL. Conversely, fractional occurrence and dwell time of a fully connected brain state partly associated with motion was positively associated with PPL and SDI. Conclusion: Our findings suggest that the acute perceptual psychedelic effects induced by psilocybin may stem from drug-level associated decreases in the occurrence and duration of lateral and medial frontoparietal connectivity motifs. We apply and argue for a modified approach to modeling eigenvectors produced by LEiDA that more fully acknowledges their underlying structure. Together these findings contribute to a more comprehensive neurobiological framework underlying acute effects of serotonergic psychedelics.

Odours from stabilized anaerobically digested wastewater sludge – biosolids can cause local community odorous impact. Contributions from some volatile organic compounds (VOCs) to nuisance odours are not well understood. The analytical identification of compounds with low odour detection thresholds (ODTs) at low concentrations, are challenging. The knowledge about the odour composition from biosolids emission is still limited. In this study thirty-six biosolids samples were taken after anaerobic stabilisation and dewatering at a wastewater treatment plant in Sydney, Australia to investigate the musty type of odorous events during gas chromatography (GC) coupled with mass spectrometer detector (MSD) and an olfactory detection port (ODP) analysis. Biosolid cake samples were stored under aerobic conditions in loosely covered trays for a period of 35 days. Emissions were collected onto Tenax TA sorbent tubes using a U.S. EPA flux hood method at storage days 1, 3, 7, 10, 14, 21 and 35. GC-MS/ODP was used to identify musty type odorous events in the biosolids emissions as potential chemical compounds, however without its chemical detection via MSD. Measured odour intensities, classified on a scale from 1 to 4, and odour characters were specified by three ODP assessors. Two musty type odorous events were identified in all biosolid cake emissions. The measured odour intensities of the musty type odorant(s) did not significantly alter as the biosolids were aged, however varied between biosolids cakes. Due to its odour intensity, similarity with biosolids odours, frequency of detection and its likely low ODT two musty odorous events should be considered as a potential odorant(-s) of concern in biosolids emissions.

Abstract Dietary niche is fundamental for determining species ecology; thus, a detailed understanding of what drives variation in dietary niche is vital for predicting ecological shifts and could have implications for species management. Gut microbiota can be important for determining an organism’s dietary preference, and therefore which food resources they are likely to exploit. Evidence for whether the composition of the gut microbiota is plastic in response to changes in diet is mixed. Also, the extent to which dietary preference can be changed following colonisation by new gut microbiota from different species is unknown. Here, we use Drosophila spp. to show that: (1) the composition of an individual’s gut microbiota can change in response to dietary changes, and (2) ingestion of foreign gut microbes can cause individuals to be attracted to food types they previously had a strong aversion to. Thus, we expose a mechanism for facilitating rapid shifts in dietary niche over short evolutionary timescales.

Introduction Depression is common among community-dwelling older adults who make use of senior centre services yet remains undertreated due to a lack of acceptable and available treatments. Emerging evidence suggests that lay health providers can offer psychosocial interventions for mental health disorders experienced by older adults. We developed a streamlined Behavioural Activation intervention (called ‘Do More, Feel Better’; DMFB) to be delivered by older adult volunteers and propose to compare its effectiveness to that of clinician-delivered behavioural activation (BA).Methods and analysis This study is a type I collaborative randomised effectiveness trial testing the effect of DMFB in comparison to BA among 288 senior centre clients (aged 60+). Participant clients will be recruited from 6 Seattle, 6 New York City and 6 Tampa area senior centres serving economically and ethnically diverse communities. Primary outcomes will be increased activity level (target) and decreased depressive symptoms. Secondary outcomes will be functioning and client satisfaction, and an exploratory outcome will be treatment fidelity.Ethics and dissemination The study received ethics approval from the University of Washington Institutional Review Board (STUDY00011434). Client, volunteer and clinician participants will all provide informed consent for study procedures through in-person or remote contact with investigators. Results of this study will be presented in peer-reviewed journals and at professional conferences.Trial registration number NCT04621877; ClinicalTrials.gov.

