The draft genome of Cochliopodium minus reveals a complete meiosis toolkit and provides insight into the evolution of sexual mechanisms in Amoebozoa.

To date, genomic analyses in amoebozoans have been mostly limited to model organisms or medically important lineages. Consequently, the vast diversity of Amoebozoa genomes remain unexplored. A draft genome of Cochliopodium minus, an amoeba characterized by extensive cellular and nuclear fusions, is presented. C. minus has been a subject of recent investigation for its unusual sexual behavior. Cochliopodium's sexual activity occurs during vegetative stage making it an ideal model for studying sexual development, which is sorely lacking in the group. Here we generate a C. minus draft genome assembly. From this genome, we detect a substantial number of lateral gene transfer (LGT) instances from bacteria (15%), archaea (0.9%) and viruses (0.7%) the majority of which are detected in our transcriptome data. We identify the complete meiosis toolkit genes in the C. minus genome, as well as the absence of several key genes involved in plasmogamy and karyogamy. Comparative genomics of amoebozoans reveals variation in sexual mechanism exist in the group. Similar to complex eukaryotes, C. minus (some amoebae) possesses Tyrosine kinases and duplicate copies of SPO11. We report a first example of alternative splicing in a key meiosis gene and draw important insights on molecular mechanism of sex in C. minus using genomic and transcriptomic data.

COVID-19: legal implications for critical care.

The COVID-19 pandemic has caused an unprecedented challenge for the provision of critical care. Anticipating an unsustainable burden on the health service, the UK Government introduced numerous legislative measures culminating in the Coronavirus Act, which interfere with existing legislation and rights. However, the existing standards and legal frameworks relevant to critical care clinicians are not extinguished, but anticipated to adapt to a new context. This new context influences the standard of care that can be reasonably provided and yields many human rights considerations, for example, in the use of restraints, or the restrictions placed on patients and visitors under the Infection Prevention and Control guidance. The changing landscape has also highlighted previously unrecognised legal dilemmas. The perceived difficulties in the provision of personal protective equipment for employees pose a legal risk for Trusts and a regulatory risk for clinicians. The spectre of rationing critical care poses a number of legal issues. Notably, the flux between clinical decisions based on best interests towards decisions explicitly based on resource considerations should be underpinned by an authoritative public policy decision to preserve legitimacy and lawfulness. Such a policy should be medically coherent, legally robust and ethically justified. The current crisis poses numerous challenges for clinicians aspiring to remain faithful to medicolegal and human rights principles developed over many decades, especially when such principles could easily be dismissed. However, it is exactly at such times that these principles are needed the most and clinicians play a disproportionate role in safeguarding them for the most vulnerable.

Experimental Demonstration of Hadron Beam Cooling Using Radio-Frequency Accelerated Electron Bunches.

Cooling of beams of gold ions using electron bunches accelerated with radio-frequency systems was recently experimentally demonstrated in the Relativistic Heavy Ion Collider at Brookhaven National Laboratory. Such an approach is new and opens the possibility of using this technique at higher energies than possible with electrostatic acceleration of electron beams. The challenges of this approach include generation of electron beams suitable for cooling, delivery of electron bunches of the required quality to the cooling sections without degradation of beam angular divergence and energy spread, achieving the required small angles between electron and ion trajectories in the cooling sections, precise velocity matching between the two beams, high-current operation of the electron accelerator, as well as several physics effects related to bunched-beam cooling. Here we report on the first demonstration of cooling hadron beams using this new approach.

Defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases.

Kinases are involved in disease development and modulation of their activity can be therapeutically beneficial. Drug-resistant mutant kinases are valuable tools in drug discovery efforts, but the prediction of mutants across the kinome is challenging. Here, we generate deep mutational scanning data to identify mutant mammalian kinases that drive resistance to clinically relevant inhibitors. We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance across the kinome. We validate predicted resistance mutations in CDK4, CDK6, ERK2, EGFR and HER2. Capitalizing on a highly predictable residue, we generate resistance mutations in TBK1, CSNK2A1 and BRAF. Unexpectedly, we uncover a potentially generalizable activation site that mediates drug resistance and confirm its impact in BRAF, EGFR, HER2 and MEK1. We anticipate that the identification of these residues will enable the broad interrogation of the kinome and its inhibitors.

