Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols.

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89%, 99:1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5)- and C(6)-position, as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O•••isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Enantioselective Synthesis of Tetra-substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution.

A general and highly enantioselective method for the preparation of tetra-substituted 3-hydroxyphthalide esters via isothiourea-catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)-HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3-hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)-, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Interventions in ambulatory healthcare settings to reduce social isolation among adults aged 18-64: a systematic review.

BACKGROUND: Social isolation is associated with increased all-cause and premature mortality, poor chronic disease management, and mental health concerns. Limited research exists on interventions addressing social isolation among individuals under 65 despite its increasing prevalence among young and middle-aged adults. AIM: To identify interventions from the extant literature that address social isolation and loneliness in ambulatory healthcare settings in adults aged 18-64, and to identify elements of successful studies for future intervention design. DESIGN & SETTING: Systematic review of interventions targeting social isolation in community-dwelling adults aged 18-64 within ambulatory healthcare settings. METHOD: A search strategy was developed to identify relevant articles in the following databases: Ovid MEDLINE, Embase, EBM Reviews, Scopus, CINAHL and PsychInfo. Data were extracted on study design and setting, intervention type, outcome related to social isolation/loneliness and scale of measure used. RESULTS: 25,078 citations were identified and underwent title and abstract screening. 75 articles met our inclusion criteria and were synthesised, including an assessment of bias. Effective interventions were delivered in community health settings, incorporated a group component, and used digital technologies. They also addressed the association between mental health and social isolation using CBT approaches and enhanced self-management and coping strategies for chronic conditions through psycho-educational interventions. CONCLUSION: Future research should prioritise adults living in low- and middle-income countries, racialized individuals, as well as those with fewer educational opportunities. There is also a need to advance research in primary care settings, where longitudinal patient-provider relationships would facilitate the success of interventions.

Chronic disease prevention and screening outcomes for patients with and without financial difficulty: a secondary analysis of the BETTER WISE cluster randomised controlled trial.

OBJECTIVE: Building on Existing Tools To improvE chronic disease pRevention and screening in primary care Wellness of cancer survIvorS and patiEnts (BETTER WISE) was designed to assess the effectiveness of a cancer and chronic disease prevention and screening (CCDPS) programme. Here, we compare outcomes in participants living with and without financial difficulty. DESIGN: Secondary analysis of a cluster-randomised controlled trial. SETTING: Patients of 59 physicians from 13 clinics enrolled between September 2018 and August 2019. PARTICIPANTS: 596 of 1005 trial participants who responded to a financial difficulty screening question at enrolment. INTERVENTION: 1-hour CCDPS visit versus usual care. OUTCOME MEASURES: Eligibility for a possible 24 CCDPS actions was assessed at baseline and the primary outcome was the percentage of eligible items that were completed at 12-month follow-up. We also compared the change in response to the financial difficulty screening question between baseline and follow-up. RESULTS: 55 of 265 participants (20.7%) in the control group and 69 of 331 participants (20.8%) in the intervention group reported living with financial difficulty. The primary outcome was 29% (95% CI 26% to 33%) for intervention and 23% (95% CI 21% to 26%) for control participants without financial difficulty (p=0.01). Intervention and control participants with financial difficulty scored 28% (95% CI 24% to 32%) and 32% (95% CI 27% to 38%), respectively (p=0.14). In participants who responded to the financial difficulty question at both time points (n=302), there was a net decrease in the percentage of participants who reported financial difficulty between baseline (21%) and follow-up (12%, p<0.001) which was similar in the control and intervention groups. The response rate to this question was only 51% at follow-up. CONCLUSION: The BETTER intervention improved uptake of CCDPS manoeuvres in participants without financial difficulty, but not in those living with financial difficulty. Improving CCDPS for people living with financial difficulty may require a different clinical approach or that social determinants be addressed concurrently with clinical and lifestyle needs or both. TRIAL REGISTRATION NUMBER: ISRCTN21333761.

Hotspots of biogeochemical activity linked to aridity and plant traits across global drylands.

