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Abstract There is a pressing need to improve risk stratification and treatment selection for HPV-negative head and neck squamous cell carcinoma (HNSCC) due to the adverse side effects of treatment. One of the most important prognostic features is lymph nodes involvement. Previously, we demonstrated that tumor formation in patient-derived xenografts (i.e. engraftment) was associated with poor clinical outcomes in patients with HPV-negative HNSCC. However, assessing engraftment is challenging in clinical settings. Here, we perform transcriptomic and proteomic profiling of 88 HNSCC patients and find the relationship between engraftment and clinical outcomes is recapitulated by molecular phenotype. We identify LAMC2 and TGM3 as candidate prognostic biomarkers and validated their utility in an independent cohort containing 404 HPV-negative HNSCC patients. Strikingly, these markers significantly improve prediction of outcomes beyond nodal status alone and can significantly stratify patients without any nodal involvement. Overall, our study demonstrates how the molecular characteristics of engraftment can inform patient prognostication.

Abstract Background Variation in development methods of Pressure Ulcer Risk Assessment Instruments has led to inconsistent inclusion of risk factors and concerns about content validity. A new evidenced-based Risk Assessment Instrument, the Pressure Ulcer Risk Primary Or Secondary Evaluation Tool - PURPOSE-T was developed as part of a National Institute for Health Research (NIHR) funded Pressure Ulcer Research Programme (PURPOSE: RP-PG-0407-10056). This paper reports the pre-test phase to assess and improve PURPOSE-T acceptability, usability and confirm content validity. Methods A descriptive study incorporating cognitive pre-testing methods and integration of service user views was undertaken over 3 cycles comprising PURPOSE-T training, a focus group and one-to-one think-aloud interviews. Clinical nurses from 2 acute and 2 community NHS Trusts, were grouped according to job role. Focus group participants used 3 vignettes to complete PURPOSE-T assessments and then participated in the focus group. Think-aloud participants were interviewed during their completion of PURPOSE-T. After each pre-test cycle analysis was undertaken and adjustment/improvements made to PURPOSE-T in an iterative process. This incorporated the use of descriptive statistics for data completeness and decision rule compliance and directed content analysis for interview and focus group data. Data were collected April 2012-June 2012. Results Thirty-four nurses participated in 3 pre-test cycles. Data from 3 focus groups, 12 think-aloud interviews incorporating 101 PURPOSE-T assessments led to changes to improve instrument content and design, flow and format, decision support and item-specific wording. Acceptability and usability were demonstrated by improved data completion and appropriate risk pathway allocation. The pre-test also confirmed content validity with clinical nurses. Conclusions The pre-test was an important step in the development of the preliminary PURPOSE-T and the methods used may have wider instrument development application. PURPOSE-T proposes a new approach to pressure ulcer risk assessment, incorporating a screening stage, the inclusion of skin status to distinguish between those who require primary prevention and those who require secondary prevention/treatment and the use of colour to support pathway allocation and decision making. Further clinical evaluation is planned to assess the reliability and validity of PURPOSE-T and it’s impact on care processes and patient outcomes.

The advent of technologies that can seamlessly operate in different environments with differing levels of security present new challenges to the cybersecurity specialist seeking to ensure the safety of data, process or output of a complex system. This paper reviews the human dimension of cybersecurity. The Human Factors Integration (HFI) framework is employed as a structure with which to consider the many ways in which the human can differentially affect the security of a system both positively and negatively. We conclude that when the human factors element is analysed when specifying and designing secure and safe systems, it is far more likely that the human can assist and increase the overall level of security. As in other high technology sectors such as aviation or petrochemical, if not considered, the human can often ‘bulldoze’ through the most carefully considered and designed security or safety barriers