Direct comparison between surface imaging and orthogonal radiographic imaging for SRS localization in phantom.

PURPOSE: Surface imaging (SI) offers a nonionizing, near real time alternative to radiographic imaging for intrafraction radiosurgery localization. In this work, we systematically compared a commercial SI system vs a commercial room mounted x-ray localization system in phantom. METHODS: An anthropomorphic head phantom with fiducial markers was imaged with linear accelerator on-board x-ray imaging, SI, and room mounted x-ray imaging (RM) at ±45° and ±90° couch angles for three different head tilts and six different isocenters (72 total positions). The shifts generated by the three systems were compared as functions of couch angle, head tilt, and isocenter position with the on-board imaging shifts used as ground truth. Two sample Kolmogorov-Smirnov tests were used to evaluate equivalence of the groups. RESULTS: The magnitude of the displacement vectors for RM minus on-board imaging and SI minus on-board imaging over all 72 phantom positions were 0.7 ± 0.3 mm for both cases. The RM and SI showed no significant difference based on couch angle or isocenter position. Both systems showed decreasing accuracy with increasing couch angle, but both systems agreed with ground truth to <=1.1 mm at all couch angles. The exaggerated chin-up head orientation showed significantly different shifts for SI and RM based on increased variance in the SI measurements, although both had submillimeter accuracy on average. The standard deviation of the real time SI displacement vector was <0.06 mm over all measurements, during which the on-board imaging panels partially blocked the lateral camera pods for half the time. CONCLUSIONS: RM and SI showed similar accuracy over measurements at 72 different phantom positions. SI showed minimal performance loss with camera pods blocked. SI is a feasible option for intra-fraction radiosurgery localization based on these phantom measurements.

Stress fractures of the foot and ankle.

Stress fractures occur as a result of microscopic injuries sustained when bone is subjected to repeated submaximal stresses. Overtime, with repeated cycles of loading, accumulation of such injuries can lead to macro-structural failure and frank fracture. There are numerous stress fractures about the foot and ankle of which a trauma and orthopaedic surgeon should be aware. These include: metatarsal, tibia, calcaneus, navicular, fibula, talus, medial malleolus, sesamoid, cuneiform and cuboid. Awareness of these fractures is important as the diagnosis is frequently missed and appropriate treatment delayed. Late identification can be associated with protracted pain and disability, and may predispose to non-union and therefore necessitate operative intervention. This article outlines the epidemiology and risk factors, aetiology, presentation and management of the range of stress fractures in the foot and ankle.

Design of a high-bunch-charge 112-MHz superconducting RF photoemission electron source.

High-bunch-charge photoemission electron-sources operating in a continuous wave (CW) mode are required for many advanced applications of particle accelerators, such as electron coolers for hadron beams, electron-ion colliders, and free-electron lasers. Superconducting RF (SRF) has several advantages over other electron-gun technologies in CW mode as it offers higher acceleration rate and potentially can generate higher bunch charges and average beam currents. A 112 MHz SRF electron photoinjector (gun) was developed at Brookhaven National Laboratory to produce high-brightness and high-bunch-charge bunches for the coherent electron cooling proof-of-principle experiment. The gun utilizes a quarter-wave resonator geometry for assuring beam dynamics and uses high quantum efficiency multi-alkali photocathodes for generating electrons.

A novel method for radiotherapy patient identification using surface imaging.

Performing a procedure on the wrong patient or site is one of the greatest errors that can occur in medicine. The addition of automation has been shown to reduce errors in many processes. In this work we explore the use of an automated patient identification process using optical surface imaging for radiotherapy treatments. Surface imaging uses visible light to align the patient to a reference surface in the treatment room. It is possible to evaluate the similarity between a daily set-up surface image and the reference image using distance to agreement between the points on the two surfaces. The higher the percentage overlapping points within a defined distance, the more similar the surfaces. This similarity metric was used to intercompare 16 left-sided breast patients. The reference surface for each patient was compared to 10 daily treatment surfaces for the same patient, and 10 surfaces from each of the other 15 patients (for a total of 160 comparisons per patient), looking at the percent of points overlapping. For each patient, the minimum same-patient similarity score was higher than the maximum different-patient score. For the group as a whole a threshold was able to classify correct and incorrect patients with high levels of accuracy. A 10-fold cross-validation using linear discriminant analysis gave cross-validation loss of 0.0074. An automated process using surface imaging is a feasible option to provide nonharmful daily patient identification verification using currently available technology.