Perennial plants create productive and biodiverse hotspots, known as fertile islands, beneath their canopies. These hotspots largely determine the structure and functioning of drylands worldwide. Despite their ubiquity, the factors controlling fertile islands under conditions of contrasting grazing by livestock, the most prevalent land use in drylands, remain virtually unknown. Here we evaluated the relative importance of grazing pressure and herbivore type, climate and plant functional traits on 24 soil physical and chemical attributes that represent proxies of key ecosystem services related to decomposition, soil fertility, and soil and water conservation. To do this, we conducted a standardized global survey of 288 plots at 88 sites in 25 countries worldwide. We show that aridity and plant traits are the major factors associated with the magnitude of plant effects on fertile islands in grazed drylands worldwide. Grazing pressure had little influence on the capacity of plants to support fertile islands. Taller and wider shrubs and grasses supported stronger island effects. Stable and functional soils tended to be linked to species-rich sites with taller plants. Together, our findings dispel the notion that grazing pressure or herbivore type are linked to the formation or intensification of fertile islands in drylands. Rather, our study suggests that changes in aridity, and processes that alter island identity and therefore plant traits, will have marked effects on how perennial plants support and maintain the functioning of drylands in a more arid and grazed world.

Prescription Opioid Exposure During Pregnancy and Risk of Spontaneous Preterm Delivery.

Importance: Opioid exposure during pregnancy has been associated with preterm birth, but prior studies have not differentiated between spontaneous and indicated preterm birth or fully investigated these associations as functions of opioid dose. Objective: To determine whether prescription opioid use during pregnancy is associated with spontaneous preterm birth and whether the association is dose-dependent. Design, Setting, and Participants: This case-control study examined a retrospective cohort of pregnant patients enrolled in Tennessee Medicaid. Enrollment files were linked to health care encounters, hospital discharge information, birth certificate data, and prescription fills. Eligible participants were pregnant people ages 15 to 44 years without opioid use disorder who experienced birth of a single fetus at 24 weeks gestation or greater between 2007 and 2019 with linked birth certificate data. Cases of spontaneous preterm birth were matched with up to 10 controls based on pregnancy start date, race, ethnicity, age at delivery within 2 years, and history of prior preterm birth. Cases and matched controls were continuously enrolled in TennCare for at least 90 days prior to the index date (case delivery date). Exposure: Total opioid MME filled during the 60 days prior to the index date. Main Outcomes and Measures: The primary outcome was spontaneous preterm birth determined by a validated algorithm using birth certificate data. Conditional logistic regression was used to estimate the association between spontaneous preterm birth and total opioid morphine milligram equivalents (MME) dispensed, adjusting for parity, prepregnancy body mass index, education level, tobacco use, hepatitis infections, and pain indications. Results: A total of 25 391 cases (median [IQR] age, 23 [20-28] years; 127 Asian [0.5%], 9820 Black [38.7%], 664 Hispanic [2.6%]; 14 748 non-Hispanic White [58.1%]) with spontaneous preterm birth were identified and matched with 225 696 controls (median [IQR] age, 23 [20-27] years; 229 Asian [0.1%], 89 819 Black [39.8%], 3590 Hispanic [1.6%]; 132 002 non-Hispanic White [58.5%]) (251 087 patients total), with 18 702 patients (7.4%) filling an opioid prescription in the 60 days prior to the index date. Each doubling of nonzero opioid MME was associated with a 4% increase in the odds of spontaneous preterm birth compared with no opioid exposure (adjusted odds ratio, 1.04; 95% CI, 1.01-1.08). Conclusions and Relevance: In this case-control study, a positive association was found between total prescription opioid dose dispensed and the odds of spontaneous preterm birth. These findings support guidance to minimize opioid exposure during pregnancy and prescribe the lowest dose necessary.

New supporting data to guide the use of evident toxicity in acute oral toxicity studies (OECD TG 420).

