Significant haemoglobinopathies: A guideline for screening and diagnosis: A British Society for Haematology Guideline: A British Society for Haematology Guideline.

Antenatal screening/testing of pregnant women should be carried out according to the guidelines of the National Health Service (NHS) Sickle Cell and Thalassaemia Screening Programme. Newborn screening and, when necessary, follow-up testing and referral, should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening Programme. All babies under 1 year of age arriving in the United Kingdom should be offered screening for sickle cell disease (SCD). Preoperative screening for SCD should be carried out in patients from ethnic groups in which there is a significant prevalence of the condition. Emergency screening with a sickle solubility test must always be followed by definitive analysis. Laboratories performing antenatal screening should utilise methods that are capable of detecting significant variants and are capable of quantitating haemoglobins A2 and F at the cut-off points required by the national antenatal screening programme. The laboratory must ensure a provisional report is available for antenatal patients within three working days from sample receipt.

Antenatal and delivery practices and neonatal mortality amongst women with institutional and non-institutional deliveries in rural Zimbabwe: observational data from a cluster randomized trial.

BACKGROUND: Despite achieving relatively high rates of antenatal care, institutional delivery, and HIV antiretroviral therapy for women during pregnancy, neonatal mortality has remained stubbornly high in Zimbabwe. Clearer understanding of causal pathways is required to inform effective interventions. METHODS: This study was a secondary analysis of data from the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial, a cluster-randomized community-based trial among pregnant women and their infants, to examine care during institutional and non-institutional deliveries in rural Zimbabwe and associated birth outcomes. RESULTS: Among 4423 pregnant women, 529 (11.9%) delivered outside a health institution; hygiene practices were poorer and interventions to minimise neonatal hypothermia less commonly utilised for these deliveries compared to institutional deliveries. Among 3441 infants born in institutions, 592 (17.2%) were preterm (< 37 weeks gestation), while 175/462 (37.9%) infants born outside health institutions were preterm (RR: 2.20 (1.92, 2.53). Similarly, rates of stillbirth [1.2% compared to 3.0% (RR:2.38, 1.36, 4.15)] and neonatal mortality [2.4% compared to 4.8% (RR: 2.01 1.31, 3.10)] were higher among infants born outside institutions. Among mothers delivering at home who reported their reason for having a home delivery, 221/293 (75%) reported that precipitous labor was the primary reason for not having an institutional delivery while 32 (11%), 34 (12%), and 9 (3%), respectively, reported distance to the clinic, financial constraints, and religious/personal preference. CONCLUSIONS: Preterm birth is common among all infants in rural Zimbabwe, and extremely high among infants born outside health institutions. Our findings indicate that premature onset of labor, rather than maternal choice, may be the reason for many non-institutional deliveries in low-resource settings, initiating a cascade of events resulting in a two-fold higher risk of stillbirth and neonatal mortality amongst children born outside health institutions. Interventions for primary prevention of preterm delivery will be crucial in reducing neonatal mortality in Zimbabwe. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov, number NCT01824940.

British Society for Haematology guidelines for the laboratory diagnosis of malaria.

The laboratory diagnosis of malaria depends on skilled examination of well-stained thick and thin blood films. Rapid diagnostic tests are a useful supplement and the use of nucleic acid-based testing in diagnostic laboratories should also be considered. These British Society for Haematology guidelines update the 2003 guidelines for malaria diagnosis. Training, quality control, incidental diagnosis, differential diagnosis and reference laboratory referral are considered.

Surgical planning during a pandemic: Identifying patients at high risk of severe disease or death due to COVID-19 in a cohort of patients on a cataract surgery waiting list.

