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With increasing facilities for antenatal diagnosis, lowering gestation for intiation of intensive care, palliative care in the perinatal period is increasingly recognized as a specialist area. There have been standards and pathways developed in the UK that provides guidance to health professionals. Providing holistic perinatal palliative care depends on close multiprofessional working between the neonatal team and the palliative care professionals who are being integrated into the core neonatal services. Even though most neonates will continue to receive end of life care within the NICU, there are increasing number of families who choose to have end of life care either at home or a hospice. There is a need to develop services across the regions to provide equitable access to excellent clinical care as well as ongoing support to families following loss of a neonate. This short article explores the issues raised in the provision of palliative care in the perinatal period and offers practical guidance for paediatricians in this emerging area.

Formalin fixed paraffin embedded tissue occasionally requires reprocessing if the histologic quality of a section is inadequate for clinical diagnosis. The Pat Dry (PD) and the Serial Xylene (SX) methods are two techniques described in the literature to reprocess under-fixed and/or under-processed tissue samples. To date, no study has compared the effects of these methods on the histologic quality of tissue sections, cost, and turnaround times. In the present study, these two methods were evaluated on 129 tissue samples taken from 40 submitted clinical specimens, 3 blocks per sampled location. Before processing, sample Group 1 (Control) was cut at routine 3-5 mm thickness. Sample Groups 2 and 3 were cut at 10 mm to ensure the thicker tissues would be poorly processed. Histotechnicians performed a subjective evaluation of all the samples at the time of embedding and microtomy. Hematoxylin and eosin stained sections from all samples were scored for histologic quality by two pathology residents. Thicker samples (Groups 2 and 3) were then reprocessed using either PD or SX methods, re-sectioned, stained, and then re-scored by the pathology residents. The two reprocessing methods equally improved quality scores and reduced the fraction of slides that were rejected. The PD method average preparation time was 66 minutes as compared to 250 minutes for the SX method. The PD method was easier to perform than the SX method, required less reagent, and was less susceptible to reagent spillage than the SX method.

The geomorphology and sediment systems of volcanic areas can be influenced by uplift (forced folding) related to subsurface migration and accumulation of magma. Seismic geomorphological analysis presents a unique tool to study how surface morphology and subsurface magma dynamics relate, given seismic reflection data can image buried landscapes and underlying intrusions in 3D at resolutions of only a few metres–decametres. However, differential compaction of the sedimentary sequence above incompressible igneous intrusions during burial modifies palaeosurface morphology. Here we use 3D seismic reflection data from offshore NW Australia to explore how the stratigraphic record of igneous intrusion and associated ground deformation can be unravelled. We focus on a forced fold that likely formed in the Early Cretaceous to accommodate intrusion of magma, but which was later amplified by burial-related differential compaction of the host sedimentary sequence. We show how: (1) marine channels and clinoforms may be deflected by syn-depositional intrusion-induced forced folds; and (2) differential compaction can locally change clinoforms depth post-deposition, potentially leading to erroneous interpretation of shoreline trajectories. Our results demonstrate seismic geomorphological analysis can help us better understand how magma emplacement translates into ground deformation, and how this shapes the landform of volcanic regions.

Groundwater-dominated catchments are often critical for nationally-important water resources. Many conceptual rainfall-runoff models used for the simulation of river flows tend to degrade in their model performance in groundwater-dominated catchments as they are rarely designed to simulate spatial groundwater behaviours or interactions with surface waters. Intercatchment groundwater flow is one such neglected variable. Efforts have been made to incorporate this process into existing models, but there is a need for greater emphasis on improving our perceptual models of groundwater-surface water interactions prior to any model edits.In this study, national meteorological, hydrological, hydrogeological, geological and artificial influence (characterising abstractions and return flows) datasets are used to develop a perceptual model of intercatchment groundwater flow and how it varies spatially and temporally across the River Thames. We characterise the water balance, presence of gaining/losing river reaches and intra-annual dynamics in 80 subcatchments of the River Thames in the UK, taking advantage of its wealth of data, densely gauged river network and geological variability.We show the prevalence of non-conservative river reaches across the study area, with heterogeneity both between, and within, geological units giving rise to a complex distribution of recharge and discharge points along the river network. We identify where non-conservative reaches can be attributed to intercatchment groundwater flow, and where other processes (e.g. human abstractions and discharge uncertainty) are likely the cause. Escarpments of Chalk and Jurassic Limestone show evidence of intercatchment groundwater flow both from headwater to downstream reaches, and out-of-catchment via springlines. We found temporal as well as spatial variability across the study area, with more seasonality and variability in river catchments on Jurassic Limestone outcrops and less on Chalk and Lower Greensand outcrops. Our results show the need for a degree of local investigation and hydrogeological perceptualisation within regional analysis, which we show to be achievable given relatively simple geological interpretation and data requirements. We then discuss the inclusion of external flow fluxes within existing models to enable calibration improvements in groundwater-dominated catchments, and, importantly, the characterisation of these fluxes given the temporal and spatial variability of intercatchment groundwater flow that our perceptual model has shown.

