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Abstract The University of Florida Health conducted a pragmatic implementation of a pharmacogenetics (PGx) panel‐based test to guide medications used for supportive care prescribed to patients undergoing chemotherapy. The implementation was in the context of a pragmatic clinical trial for patients with non‐hematologic cancers being treated with chemotherapy. Patients were randomized to either the intervention arm or control arm and received PGx testing immediately or at the end of the study, respectively. Patients completed the MD Anderson Symptom Inventory (MDASI) to assess quality of life (QoL). A total of 150 patients received PGx testing and enrolled in the study. Clinical decision support and implementation infrastructure were developed. While the study was originally planned for 500 patients, we were underpowered in our sample of 150 patients to test differences in the patient‐reported MDASI scores. We did observed a high completion rate (92%) of the questionnaires; however, there were few medication changes (n = 6 in the intervention arm) based on PGx test results. Despite this, we learned several lessons through this pragmatic implementation of a PGx panel‐based test in an outpatient oncology setting. Most notably, patients were less willing to undergo PGx testing if the cost of the test exceeded $100. In addition, to enhance PGx implementation success, reoccurring provider education is necessary, clinical decision support needs to appear in a more conducive way to fit in with oncologists' workflow, and PGx test results need to be available earlier in treatment planning.

Abstract Introduction Despite improved treatment options for plaque psoriasis within the last decades, some patients still have an inadequate response to treatment. Direct clinical evaluation between therapies used after biologic failure could facilitate physicians’ choice of treatment. Methods COBRA (NCT04533737) was a randomized (1:1), blinded (patient and assessor), 28-week, active-comparator trial conducted in Europe from December 2020 to December 2022. The objective was to compare the efficacy and safety of brodalumab versus guselkumab in adults with moderate-to-severe plaque psoriasis and inadequate response to ustekinumab. Patients received either brodalumab 210 mg or guselkumab 100 mg. The primary [having Psoriasis Area and Severity Index (PASI)-100 response at week 16] and key secondary (time to PASI-100 response) endpoints were tested in a fixed sequence. Results Due to delays and enrollment challenges, recruitment was terminated with 113 patients enrolled of 240 planned. The proportion of patients having PASI-100 at week 16 for brodalumab was 53.4% compared with 35.9% for guselkumab [odds ratio (OR) 2.05; 95% confidence interval (CI) 0.95, 4.44; p = 0.069]. As this was not statistically significant, the hierarchical testing procedure was stopped. All other secondary PASI endpoints had nominal p-values below 0.05 in favor of brodalumab. In the time to PASI response analyses, brodalumab separated from guselkumab in estimated cumulative incidence of patients achieving a response from week 2 onward, suggesting fast onset of action with brodalumab. Quality of life measures improved in both treatment groups. The safety findings were consistent with the known safety profiles. Conclusions Brodalumab showed a tendency toward better and earlier effect than guselkumab in patients who had failed ustekinumab. Thus, this trial provides important information in assisting physicians in their choice of therapy for patients who have failed their prior anti-interleukin (IL)-12/23 treatment. Trial Registration ClinicalTrials.gov identifier NCT04533737.

IntroductionNatural killer/T cell lymphoma (NKTL) is an aggressive malignancy associated with poor prognosis. This is largely due to limited treatment options, especially for relapsed patients. Immunotherapies like immune checkpoint inhibitors (ICI) and anti-CD38 therapies have shown promising but variable clinical efficacies. Combining these therapies has been suggested to enhance efficacy.MethodsWe conducted a case study on a relapsed NKTL patient treated sequentially with anti-CD38 followed by ICI (anti-PD1) using cytometry analyses.Results and DiscussionOur analysis showed an expected depletion of peripheral CD38+ B cells following anti-CD38 treatment. Further analysis indicated that circulating anti-CD38 retained their function for up to 13 weeks post-administration. Anti-PD1 treatment triggered re-activation and upregulation of CD38 on the T cells. Consequently, these anti-PD1-activated T cells were depleted by residual circulating anti-CD38, rendering the ICI treatment ineffective. Finally, a meta-analysis confirmed this counterproductive effect, showing a reduced efficacy in patients undergoing combination therapy. In conclusion, our findings demonstrate that sequential anti-CD38 followed by anti-PD1 therapy leads to a counterproductive outcome in NKTL patients. This suggests that the treatment sequence is antithetic and warrants re-evaluation for optimizing cancer immunotherapy strategies.

The paper offers a novel philosophical perspective on how research literacy should be conceptualised in the educational domain. Standard accounts of teacher research literacy consider it merely a subset of the skills of an educational researcher. Therefore, the accounts largely ignore the need to anchor or embed the mode of engagement with research in the particular demands of the professional role. By contrast, we argue that a virtue-based account of the epistemic agency involved in receiving testimony can help deliver a normatively attractive and empirically plausible account that is tailored to the role. We support the account with an original in-depth analysis of actual teacher engagement with research.

AbstractThe use of drones and remote sensing in combination with geospatial analysis is a cost-efficient way to monitor energy distribution networks, especially those in fire-prone areas. This study investigated the use of image and photogrammetric analysis together with segmentation algorithms to assess vegetation height and volume in power line corridors in Southeast Queensland, Australia. Various fuel reduction techniques, including mega-mulching, spot sprays and cool mosaic burns, were implemented, and drone-generated models were employed to evaluate their effectiveness. The fuel hazard reduction and regrowth in terms of vegetation height and volume were recorded and analysed. Importantly, the study demonstrates a robust correlation (R2 = 0.9073; df = 1,16; F = 156; p

The laparoscopic fundoplication has proven to be the standard technique of antireflux surgery and hiatal hernia (HH) repair over the last decade. However, robot-assisted surgery is more and more implemented in daily practice. Several studies have proven the feasibility and safety of robot-assisted HH repair and antireflux surgery. Both approaches seem to be similar regarding perioperative and postoperative complications, length of hospital stay, postoperative symptoms, and quality of life, as well as objective assessment of gastric acid exposure. Nevertheless, high total costs as well as a considerably longer total operating time of robot-assisted surgery need to be considered. The role of robot-assisted surgery in complex cases is promising but needs to be evaluated. Eventually, the decision regarding the technique used should be based on the surgeon’s discretion and experience.

