The Influence of the 1988 and 2003 IOM Future of Public Health Reports on the CDC.

The landmark 1988 Institute of Medicine report The Future of Public Health served the public health community well by pointing to what needed to be done, fostering a sense of urgency, and offering concrete directions to be pursued. In this article, the impact of the 1988 report, and of the subsequent 2003 report on the Centers for Disease Control and Prevention (CDC), is considered by tracing the course of the ideas that influenced the consciousness of the public health community and subsequently catalyzed concrete action. Among these ideas was that "public health is in disarray." This assessment led to an awareness that something needed to be done. Further, by stating that the public health enterprise had 3 core functions (assessment, policy development, and assurance), the 1988 report set in motion policy development to address the "disarray." At a more fundamental level, both reports championed the need for governmental public health (particularly at the CDC) to take action to strengthen the capacity of local and state public health agencies to address a growing range of public health threats and emergencies. (Am J Public Health. 2024;114(5):489-494. https://doi.org/10.2105/AJPH.2024.307598).

First principles study of layered scandium disulfide for use as Li-ion and beyond-Li-ion batteries.

The growing demand for high efficiency portable batteries has prompted a deeper exploration for alternative cathode materials. Due to low Earth abundance, scandium has not received much attention, however its low atomic mass makes it ideal for high gravimetric capacity electrodes. Here we have performed a comprehensive first-principles study to assess the performance of layered ScS2 as a potential cathode for lithium-ion and beyond-lithium-ion batteries. We have explored the configuration space of ScS2 and its intercalated compounds using a mix of machine learning and ab initio techniques, finding the ground state geometry to be layered in nature. This layered structure is found to have a high voltage, reaching above 4.5 V for Group I intercalants, ideal volume expansions below 10% for lithium and magnesium intercalation, is electronically conductive, and is ductile once intercalated. Of the intercalants considered, we find that lithium is the best choice for cathode applications, for which we have used a combination of thermodynamic phase diagrams, ab intio phonon calculations, and evaluation of the elastic tensor to conclude that ScS2 possesses a reversible capacity of 182.99 mA h g-1, on par with current state of the art cathode materials such as LiCoO2, NMC, and NCA. Finally, we substitute foreign metal species into the ScS2 material to determine their effect on key cathode properties, but find that these are overall detrimental to the performance of ScS2. This does, however, highlight the potential for improvement if scandium were mixed into other layered systems such as the layered transition metal oxides.

Patients' perceptions on the facilitators and barriers using injectable therapies in dyslipidaemia: An empirical qualitative descriptive international study.

BACKGROUND: Injectable medicines are increasingly used to manage abnormal levels of lipids, which is a major risk factor for cardiovascular events. Enhancing our understanding of patients' perceptions of these injectables, can inform practice with the aim of increasing uptake and medication adherence. AIM: To explore patient's experiences of using injectables and to identify potential facilitators and barriers to using injectable therapies in dyslipidaemia. DESIGN: A qualitative descriptive study using semi-structured interviews was conducted with patients who were using injectables to manage their cardiovascular conditions. METHODS: A total of 56 patients, 30 from the United Kingdom and 26 from Italy, were interviewed online from November 2020 to June 2021. Interviews were transcribed and schematic content analysis performed. RESULTS: Four distinct themes emerged from interviews with patients and caregivers: (i) Their behaviours and personal beliefs; (ii) Knowledge and education about injectable medication; (iii) Clinical skills and previous experiences and (iv) Organizational and governance. Participants expressed initial fears such as needle phobia, and their concerns about commencing therapy were compounded by a lack of accessible information. However, patients' pre-existing knowledge of lipid lowering medication, previous experience with statins and history of adverse side effects informed their decision-making regarding using injectables. Organization and governance-related issues were primarily around the distribution and management of medication supply within primary care, and the lack of a standardized clinical support monitoring system. CONCLUSION: Changes are needed in clinical practice to better educate and support patients to improve the uptake of injectables and optimize their use of these medications in the management of dyslipidaemia. IMPACT: This study suggests that injectable therapies were acceptable to people with cardiovascular disease. However, healthcare professionals need to play a key role in improving education and providing support to aid patients' decision-making regarding commencing and adhering to injectable therapies. REPORTING METHOD: The study adhered to the Consolidated Criteria for Reporting Qualitative Research. PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public contribution.