Background: The Coronavirus disease 2019 (COVID-19) pandemic led to healthcare system changes aimed at minimizing disease transmission that impacted experiences with obstetric healthcare. Objective: To explore experiences of clinicians providing obstetric care during the COVID-19 pandemic. Study Design: Qualitative, in-depth, semi-structured interviews were conducted with five nurse practitioners and 16 obstetrical physicians providing a mix of outpatient and inpatient obstetric care during the COVID-19 pandemic in a mid-sized, Midwestern city in the United States. Interviews elucidated challenges and facilitators of obstetric care provision and vaccination of pregnant patients against COVID-19 during the pandemic. Transcripts were coded inductively then deductively using the Health Equity Implementation Framework (HEIF), which integrates a disparities framework and implementation framework to highlight multilevel factors that influence obstetric care. Thematic analysis was conducted, and thematic saturation was reached. Results: We interviewed 21 clinicians. Clinicians recounted personal challenges such as social isolation and burnout that could be countered by social support. Challenges within the clinical encounter included implementation of infection mitigation efforts, vaccine counseling, and limitations of telehealth. However, when successfully implemented, telehealth facilitated care and circumvented barriers. Clinicians cited challenges at the healthcare system level such as rapidly evolving knowledge and recommendations, restrictive visitor policies, personnel shortage, and inadequate institutional resources to support pandemic-related stressors. However, interdisciplinary care and guidelines available for clinicians facilitated care. Clinicians reported that challenges at the societal level included financial strain, lack of childcare, medical mistrust, politicization of medicine, misinformation, and racism. Societal-level facilitators included insurance access, community outreach, positive policy changes, and fostering trust in medicine. Conclusion: The pandemic produced unique stressors and exacerbated existing challenges for clinicians providing obstetric care. Applying the HEIF to the findings emphasizes the influence of societal factors on all other levels. Identified facilitators can inform interventions to address stressors in obstetric care that have resulted from the changed sociopolitical landscape of the pandemic.

Introduction There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS.Methods and analysis MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0–6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur.Ethics and dissemination The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numbers NCT03387670; ISRCTN82598726.

Abstract Robust oxygenic photosynthesis requires a suite of accessory factors to ensure efficient assembly and repair of the oxygen-evolving photosystem two (PSII) complex. The highly conserved Ycf48 assembly factor binds to the newly synthesized D1 reaction center polypeptide and promotes the initial steps of PSII assembly, but its binding site is unclear. Here we use cryo-electron microscopy to determine the structure of a cyanobacterial PSII D1/D2 reaction center assembly complex with Ycf48 attached. Ycf48, a 7-bladed beta propeller, binds to the amino-acid residues of D1 that ultimately ligate the water-oxidising Mn4CaO5 cluster, thereby preventing the premature binding of Mn2+ and Ca2+ ions and protecting the site from damage. Interactions with D2 help explain how Ycf48 promotes assembly of the D1/D2 complex. Overall, our work provides valuable insights into the early stages of PSII assembly and the structural changes that create the binding site for the Mn4CaO5 cluster.

Cancer affects tens of millions of the world’s population each year with a stark mortality rate. It is well established that in order to be effective in treating solid tumor cancers, the current treatment methods used often sacrifice surrounding healthy tissue and cause damage at the site of treatment, inducing changes to the surrounding microenvironment. These changes to the microenvironment can lead to adverse side effects as well as long-term damage which continues to have a detrimental impact on the patient’s quality of life, even after remission. It is believed that by modulating the tumor microenvironment (TME) post-treatment, not only may the efficacy of current treatments be improved, but such associated negative side effects, as well as further complications arising from treatment, including metastasis, have the potential to be reduced. Mediating the microenvironment is also considered to aid in repairing the damaged site post-treatment, subsequently making the conditions more favourable for promoting regenerative processes. This review provides a brief overview of the alterations in the TME resulting from the three main cancer treatments–chemotherapy, radiation therapy and surgery–and the most common tissue engineering methods currently used in an attempt to mediate the TME post-cancer therapy. Furthermore, it investigates new emerging technologies within this field and the progress of such methods in terms of reaching the clinical setting.