AbstractParacetamol-induced nephrotoxicity in the absence of hepatotoxicity is only described in a few studies. The aim of this retrospective cohort study with data from the Capital Region of Denmark 2010-2017, was to examine the incidence of possible paracetamol-induced nephrotoxicity in absence of hepatotoxicity. Only one out of 5,827 admissions (0.02%) included in the study developed clinically relevant acute kidney injury (AKI) that could be attributed to paracetamol in absence of acute liver injury. This study demonstrates that clinically relevant AKI due to paracetamol overdose rarely occurs without concomitant hepatic injury when excluding other prerenal, renal, and postrenal causes of renal dysfunction, NAC interference and chronic kidney injury.

Abstract The benefits of continuous glucose monitoring (CGM) in diabetes management are extensively documented. Yet, the broader adoption of CGM systems is limited by their cost and invasiveness. Current CGM devices, requiring implantation or the use of hypodermic needles, fail to offer a convenient solution. We have demonstrated that magnetohydrodynamics (MHD) is effective at extracting dermal interstitial fluid (ISF) containing glucose, without the use of needles. Here we present the first study of ISF sampling with MHD for glucose monitoring in humans. We conducted 10 glucose tolerance tests on 5 healthy volunteers and obtained a significant correlation between the concentration of glucose in ISF samples extracted with MHD and capillary blood glucose samples. Upon calibration and time lag removal, the data indicate a Mean Absolute Relative Difference (MARD) of 12.9% and Precision Absolute Relative Difference of 13.1%. In view of these results, we discuss the potential value and limitations of MHD in needle-free glucose monitoring.

Abstract Quantifying spatiotemporally explicit interactions within animal populations facilitates the understanding of social structure and its relationship with ecological processes. Data from animal tracking technologies (Global Positioning Systems [“GPS”]) can circumvent longstanding challenges in the estimation of spatiotemporally explicit interactions, but the discrete nature and coarse temporal resolution of data mean that ephemeral interactions that occur between consecutive GPS locations go undetected. Here, we developed a method to quantify individual and spatial patterns of interaction using continuous‐time movement models (CTMMs) fit to GPS tracking data. We first applied CTMMs to infer the full movement trajectories at an arbitrarily fine temporal scale before estimating interactions, thus allowing inference of interactions occurring between observed GPS locations. Our framework then infers indirect interactions—individuals occurring at the same location, but at different times—while allowing the identification of indirect interactions to vary with ecological context based on CTMM outputs. We assessed the performance of our new method using simulations and illustrated its implementation by deriving disease‐relevant interaction networks for two behaviorally differentiated species, wild pigs (Sus scrofa) that can host African Swine Fever and mule deer (Odocoileus hemionus) that can host chronic wasting disease. Simulations showed that interactions derived from observed GPS data can be substantially underestimated when temporal resolution of movement data exceeds 30‐min intervals. Empirical application suggested that underestimation occurred in both interaction rates and their spatial distributions. CTMM‐Interaction method, which can introduce uncertainties, recovered majority of true interactions. Our method leverages advances in movement ecology to quantify fine‐scale spatiotemporal interactions between individuals from lower temporal resolution GPS data. It can be leveraged to infer dynamic social networks, transmission potential in disease systems, consumer–resource interactions, information sharing, and beyond. The method also sets the stage for future predictive models linking observed spatiotemporal interaction patterns to environmental drivers.

Abstract Intravenous immunoglobulin (IVIG) is increasingly used as a treatment for recurrent pregnancy loss (RPL) despite lack of clear evidence on efficacy. Recent data suggest IVIG might be more effective in a subgroup of women with an aberrant immunological profile. Therefore, a systematic review and meta-analysis of studies on the effectiveness of IVIG treatment on pregnancy outcome among women with RPL and underlying immunological conditions (e.g., elevated NK cell percentage, elevated Th1/Th2 ratio, diagnosis with autoimmune disorders) was conducted. Eight non-randomized controlled trials, including 478 women (intervention: 284; control: 194), met eligibility criteria. Meta-analysis showed that treatment with IVIG was associated with a two-fold increase in live birth rate (RR 1.98, 95% CI 1.44–2.73, P 12%) NK-cell percentage (RR 2.32, 95% CI 1.77–3.02, P

The social identity approach to leadership argues that leaders' capacity to influence and inspire others is grounded in a shared sense of social identity (or 'us-ness') that those leaders create, advance, represent, and embed for the groups they lead. The approach therefore argues that a key task for leaders is to develop insights and skills of (social) identity leadership that allow them to motivate and mobilize groups and transform them into a potent social and organizational force. In contrast to other approaches and programs which focus on leaders' leader identity (their 'I-ness'), the 5R leadership development program supports the development of leaders' social identity by raising awareness of the importance of social identity ('we-ness') for leadership and taking leaders through structured activities that help them build engaged and inclusive teams. The present research assessed the benefits of facilitated and learner self-directed versions of the 5R program (Ns = 27, 22 respectively) relative to a no-treatment control (N = 27). Results (including those of an intention-to-treat analysis; N = 76) indicated that, relative to leaders in the control condition, those who participated in both forms of 5R reported large increases in identity leadership knowledge, as well as medium-sized increases in both team engagement (a compound factor comprised of team identification, team OCB, team efficacy, and work engagement) and 'teamfulness' (comprised of team reflexivity, team psychological safety, team goal clarity, and inclusive team climate). We reflect on the importance of teamfulness for leadership and team functioning and on the value of programs that help leaders develop this.