Abstract Background and Objectives Current clinical guidelines recommend thromboprophylaxis for adults hospitalized with coronavirus disease 2019 (COVID‐19), yet it is unknown whether higher doses of thromboprophylaxis offer benefits beyond standard doses. Methods We studied electronic health records from 50 091 adults hospitalized with COVID‐19 in the United States between February 2020 and February 2021. We compared standard (enoxaparin 30 or 40 mg/day, fondaparinux 2.5 mg, or heparin 5000 units twice or thrice per day) versus intermediate (enoxaparin 30 or 40 mg twice daily, or up to 1.2 mg/kg of body weight daily, heparin 7500 units thrice per day or heparin 10 000 units twice or thrice per day) thromboprophylaxis. We separately examined risk of escalation to therapeutic anticoagulation, severe disease (first occurrence of high‐flow nasal cannula, noninvasive positive pressure ventilation or invasive mechanical ventilation), and death. To summarize risk, we present hazard ratios (HRs) with 95% confidence intervals (CIs) using adjusted time‐dependent Cox proportional hazards regression models. Results People whose first dose was high intensity were younger, more often obese, and had greater oxygen support requirements. Intermediate dose thromboprophylaxis was associated with increased risk of therapeutic anticoagulation (HR, 3.39; 95% CI, 3.22‐3.57), severe disease (HR, 1.22; 95% CI, 1.17‐1.28), and death (HR, 1.37; 95% CI, 1.21‐1.55). Increased risks associated with intermediate‐dose thromboprophylaxis persisted in subgroup and sensitivity analyses varying populations and definitions of exposures, outcomes, and covariates. Conclusions Our findings do not support routine use of intermediate‐dose thromboprophylaxis to prevent clinical worsening, severe disease, or death among adults hospitalized with COVID‐19.

Abstract Galactic cosmic radiation (GCR) composed of high-energy, heavy particles (HZE) poses potentially serious hazards to long-duration crewed missions in deep space beyond earth’s magnetosphere, including planned missions to Mars. Chronic effects of GCR exposure on brain structure and cognitive function are poorly understood, thereby limiting risk reduction and mitigation strategies to protect against sequelae from exposure during and after deep-space travel. Given the selective vulnerability of the hippocampus to neurotoxic insult and the importance of this brain region to learning and memory, we hypothesized that GCR-relevant HZE exposure may induce long-term alterations in adult hippocampal neurogenesis, synaptic plasticity, and hippocampal-dependent learning and memory. To test this hypothesis, we irradiated 3-month-old male and female mice with a single, whole-body dose of 10, 50, or 100 cGy 56Fe ions (600 MeV, 181 keV/μm) at Brookhaven National Laboratory. Our data reveal complex, dynamic, time-dependent effects of HZE exposure on the hippocampus. Two months post exposure, neurogenesis, synaptic plasticity and learning were impaired compared to sham-irradiated, age-matched controls. By six months post-exposure, deficits in spatial learning were absent in irradiated mice, and synaptic potentiation was enhanced. Enhanced performance in spatial learning and facilitation of synaptic plasticity in irradiated mice persisted 12 months post-exposure, concomitant with a dramatic rebound in adult-born neurons. Synaptic plasticity and spatial learning remained enhanced 20 months post-exposure, indicating a life-long influence on plasticity and cognition from a single exposure to HZE in young adulthood. These findings suggest that GCR-exposure can persistently alter brain health and cognitive function during and after long-duration travel in deep space.

