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Neutrophils have recently gained recognition for their potential in the fight against cancer. Neutrophil plasticity between the N1 anti-tumor and N2 pro-tumor subtypes is now apparent, as is the ability to polarize these individual subtypes by interventions such as intratumoral injection of various agents including bacterial products or pro-oxidants. Metabolic responses and the production of reactive oxygen species (ROS) such as hydrogen peroxide act as potent chemoattractants and activators of N1 neutrophils that facilitates their recruitment and ensuing activation of a toxic respiratory burst in tumors. Greater understanding of the precise mechanism of N1 neutrophil activation, recruitment and regulation is now needed to fully exploit their anti-tumor potential against cancers both locally and at distant sites. This systematic review critically analyzes these new developments in cancer immunotherapy.

In this research, we propose a disaster response model combining preparedness and responsiveness strategies. The selective response depends on the level of accuracy that our forecasting models can achieve. In order to decide the right geographical space and time window of response, forecasts are prepared and assessed through a spatial–temporal aggregation framework, until we find the optimum level of aggregation. The research considers major earthquake data for the period 1985–2014. Building on the produced forecasts, we develop accordingly a disaster response model. The model is dynamic in nature, as it is updated every time a new event is added in the database. Any forecasting model can be optimized though the proposed spatial–temporal forecasting framework, and as such our results can be easily generalized. This is true for other forecasting methods and in other disaster response contexts.

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from the United States, Canada, the United Kingdom, France, the Netherlands, and Spain. Here, we demonstrate the use of these real-world data, harmonized through a centralized data resource, to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharmaceutical collaborations and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledge base of increasing impact to inform clinical decision-making and bring together cancer researchers internationally.Significance:AACR Project GENIE has now accrued data from >110,000 tumors, placing it among the largest repository of publicly available, clinically annotated genomic data in the world. GENIE has emerged as a powerful resource to evaluate genome-guided clinical trial design, uncover drivers of cancer subtypes, and inform real-world use of genomic data.This article is highlighted in the In This Issue feature, p. 2007

Supplementary Table from AACR Project GENIE: 100,000 Cases and Beyond

Supplementary Figure from AACR Project GENIE: 100,000 Cases and Beyond

SummaryUnderstanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from: COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19 recovered vaccinees (convalescent, vaccinated) and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19 recovered vaccinees displayed improved antibody neutralizing activity, FcγR engagement and IgA compared to COVID-19 uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma. IgG, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased pre-existing vaccine-induced immunity to the ancestral strain. Salivary antibodies delayed initiation of boosting following breakthrough COVID-19 infection, especially Omicron BA.2, however, rose rapidly thereafter. Our data highlight how pre-existing immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.

Background: Ultraportable X-ray devices coupled with artificial intelligence (AI) are beginning to be used widely to screen for TB in remote settings. Few studies have documented their performance. Methods: We organized screening camps in Gombe and Adamawa states of Northeast Nigeria using a team of a registration officer, data entry staff, a radiographer, and a coordination officer. All consenting individuals ≥ 15 years were screened for TB symptoms (cough, fever, night sweats, and weight loss) and received a CXR. We used a MinXray Impact system interpreted by AI (qXR V3), which is a fully integrated wireless setup, can be run without electricity, and weighs approximately 30kg. We collected sputum samples from individuals with an abnormality score of .30 or higher or if they reported any TB symptoms. Samples were transported for testing with Xpert MTB/RIF. We documented the TB screening cascade and evaluated the performance of screening with different combinations of CXR read by AI and symptoms. Results: We screened 5,298 individuals during 66 camps; 2,685 (51%) were females, and 2,613 (49%) were males. Using ≥ 2 weeks of cough to define presumptive TB, 1,056 people (20%) would be identified. If a cough of any duration was used, the number with presumptive TB increased to 1,889 (36%) and to 3,084 (58%) if any of the four symptoms were used. Overall, 770 (14.5%) had abnormality scores of 0.3 or higher, and 447 (8.4%) had a score of 0.5 or higher. We collected 1,022 samples for Xpert testing and detected 85 (8%) individuals with TB. Traditional symptom screening of prolonged cough only identified 40% of people with TB, while using any symptom detected 90.6% of people with TB, but specificity was 11.4%. Using an AI abnormality score of .50, only used 424 tests to identify 89.4% of people with TB with a specificity of 62.8%. Conclusion: Ultra-portable CXR can be used to provide better TB screening in hard-to-reach areas. Symptom screening may miss large proportions of people with bacteriologically confirmed TB. Employing AI to read CXR can improve triaging when human readers are unavailable and can save expensive diagnostic testing costs.