ABSTRACT People living with HIV (PLWH) represent a vulnerable population to adverse musculoskeletal outcomes due to HIV infection, antiretroviral therapy (ART), and at‐risk alcohol use. Developing measures to prevent skeletal degeneration in this group requires a grasp of the relationship between alcohol use and low bone mass in both the PLWH population and its constituents as defined by sex, age, and race. We examined the association of alcohol use with serum biochemical markers of bone health in a diverse cohort of PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) study. To explore the effects of alcohol on bone in the context of HIV and ART and the role of estrogen, we conducted a parallel, translational study using simian immunodeficiency virus (SIV)+/ART+ female rhesus macaques divided into four groups: vehicle (Veh)/Sham; chronic binge alcohol (CBA)/Sham; Veh/ovariectomy (OVX); and CBA/OVX. Clinical data showed that both osteocalcin (Ocn) and procollagen type I N‐propeptide (PINP) levels were inversely associated with multiple measures of alcohol consumption. Age (>50 years) significantly increased susceptibility to alcohol‐associated suppression of bone formation in both female and male PLWH, with postmenopausal status appearing as an additional risk factor in females. Serum sclerostin (Scl) levels correlated positively with measures of alcohol use and negatively with Ocn. Micro‐CT analysis of the macaque tibias revealed that although both CBA and OVX independently decreased trabecular number and bone mineral density, only OVX decreased trabecular bone volume fraction and impacted cortical geometry. The clinical data implicate circulating Scl in the pathogenesis of alcohol‐induced osteopenia and suggest that bone morphology can be significantly altered in the absence of net change in osteoblast function as measured by serum markers. Inclusion of sophisticated tools to evaluate skeletal strength in clinical populations will be essential to understand the impact of alcohol‐induced changes in bone microarchitecture. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Abstract Measurement of cardiac troponin I (cTnI) should be feasible for point-of-care testing (POCT) to diagnose acute myocardial infarction (AMI). Lateral flow immunoassays (LFIAs) have been long implemented in POCT and clinical settings. However, sensitivity, matrix effect and quantitation in lateral flow immunoassays (LFIAs) have been major limiting factors. The performance of LFIAs can be improved with upconverting nanoparticle (UCNP) reporters. Here we report a new methodological approach to quantify cTnI using UCNP-LFIA technology with minimized plasma interference. The performance of the developed UCNP-LFIA was evaluated using clinical plasma samples (n = 262). The developed UCNP-LFIA was compared to two reference assays, the Siemens Advia Centaur assay and an in-house well-based cTnI assay. By introducing an anti-IgM scrub line and dried EDTA in the LFIA strip, the detection of cTnI in plasma samples was fully recovered. The UCNP-LFIA was able to quantify cTnI concentrations in patient samples within the range of 30–10,000 ng/L. The LoB and LoD of the UCNP-LFIA were 8.4 ng/L and 30 ng/L. The method comparisons showed good correlation (Spearman’s correlation 0.956 and 0.949, p

Abstract Urinary extracellular vesicles (uEVs) are enriched with glycosylated proteins which have been extensively studied as putative biomarkers of urological cancers. Here, we characterized the glycosylation and integrin profile of EVs derived from urological cancer cell lines. We used fluorescent europium‐doped nanoparticles coated with lectins and antibodies to identify a biomarker combination consisting of integrin subunit alpha 3 (ITGA3) and fucose. In addition, we used the same cancer cell line‐derived EVs as analytical standards to assess the sensitivity of the ITGA3‐UEA assay. The clinical performance of the ITGA3‐UEA assay was analysed using urine samples of various urological pathologies including diagnostically challenging benign prostatic hyperplasia (BPH), prostate cancer (PCa) and bladder cancer (BlCa). The assay can significantly discriminate BlCa from all other patient groups: PCa (9.2‐fold; p = 0.00038), BPH (5.5‐fold; p = 0.004) and healthy individuals (and 23‐fold; p = 0.0001). Our results demonstrate that aberrantly fucosylated uEVs and integrin ITGA3 can be detected with fucose‐specific lectin UEA in a simple bioaffinity assay for the detection of BlCa directly from unprocessed urine.

In this paper we describe a bottom-up exploration of the social evaluations that emerge from the gossip people hear about others in a workplace context. We used the Dual Perspective Model (DPM: Abele & Wojciszke, 2007, 2014, 2018) to code open-format gossip stories provided by 522 participants for evaluations of gossip targets’ warmth and morality (i.e., communion) and competence and assertiveness (i.e., agency). We additionally coded evaluations of work-effort, self-control, and stress, as well as the gossip topic. Our analysis revealed that communion facet evaluations were more frequent than agency facet evaluations. Additionally, gossip was predominantly negative, reflecting the fact that evaluations usually conveyed information about low warmth, morality and competence; assertiveness was an exception, with high evaluations more common than low. These negative evaluations were most frequently contained in gossip about the negative character of the target and work-related norm transgressions. Our analysis further revealed distinct patterns of co-occurrence for the DPM facets, providing further evidence of the utility of distinguishing not only between the major dimensions of social evaluation, but also their facets. This research provides new insights regarding the variety, prevalence, and valence of social evaluations that emerge from workplace gossip. Most important in the present context, it shows the usefulness of the DPM facets in understanding the content of gossip.

ObjectiveHigh-density lipoprotein (HDL) is a heterogeneous group of subpopulations differing in protein/lipid composition and in their anti-atherogenic function. There is a lack of assays that can target the functionality of HDL particles related to atherosclerosis. The objective of this study was to construct two-site apolipoprotein A-I (apoA-I) assays and to evaluate their clinical performance in patients with suspected obstructive coronary artery disease (CAD).Approach and resultsDirect two-site apoA-I assays (named 109–121 and 110–525) were developed to identify the presence of apoA-I in the HDL of patients with CAD using apoA-I antibodies as a single-chain variable fragment fused with alkaline phosphatase. ApoA-I109−121 and apoA-I110−525 were measured in 197 patients undergoing coronary computed tomography angiography (CTA) and myocardial positron emission tomography perfusion imaging due to suspected obstructive CAD. Among patients not using lipid-lowering medication (LLM, n = 125), the level of apoA-I110−525 was higher in the presence than in the absence of coronary atherosclerosis [21.88 (15.89–27.44) mg/dl vs. 17.66 (13.38–24.48) mg/dl, P = 0.01)], whereas there was no difference in apoA-I109−121, HDL cholesterol, and apoA-I determined using a polyclonal apoA-I antibody. The levels of apoA-I109−121 and apoA-I110−525 were similar in the presence or absence of obstructive CAD. Among patients not using LLM, apoA-I110−525 adjusted for age and sex identified individuals with coronary atherosclerosis with a similar accuracy to traditional risk factors [area under the curve [AUC] (95% CI): 0.75(0.66–0.84) 0.71 (0.62–0.81)]. However, a combination of apoA-I110−525 with risk factors did not improve the accuracy [AUC (95% CI): 0.73 (0.64–0.82)].ConclusionDirect two-site apoA-I assays recognizing heterogeneity in reactivity with apoA-I could provide a potential approach to identify individuals at a risk of coronary atherosclerosis. However, their clinical value remains to be studied in larger cohorts.