Advanced practice and clinical supervision: An exploration of perceived facilitators and barriers in practice.

AIM AND OBJECTIVES: The aim of this study was to investigate current advanced practice Masters students' experience of clinical supervision, to explore how clinical supervision works in practice and to identify students' perceptions of the facilitators and barriers to clinical supervision in their workplace. BACKGROUND: Advanced practitioners, and in particular nurses, play a pivotal role in delivering health care across acute and primary care settings. These non-medical professionals fulfil a rapidly expanding proportion of roles traditionally undertaken by medically qualified staff within the National Health Service in the United Kingdom and often lead specialist clinics and services. To prepare for the advanced practice role, individuals are required to undertake a Master's in advanced practice to develop the required skills and knowledge and work in clinical practice with a clinical assessor/supervisor to demonstrate competence and performance. DESIGN: A mixed method study using an online descriptive cross-sectional survey and qualitative data were collected via focus groups and has been reported using the Good Reporting of a Mixed Methods Study checklist. RESULTS: A total of 79 students completed the online survey (from 145 AP students), a response rate of 55%. Most respondents were nurses (n = 73) with 49 (62%) in a formal advanced practice trainee role, and the majority believed their clinical supervisor had a good understanding of advanced practice and the advanced practice role. Two focus groups were held with 16 participants in total. Thematic analysis revealed five themes: (a) perceived level and amount of support from clinical supervisors, (b) skill level of clinical supervisors, (c) physicians and their perceptions on supervising, Advanced practitioners (d) clinical supervisors' preparation for the role and (e) transition from trainee to qualified advanced practitioner. CONCLUSION: The survey revealed that advanced practitioner students perceived that clinical supervisors and workplace colleagues had a good understanding of the advanced practice role with good levels of support in practice. A more coherent approach is required for clinical supervision and an implementation framework that can be formally evaluated. RELEVANCE TO CLINICAL PRACTICE: Several significant barriers to clinical supervision for advanced practitioner students were identified, and there are currently more barriers (including COVID-19) than facilitators.

Clinical learning for pre-registration nursing students: a viva voce approach during COVID-19.

The COVID-19 pandemic restricted face-to-face contact between students and educators, limiting continual assessment of student's clinical skill development. This led to rapid transformational online adaptations to nursing education. This article will present and discuss the introduction of a clinical 'viva voce' approach, which has been used at one university to formatively assess students' clinical learning and reasoning skills using virtual methods. The Virtual Clinical Competency Conversation (V3C) was developed using the 'Think aloud approach' and involved facilitated one-to-one discussion based on two questions from a bank of 17 predefined clinically focused questions. A total of 81 pre-registration students completed the formative assessment process. Overall, feedback from students and academic facilitators was positive and facilitated both learning and consolidation in a safe and nurturing way. Further local evaluation is continuing to measure the impact of the V3C approach on student learning now that some aspects of face-to-face education have resumed.

The challenge of managing multimorbid atrial fibrillation: a pan-European European Heart Rhythm Association (EHRA) member survey of current management practices and clinical priorities.

