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Background: The role of neoadjuvant therapy (NAT) in gallbladder cancer (GBC) is not well established. We sought to evaluate the effect of NAT on postoperative outcomes following surgical resection of GBC. We hypothesized that patients receiving NAT would have similar rates of 30-day mortality, readmission, and postoperative complications (e.g. bile leakage and liver failure) compared to those who did not receive NAT. Methods: The 2014–2017 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Procedure-Targeted Hepatectomy database was queried for patients that underwent surgery for GBC. Propensity scores were calculated to match patients in a 1:2 ratio based on age, comorbidities, functional status, and tumor staging. Results: A total of 37 patients undergoing NAT were matched to 74 patients without NAT. There was no difference in any matched characteristics. Compared to the NAT group, the no NAT cohort had similar rates of postoperative bile leakage (NAT 13.5 % vs. no NAT 10.8 %, p = 0.31), postoperative liver failure (5.4 %, vs. 8.1 %, p = 0.60), 30-day readmission (10.8 % vs. 10.8 %, p = 1.00), and 30-day mortality (10.8 % vs. 2.7 %, p = 0.075). All 30-day complications were similar except for a higher rate of postoperative blood transfusion (NAT 32.4 % vs. no NAT 10.8 %, p = 0.005). Conclusion: In patients undergoing surgical resection for GBC, those with and without NAT had similar rates of readmission and 30-day mortality, however NAT was associated with an increased risk for transfusion. Despite use of a large national database, this study may be underpowered to adequately assess the effect of NAT on perioperative GBC outcomes and thus warrants further investigation.

Background: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking. Materials and Methods: This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code. Results: Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58–0.85]; P = 4 ×10−4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 - 0.93]; P = 0.005).Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

Objective: The study objective was to determine if intraoperative peritoneal catheter placement is associated with improved outcomes in neonates undergoing high-risk cardiac surgery with cardiopulmonary bypass. Methods: This propensity score–matched retrospective study used data from 22 academic pediatric cardiac intensive care units. Consecutive neonates undergoing Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery category 3 to 5 cardiac surgery with cardiopulmonary bypass at centers participating in the NEonatal and Pediatric Heart Renal Outcomes Network collaborative were studied to determine the association of the use of an intraoperative placed peritoneal catheter for dialysis or passive drainage with clinical outcomes, including the duration of mechanical ventilation. Results: Among 1490 eligible neonates in the NEonatal and Pediatric Heart Renal Outcomes Network dataset, a propensity-matched analysis was used to compare 395 patients with peritoneal catheter placement with 628 patients without peritoneal catheter placement. Time to extubation and most clinical outcomes were similar. Postoperative length of stay was 5 days longer in the peritoneal catheter placement cohort (17 vs 22 days, P = .001). There was a 50% higher incidence of moderate to severe acute kidney injury in the no-peritoneal catheter cohort (12% vs 18%, P = .02). Subgroup analyses between specific treatments and in highest risk patients yielded similar associations. Conclusions: This study does not demonstrate improved outcomes among neonates with placement of a peritoneal catheter during cardiac surgery. Outcomes were similar apart from longer hospital stay in the peritoneal catheter cohort. The no-peritoneal catheter cohort had a 50% higher incidence of moderate to severe acute kidney injury (12% vs 18%). This analysis does not support indiscriminate peritoneal catheter use, although it may support the utility for postoperative fluid removal among neonates at risk for acute kidney injury. A multicenter controlled trial may better elucidate peritoneal catheter effects.

Summary: Background: Contemporary surgical practices for traumatic brain injury (TBI) remain unclear. We describe the clinical profile of an 18-centre US TBI cohort with cranial surgery. Methods: The prospective, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study (2014–2018; ClinicalTrials.gov #NCT02119182) enrolled subjects who presented to trauma centre and received head computed tomography within 24-h (h) post-TBI. We performed a secondary data analysis in subjects aged ≥17-years with hospitalisation. Clinical characteristics, surgery type/timing, hospital and six-month outcomes were reported. Findings: Of 2032 subjects (age: mean = 41.4-years, range = 17–89-years; male = 71% female = 29%), 260 underwent cranial surgery, comprising 65% decompressive craniectomy, 23% craniotomy, 12% other surgery. Subjects with surgery (vs. without surgery) presented with worse neurological injury (median Glasgow Coma Scale = 6 vs. 15; midline shift ≥5 mm: 48% vs. 2%; cisternal effacement: 61% vs. 4%; p

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in “pure” models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage. The present study therefore aimed to test the potential of p38α inhibition to address dysfunction in the context of comorbid amyloid and vascular pathologies. Methods: An amyloid overexpressing mouse strain (5xFAD) was placed on an 8-week long diet to induce the hyperhomocysteinemia (HHcy) model of small vessel disease. Mice were treated with the brain-penetrant small molecule p38α inhibitor MW150 for the duration of the HHcy diet, and subsequently underwent behavioral, neuroimaging, electrophysiological, or biochemical/immunohistochemical analyses. Results: MW150 successfully reduced behavioral impairment in the Morris Water Maze, corresponding with attenuation of synaptic loss, reduction in tau phosphorylation, and a partial normalization of electrophysiological parameters. No effect of MW150 was observed on the amyloid, vascular, or neuroinflammatory endpoints measured. Conclusions: This study provides proof-of-principle that the inhibition of p38α is able to provide benefit even in the context of mixed pathological contributions to cognitive impairment. Interestingly, the benefit was mediated primarily via rescue of neuronal function without any direct effects on the primary pathologies. These data suggest a potential use for p38 inhibitors in the preservation of cognition across contexts, and in particular AD, either alone or as an adjunct to other AD therapies (i.e. anti-amyloid approaches). Future studies to delineate the precise neuronal pathways implicated in the benefit may help define other specific comorbid conditions amenable to this type of approach or suggest future refinement in pharmacological targeting.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Summary: Acute traumatic brain injury (TBI) is associated with substantial abnormalities in lipid biology, including changes in the structural lipids that are present in the myelin in the brain. We investigated the relationship between traumatic microstructural changes in white matter from magnetic resonance imaging (MRI) and quantitative lipidomic changes from blood serum. The study cohort included 103 patients from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. Diffusion tensor fitting generated fractional anisotropy (FA) and mean diffusivity (MD) maps for the MRI scans while ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry was applied to analyze the lipidome. Increasing severity of TBI was associated with higher MD and lower FA values, which scaled with different lipidomic signatures. There appears to be consistent patterns of lipid changes associating with the specific microstructure changes in the CNS white matter, but also regional specificity, suggesting that blood-based lipidomics may provide an insight into the underlying pathophysiology of TBI.