The dominant mechanism for generating free-floating planets has so far remained elusive. One suggested mechanism is that planets are ejected from planetary systems due to planet–planet interactions. Instability around a single star requires a very compactly spaced planetary system. We find that around binary star systems instability can occur even with widely separated planets that are on tilted orbits relative to the binary orbit due to combined effects of planet–binary and planet–planet interactions, especially if the binary is on an eccentric orbit. We investigate the orbital stability of planetary systems with various planet masses and architectures. We find that the stability of the system depends upon the mass of the highest-mass planet. The order of the planets in the system does not significantly affect stability, but, generally, the most massive planet remains stable and the lower-mass planets are ejected. The minimum planet mass required to trigger the instability is about that of Neptune for a circular orbit binary and a super-Earth of about 10 Earth masses for highly eccentric binaries. Hence, we suggest that planet formation around inclined binaries can be an efficient formation mechanism for free-floating planets. While most observed free-floating planets are giant planets, we predict that there should be more low-mass free-floating planets that are as of yet unobserved than higher-mass planets.

A star completely destroyed in a tidal disruption event (TDE) ignites a luminous flare that is powered by the fallback of tidally stripped debris to a supermassive black hole (SMBH) of mass M _• . We analyze two estimates for the peak fallback rate in a TDE, one being the “frozen-in” model, which predicts a strong dependence of the time to peak fallback rate, t _peak , on both stellar mass and age, with 15 days ≲ t _peak ≲ 10 yr for main sequence stars with masses 0.2 ≤ M _⋆ / M _⊙ ≤ 5 and M _• = 10 ^6 M _⊙ . The second estimate, which postulates that the star is completely destroyed when tides dominate the maximum stellar self-gravity, predicts that t _peak is very weakly dependent on stellar type, with ${t}_{\mathrm{peak}}=\left(23.2\pm 4.0\,{\rm{days}}\right){\left({M}_{\bullet }/{10}^{6}{M}_{\odot }\right)}^{1/2}$ for 0.2 ≤ M _⋆ / M _⊙ ≤ 5, while ${t}_{\mathrm{peak}}\,=\left(29.8\pm 3.6\,{\rm{days}}\right){\left({M}_{\bullet }/{10}^{6}{M}_{\odot }\right)}^{1/2}$ for a Kroupa initial mass function truncated at 1.5 M _⊙ . This second estimate also agrees closely with hydrodynamical simulations, while the frozen-in model is discrepant by orders of magnitude. We conclude that (1) the time to peak luminosity in complete TDEs is almost exclusively determined by SMBH mass, and (2) massive-star TDEs power the largest accretion luminosities. Consequently, (a) decades-long extra-galactic outbursts cannot be powered by complete TDEs, including massive-star disruptions, and (b) the most highly super-Eddington TDEs are powered by the complete disruption of massive stars, which—if responsible for producing jetted TDEs—would explain the rarity of jetted TDEs and their preference for young and star-forming host galaxies.

Quasiperiodic eruptions (QPEs) represent a novel class of extragalactic X-ray transients that are known to repeat at roughly regular intervals of a few hours to days. Their underlying physical mechanism is a topic of heated debate, with most models proposing that they originate either from instabilities within the inner accretion flow or from orbiting objects. At present, our knowledge of how QPEs evolve over an extended timescale of multiple years is limited, except for the unique QPE source GSN 069. In this study, we present results from strategically designed Swift observing programs spanning the past 3 yr, aimed at tracking eruptions from eRO-QPE1. Our main results are as follows: (1) the recurrence time of eruptions can vary from flare to flare and is in the range of 0.6–1.2 days; (2) there is no detectable secular trend in evolution of the recurrence times; (3) consistent with prior studies, their eruption profiles can have complex shapes; and (4) the peak flux of the eruptions has been declining over the past 3 yr, with the eruptions barely detected in the most recent Swift data set taken in 2023 June. This trend of weakening eruptions has been reported recently in GSN 069. However, because the background luminosity of eRO-QPE1 is below our detection limit, we cannot verify whether the weakening is correlated with the background luminosity (as is claimed to be the case for GSN 069). We discuss these findings within the context of various proposed QPE models.

