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A new technique of thoracoscopic laser ablation of pulmonary bullae suitable for patients with multiple bullae and diffuse emphysema was developed and assessed in 22 patients. 20 of 22 patients survived. Pre-operative and postoperative functional evaluation is available for the 11 patients followed up for more than a month; at 1 to 3 months postoperatively there were increases in FVC (mean 2.0 litres pre-operatively to 2.7 litres postoperatively, p less than 0.001), in FEV1 (0.74 to 1.06 litres, p = 0.01), and in maximum exercise treadmill times (5.4 min to 8.0 min, p less than 0.01). Postoperative air leaks lasted a mean of 13 days and usually resolved spontaneously. Other complications were bleeding (1 patient) and unilateral acute lung injury (1 patient). These results suggest that selected patients with diffuse emphysema and pulmonary bullae may benefit from thoracoscopic carbon dioxide laser ablation.

Urothelial cancer is the second most common cancer, and cause of cancer death, related to the genitourinary tract. The goals of imaging for pretreatment staging of urothelial cancer are to evaluate for both local and distant spread of the cancer and assessing for synchronous sites of urothelial cancer in the upper tracts and bladder. For pretreatment staging of urothelial carcinoma, patients can be stratified into one of three groups: 1) nonmuscle invasive bladder cancer; 2) muscle invasive bladder cancer; and 3) upper urinary tract urothelial carcinoma. This document is a review of the current literature for urothelial cancer and resulting recommendations for pretreatment staging imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Acute scrotum is a medical emergency that requires prompt accurate diagnosis to appropriately triage potentially surgical conditions. Numerous differential diagnoses with overlapping clinical presentations make this a diagnostic challenge. Ultrasound is the established first-line imaging modality for acute scrotal disease and can be used to diagnose most scrotal disorders promptly and with high accuracy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: V. Sharma, J. Novak, and W. C. Wilson are full-time paid employees of Masimo. S. J. Barker is a part-time employee of Masimo.

Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs are unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need to be delivered intrathecally to the central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, the oligonucleotide transport vehicle (OTV), to transport a tool ASO across the BBB in human TfR knockin (TfR mu/hu KI) mice and nonhuman primates. Intravenous injection and systemic delivery of OTV to TfR mu/hu KI mice resulted in sustained knockdown of the ASO target RNA, Malat1 , across multiple mouse CNS regions and cell types, including endothelial cells, neurons, astrocytes, microglia, and oligodendrocytes. In addition, systemic delivery of OTV enabled Malat1 RNA knockdown in mouse quadriceps and cardiac muscles, which are difficult to target with oligonucleotides alone. Systemically delivered OTV enabled a more uniform ASO biodistribution profile in the CNS of TfR mu/hu KI mice and greater knockdown of Malat1 RNA compared with a bivalent, high-affinity TfR antibody. In cynomolgus macaques, an OTV directed against MALAT1 displayed robust ASO delivery to the primate CNS and enabled more uniform biodistribution and RNA target knockdown compared with intrathecal dosing of the same unconjugated ASO. Our data support systemically delivered OTV as a potential platform for delivering therapeutic ASOs across the BBB.

We show the direct production and detection of 13 C-hyperpolarized fumarate by parahydrogen-induced polarization (PHIP) in a microfluidic lab-on-a-chip (LoC) device and achieve 8.5% 13 C polarization. This is the first demonstration of 13 C-hyperpolarization of a metabolite by PHIP in a microfluidic device. LoC technology allows the culture of mammalian cells in a highly controlled environment, providing an important tool for the life sciences. In-situ preparation of hyperpolarized metabolites greatly enhances the ability to quantify metabolic processes in such systems by microfluidic NMR. PHIP of 1 H nuclei has been successfully implemented in microfluidic systems, with mass sensitivities in the range of pmol/s. However, metabolic NMR requires high-yield production of hyperpolarized metabolites with longer spin life times than is possible with 1 H. This can be achieved by transfer of the polarization onto 13 C nuclei, which exhibit much longer T 1 relaxation times. We report an improved microfluidic PHIP device, optimized using a finite element model, that enables the direct and efficient production of 13 C-hyperpolarized fumarate.

