Tracking national neonatal transport activity and metrics using the UK Neonatal Transport Group dataset 2012-2021: a narrative review.

There are no internationally agreed descriptors for categories of neonatal transports which facilitate comparisons between settings. To continually review and enhance neonatal transport care we need robust categories to develop benchmarks. This review aimed to report on the development and application of key measures across a national neonatal transport service. The UK Neonatal Transport Group (UK-NTG) developed a core dataset and benchmarks for transported infants and collected annual national data. Data were reported back to teams to allow benchmarking and improvements. From 2012 to 2021, the rate of UK neonatal transfers increased from 18 to 22/1000 live births despite a falling birth rate. Neonatal transfers on nitric oxide increased until 2016 before plateauing. The proportion of transport services able to provide high frequency oscillation and servo-controlled therapeutic hypothermia increased over the study period. High-flow nasal cannula oxygen use increased, becoming the most frequently used non-invasive respiratory support mode. For infants <27 weeks of gestational age, transfers for uplift of care in the first 3 days of life have fallen from 420 (2016) to 288 (2020/2021) and for lack of neonatal capacity from 24 (2016) to 2 (2020/2021). The rate of ventilated infants completing transfer with CO2 out of the benchmark range varied from 9% to 13% with marked variation between transport services' rates of hypocapnia (0-10%) and hypercapnia with acidosis (0-9%). The development of the UK-NTG dataset supports national tracking of activity and clinical trends allowing comparison of patient-focused benchmarks across teams.

Expert United Kingdom consensus on the preservation of joint health in people with moderate and severe haemophilia A: A modified Delphi panel.

AIM: For people with haemophilia A (PwHA), bleeding in the joints leads to joint damage and haemophilia-related arthropathy, impacting range of motion and life expectancy. Existing guidelines for managing haemophilia A support healthcare professionals (HCPs) and PwHA in their efforts to preserve joint health. However, such guidance should be reviewed, considering emerging evidence and consensus as presented in this manuscript. METHODS: Fifteen HCPs experienced in the management of PwHA in the UK participated in a three-round Delphi panel. Consensus was defined at ≥70% of panellists agreeing or disagreeing for Likert-scale questions, and ≥70% selecting the same option for multiple- or single-choice questions. Questions not reaching consensus were revised for the next round. RESULTS: 26.8% (11/41), 44.8% (13/29) and 93.3% (14/15) of statements reached consensus in Rounds 1, 2 and 3, respectively. HCPs agreed that prophylaxis should be offered to patients with a baseline factor VIII (FVIII) level of ≤5 IU/dL and that, where there is no treatment burden, the aim of prophylaxis should be to achieve a trough FVIII level ≥15 IU/dL and maintain a longer period with FVIII levels of ≥20-30 IU/dL to provide better bleed protection. The aspirational goal for PwHA is to prevent all joint bleeds, which may be achieved by maintaining normalised (50-150 IU/dL) FVIII levels. CONCLUSION: The panel of experts were largely aligned on approaches to preserving joint health in PwHA, and this consensus may help guide HCPs.

Archaeal Hel308 suppresses recombination through a catalytic switch that controls DNA annealing.

Hel308 helicases promote genome stability in archaea and are conserved in metazoans, where they are known as HELQ. Their helicase mechanism is well characterised, but it is unclear how they specifically contribute to genome stability in archaea. We show here that a highly conserved motif of Hel308/HELQ helicases (motif IVa, F/YHHAGL) modulates both DNA unwinding and a newly identified strand annealing function of archaeal Hel308. A single amino acid substitution in motif IVa results in hyper-active DNA helicase and annealase activities of purified Hel308 in vitro. All-atom molecular dynamics simulations using Hel308 crystal structures provided a molecular basis for these differences between mutant and wild type Hel308. In archaeal cells, the same mutation results in 160000-fold increased recombination, exclusively as gene conversion (non-crossover) events. However, crossover recombination is unaffected by the motif IVa mutation, as is cell viability or DNA damage sensitivity. By contrast, cells lacking Hel308 show impaired growth, increased sensitivity to DNA cross-linking agents, and only moderately increased recombination. Our data reveal that archaeal Hel308 suppresses recombination and promotes DNA repair, and that motif IVa in the RecA2 domain acts as a catalytic switch to modulate the separable recombination and repair activities of Hel308.

Progress and Challenges in Archaeal Genetic Manipulation.

Archaea inhabit a wide variety of habitats and are well-placed to provide insights into the origins of eukaryotes. In this primer, we examine the available model archaeal genetic systems. We consider the limitations and barriers involved in genetically modifying different archaeal species, the techniques and breakthroughs that have contributed to their tractability, and potential areas for future development.

Genetic Manipulation of Haloferax Species.

In this chapter, we describe the reverse genetics methodology behind generating a targeted gene deletion or replacement in archaeal species of the genus Haloferax, which are renowned for their ease of manipulation. Individual steps in the method include the design of a gene-targeting vector, its use in transforming Haloferax to yield "pop-in" and "pop-out" clones, and techniques for validating the genetically manipulated strain. The vector carries DNA fragments of 500-1000 bp that flank the gene of interest (or a mutant allele), in addition to the pyrE2 gene for uracil biosynthesis (Bitan-Banin et al. J Bacteriol 185:772-778, 2003). The latter is used as a selectable marker for the transformation of Haloferax, wherein the vector integrates by homologous recombination at the genomic locus to generate the "pop-in" strain; this is also known as allele-coupled exchange. Culturing of these transformants in nonselective broth and subsequent plating on 5-fluoroorotic acid (5-FOA)-containing media selects for excision of the vector, yielding either wild type or mutant "pop-out" clones. These 5-FOA-resistant clones are screened to confirm the desired mutation, using a combination of phenotypic assays, colony hybridization and Southern blotting. The pop-in/pop-out method allows for the recycling of the pyrE2 marker to enable multiple gene deletions to be carried out in a single strain, thereby providing insights into the function of multiple proteins and how they interact in their respective cellular pathways.