BACKGROUND: The delivery of cataract surgery during the COVID-19 pandemic is challenging because of the risk of nosocomial SARS-CoV-2 infection when patients attend hospital for elective care. In order to ascertain the risk to patients awaiting cataract surgery, this study aimed to identify the presence of systemic comorbidities that are associated with a high risk of severe disease or death due to COVID-19. METHODS: A prospective study of 315 patients (630 eyes) was conducted from 3rd June to 31st July 2020. An electronic health record was used to identify any systemic comorbidities that would render a patient 'clinically extremely vulnerable' to COVID-19, as outlined by the Department of Health for Northern Ireland. Patient demographics, best-corrected visual acuity (VA) and risk of postoperative anisometropia were also recorded. RESULTS: The median age of patients awaiting cataract surgery was 76 years (range 22-97). Of the 315 patients, 72% were aged over 70 and 16% were aged over 85. A systemic comorbidity that would confer high risk status was identified in 21% of patients. This high risk status was attributable to severe respiratory disease, cancer, and immunosuppression therapies in the majority of cases. The high risk group were younger than those deemed non-high risk, but there were no significant differences with respect to gender, anticipated degree of surgical difficulty, VA, or whether the patient was undergoing first or second eye surgery. Of those patients awaiting first eye cataract surgery, the mean VA in the listed eye was 0.84 logMAR and 39% (70/179) had a VA <0.3 logMAR (6/12 Snellen acuity) in their fellow eye. 57% of patients were awaiting first eye surgery, and 32% of those patients would be at risk of symptomatic anisometropia postoperatively. CONCLUSION: One-fifth of patients awaiting cataract surgery were found to be at high risk of severe disease or death from COVID-19 and these patients may experience delays in their surgical care. Additional planning is required in order to minimise the morbidity associated with delayed cataract surgery.

Impact of conditional and unconditional cash transfers on health outcomes and use of health services in humanitarian settings: a mixed-methods systematic review.

BACKGROUND: Cash transfers, payments provided by formal or informal institutions to recipients, are increasingly used in emergencies. While increasing autonomy and being supportive of local economies, cash transfers are a cost-effective method in some settings to cover basic needs and extend benefits of limited humanitarian aid budgets. Yet, the extent to which cash transfers impact health in humanitarian settings remains largely unexplored. This systematic review evaluates the evidence on the effect of cash transfers on health outcomes and health service utilisation in humanitarian contexts. METHODS: Studies eligible for inclusion were peer reviewed (quantitative,qualitative and mixed-methods). Nine databases (PubMed, EMBAS, Medline, CINAHL, Global Health, Scopus, Web of Science Core Collection, SciELO and LiLACS) were searched without language and without a lower bound time restriction through 24 February 2021. The search was updated to include articles published through 8 December 2021. Data were extracted using a piloted extraction tool and quality was assessed using The Joanna Briggs Critical Appraisal Tool. Due to heterogeneity in study designs and outcomes, results were synthesised narratively and no meta-analysis was performed. RESULTS: 30 673 records were identified. After removing duplicates, 17 715 were double screened by abstract and title, and 201 in full text. Twenty-three articles from 16 countries were included reporting on nutrition outcomes, psychosocial and mental health, general/subjective health and well-being, acute illness (eg, diarrhoea, respiratory infection), diabetes control (eg, blood glucose self-monitoring, haemoglobin A1C levels) and gender-based violence. Nineteen studies reported some positive impacts on various health outcomes and use of health services, 11 reported no statistically significant impact on outcomes assessed and 4 reported potential negative impacts on health outcomes. DISCUSSION: Although there is evidence to suggest a positive relationship between cash transfers and health outcomes in humanitarian settings, high-quality empirical evidence, that is methodologically robust, investigates a range of humanitarian settings and is conducted over longer time periods is needed. This should consider factors influencing programme implementation and the differential impact of cash transfers designed to improve health versus multipurpose cash transfers. PROSPERO REGISTRATION NUMBER: CRD42021237275.

A thematic review of the use of electronic logbooks for surgical assessment in sub-Saharan Africa.