As part of the EHRS-PATHS study examining comorbidities in atrial fibrillation (AF) across Europe, the aim was (i) to evaluate how multimorbidity is currently addressed by clinicians during AF treatment to characterize the treatment structure and (ii) to assess how the interdisciplinary management of multimorbid AF is currently conducted. An online survey was distributed among European Heart Rhythm Association (EHRA) members in Europe that included 21 questions and a free-text option for comments on detection, assessment, and management of AF-related comorbidities. A total of 451 responses were received with 339 responses eligible for inclusion. Of these, 221 were male (66%), 300 (91.5%) were physicians, and 196 (57.8%) were working in academic university teaching hospitals. Half of the respondents managed between 20 and 50 patients per month with multimorbid AF. Varying rates of specialist services and referral to these services were available at each location (e.g. heart failure and diabetes), with a greater number of specialist services available at academic university teaching hospitals compared with non-teaching hospitals [e.g. anticoagulation clinic 92 (47%) vs. 50 (35%), P < 0.03]. Barriers to referring to specialist services for AF comorbidities included lack of integrated care model (n = 174, 51%), organizational or institutional issues (n = 145, 43%), and issues with patient adherence (n = 126, 37%), highlighting the need for organizational restructuring and developing an integrated collaborative evidenced-based approach to multimorbid AF care. The survey and analyses of free-text comments demonstrated the need for systematic, integrated management of AF-related comorbidities, and these results will inform the next phases of the EHRA-PATHS study.

Improving sepsis recognition through use of the Sepsis Trust's community screening tool.

Sepsis is associated with high levels of morbidity and mortality. All healthcare professionals have a responsibility to ensure they have sufficient knowledge to effectively screen patients for signs and symptoms of sepsis. In the community setting, screening for sepsis can be challenging, due to the complexity within the patient population and difficulties associated with observation for changes in the patient's condition. The Sepsis Trust community nursing sepsis screening tool provides decision-making support to community healthcare professionals, enabling them to make a rapid assessment for risk factors for sepsis, ensuring a proportionate, consistent and appropriate response. Through implementation of a decision-support tool within the clinical setting, it is likely that patients at risk of sepsis will be identified earlier, and patients will be escalated in a more consistent manner. This process of improving consistency in practice can improve patient outcomes, including mortality, morbidity and overall patient experience.

Allosteric regulation of menaquinone (vitamin K2) biosynthesis in the human pathogen Mycobacterium tuberculosis.

Menaquinone (vitamin K2) plays a vital role in energy generation and environmental adaptation in many bacteria, including the human pathogen Mycobacterium tuberculosis (Mtb). Although menaquinone levels are known to be tightly linked to the cellular redox/energy status of the cell, the regulatory mechanisms underpinning this phenomenon are unclear. The first committed step in menaquinone biosynthesis is catalyzed by MenD, a thiamine diphosphate-dependent enzyme comprising three domains. Domains I and III form the MenD active site, but no function has yet been ascribed to domain II. Here, we show that the last cytosolic metabolite in the menaquinone biosynthesis pathway, 1,4-dihydroxy-2-naphthoic acid (DHNA), binds to domain II of Mtb-MenD and inhibits its activity. Using X-ray crystallography of four apo- and cofactor-bound Mtb-MenD structures, along with several spectroscopy assays, we identified three arginine residues (Arg-97, Arg-277, and Arg-303) that are important for both enzyme activity and the feedback inhibition by DHNA. Among these residues, Arg-277 appeared to be particularly important for signal propagation from the allosteric site to the active site. This is the first evidence of feedback regulation of the menaquinone biosynthesis pathway in bacteria, identifying a protein-level regulatory mechanism that controls menaquinone levels within the cell and may therefore represent a good target for disrupting menaquinone biosynthesis in M. tuberculosis.

A new tool to measure acuity in the community: a case study.

The provision of acute healthcare within patients own home (i.e. hospital in the home) is an important method of providing individualised patient-centred care that reduces the need for acute hospital admissions and enables early hospital discharge for appropriate patient groups. The Hospital in the Home (HitH) model of care ensures that this approach maximises patient safety and limits potential risk for patients. As HitH services have seen record numbers of patient referrals in the past 2 years, there is now a greater need to measure and understand the acuity and dependency levels of the caseload. Through an expert clinician development process at one NHS trust, aspects of procedural complexity, interdisciplinary working, risk stratification and comorbidities were used to quantify acuity and dependency. This paper uses a case study approach to present a new method of measuring this important concept.

