Selective control of parasitic nematodes using bioactivated nematicides.

Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amid limited arable land1-4. Most traditional nematicides have been banned owing to poor nematode selectivity, leaving farmers with inadequate means of pest control4-12. Here we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome-p450-mediated bioactivation in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita, a highly destructive plant-parasitic nematode. Tests against numerous phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than most marketed nematicides. Selectivins are first-in-class bioactivated nematode controls that provide efficacy and nematode selectivity.

Impact of waning immunity against SARS-CoV-2 severity exacerbated by vaccine hesitancy.

The SARS-CoV-2 pandemic has generated a considerable number of infections and associated morbidity and mortality across the world. Recovery from these infections, combined with the onset of large-scale vaccination, have led to rapidly-changing population-level immunological landscapes. In turn, these complexities have highlighted a number of important unknowns related to the breadth and strength of immunity following recovery or vaccination. Using simple mathematical models, we investigate the medium-term impacts of waning immunity against severe disease on immuno-epidemiological dynamics. We find that uncertainties in the duration of severity-blocking immunity (imparted by either infection or vaccination) can lead to a large range of medium-term population-level outcomes (i.e. infection characteristics and immune landscapes). Furthermore, we show that epidemiological dynamics are sensitive to the strength and duration of underlying host immune responses; this implies that determining infection levels from hospitalizations requires accurate estimates of these immune parameters. More durable vaccines both reduce these uncertainties and alleviate the burden of SARS-CoV-2 in pessimistic outcomes. However, heterogeneity in vaccine uptake drastically changes immune landscapes toward larger fractions of individuals with waned severity-blocking immunity. In particular, if hesitancy is substantial, more robust vaccines have almost no effects on population-level immuno-epidemiology, even if vaccination rates are compensatorily high among vaccine-adopters. This pessimistic scenario for vaccination heterogeneity arises because those few individuals that are vaccine-adopters are so readily re-vaccinated that the duration of vaccinal immunity has no appreciable consequences on their immune status. Furthermore, we find that this effect is heightened if vaccine-hesitants have increased transmissibility (e.g. due to riskier behavior). Overall, our results illustrate the necessity to characterize both transmission-blocking and severity-blocking immune time scales. Our findings also underline the importance of developing robust next-generation vaccines with equitable mass vaccine deployment.

Long-term benefits of nonpharmaceutical interventions for endemic infections are shaped by respiratory pathogen dynamics.

COVID-19 nonpharmaceutical interventions (NPIs), including mask wearing, have proved highly effective at reducing the transmission of endemic infections. A key public health question is whether NPIs could continue to be implemented long term to reduce the ongoing burden from endemic pathogens. Here, we use epidemiological models to explore the impact of long-term NPIs on the dynamics of endemic infections. We find that the introduction of NPIs leads to a strong initial reduction in incidence, but this effect is transient: As susceptibility increases, epidemics return while NPIs are in place. For low R0 infections, these return epidemics are of reduced equilibrium incidence and epidemic peak size. For high R0 infections, return epidemics are of similar magnitude to pre-NPI outbreaks. Our results underline that managing ongoing susceptible buildup, e.g., with vaccination, remains an important long-term goal.

Alarming Trends in Dengue Incidence and Mortality in Bangladesh.

Bangladesh is currently experiencing the country's largest and deadliest dengue outbreak on record. This year's outbreak has been characterized by an early seasonal surge in cases, rapid geographic spread, and a high fatality rate. The alarming trends in dengue incidence and mortality this year is an urgent wake-up call for public health policymakers and researchers to pay closer attention to dengue dynamics in South Asia, to strengthen the surveillance system and diagnostic capabilities, and to develop tools and methods for guiding strategic resource allocation and control efforts.

From polarity to plurality: Perceptions of COVID-19 and policy measures in England and Scotland.