Summary: The C. elegans nervous system is compact and well described, ideal for identifying genetic programs that drive neuron-specific development, function, and connectivity. Here, we present a protocol for isolating specific neuron types for gene expression profiling by bulk or single-cell RNA sequencing. We describe steps for worm synchronization, dissociation, and fluorescence-activated cell sorting (FACS) isolation. We then detail procedures for RNA extraction and preparing cells for single-cell sequencing. This protocol is applicable to the isolation of individual cell types from larval and adult animals.For additional details on the use and execution of this protocol, see Taylor et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

In this study, we utilised computational fluid dynamics to investigate the behaviour of open-channel basaltic lava flows navigating bends on shield volcanoes. Our focus was on understanding the relationship between flow velocity, rheology, and bend geometry. Employing a simple Force Balance Model (FBM), which considers the equilibrium between hydrostatic pressure and centrifugal force, we accurately approximated the changes in the height of the lava’s free surface through various bend geometries. Our analysis includes examining the influence of channel depth, width, and bend radius on the flow, revealing that variations in these parameters significantly affect the flow’s vertical displacement. Additionally, the bend sector angle emerged as a critical factor, indicating a minimum angle necessary for the flow to fully develop before exiting the bend.Further, we assessed the applicability of the Shallow Water Equations (SWE) for modelling the inertial displacement of the lava flow in bends, finding a good fit. The study extended to comparing the FBM’s predictions of the tilt angle of the flow’s free surface with the SWE results, showing notable agreement under specific conditions, particularly at a bend angle of 90 degrees. The impact of fluid density was also considered, revealing that density is a contributing factor to the development of the wetted line in the bend, a factor that is not captured by the simple FBM model. Finally, we explored different rheologies akin to natural lava flows, such as viscoplastic flow, and determined that factors like yield stress, consistency index, and power law index have a small impact on the flow behaviour in a steady-state condition within a bend.

The occurrence of pharmaceuticals and xenoestrogen compounds (PXCs) in drinking water presents a dire human health risk challenge. The problem stems from the high anthropogenic pollution load on source water and the inefficiencies of the conventional water treatment plants in treating PXCs. This study assessed the PXCs levels and the consequential health risks of exposure to tap water from selected Ghanaian communities as well as that of raw water samples from the respective treatment plants. Thus the PXCs treatment efficiency of two drinking water treatment plants in the metropolises studied was also assessed. The study also conducted source apportionment of the PXCs in the tap water. Twenty six (26) tap and raw water samples from communities in the Cape Coast and Sekondi-Takoradi metropolises were extracted using SPE cartridges and analysed for PXCs using Ultra-fast-HPLC-UV instrument. Elevated levels of PXCs up to 24.79 and 22.02 μg/L were respectively recorded in raw and tap water samples from the metropolises. Consequently, elevated non-cancer health risk (HI > 1) to residential adults were found for tap water samples from Cape Coast metropolis and also for some samples from Sekondi-Takoradi metropolis. Again, elevated cumulative oral cancer risks >10−5 and dermal cancer risk up to 4 × 10−5 were recorded. The source apportionment revealed three significant sources of PXCs in tap water samples studied. The results revealed the inefficiency of the treatment plants in removing PXCs from the raw water during treatments. The situation thus requires urgent attention to ameliorate it, safeguarding public health. It is recommended that the conventional water treatment process employed be augmented with advanced treatment technologies to improve their efficacy in PXCs treatment.

Summary: Existing medical treatments for endometriosis-related pain are often ineffective, underscoring the need for new therapeutic strategies. In this study, we applied a computational drug repurposing pipeline to stratified and unstratified disease signatures based on endometrial gene expression data to identify potential therapeutics from existing drugs, based on expression reversal. Of 3,131 unique genes differentially expressed by at least one of six endometriosis signatures, only 308 (9.8%) were in common; however, 221 out of 299 drugs identified, (73.9%) were shared. We selected fenoprofen, an uncommonly prescribed NSAID that was the top therapeutic candidate for further investigation. When testing fenoprofen in an established rat model of endometriosis, fenoprofen successfully alleviated endometriosis-associated vaginal hyperalgesia, a surrogate marker for endometriosis-related pain. These findings validate fenoprofen as a therapeutic that could be utilized more frequently for endometriosis and suggest the utility of the aforementioned computational drug repurposing approach for endometriosis.

Summary: The basal forebrain (BF) is critical for the motivational recruitment of attention in response to reward-related cues. This finding is consistent with a role for the BF in encoding and transmitting motivational salience and readying prefrontal circuits for further attentional processing. We recorded local field potentials to determine connectivity between prelimbic cortex (PrL) and BF during the modulation of attention by reward-related cues. We find that theta and gamma power are robustly associated with behavior. Power in both bands is significantly lower during trials in which an incorrect behavioral response is made. We find strong coherence during responses that are significantly stronger when a correct response is made. We show that information flow is largely monodirectional from BF to and is strongest when correct responses are made. These experiments demonstrate that connectivity between BF and the PrL increases during periods of increased motivational recruitment of attentional resources.

Summary: Oral squamous cell carcinoma (OSCC), a prevalent and aggressive neoplasm, poses a significant challenge due to poor prognosis and limited prognostic biomarkers. Leveraging highly multiplexed imaging mass cytometry, we investigated the tumor immune microenvironment (TIME) in OSCC biopsies, characterizing immune cell distribution and signaling activity at the tumor-invasive front. Our spatial subsetting approach standardized cellular populations by tissue zone, improving feature reproducibility and revealing TIME patterns accompanying loss-of-differentiation. Employing a machine-learning pipeline combining reliable feature selection with multivariable modeling, we achieved accurate histological grade classification (AUC = 0.88). Three model features correlated with clinical outcomes in an independent cohort: granulocyte MAPKAPK2 signaling at the tumor front, stromal CD4+ memory T cell size, and the distance of fibroblasts from the tumor border. This study establishes a robust modeling framework for distilling complex imaging data, uncovering sentinel characteristics of the OSCC TIME to facilitate prognostic biomarkers discovery for recurrence risk stratification and immunomodulatory therapy development.