Initial imaging evaluation of hydronephrosis of unknown etiology is a complex subject and is dependent on clinical context. In asymptomatic patients, it is often best conducted via CT urography (CTU) without and with contrast, MR urography (MRU) without and with contrast, or scintigraphic evaluation with mercaptoacetyltriglycine (MAG3) imaging. For symptomatic patients, CTU without and with contrast, MRU without and with contrast, MAG3 scintigraphy, or ultrasound of the kidneys and bladder with Doppler imaging are all viable initial imaging studies. In asymptomatic pregnant patients, nonionizing imaging with US of the kidneys and bladder with Doppler imaging is preferred. Similarly, in symptomatic pregnant patients, US of the kidneys and bladder with Doppler imaging or MRU without contrast is the imaging study of choice, as both ionizing radiation and gadolinium contrast are avoided in pregnancy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Purpose:  Evaluate the SpO 2 -SaO 2 difference between Black and White volunteer subjects having a low perfusion index (Pi) compared to those having a normal Pi., Methods:  The Pi data were abstracted from electronic files collected on 7183 paired SpO 2 -SaO 2 samples (3201 Black and 3982 White) from a recently reported desaturation study of 75 subjects (39 Black and 36 White) where SaO 2 values were sequentially decreased from 100 to 70%. The Pi values from that dataset were divided into two groups (Pi ≤ 1 or Pi > 1) for analysis. A Pi value ≤ 1 was considered "low perfusion" and a Pi value > 1 was considered "normal perfusion". Statistical calculations included values of bias (mean difference of SpO 2 -SaO 2 ), precision (standard deviation of the difference), and accuracy (root-mean-square error [A RMS ]). During conditions of low perfusion (Pi ≤ 1, range [0.1 to 1]), overall bias and precision were + 0.48% ± 1.59%, while bias and precision were + 0.19 ± 1.53%, and + 0.91 ± 1.57%, for Black and White subjects, respectively., Results:  During normal perfusion (Pi > 1, range [1 to 12]), overall bias and precision were + 0.18% ± 1.34%, while bias and precision were -0.26 ± 1.37%, and - 0.12 ± 1.31%, for Black and White subjects, respectively. A RMS was 1.37% in all subjects with normal perfusion and 1.64% in all subjects with low perfusion., Conclusion:  Masimo SET® pulse oximeters with RD SET® sensors are accurate for individuals of both Black and White races when Pi is normal, as well as during conditions when Pi is low. The A RMS for all conditions studied is well within FDA standards. This study was conducted in healthy volunteers during well-controlled laboratory desaturations, and results could vary under certain challenging clinical conditions., (© 2024. The Author(s).)

A novel application of the Theil-Sen robust regression method for determining the temporal trends in the concentration of heavy metals in UK ambient air over the period 2005-2020 is presented and compared to other regression methods. We have demonstrated improvements over non-robust methods of regression, proving the ability to tease out trends that are small with respect to the variability of the concentration measurement. The method is used to identify, in general, large and significant trends in the concentrations of Ni, As, Pb and V over the period 2005-2020, either across the UK as a whole or at groupings of site classifications in the UK. These trends have been compared to trends in emission data determined in the same manner. Although the results for most metals provide confidence that the UK metal network of monitoring sites is successful in appropriately capturing changes in emissions, a key finding of this work is the disagreement between trends in measured concentrations and emissions for Cu, Mn and Ni, for which we suggest improvements in future network design. The results also indicate that UK emission data for V should be reviewed, as we propose that the rate of reduction of V emissions is likely to have been overestimated., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We demonstrate that enzyme-catalyzed reactions can be observed in zero- and low-field NMR experiments by combining recent advances in parahydrogen-based hyperpolarization methods with state-of-the-art magnetometry. Specifically, we investigated two model biological processes: the conversion of fumarate into malate, which is used in vivo as a marker of cell necrosis, and the conversion of pyruvate into lactate, which is the most widely studied metabolic process in hyperpolarization-enhanced imaging. In addition to this, we constructed a microfluidic zero-field NMR setup to perform experiments on microliter-scale samples of [1- 13 C]fumarate in a lab-on-a-chip device. Zero- to ultralow-field (ZULF) NMR has two key advantages over high-field NMR: the signals can pass through conductive materials (e.g., metals), and line broadening from sample heterogeneity is negligible. To date, the use of ZULF NMR for process monitoring has been limited to studying hydrogenation reactions. In this work, we demonstrate this emerging analytical technique for more general reaction monitoring and compare zero- vs low-field detection.

Chemical anomalies in polar ice core records are frequently linked to volcanism; however, without the presence of (crypto)tephra particles, links to specific eruptions remain speculative. Correlating tephras yields estimates of eruption timing and potential source volcano, offers refinement of ice core chronologies, and provides insights into volcanic impacts. Here, we report on sparse rhyolitic glass shards detected in the Roosevelt Island Climate Evolution (RICE) ice core (West Antarctica), attributed to the 1.8 ka Taupō eruption (New Zealand)-one of the largest and most energetic Holocene eruptions globally. Six shards of a distinctive geochemical composition, identical within analytical uncertainties to proximal Taupō glass, are accompanied by a single shard indistinguishable from glass of the ~25.5 ka Ōruanui supereruption, also from Taupō volcano. This double fingerprint uniquely identifies the source volcano and helps link the shards to the climactic phase of the Taupō eruption. The englacial Taupō-derived glass shards coincide with a particle spike and conductivity anomaly at 278.84 m core depth, along with trachytic glass from a local Antarctic eruption of Mt. Melbourne. The assessed age of the sampled ice is 230 ± 19 CE (95% confidence), confirming that the published radiocarbon wiggle-match date of 232 ± 10 CE (2 SD) for the Taupō eruption is robust., (© 2023. Springer Nature Limited.)