The active site of the Mycobacterium tuberculosis branched-chain amino acid biosynthesis enzyme dihydroxyacid dehydratase contains a 2Fe-2S cluster.

Iron-sulfur clusters are protein cofactors with an ancient evolutionary origin. These clusters are best known for their roles in redox proteins such as ferredoxins, but some iron-sulfur clusters have nonredox roles in the active sites of enzymes. Such clusters are often prone to oxidative degradation, making the enzymes difficult to characterize. Here we report a structural and functional characterization of dihydroxyacid dehydratase (DHAD) from Mycobacterium tuberculosis (Mtb), an essential enzyme in the biosynthesis of branched-chain amino acids. Conducting this analysis under fully anaerobic conditions, we solved the DHAD crystal structure, at 1.88 Å resolution, revealing a 2Fe-2S cluster in which one iron ligand is a potentially exchangeable water molecule or hydroxide. UV and EPR spectroscopy both suggested that the substrate binds directly to the cluster or very close to it. Kinetic analysis implicated two ionizable groups in the catalytic mechanism, which we postulate to be Ser-491 and the iron-bound water/hydroxide. Site-directed mutagenesis showed that Ser-491 is essential for activity, and substrate docking indicated that this residue is perfectly placed for proton abstraction. We found that a bound Mg2+ ion 6.5 Å from the 2Fe-2S cluster plays a key role in substrate binding. We also identified a putative entry channel that enables access to the cluster and show that Mtb-DHAD is inhibited by a recently discovered herbicide, aspterric acid, that, given the essentiality of DHAD for Mtb survival, is a potential lead compound for the design of novel anti-TB drugs.

Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3.

4-hydroxy-2-oxoglutarate aldolase (HOGA1) is a mitochondrial enzyme that plays a gatekeeper role in hydroxyproline metabolism. Its loss of function in humans causes primary hyperoxaluria type 3 (PH3), a rare condition characterised by excessive production of oxalate. In this study, we investigated the significance of the associated oxaloacetate decarboxylase activity which is also catalysed by HOGA1. Kinetic studies using the recombinant human enzyme (hHOGA1) and active site mutants showed both these dual activities utilise the same catalytic machinery with micromolar substrate affinities suggesting that both are operative in vivo. Biophysical and structural studies showed that pyruvate was a competitive inhibitor with an inhibition constant in the micromolar range. By comparison α-ketoglutarate was a weak inhibitor with an inhibition constant in the millimolar range and could only be isolated as an adduct with the active site Lys196 in the presence of sodium borohydride. These studies suggest that pyruvate inhibits HOGA1 activity during gluconeogenesis. We also propose that loss of HOGA1 function could increase oxalate production in PH3 by decreasing pyruvate availability and metabolic flux through the Krebs cycle.

State Health Official Career Advancement and Sustainability Evaluation-Description of the Methods Used in the SHO-CASE Study.

State health officials (SHOs) lead state governmental public health agencies, playing an important role in their states. However, little comprehensive research has examined SHOs or characteristics of these leaders, limiting evidence about ways to improve SHO selection and subsequent performance. This brief describes the methods of the SHO-CASE study focused on current and former SHOs in state public health agencies. Methods used include qualitative components that informed the development of survey questions, survey administration, and survey response. A total of 147 SHOs responded to the SHO survey representing every state and Washington, District of Columbia. The SHO-CASE study survey database represents the most comprehensive database of its kind regarding a range of attributes of current and former SHOs. These data can be used to explore factors contributing to SHO success including valuable insights into effectively working with the states' elected officials.

Biopsychopharmacosocial approach to assess impact of social distancing and isolation on mental health in older adults.