PurposeMonitoring levels of circulating tumor-derived DNA (ctDNA) represents a non-invasive snapshot of tumor burden and potentially clonal evolution. Here we describe how a novel statistical model that uses serial ctDNA measurements from shallow whole genome sequencing (sWGS) in metastatic breast cancer patients produces a rapid and inexpensive assessment that is predictive of treatment response and progression-free survival.Patients and MethodsA cohort of 188 metastatic breast cancer patients had DNA extracted from serial plasma samples (total 1098, median=4, mean=5.87). Plasma DNA was assessed using sWGS and the tumor fraction in total cell free DNA estimated using ichorCNA. This approach was compared with ctDNA targeted sequencing and serial CA 15-3 measurements. The longitudinal ichorCNA values were used to develop a Bayesian learning model to predict subsequent treatment response.ResultsWe identified a transition point of 7% estimated tumor fraction to stratify patients into different categories of progression risk using ichorCNA estimates and a time-dependent Cox model, validated across different breast cancer subtypes and treatments, outperforming the alternative methods. We then developed a Bayesian learning model to predict subsequent treatment response with a sensitivity of 0.75 and a specificity of 0.66.ConclusionIn patients with metastatic breast cancer, sWGS of ctDNA and ichorCNA provide prognostic and predictive real-time valuable information on treatment response across subtypes and therapies. A prospective large-scale clinical trial to evaluate clinical benefit of early treatment changes based on ctDNA levels is now warranted.

The advancements in Internet-connected drones and edge computing raise the possibility of an on-the-fly inspection service that can instantly report the results. Inspection of sites using a drone fleet requires planning to meet situational requirements while minimizing operational costs under uncertainties of inspection requests, the urgency of reports, and the availability of communication channels. In this work, with the restriction on drone flying time, we decompose the planning into two phases: i) pre-computing groups of sites and ii) three-stage stochastic programming. The former phase generates feasible groups of sites, each of which is served by a drone, and pre-computes the minimum-cost flying path for each group. The latter phase, given the feasible groups, jointly optimizes drone placement and data delivery under the uncertainties. The two-phase approach allows the planning to scale up to a practical situation. The performance evaluations show that the overall cost can be saved even if uncertainties exist, and the proposed approach significantly outperforms other methods, which do not consider the uncertainties. For a larger problem size, a heuristic algorithm is proposed to trade a loss in the optimality of 1:05-1:09 times the cost with 3:67-483:97 times speed-up in computation time.

Acute type A aortic dissection requires timely diagnosis and intervention. Previous studies have examined risk factors associated with delayed diagnosis; however, the effect of socioeconomic status (SES) has not been previously studied. Our study examined the impact of various SES measures on time to diagnosis. We examined time to diagnosis in consecutive cases of acute type A aortic dissection at a single institution. SES variables included race/ethnicity, Medicaid eligibility, and residence in a zip code with an increased Distressed Communities Index-an aggregate measure of community SES. Delayed diagnosis was defined as time to diagnosis in the upper quartile of the study population (6.6 hours). A model predicting risk factors for delayed diagnosis was created using multivariable logistic regression. Our study included 124 patients with a median time to diagnosis of 3.36 hours (interquartile range [IQR] 1.83 to 6.63). A total of 92 patients were in the nondelayed cohort (median diagnosis time of 2.59 hours, IQR 1.49 to 4.18) and 32 patients were in the delayed cohort (median diagnosis time of 15.57 hours, IQR 9.34 to 28.75). In multivariable logistic regression, residence in a high-Distressed Communities Index zip code was associated with diagnostic delay (adjusted odds ratio [aOR] 5.108, p = 0.008). Patient age (aOR 0.944, p = 0.011), chest pain at presentation (aOR 0.099, p = 0.004), back pain at presentation (aOR 0.247, p = 0.012), evidence of malperfusion syndrome (aOR 0.040, p0.001), history of hyperlipidemia (aOR 3.507, p = 0.026), and history of congestive heart failure (aOR 0.061, p = 0.036) were also significantly associated. In conclusion, our findings suggest community-level SES affects time to diagnosis in acute type A aortic dissection.