Abstract Background Breast cancer is a very common cancer that can be severe if not discovered early. The current tools to detect breast cancer need improvement. Cancer has a universal tendency to affect glycosylation. The glycosylation of circulating extracellular vesicle‐associated glycoproteins, and mucins may offer targets for detection methods and have been only explored in a limited capacity. Aim Our aim was to develop an approach to detect the aberrant glycosylation of mucins and extracellular vesicle‐associated glycoproteins from human sera using fluorescent nanoparticles, and preliminarily evaluate this approach for the differential diagnosis of breast cancer. Methods and results The assay involved immobilizing glycosylated antigens using monoclonal antibodies and then probing their glycosylation by using lectins and glycan‐specific antibodies coated on Eu+3‐doped nanoparticles. Detection of mucin 1 and mucin 16 glycosylation with wheat germ agglutinin, and detection of the extracellular vesicle‐associated CD63 were found to have better diagnostic ability for localized breast cancer than the conventional assays for mucin 1 and mucin 16 based tumor markers when the receiver operating characteristics were compared. Conclusions These results indicate that successful differential diagnosis of primary breast cancer may be aided by detecting cancer‐associated glycosylation of mucin 1 and mucin 16, and total concentration of CD63, in human serum.

Traditional course deadline policies uphold the myth of the “normal” student, assuming students face few and equal barriers to completing work on time. In contrast, flexible deadline policies acknowledge that students face unequal barriers and seek to mitigate them. Flexible deadline policies maintain structure while transferring some decision-making power from the instructor into the hands of the student. These practices align with current pedagogical movements in higher education that seek to empower all students to meet learning goals. This study explores student perspectives on, and use of, proactive extensions built into a recent university course. We compare extension use in low-stake, high-stake, individual, and team assignments; observe how extension use changed over the term; and examine student self-reported responses about the policy. Students unanimously agreed that the proactive extension policy was valuable to their learning. They reported that the proactive extensions enabled them to improve the quality of their work and to better manage their academic workloads, acting as self-regulated learners. They also frequently described reduced stress as a benefit. Extensions generally appeared to be used as needed rather than encouraging procrastination. Students also identified that the need to request extensions in other courses was a barrier. The instructor of this course also benefitted from implementing this policy. Faculty should consider implementing flexible deadline policies to improve student learning experiences and to contribute to a more equitable and inclusive learning environment.

Abstract Out of 463 million people currently with diabetes, 232 million remain undiagnosed. Diabetes is a threat to human health, which could be mitigated via continuous self-monitoring of glucose. In addition to blood, interstitial fluid is considered to be a representative sample for glucose monitoring, which makes it highly attractive for wearable on-body sensing. However, new technologies are needed for efficient and noninvasive sampling of interstitial fluid through the skin. In this report, we introduce the use of Lorentz force and magnetohydrodynamics to noninvasively extract dermal interstitial fluid. Using porcine skin as an ex-vivo model, we demonstrate that the extraction rate of magnetohydrodynamics is superior to that of reverse iontophoresis. This work seeks to provide a safe, effective, and noninvasive sampling method to unlock the potential of wearable sensors in needle-free continuous glucose monitoring devices that can benefit people living with diabetes.

Abstract Background Around 15–20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance. Methods RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling. Results RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status. Conclusions Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated.

Increased demand for sustainable timber products has resulted in large investments in agroforestry in Australia, with plantations growing various Pinus species, selected to suit a plantation’s environment. Juvenile Pinus species have a low fire tolerance. With Australia’s history of wildfires and the likelihood of climate change exacerbating that risk, the potential for a total loss of invested capital is high unless cost-effective targeted risk minimisation is part of forest management plans. Based on the belief that the understory profiles within the juvenile plantations are a major factor determining fuel hazard risks, an accurate assessment of these profiles is required to effectively mitigate those risks. At present, assessment protocols are largely reliant on ground-based observations, which are labour-intensive, time consuming, and expensive. This research project investigates the effectiveness of using geospatial analysis of drone-derived photographic data collected in the commercial pine plantations of south-eastern Queensland as a cost-saving alternative to current fuel hazard risk assessment practices. Understory composition was determined using the supervised classification of orthomosaic images together with derivations of canopy height models (CHMs). The CHMs were subjected to marker-controlled watershed segmentation (MCWS) analysis, isolating and removing the plantation pine trees, enabling the quantification of understory fuel profiles. The method used proved highly applicable to immature forest environments with minimal canopy closure, but became less reliable for close canopied older plantations.

Abstract Mortality in colorectal cancer (CRC) remains high, resulting in 860,000 deaths annually. Carcinoembryonic antigen is widely used in clinics for CRC patient follow-up, despite carrying a limited prognostic value. Thus, an obvious need exists for multivariate prognostic models. We analyzed 48 biomarkers using a multiplex immunoassay panel in preoperative serum samples from 328 CRC patients who underwent surgery at Helsinki University Hospital between 1998 and 2003. We performed a multivariate prognostic forward-stepping background model based on basic clinicopathological data, and a multivariate machine-learned prognostic model based on clinicopathological data and biomarker variables, calculating the disease-free survival using the value of importance score. From the 48 analyzed biomarkers, only IL-8 emerged as a significant prognostic factor for CRC patients in univariate analysis (HR 4.88; 95% CI 2.00–11.92; p = 0.024) after correcting for multiple comparisons. We also developed a multivariate model based on all 48 biomarkers using a random survival forest analysis. Variable selection based on a minimal depth and the value of importance yielded two tentative candidate CRC prognostic markers: IL-2Ra and IL-8. A multivariate prognostic model using machine-learning technologies improves the prognostic assessment of survival among surgically treated CRC patients.

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of “long COVID-19”, and defines key cells and cytokines that delineate true and quasi-convalescent states.

ABSTRACT Estrogen deficiency and aging play critical roles in the pathophysiology of bone as a result of increased oxidative stress. It has been suggested that prevention of NADPH oxidase‐ (Nox‐) dependent accumulation of ROS may be an approach to potentially minimize bone loss caused by these conditions. Using ovariectomized (OVX) and Nox4 gene‐deletion mouse models, we investigated the role of Nox4 in OVX‐induced bone loss and osteoblast senescence signaling. Six‐month‐old WT C57Bl6 mice were allocated to a sham control group, OVX, and OVX plus E2 treatment group for 8 weeks. Decreased bone mass including BMD and BMC were found in the OVX group compared with the sham control (p

