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Background Long COVID (LC) is a novel multisystem clinical syndrome affecting millions of individuals worldwide. The modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) is a condition-specific patient-reported outcome measure designed for assessment and monitoring of people with LC.Objectives To evaluate the psychometric properties of the C19-YRSm in a prospective sample of people with LC.Methods 1314 patients attending 10 UK specialist LC clinics completed C19-YRSm and EuroQol 5D-5L (EQ-5D-5L) longitudinally. Scale characteristics were derived for C19-YRSm subscales (Symptom Severity (SS), Functional Disability (FD) and Overall Health (OH)) and internal consistency (Cronbach’s alpha). Convergent validity was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)—Fatigue Scale. Known groups validity was assessed for the Other Symptoms subscale as tertiles, as well as by hospitalisation and intensive care admission. Responsiveness and test–retest reliability was evaluated for C19-YRSm subscales and EQ-5D-5L. The minimal important difference (MID) and minimal clinically important difference (MCID) were estimated. Confirmatory factor analysis was applied to determine the instrument’s two-factor structure.Results C19-YRSm demonstrated good scale characteristic properties. Item-total correlations were between 0.37 and 0.65 (for SS and FD), with good internal reliability (Cronbach’s alphas>0.8). Item correlations between subscales ranged between 0.46 and 0.72. Convergent validity with FACIT was good (−0.46 to −0.62). The three subscales discriminated between different levels of symptom burden (p

Abstract Global disease registries are critical to capturing common patient related information on rare illnesses, allowing patients and their families to provide information about their condition in a safe, accessible, and engaging manner that enables researchers to undertake critical research aimed at improving outcomes. Typically, English is the default language of choice for these global digital health platforms. Unfortunately, language barriers can significantly inhibit participation from non-English speaking participants. In addition, there is potential for compromises in data quality and completeness. In contrast, multinational commercial entities provide access to their websites in the local language of the country they are operating in, and often provide multiple options reflecting ethnic diversity. This paper presents a case study of how the Global Angelman Syndrome Registry (GASR) has used a novel approach to enable multiple language translations for its website. Using a “semi-automated language translation” approach, the GASR, which was originally launched in English in September 2016, is now available in several other languages. In 2020, the GASR adopted a novel approach using crowd-sourcing and machine translation tools leading to the availability of the GASR in Spanish, Traditional Chinese, Italian, and Hindi. As a result, enrolments increased by 124% percent for Spain, 67% percent for Latin America, 46% percent for Asia, 24% for Italy, and 43% for India. We describe our approach here, which we believe presents an opportunity for cost-effective and timely translations responsive to changes to the registry and helps build and maintain engagement with global disease communities.

Nucleic acid-based gene interference and editing strategies, such as antisense oligonucleotides, ribozymes, RNA interference (RNAi), and CRISPR/Cas9 coupled with guide RNAs, are exciting research tools and show great promise for clinical applications in treating various illnesses. RNase P ribozymes have been engineered for therapeutic applications against human viruses such as human cytomegalovirus (HCMV). M1 ribozyme, the catalytic RNA subunit of RNase P from Escherichia coli, can be converted into a sequence-specific endonuclease, M1GS ribozyme, which is capable of hydrolyzing an mRNA target base-pairing with the guide sequence. M1GS RNAs have been shown to hydrolyze essential HCMV mRNAs and block viral progeny production in virus-infected cell cultures. Furthermore, RNase P ribozyme variants with enhanced hydrolyzing activity can be generated by employing in vitro selection procedures and exhibit better ability in suppressing HCMV gene expression and replication in cultured cells. Additional studies have also examined the antiviral activity of RNase P ribozymes in mice in vivo. Using cytomegalovirus infection as an example, this review summarizes the principles underlying RNase P ribozyme-mediated gene inactivation, presents recent progress in engineering RNase P ribozymes for applications in vitro and in mice, and discusses the prospects of using M1GS technology for therapeutic applications against HCMV as well as other pathogenic viruses.

Abstract Background Colorectal cancer (CRC) is a heterogeneous disease, with subtypes that have different clinical behaviours and subsequent prognoses. There is a growing body of evidence suggesting that right-sided colorectal cancer (RCC) and left-sided colorectal cancer (LCC) also differ in treatment success and patient outcomes. Biomarkers that differentiate between RCC and LCC are not well-established. Here, we apply random forest (RF) machine learning methods to identify genomic or microbial biomarkers that differentiate RCC and LCC. Methods RNA-seq expression data for 58,677 coding and non-coding human genes and count data for 28,557 human unmapped reads were obtained from 308 patient CRC tumour samples. We created three RF models for datasets of human genes-only, microbes-only, and genes-and-microbes combined. We used a permutation test to identify features of significant importance. Finally, we used differential expression (DE) and paired Wilcoxon-rank sum tests to associate features with a particular side. Results RF model accuracy scores were 90%, 70%, and 87% with area under curve (AUC) of 0.9, 0.76, and 0.89 for the human genomic, microbial, and combined feature sets, respectively. 15 features were identified as significant in the model of genes-only, 54 microbes in the model of microbes-only, and 28 genes and 18 microbes in the model with genes-and-microbes combined. PRAC1 expression was the most important feature for differentiating RCC and LCC in the genes-only model, with HOXB13, SPAG16, HOXC4, and RNLS also playing a role. Ruminococcus gnavus and Clostridium acetireducens were the most important in the microbial-only model. MYOM3, HOXC4, Coprococcus eutactus, PRAC1, lncRNA AC012531.25, Ruminococcus gnavus, RNLS, HOXC6, SPAG16 and Fusobacterium nucleatum were most important in the combined model. Conclusions Many of the identified genes and microbes among all models have previously established associations with CRC. However, the ability of RF models to account for inter-feature relationships within the underlying decision trees may yield a more sensitive and biologically interconnected set of genomic and microbial biomarkers.

Background Proximal radial artery (pRA) access for cardiac catheterization is safe but can jeopardize subsequent use of the artery because of occlusion. Distal radial artery (dRA) access in the anatomical snuffbox preserves the radial artery, but safety and potential detrimental effects on hand function are unknown. Methods and Results In the DIPRA (Distal Versus Proximal Radial Artery Access for Cardiac Catheterization and Intervention) study, a single‐center trial, 300 patients were randomized 1:1 to cardiac catheterization through dRA or pRA. The primary end point of change in hand function from baseline to 30 days was a composite of the QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) questionnaire, hand‐grip test, and thumb forefinger pinch test. Secondary end points included access feasibility and complications; 254 of 300 patients completed follow‐up at 30 days; of these, 128 were randomized to dRA and 126 to pRA with balanced demographic and procedural characteristics. Both groups had similar rates of access site bleeding (dRA 0% versus pRA 1.4%; P=0.25). Six patients with dRA failed access compared with 2 patients with pRA. Radial artery occlusion occurred in 2 pRA versus none in dRA. There were no significant differences in change in hand function, median hand‐grip (dRA 0 [−3.2, 3.3] versus pRA 0.7 [−2.3, 3.3] kg; P=0.21), pinch‐grip (dRA −0.3 [−1.2, 0.5] versus pRA 0 [−0.9, 0.9] kg; P=0.09), and QuickDASH (dRA 0 [−4.6, 2.3] versus pRA 0 [−4.6, 2.3] points, P=0.96). There was no significant difference in the composite of hand function between pRA and dRA. Conclusions dRA is a safe strategy for cardiac catheterization with a low complication rate. Compared with pRA, there is no increased risk of hand dysfunction at 30 days. Registration URL: https://www.ClinicalTrials.gov. Unique identifier: NCT04318990.