Gamma-ray bursts (GRBs) are traditionally classified as either short GRBs with durations ≲2 s that are powered by compact object mergers or long GRBs with durations ≳2 s that are powered by the deaths of massive stars. Recent results, however, have challenged this dichotomy and suggest that there exists a population of merger-driven long bursts. One such example, GRB 191019A, has a t _90 ≈ 64 s, but many of its other properties—including its host galaxy, afterglow luminosity and lack of associated supernova—are more consistent with a short GRB. Here we propose an alternative interpretation: that GRB 191019A (which is located in the nucleus of its host) is an atypical jetted tidal disruption event (TDE). In particular, we suggest the short timescale and rapid decline, not expected for standard TDEs, are the result of an “ultradeep” encounter, in which the star came well within the tidal radius of the black hole and promptly self-intersected, circularized, accreted, and launched a relativistic outflow. This model reproduces the timescale and luminosity through a prompt super-Eddington accretion phase and accounts for the lack of late optical emission. This would make GRB 191019A only the fifth jetted TDE and the first discovered ultradeep TDE. The ultradeep TDE model can be distinguished from merger-driven long GRBs via the soft X-ray flash that results from prompt self-intersection of the debris stream; the detection of this flash will be possible with wide-field and soft-X-ray satellites such as Einstein Probe or SVOM.

The tidal disruption event (TDE) AT2018fyk showed a rapid dimming event 500 days after discovery, followed by a rebrightening roughly 700 days later. It has been hypothesized that this behavior results from a repeating partial TDE (rpTDE), such that prompt dimmings/shutoffs are coincident with the return of the star to pericenter and rebrightenings generated by the renewed supply of tidally stripped debris. This model predicted that the emission should shut off again around August of 2023. We report AT2018fyk’s continued X-ray and UV monitoring, which shows an X-ray (UV) drop-in flux by a factor of 10 (5) over a span of two months, starting 2023 August 14. This sudden change can be interpreted as the second emission shutoff, which (1) strengthens the rpTDE scenario for AT2018fyk, (2) allows us to constrain the orbital period to a more precise value of 1306 ± 47 days, and (3) establishes that X-ray and UV/optical emission track the fallback rate onto this supermassive black hole—an often-made assumption that otherwise lacks observational verification—and therefore, the UV/optical lightcurve is powered predominantly by processes tied to X-rays. The second cutoff implies that another rebrightening should happen between 2025 May and August, and if the star survived the second encounter, a third shutoff is predicted to occur between 2027 January and July. Finally, low-level accretion from the less-bound debris tail (which is completely unbound/does not contribute to accretion in a nonrepeating TDE) can result in a faint X-ray plateau that could be detectable until the next rebrightening.

Background: Iatrogenic injury of the parathyroid glands is the most frequent complication after total thyroidectomy. Objective: To determine the effectiveness of near-infrared autofluorescence (NIRAF) in reducing postoperative hypocalcemia following total thyroidectomy. Methods: PubMed, Scopus, and Google Scholar databases were searched. Randomised trials reporting at least one hypocalcemia outcome following total thyroidectomy using NIRAF were included. Results: The qualitative data synthesis comprised 1363 patients from nine randomised studies, NIRAF arm = 636 cases and non-NIRAF arm = 637 cases. There was a statistically significant difference in the overall rate of hypocalcemia log(OR) = −0.7 [(−1.01, −0.40), M-H, REM, CI = 95%] and temporary hypocalcemia log(OR) = −0.8 [(−1.01, −0.59), M-H, REM, CI = 95%] favouring the NIRAF. The difference in the rate of permanent hypocalcemia log(OR) = −1.09 [(−2.34, 0.17), M-H, REM, CI = 95%] between the two arms was lower in the NIRAF arm but was not statistically significant. Conclusions: NIRAF during total thyroidectomy helps in reducing postoperative hypocalcemia. Level of evidence—1.

We study the effects of general relativity (GR) on the evolution and alignment of circumbinary disks around binaries on all scales. We implement relativistic apsidal precession of the binary into the hydrodynamics code phantom . We find that the effects of GR can suppress the stable polar alignment of a circumbinary disk, depending on how the relativistic binary apsidal precession timescale compares to the disk nodal precession timescale. Studies of circumbinary disk evolution typically ignore the effects of GR, which is an appropriate simplification for low-mass or widely separated binary systems. In this case, polar alignment occurs, provided that the disks initial misalignment is sufficiently large. However, systems with a very short relativistic precession timescale cannot polar align and instead move toward coplanar alignment. In the intermediate regime where the timescales are similar, the outcome depends upon the properties of the disk. Polar alignment is more likely in the wavelike disk regime (where the disk viscosity parameter is less than the aspect ratio, α < H / r ), since the disk is in good radial communication. In the viscous disk regime, disk breaking is more likely. Multiple rings can destructively interact with one another, resulting in short disk lifetimes and the disk moving toward coplanar alignment. Around main-sequence star or stellar mass black hole binaries, polar alignment may be suppressed far from the binary, but in general, the inner parts of the disk can align to polar. Polar alignment may be completely suppressed for disks around supermassive black holes for close binary separations.