Chest pain is a common presenting complaint with a broad differential diagnosis. Even after the full array of special investigations, a cause cannot be found in some patients. Psychological factors can play a significant role in the perception of chest pain. Patients with such a psychological disturbance may not meet the full criteria for a diagnosable psychiatric illness, and thus cannot be assigned a specific diagnosis. Not knowing how to manage this situation can lead to poor rapport between doctor and patient. Through their clinical acumen, judicious use of special investigations and by forming a therapeutic alliance, clinicians can identify and help these patients.

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The intent of this paper is to reveal the must know current trends and perspectives in countering Human Immunodeficiency Virus Infection amp Acquired Immuno deficiency Syndrome HIVAIDS locally and globally. The different perspectives include physical interventions pharmacological interventions psychobehavioural interventions social interventions and interventions related to vocation plus finances to enhance amp sustain the quality of life of people living with HIVAIDS in terms of wellbeing. The aim of this paper was to unveil the new strategies in dealing with prevention and control of HIVAIDS with efforts to elevate the sense of negativity and manifest the acceptable or affordable living standards of people diagnosed with HIVAIDS

The burgeoning field of twistronics, which concerns how changing the relative twist angles between two materials creates new optoelectronic properties, offers a novel platform for studying twist-angle dependent excitonic physics. Herein, by surveying a range of hexagonal phase transition metal dichalcogenides (TMD) twisted homobilayers, we find that 21.8 ± 1.0°-twisted (

Drawing on literature on values in science and a case-study of UK cancer policy, this paper argues for a novel account of the demarcation project in terms of trustworthiness. The first part of the paper addresses the relationship between science, politics and demarcation. In 2010, the UK government decided to pay more for cancer drugs than for drugs for other diseases; in 2016, this Cancer Drugs Fund was reformed so as to lower the evidential standards for approving cancer drugs, rather than paying more for them. Are these two ways of treating cancer as “special” importantly different? This paper argues that, if we the argument from inductive risk seriously, they seem equivalent. This result provides further reason to doubt the notion of demarcating science from non-science. However, the second part of the paper complicates this story, arguing that considerations of epistemic trust might give us reasons to prefer epistemic communities centred around “broadly acceptable” standards, and which are “sociologically well-ordered”, regardless of inductive risk concerns. After developing these claims through the cancer case-study, the final section suggests how these concerns might motivate novel versions of the demarcation project.

The feasibility of the Northern Sea Route is assessed for seasonal operations of oil product tankers using alternative fuel types. A speed optimisation model is used that minimises the required freight rate (RFR) of a Long Range 2 (LR2) tanker against alternative routes. A cost model is developed that incorporates real hourly speed data from tanker voyages between the 2011 and 2019 summer/autumn seasons, and primary and secondary data regarding cost and operational factors. The analysis is based on naphtha and jet fuel/kerosene trades between Europe and Asia. A prospective ban on the use of High Sulphur Fuel Oil (HSFO) in the Arctic, and alternative fuels, such as the new Very Low Sulphur Fuel Oil (VLSFO) and Liquified Natural Gas (LNG) are included to take into account of the International Maritime Organisation (IMO) 2020 global sulphur limit and its long-term strategy towards the reduction of greenhouse gas emissions.

Respiratory disease is a leading cause of death in children under 5 years of age worldwide, and most of these deaths occur in low- to middle-income countries (LMICs) where advanced respiratory care technology is often limited. Much of the equipment required to provide advanced respiratory care is unavailable in these areas due to high costs, the need for specialty trained personnel, and myriad other resource constraints that limit uptake and sustainable use of these devices, including reliable access to electricity, sensitive equipment needing frequent maintenance, single-patient-use supplies, and lack of access to sterilization equipment. Compounding the problem, pediatrics is uniquely challenging in that one size does not fit all, or even most patients. Despite these substantial barriers, numerous innovations in respiratory care technology have been made in recent years that have brought increasing access to high quality respiratory care in some of the most remote areas of the world. In this article, we intend to review the global burden of respiratory diseases for children, highlight the prototypical innovations that have been made in bringing respiratory care to LMICs, spotlight some of the technologies being actively developed to improve respiratory care in resource-constrained settings, and conclude with a discussion highlighting areas where further innovation is still needed.