Prostate cancer is second leading cause of death from malignancy after lung cancer in American men. The primary goal during pretreatment evaluation of prostate cancer is disease detection, localization, establishing disease extent (both local and distant), and evaluating aggressiveness, which are the driving factors of patient outcomes such as recurrence and survival. Prostate cancer is typically diagnosed after the recognizing elevated serum prostate-specific antigen level or abnormal digital rectal examination. Tissue diagnosis is obtained by transrectal ultrasound-guided biopsy or MRI-targeted biopsy, commonly with multiparametric MRI without or with intravenous contrast, which has recently been established as standard of care for detecting, localizing, and assessing local extent of prostate cancer. Although bone scintigraphy and CT are still typically used to detect bone and nodal metastases in patients with intermediate- or high-risk prostate cancer, novel advanced imaging modalities including prostatespecific membrane antigen PET/CT and whole-body MRI are being more frequently utilized for this purpose with improved detection rates. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Recent publications have suggested that pulse oximeters exhibit reduced accuracy in dark-skinned patients during periods of hypoxemia. Masimo SET® (Signal Extraction Technology®) has been designed, calibrated, and validated using nearly equal numbers of dark and light skinned subjects, with the goal of eliminating differences between pulse oximetry saturation (SpO 2 ) and arterial oxygen saturation (SaO 2 ) values due to skin pigmentation. The accuracy concerns reported in dark-skinned patients led us to perform a retrospective analysis of healthy Black and White volunteers. Seventy-five subjects who self-identified as being racially Black or White underwent a desaturation protocol where SaO 2 values were decreased from 100 to 70%, while simultaneous SpO 2 values were recorded using Masimo RD SET® sensors. Statistical bias (mean difference) and precision (standard deviation of difference) were - 0.20 ± 1.40% for Black and - 0.05 ± 1.35% for White subjects. Plots of SpO 2 versus SaO 2 show no significant visible differences between races throughout the saturation range from 70 to 100%. Box plots grouped in 1% saturation bins, from 89-96%, and plotted against concomitant SaO 2 values, show that occult hypoxemia (SaO 2  < 88% when SpO 2  = 92-96%) occurred in only 0.2% of White subject data pairs, but not in any Black subjects. There were no clinically significant differences in bias (mean difference of SpO 2 -SaO 2 ) found between healthy Black and White subjects. Occult hypoxemia was rare and did not occur in Black subjects. Masimo RD SET® can be used with equal assurance in people with dark or light skin. These laboratory results were obtained in well-controlled experimental conditions in healthy volunteers-not reflecting actual clinical conditions/patients., (© 2022. The Author(s).)

Objectives: Current guidelines recommend magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) for risk stratification of intraductal papillary mucinous neoplasms (IPMNs). We assessed the interobserver agreement among radiologists in evaluating and risk stratifying IPMNs., Methods: This single-center study evaluated 30 patients with IPMNs who had undergone MRI/MRCP, endoscopic ultrasound, and/or surgical resection. Six abdominal radiologists evaluated the MRI/MRCPs to document multiple parameters. The analysis applied Landis and Koch κ interpretation for categorical variables and intraclass correlation coefficient (r) for continuous variables., Results: Radiologists demonstrated almost perfect agreement for location (κ = 0.81, 95% confidence interval [CI], 0.74-0.87), size (r = 0.95; 95% CI, 0.89-0.98), and main pancreatic duct diameter (r = 0.98; 95% CI, 0.96-0.99). Substantial agreement was observed for communication with the main pancreatic duct (κ = 0.66; 95% CI, 0.57-0.75) and classification of IPMN subtype (κ = 0.77; 95% CI, 0.67-0.86). Presence of intracystic nodules (κ = 0.31; 95% CI, 0.21-0.42) and wall thickening (κ = 0.09; 95% CI, -0.01 to 0.18) reached only fair and slight agreement, respectively., Conclusions: Although MRI/MRCP is excellent in the evaluation of spatial aspects, there is lower reliability for nondimensional characteristics of IPMNs. These data support guideline-recommended complementary evaluation of IPMNs with MRI/MRCP and endoscopic ultrasound., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

In a recent publication in BMC Anesthesiology, Rincon, et al.present accuracy data for three pulse oximeters with sensors located at three different anatomic sites. Their results for the Masimo Radical with fingertip sensor are erroneous, and we present valid data here. Rincon, et al.show a Bias ± Precision of 2.02 ± 4.6, while the correct laboratory values are -0.01 ± 1.16. The most probable reason for these invalid data is that insufficient time was used at each saturation plateau to allow stabilization of SpO 2 readings on a fingertip sensor. It has been shown in the literature that fingertip sensors require at least a full minute of stable oxygenation conditions before their readings will be the same as earlobe sensors., (© 2022. The Author(s).)