Oxalate is a small compound found in certain plant-derived foods and is a major component of calcium oxalate (CaOx) kidney stones. Individuals that consume oxalate enriched meals have an increased risk of forming urinary crystals, which are precursors to CaOx kidney stones. We previously reported that a single dietary oxalate load induces nanocrystalluria and reduces monocyte cellular bioenergetics in healthy adults. The purpose of this study was to extend these investigations to identify specific oxalate-mediated mechanisms in monocytes and macrophages. We performed RNA-Sequencing analysis on monocytes isolated from healthy subjects exposed to a high oxalate (8 mmol) dietary load. RNA-sequencing revealed 1,198 genes were altered and Ingenuity Pathway Analysis demonstrated modifications in several pathways including Interleukin-10 (IL-10) anti-inflammatory cytokine signaling, mitochondrial metabolism and function, oxalic acid downstream signaling, and autophagy. Based on these findings, we hypothesized that oxalate induces mitochondrial and lysosomal dysfunction in monocytes and macrophages via IL-10 and reactive oxygen species (ROS) signaling which can be reversed with exogenous IL-10 or Mitoquinone (MitoQ; a mitochondrial targeted antioxidant). We exposed monocytes and macrophages to oxalate in an in-vitro setting which caused oxidative stress, a decline in IL-10 cytokine levels, mitochondrial and lysosomal dysfunction, and impaired autophagy in both cell types. Administration of exogenous IL-10 and MitoQ attenuated these responses. These findings suggest that oxalate impairs metabolism and immune response via IL-10 signaling and mitochondrial ROS generation in both monocytes and macrophages which can be potentially limited or reversed. Future studies will examine the benefits of these therapies on CaOx crystal formation and growth in vivo.

Purpose: Clinical trials comparing the efficacy of adjuvant chemotherapy (CT) and chemo radiation therapy (CTRT) for stomach adenocarcinoma have reported equivocal results. Hence, the current retrospective cohort study assessed the long-term survival and recurrence outcomes of these therapies, to generate evidence in a real-world scenario. Methods and Materials: Pathologically confirmed patients with stomach adenocarcinoma aged ≥18 years who underwent gastrectomy and D2 lymph nodal dissection at a tertiary cancer hospital from January 2010 to October 2017 were enrolled. Hospital-based follow-up was performed until December 2021. Data were gathered from electronic medical records, supplemented by telephonic interviews for patients who could not come for physical follow-up. CT-alone and CTRT cohorts were compared in terms of survival and recurrence outcomes. Results: The analysis included 158 patients (mean age, 56.42 years; 63.9% male; CT-alone cohort, 69; CTRT cohort, 89). Patients in the CTRT cohort had significantly worse tumor characteristics at baseline (29.2% had the diffuse type of tumor, 94.4% had stage II or III, 68.5% had lympho-vascular space invasion, and 85.4% had lymph node involvement). Recurrence was observed in 13 (19.7%) of the 76 followed-up patients. Although locoregional recurrence was higher in the CT-alone cohort (7 vs 2), distant metastasis was higher in the CTRT cohort (3 vs 1). The overall 5-year survival was 67.0% (SE, 5.0%) and 5-year recurrence-free survival (RFS) was 75.0% (SE, 5.0%). On multivariate Cox regression, no variable was significantly associated with the overall survival, whereas age, positive lymph nodes without extracapsular extension, and lymph node-negative were significantly associated with RFS. The CTRT cohort had significantly (84.0%) higher RFS (hazard ratio, 0.161; 95% CI, 0.056-0.464; P < .001). Conclusions: Patients who received adjuvant CTRT after D2 dissection showed similar overall survival but significantly higher RFS than the CT-alone cohort, despite having worse baseline tumor characteristics.

Summary: Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014–2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12–26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p

Summary: System-level analysis of single-cell data is rapidly transforming the field of immunometabolism. Given the competitive demand for nutrients in immune microenvironments, there is a need to understand how and when immune cells access these nutrients. Here, we describe a new approach for single-cell analysis of nutrient uptake where we use in-cell biorthogonal labeling of a functionalized amino acid after transport into the cell. In this manner, the bona fide active uptake of glutamine via SLC1A5/ASCT2 could be quantified. We used this assay to interrogate the transport capacity of complex immune subpopulations, both in vitro and in vivo. Taken together, our findings provide an easy sensitive single-cell assay to assess which cells support their function via SLC1A5-mediated uptake. This is a significant addition to the single-cell metabolic toolbox required to decode the metabolic landscape of complex immune microenvironments.

BACKGROUND: Blood proteins are frequently measured in serum or plasma, because they provide a wealth of information. Differences in the ex vivo processing of serum and plasma raise concerns that proteomic health and disease signatures derived from serum or plasma differ in content and quality. However, little is known about their respective power to predict feto-maternal health outcomes. Predictive power is a sentinel characteristic to determine the clinical use of biosignatures. OBJECTIVE: This study aimed to compare the power of serum and plasma proteomic signatures to predict a physiological pregnancy outcome. STUDY DESIGN: Paired serum and plasma samples from 73 women were obtained from biorepositories of a multinational prospective cohort study on pregnancy outcomes. Gestational age at the time of sampling was the predicted outcome, because the proteomic signatures have been validated for such a prediction. Multivariate and cross-validated models were independently derived for serum and plasma proteins. RESULTS: A total of 1116 proteins were measured in 88 paired samples from 73 women with a highly multiplexed platform using proximity extension technology (Olink Proteomics Inc, Watertown, MA). The plasma proteomic signature showed a higher predictive power (R=0.64; confidence interval, 0.42–0.79; P=3.5×10-6) than the serum signature (R=0.45; confidence interval, 0.18–0.66; P=2.2×10-3). The serum signature was validated in plasma with a similar predictive power (R=0.58; confidence interval, 0.34–0.75; P=4.8×10-5), whereas the plasma signature was validated in serum with reduced predictive power (R=0.53; confidence interval, 0.27–0.72; P=2.6×10-4). Signature proteins largely overlapped in the serum and plasma, but the strength of association with gestational age was weaker for serum proteins. CONCLUSION: Findings suggest that serum proteomics are less informative than plasma proteomics. They are compatible with the view that the partial ex-vivo degradation and modification of serum proteins during sample processing are an underlying reason. The rationale for collecting and analyzing serum and plasma samples should be carefully considered when deriving proteomic biosignatures to ascertain that specimens of the highest scientific and clinical yield are processed. Findings suggest that plasma is the preferred matrix.