INTRODUCTION: Ensuring that surgical training programmes in low- and middle-income countries (LMICs) provide high quality training, including adequate operative experience, is of crucial importance in meeting the goals set out in the Lancet Global Surgery 2030. Electronic logbooks (eLogbooks) have been adopted to monitor both individual trainee progression and the performance of surgical training programmes. METHODS: We performed a thematic review of the current evidence base surrounding the use of eLogbooks for the assessment of surgeons in training in sub-Saharan Africa, with a view to identifying the learning to date and areas for future research. RESULTS: Whilst there are multiple papers highlighting the use of surgical eLogbooks in high-income countries, we identified only three papers which discussed their use in sub-Saharan Africa. Four common themes emerged which related to the use of surgical eLogbooks throughout sub-Saharan Africa: ease of analysis, centralised databases, discrepancies in reporting and technology limitations. CONCLUSIONS: Robust data to demonstrate trainee progression and the quality of surgical training programmes are of crucial importance in ensuring that surgical training programmes can rapidly scale up to deliver large numbers of well-trained surgical providers to address the unmet patient need in LMICs in the next decade. The limited data on the use of well designed, centralised electronic surgical logbooks indicate that this tool may play an important role in providing key data to underpin these training programmes.

Radiation oncology teaching provision and practice prior to and during the first wave of the COVID-19 pandemic in medical schools in the United Kingdom and the Republic of Ireland: a cross-sectional survey.

OBJECTIVES: Radiotherapy is a key cancer treatment modality but is poorly understood by doctors. We sought to evaluate radiation oncology (RO) teaching in medical schools within the United Kingdom (UK) and Republic of Ireland (RoI), as well as any impacts on RO teaching delivery from the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A bespoke online survey instrument was developed, piloted and distributed to oncology teaching leads at all UK and RoI medical schools. Questions were designed to capture information on the structure, format, content and faculty for RO teaching, as well as both the actual and the predicted short- and long-term impacts of COVID-19. RESULTS: Responses were received from 29/41 (71%) UK and 5/6 (83%) RoI medical schools. Pre-clinical and clinical oncology teaching was delivered over a median of 2 weeks (IQR 1-6), although only 9 (27%) of 34 responding medical schools had a standalone RO module. RO teaching was most commonly delivered in clinics or wards (n = 26 and 25 respectively). Few medical schools provided teaching on the biological basis for radiotherapy (n = 11) or the RO career pathway (n = 8), and few provide teaching delivered by non-medical RO multidisciplinary team members. There was evidence of short- and long-term disruption to RO teaching from COVID-19. CONCLUSIONS: RO teaching in the UK and RoI is limited with minimal coverage of relevant theoretical principles and little exposure to radiotherapy departments and their non-medical team members. The COVID-19 pandemic risks exacerbating trainee doctors' already constrained exposure to radiotherapy. ADVANCES IN KNOWLEDGE: This study provides the first analysis of radiotherapy-related teaching in the UK and RoI, and the first to explore the impact of the COVID-19 pandemic on radiationoncology teaching.

Predicting bacteraemia in maternity patients using full blood count parameters: A supervised machine learning algorithm approach.

INTRODUCTION: Bacteraemia in pregnancy and the post-partum period can lead to maternal and newborn morbidly. The purpose of this study was to use machine learning tools to identify if bacteraemia in pregnant or post-partum women could be predicted by full blood count (FBC) parameters other than the white cell count. METHODS: The study was performed on 129 women with a positive blood culture (BC) for a clinically significant organism, who had a FBC taken at the same time. They were matched with controls who had a negative BC taken at the same time as a FBC. The data were split in to a training (70%) and test (30%) data set. Machine learning techniques such as recursive partitioning and classification and regression trees were used. RESULTS: A neutrophil/lymphocyte ratio (NLR) of >20 was found to be the most clinically relevant and interpretable construct of the FBC result to predict bacteraemia. The diagnostic accuracy of NLR >20 to predict bacteraemia was then examined. Thirty-six of the 129 bacteraemia patients had a NLR >20, while only 223 of the 3830 controls had a NLR >20. This gave a sensitivity of 27.9% (95% CI 20.3-36.4), specificity of 94.1% (93.3-94.8), positive predictive value of 13.9% (10.6-17.9) and a negative predictive value (NPV) of 97.4% (97.2-97.7) when the prevalence of bacteraemia was 3%. CONCLUSION: The NLR should be considered for use in routine clinical practice when assessing the FBC result in patients with suspected bacteraemia during pregnancy or in the post-partum period.