Understanding how normal faults grow is critical to an accurate assessment of seismic hazards, for successful exploration of natural (including low-carbon) resources and for safe subsurface carbon storage. Our current knowledge of fault growth is, in large parts, derived from seismic reflection data of continental rifts and margins. These seismic datasets do however suffer from limited data coverage and resolution. In addition, detailed fault mapping in increasingly large seismic reflection data requires a large amount of expertise and time from interpreters. Here we map faults across the entire northern North Sea rift using a combination of supervised deep learning and broadband 3-D seismic reflection data. This approach requires us to interpret 90%) are closely spaced (< 5 km) and relatively short (

Value of information (VoI) is a decision-theoretic approach to estimating the expected benefits from collecting further information of different kinds, in scientific problems based on combining one or more sources of data. VoI methods can assess the sensitivity of models to different sources of uncertainty and help to set priorities for further data collection. They have been widely applied in healthcare policy making, but the ideas are general to a range of evidence synthesis and decision problems. This article gives a broad overview of VoI methods, explaining the principles behind them, the range of problems that can be tackled with them, and how they can be implemented, and discusses the ongoing challenges in the area. Expected final online publication date for the Annual Review of Statistics, Volume 9 is March 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Supraventricular tachycardia are common dysrhythmias seen in hospitalized patients. Electrolyte derangements and cardiomyopathy are among the most common causes. Rarely, blood culture negative endocarditis can lead to unexplained recurrentsupraventricular tachycardia. Herein, we present a case of recurrent atrioventricular nodal reentrant tachycardia in a patient with no previous history of cardiovascular disease.

Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive therapeutic targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate Master Regulators (MRs), predicted to mechanistically regulate TI-Tregs transcriptional state. In vivo, pooled CRISPR-KO screening, using a hematopoietic stem cell transplant model, confirmed essentiality of 7 of 17 MRs in TI-Treg recruitment and/or retention to the TME, without affecting other T cell subtypes, while individual knockout of the most significant MR (TRPS1) significantly reduced tumor allograft growth. TI-Treg drug perturbation profile analysis identified drugs capable of inverting the TI-Treg-specific MR activity signature at low concentration. Low dose treatment with gemcitabine (top prediction) inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased PD-1 inhibitor efficacy, and depleted TI-Tregs in vivo. The study provides key insight into Treg infiltration mechanism and a gene reporter assay to identify additional small molecule inhibitors.Graphical Abstract

Mechanical stratigraphy controls the growth patterns and dimensions of relatively small normal faults, yet how it influences the development of much larger structures remains unclear. Here, we use 3D seismic reflection data from the Outer Kwanza Basin, offshore Angola to constrain the geometry and kinematics of several normal faults formed in a deep-water clastic succession. The faults are up to 6.3-km long and 1.9-km tall and have up to 44 m of throw. Aspect ratios and lower-tip throw gradients are greater for faults that terminate downward at a c. 100 m thick, mass-transport complex (MTC; up to 5.2 and 0.12) than for those that offset it (up to 2.7 and 0.01). Faults that offset the MTC invariably have >30 m of throw. Based on their geometric properties and throw patterns, we interpret that the faults nucleated above the MTC and propagated down toward it. Upon encountering this unit, which we infer behaved in a more ductile manner than encasing strata, tip propagation was halted until tip stresses were sufficiently high (corresponding to minimum throw of c. 30 m) to breach it. Faults with smaller throw were unable to breach the MTC. We argue that using only geometric criteria to determine fault growth patterns can mask the significant control mechanical stratigraphy has on fault kinematics. Mechanical stratigraphy is therefore a key control on the growth of large, seismic-scale normal faults, in a similar way to that observed for far smaller structures