Purpose/Objective: Magnetic resonance-guided radiation therapy (MRgRT) utilization is rapidly expanding worldwide, driven by advanced capabilities including continuous intrafraction visualization, automatic triggered beam delivery, and on-table adaptive replanning (oART). Our objective was to describe patterns of 0.35Tesla(T)-MRgRT (MRIdian) utilization in the United States (US) among early adopters of this novel technology. Materials/Methods: Anonymized administrative data from all US MRIdian treatment systems were extracted for patients completing treatment from 2014 to 2020. Detailed treatment information was available for all MRIdian linear accelerator (linac) systems and some cobalt systems. Results: Seventeen systems at 16 centers delivered 5736 courses and 36,389 fractions (fraction details unavailable for 1223 cobalt courses), of which 21.1% were adapted. Ultra-hypofractionation (UHfx) (1–5 fractions) was used in 70.3% of all courses. At least one adaptive fraction was used for 38.5% of courses (average 1.7 adapted fractions/course), with higher oART use in UHfx dose schedules (47.7% of courses, average 1.9 adapted fractions per course). The most commonly treated organ sites were pancreas (20.7%), liver (16.5%), prostate (12.5%), breast (11.5%), and lung (9.4%). Temporal trends show a compounded annual growth rate (CAGR) of 59.6% in treatment courses delivered, with a dramatic increase in use of UHfx to 84.9% of courses in 2020 and similar increase in use of oART to 51.0% of courses. Conclusions: This is the first comprehensive study reporting patterns of utilization among early adopters of MRIdian in the US. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of adaptive radiation therapy has led to a substantial transition to ultra-hypofractionated regimens. 0.35 T-MRgRT has been predominantly used to treat abdominal and pelvic tumors with increasing use of on-table adaptive replanning, which represents a paradigm shift in radiation therapy.

AbstractThis is a case of a 23-year-old female who presented to the emergency department (ED) comatose after ingesting 7.8 g of propafenone and 11.7 g of valsartan. Upon arrival to the ED, the patient had seizures and required intubation. Several boluses of sodium bicarbonate were given as well as a continuous infusion to normalize QRS intervals. Norepinephrine and intravenous lipid emulsion (ILE) therapy were initiated. In the intensive care unit (ICU), the patient experienced persistent seizures and a 5-minute period of pulseless ventricular tachycardia. Subsequently, hyperinsulinemic-euglycemic therapy (HIET) was initiated. The patient received a 1 unit/kg intravenous bolus of regular insulin followed by a continuous infusion starting at 1 unit/kg/hr. Norepinephrine infusion was weaned off after 27 h of HIET. Within 48 h of presentation, the patient was transferred out of the ICU. This case exhibits the successful management of a mixed overdose with propafenone and valsartan utilizing a multimodal approach. In addition to supportive care, the patient received sodium bicarbonate, HIET, ILE and vasopressors to manage the cardiovascular collapse associated with these toxicities.

The US drone strike programme has prompted debate between pro- and anti-drone lawyers over interpretations of self-defence and the laws of war. The debate frequently neglects the effects of drone technology on interpreting these laws. This article argues that drone strikes are best understood as techno-legal assemblages that combine technoscience and law to make killing lawful. The argument proceeds in three parts. Part one analyses the formal legal debate concerning drone strikes. The seeds of the debate are in the US’s response to terrorism in the 1980s, when it developed legal strategies to overcome the obstacles of territorial sovereignty and the ban on assassination. The contemporary debate on the law of self-defence divides into supporters and critics of the US’s legal position. However, the debate neglects what critical drone scholars have argued is an essential link between drone technology and legal ambiguity. Part two analyses the technoscientific practices of drone strikes and how they interpret and implement the laws of war. Armed drones are part of a widespread surveillance system that converts people into information, which the US uses to target individuals. The thresholds that distinguish between military and civilian objects, and that delineate the spaces, temporal order, and legal subjects of conflict, are all interpreted through the lens of the surveillance system. These techno-legal practices become a legal justification for drone killing that goes beyond positive law. Part three argues that drone strikes are techno-legal assemblages that are part of a general collective of assemblages of control. The enmeshing of law and technology in drone strikes reflects the expansion of the law to cover more subjects and more areas. Drone strikes, then, are not a radical break from the law, but a techno-legal continuation of patterns of colonial warfare.

Penelitian ini bertujuan untuk mengetahui apakah model pembelajaran artikulasi berpengaruh penggunaanya terhadap hasil belajar siswa pada mata pelajaran IPA terpadu. Metode penelitian ini menggunakan metode penelitian kuantitatif dan jenis penelitian adalah quasi eksperimen. Populasi dalam penelitian adalah seluruh siswa kelas IX SMP Negeri 1 Toma yang berjumlah 116 orang. Sampel penelitian adalah kelas IX-B sebagai kelas eksperimen dengan jumlah 29 orang dan kelas IX-C sebagai kelas kontrol berjumlah 27 orang. Instrumen yang digunakan adalah tes hasil belajar siswa yaitu tes awal dan tes akhir. Berdasarkan pengolahan data yang telah dilaksanakan, maka ada beberapa yang menjadi kesimpulan yaitu (1) berdasarkan perhitungan nilai rata-rata tes awal pada kelas eksperimen diperoleh sebesar 42.93 sedangkan kelas kontrol sebesar 54.26. (2) berdasarkan perhitungan nilai rata-rata tes akhir pada kelas eksperimen diperoleh sebesar 66.04 sedangkan pada kelas kontrol sebesar 45.66. (3) berdasarkan perhitungan uji hipotesis thitung = 8,228 dan ttabel = 1.671, sehingga thitung > ttabel yaitu 8,228 > 1.671. Maka Ha diterima dan Ho ditolak. Dapat disimpulkan bahwa ada pengaruh model pembelajaran artikulasi terhadap hasil belajar siswa pada mata pelajaran IPA Terpadu di SMP Negeri 1 Toma.

We experimentally assess the suitability of transmon qubits with fixed frequencies and fixed interactions for the realization of analogue quantum simulations of spin systems. We test a set of necessary criteria for this goal on a commercial quantum processor using full quantum process tomography and more efficient Hamiltonian tomography. Significant single qubit errors at low amplitudes are identified as a limiting factor preventing the realization of analogue simulations on currently available devices. We additionally find spurious dynamics in the absence of drive pulses, which we identify with coherent coupling between the qubit and a low dimensional environment. With moderate improvements, analogue simulation of a rich family of time-dependent many-body spin Hamiltonians may be possible.

Repeated projective measurements in unitary circuits can lead to an entanglement phase transition as the measurement rate is tuned. In this work, we consider a different setting in which the projective measurements are replaced by dynamically chosen unitary gates that minimize the entanglement. This can be seen as a one-dimensional unitary circuit game in which two players get to place unitary gates on randomly assigned bonds at different rates: the “entangler” applies a random local unitary gate with the aim of generating extensive (volume-law) entanglement. The “disentangler,” based on limited knowledge about the state, chooses a unitary gate to reduce the entanglement entropy on the assigned bond with the goal of limiting to only finite (area-law) entanglement. In order to elucidate the resulting entanglement dynamics, we consider three different scenarios: (i) a classical discrete height model, (ii) a Clifford circuit, and (iii) a general U(4) unitary circuit. We find that both the classical and Clifford circuit models exhibit phase transitions as a function of the rate that the disentangler places a gate, which have similar properties that can be understood through a connection to the stochastic Fredkin chain. In contrast, the entangler always wins when using Haar random unitary gates and we observe extensive, volume-law entanglement for all nonzero rates of entangling.