Analysing the Operative Experience of Paediatric Surgical Trainees in Sub-Saharan Africa Using a Web-Based Logbook.

BACKGROUND: The expansion of local training programmes is crucial to address the shortages of specialist paediatric surgeons across Sub-Saharan Africa. This study assesses whether the current training programme for paediatric surgery at the College of Surgeons of East, Central and Southern Africa (COSECSA) is exposing trainees to adequate numbers and types of surgical procedures, as defined by local and international guidelines. METHODS: Using data from the COSECSA web-based logbook, we retrospectively analysed numbers and types of operations carried out by paediatric surgical trainees at each stage of training between 2015 and 2019, comparing results with indicative case numbers from regional (COSECSA) and international (Joint Commission on Surgical Training) guidelines. RESULTS: A total of 7,616 paediatric surgical operations were recorded by 15 trainees, at different stages of training, working across five countries in Sub-Saharan Africa. Each trainee recorded a median number of 456 operations (range 56-1111), with operative experience increasing between the first and final year of training. The most commonly recorded operation was inguinal hernia (n = 1051, 13.8%). Trainees performed the majority (n = 5607, 73.6%) of operations recorded in the eLogbook themselves, assisting in the remainder. Trainees exceeded both local and international recommended case numbers for general surgical procedures, with little exposure to sub-specialities. CONCLUSIONS: Trainees obtain a wide experience in common and general paediatric surgical procedures, the number of which increases during training. Post-certification may be required for those who wish to sub-specialise. The data from the logbook are useful in identifying individuals who may require additional experience and centres which should be offering increased levels of supervised surgical exposure.

Mechanism of resonant electron emission from the deprotonated GFP chromophore and its biomimetics.

The Green Fluorescent Protein (GFP), which is widely used in bioimaging, is known to undergo light-induced redox transformations. Electron transfer is thought to occur resonantly through excited states of its chromophore; however, a detailed understanding of the electron gateway states of the chromophore is still missing. Here, we use photoelectron spectroscopy and high-level quantum chemistry calculations to show that following UV excitation, the ultrafast electron dynamics in the chromophore anion proceeds via an excited shape resonance strongly coupled to the open continuum. The impact of this state is found across the entire 355-315 nm excitation range, from above the first bound-bound transition to below the opening of higher-lying continua. By disentangling the electron dynamics in the photodetachment channels, we provide an important reference for the adiabatic position of the electron gateway state, which is located at 348 nm, and discover the source of the curiously large widths of the photoelectron spectra that have been reported in the literature. By introducing chemical modifications to the GFP chromophore, we show that the detachment threshold and the position of the gateway state, and hence the underlying excited-state dynamics, can be changed systematically. This enables a fine tuning of the intrinsic electron emission properties of the GFP chromophore and has significant implications for its function, suggesting that the biomimetic GFP chromophores are more stable to photooxidation.

The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis.

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed.

Selective Expression of Flt3 within the Mouse Hematopoietic Stem Cell Compartment.