Some electromagnetic outbursts from the nuclei of distant galaxies have been found to repeat on months-to-years timescales, and each of these sources can putatively arise from the accretion flares generated through the repeated tidal stripping of a star on a bound orbit about a supermassive black hole (SMBH), i.e., a repeating partial tidal disruption event (rpTDE). Here, we test the rpTDE model through analytical estimates and hydrodynamical simulations of the interaction between a range of stars, which differ from one another in mass and age, and an SMBH. We show that higher-mass (≳1 M _⊙ ), evolved stars can survive many (≳10−100) encounters with an SMBH while simultaneously losing few × 0.01 M _⊙ , resulting in accretion flares that are approximately evenly spaced in time with nearly the same amplitude, quantitatively reproducing ASASSN-14ko. We also show that the energy imparted to the star via tides can lead to a change in its orbital period that is comparable to the observed decay in the recurrence time of ASASSN-14ko’s flares, $\dot{P}\simeq -0.0026$ . Contrarily, lower-mass and less-evolved stars lose progressively more mass and produce brighter accretion flares on subsequent encounters for the same pericenter distances, leading to the rapid destruction of the star and cessation of flares. Such systems cannot reproduce ASASSN-14ko-like transients, but are promising candidates for recreating events such as AT2020vdq, which displayed a second and much brighter outburst compared to the first. Our results imply that the lightcurves of repeating transients are tightly coupled with stellar type.

Human interaction is one of the most consistently effective interventions that can improve the welfare of shelter-living dogs. Time out of the kennel with a person has been shown to reduce physiological measures of stress as can leaving the shelter for a night or more in a foster home. In this study, we assessed the effects of brief outings and temporary fostering stays on dogs’ length of stay and outcomes. In total, we analyzed data of 1955 dogs from 51 animal shelters that received these interventions as well as 25,946 dogs residing at these shelters that served as our controls. We found that brief outings and temporary fostering stays increased dogs’ likelihood of adoption by 5.0 and 14.3 times, respectively. While their lengths of stay were longer in comparison to control dogs, this difference was present prior to the intervention. Additionally, we found that these programs were more successful when greater percentages of community members (as compared to volunteers and staff) were involved in caregiving as well as when programs were implemented by better-resourced shelters. As such, animal welfare organizations should consider implementing these fostering programs as evidence-based best practices that can positively impact the outcomes of shelter dogs.

The competitive dynamics of mitochondrial haplotypes juxtaposed within the same cell are poorly studied. Here the authors show, in the context of a transmissible cancer, that one haplotype has recurrently entered cancer cells by horizontal transfer and appears to have a ‘selfish’ selective advantage.

Objective This study aimed to measure the impact of COVID-19 on the quality of life (QoL) of survivors and their partners and family members.Design and setting A prospective cross-sectional global online survey using social media.Participants Patients with COVID-19 and partners or family members (age ≥18 years).Intervention Online survey from June to August 2020.Main outcome measure The EuroQol group five dimensions three level (EQ-5D-3L) to measure the QoL of survivors of COVID-19, and the Family Reported Outcome Measure (FROM-16) to assess the impact on their partner/family member’s QoL.Results The survey was completed by 735 COVID-19 survivors (mean age=48 years; females=563) at a mean of 12.8 weeks after diagnosis and by 571 partners and 164 family members (n=735; mean age=47 years; females=246) from Europe (50.6%), North America (38.5%) and rest of the world (10.9%). The EQ-5D mean score for COVID-19 survivors was 8.65 (SD=1.9, median=9; range=6–14). 81.1% (596/735) reported pain and discomfort, 79.5% (584/735) problems with usual activities, 68.7% (505/735) anxiety and depression and 56.2% (413/735) problems with mobility. Hospitalised survivors (20.1%, n=148) and survivors with existing health conditions (30.9%, n=227) reported significantly more problems with mobility and usual activities (p