Pre-rift salt controls structural style variability within rifts by decoupling sub- and supra-salt faults. However, the way in which this variability controls sediment erosion and dispersal, and facies distributions within the coeval syn-rift stratigraphic succession, remains poorly known. We here use 3D seismic reflection and borehole data to study the tectono-stratigraphic development of the Halten Terrace, offshore Mid-Norway, a salt-influenced rifted margin formed during Middle to Late Jurassic extension. On the eastern basin margin the rift structural style passes southwards from an unbreached extensional growth fold dissected by numerous horst and graben (Bremstein Fault Complex), into a single, through-going normal fault (Vingleia Fault Complex). This southwards change in structural style is likely related to the pinch-out of or a change in the dominant lithology (and thus rheology) within a pre-rift (Triassic) evaporite layer, which was thick and/or mobile enough in the north to decouple basement- and cover-involved faulting, and to permit extensional forced folding. As a result, the salt-influenced Bremstein Fault Complex underwent limited footwall uplift, with minor erosion of relatively small horsts supplying only limited volumes of sediment to the main downdip depocentre. In contrast, the Vingleia Fault Complex, which was directly coupled to basement, experienced significant uplift and extensive footwall erosion. The footwall of this structure also locally underwent salt-detached gravity gliding and collapse as the pre-rift detachment was tilted. Our results show that where through-going normal faults develop along the rift flanks, the presence of a pre-rift salt layer will suppress the topographic expression of the footwall. The pre-rift salt layer may however facilitate footwall collapse and limit the volume of sediment supplied to downdip basins. Our results also show that variable topography along the rift flanks facilitated the development of relatively small, localised, intra-rift flank accommodation that trapped flank-derived sediment, and which meant basins nearer the rift axis were starved of sediment.

The Santos Basin, offshore Brazil contains a complex set of salt-tectonic structures, the origins of which are debated, that is, the Albian Gap and the São Paulo Plateau (SPP). The Albian Gap is a ca. 450 km long, 60 km wide feature characterized by a post-Albian, counter-regional rollover overlying depleted Aptian salt, and in which the Albian is largely absent. The SPP, located immediately downdip, is defined by a pre-salt structural high overlain by ca. 2.5 km thick salt. Another prominent feature is the Merluza Graben, a rift-related depocentre that underlies the southern portion of the Albian Gap and displays significant (3–4 km) base-salt relief along its main faults. Two competing hypotheses have been proposed to explain the kinematics of these provinces. One invokes post-Albian extension in the Albian Gap and kinematically-linked contraction in the SPP. The other invokes post-Albian salt expulsion in the Albian Gap and salt inflation in the SPP. Recent studies, however, suggest these processes likely alternate in time and space, contributing nearly equally to the evolution of these domains. We apply 3D physical modelling to (i) test this hypothesis; and (ii) to more generally understand how gravity gliding and spreading over three-dimensionally variable base-salt relief control regional salt tectonics. The results show a similar salt-related evolution and structural styles to those proposed in the most recent studies. They also (i) explain the origin of the ca. 25 km wide diapir precursor of the Albian Gap by early salt inflation against base-salt steps; (ii) show that normal faults with different polarities and rollover types form due to the interplay between gliding and spreading over different base-salt domains and (iii) provide a mechanism for the origin of strata encased within salt structures. This improves our understanding of the distribution and origin of salt-related structural styles in worldwide salt basins. publishedVersion

COVID-19 caused significant disruption to cancer services around the world. The health system in Aotearoa New Zealand has fared better than many other regions, with the country being successful, so far, in avoiding sustained community transmission. However, there was a significant initial disruption to services across the cancer continuum, resulting in a decrease in the number of new diagnoses of cancer in March and April 2020. Te Aho o Te Kahu, Aotearoa New Zealand's national Cancer Control Agency, coordinated a nationwide response to minimise the impact of COVID-19 on people with cancer. The response, outlined in this paper, included rapid clinical governance, a strong equity focus, development of national clinical guidance, utilising new ways of delivering care, identifying and addressing systems issues and close monitoring and reporting of the impact on cancer services. Diagnostic procedures and new cancer registrations increased in the months following the national lockdown, and the cumulative number of cancer registrations in 2020 surpassed the number of registrations in 2019 by the end of September. Cancer treatment services – surgery, medical oncology, radiation oncology and haematology – continued during the national COVID-19 lockdown in March and April 2020 and continued to be delivered at pre-COVID-19 volumes in the months since. We are cautiously optimistic that, in general, the COVID-19 pandemic does not appear to have increased inequities in cancer diagnosis and treatment for Māori in Aotearoa New Zealand.