Into a brave new world: Haemophilia A & von Willebrand Disease Surgery with novel therapies.

INTRODUCTION: Haemophilia & von Willebrand disease are both recognised inherited bleeding disorders. With increased access to highly efficient and safe replacement and novel therapies, management of surgical interventions in this group can be safely managed by experienced multidisciplinary teams. AIM: To review the evidence for managing surgery in the era of novel therapies. METHOD: We explore four cases and establish the role of the clinical nurse specialist within the surgical pathway. RESULTS: All of these cases evidence the continued important role of both the multidisciplinary planning prior to any surgical interventions in people with bleeding disorders and the key role of the Nurse Specialist in ensuring this plan is then implemented. Key focuses of communication with all parties involved in the patient journey, performing education for the patient, family and wider healthcare team about the underlying bleeding disorder and the importance of time critical medicines being given on time is essential. CONCLUSION: These cases demonstrate that individuals with bleeding disorders are at risk of developing other rare conditions alongside their life long condition, in addition to comorbidities associated with ageing. Evidence for rare plus rare is likely to be minimal as demonstrated within the cases, and recognition of how to reach out to international peers in the field is important. Sharing complex case management at national & international meetings and in publication has never been so important.

Cardiovascular disease in hereditary haemophilia: The challenges of longevity.

The development of effective and safe treatments has significantly increased the life expectancy of persons with haemophilia (PWH). This has been accompanied by an increase in the comorbidities of ageing including cardiovascular disease, which poses particular challenges due to the opposing risks of bleeding from haemophilia and antithrombotic treatments versus thrombosis. Although mortality secondary to coronary artery disease in PWH is less than in the general population, the rate of atherosclerosis appears similar. The prevalence of atrial fibrillation in PWH and risk of secondary thromboembolic stroke are not well established. PWH can be safely supported through acute coronary interventions but data on the safety and efficacy of long-term antithrombotics are scarce. Increased awareness and research on cardiovascular disease in PWH will be crucial to improve primary prevention, acute management, secondary prevention and to best support ageing PWH.

Thrombotic thrombocytopenic Purpura: A nurse's perspective on a decade of treatment in Sheffield, United Kingdom.

TTP is a rare, life threatening condition, with an annual incidence of 3-11 cases per million people. A deficiency of a vWF multimer cleaving protein, ADAMTS13 is the cause of the condition. Quick & accurate diagnosis is crucial in the safe & effective treatment of individuals presenting with this condition. First line treatment is the removal of the resulting ulta-large vWF multimers left in the circulation by the lack of ADAMTS13 & immunosuppression of antibodies against ADAMTS13. In the last 3 years, introduction of a targeted therapy called Caplacizumab has seen a change in treatment. This paper provides an overview of the experience of the Sheffield, UK treatment team in the changes in TTP treatment pathways in the region. Finally exploring the impact introducing Caplacizumab into routine management has had on patient care & outcomes from a local nurse's perspective.

The UK haemophilia specialist nurse: Competencies fit for practice in the 21st century.

INTRODUCTION: Nurses play a central co-ordinating role in delivering comprehensive care for people with haemophilia and allied bleeding disorders, for which they need a broad range of competencies. The UK Haemophilia Nurses Association (HNA) published a role description in 1994 which was developed into a competency framework in 2014. This has now been updated to reflect current educational and clinical practice. AIM: To summarize the evidence supporting the nurse's advanced role within haemophilia care and develop new competencies to deliver comprehensive care within a multidisciplinary team. METHODS: Systematic reviews were identified by PubMed literature search. The HNA conducted workshops to consult its membership, and the authors incorporated this input to update its competency framework within the structure outlined by Health Education England in multiprofessional framework for advanced clinical practice in England (2017). RESULTS: The proposed framework includes five domains (Clinical knowledge, Clinical/direct care, Communication and support, Collaborative practice and Research) supported by indicators for four levels of practice (beginner, competent, proficient and expert). The framework is a tool which nurses and their managers can use to assess skills and knowledge, and identify learning needs appropriate to personal development and improve patient care and outcomes. CONCLUSION: The HNA has developed a new competency framework to provide a strong foundation for haemophilia specialist nurses to continue improving services for people living with bleeding disorders and their families, as well as supporting personal development alongside new therapeutic options, models of care and follow-up.

The continuing impact of capacity on a region's in utero transfer requests.

AIM: The Yorkshire and Humber operational delivery network (ODN) aims to ensure 85% of preterm babies are delivered in tertiary centres. Auditing in utero transfers provides key data for streamlining this process. Our study aimed to determine reasons and outcomes of in utero transfers as well as review the impact of staffing on capacity transfer requests. METHODS: All in utero transfer referrals between September 2014 and August 2015 were reviewed, and delivery outcome data were sought from the national data platform, Badgernet. ODN records provided cot occupancy and staffing data. RESULTS: A total of 479 referrals were made, and 379 transfers were completed. The majority of requests were due to reduced capacity which was linked to poor staffing levels (51.3%). Patients travelled significant distances, with a mean distance of 42.3 miles within network, and 70.3 miles, out of network. Despite the travel burden, only 35.1% of women delivered within 48 hours of transfer. CONCLUSION: In utero transfers remain difficult and time-consuming to facilitate. Neonatal staffing at referral units contributes significantly to the decision to transfer women. Challenges remain in predicting which women will deliver after an in utero transfer, as well as obtaining outcome data for these cases.