School-based interventions for the prevention of dating and relationship violence (DRV) and gender-based violence (GBV) take advantage of universal opportunities for intervention. Information on differential effectiveness of interventions is important to assess if they ameliorate or worsen social gradients in specific outcomes. This is especially important in DRV and GBV prevention given the gendered context of these behaviours and their common aetiologies in patriarchal gender norms, and social acceptance in school contexts of sexual harassment, such as catcalling or unwanted groping. We undertook a systematic review of moderation analyses in randomised trials of school-based interventions for DRV and GBV prevention. We searched 21 databases and used supplementary search methods without regard to publication type, language or year of publication, and synthesised moderation tests relating to equity-relevant characteristics (principally sex and prior history of the outcome) for DRV and GBV perpetration and victimisation. Across 23 included outcome evaluations, programme effects on DRV victimisation were not moderated by gender or prior experience of DRV victimisation, but DRV perpetration outcomes were greater for boys, particularly for emotional and physical DRV perpetration. Findings for GBV outcomes were counterintuitive. Our findings suggest that practitioners should carefully monitor local intervention effectiveness and equity to ensure that interventions are working as intended. However, one of the most surprising findings from our analysis—with clear relevance for uncertainties in practice—was that differential impacts by sexuality or sexual minority status were not frequently evaluated.

Purpose: The objective of this study was to assess the association between the Oncotype DX Genomic Prostate Score (GPS) assay and long-term outcomes in men with localized prostate cancer (PCa) after radiation therapy (RT). We hypothesized that the GPS assay is prognostic for biochemical failure (BCF), along with distant metastasis (DM) and PCa-specific mortality in patients with PCa receiving RT. Methods and Materials: We retrospectively studied men with localized PCa treated with definitive RT at Georgia Urology from 2010 to 2016. The primary objective was to assess the association between GPS results and time to BCF per the Phoenix criteria; we also assessed time to DM and PCa-specific mortality. We used Cox proportional hazards regression models for all analyses, with clinicopathologic covariates determined a priori for multivariable modeling. Results: A total of 450 patients (median age, 65 years; 35% Black) met eligibility criteria. There was a strong univariable association between GPS result and time to BCF (hazard ratio [HR] per 20-unit increase = 3.08; 95% confidence interval [CI], 2.11-4.46; P < .001), which persisted after adjusting for clinicopathologic characteristics in multivariable analyses. We also observed this association for time to DM (HR = 5.19; 95% CI, 3.06-8.77; P < .001) and PCa-specific mortality (HR = 13.07; 95% CI, 4.42-49.39; P < .001). Race was not a predictor of time to BCF or DM, and the GPS assay was strongly prognostic for all endpoints in Black and White patients. Conclusions: In a community-based cohort, the GPS assay was strongly prognostic for time to BCF as well as long-term outcomes in men treated with RT for localized PCa.

Kinetic studies are important for the design and optimisation of thermochemical processes. This study involved analysis of the pyrolysis and combustion behaviour of the agricultural residues (bean straw and maize cob) by non-isothermal thermogravimetric analysis. Increasing the heating rate from 10 to 40 K min−1 during both combustion and pyrolysis increased the degradation rate of both feedstocks and the gaseous yields of H2O, CO and CO2. The activation energies determined by the Flynn-Wall-Ozawa and Kissinger-Akahira-Sunose methods varied which reveals that the pyrolysis and combustion of these agricultural residues are complex processes involving multiple reactions. The average activation energy of maize cob and bean straw were 214.15 and 252.09 kJ mol−1 for pyrolysis and 202.26 and 165.64 kJ mol−1 for combustion, respectively. The order of reaction ranged between 9.0-10.3 and 6.3–13.3 for both feedstocks in combustion and inert environments, respectively. Modelled data is important to enable the optimisation of reactor design for pyrolysis and combustion for energy generation from agricultural residues.

Oncolytic virotherapies (OV) hold immense clinical potential. OV based on human adenoviruses (HAdV) derived from HAdV with naturally low rates of pre-existing immunity will be beneficial for future clinical translation. We generated a low-seroprevalence HAdV-D10 serotype vector incorporating an αvβ6 integrin-selective peptide, A20, to target αvβ6-positive tumor cell types. HAdV-D10 has limited natural tropism. Structural and biological studies of HAdV-D10 knob protein highlighted low-affinity engagement with native adenoviral receptors CAR and sialic acid. HAdV-D10 fails to engage blood coagulation factor X, potentially eliminating “off-target” hepatic sequestration in vivo. We engineered an A20 peptide that selectively binds αvβ6 integrin into the DG loop of HAdV-D10 fiber knob. Assays in αvβ6+ cancer cell lines demonstrated significantly increased transduction mediated by αvβ6-targeted variants compared with controls, confirmed microscopically. HAdV-D10.A20 resisted neutralization by neutralizing HAdV-C5 sera. Systemic delivery of HAdV-D10.A20 resulted in significantly increased GFP expression in BT20 tumors. Replication-competent HAdV-D10.A20 demonstrated αvβ6 integrin-selective cell killing in vitro and in vivo. HAdV-D10 possesses characteristics of a promising virotherapy, combining low seroprevalence, weak receptor interactions, and reduced off-target uptake. Incorporation of an αvβ6 integrin-selective peptide resulted in HAdV-D10.A20, with significant potential for clinical translation.