Abstract Background Small intestinal bacterial overgrowth (SIBO) is a condition of unknown prevalence characterized by an excessive amount of bacteria in the small bowel, typically resulting in vague gastrointestinal symptoms with bloating being most commonly reported. Here we describe a severe case of SIBO leading to small bowel necrosis requiring surgical intervention. Case presentation A 55-year-old Hispanic female with gastric outlet obstruction secondary to a newly diagnosed gastric adenocarcinoma, receiving neoadjuvant chemotherapy, developed bloody gastrostomy output and rapidly progressing nausea and abdominal distention 3 days after jejunostomy tube placement and initiation of jejunal enteral nutrition. Imaging revealed diffuse pneumatosis and portal venous gas. Surgical exploration confirmed segmental bowel necrosis requiring resection. Histologic findings were consistent with SIBO. Conclusions Presentation of severe SIBO in the setting of intestinal stasis secondary to gastric outlet after initiation of enteral feeds is a rare phenomenon. Early recognition and diagnosis of SIBO is critical in minimizing patient morbidity and mortality.

Background Effective development and retention of talented early-career researchers (ECRs) is essential to the continued success of biomedical science research fields. To this end, formal mentorship programmes (where researchers are paired with one or more mentors beyond their direct manager) have proven to be successful in providing support and expanding career development opportunities. However, many programmes are limited to pools of mentors and mentees within one institute or geographical area, highlighting that cross-regional connections may be a missed opportunity in many mentorship schemes. Methods Here, we aimed to address this limitation through our pilot cross-regional mentorship scheme, creating reciprocal mentor-mentee pairings between two pre-established networks of Alzheimer’s Research UK (ARUK) Network-associated researchers. We carefully created 21 mentor-mentee pairings between the Scotland and University College London (UCL) networks in 2021, with surveys conducted to assess mentor/mentee satisfaction with the programme. Results Participants reported very high satisfaction with the nature of the pairings and the mentors’ contribution to the career development of mentees; a majority also reported that the mentorship scheme increased their connections outside of their home network. Our assessment of this pilot programme is that it supports the utility of cross-regional mentorship schemes for ECR development. At the same time, we highlight the limitations of our programme and recommend areas for improvement in future programmes, including greater consideration of support for minoritized groups and the need for additional training for mentors. Conclusions In conclusion, our pilot scheme generated successful and novel mentor-mentee pairings across pre-existing networks; both of which reported high satisfaction with pairings, ECR career and personal development, and the formation of new cross-network connections. This pilot may serve as a model for other networks of biomedical researchers, where existing networks within medical research charities can act as a scaffold to build new cross-regional career development opportunities for researchers.

Simulating time evolution of generic quantum many-body systems using classical numerical approaches has an exponentially growing cost either with evolution time or with the system size. In this work we present a polynomially scaling hybrid quantum-classical algorithm for time evolving a one-dimensional uniform system in the thermodynamic limit. This algorithm uses a layered uniform sequential quantum circuit as a variational Ansatz to represent infinite translation-invariant quantum states. We show numerically that this Ansatz requires a number of parameters polynomial in the simulation time for a given accuracy. Furthermore, this favorable scaling of the Ansatz is maintained during our variational evolution algorithm. All steps of the hybrid optimization are designed with near-term digital quantum computers in mind. After benchmarking the evolution algorithm on a classical computer, we demonstrate the measurement of observables of this uniform state using a finite number of qubits on a cloud-based quantum processing unit. With more efficient tensor contraction schemes, this algorithm may also offer improvements as a classical numerical algorithm.

Abstract An exceptionally large coral Porites sp. has been identified and measured at Goolboodi (Orpheus Island), Great Barrier Reef (GBR). This coral was measured in March 2021 during citizen science research of coral reefs in the Palm Islands group. We conducted a literature review and consulted scientists to compare the size, age and health of the Porites with others in the GBR and internationally. This is the largest diameter Porites coral measured by scientists and the sixth highest coral measured in the GBR. The health of the Porites was assessed as very good with over 70% live coral cover and minor percentages of sponge, live coral rock and macroalgae. An estimated age of 421–438 years was calculated based on linear growth models. Manbarra Traditional Owners were consulted and suggested that the Porites be named Muga dhambi (big coral) to communicate traditional knowledge, language and culture to indigenous, tourists, scientists and students.

Healthy agroecosystems are dependent on a complex web of factors and inter-species interactions. Flowers are hubs for pathogen transmission, including the horizontal or vertical transmission of plant-viruses and the horizontal transmission of bee-viruses. Pollination by the European honey bee (Apis mellifera) is critical for industrial fruit production, but bees can also vector viruses and other pathogens between individuals. Here, we utilized commercial honey bee pollination services in blueberry (Vaccinium corymbosum) farms for a metagenomics-based bee and plant virus monitoring system. Following RNA sequencing, viruses were identified by mapping reads to a reference sequence database through the bioinformatics portal Virtool. In total, 29 unique plant viral species were found at two blueberry farms in British Columbia (BC). Nine viruses were identified at one site in Ontario (ON), five of which were not identified in BC. Ilarviruses blueberry shock virus (BlShV) and prune dwarf virus (PDV) were the most frequently detected viruses in BC but absent in ON, while nepoviruses tomato ringspot virus and tobacco ringspot virus were common in ON but absent in BC. BlShV coat protein (CP) nucleotide sequences were nearly identical in all samples, while PDV CP sequences were more diverse, suggesting multiple strains of PDV circulating at this site. Ten bee-infecting viruses were identified, with black queen cell virus frequently detected in ON and BC. Area-wide bee-mediated pathogen monitoring can provide new insights into the diversity of viruses present in, and the health of, bee-pollination ecosystems. This approach can be limited by a short sampling season, biased towards pollen-transmitted viruses, and the plant material collected by bees can be very diverse. This can obscure the origin of some viruses, but bee-mediated virus monitoring can be an effective preliminary monitoring approach.

Quantum computers promise to perform computations beyond the reach of modern computers with profound implications for scientific research. Due to remarkable technological advances, small scale devices are now becoming available for use. One of the most apparent applications for such a device is the study of complex many-body quantum systems, where classical computers are unable to deal with the generic exponential complexity of quantum states. Even zero-temperature equilibrium phases of matter and the transitions between them have yet to be fully classified, with topologically protected phases presenting major difficulties. We construct and measure a continuously parametrized family of states crossing a symmetry protected topological phase transition on the IBM Q quantum computers. We present two complementary methods for measuring string order parameters that reveal the transition, and additionally analyze the effects of noise in the device using simple error models. The simulation that we perform is easily scalable and is a practical demonstration of the utility of near-term quantum computers for the study of quantum phases of matter and their transitions.

Gynandromorphy is an anomaly that results in an organism phenotypically expressing both male and female characteristics. Here we describe the first gynandromorph of the bee species Megalopta amoena (Spinola, 1853) (Halictidae, Augochlorini) and the second record of this anomaly within the genus Megalopta. Additionally, we analyzed the bee’s circadian rhythm, which has never before been quantified for a gynandromorph. The gynandromorph showed a deviant activity pattern; it was intermediate between that of the male and female M. amoena. Our results imply that the brains of bilateral gynandromorphs may have mixed sex-specific signaling. Based on four days of recording, the gynandromorph circadian rhythm was shifted earlier in the day relative to the male and female M. amoena, and it exhibited intensity similar to the female.