AIM: The aim of this study was to uncover perspectives on the COVID-19 pandemic and the responses implemented by the UK and Scottish Governments to help control the spread of infection. Such understanding could help to inform future responses to pandemics at individual, community and national levels. METHOD: Q methodology was used to elicit perspectives from people in England and Scotland with different experiences of the pandemic including public health officials, key workers, those on furlough, those who were unvaccinated or vaccinated to different levels, those who were 'shielding' because they were at higher risk and people with different scientific expertise. Participants rank-ordered phrases about different aspects of COVID-19 according to their viewpoint. Factor analysis was then conducted in conjunction with interview material from the same respondents. RESULTS: A four-factor solution was statistically supported and was interpretable alongside the qualitative accounts of participants loading on these factors. These four perspectives are titled Dangerous and Unaccountable Leadership, Fear and Anger at Policy and Public responses, Governing Through a Crisis and Injustices Exposed. CONCLUSION: The four perspectives demonstrate plurality and nuance in views on COVID-19 and the associated policies and restrictions, going beyond a binary narrative that has been apparent in popular and social media. The four perspectives include some areas of common ground, as well as disagreement. We argue that understanding the detail of different perspectives might be used to build cohesion around policy initiatives in future. PATIENT OR PUBLIC CONTRIBUTION: The development of the statement set, which is rank-ordered by participants in a Q study, and factor interpretations were informed by views of the general public. The statement set was initially developed using existing publicly available material based on members of the general public experiencing the pandemic first hand. It was then piloted with members of the public experiencing different challenges as a result of COVID-19 and the subsequent lockdown and updated based on feedback. Finally, interpretations of the identified factors were presented publicly and edited according to their feedback.

Toward Improving the Selectivity of Organic Halide Electrocarboxylation with Mechanistically Informed Solvent Selection.

The use of a liquid electrolyte is nearly ubiquitous in electrosynthetic systems and can have a significant impact on the selectivity and efficiency of electrochemical reactions. Solvent selection is thus a key step during optimization, yet this selection process usually involves trial-and-error. As a step toward more rational solvent selection, this work examines how the electrolyte solvent impacts the selectivity of electrocarboxylation of organic halides. For the carboxylation of a model alkyl bromide, hydrogenolysis is the primary side reaction. Isotope-labeling studies indicate the hydrogen atom in the hydrogenolysis product comes solely from the aprotic electrolyte solvent. Further mechanistic studies reveal that under synthetically relevant electrocarboxylation conditions, the hydrogenolysis product is formed via deprotonation of the solvent. Guided by these mechanistic findings, a simple computational descriptor based on the free energy to deprotonate a solvent molecule was shown to correlate strongly with carboxylation selectivity, overcoming limitations of traditional solvent descriptors such as pKa. Through careful mechanistic analysis surrounding the role of the solvent, this work furthers the development of selective electrocarboxylation systems and more broadly highlights the benefits of such analysis to electrosynthetic reactions.

Policy actors' perceptions of public participation to tackle health inequalities in Scotland: a paradox?

BACKGROUND: Health inequalities are persistent and widening with transformative policy change needed. Radically shifting policy to tackle upstream causes of inequalities is likely to require public participation to provide a mandate, evidence and to address questions of co-design, implementation and acceptability. The aim of this paper is to explore perceptions among policy actors on why and how the public should be involved in policymaking for health inequalities. METHODS: In 2019-2020, we conducted exploratory, in-depth, semi-structured interviews with 21 Scottish policy actors from a range of public sector bodies and agencies and third sector organisations that work in, or across, health and non-health sectors. Data were analysed thematically and used to examine implications for the development of participatory policymaking. RESULTS: Policy actors viewed public participation in policymaking as intrinsically valuable for democratic reasons, but the main, and more challenging, concern was with how it could affect positive policy change. Participation was seen as instrumental in two overlapping ways: as evidence to improve policies to tackle health inequalities and to achieve public acceptance for implementing more transformative policies. However, our analysis suggests a paradox: whilst policy actors place importance on the instrumental value of public participation, they simultaneously believe the public hold views about health inequalities that would prevent transformative change. Finally, despite broad agreement on the need to improve public participation in policy development, policy actors were uncertain about how to make the necessary changes due to conceptual, methodological and practical challenges. CONCLUSIONS: Policy actors believe in the importance of public participation in policy to address health inequalities for intrinsic and instrumental reasons. Yet, there is an evident tension between seeing public participation as a route to upstream policies and a belief that public views might be misinformed, individualistic, short-term or self-interested and doubts about how to make public participation meaningful. We lack good insight into what the public think about policy solutions to health inequalities. We propose that research needs to shift from describing the problem to focusing more on potential solutions and outline a potential way forward to undertake effective public participation to tackle health inequalities.