Currently there are three test guidelines (TG) for acute oral toxicity studies of substances or mixtures from the Organisation for Economic Co-operation and Development (OECD). TG 423 and TG 425 use lethality as an endpoint, while TG 420 replaces death with 'evident toxicity', defined as clear signs that exposure to a higher dose would result in death. However, the perceived subjectivity of 'evident toxicity' may be preventing wider use of TG 420. To address this, the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and the European Partnership for Alternative Approaches to Animal Testing (EPAA) collaborated to provide recommendations on the recognition of 'evident toxicity'. Historical data from acute oral toxicity studies were analysed for clinical signs at the lower dose that could have predicted death at the higher dose. Several signs including ataxia, laboured respiration, and eyes partially closed, alone or in combination, are highly predictive. Others such as lethargy, decreased respiration, and loose faeces have lower but still appreciable positive predictive value (PPV). The data has been used to develop recommendations to promote use of TG 420 and thus reduce the suffering and numbers of animals used in acute oral toxicity studies.

Evaluating maternal health capacity building in rural and underserved areas: a research protocol.

INTRODUCTION: The US is currently experiencing a maternal health crisis. Maternal morbidity and mortality in the US are higher than in other developed nations and continue to rise. Infant mortality, likewise, is higher in the US than in other developed nations. Limited availability of maternal health services, particularly in rural areas, contributes to this crisis. Maternal health outcomes are poorer, and maternal care workforce shortages are more severe in rural areas of the US. In rural areas where obstetric specialists are rare, many patients rely on family medicine physicians for maternity care. However, the number of family medicine physicians who provide maternal care services is decreasing, aggravating shortages. Calls have been made to build maternal care capacity in rural areas. The role family medicine will play in addressing the maternal health crisis is not clear. Maternal care shortages are complex issues resulting from multiple factors; likewise, efforts to build maternal health capacity are challenging and require multifaceted approaches. METHODS: With funding from the Health Resources and Services Administration (HRSA), the University of Utah seeks to address the shortage of quality maternity care in rural and underserved areas of Utah by strengthening partnerships, enhancing maternal care training of family medicine residents and obstetrics fellows, and improving the transition from training to rural practice for residents and fellows. This protocol describes the evaluation of the HRSA-funded project. The evaluation includes three components. Component 1 consists of qualitative interviews with a diverse group of maternal health providers, administrators, educators and academics, patients, and others. Interviews will be analyzed using qualitative content analysis. Component 2 is a survey of family medicine residents and obstetrics fellows, which aims to increase understanding of the factors and circumstances influencing intention to practice in rural or underserved areas and to provide maternal health services. Component 3 involves surveying fellowship alumni and tracking graduates to assess effectiveness of training programs in producing physicians who provide maternal health services in rural and underserved areas. Surveys will be analyzed with descriptive statistics including means, frequencies, and cross-tabulations. If sample size and participation provide sufficient power, statistical tests will be included in analyses. RESULTS: Evaluation results will help to fill an important gap in research literature concerning outcomes of projects and initiatives designed to build maternal care capacity in rural areas of the US. In addition, results will provide valuable information regarding effective practices for building capacity, which can be adopted elsewhere to address maternal care shortages. Finally, results will help to define the role of family medicine in addressing the maternal health crisis. Amid maternal care shortages, fewer and fewer family medicine physicians are providing maternal care in their practice. Evaluation results will clarify the role of training and preparation of family medicine residents in addressing workforce shortages. CONCLUSION: This evaluation will provide important contributions, but additional research is needed, including research protocols and studies of project outcomes, to understand how best to resolve the maternal care crisis in the US.

Description of Uniphylus gen. nov., a new genus of Carcharodini (Lepidoptera, Hesperiidae, Pyrginae) for Staphylus evemerus Godman & Salvin, 1896.

Staphylus evemerus Godman & Salvin, 1896 is a species with a unique set of morphological characters within Carcharodini. Also, mitochondrial cytochrome oxidase subunit 1 (COI) sequences analysis demonstrated a large genetic distance with other related genera of the tribe. Therefore, this paper aims to describe a new genus for this species, which is named as Uniphylus gen. nov. Besides the morphological redescription of the male of Uniphylus evemerus (Godman & Salvin, 1896) new comb., the description of the female is provided for the first time, as well as an updated distributional map with all records known so far for this species.