Background: \ud The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes.\ud \ud Methods: \ud This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status.\ud \ud Findings: \ud Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low.\ud \ud Interpretation: \ud This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

We, the undersigned, write on behalf of a growing number of concerned academics who are dismayed at the recent decision by the Australian Research Council (ARC) to rule a number of grant applications across two hallmark schemes ineligible due to references to preprints. Since preprints play a crucial role in the making and dissemination of new knowledge, we are writing to ask the ARC to reconsider their decision. In short, we call on the ARC to ensure the long-term integrity of the grant system through a range of measures.

Malignant melanotic nerve sheath tumor (MMNST) is an exceedingly rare and aggressive neoplasm of Schwann cell origin that has seldom been described in the cytopathology literature. Herein we present a case of a 60-year-old female with a 3.8 cm presacral mass that was diagnosed as a MMNST. A molecular workup demonstrated TERT promoter -124C > T and TET2 Q891* gene mutations. Within 2 years of her initial diagnosis, she had developed widespread metastasis and pleural effusions. A cytologic workup of the pleural fluid revealed clusters of vacuolated epithelioid cells with enlarged nuclei, prominent nucleoli, and occasional multinucleation. The lesional cells were positive for SOX10, S100-protein, Melan-A, and HMB45, while negative for Calretinin, MOC31, and monoclonal CEA. In this clinicopathologic context, a diagnosis of metastatic MMNST was rendered. Awareness of this entity and its clinical presentation, along with a critical understanding of its molecular findings and that of imitators, is crucial in achieving an accurate diagnosis.

BackgroundUnderstanding the risk factors associated with hospital burden of COVID-19 is crucial for healthcare planning for any future waves of infection.MethodsAn observational cohort study is performed, using data on all PCR-confirmed cases of COVID-19 in Regione Lombardia, Italy, during the first wave of infection from February-June 2020. A multi-state modelling approach is used to simultaneously estimate risks of progression through hospital to final outcomes of either death or discharge, by pathway (via critical care or not) and the times to final events (lengths of stay). Logistic and time-to-event regressions are used to quantify the association of patient and population characteristics with the risks of hospital outcomes and lengths of stay respectively.ResultsRisks of severe outcomes such as ICU admission and mortality have decreased with month of admission (for example, the odds ratio of ICU admission in June vs March is 0.247 [0.120–0.508]) and increased with age (odds ratio of ICU admission in 45–65 vs 65 + age group is 0.286 [0.201–0.406]). Care home residents aged 65 + are associated with increased risk of hospital mortality and decreased risk of ICU admission. Being a healthcare worker appears to have a protective association with mortality risk (odds ratio of ICU mortality is 0.254 [0.143–0.453] relative to non-healthcare workers) and length of stay. Lengths of stay decrease with month of admission for survivors, but do not appear to vary with month for non-survivors.ConclusionsImprovements in clinical knowledge, treatment, patient and hospital management and public health surveillance, together with the waning of the first wave after the first lockdown, are hypothesised to have contributed to the reduced risks and lengths of stay over time.