IntroductionThe World Health Organization recognizes dementia as a public health priority and highlights research as an action to respond to the consequences, with early career dementia researchers (ECDRs) representing the key driving force. Due to the COVID-19 pandemic, however, biomedical and psychosocial dementia research was strained worldwide. The aim of this study was to understand the impact of the pandemic on ECDRs.MethodsIn autumn 2021, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) Professional Interest Area to Elevate Early Career Researchers (PEERs) and University College London conducted an online survey querying ECDRs' experiences during the COVID-19 pandemic. The survey was shared through the ISTAART network, social media, podcasts, and emailing lists. Data were analyzed using descriptive and inferential statistics.ResultsSurvey data from n = 321 ECDRs from 34 countries were analyzed (67.6% women; 78.8% working in academia). Overall, 77.8% of ECDRs surveyed indicated research delays, 53.9% made project adjustments, 37.9% required additional or extended funding, and 41.8% reported a negative impact on career progression. Moreover, 19.9% felt unsupported by their institutions and employers (33% felt well supported, 42.7% somewhat supported). ECDR's conference attendance remained the same (26.5%) or increased (More: 28.6%; a lot more: 5.6%) since the start of the pandemic. Continental differences were visible, while the impact of the pandemic did not differ greatly based on ECDRs' sociodemographic characteristics.ConclusionsThe COVID-19 pandemic had a substantial impact on ECDRs worldwide and institutions, employers, and funding bodies are urged to consider the implications and lessons-learned when working with, managing, and promoting ECDRs. Strategies related to the pandemic and general career support to improve ECDRs career progression are discussed, including social media training, digital networking, and benefits of hybrid events. Global resources specific for ECDRs are highlighted.

While coral reefs in Australia have historically been a showcase of conventional management informed by research, recent declines in coral cover have triggered efforts to innovate and integrate intervention and restoration actions into management frameworks. Here we outline the multi-faceted intervention approaches that have developed in Australia since 2017, from newly implemented in-water programs, research to enhance coral resilience and investigations into socio-economic perspectives on restoration goals. We describe in-water projects using coral gardening, substrate stabilisation, coral repositioning, macro-algae removal, and larval-based restoration techniques. Three areas of research focus are also presented to illustrate the breadth of Australian research on coral restoration, (1) the transdisciplinary Reef Restoration and Adaptation Program (RRAP), one of the world's largest research and development programs focused on coral reefs, (2) interventions to enhance coral performance under climate change, and (3) research into socio-cultural perspectives. Together, these projects and the recent research focus reflect an increasing urgency for action to confront the coral reef crisis, develop new and additional tools to manage coral reefs, and the consequent increase in funding opportunities and management appetite for implementation. The rapid progress in trialling and deploying coral restoration in Australia builds on decades of overseas experience, and advances in research and development are showing positive signs that coral restoration can be a valuable tool to improve resilience at local scales (i.e., high early survival rates across a variety of methods and coral species, strong community engagement with local stakeholders). RRAP is focused on creating interventions to help coral reefs at multiple scales, from micro scales (i.e., interventions targeting small areas within a specific reef site) to large scales (i.e., interventions targeting core ecosystem function and social-economic values at multiple select sites across the Great Barrier Reef) to resist, adapt to and recover from the impacts of climate change. None of these interventions aim to single-handedly restore the entirety of the Great Barrier Reef, nor do they negate the importance of urgent climate change mitigation action.

Identified in December 2019, SARS-CoV-2 quickly spread worldwide with a resultant increase in global morbidity, mortality, and economic disruption on a scale not seen since the 1918 Spanish flu. Health officials recommended universal masking to further reduce human-to-human spread of SARS-CoV-2. The state of Hawaii and the Department of Defense (DOD) adopted strict mask policies early in the pandemic and is shown to be effective at reducing transmission. We report a case of Staphylococcus aureus bacteremia in an immunocompetent 21-year-old man attributed to local skin irritation with resultant infection in the setting of continuous reuse of a mask that resulted in bilateral cavernous venous thrombosis and septic pulmonary embolism.

Objectives: Standard molecular testing for patients with stage IV non-small cell lung cancer (NSCLC) in the Canadian publicly funded health system includes single gene testing for EGFR, ALK, and ROS-1. Comprehensive genomic profiling (CGP) may broaden treatment options for patients. This study examined the impact of CGP in a publicly funded health system. Methods: Consenting patients with stage IV NSCLC without known targetable alterations underwent CGP on diagnostic samples. Patients that had progressed on targeted therapy were also eligible. The CGP assay was a hybrid capture next generation sequencing (NGS) panel (Oncomine Comprehensive Assay Version 3, ThermoFisher). The number of actionable alterations, changes in treatment, clinical trial eligibility and costs as a result of CGP were evaluated and patient willingness-to-pay. Results: Of 182 screened patients,134 (74%) had successful CGP testing. Twenty percent had received prior targeted therapy. Incremental actionable alterations were identified in 31% of patients. The most common novel targets identified were mutations in ERBB2 (exon 20 insertions), MET (exon 14 skipping) and KRAS (G12C). At data cut off (31/12/2020), 16% of patients had a change in treatment as a result of CGP. Additional clinical trial options were identified for 75% of patients. The incremental direct laboratory cost for CGP beyond public reimbursement for single gene tests was $747 CAD/case. Conclusion: CGP identifies additional actionable targets beyond single gene tests with a direct impact on patient treatment and increased clinical trial eligibility. These benefits highlight the value of CGP in patients with NSCLC in public health systems.

OBJECTIVES:. To summarize selected meta-analyses and trials related to critical care pharmacotherapy published in 2020. DATA SOURCES:. The Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update group screened 36 journals monthly for impactful publications. STUDY SELECTION:. The group reviewed a total of 119 articles during 2020 according to relevance for practice. DATA EXTRACTION:. Articles were selected with consensus and importance to clinical practice from those included in the monthly Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. The group reviewed articles according to Grading of Recommendations, Assessment, Development, and Evaluations criteria. Articles with a 1A grade were selected. DATA SYNTHESIS:. Several trials were summarized, including two meta-analyses and five original research trials. Original research trials evaluating vitamin C, hydrocortisone, and thiamine versus hydrocortisone in sepsis, the use of nonsedation strategies, dexmedetomidine in cardiac surgery, remdesivir for severe acute respiratory syndrome coronavirus 2, and thrombectomy in acute ischemic stroke. Two meta-analyses determining the impact of norepinephrine initiation in patients with septic shock and the use of corticosteroids in severe acute respiratory syndrome coronavirus 2 was included. CONCLUSIONS:. This clinical review provides summary and perspectives of clinical practice impact on influential critical care pharmacotherapy publications in 2020.

Purpose: The Lean methodology was applied to clinical metrics by a critical care pharmacy team. The experiences associated with the development and implementation of clinical metrics and their impact on daily workflow are described. Summary: The Lean methodology has been introduced into the healthcare system as a means of process improvement, which can eliminate waste through appropriate medication utilization. At OhioHealth Riverside Methodist Hospital, the department of pharmacy was tasked with the development of clinical metrics after a health system wide Gemba walk was initiated. The pharmacy department's critical care team developed a strategy identifying and evaluating clinical metrics pertaining to their everyday workflow. Each clinical metric was evaluated in accordance with a pre-defined goal. Metrics requiring heavy documentation and those in which the pharmacist does not have autonomous authority to manage were often challenging to implement and were less successful. Throughout this process, the lessons learned focused on generating ideas that were easily documented, evidence-based, and department specific. The critical care team discovered that the outcome of the most successful metrics highlighted clinical pharmacist value and data generated could be used to support funding for additional resources. Conclusion: The critical care pharmacy team developed a streamlined process to implement clinical metrics as means of identifying areas for improvement using the Lean methodology.