In this Pro-Con commentary article, we discuss whether or not code sharing should be mandatory for scientific publications. Scientific programming is an increasingly prevalent tool in research. However, there are not unified guidelines for code availability requirements. Some journals require code sharing. Others require code descriptions. Yet others have no policies around code sharing. The Pro side presented here argues that code sharing should be mandatory for all scientific publications involving code. This Pro argument comes in 2 parts. First, any defensible reason for not sharing code is an equally valid a reason for the manuscript itself not being published. Second, lack of code sharing requirements creates 2 tiers of science: one where reproducibility is required and one where it is not. Additionally, the Pro authors suggest that a debate over code sharing is itself a decade out-of-date due to the emerging availability of containerization and virtual environment sharing software. The Pro argument concludes with an appeal that authors release code to make their work more understandable by other researchers. The Con side presented here argues that computer source codes of medical technology equipment should not be subject to mandatory public disclosure. The source code is a crucial part of what makes a particular device unique and allows that device to outperform its competition. The Con authors believe that public disclosure of this proprietary information would destroy all incentives for businesses to develop new and improved technologies. Competition in the free marketplace is what drives companies to constantly improve their products, to develop new and better medical devices. The open disclosure of these "trade secret" details would effectively end that competitive drive. Why invest time, money, and energy developing a "better mousetrap" if your competitors can copy it and produce it the next day?, Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

The staging and surveillance of testicular cancer is a complex topic, which integrates clinical, biochemical, and imaging components. The use of imaging for staging and surveillance of testicular cancer is individually tailored to each patient by considering tumor histology and prognosis. This document discusses the rationale for use of imaging by imaging modality during the initial staging of testicular seminoma and nonseminoma tumors and during the planned surveillance of stage IA and IB testicular cancer by histological subtype integrating clinical suspicion for disease recurrence in surveillance protocols. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2022 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Microfluidic systems hold great potential for the study of live microscopic cultures of cells, tissue samples, and small organisms. Integration of hyperpolarization would enable quantitative studies of metabolism in such volume limited systems by high-resolution NMR spectroscopy. We demonstrate, for the first time, the integrated generation and detection of a hyperpolarized metabolite on a microfluidic chip. The metabolite [1- 13 C]fumarate is produced in a nuclear hyperpolarized form by (i) introducing para-enriched hydrogen into the solution by diffusion through a polymer membrane, (ii) reaction with a substrate in the presence of a ruthenium-based catalyst, and (iii) conversion of the singlet-polarized reaction product into a magnetized form by the application of a radiofrequency pulse sequence, all on the same microfluidic chip. The microfluidic device delivers a continuous flow of hyperpolarized material at the 2.5 μL/min scale, with a polarization level of 4%. We demonstrate two methods for mitigating singlet-triplet mixing effects which otherwise reduce the achieved polarization level.

Recent increases in human longevity have been accompanied by a rise in the incidence of dementia, highlighting the need to preserve cognitive function in an aging population. A small percentage of individuals with pathological hallmarks of neurodegenerative disease are able to maintain normal cognition. Although the molecular mechanisms that govern this neuroprotection remain unknown, individuals that exhibit cognitive resilience (CgR) represent a unique source of therapeutic insight. For both humans and animal models, living in an enriched, cognitively stimulating environment is the most effective known inducer of CgR. To understand potential drivers of this phenomenon, we began by profiling the molecular changes that arise from environmental enrichment in mice, which led to the identification of MEF2 transcription factors (TFs). We next turned to repositories of human clinical and brain transcriptomic data, where we found that the MEF2 transcriptional network was overrepresented among genes that are most predictive of end-stage cognition. Through single-nucleus RNA sequencing of cortical tissue from resilient and nonresilient individuals, we further confirmed up-regulation of MEF2C in resilient individuals to a subpopulation of excitatory neurons. Last, to determine the causal impact of MEF2 on cognition in the context of neurodegeneration, we overexpressed Mef2a/c in the PS19 mouse model of tauopathy and found that this was sufficient to improve cognitive flexibility and reduce hyperexcitability. Overall, our findings reveal a previously unappreciated role for MEF2 TFs in promoting CgR, highlighting their potential as biomarkers or therapeutic targets for neurodegeneration and healthy aging.