A prospective evaluation of open face masks for head and neck radiation therapy.

PURPOSE: Head and neck (HN) radiation therapy patients are typically immobilized with closed thermoplastic masks that cover the face and may cause discomfort. In this work, we examine the use of open masks for HN radiation therapy. METHODS AND MATERIALS: Fifty HN patients were prospectively randomized into 2 groups (25 closed masks, 25 open masks). The open-mask group was monitored with surface imaging to evaluate intrafraction motion. Both groups underwent daily volumetric imaging. All daily images were rigidly registered to their respective planning images to evaluate spinal canal and mandible position as a check for interfraction posture change. Posture changes were determined by the amount the spinal canal and mandible contours from the planning images had to be expanded to cover the structures on each daily image set. The vector length (VL) of the intrafraction linear translations, spine, and mandible positions for each open-mask patient were checked for correlation with fraction number using the Pearson r value. All patients were given a weekly survey ranking anxiety and claustrophobia from 0 to 10 (0 = no issue, 10 = extreme issue). RESULTS: The mean VL for all open-mask patients was 0.9 ± 0.5 mm (1 standard deviation). Only 1 patient showed significant correlation between VL and fraction number. The mean contour expansions to cover the spine and mandible were 1.5 ± 0.9 mm and 1.8 ± 1.3 mm for the closed-mask group, and 1.6 ± 0.8 mm and 1.8 ± 1.1 mm for the open-mask group. Both groups showed similar behavior relative to fraction number. The mean anxiety and claustrophobia scores were 1.63 and 1.44 for the closed-mask group, and 0.81 and 0.63 for the open-mask group. The groups were not significantly different. CONCLUSIONS: Open masks provide comparable immobilization and posture preservation to closed masks for HN radiation therapy.

Selective patellar resurfacing in total knee arthroplasty: a prospective, randomized, double-blind study.

350 knees were evaluated in a prospective, randomized, double-blinded study of selective patellar resurfacing in primary total knee arthroplasty. Knees with exposed bone on the patellar articular surface were excluded. 327 knees were evaluated at a mean follow-up of 7.8years. 114 knees followed for greater than 10 years were analyzed separately. Satisfaction was higher in patients with a resurfaced patella. In patients followed for at least 10 years, no significant difference was found. No difference was found in KSS scores or survivorship. No complications of patellar resurfacing were identified. The vast majority of patients with remaining patellar articular cartilage do very well with total knee arthroplasty regardless of patellar resurfacing. Patient satisfaction may be slightly higher with patellar resurfacing.

Self-motivated learning with gamification improves infant CPR performance, a randomised controlled trial.

Background: Effective paediatric basic life support improves survival and outcomes. Current cardiopulmonary resuscitation (CPR) training involves 4-yearly courses plus annual updates. Skills degrade by 3-6 months. No method has been described to motivate frequent and persistent CPR practice. To achieve this, we explored the use of competition and a leaderboard, as a gamification technique, on a CPR training feedback device, to increase CPR usage and performance. Objective: To assess whether self-motivated CPR training with integrated CPR feedback improves quality of infant CPR over time, in comparison to no refresher CPR training. Design: Randomised controlled trial (RCT) to assess the effect of self-motivated manikin-based learning on infant CPR skills over time. Setting: A UK tertiary children's hospital. Participants: 171 healthcare professionals randomly assigned to self-motivated CPR training (n=90) or no refresher CPR training (n=81) and followed for 26 weeks. Intervention: The intervention comprised 24 h a day access to a CPR training feedback device and anonymous leaderboard. The CPR training feedback device calculated a compression score based on rate, depth, hand position and release and a ventilation score derived from rate and volume. Main outcome measure: The outcome measure was Infant CPR technical skill performance score as defined by the mean of the cardiac compressions and ventilations scores, provided by the CPR training feedback device software. The primary analysis considered change in score from baseline to 6 months. Results: Overall, the control group showed little change in their scores (median 0, IQR -7.00-5.00) from baseline to 6 months, while the intervention group had a slight median increase of 0.50, IQR 0.00-33.50. The two groups were highly significantly different in their changes (p<0.001). Conclusions: A significant effect on CPR performance was demonstrated by access to self-motivated refresher CPR training, a competitive leaderboard and a CPR training feedback device.