Developing a combined framework for priority setting in integrated health and social care systems.

BACKGROUND: There is an international move towards greater integration of health and social care to cope with the increasing demand on services.. In Scotland, legislation was passed in 2014 to integrate adult health and social care services resulting in the formation of 31 Health and Social Care Partnerships (HSCPs). Greater integration does not eliminate resource scarcity and the requirement to make (resource) allocation decisions to meet the needs of local populations. There are different perspectives on how to facilitate and improve priority setting in health and social care organisations with limited resources, but structured processes at the local level are still not widely implemented. This paper reports on work with new HSCPs in Scotland to develop a combined multi-disciplinary priority setting and resource allocation framework. METHODS: To develop the combined framework, a scoping review of the literature was conducted to determine the key principles and approaches to priority setting from economics, decision-analysis, ethics and law, and attempts to combine such approaches. Co-production of the combined framework involved a multi-disciplinary workshop including local, and national-level stakeholders and academics to discuss and gather their views. RESULTS: The key findings from the literature review and the stakeholder workshop were taken to produce a final combined framework for priority setting and resource allocation. This is underpinned by principles from economics (opportunity cost), decision science (good decisions), ethics (justice) and law (fair procedures). It outlines key stages in the priority setting process, including: framing the question, looking at current use of resources, defining options and criteria, evaluating options and criteria, and reviewing each stage. Each of these has further sub-stages and includes a focus on how the combined framework interacts with the consultation and involvement of patients, public and the wider staff. CONCLUSIONS: The integration agenda for health and social care is an opportunity to develop and implement a combined framework for setting priorities and allocating resources fairly to meet the needs of the population. A key aim of both integration and the combined framework is to facilitate the shifting of resources from acute services to the community.

The impact of COVID-19 nonpharmaceutical interventions on the future dynamics of endemic infections.

Nonpharmaceutical interventions (NPIs) have been employed to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), yet these measures are already having similar effects on other directly transmitted, endemic diseases. Disruptions to the seasonal transmission patterns of these diseases may have consequences for the timing and severity of future outbreaks. Here we consider the implications of SARS-CoV-2 NPIs for two endemic infections circulating in the United States of America: respiratory syncytial virus (RSV) and seasonal influenza. Using laboratory surveillance data from 2020, we estimate that RSV transmission declined by at least 20% in the United States at the start of the NPI period. We simulate future trajectories of both RSV and influenza, using an epidemic model. As susceptibility increases over the NPI period, we find that substantial outbreaks of RSV may occur in future years, with peak outbreaks likely occurring in the winter of 2021-2022. Longer NPIs, in general, lead to larger future outbreaks although they may display complex interactions with baseline seasonality. Results for influenza broadly echo this picture, but are more uncertain; future outbreaks are likely dependent on the transmissibility and evolutionary dynamics of circulating strains.

Type 1 Diabetes Continuous Glucose Monitoring Use in the Pediatric Emergency Department Affects Laboratory Test Frequency but Not Treatment Timing.

Regular use of continuous glucose monitoring (CGM) in type 1 diabetes management increases the achievement of glycemic targets and reduces health care utilization, specifically emergency department (ED) visits. This retrospective chart review examined the effects of CGM use in patients with type 1 diabetes in a pediatric ED. Use of CGM was associated with several differences in patient management in the ED. This work is a first step toward development of guidelines for the appropriate use of CGM in the pediatric ED. In the future, CGM use in type 1 diabetes may lead to reduced ED-specific health care costs.

Escape the Monotony: Gamification Enhances Nursing Education.

INTRODUCTION: Creating meaningful and engaging learning opportunities can be challenged by budgets, time, and learning management systems with limited methods of interaction. An innovative method was necessary to meet competency evaluation and continuing education needs for emergency department staff. DESIGN: Gamification and simulation techniques were combined to offer an interactive learning opportunity through an escape room format to improve engagement and knowledge retention. This educational offering was designed to enhance staff learning of trauma care and processes at emergency departments that are not designated trauma centers. OUTCOMES: Emergency department team members completed the trauma escape room challenge, and postsurvey results demonstrated favorable ratings of new knowledge acquisition, skill competency, teamwork, and confidence when providing care for a trauma patient. DISCUSSION: Nurse educators can "escape" the monotony of passive learning by using active learning strategies including the fun of gamification to improve clinical skills and confidence.