The fms-like tyrosine kinase 3 (Flt3) is a cell surface receptor that is expressed by various hematopoietic progenitor cells (HPC) and Flt3-activating mutations are commonly present in acute myeloid and lymphoid leukemias. These findings underscore the importance of Flt3 to steady-state and malignant hematopoiesis. In this study, the expression of Flt3 protein and Flt3 mRNA by single cells within the hematopoietic stem cell (HSC) and HPC bone marrow compartments of C57/BL6 mice was investigated using flow cytometry and the quantitative reverse transcription polymerase chain reaction. Flt3 was heterogeneously expressed by almost all of the populations studied, including long-term reconstituting HSC and short-term reconstituting HSC. The erythropoietin receptor (EpoR) and macrophage colony-stimulating factor receptor (M-CSFR) were also found to be heterogeneously expressed within the multipotent cell compartments. Co-expression of the mRNAs encoding Flt3 and EpoR rarely occurred within these compartments. Expression of both Flt3 and M-CSFR protein at the surface of single cells was more commonly observed. These results emphasize the heterogeneous nature of HSC and HPC and the new sub-populations identified are important to understanding the origin and heterogeneity of the acute myeloid leukemias.

Versatility of stem and progenitor cells and the instructive actions of cytokines on hematopoiesis.

For many years, developing hematopoietic cells have been strictly compartmentalized into a rare population of multi-potent self-renewing hematopoietic stem cells (HSC), multi-potent hematopoietic progenitor cells (MPP) that are undergoing commitment to particular lineage fates, and recognizable precursor cells that mature towards functional blood and immune cells. A single route to each end-cell type is prescribed in the "classical" model for the architecture of hematopoiesis. Recent findings have led to the viewpoint that HSCs and MPPs are more versatile than previously thought. Underlying this are multiple routes to a particular fate and cells having clandestine fate options even when they have progressed some way along a pathway. The primary role of cytokines during hematopoiesis has long been seen to be regulation of the survival and proliferation of developing hematopoietic cells. Some cytokines now clearly have instructive actions on cell-fate decisions. All this leads to a new way of viewing hematopoiesis whereby versatile HSC and MPP are directed towards lineage outcomes via cytokine regulated cell-fate decisions. This means greater flexibility to the shaping of hematopoiesis.

Hedgehog and Resident Vascular Stem Cell Fate.

The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The discovery of resident multipotent vascular stem cells and adventitial progenitors within the vessel wall has transformed our understanding of the origin of medial and neointimal vascular smooth muscle cells (SMCs) during vessel repair in response to injury, lesion formation, and overall disease progression. This review highlights the importance of components of the Hh and Notch signalling pathways within the medial and adventitial regions of adult vessels, their recapitulation following vascular injury and disease progression, and their putative role in the maintenance and differentiation of resident vascular stem cells to vascular lineages from discrete niches within the vessel wall.

Controlling radical formation in the photoactive yellow protein chromophore.

To understand how photoactive proteins function, it is necessary to understand the photoresponse of the chromophore. Photoactive yellow protein (PYP) is a prototypical signaling protein. Blue light triggers trans-cis isomerization of the chromophore covalently bound within PYP as the first step in a photocycle that results in the host bacterium moving away from potentially harmful light. At higher energies, photoabsorption has the potential to create radicals and free electrons; however, this process is largely unexplored. Here, we use photoelectron spectroscopy and quantum chemistry calculations to show that the molecular structure and conformation of the isolated PYP chromophore can be exploited to control the competition between trans-cis isomerization and radical formation. We also find evidence to suggest that one of the roles of the protein is to impede radical formation in PYP by preventing torsional motion in the electronic ground state of the chromophore.

Adult vascular smooth muscle cells in culture express neural stem cell markers typical of resident multipotent vascular stem cells.