Background Whole-body hyperthermia (WBH) has shown promise as a non-pharmacologic treatment for major depressive disorder (MDD) in prior trials that used a medical (infrared) hyperthermia device. Further evaluation of WBH as a treatment for MDD has, however, been stymied by regulatory challenges. Objective We examined whether a commercially available infrared sauna device without FDA-imposed limitations could produce the degree of core body temperature (101.3 °F) associated with reduced depressive symptoms in prior WBH studies. We also assessed the frequency of adverse events and the amount of time needed to achieve this core body temperature. We explored changes (pre-post WBH) in self-reported mood and affect. Methods Twenty-five healthy adults completed a single WBH session lasting up to 110 min in a commercially available sauna dome (Curve Sauna Dome). We assessed core body temperature rectally during WBH, and mood and affect at timepoints before and after WBH. Results All participants achieved the target core body temperature (101.3 °F). On average, it took participants 82.12 min (SD = 11.3) to achieve this temperature (range: 61–110 min), and WBH ended after a participant maintained 101.3 °F for two consecutive minutes. In exploratory analyses of changes in mood and affect, we found that participants evidenced reductions (t[24] = 2.03, M diff = 1.00, p=.054, 95% CI [−2.02,0.02]) in self-reported depression symptoms from 1 week pre- to 1 week post-WBH, and reductions (t[24]= −2.93, M diff= −1.72, p=.007, 95% CI [−2.93, −0.51]) in self-reported negative affect pre-post-WBH session. Conclusion This novel WBH protocol holds promise in further assessing the utility of WBH in MDD treatment. Trial registration This trial was registered at clinicaltrivals.gov (NCT04249700).

ObjectivesUnderstanding the dynamics of reorganized network-level brain functions after hemispherectomy is important for treatment, prognostication, and rehabilitation of brain injury, but also for investigating questions of fundamental neurobehavioral interest: How does the brain promote consciousness despite loss of one hemisphere?MethodsWe studied resting-state functional connectivity (RSFC) in a high-functioning middle-aged man 6 years after functional hemispherectomy following malignant middle cerebral artery infarction, and we compared results to RSFC in 20 healthy controls.ResultsOur analysis indicates increased between-network connectivity for all seven networks examined in the patient's preserved hemisphere, compared to healthy controls, suggesting a shift toward increased between-network connectivity following near-complete loss of one hemisphere during adulthood.ConclusionsThese data corroborate and extend recent findings of increased between-network connectivity in the remaining hemisphere after surgical hemispherectomy for intractable epilepsy during childhood. Our results support a neuroplasticity model with reorganization of distributed brain connectivity within the preserved hemisphere as part of the road to recovery after brain injury, as well as recovery of consciousness and cognitive functions, after hemispherectomy.

Climate change is expanding drylands even as land use practices degrade them. Representing ∼40% of Earth’s terrestrial surface, drylands rely on biological soil crusts (biocrusts) for key ecosystem functions including soil stability, biogeochemical cycling, and water capture. Understanding how biocrusts adapt to climate change is critical to understanding how dryland ecosystems will function with altered climate. We investigated the sensitivity of biocrusts to experimentally imposed novel climates to track changes in productivity and stability under both warming and cooling scenarios. We established three common gardens along an elevational-climate gradient on the Colorado Plateau. Mature biocrusts were collected from each site and reciprocally transplanted intact. Over 20 months we monitored visible species composition and cover, chlorophyll a, and the composition of soil bacterial communities using high throughput sequencing. We hypothesized that biocrusts replanted at their home site would show local preference, and biocrusts transplanted to novel environments would maintain higher cover and stability at elevations higher than their origin, compared to at elevations lower than their origin. We expected responses of the visible biocrust cover and soil bacterial components of the biocrust community to be coupled, with later successional taxa showing higher sensitivity to novel environments. Only high elevation sourced biocrusts maintained higher biocrust cover and community stability at their site of origin. Biocrusts from all sources had higher cover and stability in the high elevation garden. Later successional taxa decreased cover in low elevation gardens, suggesting successional reversal with warming. Visible community composition was influenced by both source and transplant environment. In contrast, soil bacterial community composition was not influenced by transplant environments but retained fidelity to the source. Thus, responses of the visible and soil bacterial components of the biocrust community were not coupled. Synthesis: Our results suggest biocrust communities are sensitive to climate change, and loss of species and function can be expected, while associated soil bacteria may be buffered against rapid change.