The Santos Basin presents a complex and controversial evolution and distribution of salt tectonics domains. The controversies revolve mainly around the kinematically- linked Albian Gap and São Paulo Plateau. The Albian Gap is a ~450 km long and 60 km wide feature characterized by a post-Albian counter-regional rollover overlying depleted Aptian salt and in which the Albian is absent. The São Paulo Plateau is defined by a pre-salt structural high with significant base-salt topography and overlain by ~2.5 km thick salt. Another prominent feature is the Merluza Graben, a rift depocentre that underlies the southern portion of the Albian Gap and displays significant (3-4 km) of base-salt relief. Two competing hypotheses have been proposed to explain the origin and kinematics of these provinces. One invokes post- Albian extension within the Albian Gap and contraction in the Sao Paulo Plateau. The other invokes post-Albian salt expulsion in the Albian Gap and salt inflation in the São Paulo Plateau without significant lateral deformation. A recent study shows these processes contribute equally to the evolution of these domains, also demonstrating the importance of the previously neglected base-salt relief. We apply 3D physical modelling to test these new concepts and understand the interplay between laterally- variable base-salt relief, gliding and spreading on salt tectonics. Our results show a remarkably-similar salt and post-salt evolution and architecture to the Santos Basin as proposed in recent studies. They improve the understanding on the distribution and interaction of salt-related structural styles and gravity-driven processes, being also applicable to other salt-bearing margins.

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated "risk of bias" tool to assess study quality. Four separate Phase I-II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5-34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I-III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.

O6-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O6-position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide, providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches that could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing. Temozolomide, unlike other alkylators, activated the ataxia telangiectasia and Rad3–related (ATR)–checkpoint kinase 1 (Chk1) axis in a manner that was highly dependent on MGMT status. Temozolomide induced growth delay, DNA double-strand breaks, and G2–M cell-cycle arrest, which led to ATR-dependent phosphorylation of Chk1; this effect was dependent on reduced MGMT expression. Treatment of MGMT-deficient cells with temozolomide increased sensitivity to ATR inhibitors both in vitro and in vivo across numerous tumor cell types. Taken together, this study reveals a novel approach for selectively targeting MGMT-deficient cells with ATR inhibitors and temozolomide. As ATR inhibitors are currently being tested in clinical trials, and temozolomide is a commonly used chemotherapeutic, this approach is clinically actionable. Furthermore, this interaction potently exploits a DNA-repair defect found in many cancers. Significance: Monofunctional alkylating agents sensitize MGMT-deficient tumor cells to ATR inhibitors.

Breast cancer can be diagnosed during pregnancy and in the peri-partum period, and the potential exposure of a foetus or neonate to chemotherapy is of concern to mothers and clinicians. Paclitaxel is a commonly used agent in breast cancer, but little is known about its excretion in breast milk. Breastfeeding during chemotherapy has been traditionally cautioned against due to the risk of neonatal exposure to chemotherapy agents, however, data are limited. We measured serum and breast milk concentrations of paclitaxel in a 33-year-old woman with an early breast cancer diagnosed during pregnancy and treated with weekly paclitaxel 80 mg/m2. We found breast milk paclitaxel levels drop below the minimum quantifiable dose at 72 h following chemotherapy, with a relative infant dose of 0.091%. Breast milk excretion of paclitaxel following a dose of 80 mg/m2 is negligible at 72 h, and this may be a safe time to recommence breastfeeding following exposure.

Infrared scene projectors based on superlattice light emitting diodes (SLEDs) have evolved rapidly over the past decade. Much of this development has been enabled by the design of a flexible support system for driving the SLEDs. This paper describes the system and its benefits.

The close support electronics driving the SLEDs IRSP systems must evolve to match increased resolution and frame-rate demands. This paper describes the design and implementation of the next generation NESSIE2 CSE. Design considerations for a more robust third generation NESSIE3 distributed FPGA CSE are discussed.