Abstract Background Systematic reviews (SRs) depend on comprehensive searches for evidence to provide balanced, accurate results. Requesting published and unpublished studies from pharmaceutical manufacturers has been proposed as a method to engage industry stakeholders and potentially reduce reporting bias. The Drug Effectiveness Review Project (DERP) has been requesting such evidence since 2003; the purpose of this study was to retrospectively evaluate the type and impact of the evidence received. Methods Data from “dossiers” submitted by pharmaceutical manufacturers for a set of 40 SRs conducted for DERP from July 2006 to June 2015 were retrospectively evaluated. Characteristics of data submitted in dossiers, including numbers, types, and characteristics of studies submitted and then included in DERP SRs, were abstracted. Time trends, study quality, publication status, and whether the submission represented a unique study or supplemental data to a published study were assessed. The impact of this evidence on SR conclusions was assessed using dual review. Differences were resolved through a consensus. Results Over 9 years, 160 dossiers were received, relating to 40 DERP SRs. Out of 7360 studies/datasets submitted, 2.2% (160) were included in a SR. The ratio of submitted-to-included increased over time. Most were unique studies (23% were supplemental data sets), and almost 42% of the studies were unpublished. The majority of the studies were rated fair quality, with 7.3% rated good and 14% rated poor quality by the original SR authors. Considering all literature search sources, 7.2% of all studies included in the 40 SRs came from a dossier, and 16% of dossier studies were included in a meta-analysis. The dossier studies resulted in changes to conclusions in 42% of the SRs. Out of 46 unpublished unique studies included in a SR, 25 (54%) influenced the conclusions in favor of the manufacturers drug, 8% favored a competitor drug, and 40% favored neither. In 92% of cases favoring the manufacturer’s drug, the dossier study was the only evidence for that drug in a specific population or outcome. Conclusions In SRs conducted for DERP, few studies submitted by pharmaceutical manufacturers were ultimately included in a SR. The included data helped to reduce reporting and publication bias by filling important gaps and in some cases led to altered conclusions.

We estimated the seroprevalence of Heartland virus antibodies to be 0.9% (95% CI 0.4%–4.2%) in a convenience sample of blood donors from northwestern Missouri, USA, where human cases and infected ticks have been identified. Although these findings suggest that some past human infections were undetected, the estimated prevalence is low.

Marae Ora, Kainga Ora (MOKO) is a three-year research study established as a marae-led intervention project to strengthen the provision of housing with five urban marae in South Auckland, Aotearoa New Zealand. In brief, marae are primarily places for cultural gatherings and are the centres of activity for Māori communities. Though just one of the marae involved is part of a pre-European tribal settlement, the four other marae were established to meet the cultural needs of Māori who had relocated many decades ago from their tribal areas outside of the Auckland region. The project works with Marae Research Coordinators (MRC) nominated by each marae to build research and development capacity and capability through the sharing of skills, information, and resources. Each MRC is affiliated with their respective marae, either through whakapapa (genealogical links) or through their contributions of service and leadership. The role of the MRC is critical in capturing the lived realities, experiences, and aspirations of their marae community. This was evident in the first year of the project (2020) when three of the five marae actively responded to the needs of their communities during COVID-19 lockdowns in Auckland. While the project has a housing focus, the marae involved demonstrate, in their own distinctive ways, how health and wellbeing is intrinsic to their core function.

Identity construction – the process of creating and building a new future self – is an integral part of a person’s professional career development. However, at present we have little understanding of the psychological mechanisms that underpin this process. Likewise, we have little understanding of the barriers that obstruct it, and which thus may contribute to inequality in career outcomes. Using a social identity lens, and particularly the Social Identity Model of Identity Change (SIMIC), we explore the process of academic identity construction among doctoral students. Through thematic analysis of semi-structured interviews with 22 Ph.D. candidates, we observe that the identity construction process relies on a person’s perception of a navigable pathway between their current self and their future self. Importantly, participants who were able to access multiple identity resources were more likely to perceive a navigable pathway to a future professional self (e.g., as an academic), unless they perceived these identities to be incompatible with those held by leading members of the profession (e.g., their supervisors). This research suggests that the identities that people are able to access as they progress in their careers may play an important role in their ongoing professional identity construction and career success.

Cancer antigen 15-3 (CA15-3) is widely utilized for monitoring metastatic breast cancer (BC). However, its utility for early detection of breast cancer is severely limited due to poor clinical sensitivity and specificity. The glycosylation of CA15-3 is known to be affected by BC, and therefore it might offer a way to construct CA15-3 glycovariant assays with improved cancer specificity. To this end, we performed lectin-based glycoprofiling of BC-associated CA15-3. CA15-3 expressed by a BC cell line was immobilized on microtitration wells using an anti-CA15-3 antibody. The glycosylation of the immobilized CA15-3 was then detected by using lectins coated onto europium (III)-doped nanoparticles (Eu+3-NPs) and measuring the time-resolved fluorescence of Eu. Out of multiple lectin-Eu+3-NP preparations, wheat germ agglutinin (WGA) and macrophage galactose-type lectin (MGL) -Eu3+-NPs bound to the BC cell line-dericed CA15-3 glycovariants (CA15-3Lectin). To evaluate the clinical performance of these two lectin-based assays, plasma samples from metastatic BC patients (n = 53) and healthy age-matched women (n = 20).Plasma CA15-3Lectin measurements better distinguished metastatic BC patients from healthy controls than the conventional CA15-3 immunoassay. At 90% specificity, the clinical sensitivity of the assays was 66.0, 67.9 and 81.1% for the conventional CA15-3, CA15-3MGL and CA15-3WGA assays, respectively. Baseline CA15-3MGL and CA15-3WGA were correlated to conventional baseline CA15-3 levels (r = 0.68, p0.001, respectively). However, very low baseline CA15-3MGL levels ≤ 5 U/mL were common in this metastatic breast cancer patient population.In conclusion, the new CA15-3Lectin concept could considerably improve the clinical sensitivity of BC detection compared to the conventional CA15-3 immunoassays and should be validated further on a larger series of subjects with different cancer subtypes and stages.

There is evidence that the social groups to which people belong can be a source of resilience in challenging times. In this paper, we examine whether social group memberships can also increase resilience in the face of negative performance feedback by encouraging task persistence. In two experiments (Ns = 63, 61) participants completed three rounds of a performance task. In the experimental conditions (but not the control) participants were first asked to think about, and consider the importance of, either one or five important social groups of which they were members. In both experiments, participants who reflected on important social groups were more likely to persist in practicing the task after negative performance feedback than those in the control condition. In Experiment 2 only, there was also evidence of performance improvement after negative feedback for participants in experimental but not control conditions. There was no evidence that self-reported confidence, motivation, or self-efficacy accounted for the observed effects. Overall, this is the first study to provide evidence that salient group memberships can increase resilience in a sensorimotor task. Significantly, the findings suggest that groups are not just a context but also a critical psychological resource for performance following failure feedback.