The requirements for offshore drilling continue to evolve to meet the needs of the industry, new technologies and drilling practices need to be adopted to accommodate these increasingly challenging environments. These new environments present challenges that include, but are not limited to, hole cleaning, wellbore stability, narrow margin drilling, and drilling fluid system stability over a wide range of temperatures. A high degree of planning and preparation is required in order to execute these wells, which will reduce any chance for a nonproductive time and deliver expected return on investment of the project. The need for a drilling fluid system that is designed to drill these challenging wells, is crucial to ensure the success of a project. The well presented in this paper was the first well drilled in Lebanon and emphasizes the benefits of a low equivalent circulating density (ECD) impact drilling fluid when utilized in a deep-water environment. During the drilling phase of the project, the fluid was able to meet the demands of the operation by providing a low ECD while dealing with a range of temperature gradients that are associated with deep-water environments. The drilling fluid's unique performance ensured that any relevant nonproductive time events were mitigated and ensured the final delivery of the well. In addition, the fluid was able to meet these challenges with no additional treatment or modifications to the original planned fluid parameters for the project. The low-impact, non-aqueous drilling fluid (LDIF) provided shear-thinning properties, flat rheological profile and non-progressive rapid-set/easy break gels. The fluid system benefited from a unique design that allowed the use of high yielding organophilic clay while utilizing an industry established low viscosity base oil. The synergy of the drilling fluid system when tailored to the base oil with kinematic viscosity as low as 1.7 cSt was able to provide rheological properties commonly associated to a clay-free non-aqueous base drilling fluid. The drilling fluid was able to provide a rheology that delivered a flat profile over the operating temperature range, while facilitating control of the ECD through the well. This operational experience shows how the choice of a proper fluid system together with a proper base fluid can ensure the unique challenges for the industry today can be successfully met.

During the early stages of the Covid pandemic, the oil and gas industry was faced with significant challenges in executing inspections for ageing offshore oil and gas infrastructure together with the management of various operational integrity threats. These challenges were addressed through the collaborative development of remote, digital techniques to minimise inspector time offshore and maximise efficiency. This initially involved a review and challenge of our existing operational integrity management lifecycle, comprising systems data, risk-based strategy development, inspection planning, inspection execution, data management, anomaly management (including fabric maintenance and engineering repairs) and close-out. Working with our partner, GDi, we sought to drive a step change into digital integrity management, combined with streamlined workflows, activities, and administrative tasks. The pilot development involved comprehensive laser scanning of a floating production storage and offloading (FPSO) facility to generate a dimensionally accurate digital twin, overlayed with 360° HD photogrammetry to provide a thorough baseline for subsequent general visual inspections of pressure equipment, piping systems and structural elements. General visual inspections can now be executed remotely, without the requirement for an offshore inspector. The digital twin environment also supported transformation of inspector-led activities, through optimisation of processes, digital inspection workflows via tablets and seamless integration with the integrity management platform. The pilot development also involved enhancing the anomaly risk management process, including management of mitigations (such as temporary repairs) and actions required to resolve and close anomalies. For the anomaly actions, the digital twin environment enables the accurate estimation of fabric maintenance scopes and dimensionally accurate repairs for corrective work orders. The system also facilitates a unique overview of cumulative risk via the plotting of anomalies in the digital twin space. The digitally enhanced operational integrity management system has substantially reduced direct costs and personnel safety risks, enabled substantial improvements in productivity (up to 200% for inspections), and improved the quality of integrity management outcomes.