Designing Endocrine Disruption Out of the Next Generation of Chemicals.

A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via different endocrinological mechanisms through the protocol using published literature. Each was identified as endocrine active by one or more tiers. We believe that this voluntary testing protocol will be a dynamic tool to facilitate efficient and early identification of potentially problematic chemicals, while ultimately reducing the risks to public health.

Queensland Lung Cancer Screening Study: rationale, design and methods.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in Australia. Screening using low-dose computed tomography (LDCT) can reduce lung cancer mortality. The feasibility of screening in Australia is unknown. This paper describes the rationale, design and methods of the Queensland Lung Cancer Screening Study. AIMS: The aim of the study is to describe the methodology for a feasibility study of lung cancer screening by LDCT in Australia. METHODS: The Queensland Lung Cancer Screening Study is an ongoing, prospective observational study of screening by LDCT at a single tertiary institution. Healthy volunteers at high risk of lung cancer (age 60-74 years; smoking history ≥30 pack years, current or quit within 15 years; forced expiratory volume in 1s ≥50% predicted) are recruited from the general public through newspaper advertisement and press release. Participants receive a LDCT scan of the chest at baseline, year 1 and year 2 using a multidetector helical computed tomography scanner and are followed up for a total of 5 years. Feasibility of screening will be assessed by cancer detection rates, lung nodule prevalence, optimal management strategies for lung nodules, economic costs, healthcare utilisation and participant quality of life. CONCLUSIONS: Studying LDCT screening in the Australian setting will help us understand how differences in populations, background diseases and healthcare structures modulate screening effectiveness. This information, together with results from overseas randomised studies, will inform and facilitate local policymaking.

In-home walking speeds and variability trajectories associated with mild cognitive impairment.

OBJECTIVE: To determine whether unobtrusive long-term in-home assessment of walking speed and its variability can distinguish those with mild cognitive impairment (MCI) from those with intact cognition. METHODS: Walking speed was assessed using passive infrared sensors fixed in series on the ceiling of the homes of elderly individuals participating in the Intelligent Systems for Assessing Aging Change (ISAAC) cohort study. Latent trajectory models were used to analyze weekly mean speed and walking speed variability (coefficient of variation [COV]). RESULTS: ISAAC participants living alone included 54 participants with intact cognition, 31 participants with nonamnestic MCI (naMCI), and 8 participants with amnestic MCI at baseline, with a mean follow-up of 2.6 ± 1.0 years. Trajectory models identified 3 distinct trajectories (fast, moderate, and slow) of mean weekly walking speed. Participants with naMCI were more likely to be in the slow speed group than in the fast (p = 0.01) or moderate (p = 0.04) speed groups. For COV, 4 distinct trajectories were identified: group 1, the highest baseline and increasing COV followed by a sharply declining COV; groups 2 and 3, relatively stable COV; and group 4, the lowest baseline and decreasing COV. Participants with naMCI were more likely to be members of either highest or lowest baseline COV groups (groups 1 or 4), possibly representing the trajectory of walking speed variability for early- and late-stage MCI, respectively. CONCLUSION: Walking speed and its daily variability may be an early marker of the development of MCI. These and other real-time measures of function may offer novel ways of detecting transition phases leading to dementia.

Three ways of understanding development as a teacher.

The demands on faculty in terms of teaching are increasing, but until recently there has been little discussion of how faculty perceive that development as a teacher can be achieved or what approaches they use or suggest themselves. The aim of this study is to explore how teachers in dentistry and medicine understand development as teachers. For this study, 20 teachers were interviewed. The interviews were analysed using a phenomenographic approach. Three different ways of understanding development were identified: 1) Development as a dental or medical clinician/expert as the teacher role is seen as a tacit part of the role of the clinician. 2) Experience and professional and personal maturation, related to personal and professional development and confidence in ones clinical role. 3) Knowledge in education and systematic teacher training as in this category, being a teacher is seen as a separate role from that of being a clinician. The differences in these three ways of understanding development as a teacher are shown in their different aims of development, what kind of knowledge that may be used and what methods they suggested. The way teachers understand what it means to develop as a teacher will affect their motivation for engaging in development activities, which activities they choose and their own aims of development. This means that awareness of teachers' understanding of development is central when developing support or faculty development activities for teachers.