Rapid diagnostic tests (RDTs) are often used for the detection of anti-human immunodeficiency virus (HIV) antibodies in remote locations in low- and middle-income countries (LMIC) with low or limited access to central laboratories. The typical format of an RDT is a lateral flow assay (LFA) with visual interpretation prone to subjectivity. This risk of misinterpretation can be overcome with luminescent upconverting nanoparticle reporters (UCNPs) measured with a miniaturized easy-to-use reader instrument. An LFA with UCNPs for anti-HIV-1/2 antibodies was developed and the assay performance was evaluated extensively with challenging patient sample panels. Sensitivity (n = 145) of the UCNP-LFA was 96.6% (95% CI: 92.1–98.8%) and specificity (n = 309) was 98.7% (95% CI: 96.7–99.7%). Another set of samples (n = 200) was used for a comparison between the UCNP-LFA and a conventional visual RDT. In this comparison, the sensitivities for HIV-1 were 96.4% (95% CI: 89.8–99.3%) and 97.6% (95% CI: 91.6–99.7%), for the UCNP-LFA and conventional RDT, respectively. The specificity was 100% (95% CI: 96.4–100%) for both assays. The developed UCNP-LFA demonstrates the applicability of UCNPs for the detection of anti-HIV antibodies. The signal measurement is done by a reader instrument, which may facilitate automated result interpretation, archiving and transfer of data from de-centralized locations.

This is the preliminary finding of a study elaborating the total energy consumption when paratransits in Bandung are altered into electric and the scenario to fulfill it. Therefore, there are lots to be done further concerning result of this initial research, of which will be discussed in another publication. In this paper calculation was done to find out the volume of power needed to fuel electric paratransits in Bandung. Steps carried out include computing total energy consumption for all paratransits, clustering stations from classified routes established by local Department of Transport, and estimating the electricity demand in every clustered station. Data used for this study was acquired from Badan Pusat Statistik Kota Bandung and PT PLN DJA APD Jawa Barat and Banten. A total demand of 61.12 MWh per month will surface to charge the total of 5,521 paratransits from 38 available routes in 15 clustered stations under the assumptions that all paratransits only make 6 return travels per day, operate 30 days per month, and use batteries with 50% State of Charge.

Anxiety is an important comorbidity in chronic obstructive pulmonary disease (COPD). We investigated if cognitive behavioural therapy (CBT), delivered by respiratory nurses, reduced symptoms of anxiety and was cost-effective. Patients with COPD and anxiety were randomised to CBT or self-help leaflets. Anxiety, depression and quality of life were measured at baseline, 3, 6 and 12 months. A cost-effectiveness analysis was conducted from a National Health Service hospital perspective and quality-adjusted life-years estimated using the EuroQol-5D questionnaire. In total, 279 patients were recruited. Group mean change from baseline to 3 months in the Hospital Anxiety and Depression Anxiety Subscale was 3.4 (95% CI 2.62–4.17, p

Objective Antibiotic overuse contributes to antibiotic resistance and adverse consequences. Acute respiratory tract infections (RTIs) are the most common reason for antibiotic prescribing in primary care, but such infections often do not require antibiotics. We summarized and updated a previously performed systematic review of interventions to reduce inappropriate use of antibiotics for acute RTIs. Methods To update the review, we searched MEDLINE®, the Cochrane Library (until January 2018), and reference lists. Two reviewers selected the studies, extracted the study data, and assessed the quality and strength of evidence. Results Twenty-six interventions were evaluated in 95 mostly fair-quality studies. The following four interventions had moderate-strength evidence of improved/reduced antibiotic prescribing and low-strength evidence of no adverse consequences: parent education (21% reduction, no increase return visits), combined patient/clinician education (7% reduction, no change in complications/satisfaction), procalcitonin testing for adults with RTIs of the lower respiratory tract (12%–72% reduction, no increased adverse consequences), and electronic decision support systems (24%–47% improvement in appropriate prescribing, 5%–9% reduction, no increased complications). Conclusions The best evidence supports use of specific educational interventions, procalcitonin testing in adults, and electronic decision support to reduce inappropriate antibiotic prescribing for acute RTIs without causing adverse consequences.

This paper describes a feasibility analysis of conventional and retrofitted paratransits, comparing economic performance of conventional paratransit with those using lead acid and lithium batteries. Research object is Dago-Kalapa paratransit in Bandung, West Java, travelling the distance of 11 km in town, under 8 peak hour operation. After calculating the estimated annual cost and benefit; net present value (NPV), payback period (PBP) and internal rate of return (IRR) then were quantified to provide feasibility description of those three paratransits. In addition, a sensitivity analysis regarding discount rate, gasoline price and battery price is given to offer broader sense of factors embraced. It is found that both gasoline and lead acid paratransit have big NPVs with only slight differences, while lithium paratransit has negative NPV. This phenomenon applies to their PBPs and IRRs as well. Only when gasoline costs reaches IDR 15,000 will electric paratransit prevails over conventional one. Thus, it can be inferred that at the moment, paratransit runs with gasoline is still the most cost effective compared to its counterparts. However, starting retrofitting from now is endorsed due to its environmental benefit.

Das Basel Register of Thesauri, Ontologies & Classifications (BARTOC) hat sich innerhalb weniger Jahre mit mehr als 2.700 Einträgen zu einem umfangreichen Verzeichnis von Wissensorganisationssystemen entwickelt. Im Sommersemester 2017 wurde diese Entwicklung von einem Projektseminar mit Bachelor-Studierenden der Hochschule Hannover begleitet. Eine Revision und Erweiterung der Inhalte von BARTOC führte zu einer besseren Abdeckung ausgewählter Metadatenfelder. Darüber hinaus wurden verschiedene Statistiken, Informationsmaterialien und ein neues Logo erstellt.