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein.

PURPOSE: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. METHODS: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. RESULTS: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. CONCLUSION: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.

Predictive value of incidental right ventricular abnormalities identified on SPECT for mortality and pulmonary hypertension.

BACKGROUND: The clinical significance of incidentally found RV abnormalities on low-risk SPECT studies is not well-defined. The objective of this study was to determine the predictive value of incidental right ventricular (RV) abnormalities identified on single photon emission computed tomography (SPECT) scans for mortality and pulmonary hypertension (PH). METHODS: We retrospectively analyzed all low-risk SPECT studies in patients without known coronary artery or pulmonary vascular disease, performed at our institution, from 2007-2020. Adjusted Cox proportional hazards models were used to evaluate the association between incidental RV abnormalities on low-risk SPECT studies and outcomes. RESULTS: Of the 4761 patients included in the analysis, mortality events were present in 494, and echocardiographic PH was present in 619. Incidental RV abnormalities on low-risk SPECT studies were significantly and independently associated with all-cause mortality (HR = 1.41, CI [1.07-1.86], P = 0.0152) and echocardiographic PH (HR = 2.06, CI [1.64-2.60], P < 0.0001). CONCLUSIONS: These data suggest incidental RV abnormalities found on low-risk SPECT imaging studies are significantly and independently associated with increased mortality and risk of developing echocardiographic PH, and could identify high-risk patients for closer monitoring and additional diagnostic testing.

Staphylococcal Scalded Skin Syndrome, Identification, and Wound Care: A Case Report Series.

INTRODUCTION: Methicillin-susceptible Staphylococcus aureus (MSSA) infections cause diseases ranging from localized skin infections to serious invasive infections. Neonates are immunosuppressed, placing them at increased risk for MSSA infections, including staphylococcal scalded skin syndrome (SSSS), a rare severe skin presentation of MSSA. CLINICAL FINDINGS: We present a case series of 3 preterm infants with SSSS receiving care at a level 3 neonatal intensive care unit. PRIMARY DIAGNOSIS: The infants presented with symptoms of sepsis, including temperature instability, apnea, and bradycardia episodes. The infants had peeling skin at sites of external pressure, including peripheral intravenous (IV) sites, under dressings, or where devices had been in contact with skin. INTERVENTIONS: The infants were soaked in a tub with gel baby wash and water to remove leads without traumatizing the skin. Laboratory values were drawn, and cultures were obtained. Wound care was provided using mupirocin, soft silicone mesh wound contact layer, and soft cotton bandage gauze. Supportive respiratory care was provided, and IV antibiotics were administered. OUTCOMES: The infants were discharged to their homes with intact skin. One infant experienced a loss of pigment that persisted several weeks. All patients were without scarring by early childhood. PRACTICE RECOMMENDATIONS: Thorough assessment and careful hygiene of neonates' skin is crucial. MSSA is an infection that can appear on the skin. It is important to quickly diagnose and treat this type of infection, especially when it presents as a localized pustule, boil, tear, peeling, or crust before it becomes systemic.

Augmentative and alternative communication for Aboriginal Australians: Developing core vocabulary for Yolŋu speakers.

Yolŋu, Aboriginal people from Arnhem Land, Australia are at risk of Machado-Joseph disease, with progressive loss of speech. Yolŋu are interested in developing augmentative and alternative communication (AAC) systems in their own languages. This research aimed to develop a culturally responsive process to explore and create a core vocabulary word list for Yolŋu adults living with the disease for inclusion in AAC system prototypes. A list of 243 Yolŋu words and morphemes was created. In this highly collaborative, mixed methods, participatory action research, Balanda (the Yolŋu word for non-Aboriginal people) and Yolŋu researchers conducted cycles of transcription and analysis of a language sample, with oral group discussions to identify which words to include, omit, or add, based on Yolŋu perceptions of the structure and use of their languages. A Yolŋu metaphor, Gulaka-buma ("Harvesting yams"), was identified by Yolŋu researchers to represent and share the research process and findings. Three key themes were identified that summarize the main cultural and linguistic considerations related to changes made to the core vocabulary. Study findings emphasized the role of language as an expression of culture and identity for Indigenous peoples and the importance of considering cultural and linguistic factors in selecting vocabulary for AAC systems.