Objectives: Injuries associated with bicycles can generally be categorized into 2 types: injuries from falling from/off bicycles and injuries from striking the bicycle. In the second mechanism category, most occur as a result of children striking their body against the bicycle handlebar. The purpose of this study was to evaluate the presentation, body location, injury severity, and need for intervention for pediatric handlebar injuries at a single level one pediatric trauma center and contrast these against other bicycle-related injuries in children., Methods: This work is a retrospective review of the trauma registry over an 8-year period. Individual charts were then reviewed for patients' demographic factors, injury details, and other clinical/radiographic findings. Each patient was then categorized as either having a handlebar versus nonhandlebar injury. Additionally, each patient's injuries were classified according to affected body "zone(s)" and the need for intervention in relation to these injuries. During the course of chart review, several unique radiographic and history/physical findings were noted and are also reported., Results: During the study period, 385 patients were identified that met study criteria. Bicycle handlebars were involved in 27.8% (107/385) of injuries and 72.2% (278/385) were nonhandlebar injuries. There were differences in injury severity score, Head Abbreviated Injury Scale, length of stay between patients with handlebar versus nonhandlebar injuries, respectively. There were also differences in incidence of injuries across most body zones between patients with handlebar versus nonhandlebar injuries. There was statistically significant difference in need for intervention for abdominal solid organ injuries among handlebar versus nonhandlebar injuries mechanisms (21.6% vs 0%; P = 0.026), respectively. Sixteen patients with a handlebar injury underwent abdominal computed tomography (CT), which found only pericolic/pelvic free fluid or were negative for any disease and had normal/mildly elevated liver function test results at the time of arrival with otherwise normal laboratory workup results. Two patients required laparotomy for bowel injury and presented with peritonitis less than 12 hours after injury. The remaining patients did not have peritonitis on examination and were discharged without operative intervention 12 to 24 hours after injury without further event., Conclusions: The bicycle handlebar is a unique mechanism of injury. The location, need for intervention, and the nature of the injury can vary significantly compared to other bicycle injuries. Handlebar injuries are more likely to cause abdominal and soft tissue injuries, whereas nonhandlebar injuries are more likely to cause extremity and skull/neck/central nervous system injuries. Because more than 20% of the reported handlebar injuries did not involve the abdomen or thoracoabdominal/extremity soft tissue as well as the variable presentation of handlebar injuries, it is imperative for the physician to consider this mechanism in all bicycle injuries. In addition, even within the same area of the body, handlebar injuries can be very different compared to nonhandlebar (i.e., orthopedic vs vascular injuries in the extremities). Physical examination and observation remain paramount when laboratory and radiographic workups are equivocal., Competing Interests: Disclosure: The authors declare conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Anthropogenic climate change and invasive species are two of the greatest threats to biodiversity, affecting the survival, fitness and distribution of many species around the globe. Invasive species are often expected to have broad thermal tolerance, be highly plastic, or have high adaptive potential when faced with novel environments. Tropical island ectotherms are expected to be vulnerable to climate change as they often have narrow thermal tolerance and limited plasticity. In Fiji, only one species of endemic bee, Homalictus fijiensis , is commonly found in the lowland regions, but two invasive bee species, Braunsapis puangensis and Ceratina dentipes , have recently been introduced into Fiji. These introduced species pollinate invasive plants and might compete with H. fijiensis and other native pollinators for resources. To test whether certain performance traits promote invasiveness of some species, and to determine which species are the most vulnerable to climate change, we compared the thermal tolerance, desiccation resistance, metabolic rate and seasonal performance adjustments of endemic and invasive bees in Fiji. The two invasive species tended to be more resistant to thermal and desiccation stress than H. fijiensis , while H. fijiensis had greater capacity to adjust their CT max with season, and H. fijiensis females tended to have higher metabolic rates than B. puangensis females. These findings provide mixed support for current hypotheses for the functional basis of the success of invasive species; however, we expect the invasive bees in Fiji to be more resilient to climate change because of their increased thermal tolerance and desiccation resistance., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Purpose: The effect of preoperative cardiac troponin level on outcomes after coronary artery bypass grafting (CABG) is unclear. We investigated the impact of preoperative cardiac troponin I (cTnI) level as well as the time interval between maximum cTnI and surgery on CABG outcomes., Methods: All patients who underwent isolated CABG at our institution between 2009 and 2016 and had preoperative cTnI level available were identified using our Society of Thoracic Surgeons registry. Receiver operating characteristic (ROC) analysis was performed to identify a cTnI threshold level. Subjects were divided into groups based on this value and outcomes compared., Results: A total of 608 patients were included. ROC analysis identified 5.74 µg/dL as the threshold value associated with worse postoperative outcomes. Patients with peak cTnI >5.74 µg/dL underwent CABG approximately 1 day later, had twice the risk of adverse postoperative events, and had 2.8 day longer postoperative length of stay than those with peak cTnI ≤5.74 µg/dL. cTnI level was not associated with mortality or 30-day readmission. Time interval between peak cTnI and surgery did not affect outcomes., Conclusion: Elevated preoperative cTnI level beyond a certain threshold value is associated with adverse postoperative outcomes but is not a marker for increased mortality. Time from peak cTnI does not affect postoperative outcomes or mortality and may not need to be considered when deciding timing of CABG., (© 2020 Wiley Periodicals LLC.)