It is impossible to predict or comprehend the impact of the ongoing COVID-19 pandemic. The UK Government's advice for vulnerable people, including older adults, to move towards self-isolation and social distancing is likely to reduce rates of transmission, the risk of severe illness and the impact on the acute health services. Although justified and necessary, this process of isolation is likely to have a negative impact on the mental health of these vulnerable groups, especially older people. It will become increasingly important for community health professionals to assess subtle changes in older persons' mental health, as the duration of this period of isolation remains unclear. The biopsychopharmacosocial model provides one method of assessing mental health and planning health and social care needs. This article hopes to guide community health professionals through the specifics of this assessment model in relation to the growing COVID-19 pandemic.

Stress control for a well-structured life.

Aerobic life brings with it a need to respond to external redox stress in ways that preserve key processes. Suppressor of copper sensitivity (Scs) proteins contribute to this response in some bacteria, but have poorly defined molecular functions. Furlong et al. now demonstrate that two Scs proteins from Proteus mirabilis provide a redox relay functionally equivalent to, but structurally distinct from, the Dsb proteins that orchestrate disulfide bonding in Escherichia coli, emphasizing the wide prevalence of this mechanism in bacteria.

Group A Streptococcus T Antigens Have a Highly Conserved Structure Concealed under a Heterogeneous Surface That Has Implications for Vaccine Design.

Group A Streptococcus (GAS) (Streptococcus pyogenes) is an important human pathogen associated with significant global morbidity and mortality for which there is no safe and efficacious vaccine. The T antigen, a protein that polymerizes to form the backbone of the GAS pilus structure, is a potential vaccine candidate. Previous surveys of the tee gene, which encodes the T antigen, have identified 21 different tee types and subtypes such that any T antigen-based vaccine must be multivalent and carefully designed to provide broad strain coverage. In this study, the crystal structures of three two-domain T antigens (T3.2, T13, and T18.1) were determined and found to have remarkable structural similarity to the previously reported T1 antigen, despite moderate overall sequence similarity. This has enabled reliable modeling of all major two-domain T antigens to reveal that T antigen sequence variation is distributed along the full length of the protein and shields a highly conserved core. Immunoassays performed with sera from immunized animals and commercial T-typing sera identified a significant cross-reactive antibody response between T18.1, T18.2, T3.2, and T13. The existence of shared epitopes between T antigens, combined with the remarkably conserved structure and high level of surface sequence divergence, has important implications for the design of multivalent T antigen-based vaccines.

A rapid review of educational preparedness of advanced clinical practitioners.

AIM: The aim of this study was to synthesize available data on current educational provision related to preparation for the advanced clinical practice role. DESIGN: A mixed methods rapid review of the literature. DATA SOURCES: A search of Ovid Medline and Ovid EMBASE for English language papers published 2006-2018 resulted in 38 publications, which met the criteria for inclusion. REVIEW METHODS: Using Tricco's seven-stage process, following an identification of relevant papers and data extraction, a data-based convergent synthesis was used to convert quantitative papers into qualitative data prior to completing a narrative synthesis. RESULTS: The four themes identified from data synthesis were consolidation; theory to practice gap; competency and mentoring. A lack of preparedness for new advanced clinical practitioners completing an educational programme was noted with a need identified for a clinically focussed consolidation period to enable practitioners to develop their skills under supervision in the clinical environment. CONCLUSION: As the needs for different models of health care evolve with the expansion of advanced practice, appropriate education and clinical supervision are important aspects in the delivery of programmes that allow individuals to be competent and confident practitioners providing safe and effective health care. IMPACT: There is a paucity of papers on educational preparedness of advanced clinical practitioners. Our findings demonstrate a lack of preparedness and the need for a clinically focussed consolidation period with good role models and mentors following completion of a Master's programme. Employers and higher education institutions need to ensure a protected period of time is available for newly qualified advanced clinical practitioners to allow consolidation of clinical practice.

Mechanistic insights into F420-dependent glucose-6-phosphate dehydrogenase using isotope effects and substrate inhibition studies.