SARS-CoV-2 is notable both for its rapid spread, and for the heterogeneity of its patterns of transmission, with multiple published incidences of superspreading behaviour. Here, we applied a novel network reconstruction algorithm to infer patterns of viral transmission occurring between patients and health care workers (HCWs) in the largest clusters of COVID-19 infection identified during the first wave of the epidemic at Cambridge University Hospitals NHS Foundation Trust, UK. Based upon dates of individuals reporting symptoms, recorded individual locations, and viral genome sequence data, we show an uneven pattern of transmission between individuals, with patients being much more likely to be infected by other patients than by HCWs. Further, the data were consistent with a pattern of superspreading, whereby 21% of individuals caused 80% of transmission events. Our study provides a detailed retrospective analysis of nosocomial SARS-CoV-2 transmission, and sheds light on the need for intensive and pervasive infection control procedures., eLife digest The COVID-19 pandemic, caused by the SARS-CoV-2 virus, presents a global public health challenge. Hospitals have been at the forefront of this battle, treating large numbers of sick patients over several waves of infection. Finding ways to manage the spread of the virus in hospitals is key to protecting vulnerable patients and workers, while keeping hospitals running, but to generate effective infection control, researchers must understand how SARS-CoV-2 spreads. A range of factors make studying the transmission of SARS-CoV-2 in hospitals tricky. For instance, some people do not present any symptoms, and, amongst those who do, it can be difficult to determine whether they caught the virus in the hospital or somewhere else. However, comparing the genetic information of the SARS-CoV-2 virus from different people in a hospital could allow scientists to understand how it spreads. Samples of the genetic material of SARS-CoV-2 can be obtained by swabbing infected individuals. If the genetic sequences of two samples are very different, it is unlikely that the individuals who provided the samples transmitted the virus to one another. Illingworth, Hamilton et al. used this information, along with other data about how SARS-CoV-2 is transmitted, to develop an algorithm that can determine how the virus spreads from person to person in different hospital wards. To build their algorithm, Illingworth, Hamilton et al. collected SARS-CoV-2 genetic data from patients and staff in a hospital, and combined it with information about how SARS-CoV-2 spreads and how these people moved in the hospital . The algorithm showed that, for the most part, patients were infected by other patients (20 out of 22 cases), while staff were infected equally by patients and staff. By further probing these data, Illingworth, Hamilton et al. revealed that 80% of hospital-acquired infections were caused by a group of just 21% of individuals in the study, identifying a ‘superspreader’ pattern. These findings may help to inform SARS-CoV-2 infection control measures to reduce spread within hospitals, and could potentially be used to improve infection control in other contexts.

With recent improvements to the 1Kx1K Infrared LED Scene Projector (IRSP) system, Chip Design Systems (CDS) and the University of Delaware (UDel) are in the process of transitioning this technology from research and development (R&D) to production level. (Abstract))

Many decisions in health care aim to maximise health, requiring judgements about interventions that may have higher health effects but potentially incur additional costs (cost-effectiveness framework). The evidence used to establish cost-effectiveness is typically uncertain and it is important that this uncertainty is characterised. In situations in which evidence is uncertain, the experience of experts is essential. The process by which the beliefs of experts can be formally collected in a quantitative manner is structured expert elicitation. There is heterogeneity in the existing methodology used in health-care decision-making. A number of guidelines are available for structured expert elicitation; however, it is not clear if any of these are appropriate for health-care decision-making.The overall aim was to establish a protocol for structured expert elicitation to inform health-care decision-making. The objectives are to (1) provide clarity on methods for collecting and using experts' judgements, (2) consider when alternative methodology may be required in particular contexts, (3) establish preferred approaches for elicitation on a range of parameters, (4) determine which elicitation methods allow experts to express uncertainty and (5) determine the usefulness of the reference protocol developed.A mixed-methods approach was used: systemic review, targeted searches, experimental work and narrative synthesis. A review of the existing guidelines for structured expert elicitation was conducted. This identified the approaches used in existing guidelines (the 'choices') and determined if dominant approaches exist. Targeted review searches were conducted for selection of experts, level of elicitation, fitting and aggregation, assessing accuracy of judgements and heuristics and biases. To sift through the available choices, a set of principles that underpin the use of structured expert elicitation in health-care decision-making was defined using evidence generated from the targeted searches, quantities to elicit experimental evidence and consideration of constraints in health-care decision-making. These principles, including fitness for purpose and reflecting individual expert uncertainty, were applied to the set of choices to establish a reference protocol. An applied evaluation of the developed reference protocol was also undertaken.For many elements of structured expert elicitation, there was a lack of consistency across the existing guidelines. In almost all choices, there was a lack of empirical evidence supporting recommendations, and in some circumstances the principles are unable to provide sufficient justification for discounting particular choices. It is possible to define reference methods for health technology assessment. These include a focus on gathering experts with substantive skills, eliciting observable quantities and individual elicitation of beliefs. Additional considerations are required for decision-makers outside health technology assessment, for example at a local level, or for early technologies. Access to experts may be limited and in some circumstances group discussion may be needed to generate a distribution.The major limitation of the work conducted here lies not in the methods employed in the current work but in the evidence available from the wider literature relating to how appropriate particular methodological choices are.The reference protocol is flexible in many choices. This may be a useful characteristic, as it is possible to apply this reference protocol across different settings. Further applied studies, which use the choices specified in this reference protocol, are required.This project was funded by the NIHR Health Technology Assessment programme and will be published in full inDecisions in health care aim to maximise health, requiring judgements about treatments. The evidence used to make these judgements is typically uncertain. In these situations, the experience of experts is essential. Structured expert elicitation collects beliefs from experts. There are different guidelines available for structured expert elicitation; however, it is not clear if any of these be can be used in health-care decision-making, for example in considering if a treatment should be made available in the NHS. This project aimed to develop a guidance for structured expert elicitation to inform health-care decision-making.Reviews and experimental techniques were used to gather a list of methods to conduct structured expert elicitation. The suitability of these choices in health-care decision-making was then determined by comparing these with a set of standards that support the use of structured expert elicitation in health-care decision-making.Different guidelines prefer different approaches to conduct structured expert elicitation. There is a lack of evidence available to determine which of these methods is most appropriate across the whole of health-care decision-making. It is possible to define reference protocol methods that could be used in a particular type of health-care decision-making, health technology assessment. This includes gathering experts with knowledge of the clinical area, asking experts about things that they observe in clinical practice and asking experts individually for their beliefs. For decision-makers working outside health technology assessment, for example at a local level, or for treatments that are not yet available to patients, these choices may not be appropriate.This flexibility of this guidance is a useful feature. It is possible for different decision-makers in health care to interpret the reference protocol for their own circumstances.