Introduction: Onchocerciasis is the world's second leading cause of infectious blindness and remains a major problem in parts of Africa. In light of the efforts targeted towards improving ongoing elimination program, this study assessed onchocerca-induced visual impairments in Gashaka local government areas (LGA) in Taraba State, north-eastern Nigeria. Methods: In 2019, we recruited 158 consenting visually impaired persons across three communities in Garbabi ward of Gashaka LGA. To avoid confusion with co-endemic trachoma, the integrity of the tarsal conjunctiva, eyelashes were assessed using direct light. The anterior segment of the eye was also examined using a torchlight with oblique illumination. However, the posterior segment of the eye was assessed using a fundus camera. Two photographic images for the left and right eye of each participant were captured using the clinical fundus camera. The photographic eye images that were too dark were discarded, and only clear images were analyzed by two ophthalmologists. An ocular manifestation report was recorded for each participant following consensus between the ophthalmologists. Results: Of the 316 photographic eye images, almost half 146 (46.2%) from 73 participants were just too destroyed for light to penetrate and was not included in the analysis. Only 170 from 85 participants were clear and examinable. A total of 33 (39%) participants had chorioretinitis suggestive of onchocerciasis, including 22(25.9%) with chorio-retinal atrophy, 7(8.2%) and 4(4.7%) had chorioretinal atrophy in combination with early cataract and signs of trachoma respectively. In addition, 3(3.5%) of the participant had eye images which showed lens opacities, 1(1.2%) showed signs of keratoconus and 1(1.2%) showed a scared and pigmented cornea, possibly due to onchocerciasis. Furthermore, 28 (32.9%) had some ill-defined changes and 19 (22.4%) showed poorly defined chorio-retinal atrophy. Conclusion: In a bid to sustain MDA gains towards elimination of onchocerciasis, this work highlights the need for continuous assessment of onchocerciasis induced visual impairment, strengthening of ivermectin delivery and optimizing compliance and patient care among affected populations. These would require resource acquisition and local capacity building. Our preliminary findings call for further operational research on ocular morbidity as well as future stakeholders' consultations in this important and understudied area.

K0.5Na0.5NbO3 (KNN) based ceramics are considered optimal candidates to replace the toxic Pb-based piezoelectric materials; nonetheless, they are quite difficult to process. Therefore, obtaining an efficient glass-ceramic (GC) will have several advantages in lead-free piezoelectric production. The first step to developing advantageous functional GCs is to determine an adequate glass matrix and the network connectivity of the different structural entities depending on the bulk chemistry. Here, we investigated the structural variations occurring in aluminosilicate systems having Na2O/Al2O3 molar ratios from 1 to 5.7 upon the addition of KNN (0.4 up to 30 mol%) to understand how the bulk composition influences KNN incorporation and the properties of the glasses.Our study shows that more depolymerized aluminosilicate systems incorporate a larger amount of KNN because the Nb structural environment's evolution strongly depends on glass polymerization and the availability of charge compensator ions. No strong crosslinking between [SiO4], [AlO4], and [NbO6] structural entities was found, and there is an evolution from a heterogeneous environment with isolated [NbO6] units having different degrees of distortion to Nb–O–Nb linkages, up to the formation of clusters composed of corner-shared slightly distorted [NbO6]. All glass series tend to move toward these 3D clusters whenever the starting structure includes different entities or a more homogeneous environment. The evolution of the different niobate entities marks the changes in the properties that show non-linear variations with KNN content. Furthermore, the glass chemistry influences the crystallization kinetics, with activation energies for crystallization that vary from ∼300 ± 10 kJ/mol to ∼220 ± 10 kJ/mol depending on the alkali/Al2O3 molar ratios.The developed niobo-aluminosilicate glasses show high refractive indices, high transparency in the visible– NIR region and intense UV absorption. Therefore, these glasses are excellent candidates for photonic applications and optoelectronic devices. The stabilization of a perovskite-like phase upon crystallization confirms the potentiality for use as electro-optical glass-ceramics.

Summary: The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments.

High-level brain functions are widely believed to emerge from the orchestrated activity of multiple neural systems. However, lacking a formal definition and practical quantification of emergence for experimental data, neuroscientists have been unable to empirically test this long-standing conjecture. Here we investigate this fundamental question by leveraging a recently proposed framework known as “Integrated Information Decomposition,” which establishes a principled information-theoretic approach to operationalise and quantify emergence in dynamical systems — including the human brain. By analysing functional MRI data, our results show that the emergent and hierarchical character of neural dynamics is significantly diminished in chronically unresponsive patients suffering from severe brain injury. At a functional level, we demonstrate that emergence capacity is positively correlated with the extent of hierarchical organisation in brain activity. Furthermore, by combining computational approaches from network control theory and whole-brain biophysical modelling, we show that the reduced capacity for emergent and hierarchical dynamics in severely brain-injured patients can be mechanistically explained by disruptions in the patients’ structural connectome. Overall, our results suggest that chronic unresponsiveness resulting from severe brain injury may be related to structural impairment of the fundamental neural infrastructures required for brain dynamics to support emergence.

Overactivated NLRP3 inflammasome has been shown to associate with an increasing number of disease conditions. Activation of the NLRP3 inflammasome results in caspase-1-catalyzed formation of active pro-inflammatory cytokines (IL-1β and IL-18) resulting in pyroptosis. The multi-protein composition of the NLRP3 inflammasome and its sensitivity to several damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) make this extensively studied inflammasome an attractive target to treat chronic conditions. However, none of the known NLRP3 inhibitors has been approved for clinical use. Sulfonylurea and covalent inhibitors with electrophilic warhead (Michael acceptor) are among the prominent classes of compounds explored for their NLRP3 inhibitory effects. Chalcone, a small molecule with α, β unsaturated carbonyl group (Michael acceptor), has also been studied as a promising scaffold for the development of NLRP3 inhibitors. Low molecular weight, easy to manipulate lipophilicity and cost-effectiveness have attracted many to use chalcone scaffold for drug development. In this review, we highlight chalcone derivatives with NLRP3 inflammasome inhibitory activities. Recent developments and potential new directions summarized here will, hopefully, serve as valuable perspectives for investigators including medicinal chemists and drug discovery researchers to utilize chalcone as a scaffold for developing novel NLRP3 inflammasome inhibitors.

Summary: Prevention of hazardous drug exposure is essential in averting unnecessary health risks to health care workers (HCW). To address the risk to HCWs when handling hazardous drugs, engineering controls can be utilized to reduce the exposure. A closed system transfer device (CSTD) was introduced for hazardous drugs administration in 6 oncology wards; this new CSTD was associated with a significant increase in CLABSI rates.