The largest underwater sculpture in the world, the ‘Coral Greenhouse’ by artist Jason deCaires Taylor, was commissioned by the Museum of Underwater Art and installed at John Brewer Reef, Australia, in December 2019. The planning process required certified engineering design drawings associated with design life, durability and suitability of materials, and baseline ecological surveys. Following approval, the operational phase required annual monitoring of substrate, ecology, social values, and marine debris. We geo-referenced three permanent transects and designed a before/after rapid monitoring assessment of substrate, fish, and invertebrates. Substrate surveys indicated 11% concrete and 89% sand. Fish surveys indicated significant increases of diversity and abundance, with 12 species and 65 individuals recorded in 2018 compared to 46 species and 365 individuals recorded in 2022. Macroinvertebrate species maintained no significant trends in abundance, species richness, and diversity with respect to time between 2018 and 2022. We monitored coral restoration and natural recruitment at the site, measuring aesthetics, survivorship of planted corals, and coral recruitment. Of 131 corals transplanted in March 2020, survivorship was 100% at 1 month, 92% at 6 months, and 91.6% at 12 months. Hard and soft corals were recruited to the structure at a density of 8.35 hard corals/m2 and 10.9 soft corals/m2 over 26 months.

The finding of physical realizations of topologically ordered states in experimental settings, from condensed matter to artificial quantum systems, has been the main challenge en route to utilizing their unconventional properties. We show how to realize a large class of topologically ordered states and simulate their quasiparticle excitations on a digital quantum computer. To achieve this, we design a set of linear-depth quantum circuits to generate ground states of general string-net models together with unitary open-string operators to simulate the creation and braiding of Abelian and non-Abelian anyons. We show that the Abelian (non-Abelian) unitary string operators can be implemented with a constant- (linear-) depth quantum circuit. Our scheme allows us to directly probe characteristic topological properties, including topological entanglement entropy, braiding statistics, and fusion channels of anyons. Moreover, this set of efficiently prepared topologically ordered states has potential applications in the development of fault-tolerant quantum computers.

The advent of noisy-intermediate scale quantum computers has introduced the exciting possibility of achieving quantum speedups in machine learning tasks. These devices, however, are composed of a small number of qubits and can faithfully run only short circuits. This puts many proposed approaches for quantum machine learning beyond currently available devices. We address the problem of compressing classical data into efficient representations on quantum devices. Our proposed methods allow both the required number of qubits and depth of the quantum circuit to be tuned. We achieve this by using a correspondence between matrix-product states and quantum circuits and further propose a hardware-efficient quantum circuit approach, which we benchmark on the Fashion-MNIST dataset. Finally, we demonstrate that a quantum circuit-based classifier can achieve competitive accuracy with current tensor learning methods using only 11 qubits.

We developed and applied a method to quantify spearfisher effort and catch, shark interactions and shark depredation in a boat-based recreational spearfishing competition in the Great Barrier Reef Marine Park in Queensland. Survey questions were designed to collect targeted quantitative data whilst minimising the survey burden of spearfishers. We provide the first known scientific study of shark depredation during a recreational spearfishing competition and the first scientific study of shark depredation in the Great Barrier Reef region. During the two-day spearfishing competition, nine vessels with a total of 33 spearfishers reported a catch of 144 fish for 115 h of effort (1.25 fish per hour). A subset of the catch comprised nine eligible species under competition rules, of which 47 pelagic fish were weighed. The largest fish captured was a 34.4 kg Sailfish (Istiophorus platypterus). The most common species captured and weighed was Spanish Mackerel (Scomberomorus commerson). The total weight of eligible fish was 332 kg and the average weight of each fish was 7.1 kg. During the two-day event, spearfishers functioned as citizen scientists and counted 358 sharks (115 h effort), averaging 3.11 sharks per hour. Grey Reef Sharks (Carcharhinus amblyrhynchos) comprised 64% of sightings. Nine speared fish were fully depredated by sharks as spearfishers attempted to retrieve their catch, which equates to a depredation rate of 5.9%. The depredated fish included four pelagic fish and five reef fish. The shark species responsible were Grey Reef Shark (C. amblyrhynchos) (66%), Bull Shark (Carcharhinus leucas) (11%), Whitetip Reef Shark (Triaenodon obesus) (11%) and Great Hammerhead (Sphyrna mokarran) (11%). There were spatial differences in fish catch, shark sightings and rates of depredation. We developed a report card that compared average catch of fish, sightings of sharks per hour and depredation rate by survey area, which assists recreational fishers and marine park managers to assess spatio-temporal changes. The participating spearfishers can be regarded as experienced (average 18 days a year for average 13.4 years). Sixty percent of interviewees perceived that shark numbers have increased in the past 10 years, 33% indicated no change and 7% indicated shark numbers had decreased. Total fuel use of all vessels was 2819 L and was equivalent to 6.48 tons of greenhouse gas emissions for the competition.

Empathy and mindfulness are currently major topics of scientific interest. Although it is well-known that mindfulness—typically as an outcome related to meditation—generates empathy at the state level, only a small number of studies have documented the trait (i.e., personality) level association between mindfulness and empathy. Furthermore, the underlying mechanisms (subcomponents and mediator variables) that support this association remain unclear. Thus, here, with a focus on the trait level, we investigated relationships among multiple subcomponents of trait mindfulness and trait empathy (Study 1). Next, we reexamined the aforementioned relationships in an independent sample, with the further aim of investigating relevant mediation factors (Study 2). We found that two attention-related components of trait mindfulness—observing and acting with awareness—reliably and positively related to both affective and cognitive dimensions of trait empathy (i.e., empathic concern and perspective taking). Furthermore, we found that effortful control, reappraisal, and trait alexithymia mediated relationships between the aforementioned attention-related components of trait mindfulness and empathic concern. Taken together, our results suggest that the links between mindfulness and empathy are multidimensional and complex. These findings may ultimately contribute to an understanding of the mechanisms underlying the positive effects of meditation on empathy.

The scaling of the entanglement entropy at a quantum critical point allows us to extract universal properties of the state, e.g., the central charge of a conformal field theory. With the rapid improvement of noisy intermediate-scale quantum (NISQ) devices, these quantum computers present themselves as a powerful tool to study critical many-body systems. We use finite-depth quantum circuits suitable for NISQ devices as a variational ansatz to represent ground states of critical, infinite systems. We find universal finite-depth scaling relations for these circuits and verify them numerically at two different critical points, i.e., the critical Ising model with an additional symmetry-preserving term and the critical XXZ model.

The Sendai Framework for Disaster Risk Reduction provides quantitative indicators for nations to measure progress in the reduction of disaster losses. The collection and analysis of disaster loss data under the Sendai Framework improves our understanding of the effectiveness of national disaster risk reduction strategies and interventions. The Sendai Framework has enhanced cooperation among Federal agencies to collect and track disaster loss data in the U.S., yet challenges remain for reporting disaster losses. Based on our experiences collecting and reporting U.S. data to the Sendai Monitor, we identify opportunities to improve disaster loss reporting in the U.S.