Objective We evaluated the safety of baricitinib 4 mg at 24 weeks for the treatment of moderate to severe rheumatoid arthritis (RA). Methods Multiple databases were searched from inception up to November 26, 2019 for randomized controlled trials comparing baricitinib 4 mg with placebo for the treatment of moderate to severe RA. The safety outcomes of interest were the incidence of serious adverse events, adverse events leading to study discontinuation, all infections, and serious infections. Adjusted risk ratios (RRs) with 95% confidence intervals (CIs) were pooled for safety outcomes. The Cochrane tool was used to assess the risk of bias. Results This analysis included four randomized controlled trials with 3106 patients. For serious adverse events, the pooled RR (95% CI) was 1.09 (0.76-1.57). For adverse events leading to study discontinuation, the pooled RR (95% CI) was 1.41 (0.94-2.11). For all reported infections, the pooled RR (95% CI) was 1.24 (1.10-1.40), For serious infections, pooled RR (95% CI) was 0.97 (0.51-2.57). Conclusions Patients with RA taking 4 mg baricitinib daily did have an increased risk of infections; however, the incidence of serious adverse events, adverse events leading to study discontinuation, or serious infections were not significantly different in patients treated with baricitinib 4 mg compared with placebo.

The expected value of partial perfect information (EVPPI) provides an upper bound on the value of collecting further evidence on a set of inputs to a cost-effectiveness decision model. Standard Monte Carlo (MC) estimation of EVPPI is computationally expensive as it requires nested simulation. Alternatives based on regression approximations to the model have been developed, but are not practicable when the number of uncertain parameters of interest is large and when parameter estimates are highly correlated. The error associated with the regression approximation is difficult to determine, while MC allows the bias and precision to be controlled. In this paper, we explore the potential of Quasi Monte-Carlo (QMC) and Multilevel Monte-Carlo (MLMC) estimation to reduce computational cost of estimating EVPPI by reducing the variance compared with MC, while preserving accuracy. In this paper, we develop methods to apply QMC and MLMC to EVPPI, addressing particular challenges that arise where Markov Chain Monte Carlo (MCMC) has been used to estimate input parameter distributions. We illustrate the methods using a two examples: a simplified decision tree model for treatments for depression, and a complex Markov model for treatments to prevent stroke in atrial fibrillation, both of which use MCMC inputs. We compare the performance of QMC and MLMC with MC and the approximation techniques of Generalised Additive Model regression (GAM), Gaussian process regression (GP), and Integrated Nested Laplace Approximations (INLA-GP). We found QMC and MLMC to offer substantial computational savings when parameter sets are large and correlated, and when the EVPPI is large. We also find GP and INLA-GP to be biased in those situations, while GAM cannot estimate EVPPI for large parameter sets.