Lightning fatality identification relies primarily on soft tissue traumatic pattern recognition, prohibiting cause of death identification in cases of full skeletonisation. This study explores the effects of high impulse currents on human bone, simulating lightning-level intensities and characterising electrically induced micro-trauma through conventional thin-section histology and micro-focus X-ray computed tomography (μXCT). An experimental system for high impulse current application was applied to bone extracted from donated cadaveric lower limbs (n = 22). μXCT was undertaken prior to and after current application. Histological sections were subsequently undertaken. μXCT poorly resolved micro-trauma compared to conventional histology which allowed for identification and classification of lightning-specific patterns of micro-trauma. Statistical analyses demonstrated correlation between current intensity, extent and damage typology suggesting a multifaceted mechanism of trauma propagation - a combination of electrically, thermally and pressure induced alterations. This study gives an overview of high impulse current trauma to human bone, providing expanded definitions of associated micro-trauma.

The naturally transformable cyanobacterium Synechocystis sp. PCC 6803 is a widely used chassis strain for the photosynthetic production of chemicals. However, Synechocystis possesses multiple genome copies per cell which means that segregating mutations across all genome copies can be time-consuming. Here we use flow cytometry in combination with DNA staining to investigate the effect of phosphate deprivation on the genome copy number of the glucose-tolerant GT-P sub-strain of Synechocystis 6803. Like the PCC 6803 wild type strain, the ploidy of GT-P cells grown in BG-11 medium is growth phase dependent with an average genome copy number of 6.05 ± 0.27 in early growth (OD740 = 0.1) decreasing to 2.49 ± 0.11 in late stationary phase (OD740 = 7). We show that a 10-fold reduction in the initial phosphate concentration of the BG-11 growth medium reduces the average genome copy number of GT-P cells from 4.51 ± 0.20 to 2.94 ± 0.13 and increases the proportion of monoploid cells from 0 to 6% after 7 days of growth. In addition, we also show that the DnaA protein, which unusually for bacteria is not required for DNA replication in Synechocystis, plays a role in restoring polyploidy upon subsequent phosphate supplementation. Based on these observations, we have developed an alternative natural transformation protocol involving phosphate depletion that decreases the time required to obtain fully segregated mutants.

The formation and recall of long-term memory (LTM) requires neuron activity-induced gene expression. Transcriptome analysis has been used to identify genes that have altered expression after memory acquisition, however, we still have an incomplete picture of the transcriptional changes that are required for LTM formation. The complex spatial and temporal dynamics of memory formation creates significant challenges in defining memory-relevant gene expression changes. The Drosophila mushroom body (MB) is a signaling hub in the insect brain that integrates sensory information to form memories across several different experimental memory paradigms. Here, we performed transcriptome analysis in the MB at two time points after the acquisition of LTM: 1 hr and 24 hr. The MB transcriptome was compared to biologically paired whole head (WH) transcriptomes. In both, we identified more transcript level changes at 1 hr after memory acquisition (WH = 322, MB = 302) than at 24 hr (WH = 23, MB = 20). WH samples showed downregulation of developmental genes and upregulation of sensory response genes. In contrast, MB samples showed vastly different changes in transcripts involved in biological processes that are specifically related to LTM. MB-downregulated genes were highly enriched for metabolic function. MB-upregulated genes were highly enriched for known learning and memory processes, including calcium-mediated neurotransmitter release and cAMP signaling. The neuron activity inducible genes Hr38 and sr were also specifically induced in the MB. These results highlight the importance of sampling time and cell type in capturing biologically relevant transcript level changes involved in learning and memory. Our data suggests that MB cells transiently upregulate known memory-related pathways after memory acquisition and provides a critical frame of reference for further investigation into the role of MB-specific gene regulation in memory.