F420-dependent glucose-6-phosphate dehydrogenase (FGD) is involved in the committed step of the pentose phosphate pathway within mycobacteria, where it catalyzes the reaction between glucose-6-phosphate (G6P) and the F420 cofactor to yield 6-phosphogluconolactone and the reduced cofactor, F420H2. Here, we aim to probe the FGD reaction mechanism using dead-end inhibition experiments, as well as solvent and substrate deuterium isotope effects studies. The dead-end inhibition studies performed using citrate as the inhibitor revealed competitive and uncompetitive inhibition patterns for G6P and F420 respectively, thus suggesting a mechanism of ordered addition of substrates in which the F420 cofactor must first bind to FGD before G6P binding. The solvent deuterium isotope effects studies yielded normal solvent kinetic isotope effects (SKIE) on kcat and kcat/Km for both G6P and F420. The proton inventory data yielded a fractionation factor of 0.37, suggesting that the single proton responsible for the observed SKIE is likely donated by Glu109 and protonates the cofactor at position N1. The steady state substrate deuterium isotope effects studies using G6P and G6P-d1 yielded KIE of 1.1 for both kcat and kcat/Km, while the pre-steady state KIE on kobs was 1.4. Because the hydride transferred to C5 of F420 was the one targeted for isotopic substitution, these KIE values provide further evidence to support our previous findings that hydride transfer is likely not rate-limiting in the FGD reaction.

Anthranilate phosphoribosyltransferase: Binding determinants for 5'-phospho-alpha-d-ribosyl-1'-pyrophosphate (PRPP) and the implications for inhibitor design.

Phosphoribosyltransferases (PRTs) bind 5'-phospho-α-d-ribosyl-1'-pyrophosphate (PRPP) and transfer its phosphoribosyl group (PRib) to specific nucleophiles. Anthranilate PRT (AnPRT) is a promiscuous PRT that can phosphoribosylate both anthranilate and alternative substrates, and is the only example of a type III PRT. Comparison of the PRPP binding mode in type I, II and III PRTs indicates that AnPRT does not bind PRPP, or nearby metals, in the same conformation as other PRTs. A structure with a stereoisomer of PRPP bound to AnPRT from Mycobacterium tuberculosis (Mtb) suggests a catalytic or post-catalytic state that links PRib movement to metal movement. Crystal structures of Mtb-AnPRT in complex with PRPP and with varying occupancies of the two metal binding sites, complemented by activity assay data, indicate that this type III PRT binds a single metal-coordinated species of PRPP, while an adjacent second metal site can be occupied due to a separate binding event. A series of compounds were synthesized that included a phosphonate group to probe PRPP binding site. Compounds containing a "bianthranilate"-like moiety are inhibitors with IC50 values of 10-60µM, and Ki values of 1.3-15µM. Structures of Mtb-AnPRT in complex with these compounds indicate that their phosphonate moieties are unable to mimic the binding modes of the PRib or pyrophosphate moieties of PRPP. The AnPRT structures presented herein indicated that PRPP binds a surface cleft and becomes enclosed due to re-positioning of two mobile loops.

A functional role of Rv1738 in Mycobacterium tuberculosis persistence suggested by racemic protein crystallography.

Protein 3D structure can be a powerful predictor of function, but it often faces a critical roadblock at the crystallization step. Rv1738, a protein from Mycobacterium tuberculosis that is strongly implicated in the onset of nonreplicating persistence, and thereby latent tuberculosis, resisted extensive attempts at crystallization. Chemical synthesis of the L- and D-enantiomeric forms of Rv1738 enabled facile crystallization of the D/L-racemic mixture. The structure was solved by an ab initio approach that took advantage of the quantized phases characteristic of diffraction by centrosymmetric crystals. The structure, containing L- and D-dimers in a centrosymmetric space group, revealed unexpected homology with bacterial hibernation-promoting factors that bind to ribosomes and suppress translation. This suggests that the functional role of Rv1738 is to contribute to the shutdown of ribosomal protein synthesis during the onset of nonreplicating persistence of M. tuberculosis.