Local differential privacy is a widely studied restriction on distributed algorithms that collect aggregates about sensitive user data, and is now deployed in several large systems. We initiate a systematic study of a fundamental limitation of locally differentially private protocols: they are highly vulnerable to adversarial manipulation. While any algorithm can be manipulated by adversaries who lie about their inputs, we show that any noninteractive locally differentially private protocol can be manipulated to a much greater extent---when the privacy level is high, or the domain size is large, a small fraction of users in the protocol can completely obscure the distribution of the honest users' input. We also construct protocols that are optimally robust to manipulation for a variety of common tasks in local differential privacy. Finally, we give simple experiments validating our theoretical results, and demonstrating that protocols that are optimal without manipulation can have dramatically different levels of robustness to manipulation. Our results suggest caution when deploying local differential privacy and reinforce the importance of efficient cryptographic techniques for the distributed emulation of centrally differentially private mechanisms.

Abstract Introduction Barriers to recruitment for dementia studies are well documented. As part of the UK government's Dementia 2020 strategy, a nationally consistent system to increase public engagement and participation in research was launched in February 2015. Methods We describe the development of the “Join Dementia Research” registry, including evolution of policy, involvement of people with dementia in co‐production, data requirements, governance, technology, and the impact on study recruitment and what factors may have contributed to the services success. Results The UK‐wide online, telephone, and postal service has registered 47,071 volunteers, with 33,139 people (67.9% of all volunteers) taking part in 378 studies, with 49,954 total study enrolments. This has taken place across 295 research sites, involved 1522 researchers, and resulted in 134 peer‐reviewed publications. Discussion Public registries of individuals interested in research, with user‐provided data enabling basic phenotyping, are effective at increasing public engagement with research and removing barriers to study recruitment. Deeper pheno/genotyping could be undertaken to improve matching, but how and when that information is collected will be a key factor.

Although Amorphous Solid Dispersions (ASDs) effectively increase bioavailability, tablet mass can be high due to the large fraction of excipients needed to stabilize the amorphous drug in the solid state, extend drug supersaturation in solution and achieve robust manufacturability. The aim of this work was to reduce tablet mass of an ASD tablet comprising a low glass transition temperature (Tg), rapidly crystallizing drug without compromising these key attributes.In this approach, erlotinib (Tg = 42 °C, Tm/Tg = 1.4 K/K) was spray dried with the high Tg polymer poly(methyl methacrylate-co-methacrylic acid) (Eudragit® L100, Evonik) (Tg = 187 °C) to facilitate high drug loading while maintaining physical stability. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) (AQOAT® HF, Shin-Etsu) was granulated with the ASD to extend supersaturation in solution. For comparison, a benchmark ASD was spray dried at a lower drug loading with HPMCAS-H (Tg = 119 °C).This High Loaded Dosage Form (HLDF) approach reduced tablet mass by 40%, demonstrated similar physical stability and in vitro performance as the benchmark and exhibited excellent downstream manufacturability. Strategically combining two different polymers in a tablet to maintain physical stability and sustain supersaturation in solution can decrease tablet mass of some low Tg, rapidly crystallizing amorphous drugs.

Coral reef ecosystems have suffered an unprecedented loss of habitat-forming hard corals in recent decades. While marine conservation has historically focused on passive habitat protection, demand for and interest in active restoration has been growing in recent decades. However, a disconnect between coral restoration practitioners, coral reef managers and scientists has resulted in a disjointed field where it is difficult to gain an overview of existing knowledge. To address this, we aimed to synthesise the available knowledge in a comprehensive global review of coral restoration methods, incorporating data from the peer-reviewed scientific literature, complemented with grey literature and through a survey of coral restoration practitioners. We found that coral restoration case studies are dominated by short-term projects, with 60% of all projects reporting less than 18 months of monitoring of the restored sites. Similarly, most projects are relatively small in spatial scale, with a median size of restored area of 100 m2. A diverse range of species are represented in the dataset, with 229 different species from 72 coral genera. Overall, coral restoration projects focused primarily on fast-growing branching corals (59% of studies), and report survival between 60 and 70%. To date, the relatively young field of coral restoration has been plagued by similar 'growing pains' as ecological restoration in other ecosystems. These include 1) a lack of clear and achievable objectives, 2) a lack of appropriate and standardised monitoring and reporting and, 3) poorly designed projects in relation to stated objectives. Mitigating these will be crucial to successfully scale up projects, and to retain public trust in restoration as a tool for resilience based management. Finally, while it is clear that practitioners have developed effective methods to successfully grow corals at small scales, it is critical not to view restoration as a replacement for meaningful action on climate change.

The international framework for maritime search and rescue relies on state actors establishing regions of responsibility supported by private shipmasters acting in compliance with traditional duties to rescue persons in distress at sea. Despite revisions to the framework’s foundational treaty, questions persist about the extent of state responsibilities and the interaction between those responsibilities and international human rights law. Over the past three years, non-governmental organizations (NGOs) have provided significant support to the efforts of sovereign actors responding to the migration crisis in the Central Mediterranean. Regional governments and civil society initially praised NGO operations, but in recent months these groups have come to criticize and challenge such operations. Italian authorities have threatened criminal prosecution of NGO deployers and proposed closing national ports to them. Libyan authorities have harassed NGO vessels and sought to exclude them from international waters. These actions are consistent with non-entrée strategies employed by Mediterranean states in recent years, but are in certain cases of questionable legality. Although controlling irregular migration is properly the responsibility of state actors, recent policies are inconsistent with principles of rule of law and good governance.

Models whose ground states can be written as an exact matrix-product state (MPS) provide valuable insights into phases of matter. While MPS-solvable models are typically studied as isolated points in a phase diagram, they can belong to a connected network of MPS-solvable models, which we call the MPS skeleton. As a case study where we can completely unearth this skeleton, we focus on the one-dimensional BDI class—noninteracting spinless fermions with time-reversal symmetry. This class, labeled by a topological winding number, contains the Kitaev chain and is Jordan-Wigner-dual to various symmetry-breaking and symmetry-protected topological (SPT) spin chains. We show that one can read off from the Hamiltonian whether its ground state is an MPS: defining a polynomial whose coefficients are the Hamiltonian parameters, MPS-solvability corresponds to this polynomial being a perfect square. We provide an explicit construction of the ground state MPS, its bond dimension growing exponentially with the range of the Hamiltonian. This complete characterization of the MPS skeleton in parameter space has three significant consequences: (i) any two topologically distinct phases in this class admit a path of MPS-solvable models between them, including the phase transition which obeys an area law for its entanglement entropy; (ii) we illustrate that the subset of MPS-solvable models is dense in this class by constructing a sequence of MPS-solvable models which converge to the Kitaev chain (equivalently, the quantum Ising chain in a transverse field); (iii) a subset of these MPS states can be particularly efficiently processed on a noisy intermediate-scale quantum computer.

The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including aggression, social learning and memory. Genetic removal of Avpr1b from mouse models results in deficits in aggression and short-term social recognition in adults. Avpr1b gene expression is highly enriched in the pyramidal neurons of the hippocampal cornu ammonis 2 (CA2) region. Activity of the hippocampal CA2 has been shown to be required for normal short-term social recognition and aggressive behaviors. Vasopressin acts to enhance synaptic responses of CA2 neurons through a NMDA-receptor dependent mechanism. Genetic removal of the obligatory subunit of the NMDA receptor (Grin1) within distinct hippocampal regions impairs non-social learning and memory. However, the question of a direct role for NMDA receptor activity in Avpr1b neurons to modulate social behavior remains unclear. To answer this question, we first created a novel transgenic mouse line with Cre recombinase knocked into the Avpr1b coding region to genetically target Avpr1b neurons. We confirmed this line has dense Cre expression throughout the dorsal and ventral CA2 regions of the hippocampus, along with scattered expression within the caudate-putamen and olfactory bulb (OB). Conditional removal of the NMDA receptor was achieved by crossing our line to an available floxed Grin1 line. The resulting mice were measured on a battery of social and memory behavioral tests. Surprisingly, we did not observe any differences between Avpr1b-Grin1 knockout mice and their wildtype siblings. We conclude that mice without typical NMDA receptor function in Avpr1b neurons can develop normal aggression as well as short-term social and object memory performance.

