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.

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.

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.

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.

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.

HOw Patients view Extended half-life products: Impressions from real-world experience (The HOPE study).

INTRODUCTION: Extended half-life (EHL) clotting factors have been shown to offer people with haemophilia (PwH) protection from bleeding with fewer infusions, which might reduce treatment burden. AIM: The HOw Patients view Extended half-life products (HOPE) study aimed to explore, understand and describe patient expectations around the prophylactic use of EHL products and to establish whether these expectations were met through individual follow-up analysis. METHODS: The HOPE study was a prospective, qualitative cohort study conducted among PwH who had switched to Fc fusion protein EHL products in routine clinical care and who had not been recruited to clinical trials of these products. Semi-structured audio-recorded interviews were undertaken over two time points; transcripts were analysed to systematically generate theory from data that contains both inductive and deductive thinking. RESULTS: Forty-three interviews were conducted with 25 participants. Most participants were positive about EHL treatment and intended to continue using them. Reduced frequency of infusions meant lives were less disrupted or dominated by haemophilia, and there was less perceived stress on overused veins. For those PwH who did not reduce infusion frequency, there were other perceived benefits from EHLs with respect to greater protection with higher trough levels and fewer bleeds. CONCLUSION: Patients switching to EHL treatments believe these products will result in fewer infusions and less disruption of everyday life, leaving them feeling more protected with fewer bleeds and increased activity levels, as well as enhanced well-being and mental health. Understanding patient expectation and experience around using products adds real-world data to clinical trial experience.

Five-country manikin study found that neonatologists preferred using the LISAcath rather than the Angiocath for less invasive surfactant administration.

AIM: Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting. METHODS: This was a multinational, multicentre study, conducted in October 2016, which involved 39 neonatologists who were recruited by employees of the sponsor from large, well-recognised neonatal intensive care units across Europe. LISA was not the standard of care in these units in Austria, Belgium, Poland, Spain and the United Kingdom at the time of the study. After training, participants simulated LISA on a neonatal manikin, once with the LISAcath and once with Angiocath, then answered a 10-item questionnaire. RESULTS: The responses to nine of 10 questions showed that 67-95% of the respondents preferred the LISAcath to the Angiocath, with most of the remainder indicating no preference. The only exception was the luer connection question, with two-thirds expressing no preference. The LISAcath was considered potentially safer by 33 of 39 participants, with no votes for the Angiocath. CONCLUSION: Overall, neonatologists preferred using the LISAcath rather than the Angiocath on a neonatal manikin.

The burden and outcome of in utero transfers.

AIM: To quantify the number of intrauterine transfers (IUTs) arranged by Embrace Yorkshire and Humber Infant and Children's Transport Service and, to determine the outcome of when women delivered their babies, or when they were discharged following transfer. METHODS: Identification of all IUTs Embrace arranged between January 1, 2011 and February 29, 2012 with data collection to determine delivery time or date of discharge. RESULTS: There were 623 IUT referrals with a mean time taken to arrange a transfer of 109 minutes. The mean distance of IUT was 42.5 miles, and the main reason for IUT request was capacity of referring unit. 247 (52%) women delivered during the same admission and 156 delivered within 48 hours of transfer. Of those undelivered, 111 (48.7%) were discharged within 48 hours. Fibronectin test was used in 51 patients. CONCLUSION: The IUT service provided by Embrace is busy, with significant demands on administrative staff time. Neonatal cot capacity and gestation are the main reasons for transfer. There is potentially a cohort of women who may not have benefitted from IUT. We suggest the use of obstetric expertise will enhance the service, while ongoing work looking at neonatal unit cot capacity problems continues.

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.