Exploring the Stability and Disorder in the Polymorphs of L-Cysteine through Density Functional Theory and Vibrational Spectroscopy.

Static and dynamic density functional calculations are reported for the four known polymorphs of l-cysteine. Static calculations are used to explore the relative free energies (within the harmonic approximation) of the polymorphs as a function of pressure. An important feature of the structural differences between the polymorphs is shown to be the dihedral angle of the C-C-S-H bond. It is shown that, by varying this angle, it is possible to move between hydrogen bonding motifs S-H···S and S-H···O in all four polymorphs. The energetics for dihedral angle rotation are explored, and the barriers for rotation between the hydrogen bonding motifs have been calculated for each polymorph. Two possible models for the experimental disorder observed in Form I at room temperature are explored using both static and dynamic methods; a domain disorder model, where the disorder is localized, and a dispersed disorder model, where the disorder is randomly distributed throughout the crystal. Molecular dynamics calculations show transitions between the two hydrogen bonding motifs occurring in the dispersed disorder model at 300 and 350 K. In addition, molecular dynamics calculations of Form IV also showed the onset of hydrogen bond disorder at 300 K. Calculations of the predicted infrared and terahertz absorption are performed for both the static and dynamic simulations, and the results are compared with experimental results to understand the influence of disorder on the observed spectra.

Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies.

Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7-100 ng ml-1. These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future.

An Artificial Intelligence Training Workshop for Diagnostic Radiology Residents.

Purpose: To develop, implement, and evaluate feedback for an artificial intelligence (AI) workshop for radiology residents that has been designed as a condensed introduction of AI fundamentals suitable for integration into an existing residency curriculum. Materials and Methods: A 3-week AI workshop was designed by radiology faculty, residents, and AI engineers. The workshop was integrated into curricular academic half-days of a competency-based medical education radiology training program. The workshop consisted of live didactic lectures, literature case studies, and programming examples for consolidation. Learning objectives and content were developed for foundational literacy rather than technical proficiency. Identical prospective surveys were conducted before and after the workshop to gauge the participants' confidence in understanding AI concepts on a five-point Likert scale. Results were analyzed with descriptive statistics and Wilcoxon rank sum tests to evaluate differences. Results: Twelve residents participated in the workshop, with 11 completing the survey. An average score of 4.0 ± 0.7 (SD), indicating agreement, was observed when asking residents if the workshop improved AI knowledge. Confidence in understanding AI concepts increased following the workshop for 16 of 18 (89%) comprehension questions (P value range: .001 to .04 for questions with increased confidence). Conclusion: An introductory AI workshop was developed and delivered to radiology residents. The workshop provided a condensed introduction to foundational AI concepts, developed positive perception, and improved confidence in AI topics.Keywords: Medical Education, Machine Learning, Postgraduate Training, Competency-based Medical Education, Medical Informatics Supplemental material is available for this article. © RSNA, 2023.

Prioritisation of Informed Health Choices (IHC) key concepts to be included in lower secondary school resources: A consensus study.

BACKGROUND: The Informed Health Choices Key Concepts are principles for thinking critically about healthcare claims and deciding what to do. The Key Concepts provide a framework for designing curricula, learning resources, and evaluation tools. OBJECTIVES: To prioritise which of the 49 Key Concepts to include in resources for lower secondary schools in East Africa. METHODS: Twelve judges used an iterative process to reach a consensus. The judges were curriculum specialists, teachers, and researchers from Kenya, Uganda, and Rwanda. After familiarising themselves with the concepts, they pilot-tested draft criteria for selecting and ordering the concepts. After agreeing on the criteria, nine judges independently assessed all 49 concepts and reached an initial consensus. We sought feedback on the draft consensus from other stakeholders, including teachers. After considering the feedback, nine judges independently reassessed the prioritised concepts and reached a consensus. The final set of concepts was determined after user-testing prototypes and pilot-testing the resources. RESULTS: The first panel of judges prioritised 29 concepts. Based on feedback from teachers, students, curriculum specialists, and members of the research team, two concepts were dropped. A second panel of nine judges prioritised 17 of the 27 concepts that emerged from the initial prioritisation and feedback. Based on feedback on prototypes of lessons and pilot-testing a set of 10 lessons, we determined that it was possible to introduce nine concepts in 10 single-period (40-minute) lessons. We included eight of the 17 prioritised concepts and one additional concept. CONCLUSION: Using an iterative process with explicit criteria, we prioritised nine concepts as a starting point for students to learn to think critically about healthcare claims and choices.

