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Steven Okoli, Claire HarrisonDepartment of Haematology, Guy's and St Thomas' NHS Foundation Trust, Great Maze Pond, London, UKAbstract: In 1934, Epstein and Goedel used the term hemorrhagic thrombocythemia to describe a disorder characterized by permanent elevation of a platelet count to more than three times normal, hyperplasia of megakaryocytes, and the tendency for venous thrombosis and spontaneous hemorrhage. Over the last 75 years, and particularly in the past 6 years, major progress has been made in our understanding of essential thrombocythemia (ET) and its pathogenesis with the identification of the highly prevalent JAK-2 V617F and other mutations. Current management of this condition is based upon historical data and with treatments that have not changed significantly for nearly two decades. This study discusses this and recent progress, highlighting exciting new data with old and new drugs, as well as which patients in particular should be evaluated for these new therapies.Keywords: essential thrombocythemia, interferon, JAK inhibitor

Electric power generator is an essential household facility particularly in developing countries. It is made by various manufacturers in sizes and capacities and found in business centres, offices, workshops and factories. The attendant environmental risks of this source of power supply are major challenges to users both at household and industrial level. Efforts through research and development are still ongoing to mitigate the prevailing health hazards. This study investigates noise level of typical portable generator (2 kW/220 V, 18 kg, and 370—330—320 mm) and the sound absorbance capacity of an acoustic enclosure (440—440—440 mm) developed from a multilayer panel made of locally sourced galvanized metal sheet (0.90 mm), Polyurethane acoustic foam (7.50 mm), Particle board (35.0 mm) and plywood (10.0 mm). The noise produced by the generator when on load and no load were considered for cases of it being placed inside and outside the enclosure and compared with acceptable OSHA safe thresholds noise level for the school environment where the study was carried out using Sound Level Meter HD600 (IEC 61672-1) by Extech Inc. USA. The result shows a significant reduction of noise produced indicating a shift from very laud threshold with average of 86.23 dB (A) for no load and no enclosure to moderately low noise level (average of 69.34 dB(A)) for the case of no load using enclosure. Likewise considering loaded scenario similar trend was recorded with average acoustic capacity of the enclosure of 23.20 dB(A). The effect of the enclosure was noticed and the potential benefits of improved noise absorption panels to enhance better performance of the developed enclosure for office and household generators was established.

Vehicular emissions have been found to constitute the major source of environmental pollution. Unfortunately, it has been observed that in most developing countries like Nigeria, the contribution of vehicular emission to soil pollution and its implication on the environment is yet to be understood. This study focused on estimating the extent of soil pollution resulting from vehicular emission. Since the most serious effect of pollution with regard to heavy metals is associated with Lead, therefore it was considered as the key element in the investigations. Three locations within Nsukka including a motor Park (A), a primary school (B) and a location off town (C) with little or no traffic were chosen for collection of soil samples. A total of 63 samples were collected from the 3 sampling point sover a 3month period. The method of analysis used for determination of lead concentration was the calorimetric -- sulphide method. This involved the use of chemicals and a spectrometer to determine the amount of lead (ppm) present in a given soil sample. Analysis of the results indicated higher level of Lead concentration at locations exposed to relatively higher levels of vehicular emission. Samples from location A had highest levels of Lead concentration (max = 3.7ppm) followed by location B (max =0.86 ppm). Interestingly, Samples from location C which is not exposed to vehicular traffic consistently had zero level of Lead concentration. Results of the studies did not indicate any correlation between Lead concentration and recorded rainfall amounts. Considering the health hazards that could result from vehicular soil pollution there is need for the establishment of comprehensive monitoring system and information gathering on pollution levels in our environment, including soil. The use of leaded petrol should be regulated. [ABSTRACT FROM AUTHOR]