Elevated levels of pharmaceuticals, steroid hormones and xenoestrogens (PSHXEs) in the aquatic environment pose a serious threat to the ecological balance. The endocrine disrupting PSHXEs in aquatic systems are linked to several adverse effects like reproductive health impairment, feminization, high mortality rate, decreased biodiversity etc. This study, therefore, sought to investigate the occurrence and the ecological risks posed by some selected PSHXEs and also conduct source apportionment of the PSHXEs in the Ghanaian aquatic environments. A total of 48 samples comprising 24 sediments and water each were taken from six waterbodies in Ghana. The samples were extracted using SPE cartridges for water and QuEChERS-dSPE for sediments. The analyses were done using Shimadzu Prominence UFLC 20A series. Ecological risk assessments were also conducted with the aid of USEPA T.E.S.T., whereas source apportionments were conducted using the APCS-MLR receptor model. Elevated mean total levels of PSHXEs ranging between 12,187 and 52,117 ng/L and 2,022–6,047 ng/g for water and sediment samples respectively were found. The risk quotients (RQ > 1) suggested a high risk posed by PSHXEs in water to organisms at the three trophic levels and also to benthic organisms in sediments of the Ghanaian aquatic environments for a short-term period. The APCS-MLR receptor model suggested three statistically significant sources (p

Human-infecting Cyclospora was recently characterized as three species, two of which (C. cayetanensis and C. ashfordi) are currently responsible for all known human infections in the USA, yet much remains unknown about the genetic structure within these two species. Here, we investigate Cyclospora genotyping data from 2018 through 2022 to ascertain if there are temporal patterns in the genetic structure of Cyclospora parasites that cause infections in US residents from year to year. First, we investigate three levels of genetic characterization: species, subpopulation, and strain, to elucidate annual trends in Cyclospora infections. Next, we determine if shifts in genetic diversity can be linked to any of the eight loci used in our Cyclospora genotyping approach. We observed fluctuations in the abundance of Cyclospora types at the species and subpopulation levels, but no significant temporal trends were identified; however, we found recurrent and sporadic strains within both C. ashfordi and C. cayetanensis. We also uncovered major shifts in the mitochondrial genotypes in both species, where there was a universal increase in abundance of a specific mitochondrial genotype that was relatively abundant in 2018 but reached near fixation (was observed in over 96% of isolates) in C. ashfordi by 2022. Similarly, this allele jumped from 29% to 82% relative abundance of isolates belonging to C. cayetanensis. Overall, our analysis uncovers previously unknown temporal-genetic patterns in US Cyclospora types from 2018 through 2022 and is an important step to presenting a clearer picture of the factors influencing cyclosporiasis outbreaks in the USA.

Introduction: The epidemiology and prognosis of the isolated traumatic brain injury (TBI) and spinal cord injury (SCI) are well studied. However, the knowledge of the impact of concurrent neurotrauma is very limited. Research questions: To characterize the longitudinal incidence of concurrent TBI and SCI and to investigate their combined impact on clinical care and outcomes, compared to a comparative but isolated SCI or TBI. Materials and methods: Data from 167,793 patients in the Trauma Audit and Research Network (TARN) registry collected in England and Wales between 2008 and 2018 were analysed. Tandem neurotrauma was defined as patients with concurrent TBI and SCI. The patient with isolated TBI or SCI was matched to the patient with tandem neurotrauma using propensity scores. Results: The incidence of tandem neurotrauma increased tenfold between 2008 and 2018, from 0.21 to 2.21 per 100,000 person-years. Patients in the tandem neurotrauma group were more likely to require multiple surgeries, ICU admission, longer ICU and hospital LOS, higher 30-day mortality, and were more likely to be transferred to acute hospitals and rehabilitation or suffer death at discharge, compared to patients with isolated TBI. Likewise, individuals with tandem neurotrauma compared to those with isolated SCI had a higher tendency to receive more than one surgery, ICU admission, longer LOS for ICU and higher mortality either at 30-day follow-up or at discharge. Discussion and conclusions: The incidence of tandem neurotrauma has increased steadily during the past decade. Its occurrence leads to greater mortality and care requirements, particularly when compared to TBI alone. Further investigations are warranted to improve outcomes in tandem neurotrauma.

The main challenges facing smallholder farmers in sub-Saharan Africa (SSA) are soil fertility decline and climate change, culminating in increased food insecurity. The double effect of climate change and soil fertility decline could be devastating among the poor rural smallholder farmers, who solely depend on rain-fed agriculture with little investment in adaptive mechanisms. Using inorganic fertilizers and careful selection of climate-resilient crops such as sorghum could improve the livelihoods of smallholder farmers through improved soil health and crop yields. However, information on the effects of inorganic fertilizer on sorghum production remains uncertain, especially in SSA. We evaluated the effects of inorganic fertilizers on sorghum yields among smallholder farmers in Western Kenya. We conducted a cross-sectional survey and collected data from 300 smallholder sorghum farmers. We employed a multi-stage sampling procedure to collect data from the specific smallholder farmers from the target population. We employed endogenous switching regression (ESR) modeling to control observed and unobserved bias in predicting the effects of inorganic fertilizer use on productivity. Smallholder farmers applied a limited amount of inorganic fertilizer. We established that hired labor, agricultural training, and farmers' perception of soil erosion were significant positive determinants of inorganic fertilizer use. Location and access to weather forecast information were key negative determinants of inorganic fertilizer use. The use of inorganic fertilizer increased crop yields by 14%. The findings suggested that inorganic amendments could promote food security and improve purchasing power, thus enhancing smallholder farmers' capacity to cope with declining soil fertility and climate change-related challenges. Therefore, agricultural policies targeting improved productivity of smallholder sorghum farmers could enhance inorganic fertilizer use while considering the determinants.

Background: The growth in multi-center neuroimaging studies generated a need for methods that mitigate the differences in hardware and acquisition protocols across sites i.e., scanner effects. ComBat harmonization methods have shown promise but have not yet been tested on all the data types commonly studied with magnetic resonance imaging (MRI). This study aimed to validate neuroCombat, longCombat and gamCombat on both structural and diffusion metrics in both cross-sectional and longitudinal data. Methods: We used a travelling subject design whereby 73 healthy volunteers contributed 161 scans across two sites and four machines using one T1 and five diffusion MRI protocols. Scanner was defined as a composite of site, machine and protocol. A common pipeline extracted two structural metrics (volumes and cortical thickness) and two diffusion tensor imaging metrics (mean diffusivity and fractional anisotropy) for seven regions of interest including gray and (except for cortical thickness) white matter regions. Results: Structural data exhibited no significant scanner effect and therefore did not benefit from harmonization in our particular cohort. Indeed, attempting harmonization obscured the true biological effect for some regions of interest. Diffusion data contained marked scanner effects and was successfully harmonized by all methods, resulting in smaller scanner effects and better detection of true biological effects. LongCombat less effectively reduced the scanner effect for cross-sectional white matter data but had a slightly lower probability of incorrectly finding group differences in simulations, compared to neuroCombat and gamCombat. False positive rates for all methods and all metrics did not significantly exceed 5%. Conclusions: Statistical harmonization of structural data is not always necessary and harmonization in the absence of a scanner effect may be harmful. Harmonization of diffusion MRI data is highly recommended with neuroCombat, longCombat and gamCombat performing well in cross-sectional and longitudinal settings.