Evolutionary models and empirical evidence suggest that outgroup threat is one of the strongest factors inducing group cohesion; however, little is known about the process of forming such cohesive groups. We investigated how outgroup threat galvanizes individuals to affiliate with others to form engaged units that are willing to act on behalf of their in-group. A total of 864 participants from six countries were randomly assigned to an outgroup threat, environmental threat, or no-threat condition. We measured the process of group formation through physical proximity and movement mirroring along with activity toward threat resolution, and found that outgroup threat induced activity and heightened mirroring in males. We also observed higher mirroring and proximity in participants who perceived the outgroup threat as a real danger, albeit the latter results were imprecisely estimated. Together, these findings help understand how sharing subtle behavioral cues influences collaborative aggregation of people under threat.

Background DNA damage resistance is a major barrier to effective DNA-damaging anticancer therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense therapy targeting ILF2, an important DNA damage regulator in 1q21 MM. Method We continuously treated MM cells with an ILF2-targeting antisense (ILF2-ASO) or control non-targeting antisense (NT-ASO) for 3 weeks to see if ILF2-ASO exposure leads to the selection of MM clones intrinsically resistant to DNA damage or activates compensatory mechanisms to overcome ILF2 depletion-induced DNA damage. Results Single-cell RNA sequencing (scRNA-seq) analysis revealed that DNA damage-resistant ILF2-ASO-treated cells had significantly upregulated oxidative phosphorylation (OXPHOS), DNA repair signaling, and reactive oxidative species (ROS). Metabolomic analysis of MM cells after long-term exposure to ILF2-ASO showed a significant enrichment of tricarboxylic acid cycle (TCA) intermediates. Consistent with these results, ILF2-ASO-resistant MM cells were significantly more sensitive to the OXPHOS inhibitor IACS-010759 than ILF2-ASO-sensitive cells were. These data suggest that MM cells can undergo an adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage. We then hypothesized that ILF2-ASO-resistant cells’ metabolic reprogramming relies on the repair of DNA damage induced by ILF2 depletion or by the generation of ROS from activated mitochondrial metabolism and that targeting DNA repair proteins involved in these processes overcomes DNA damage resistance. We used a CRISPR/Cas9 screening strategy to identify DNA repair genes whose loss of function suppresses MM cells’ ability to overcome ILF2-ASO-induced DNA damage. Compared with those in NT-ASO-treated cells, DNA2-targeting sgRNAs in ILF2-ASO-treated JJN3 cells were significantly depleted after 3 weeks of treatment, suggesting that DNA2 is needed to promote resistance to ILF2 depletion. Accordingly, the DNA2 inhibitor NSC105808 (NSC) significantly enhanced ILF2-ASO-induced apoptosis. To dissect the mechanisms of DNA2 inhibition-induced synthetic lethality, we evaluated whether DNA2 activity is essential to maintain activated OXPHOS, which ILF2-ASO-resistant cells require to survive. The quantification of mitochondrial respiratory activity in NT-ASO- and ILF2-ASO-treated MM cells exposed to NSC for 3 days showed that DNA2 activity inhibition significantly decreased the oxygen consumption rate while increasing ROS production in only ILF2-depleted cells. Transmission electron microscopy analysis showed that NSC-treated ILF2-depleted cells had fragmented mitochondrial cristae structures, whose perturbations affect the OXPHOS system structure and impair cell metabolism. Conclusion In conclusion, our study has revealed a novel mechanism through which MM cells counteract oxidative DNA damage and maintain mitochondrial respiration after metabolic reprogramming.

SARS-CoV-2 is notable both for its rapid spread, and for the heterogeneity of its patterns of transmission, with multiple published incidences of superspreading behaviour. Here, we applied a novel network reconstruction algorithm to infer patterns of viral transmission occurring between patients and health care workers (HCWs) in the largest clusters of COVID-19 infection identified during the first wave of the epidemic at Cambridge University Hospitals NHS Foundation Trust, UK. Based upon dates of individuals reporting symptoms, recorded individual locations, and viral genome sequence data, we show an uneven pattern of transmission between individuals, with patients being much more likely to be infected by other patients than by HCWs. Further, the data were consistent with a pattern of superspreading, whereby 21% of individuals caused 80% of transmission events. Our study provides a detailed retrospective analysis of nosocomial SARS-CoV-2 transmission, and sheds light on the need for intensive and pervasive infection control procedures.