The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty: a randomized, double-blind, active-control study.

BACKGROUND: Breast augmentation can result in significant postsurgical pain. OBJECTIVES: The authors evaluate the extent and duration of analgesia achieved with extended-release DepoFoam bupivacaine (Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty under general anesthesia. METHODS: In this randomized, multicenter, double-blind study, patients received a single dose of DepoFoam bupivacaine 600 mg or bupivacaine HCl 200 mg divided into the implant pockets at the conclusion of surgery. The primary efficacy measure was cumulative pain score with activity through 72 hours postoperatively. Secondary efficacy measures included pain intensity with activity and at rest, postsurgical consumption of rescue opioids, and integrated rank analysis combining pain scores at rest with the amount of opioid used. RESULTS: One hundred thirty-six patients were randomized and treated (DepoFoam bupivacaine, n = 66; bupivacaine HCl, n = 70). Reflecting the underpowered nature of the study, the mean cumulative pain score (numeric rating scale with activity through 72 hours) was 441.5 with DepoFoam bupivacaine versus 468.2 with bupivacaine HCl (P = .3999). Total amounts of opioid consumed were significantly lower in the DepoFoam bupivacaine group through 24 hours (P = .0211) and through 48 hours (P = .0459). The prespecified integrated rank analysis showed statistically-significant differences at multiple time points up to and including 60 hours; results on most other efficacy measures trended in favor of DepoFoam bupivacaine. No serious adverse events were reported, and no patients discontinued the study due to adverse events. CONCLUSIONS: DepoFoam bupivacaine trended toward benefit versus bupivacaine HCl on most efficacy measures. Due to early termination, the study was underpowered to achieve statistical significance.

Perspectives on being a mentor for undergraduate dental students.

As part of the new study programme in Dentistry, an obligatory mentor programme was introduced during autumn 2005 for all student dentists at Karolinska Institutet, Sweden. The aim of the programme is to provide support and guidance for the students in their professional role as dentists. All mentors in the programme are licenced dentists and lecturers at the Department of Dental Medicine. The mentors follow three to five mentees throughout the entire 5 year programme. This study aims to evaluate the programme from the mentors' perspective and to explore the perceived effects of being a mentor. Following an exploratory focus group, questionnaires were distributed to all mentors (n = 66, response rate 83%). The results of the evaluation of the programme show that being a mentor is perceived to be rewarding in many different ways, including an increased understanding of the students' situation and some professional development as a teacher.

The cause of global amphibian declines: a developmental endocrinologist's perspective.

Greater than 70% of the world's amphibian species are in decline. We propose that there is probably not a single cause for global amphibian declines and present a three-tiered hierarchical approach that addresses interactions among and between ultimate and proximate factors that contribute to amphibian declines. There are two immediate (proximate) causes of amphibian declines: death and decreased recruitment (reproductive failure). Although much attention has focused on death, few studies have addressed factors that contribute to declines as a result of failed recruitment. Further, a great deal of attention has focused on the role of pathogens in inducing diseases that cause death, but we suggest that pathogen success is profoundly affected by four other ultimate factors: atmospheric change, environmental pollutants, habitat modification and invasive species. Environmental pollutants arise as likely important factors in amphibian declines because they have realized potential to affect recruitment. Further, many studies have documented immunosuppressive effects of pesticides, suggesting a role for environmental contaminants in increased pathogen virulence and disease rates. Increased attention to recruitment and ultimate factors that interact with pathogens is important in addressing this global crisis.

Mucosal T-cell responses to HIV: responding at the front lines.

Mucosal surfaces of the body serve as the major portal of entry for human immunodeficiency virus (HIV). These tissues also house a majority of the body's lymphocytes, including the CD4(+) T cells that are the major cellular target for HIV infection. Mucosal surfaces are defended by innate and adaptive immune mechanisms, including secreted antibodies and CD8(+) cytotoxic T cells (CTL). CTL in mucosal lymphoid tissues may serve to limit viral replication, decreasing the host's viral burden as well as reducing the likelihood of sexual transmission to a naïve host. This review summarizes recent literature on HIV-specific T-cell responses in mucosal tissues, with an emphasis on the gastrointestinal tract.