Agency (A) and communion (C) are fundamental content dimensions. We propose a facet-model that differentiates A into assertiveness (AA) and competence (AC) and C into warmth (CW) and morality (CM). We tested the model in a cross-cultural study by comparing data from Asia, Australia, Europe, and the USA (overall N = 1.808). Exploratory and confirmatory factor analyses supported our model. Both the two-factor model and the four-factor model showed good fit indices across countries. Participants answered additional measures intended to demonstrate the fruitfulness of distinguishing the facets. The findings support the model’s construct validity by positioning the fundamental dimensions and their facets within a network of self-construal, values, impression management, and the Big Five personality factors: In all countries, A was related to independent self-construal and to agentic values, C was related to interdependent self-construal and to communal values. Regarding the facets, AA was always related to A values, but the association of AC with A values fell below our effect size criterion in four of the five countries. A (both AA and AC) was related to agentic impression management. However, C (both CW and CM) was neither related to communal nor to agentic impression management. Regarding the Big Five personality factors, A was related to emotional stability, to extraversion, and to conscientiousness. C was related to agreeableness and to extraversion. AA was more strongly related to emotional stability and extraversion than AC. CW was more strongly related to extraversion and agreeableness than CM. We could also show that self-esteem was more related to AA than AC; and that it was related to CM, but not to CW. Our research shows that (a) the fundamental dimensions of A and C are stable across cultures; and (b) that the here proposed distinction of facets of A and C is fruitful in analyzing self-perception. The here proposed measure, the AC-IN, may be a useful tool in this research area. Applications of the facet model in social perception research are discussed.

[This corrects the article DOI: 10.1371/journal.pone.0155901.].

The present article provides a comprehensive examination of the relationship between playing position and leadership in sport. More particularly, it explores links between leadership and a player's interactional centrality-defined as the degree to which their playing position provides opportunities for interaction with other team members. This article examines this relationship across different leadership roles, team sex, and performance levels.Study 1 (N = 4443) shows that athlete leaders (and the task and motivational leader in particular) are more likely than other team members to occupy interactionally central positions in a team. Players with high interactional centrality were also perceived to be better leaders than those with low interactional centrality. Study 2 (N = 308) established this link for leadership in general, while Study 3 (N = 267) and Study 4 (N = 776) revealed that the same was true for task, motivational, and external leadership. This relationship is attenuated in sports where an interactionally central position confers limited interactional advantages. In other words, the observed patterns were strongest in sports that are played on a large field with relatively fixed positions (e.g., soccer), while being weaker in sports that are played on a smaller field where players switch positions dynamically (e.g., basketball, ice hockey). Beyond this, the pattern is broadly consistent across different sports, different sexes, and different levels of skill.The observed patterns are consistent with the idea that positions that are interactionally central afford players greater opportunities to do leadership-either through communication or through action. Significantly too, they also provide a basis for them to be seen to do leadership by others on their team. Thus while it is often stated that "leadership is an action, not a position," it is nevertheless the case that, when it comes to performing that action, some positions are more advantageous than others.

The identification and validation of biomarkers for clinical applications remains an important issue for improving diagnostics and therapy in many diseases, including prostate cancer. Gene expression profiles are routinely applied to identify diagnostic and predictive biomarkers or novel targets for cancer. However, only few predictive markers identified in silico have also been validated for clinical, functional or mechanistic relevance in disease progression. In this study, we have used a broad, bioinformatics-based approach to identify such biomarkers across a spectrum of progression stages, including normal and tumor-adjacent, premalignant, primary and late stage lesions. Bioinformatics data mining combined with clinical validation of biomarkers by sensitive, quantitative reverse-transcription PCR (qRT-PCR), followed by functional evaluation of candidate genes in disease-relevant processes, such as cancer cell proliferation, motility and invasion. From 300 initial candidates, eight genes were selected for validation by several layers of data mining and filtering. For clinical validation, differential mRNA expression of selected genes was measured by qRT-PCR in 197 clinical prostate tissue samples including normal prostate, compared against histologically benign and cancerous tissues. Based on the qRT-PCR results, significantly different mRNA expression was confirmed in normal prostate versus malignant PCa samples (for all eight genes), but also in cancer-adjacent tissues, even in the absence of detectable cancer cells, thus pointing to the possibility of pronounced field effects in prostate lesions. For the validation of the functional properties of these genes, and to demonstrate their putative relevance for disease-relevant processes, siRNA knock-down studies were performed in both 2D and 3D organotypic cell culture models. Silencing of three genes (DLX1, PLA2G7 and RHOU) in the prostate cancer cell lines PC3 and VCaP by siRNA resulted in marked growth arrest and cytotoxicity, particularly in 3D organotypic cell culture conditions. In addition, silencing of PLA2G7, RHOU, ACSM1, LAMB1 and CACNA1D also resulted in reduced tumor cell invasion in PC3 organoid cultures. For PLA2G7 and RHOU, the effects of siRNA silencing on proliferation and cell-motility could also be confirmed in 2D monolayer cultures. In conclusion, DLX1 and RHOU showed the strongest potential as useful clinical biomarkers for PCa diagnosis, further validated by their functional roles in PCa progression. These candidates may be useful for more reliable identification of relapses or therapy failures prior to the recurrence local or distant metastases.

Treponema pallidum subspecies pallidum (Tp) is the causative agent of syphilis which mainly spreads through sexual contact, blood transfusion and perinatal route. In order to curtail the spread of the infection and to clinically manage the disease, timely, accurate and reliable diagnosis is very important. We have developed an immunoassay for the detection of treponemal antibodies in human serum or plasma samples. In vivo biotinylated and non-biotinylated versions of the recombinant antigen were designed by the fusion of three Tp-specific antigens namely Tp15, Tp17 and Tp47. These fusion antigens were expressed in E. coli and purified using single-step metal affinity chromatography. Biotinylated fusion antigen immobilized on streptavidin coated plate was used to capture the treponemal antibodies and the non-biotinylated antigen coated on europium nanoparticles was used as tracer. Assays with two different incubation times of 10 min and 1 h were developed, and following the incubation the europium fluorescence was measured using time-resolved fluorometry. The developed time-resolved fluorometric (TRF) immunoassays were evaluated with in-house and commercial serum/plasma sample panels. For well-established treponemal antibodies positive or negative samples, the sensitivity of TRF immunoassay with 10 min incubation time was 97.4%, and of TRF immunoassay with 1 h incubation time was 98.7%, and the specificities of both the TRF immunoassays were 99.2%. For the samples with discordant results with the reference assays, both the TRF immunoassays showed better specificity than the Enzygnost syphilis enzyme immunoassay as a screening test. The two different incubation times did not have any significant effect on the signal to cutoff (S/Co) ratios obtained with the two immunoassays (p=0.06). Our results indicate that the developed immunoassay with a short incubation time of 10 min has the potential to be used in clinical laboratories and in blood-bank settings as a screening test for treponemal antibodies.