Background: Invasive lobular cancer (ILC) of the breast can provide diagnostic and therapeutic challenges due to its often mammographically occult and multifocal nature. UK guidelines recommend magnetic resonance imaging (MRI) when considering breast conserving surgery (BCS) in women with a diagnosis of ILC. A small number of studies have shown that due to its low specificity, MRI can lead to additional invasive investigations whilst rarely identifying additional tumour foci that affect management. We carried out a retrospective study of patients diagnosed with ILC to assess the impact of MRI on management and to evaluate if breast density on mammography could indicate likelihood of additional disease being found on MRI., Methods: A retrospective analysis of the electronic patient records for all cases of ILC diagnosed between January 2013 and December 2016 was carried out., Results: A total of 110 cases of ILC were identified of which 69 women were considered for BCS and 58 (84.1%) women underwent MRI. A further abnormality was seen in 22 (37.9%) patients of whom 13 (59.1%) had a further core biopsy with 4 cases being positive for malignancy. Overall MRI changed the surgical plan from BCS to mastectomy in 7 (10.1%). Breast density did not predict the presence of additional findings on MRI., Conclusions: MRI assessment of ILC rarely affects the management when BCS is considered. Having radiologically denser breasts did not correlate with increased reoperation rate. Larger prospective studies may provide further guidance on MRI specificity and breast density., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Root-fungal symbioses such as mycorrhizas and endophytes are key components of terrestrial ecosystems. Diverse in trophy habits (obligate, facultative or hemi-biotrophs) and symbiotic relations (from mutualism to parasitism), these associations also show great variability in their root colonization and nutritional strategies. Specialized interface structures such as arbuscules and Hartig nets are formed by certain associations while others are restricted to non-specialized intercellular or intracellular hyphae in roots. In either case, there are documented examples of active nutrient exchange, reinforcing the fact that specialized structures used to define specific mycorrhizal associations are not essential for reciprocal exchange of nutrients and plant growth promotion. In feremycorrhiza (with Austroboletus occidentalis and eucalypts), the fungal partner markedly enhances plant growth and nutrient acquisition without colonizing roots, emphasizing that a conventional focus on structural form of associations may have resulted in important functional components of rhizospheres being overlooked. In support of this viewpoint, mycobiome studies using the state-of-the-art DNA sequencing technologies have unearthed much more complexity in root-fungal relationships than those discovered using the traditional morphology-based approaches. In this review, we explore the existing literature and most recent findings surrounding structure, functioning, and ecology of root-fungal symbiosis, which highlight the fact that plant fitness can be altered by taxonomically/ecologically diverse fungal symbionts regardless of root colonization and interface specialization. Furthermore, transition from saprotrophy to biotrophy seems to be a common event that occurs in diverse fungal lineages (consisting of root endophytes, soil saprotrophs, wood decayers etc.), and which may be accompanied by development of specialized interface structures and/or mycorrhiza-like effects on plant growth and nutrition., Competing Interests: Mark Tibbett is an Academic Editor for PeerJ.

Mycorrhizal symbiosis requires several common symbiosis genes including CYCLOPS/IPD3. The reduced mycorrhizal colonisation (rmc) tomato mutant has a deletion of five genes including CYCLOPS/IPD3, and rmc is more susceptible to Fusarium wilt than its wild-type parental line. This study investigated the genetic defects leading to both fungal interaction phenotypes and whether these were separable. Complementation was performed in rmc to test the requirement for CYCLOPS/IPD3 in mycorrhiza formation and Fusarium wilt tolerance. Promoter analysis via GFP expression in roots was conducted to determine the role of native regulatory elements in the proper functioning of CYCLOPS/IPD3. CYCLOPS/IPD3 regulated by its native promoter, but not a 2×35S promoter, restores mycorrhizal association in rmc. GFP regulated by the 2×35S promoter is not expressed in epidermal cells of roots, indicating that expression of CYCLOPS/IPD3 in these cells is required for colonisation by the fungi utilised in this research. CYCLOPS/IPD3 did not restore Fusarium wilt tolerance, however, showing that the genetic requirements for mycorrhizal association and Fusarium wilt tolerance are different. Our results confirm the expected role of CYCLOPS/IPD3 in mycorrhizal symbiosis and suggest that Fusarium tolerance is conferred by one of the other four genes affected by the deletion.

The reduced mycorrhizal colonization ( rmc ) tomato mutant is unable to form mycorrhiza and is more susceptible to Fusarium wilt compared with its wild-type isogenic line 76R. The rmc mutant has a chromosomal deletion affecting five genes, one of which is similar to CYCLOPS. Loss of this gene is responsible for non-mycorrhizality in rmc but not enhanced Fusarium wilt susceptibility. Here, we describe assessment of a second gene in the rmc deletion, designated Solyc08g075770 that is expressed in roots. Sequence analyses show that Solyc08g075770 encodes a small transmembrane protein with putative phosphorylation and glycosylation sites. It is predicted to be localized in the plasma membrane and may function in transmembrane ion transport and/or as a cell surface receptor. Complementation and knock-out strategies were used to test its function. Some putative CRISPR/Cas-9 knock-out transgenic events exhibited Fusarium wilt susceptibility like rmc and some putative complementation lines were 76R-like, suggesting that the tomato Solyc08g075770 functions in Fusarium wilt tolerance. This is the first study to demonstrate that Solyc08g075770 is the contributor to the Tfw locus, conferring tolerance to Fusarium wilt in 76R which was lost in rmc.