Abstract Background The prevalence of Human Immunodeficiency Virus (HIV) among adults and children in Uganda is 6.2% and 0.5% respectively. The prevalence of viral load suppression in Uganda among all adults and children living with HIV is 59.6% and 39.3% respectively. High viral load compromises on the quality of life of an individual, and as well increases on the risk of transmission of the virus to the unborn for pregnant mothers and to the spouse. The UNAID 90-90-90 campaign recommends that 90% know their status, 90% get treatment and 90% have viral suppression. Non-adherence to Antiretroviral Therapy (ART) is one of the causes of the high viral load. The world health organization recommends Intensified Adherence Counselling (IAC) be given to all individuals with a high viral load. The perceptions, attitudes and practices of people receiving IAC is important in understanding how best IAC should be implemented. Methods A qualitative study was done among 30 purposively selected individuals/guardians of children receiving ART and IAC at Kyabugimbi Health Center Four [HC IV (mini-hospital headed by a medical doctor)]. Data collected from Focus Group Discussion as audio-recordings in local language (Runyankole) was transcribed and later translated into English. Translated transcripts were analyzed manually using thematic content analysis. Results The major themes identified include: adherence to ART; change of attitude towards ART after IAC, IAC expectation and outcomes, IAC and stigma, and improving social support through IAC for PLWHIV. Conclusion Participating in IAC to be informative and led to change in their perceptions of HIV and better understanding the reasons for adherence to ART. IAC influenced the change in attitude and behavior thus seeking social support and mitigate stigma, which lead to a better ART adherence. However, there is need to improve on the way it is delivered both in structural setting and break down and packaging of information.

Competing Interests: Conflict of interest: None declared.

Background: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome., Methods: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants., Results: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving., Conclusions: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing., (© 2023. Crown.)

The incidence of melanoma is increasing and prolonged exposure to ultraviolet (UV) radiation remains the main risk factor. Public health measures have been vital in tackling the increased incidence and prevalence of melanoma. The management of melanoma has been revolutionised with the approval of new immunotherapy treatments (anti PD-1, CTLA-4 and LAG-3 antibodies) and targeted therapies (BRAF and MEK inhibitors). With some of these therapies becoming the standard of care in the management of advanced disease, it is likely we will see their use increase in the adjuvant and neoadjuvant setting. Recently, literature has demonstrated the benefits patients could derive from the combination of immune checkpoint inhibitors (ICIs) due to the promising results on its efficacy when compared to monotherapy. However, greater clarity on its use is needed in more unique presentations such as BRAF-wild type melanoma, where the lack of driver mutations makes disease management more challenging. Surgical resection remains an integral part of the management of earlier stages of the disease with a consequent decrease in reliance on other forms of therapy such as chemotherapy and radiotherapy. Finally, we evaluated the novel emerging experimental approaches to treatment such as adoptive T cell therapy, novel oncolytic treatments and cancer vaccines. We discussed how their use could improve patients' prognosis, enhance treatment efficacy, and potentially achieve cure.

Thrombotic thrombocytopenic purpura (TTP), caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13, is a medical emergency with life-threatening complications and a 90% mortality rate if left untreated. It presents a diagnostic challenge given the multiorgan involvement of the cardiovascular, gastrointestinal, and central nervous systems. Furthermore, the well-known full pentad of fever, hemolytic anemia, bleeding associated with thrombocytopenia, neurological signs, and renal disease is often absent in patients with TTP. We present a 51-year-old male adult with TTP. We utilized the PLASMIC scoring system, which predicts the likelihood of ADAMST13 activity in adults with features of thrombotic microangiopathy and thrombocytopenia with high sensitivity and specificity. We further review the literature supporting the expert statement on ICU management of patients with TTP that plasma exchange (PEX) should be initiated within 6 hours of diagnosis with adjunctive glucocorticoids, rituximab, and caplacizumab. If PEX is unavailable, plasma infusion can be started while the patient awaits transfer to a center with PEX capabilities.

The investigation of inherited disorders of erythropoiesis has elucidated many of the principles underlying the production of normal red blood cells and how this is perturbed in human disease. Congenital Dyserythropoietic Anaemia type 1 (CDA-I) is a rare form of anaemia caused by mutations in two genes of unknown function: CDAN1 and CDIN1 (previously called C15orf41), whilst in some cases, the underlying genetic abnormality is completely unknown. Consequently, the pathways affected in CDA-I remain to be discovered. To enable detailed analysis of this rare disorder we have validated a culture system which recapitulates all of the cardinal haematological features of CDA-I, including the formation of the pathognomonic 'spongy' heterochromatin seen by electron microscopy. Using a variety of cell and molecular biological approaches we discovered that erythroid cells in this condition show a delay during terminal erythroid differentiation, associated with increased proliferation and widespread changes in chromatin accessibility. We also show that the proteins encoded by CDAN1 and CDIN1 are enriched in nucleoli which are structurally and functionally abnormal in CDA-I. Together these findings provide important pointers to the pathways affected in CDA-I which for the first time can now be pursued in the tractable culture system utilised here.

Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the 'discoverability' of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family., (© 2016 John Wiley & Sons Ltd.)