Artificial Intelligence in Periodontology: A Scoping Review.

Artificial intelligence (AI) is the development of computer systems whereby machines can mimic human actions. This is increasingly used as an assistive tool to help clinicians diagnose and treat diseases. Periodontitis is one of the most common diseases worldwide, causing the destruction and loss of the supporting tissues of the teeth. This study aims to assess current literature describing the effect AI has on the diagnosis and epidemiology of this disease. Extensive searches were performed in April 2022, including studies where AI was employed as the independent variable in the assessment, diagnosis, or treatment of patients with periodontitis. A total of 401 articles were identified for abstract screening after duplicates were removed. In total, 293 texts were excluded, leaving 108 for full-text assessment with 50 included for final synthesis. A broad selection of articles was included, with the majority using visual imaging as the input data field, where the mean number of utilised images was 1666 (median 499). There has been a marked increase in the number of studies published in this field over the last decade. However, reporting outcomes remains heterogeneous because of the variety of statistical tests available for analysis. Efforts should be made to standardise methodologies and reporting in order to ensure that meaningful comparisons can be drawn.

Moral distress in carers for people with an intellectual disability who died during the COVID-19 pandemic, a template analysis extending the Barlem and Ramos model of moral distress.

BACKGROUND: This article aims to understand moral distress in carers of people with an intellectual disability during the COVID-19 pandemic. METHOD: Nine staff carers of seven people with an intellectual disability, who had been participants of the IDS-TILDA study in Ireland, who died during the COVID-19 pandemic participated in in-depth, semi-structured telephone interviews. Template analysis was used to analyze the interviews. RESULTS: Obstructions in performing their duties left carers feeling powerless and experiencing moral conflict distress, moral constraint distress and moral uncertainty distress. Most managed to connect to the moral dimension in their work through peer support, understanding they fulfilled the wishes of the deceased, and/or thinking about how they or others did the best they could for the person they were caring for. CONCLUSIONS: This research demonstrates that while restrictions may have been effective in reducing the spread of COVID-19, they were potentially damaging to carer wellbeing.

Radio Frequency - Assisted Ultrasonic Spray Freeze Drying for Pharmaceutical Protein Solids.

This study examined physical stability of spray freeze dried (SFD) bovine serum albumin (BSA) solids produced using the radio frequency (RF)-assisted drying technique. BSA formulations were prepared with varying concentrations of trehalose and mannitol, using an excipient-free formulation as control. These formulations were produced using either traditional ultrasonic spray freeze drying (SFD) or RF-assisted ultrasonic spray freeze drying (RFSFD). The dried formulations were then characterized using Karl Fischer moisture content measurement, powder X-ray diffraction (PXRD), size exclusion chromatography (SEC), and solid-state hydrogen/deuterium exchange with mass spectrometry (ssHDX-MS). Moisture content did not have a good correlation with the physical stability of the formulations measured by SEC. ssHDX-MS metrics such as deconvoluted peak areas of the deuterated samples showed a satisfactory correlation (R2 = 0.914) with the SEC stability data. RFSFD improved the stability of formulations with 20 mg/ml of trehalose and no mannitol, and had similar stability with all other formulations as compared to SFD. This study demonstrated that RFSFD technique can significantly reduce the duration of primary drying cycle from 48.0 h to 27.5 h while maintaining or improving protein physical stability as compared to traditional lyophilization.

Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces.

Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces1-4. ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses5-7. However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines8,9 and the release of tissue-protective amphiregulin (AREG)10-12. Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions13-15. Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.