Pre-treatment is essential to reduce logistic costs of agricultural residues. This work examined the interactions between pre-treatment conditions and thermo-chemical behaviour on product yields and properties. The effect of pyrolysis operating and briquetting conditions (i.e., temperature, pressure and bean straw-maize cob blend) on yields and properties of pyrolysis products from maize cob, bean straw and blended briquettes were investigated. It was found that briquetting conditions, heating rate and carrier gas flow rate had negligible effects on yields and properties of pyrolysis products. Temperature was the dominant factor that effected the yield and properties of the pyrolysis products. Increasing pyrolysis temperature increased the gas and reduced the char yield. Up to ∼ 45 % of the energy content of the raw material can be stored in smokeless char like material that can be easily transported and used for energy production e.g., household cooking. Pyrolysis of agricultural residues has the potential to reduce harmful particulate emissions whereas the high-water content bio-oil can be used as a binder in briquette production to reduce the pressure and temperature applied.

Low- and middle-income countries around the world are expanding investments in early childhood development (ECD) programs, but few evaluations of ECD programs measure impacts on maternal mental health as well as on other, closely associated psychosocial domains. One reason may be a lack of familiarity with appropriate survey instruments for measuring different aspects of maternal psychosocial well-being among ECD-focused researchers. We identified 478 empirical studies of ECD programs in low- and middle-income countries; 55 of them measure impacts on maternal mental health and related domains. In this article, we identify 22 instruments used to measure maternal depression, stress, anxiety, and other aspects of psychosocial well-being. We provide guidance on the uses of each instrument and examples of country contexts where each has been implemented.

Purpose: Previous studies have shown an increased risk of second primary malignancies (SPMs) in survivors of diffuse large B-cell lymphoma (DLBCL). Survivors live longer due to the intensification of and improvements in therapy; thus, we aimed to characterize SPM patterns in patients with DLBCL by treatment modality. Methods and Materials: Standardized incidence ratio and absolute excess risk of SPMs were assessed in patients with primary DLBCL from 1975 to 2016 in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. A subgroup analyses based on, sex, race, age at the time of diagnosis, latency, and treatment modality were performed. Propensity score-adjusted cumulative incidence curves were generated, stratified by treatment and accounting for death as a competing risk. Results: In total, 45,946 patients with DLBCL were identified with a mean follow up of 70 months. Overall, 9.2% of patients developed an SPM with a standardized incidence ratio of 1.23 (95% confidence interval, 1.20-1.27). There was no difference in SPM risk between men and women or Black and White patients. Patients age

Health is influenced by a broad range of factors beyond the typical remit of public health. It is therefore increasingly recognized that multiple sectors need to be engaged to improve population health. Health in All Policies (HiAP) is an approach to systematically consider health across policies and programs. This study assessed best practices and gaps in HiAP operationalization to inform practitioners aiming to incorporate HiAP in their work. We used Delaware as a model state to examine operationalization factors in a jurisdiction planning to implement HiAP.Methods included document review, key informant interviews, focus groups, and a questionnaire conducted in Delaware and virtually. Thematic analysis was used to analyze qualitative data to provide information on best practices and gaps in existing HiAP programs and context in Delaware. Descriptive statistics were used to examine collaboration in Delaware and to support or refute qualitative findings.We identified two gaps that can hinder HiAP implementation: 1) HiAP practitioners do not adequately use strategic communications to increase buy-in across sectors; 2) practitioners do not fully recognize the importance of being adaptable throughout HiAP implementation, which hinders sustainability. Qualitative findings from Delaware offer insight to these gaps and opportunities to address them.Refining the essential elements of HiAP to add: 1) strategic communications across sectors and 2) flexibility throughout HiAP implementation may point the way to more successful adoption of HiAP approaches across jurisdictions. This research demonstrated the importance of examining local perspectives on HiAP before implementation based on a jurisdiction’s context.

Summary: GPI-APs are a family of proteins attached to the plasma membrane by a glycoplipid that undergoes remodeling of the glycan and lipid structure during transport to the cell surface. We describe a protocol to induce the synthesis of a GPI-anchored protein whereby EtNP is added to Man2 but not removed. By temporally manipulating the expression of Gpi7p, the enzyme that adds EtNP to Man2, in ted1Δ dcr2Δ cells prior to the expression of a canonical GPI-AP (mNeon-Gas1p), EtNP is attached to Man2 of de novo synthesized mNeon-Gas1p and cannot be removed. This strategy provides a means to temporally and spatially track the transport of remodeling-defective GPI-APs in yeast cells.For complete details on the use and execution of this protocol, please refer to Chen et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Determining the protection an individual has to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VoCs) is crucial for future immune surveillance, vaccine development, and understanding of the changing immune response. We devised an informative assay to current ELISA-based serology using multiplexed, baited, targeted proteomics for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. Serum from individuals collected after infection or first- and second-dose vaccination demonstrates this approach and shows concordance with existing serology and neutralization. Our assays show altered responses of both immunoglobulins and complement to the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.1) VoCs and a reduced response to Omicron (B1.1.1529). We were able to identify individuals who had prior infection, and observed that C1q is closely associated with IgG1 (r > 0.82) and may better reflect neutralization to VoCs. Analyzing additional immunoproteins beyond immunoglobulin (Ig) G, provides important information about our understanding of the response to infection and vaccination. Motivation: Assays for measuring serum antibody responses are typically limited to measurement of a total or single immunoglobulin isotype. The antibody response is far more complex, with multiple immunoglobulin classes, isotypes, and complement factors involved. This is a potential wealth of information that is typically understudied and missed by existing tests. The global COVID-19 pandemic has highlighted the need to understand better the immune response in respect to vaccine development and emerging new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants. Using the ability of tandem mass spectrometry to multiplex and directly and accurately measure the antibody complex, we devised an alternative assay to capture this valuable information.