The prevention and treatment of malaria requires a multi-pronged approach, including the development of drugs that have novel modes of action. Histone deacetylases (HDACs), enzymes involved in post-translational protein modification, are potential new drug targets for malaria. However, the lack of recombinant P. falciparum HDACs and suitable activity assays, has made the investigation of compounds designed to target these enzymes challenging. Current approaches are indirect and include assessing total deacetylase activity and protein hyperacetylation via Western blot. These approaches either do not allow differential compound effects to be determined or suffer from low throughput. Here we investigated dot blot and ELISA methods as new, higher throughput assays to detect histone lysine acetylation changes in P. falciparum parasites. As the ELISA method was found to be superior to the dot blot assay using the control HDAC inhibitor vorinostat, it was used to evaluate the histone H3 and H4 lysine acetylation changes mediated by a panel of six HDAC inhibitors that were shown to inhibit P. falciparum deacetylase activity. Vorinostat, panobinostat, trichostatin A, romidepsin and entinostat all caused an ~3-fold increase in histone H4 acetylation using a tetra-acetyl lysine antibody. Tubastatin A, the only human HDAC6-specific inhibitor tested, also caused H4 hyperacetylation, but to a lesser extent than the other compounds. Further investigation revealed that all compounds, except tubastatin A, caused hyperacetylation of the individual N-terminal H4 lysines 5, 8, 12 and 16. These data indicate that tubastatin A impacts P. falciparum H4 acetylation differently to the other HDAC inhibitors tested. In contrast, all compounds caused hyperacetylation of histone H3. In summary, the ELISA developed in this study provides a higher throughput approach to assessing differential effects of antiplasmodial compounds on histone acetylation levels and is therefore a useful new tool in the investigation of HDAC inhibitors for malaria.

Abstract Elevated core temperature constitutes an important biomarker for COVID-19 infection; however, no standards currently exist to monitor fever using wearable peripheral temperature sensors. Evidence that sensors could be used to develop fever monitoring capabilities would enable large-scale health-monitoring research and provide high-temporal resolution data on fever responses across heterogeneous populations. We launched the TemPredict study in March of 2020 to capture continuous physiological data, including peripheral temperature, from a commercially available wearable device during the novel coronavirus pandemic. We coupled these data with symptom reports and COVID-19 diagnosis data. Here we report findings from the first 50 subjects who reported COVID-19 infections. These cases provide the first evidence that illness-associated elevations in peripheral temperature are observable using wearable devices and correlate with self-reported fever. Our analyses support the hypothesis that wearable sensors can detect illnesses in the absence of symptom recognition. Finally, these data support the hypothesis that prediction of illness onset is possible using continuously generated physiological data collected by wearable sensors. Our findings should encourage further research into the role of wearable sensors in public health efforts aimed at illness detection, and underscore the importance of integrating temperature sensors into commercially available wearables.

Primitive sterol evolution plays an important role in fossil record interpretation and offers potential therapeutic avenues for human disease resulting from nematode infections. Recognizing that C4-methyl stenol products [8(14)-lophenol] can be synthesized in bacteria while C4-methyl stanol products (dinosterol) can be synthesized in dinoflagellates and preserved as sterane biomarkers in ancient sedimentary rock is key to eukaryotic sterol evolution. In this regard, nematodes have been proposed to convert dietary cholesterol to 8(14)-lophenol by a secondary metabolism pathway that could involve sterol C4 methylation analogous to the C2 methylation of hopanoids (radicle-type mechanism) or C24 methylation of sterols (carbocation-type mechanism). Here, we characterized dichotomous cholesterol metabolic pathways in Caenorhabditis elegans that generate 3-oxo sterol intermediates in separate paths to lophanol (4-methyl stanol) and 8(14)-lophenol (4-methyl stenol). We uncovered alternate C3-sterol oxidation and Δ7 desaturation steps that regulate sterol flux from which branching metabolite networks arise, while lophanol/8(14)-lophenol formation is shown to be dependent on a sterol C4α-methyltransferse (4-SMT) that requires 3-oxo sterol substrates and catalyzes a newly discovered 3-keto-enol tautomerism mechanism linked to S-adenosyl-l-methionine-dependent methylation. Alignment-specific substrate-binding domains similarly conserved in 4-SMT and 24-SMT enzymes, despite minimal amino acid sequence identity, suggests divergence from a common, primordial ancestor in the evolution of methyl sterols. The combination of these results provides evolutionary leads to sterol diversity and points to cryptic C4-methyl steroidogenic pathways of targeted convergence that mediate lineage-specific adaptations.­­