Differentiation of resident multipotent vascular stem cells (MVSCs) or de-differentiation of vascular smooth muscle cells (vSMCs) might be responsible for the SMC phenotype that plays a major role in vascular diseases such as arteriosclerosis and restenosis. We examined vSMCs from three different species (rat, murine and bovine) to establish whether they exhibit neural stem cell characteristics typical of MVSCs. We determined their SMC differentiation, neural stem cell marker expression and multipotency following induction in vitro by using immunocytochemistry, confocal microscopy, fluorescence-activated cell sorting analysis and quantitative real-time polymerase chain reaction. MVSCs isolated from rat aortic explants, enzymatically dispersed rat SMCs and rat bone-marrow-derived mesenchymal stem cells served as controls. Murine carotid artery lysates and primary rat aortic vSMCs were both myosin-heavy-chain-positive but weakly expressed the neural crest stem cell marker, Sox10. Each vSMC line examined expressed SMC differentiation markers (smooth muscle α-actin, myosin heavy chain and calponin), neural crest stem cell markers (Sox10(+), Sox17(+)) and a glia marker (S100ß(+)). Serum deprivation significantly increased calponin and myosin heavy chain expression and decreased stem cell marker expression, when compared with serum-rich conditions. vSMCs did not differentiate to adipocytes or osteoblasts following adipogenic or osteogenic inductive stimulation, respectively, or respond to transforming growth factor-ß1 or Notch following γ-secretase inhibition. Thus, vascular SMCs in culture express neural stem cell markers typical of MVSCs, concomitant with SMC differentiation markers, but do not retain their multipotency. The ultimate origin of these cells might have important implications for their use in investigations of vascular proliferative disease in vitro.

Competition between photodetachment and autodetachment of the 2(1)ππ* state of the green fluorescent protein chromophore anion.

Using a combination of photoelectron spectroscopy measurements and quantum chemistry calculations, we have identified competing electron emission processes that contribute to the 350-315 nm photoelectron spectra of the deprotonated green fluorescent protein chromophore anion, p-hydroxybenzylidene-2,3-dimethylimidazolinone. As well as direct electron detachment from S0, we observe resonant excitation of the 2(1)ππ* state of the anion followed by autodetachment. The experimental photoelectron spectra are found to be significantly broader than photoelectron spectrum calculated using the Franck-Condon method and we attribute this to rapid (∼10 fs) vibrational decoherence, or intramolecular vibrational energy redistribution, within the neutral radical.

Embryonic rat vascular smooth muscle cells revisited - a model for neonatal, neointimal SMC or differentiated vascular stem cells?

BACKGROUND: The A10 and A7r5 cell lines derived from the thoracic aorta of embryonic rat are widely used as models of non-differentiated, neonatal and neointimal vascular smooth muscle cells in culture. The recent discovery of resident multipotent vascular stem cells within the vessel wall has necessitated the identity and origin of these vascular cells be revisited. In this context, we examined A10 and A7r5 cell lines to establish the similarities and differences between these cell lines and multipotent vascular stem cells isolated from adult rat aortas by determining their differentiation state, stem cell marker expression and their multipotency potential in vitro. METHODS: Vascular smooth muscle cell differentiation markers (alpha-actin, myosin heavy chain, calponin) and stem cell marker expression (Sox10, Sox17 and S100ß) were assessed using immunocytochemistry, confocal microscopy, FACS analysis and real-time quantitative PCR. RESULTS: Both A10 and A7r5 expressed vascular smooth muscle differentiation, markers, smooth muscle alpha - actin, smooth muscle myosin heavy chain and calponin. In parallel analysis, multipotent vascular stem cells isolated from rat aortic explants were immunocytochemically myosin heavy chain negative but positive for the neural stem cell markers Sox10+, a neural crest marker, Sox17+ the endoderm marker, and the glia marker, S100ß+. This multipotent vascular stem cell marker profile was detected in both embryonic vascular cell lines in addition to the adventitial progenitor stem cell marker, stem cell antigen-1, Sca1+. Serum deprivation resulted in a significant increase in stem cell and smooth muscle cell differentiation marker expression, when compared to serum treated cells. Both cell types exhibited weak multipotency following adipocyte inductive stimulation. Moreover, Notch signaling blockade following γ-secretase inhibition with DAPT enhanced the expression of both vascular smooth muscle and stem cell markers. CONCLUSIONS: We conclude that A10 and A7r5 cells share similar neural stem cell markers to both multipotent vascular stem cells and adventitial progenitors that are indicative of neointimal stem-derived smooth muscle cells. This may have important implications for their use in examining vascular contractile and proliferative phenotypes in vitro.