Summary: Background: The most widely used copper intrauterine device (IUD) in the world (the TCu380A), and the only product available in many countries, causes side effects and early removals for many users. These problems are exacerbated in nulliparous women, who have smaller uterine cavities compared to parous women. We compared first-year continuation rates and reasons/probabilities for early removal of the TCu380A versus a smaller Belgian copper IUD among nulliparous users. Methods: This 12-month interim report is derived from a pre-planned interim analysis of a sub population and focused on key secondary comparative endpoints. In this participant-blinded trial at 16 centres in the USA, we randomised participants aged 17–40 in a 4:1 ratio to the NT380-Mini or the TCu380A. In the first year, participants had follow-up visits at 6-weeks and 3, 6, and 12-months, and a phone contact at 9 months; we documented continued use, expulsions, and reasons for removal. Among participants with successful IUD placement, we compared probabilities of IUD continuation and specific reasons for discontinuation using log-rank tests. This trial is registered with ClinicalTrials.gov number NCT03124160 and is closed to recruitment. Findings: Between June 1, 2017, and February 25, 2019, we assigned 927 nulliparous women to either the NT380-Mini (n = 744) or the TCu380A (n = 183); the analysis population was 732 (NT380-Mini) and 176 (TCu380A). Participants using the NT380-Mini, compared to the TCu380A, had higher 12-month continuation rates (78·7% [95% CI: 72·9–84·5%] vs. 70·2% [95% CI: 59·7–80·7], p = 0·014), lower rates of removal for bleeding and/or pain (8·1% vs. 16·2%, p = 0·003) and lower IUD expulsion rates (4·8% vs. 8·9%, p = 0·023), respectively. Interpretation: The NT380-Mini offers important benefits for a nulliparous population compared to the TCu380A in the first twelve months, when pivotal experiences typically occur. Higher continuation rates with the NT380-Mini may avert disruptions in contraceptive use and help users avoid unintended pregnancy. Funding: Bill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Mona Lisa, N.V. (Belgium).

Small world topologies are thought to provide a valuable insight into human brain organisation and consciousness. However, functional magnetic resonance imaging studies in consciousness have not yielded consistent results. Given the importance of dynamics for both consciousness and cognition, here we investigate how the diversity of small world dynamics (quantified by sample entropy; dSW-E11 dSW-E= dynamic small world entropy) scales with decreasing levels of awareness (i.e., sedation and disorders of consciousness). Paying particular attention to result reproducibility, we show that dSW-E is a consistent predictor of levels of awareness even when controlling for the underlying functional connectivity dynamics. We find that dSW-E of subcortical, and cortical areas are predictive, with the former showing higher and more robust effect sizes across analyses. We find that the network dynamics of intermodular communication in the cerebellum also have unique predictive power for levels of awareness. Consequently, we propose that the dynamic reorganisation of the functional information architecture, in particular of the subcortex, is a characteristic that emerges with awareness and has explanatory power beyond that of the complexity of dynamic functional connectivity.

Background: In 2016, three European scientific societies called for standardization to the “2222” as a European unique phone number in case of in-hospital emergencies. This study describes the management of in-hospital emergency calls in all French military training hospitals and aims to detail their original transition, for the first time in France, to the “2222”. Methods: An electronic standardized questionnaire was emailed to heads of rapid response teams in the eight French military training hospitals. Results: All participants answered the questionnaire (100%). The eight French military training hospitals had a specific procedure for management of in-hospital emergencies. Six hospitals already used a unique phone number for in-hospital emergencies, but none of them were using the 2222 in March 2019. Two hospitals still used several phone numbers for in-hospital emergencies, mainly due to historical and local arrangements. Rapid response teams included at least a physician and a nurse. There was a discussion to switch to “2222” as the unique phone number for in-hospital emergencies in two hospitals. In both, the discussions involved hospital executive officers, medical teams, rapid response teams and technical teams leading to a step-by-step transition. Finally, in October 2019, these two hospitals launched the “2222” procedure for in-hospital emergencies. Conclusion: This study found a large disparity in the eight French military training hospitals, concerning in-hospital emergency protocols. Two French military training hospitals launched the “2222” procedure for the first time in France. Further efforts are still needed to continue to promote the use of the 2222 as a European unique phone number for in-hospital emergencies.

Summary: Background: Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods: 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings: COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=​​0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation: Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed. Funding: This work was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC), NIHR Cambridge Clinical Research Facility (BRC-1215-20014), the Addenbrooke's Charities Trust and NIHR COVID-19 BioResource RG9402. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. JBR is supported by the Wellcome Trust (220258) and Medical Research Council (SUAG/051 G101400). VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Purpose: The benefits of intensity modulated radiation therapy (IMRT) compared with standard 3-dimensional conformal radiation therapy have been demonstrated in many cancer sites and include decreased acute and late toxicity, improved quality of life, and opportunities for dose escalation. Limited literature suggests non-white patients may have lower utilization of IMRT. We hypothesized that as the use of IMRT has increased in recent years, racial inequities have persisted and disproportionately affect non-Hispanic Black (NHB) patients. We aim to evaluate temporal trends in IMRT utilization focusing on disparities among minoritized populations. Methods and Materials: The National Cancer Database was queried to identify the 10 disease sites with the highest total number of cancer patients treated with definitive intent IMRT in 2017, the most recent year for which data are available. Exclusions included stage IV, age

Quantitative susceptibility mapping (QSM) is an MRI-based, computational method for anatomically localizing and measuring concentrations of specific biomarkers in tissue such as iron. Growing research suggests QSM is a viable method for evaluating the impact of iron overload in neurological disorders and on cognitive performance in aging. Several software toolboxes are currently available to reconstruct QSM maps from 3D GRE MR Images. However, few if any software packages currently exist that offer fully automated pipelines for QSM-based data analyses: from DICOM images to region-of-interest (ROI) based QSM values. Even less QSM-based software exist that offer quality control measures for evaluating the QSM output. Here, we address these gaps in the field by introducing and demonstrating the reliability and external validity of Ironsmith; an open-source, fully automated pipeline for creating and processing QSM maps, extracting QSM values from subcortical and cortical brain regions (89 ROIs) and evaluating the quality of QSM data using SNR measures and assessment of outlier regions on phase images. Ironsmith also features automatic filtering of QSM outlier values and precise CSF-only QSM reference masks that minimize partial volume effects. Testing of Ironsmith revealed excellent intra- and inter-rater reliability. Finally, external validity of Ironsmith was demonstrated via an anatomically selective relationship between motor performance and Ironsmith-derived QSM values in motor cortex. In sum, Ironsmith provides a freely-available, reliable, turn-key pipeline for QSM-based data analyses to support research on the impact of brain iron in aging and neurodegenerative disease.