African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei (T. brucei) and spread by the tsetse fly in sub-Saharan Africa. The trypanosome relies on heat shock proteins for survival in the insect vector and mammalian host. Heat shock protein 90 (HSP90) plays a crucial role in the stress response at the cellular level. Inhibition of its interactions with chaperones and co-chaperones is being explored as a potential therapeutic target for numerous diseases. This study provides an in silico overview of HSP90 and its co-chaperones in both T. brucei brucei and T. brucei gambiense in relation to human and other trypanosomal species, including non-parasitic Bodo saltans and the insect infecting Crithidia fasciculata. A structural analysis of T. brucei HSP90 revealed differences in the orientation of the linker and C-terminal domain in comparison to human HSP90. Phylogenetic analysis displayed the T. brucei HSP90 proteins clustering into three distinct groups based on subcellular localizations, namely, cytosol, mitochondria, and endoplasmic reticulum. Syntenic analysis of cytosolic HSP90 genes revealed that T. b. brucei encoded for 10 tandem copies, while T. b. gambiense encoded for three tandem copies; Leishmania major (L. major) had the highest gene copy number with 17 tandem copies. The updated information on HSP90 from recently published proteomics on T. brucei was examined for different life cycle stages and subcellular localizations. The results show a difference between T. b. brucei and T. b. gambiense with T. b. brucei encoding a total of twelve putative HSP90 genes, while T. b. gambiense encodes five HSP90 genes. Eighteen putative co-chaperones were identified with one notable absence being cell division cycle 37 (Cdc37). These results provide an updated framework on approaching HSP90 and its interactions as drug targets in the African trypanosome.

TheVarroa destructorectoparasitic mite has spread globally and in conjunction with Deformed Wing Virus has killed millions of honeybee (Apis mellifera) colonies. This has forced Northern hemisphere beekeepers into using miticides to avoid mass colony losses. However, in many Southern hemisphere countries widespread treatment did not occur since miticides were prohibitively expensive, or a centralised choice was made not to treat, both allowing natural selection to act. The Varroa mite initially caused high losses before mite-resistance appeared in the honeybee populations. Initially, mite-resistance was only associated with African and Africanised honeybees. Although recently, several isolated mite-resistant European honeybee populations have appeared. Here we studied the mite-resistance in Cuba and found high rates of recapping of infested worker cells (77%), high removal of mites (80%) and corresponding low mite fertility (r = 0.77). These are all traits found in all naturally evolved Varroa-resistant populations. We can confirm Cuba has the world’s largest European mite-resistant population with 220,000 colonies that have been treatment-free for over two decades and illustrating the power of natural selection. Cuban honeybees are also highly productive, 40–70 kg of honey produced annually, and are mild mannered. Cuba is an excellent example of what is possible when honeybees are allowed to adapt naturally to Varroa with minimal human interference.

PurposeThis paper provides a contextualised review of research in the area of humanitarian and emergency relief logistics, providing insights with particular emphasis on lessons learned. The paper tracks the evolution of research against the development of partner networks and key global events; information was collated and assimilated from cross-cutting themes such as disaster preparedness, emergency response structures and the transferability of commercial-world concepts and principles (such as sustainability) into volatile and fragile environments. It concludes by suggesting possible future challenges which could steer humanitarian response on the ground and will influence the path of academic research going forward.Design/methodology/approachThe paper provides a general review of work undertaken in the area of Humanitarian Logistics. Use is made of vignettes of case studies in order to provide focus to the discussion and to highlight key issues that emerged from the research reviewed.FindingsThe findings show that there are several new areas of research which will need to be addressed in the humanitarian logistics arena. The discussion demonstrates that research into crisis response is arguably even more important today than it has been previously. Research therefore likely needs to be expanded considerably over the next decade and beyond.Originality/valueThis paper contextualises and synthesises past research into humanitarian logistics responses, highlights key themes and suggests areas for further research.

Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.

Domain-specific BET bromodomain ligands represent an attractive target for drug discovery with the potential to unlock the therapeutic benefits of antagonizing these proteins without eliciting the toxicological aspects seen with pan-BET inhibitors. While we have reported several distinct classes of BD2 selective compounds, namely, GSK620, GSK549, and GSK046, only GSK046 shows high aqueous solubility. Herein, we describe the lead optimization of a further class of highly soluble compounds based upon a picolinamide chemotype. Focusing on achieving >1000-fold selectivity for BD2 over BD1 ,while retaining favorable physical chemical properties, compound 36 was identified as being 2000-fold selective for BD2 over BD1 (Brd4 data) with >1 mg/mL solubility in FaSSIF media. 36 represents a valuable new in vivo ready molecule for the exploration of the BD2 phenotype.