Lipid-coated perfluorocarbon nanodroplets are submicrometer-diameter liquid-filled droplets with proposed applications in molecularly targeted therapeutics and ultrasound (US) imaging. Ultrasonic molecular imaging is unique in that the optimal application of these agents depends not only on the surface chemistry, but also on the applied US field, which can increase receptor-ligand binding and membrane fusion. Theory and experiments are combined to demonstrate the displacement of perfluorocarbon nanoparticles in the direction of US propagation, where a traveling US wave with a peak pressure on the order of megapascals and frequency in the megahertz range produces a particle translational velocity that is proportional to acoustic intensity and increases with increasing center frequency. Within a vessel with a diameter on the order of hundreds of micrometers or larger, particle velocity on the order of hundreds of micrometers per second is produced and the dominant mechanism for droplet displacement is shown to be bulk fluid streaming. A model for radiation force displacement of particles is developed and demonstrates that effective particle displacement should be feasible in the microvasculature. In a flowing system, acoustic manipulation of targeted droplets increases droplet retention. Additionally, we demonstrate the feasibility of US-enhanced particle internalization and therapeutic delivery.

Abstract Introduction Wegener’s granulomatosis presenting as diffuse alveolar hemorrhage is uncommon. However, the recognition of multisystem disease involving joints, kidney, eye and lung is critical for diagnosing Wegener's vasculitis. This is not the first report of this kind in the literature. Case presentation A 51-year-old Croatian woman presented to our Emergency Department with a history of progressively worsening productive cough and shortness of breath, epistaxis and two episodes of hemoptysis. She developed respiratory failure due to diffuse alveolar hemorrhage, which was successfully treated with high-dose steroids, cyclophosphamide and plasmapheresis. Her clinical course was complicated with methicillin-resistant Staphyloccocus aureus pneumonia, which has been associated with Wegener’s granulomatosis flares. Conclusion The recognition of multisystem disease is critical for diagnosing Wegener's vasculitis. Diffuse alveolar hemorrhage can be a fulminant manifestation of Wegener’s granulomatosis, in which case immediate and aggressive treatment with pulse steroids, high-dose cyclophosphamide and plasma exchange can be life-saving.

Abstract Background Surgical treatment of neuromas involves excision of neuromas proximally to the level of grossly "normal" fascicles; however, proximal changes at the axonal level may have both functional and therapeutic implications with regard to amputated nerves. In order to better understand the retrograde "zone of injury" that occurs after nerve transection, we investigated the gross and histologic changes in transected nerves using a rabbit forelimb amputation model. Methods Four New Zealand White rabbits underwent a forelimb amputation with transection and preservation of the median, radial, and ulnar nerves. After 8 weeks, serial sections of the amputated nerves were then obtained in a distal-to-proximal direction toward the brachial plexus. Quantitative histomorphometric analysis was performed on all nerve specimens. Results All nerves demonstrated statistically significant increases in nerve cross-sectional area between treatment and control limbs at the distal nerve end, but these differences were not observed 10 mm more proximal to the neuroma bulb. At the axonal level, an increased number of myelinated fibers were seen at the distal end of all amputated nerves. The number of myelinated fibers progressively decreased in proximal sections, normalizing at 15 mm proximally, or the level of the brachial plexus. The cross-sectional area of myelinated fibers was significantly decreased in all sections of the treatment nerves, indicating that atrophic axonal changes proceed proximally at least to the level of the brachial plexus. Conclusions Morphologic changes at the axonal level extend beyond the region of gross neuroma formation in a distal-to-proximal fashion after nerve transection. This discrepancy between gross and histologic neuromas signifies the need for improved standardization among neuroma models, while also providing a fresh perspective on how we should view neuromas during peripheral nerve surgery.

Abstract Background The forelimb amputee poses many reconstructive challenges in the clinical setting, and there is a paucity of established surgical models for study. To further elucidate the pathogenic process in amputation neuroma formation, we created a reproducible, well-tolerated rabbit forelimb amputation model. Methods Upon approval from the Institutional Animal Care and Use Committee, 5 New Zealand White rabbits underwent left forelimb amputation. During this initial surgery, the median, radial and ulnar nerves were transected 1.6-2.5 (mean 2.0) cm distal to the brachial plexus, transposed onto the anterior chest wall and preserved at length. Six weeks subsequent to the amputation, the distal 5 mm of each neuroma was excised, and the remaining stump underwent histomorphometric analysis. Results The nerve cross sectional areas increased by factors of 1.99, 3.17, and 2.59 in the median (p = 0.077), radial (p < 0.0001) and the ulnar (p = 0.0026) nerves, respectively. At the axonal level, the number and cross-sectional area of myelinated fibers demonstrated an inverse relationship whereby the number of myelinated fibers in the median, radial and ulnar nerves increased by factors of 5.13 (p = 0.0043), 5.25 (p = 0.0056) and 5.59 (p = 0.0027), and the cross-sectional areas of these myelinated fibers decreased by factors of 4.62 (p < 0.001), 3.51 (p < 0.01), and 4.29 (p = 0.0259), respectively. Conclusion Given that the surgical model appears well-tolerated by the rabbits and that patterns of morphologic change are consistent and reproducible, we are encouraged to further investigate the utility of this model in the pathogenesis of neuroma formation.

Post-traumatic epilepsy (PTE) is a debilitating neurological disorder that develops after traumatic brain injury (TBI). Despite the high prevalence of PTE, current methods for predicting its occurrence remain limited. In this study, we aimed to identify imaging-based markers for the prediction of PTE using machine learning. Specifically, we examined three imaging features: Lesion volumes, resting-state fMRI-based measures of functional connectivity, and amplitude of low-frequency fluctuation (ALFF). We employed three machine-learning methods, namely, kernel support vector machine (KSVM), random forest, and an artificial neural network (NN), to develop predictive models. Our results showed that the KSVM classifier, with all three feature types as input, achieved the best prediction accuracy of 0.78 AUC (area under the receiver operating characteristic (ROC) curve) using nested cross-validation. Furthermore, we performed voxel-wise and lobe-wise group difference analyses to investigate the specific brain regions and features that the model found to be most helpful in distinguishing PTE from non-PTE populations. Our statistical analysis uncovered significant differences in bilateral temporal lobes and cerebellum between PTE and non-PTE groups. Overall, our findings demonstrate the complementary prognostic value of MR-based markers in PTE prediction and provide new insights into the underlying structural and functional alterations associated with PTE., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)