Hypothesis: When the distal fracture fragment in distal radius fractures displaces, it commonly rotates as well as shortens and angulates. Aim: The aim of this study was to assess the frequency and magnitude of malrotation of the distal fracture fragment using computed tomography (CT). Methods: A retrospective radiological assessment of 85 CT scans of the distal radius, 35 following fracture and 50 normal radii, was carried out. We developed and applied a simple method for measuring rotation of the distal radius relative to the diaphysis using routine CT scans of the wrist. A Mann–Whitney analysis was used to identify differences in radial rotation between fractures and controls. Intra- and inter-observer reliability were analyzed using intra-class correlation coefficients (ICCs) and Bland–Altman plots. Results: The articular surface of the distal radius is normally rotated in the long axis of the forearm relative to the diaphysis, either into pronation or into supination. The median radial rotation angle of controls was 1° pronation (range −15° to 4°) compared to 3° pronation (range −24° to 31°) in the fracture group. The absolute rotation angle was significantly greater in the fracture group (median 10°, range 0–31° vs. 3°, range 0–15°; p < 0.001) and outside the “normal range” of controls in 26 cases indicating that 75% had rotated appreciably following injury. Intra- and inter-observer reliability of measurements were good with ICCs of 0.99 and 0.98, respectively. Conclusions: Malrotation of the distal radius appears common following distal radius fracture. Malrotation of the distal fracture fragment has been shown to affect distal radio-ulnar joint function. Despite this, rotational deformity is rarely addressed in clinical practice as it is difficult to appreciate on simple radiographs. The simplified method described here is easy to use in routine clinical practice and also appears reliable. Measuring radial rotation may be an important consideration when planning both primary treatment and corrective osteotomy for patients with distal radial malunion.

Background: Dyspepsia guidelines recommend that patients treated with proton pump inhibitors (PPIs) should step down to the lowest effective dose or return to self-care, but rebound hyperacidity can make this difficult. Many patients continue on PPIs in the long term, which may lead to safety and financial implications. Aim: To determine if a nurse-led educational support programme and rescue therapy for rebound symptoms can help patients achieve a sustained reduction in PPI use. Design & setting: A prospective interventional study was conducted at 26 surgeries across the UK. Method: Adult patients, treated with PPIs for ≥2 consecutive months with an active repeat prescription, were invited to a 20-minute dyspepsia clinic appointment with a trained nurse adviser. An action plan to reduce and/or stop their PPI usage was agreed and alginate supplied for the self-management of rebound symptoms. After 12 months, PPI status was reviewed and prescribing cost savings calculated. Results: After 12 months, 75.1% of 6249 eligible patients stepped down or off PPIs (35.3% stepped off; 5.0% stepped down then off; 34.8% stepped down only), while 8.7% of patients had reverted to their original PPI dose. PPI prescriptions fell from 89 915 to 45 880 and alginate prescriptions increased from 2405 to 6670. An average of 1.7 bottles (500 ml each) of alginate were used per patient who stepped down or off. Estimated annual cost-saving on prescriptions was £31 716.30. Conclusion: A programme of education and short-term rebound symptom management helped the majority of patients to successfully step down or off PPIs, significantly reducing the potential risks associated with chronic therapy.

Background: The drainage, irrigation and fibrinolytic therapy (DRIFT) trial, conducted in 2003–6, showed a reduced rate of death or severe disability at 2 years in the DRIFT compared with the standard treatment group, among preterm infants with intraventricular haemorrhage (IVH) and post-haemorrhagic ventricular dilatation. Objectives: To compare cognitive function, visual and sensorimotor ability, emotional well-being, use of specialist health/rehabilitative and educational services, neuroimaging, and economic costs and benefits at school age. Design: Ten-year follow-up of a randomised controlled trial. Setting: Neonatal intensive care units (Bristol, Katowice, Glasgow and Bergen). Participants: Fifty-two of the original 77 infants randomised. Interventions: DRIFT or standard therapy (cerebrospinal fluid tapping). Main outcome measures: Primary – cognitive disability. Secondary – vision; sensorimotor disability; emotional/behavioural function; education; neurosurgical sequelae on magnetic resonance imaging; preference-based measures of health-related quality of life; costs of neonatal treatment and of subsequent health care in childhood; health and social care costs and impact on family at age 10 years; and a decision analysis model to estimate the cost-effectiveness of DRIFT compared with standard treatment up to the age of 18 years. Results: By 10 years of age, 12 children had died and 13 were either lost to follow-up or had declined to participate. A total of 52 children were assessed at 10 years of age (DRIFT, n = 28; standard treatment, n = 24). Imbalances in gender and birthweight favoured the standard treatment group. The unadjusted mean cognitive quotient (CQ) score was 69.3 points [standard deviation (SD) 30.1 points] in the DRIFT group compared with 53.7 points (SD 35.7 points) in the standard treatment group, a difference of 15.7 points, 95% confidence interval (CI) –2.9 to 34.2 points; p = 0.096. After adjusting for the prespecified covariates (gender, birthweight and grade of IVH), this evidence strengthened: children who received DRIFT had a CQ advantage of 23.5 points (p = 0.009). The binary outcome, alive without severe cognitive disability, gave strong evidence that DRIFT improved cognition [unadjusted odds ratio (OR) 3.6 (95% CI 1.2 to 11.0; p = 0.026) and adjusted OR 10.0 (95% CI 2.1 to 46.7; p = 0.004)]; the number needed to treat was three. No significant differences were found in any secondary outcomes. There was weak evidence that DRIFT reduced special school attendance (adjusted OR 0.27, 95% CI 0.07 to 1.05; p = 0.059). The neonatal stay (unadjusted mean difference £6556, 95% CI –£11,161 to £24,273) and subsequent hospital care (£3413, 95% CI –£12,408 to £19,234) costs were higher in the DRIFT arm, but the wide CIs included zero. The decision analysis model indicated that DRIFT has the potential to be cost-effective at 18 years of age. The incremental cost-effectiveness ratio (£15,621 per quality-adjusted life-year) was below the National Institute for Health and Care Excellence threshold. The cost-effectiveness results were sensitive to adjustment for birthweight and gender. Limitations: The main limitations are the sample size of the trial and that important characteristics were unbalanced at baseline and at the 10-year follow-up. Although the analyses conducted here were prespecified in the analysis plan, they had not been prespecified in the original trial registration. Conclusions: DRIFT improves cognitive function when taking into account birthweight, grade of IVH and gender. DRIFT is probably effective and, given the reduction in the need for special education, has the potential to be cost-effective as well. A future UK multicentre trial is required to assess efficacy and safety of DRIFT when delivered across multiple sites. Trial registration: Current Controlled Trials ISRCTN80286058. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 4. See the NIHR Journals Library website for further project information. The DRIFT trial and 2-year follow-up was funded by Cerebra and the James and Grace Anderson Trust.