Approximately 0.5 million people worldwide die from metastatic breast cancer (mBC) every year. This manuscript provides an overview on the status of mBC in several regions of the world, highlighting the gaps in care, resources, and support available for patients with mBC. Primary research was conducted in 2015 and 2016, comprising four global qualitative and quantitative surveys of approximately 15,000 individuals in 34 countries. Secondary research was conducted using literature reviews of peer-reviewed publications, patient survey reports, and media or online articles. There have been modest improvements in mBC outcomes over the past decade. Patients are not provided with adequate information about mBC. There is a need for open discussion with patients and caregivers about realistic goals; however, physicians are not trained in communicating with patients about their disease. Maintaining patients' quality of life is a crucial goal; however, this has not improved, and in some cases, may have declined in the past decade. Public awareness and understanding of mBC is limited, with damaging consequences for patients and caregivers. Issues affecting employment remain relevant to patients with mBC and their caregivers. Globally, mBC is associated with a substantial economic burden. Relationships with caregivers are crucial to patients with mBC, and caregiver support needs are often overlooked. A strong and united global effort among healthcare professionals, including clinicians, oncologists, pharmaceutical manufacturers, payers, and policy makers, and with advocates, families, and patients, is necessary to improve the outcome and quality of life for patients with mBC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background/aims: Ulcerative colitis is a remitting and relapsing inflammatory bowel disorder. Current treatments are limited, and if poorly controlled, colitis may progress to colorectal cancer. Previously, Emu Oil protected the intestine in experimental models of gut damage. We aimed to determine whether Emu Oil could reduce the severity of chronic colitis and prevent the onset of neoplasia in a mouse model of colitis-associated colorectal cancer., Methods: Female C57BL/6 mice were injected (day 0) with azoxymethane, followed by ad libitum access to three dextran sulfate sodium/water cycles (7 days of dextran sulfate sodium and 14 days of water). Mice (n = 9/group) were orally administered either water or Emu Oil (low dose 80 µL or high dose 160 µL), thrice weekly for 9 weeks. Bodyweight and disease activity index were measured daily. Colitis progression was monitored by colonoscopy on days 20, 41 and 62. At killing, tumor number and size were recorded., Results: Azoxymethane/dextran sulfate sodium induced significant bodyweight loss (maximum 24%) which was attenuated by Emu Oil treatment (low dose days 9, 10, 14: maximum 7%; high dose days 7-15, 30-36: maximum 11%; p < 0.05). Emu Oil reduced disease activity index of azoxymethane/dextran sulfate sodium mice at most time points (maximum 20%; p < 0.05). Additionally, Emu Oil reduced colonoscopically assessed colitis severity (days 20 and 62) compared to disease controls (p < 0.05). Finally, in azoxymethane/dextran sulfate sodium mice, low-dose Emu Oil resulted in fewer small colonic tumors (p < 0.05) compared to controls., Conclusions: Emu Oil improved clinical indicators and reduced severity of colitis-associated colorectal cancer, suggesting therapeutic potential in colitis management.

Rubin et al (Reports, 16 June 2017, p. 1154) proposed that gradients in lithium abundance in zircons from a rhyolitic eruption in New Zealand reflected short-lived residence at magmatic temperatures interleaved with long-term "cold" (<650°C) storage. Important issues arise with the interpretation of these lithium gradients and consequent crystal thermal histories that raise concerns about the validity of this conclusion., (Copyright © 2017, American Association for the Advancement of Science.)

Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δ p35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation. SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aβ accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δ p35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Δp35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems., (Copyright © 2017 the authors 0270-6474/17/379918-08$15.00/0.)

Background: Health workers (HWs) in resource-limited settings are at high-risk of exposure to tuberculosis (TB) at work. The aim of this study was to estimate the rate of TB disease among HWs in the Free State Province of South Africa between 2002 and 2012 and to compare demographic and clinical characteristics between HWs and the general population with TB. This study also explores the effect of occupational variables on risk of TB among HWs., Methods: Probabilistic record linkage was utilized to identify HWs who were also registered as TB patients. This historical prospective cohort study calculated incidence rate ratios (IRR) for TB disease among HWs in Free State from 2002 to 2012. Generalized linear mixed-effects regression was used to model the association between sex, race, facility type, occupation, duration of employment, and the rate of TB., Results: There were 2677 cases of TB diagnosed among HWs from 2002 to 2012 and 1280 cases were expected. The overall TB incidence rate in HWs during the study period was 1496·32 per 100,000 compared to an incidence rate of 719·37 per 100,000 in the general population during the same time period. IRR ranged from 1·14 in 2012 to 3·12 in 2005. HWs who were male, black, coloured and employed less than 20 years had higher risk of TB. Facility type and occupation were not associated with increased risk of TB when adjusted for other covariates., Conclusion: HWs in South Africa have higher rates of TB than the general population. Improved infection prevention and control measures are necessary in all high-burden TB healthcare settings.

In this issue of Neuron, Weng et al. (2017) reveal a role for active DNA demethylation in allowing axon regeneration to occur in the mature nervous system following axonal injury., (Published by Elsevier Inc.)