Designing augmentative and alternative communication systems with Aboriginal Australians: vocabulary representation, layout, and access.

Yolŋu (Aboriginal Australians of northeast Arnhem Land) are interested in developing augmentative and alternative communication (AAC) systems in their own languages to support communication opportunities and participation for their family members living with Machado-Joseph disease. Designing AAC systems in Aboriginal languages requires consideration of unique linguistic and cultural elements. Participatory action research in strength-based communication contexts was carried out by Yolŋu and Balanda (the Yolŋu word for non-Aboriginal people) researchers working together through a collaborative intercultural process. Culturally responsive literacy, language, and AAC activities were used to develop four prototype Yolŋu AAC sytems for Yolŋu with varied literacy skills. Data were coded using gerunds to identify and focus on action in the data. Reflective and analytical collaborative, oral group discussions were used to identify key considerations and, ultimately, a Yolŋu metaphor for the research. Yolŋu language, culture and worldview impacted all aspects of prototype design and decision making. Salient considerations related to representation, organization, layout, and access, are presented. Clinical implications and future research considerations are outlined.

Dearomative Cyclopropanation of Naphthols via Cyclopropene Ring-Opening.

The dearomatization of 2-naphthols represents a simple method for the construction of complex 3D structures from simple planar starting materials. We describe a cyclopropanation of 2-naphthols that proceeds via cyclopropene ring-opening using rhodium and acid catalysis under mild conditions. The vinyl cyclopropane molecules were formed with high chemoselectivity and scalability, which could be further functionalized at different sites. Both computational and experimental evidence were used to elucidate the reaction mechanism.

Dynamic architecture of the Escherichia coli structural maintenance of chromosomes (SMC) complex, MukBEF.

Ubiquitous Structural Maintenance of Chromosomes (SMC) complexes use a proteinaceous ring-shaped architecture to organize and individualize chromosomes, thereby facilitating chromosome segregation. They utilize cycles of adenosine triphosphate (ATP) binding and hydrolysis to transport themselves rapidly with respect to DNA, a process requiring protein conformational changes and multiple DNA contact sites. By analysing changes in the architecture and stoichiometry of the Escherichia coli SMC complex, MukBEF, as a function of nucleotide binding to MukB and subsequent ATP hydrolysis, we demonstrate directly the formation of dimer of MukBEF dimer complexes, dependent on dimeric MukF kleisin. Using truncated and full length MukB, in combination with MukEF, we show that engagement of the MukB ATPase heads on nucleotide binding directs the formation of dimers of heads-engaged dimer complexes. Complex formation requires functional interactions between the C- and N-terminal domains of MukF with the MukB head and neck, respectively, and MukE, which organizes the complexes by stabilizing binding of MukB heads to MukF. In the absence of head engagement, a MukF dimer bound by MukE forms complexes containing only a dimer of MukB. Finally, we demonstrate that cells expressing MukBEF complexes in which MukF is monomeric are Muk-, with the complexes failing to associate with chromosomes.

Preoperative Intravenous Versus Oral Acetaminophen in Outpatient Surgery: A Double-Blinded, Randomized Control Trial.

PURPOSE: Preoperative acetaminophen is recognized as an effective part of the multimodal approach to perioperative pain management. The present study, conducted between April 12, 2018 and February 14, 2019, examined whether there are differences in patient-reported pain, postoperative opioid consumption, negative opioid effects, length of postanesthesia care unit stay, and patient satisfaction with pain control between patients who receive intravenous (IV) acetaminophen and patients who receive oral acetaminophen. DESIGN: This double-blinded, randomized controlled trial was conducted among 120 patients undergoing outpatient surgery. METHODS: Patients were randomized to receive preoperatively either intravenous (IV) acetaminophen (and oral placebo) or oral acetaminophen (and IV placebo). Results were analyzed using SPSS statistical software; statistical analyses consisted of Mann-Whitney U test, independent samples t test, and χ2 test. In all analyses, a P value less than .05 was considered significant. FINDINGS: There were no significant differences in any outcome measures based on the route of acetaminophen administration. CONCLUSIONS: The findings of the present study support the practice of administering oral acetaminophen, as opposed to IV acetaminophen, preoperatively as part of the multimodal approach to manage postoperative pain in patients able to tolerate preoperative oral medications.