The aesthetic appreciation of natural places is one of the most fundamental ways in which people relate to their environment. It provides wellbeing, an opportunity for recreation and reflection, a sense of place, and cultural enrichment. It also motivates people to take care of natural places and to conserve them for current and future appreciation. Aesthetically valuable places also support significant economic activity. However, there is little guidance available to assist environmental managers and policy-makers to consider and integrate aesthetic values into decision-making processes. In this study, we present an approach for developing robust and practical indicators of aesthetic value to enable environmental managers to consider, assess and report on aesthetic condition and trend. We demonstrate its utility using the case of the Great Barrier Reef, a region currently undergoing significant social, economic and environmental change and an area formally protected, in part, for its aesthetic values. A qualitative scoping study with 30 key informants identified over 180 potential qualities contributing to reef aesthetics. We tested five for their utility in capturing key aspects of the coral reef aesthetic: (i) coral cover, (ii) coral pattern, (iii) coral topography, (iv) fish abundance, and (v) visibility. We asked 1,417 online Australians to aesthetically rate 50 out of 181 underwater coral reef images that varied in relation to these five attributes. Coral topography, fish abundance, and visibility were significantly correlated with aesthetic ratings, whilst coral cover and coral pattern were not. We also tested for demographic patterns in aesthetic ratings. Our pilot study has demonstrated that readily measurable characteristics of coral reefs can provide useful indicators of aesthetic quality, opening up opportunities for coral reef managers and policymakers to assess and track changes in aesthetics in ways that are relevant to the public. There is considerable scope to further advance capacity for monitoring and managing aesthetic values of coral reefs through additional research that resolves nuances in the meanings associated with aesthetics in coral reef settings.

Introduction: Despite awareness of overall poor survival rates following cardiopulmonary resuscitation (CPR), some orthopedic patients with significant comorbidities continue to have inappropriate resuscitation plans. Furthermore, in certain injury groups such as patients with hip fractures, survival outcome data are very limited; current discussions regarding resuscitation plans may be inaccurate. This study assesses survival in orthopedic patients following CPR, to inform decision-making between physicians, surgeons, and patients. Methods: A dual center, retrospective cohort study was performed analyzing all orthopedic admissions that received CPR over a 25-month period, with a minimum of 1 year follow-up. National Cardiac Arrest Audit data, “mortality and morbidity” meeting records, National Hip Fracture Databases, and electronic notes were analyzed. Survival duration was measured, alongside reason for admission, location CPR occurred, and initial rhythm encountered. Results: Thirty-two patients received CPR over the 25-month period (median age: 83; range: 30-96). Three (9%) of 32 patients survived to discharge. Only 1 of the 26 patients older than 65 years survived to discharge. Fifteen (47%) of 32 had hip fractures, where 4 (27%) of 15 of this group survived 24 hours; none survived to discharge. When recorded, 22 (92%) of 24 initially had a nonshockable rhythm. Discussion: Cardiopulmonary resuscitation was conceptualized as a treatment for reversible cardiopulmonary causes. When used in trauma and orthopedic patients, especially older and/or hip fracture patients, it seldom led to hospital discharge. Different admission practices such as “front door” orthogeriatric reviews may explain the contrast in usage of CPR between the hospitals. Conclusion: Survival rates following CPR were very low, with it proving specifically ineffective in hip fracture patients. Although every decision about resuscitation should be patient centered and individualized, this study will allow clinicians to be more realistic about outcomes from CPR, particularly in the hip fracture group.

Rest in peace, Steve Fienberg.

Woody plant encroachment into grasslands ecosystems causes significantly ecological destruction and economic losses. Effective and efficient management largely benefits from accurate and timely detection of encroaching species at an early development stage. Recent advances in unmanned aircraft systems (UAS) enabled easier access to ultra-high spatial resolution images at a centimeter level, together with the latest machine learning based image segmentation algorithms, making it possible to detect small-sized individuals of target species at early development stage and identify them when mixed with other species. However, few studies have investigated the optimal practical spatial resolution of early encroaching species detection. Hence, we investigated the performance of four popular semantic segmentation algorithms (decision tree, DT; random forest, RF; AlexNet; and ResNet) on a multi-species forest classification case with UAS-collected RGB images in original and down-sampled coarser spatial resolutions. The objective of this study was to explore the optimal segmentation algorithm and spatial resolution for eastern redcedar (Juniperus virginiana, ERC) early detection and its classification within a multi-species forest context. To be specific, firstly, we implemented and compared the performance of the four semantic segmentation algorithms with images in the original spatial resolution (0.694 cm). The highest overall accuracy was 0.918 achieved by ResNet with a mean interaction over union at 85.0%. Secondly, we evaluated the performance of ResNet algorithm with images in down-sampled spatial resolutions (1 cm to 5 cm with 0.5 cm interval). When applied on the down-sampled images, ERC segmentation performance decreased with decreasing spatial resolution, especially for those images coarser than 3 cm spatial resolution. The UAS together with the state-of-the-art semantic segmentation algorithms provides a promising tool for early-stage detection and localization of ERC and the development of effective management strategies for mixed-species forest management.

Calquence® (crystalline acalabrutinib), a commercially marketed tyrosine kinase inhibitor (TKI), exhibits significantly reduced oral exposure when taken with acid-reducing agents (ARAs) due to the low solubility of the weakly basic drug at elevated gastric pH. These drug–drug interactions (DDIs) negatively impact patient treatment and quality of life due to the strict dosing regimens required. In this study, reduced plasma drug exposure at high gastric pH was overcome using a spray-dried amorphous solid dispersion (ASD) comprising 50% acalabrutinib and 50% hydroxypropyl methylcellulose acetate succinate (HPMCAS, H grade) formulated as an immediate-release (IR) tablet. ASD tablets achieved similar area under the plasma drug concentration–time curve (AUC) at low and high gastric pH and outperformed Calquence capsules 2.4-fold at high gastric pH in beagle dogs. In vitro multicompartment dissolution testing conducted a priori to the in vivo study successfully predicted the improved formulation performance. In addition, ASD tablets were 60% smaller than Calquence capsules and demonstrated good laboratory-scale manufacturability, physical stability, and chemical stability. ASD dosage forms are attractive for improving patient compliance and the efficacy of acalabrutinib and other weakly basic drugs that have pH-dependent absorption.

The current generation of noisy intermediate-scale quantum computers introduces new opportunities to study quantum many-body systems. In this paper, we show that quantum circuits can provide a dramatically more efficient representation than current classical numerics of the quantum states generated under nonequilibrium quantum dynamics. For quantum circuits, we perform both real- and imaginary-time evolution using an optimization algorithm that is feasible on near-term quantum computers. We benchmark the algorithms by finding the ground state and simulating a global quench of the transverse-field Ising model with a longitudinal field on a classical computer. Furthermore, we implement (classically optimized) gates on a quantum processing unit and demonstrate that our algorithm effectively captures real-time evolution.

The infamous sign problem leads to an exponential complexity in Monte Carlo simulations of generic many-body quantum systems. Nevertheless, many phases of matter are known to admit a sign-problem-free representative, allowing efficient simulations on classical computers. Motivated by long-standing open problems in many-body physics, as well as fundamental questions in quantum complexity, the possibility of intrinsic sign problems, where a phase of matter admits no sign-problem-free representative, was recently raised but remains largely unexplored. Here we establish the existence of an intrinsic sign problem in a broad class of gapped, chiral, topological phases of matter. Within this class, we exclude the possibility of stoquastic Hamiltonians for bosons (or “qudits”) and of sign-problem-free determinantal Monte Carlo algorithms for fermions. The intrinsically sign-problematic class of phases we identify is defined in terms of topological invariants with clear observable signatures: the chiral central charge and the topological spins of anyons. We obtain analogous results for phases that are spontaneously chiral, and present evidence for an extension of our results that applies to both chiral and nonchiral topological matter.