Involved in various diseases, hyaluronic acid is an important indicator of pathophysiology. Here, the authors report on a solid-state nanopore for the detection of the molecular weight and abundance of hyaluronic acid and demonstrate the system by studying an equine model of osteoarthritis

Immunotherapy often fails as a single option treatment in cancer. Here, the authors show that targeting of DNA methyltransferases, such as DNMT1, can potentiate anti-tumor immunity and response to checkpoint inhibition by increasing MHC gene expression and the recruitment of CD8+ T cells.

Technology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders such as intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodelling complex is one of the most over-represented cellular components disrupted in ID. We investigated the role of individual subunits of this large protein complex using targeted RNA interference in post-mitotic memory-forming neurons of the Drosophila mushroom body (MB). Knockdown flies were tested for defects in MB morphology, short-term memory and long-term memory. Using this approach, we identified distinct roles for individual subunits of the Drosophila SWI/SNF complex. Bap60, Snr1 and E(y)3 are required for pruning of the MBγ neurons during pupal morphogenesis, while Brm and Osa are required for survival of MBγ axons during ageing. We used the courtship conditioning assay to test the effect of MB-specific SWI/SNF knockdown on short- and long-term memory. Several subunits, including Brm, Bap60, Snr1 and E(y)3, were required in the MB for both short- and long-term memory. In contrast, Osa knockdown only reduced long-term memory. Our results suggest that individual components of the SWI/SNF complex have different roles in the regulation of structural plasticity, survival and functionality of post-mitotic MB neurons. This study highlights the many possible processes that might be disrupted in SWI/SNF-related ID disorders. Our broad phenotypic characterization provides a starting point for understanding SWI/SNF-mediated gene regulatory mechanisms that are important for development and function of post-mitotic neurons.

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing health problem in the developing and developed world. In recent years, there have been major changes in the treatment paradigms for OPSCC. This is because of a number of reasons: the understanding and discovery of a new viral etiology (the human papillomavirus [HPV]), changes in practice patterns owing to advances in radiotherapy, and then an organ preservation strategy with the increased use of chemotherapy. Next came the development of new surgical technologies and the emergence of a new treatment modality, immunotherapy. In this article, we discuss the evolution of OPSCC treatments, starting with the traditional tobacco era. Treatment paradigms then evolved during the organ preservation era, the HPV era, and the minimally invasive surgery era. We are currently in the immunotherapy era, with a number of new drugs becoming available both on trial and by approval for use in the clinical setting for head and neck cancer patients. We discuss a number of trials and the reasons behind attempts at both treatment escalation and treatment de-escalation.

Abstract Background Greater transparency and, in particular, sharing of patient-level data for further scientific research is an increasingly important topic for the pharmaceutical industry and other organisations who sponsor and conduct clinical trials as well as generally in the interests of patients participating in studies. A concern remains, however, over how to appropriately prepare and share clinical trial data with third party researchers, whilst maintaining patient confidentiality. Clinical trial datasets contain very detailed information on each participant. Risk to patient privacy can be mitigated by data reduction techniques. However, retention of data utility is important in order to allow meaningful scientific research. In addition, for clinical trial data, an excessive application of such techniques may pose a public health risk if misleading results are produced. After considering existing guidance, this article makes recommendations with the aim of promoting an approach that balances data utility and privacy risk and is applicable across clinical trial data holders. Discussion Our key recommendations are as follows: 1. Data anonymisation/de-identification: Data holders are responsible for generating de-identified datasets which are intended to offer increased protection for patient privacy through masking or generalisation of direct and some indirect identifiers. 2. Controlled access to data, including use of a data sharing agreement: A legally binding data sharing agreement should be in place, including agreements not to download or further share data and not to attempt to seek to identify patients. Appropriate levels of security should be used for transferring data or providing access; one solution is use of a secure ‘locked box’ system which provides additional safeguards. Summary This article provides recommendations on best practices to de-identify/anonymise clinical trial data for sharing with third-party researchers, as well as controlled access to data and data sharing agreements. The recommendations are applicable to all clinical trial data holders. Further work will be needed to identify and evaluate competing possibilities as regulations, attitudes to risk and technologies evolve.