Many plant species adapted to P-impoverished soils, including jarrah (Eucalyptus marginata), develop toxicity symptoms when exposed to high doses of phosphate (Pi) and its analogs such as phosphite (Phi) and arsenate (AsV). The present study was undertaken to investigate the effects of fungal symbionts Scutellospora calospora, Scleroderma sp., and Austroboletus occidentalis on the response of jarrah to highly toxic pulses (1.5 mmol kg(-1) soil) of Pi, Phi, and AsV. S. calospora formed an arbuscular mycorrhizal (AM) symbiosis while both Scleroderma sp. and A. occidentalis established a non-colonizing symbiosis with jarrah plants. All these interactions significantly improved jarrah growth and Pi uptake under P-limiting conditions. The AM fungal colonization naturally declines in AM-eucalypt symbioses after 2-3 months; however, in the present study, the high Pi pulse inhibited the decline of AM fungal colonization in jarrah. Four weeks after exposure to the Pi pulse, plants inoculated with S. calospora had significantly lower toxicity symptoms compared to non-mycorrhizal (NM) plants, and all fungal treatments induced tolerance against Phi toxicity in jarrah. However, no tolerance was observed for AsV-treated plants even though all inoculated plants had significantly lower shoot As concentrations than the NM plants. The transcript profile of five jarrah high-affinity phosphate transporter (PHT1 family) genes in roots was not altered in response to any of the fungal species tested. Interestingly, plants exposed to high Pi supplies for 1 day did not have reduced transcript levels for any of the five PHT1 genes in roots, and transcript abundance of four PHT1 genes actually increased. It is therefore suggested that jarrah, and perhaps other P-sensitive perennial species, respond positively to Pi available in the soil solution through increasing rather than decreasing the expression of selected PHT1 genes. Furthermore, Scleroderma sp. can be considered as a fungus with dual functional capacity capable of forming both ectomycorrhizal and non-colonizing associations, where both pathways are always accompanied by evident growth and nutritional benefits.

In common with many plants native to low P soils, jarrah (Eucalyptus marginata) develops toxicity symptoms upon exposure to elevated phosphorus (P). Jarrah plants can establish arbuscular mycorrhizal (AM) and ectomycorrhizal (ECM) associations, along with a non-colonizing symbiosis described recently. AM colonization is known to influence the pattern of expression of genes required for P uptake of host plants and our aim was to investigate this phenomenon in relation to P sensitivity. Therefore, we examined the effect on hosts of the presence of AM and ECM fungi in combination with toxic pulses of P and assessed possible correlations between the induced tolerance and the shoot P concentration. The P transport dynamics of AM (Rhizophagus irregularis and Scutellospora calospora), ECM (Scleroderma sp.), non-colonizing symbiosis (Austroboletus occidentalis), dual mycorrhizal (R. irregularis and Scleroderma sp.), and non-mycorrhizal (NM) seedlings were monitored following two pulses of P. The ECM and A. occidentalis associations significantly enhanced the shoot P content of jarrah plants growing under P-deficient conditions. In addition, S. calospora, A. occidentalis, and Scleroderma sp. all stimulated plant growth significantly. All inoculated plants had significantly lower phytotoxicity symptoms compared to NM controls 7 days after addition of an elevated P dose (30 mg P kg(-1) soil). Following exposure to toxicity-inducing levels of P, the shoot P concentration was significantly lower in R. irregularis-inoculated and dually inoculated plants compared to NM controls. Although all inoculated plants had reduced toxicity symptoms and there was a positive linear relationship between rank and shoot P concentration, the protective effect was not necessarily explained by the type of fungal association or the extent of mycorrhizal colonization.

Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations ("strains") in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

• Most terrestrial plants form mutually beneficial symbioses with specific soil-borne fungi known as mycorrhiza. In a typical mycorrhizal association, fungal hyphae colonize plant roots, explore the soil beyond the rhizosphere and provide host plants with nutrients that might be chemically or physically inaccessible to root systems. • Here, we combined nutritional, radioisotopic ((33)P) and genetic approaches to describe a plant growth promoting symbiosis between the basidiomycete fungus Austroboletus occidentalis and jarrah (Eucalyptus marginata), which has quite different characteristics. • We show that the fungal partner does not colonize plant roots; hyphae are localized to the rhizosphere soil and vicinity and consequently do not transfer nutrients located beyond the rhizosphere. Transcript profiling of two high-affinity phosphate (Pi) transporter genes (EmPHT1;1 and EmPHT1;2) and hyphal-mediated (33)Pi uptake suggest that the Pi uptake shifts from an epidermal to a hyphal pathway in ectomycorrhizal plants (Scleroderma sp.), similar to arbuscular mycorrhizal symbioses, whereas A. occidentalis benefits its host indirectly. The enhanced rhizosphere carboxylates are linked to growth and nutritional benefits in the novel symbiosis. • This work is a starting point for detailed mechanistic studies on other basidiomycete-woody plant relationships, where a continuum between heterotrophic rhizosphere fungi and plant beneficial symbioses is likely to exist., (© 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.)