Liverpool School Of Tropical Medicine Research Articles

A feasibility study of controlled human infection with intradermal Bacillus Calmette–Guérin (BCG) injection: Pilot BCG controlled human infection model

Tuberculosis (TB) caused 1.5 million deaths in 2020, making it the leading infectious killer after COVID-19. Bacille Calmette-Guerin (BCG) is the only licensed vaccine against TB but has sub-optimal efficacy against pulmonary TB and reduced effectiveness in regions close to the equator with high burden. Efforts to find novel vaccines are hampered due to the need for large-scale, prolonged, and costly clinical trials. Controlled human infection models (CHIMs) for TB may be used to accelerate vaccine development by ensuring only the most promising vaccine candidates are selected for phase 3 trials, but it is not currently possible to give participants Mycobacterium tuberculosis as a challenge agent. This study aims to replicate and refine an established BCG CHIM at the Liverpool School of Tropical Medicine. Participants will receive an intradermal injection with licensed BCG vaccine (Statens Serum Institut strain). In phase A, participants will undergo punch biopsy two weeks after administration, paired with minimally invasive methods of skin sampling (skin swab, microbiopsy, skin scrape). BCG detection by classical culture and molecular methods will be compared between these techniques and gold standard punch biopsy. Techniques meeting our pre-defined sensitivity and specificity criteria will be applied in Phase B to longitudinally assess intradermal BCG growth two, seven and fourteen days after administration. We will also measure compartmental immune responses in skin, blood and respiratory mucosa in Phase B. This feasibility study will transfer and refine an existing and safe model of BCG controlled human infection. Longitudinal BCG quantification has the potential to increase model sensitivity to detect vaccine and therapeutic responses. If successful, we aim to transfer the model to Malawi in future studies, a setting with endemic TB disease, to accelerate development of vaccines and therapeutics relevant for underserved populations who stand to benefit the most. Registration: ISRCTN: ISRCTN94098600 and ClinicalTrials.gov: NCT0582059

Confirmation of the presence of Anopheles stephensi among internally displaced people’s camps and host communities in Aden city, Yemen

BackgroundDeclines in global malaria cases and deaths since the millennium are currently challenged by multiple factors including funding limitations, limits of, and resistance to vector control tools, and also recent spread of the invasive vector species, Anopheles stephensi—especially into novel urban settings where malaria rates are typically low. Coupled with general increases in urbanization and escalations in the number of conflicts creating rapid and unplanned population displacement into temporary shelter camps within host urban areas, particularly in the Middle East and sub-Saharan Africa, increased urban malaria is a major threat to control and elimination.MethodsEntomological monitoring surveys (targeting Aedes aegypti) of water containers across urban areas hosting internally displaced people (IDP) communities in Aden city, Yemen, were performed by The MENTOR Initiative, a non-governmental organisation. As part of these surveys in 2021 23 larvae collected and raised to adults were morphologically identified as An. stephensi. Twelve of the samples were sent to Liverpool School of Tropical Medicine for independent morphological assessment and genetic analysis by sequencing the ribosomal ITS2 region and the mitochondrial COI gene.ResultsAll twelve samples were confirmed morphologically and by sequence comparison of the single ITS2 and COI haplotype detected to the NCBI BLAST database as An. stephensi. Phylogenetic analysis with comparable COI sequences indicated close relationship to haplotypes found in Djibouti and Ethiopia.ConclusionThe study results confirm the presence of An. stephensi in Yemen. Confirmation of the species in multiple urban communities hosting thousands of IDPs living in temporary shelters with widescale dependency on open water containers is of particular concern due to the vulnerability of the population and abundance of favourable breeding sites for the vector. Proactive monitoring and targeted integrated vector management are required to limit impacts in this area of typically low malaria transmission, and to prevent further the spread of An. stephensi within the region.

Development and evaluation of TaqMan-based, one-step, real-time RT-PCR assays for pepper mild mottle virus detection for near source tracking and wastewater-based epidemiology validation.

Emergence of novel human pathogens pose significant challenges to human health as highlighted by the SARS-CoV-2 pandemic. Wastewater based epidemiology (WBE) has previously been employed to identify viral pathogens and outbreaks by testing samples from regional wastewater treatment plants. Near source tracking (NST) allows for more targeted WBE by analysing samples from individual buildings such as schools or even individual floors such as in multi-floor office buildings. Despite the public health advantages of WBE, few strategies exist for optimising NST sampling methodologies. Therefore, we developed a protocol to evaluate virus detection in NST sampling using Pepper Mild Mottle Virus (PMMoV) as a proxy for RNA viruses. PMMoV is the most abundant enteric human associated RNA virus and is present in peppers/pepper-containing foods. Two bespoke TaqMan RT-PCR assays were developed to detect a PMMoV genomic 5' region and a capsid associated gene. To evaluate the protocol against field samples, pepper homogenates were flushed down an in-use toilet (Liverpool School of Tropical Medicine, UK) to spike wastewater with PMMoV on multiple days, and samples collected from two sewage access points to validate NST samplers. These wastewater samples were assessed for PMMoV based on Ct values and results compared to pepper and Tabasco derived PMMoV positive controls. Positive detection of PMMoV was comparable and consistent in ten independent samples across two NST samplers regardless of pepper homogenate spiking. We have developed two novel one step TaqMan assays that amplify both PMMoV targets in viral RNA extractions from peppers, Tabasco, and wastewater samples with cDNA synthesis through to RT-PCR results taking approximately 30 minutes. Pepper homogenate flushing was not required to detect PMMoV in our wastewater samples, however this strategy of flushing PMMoV containing materials outlined here could be valuable in assessing and validating NST in buildings with no previous or current sewage flow.

Screening for Aspiration Risk Associated With Dysphagia in Acute Stroke

HomeStrokeVol. 53, No. 9Screening for Aspiration Risk Associated With Dysphagia in Acute Stroke No AccessArticle CommentaryRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessArticle CommentaryRequest AccessFull TextScreening for Aspiration Risk Associated With Dysphagia in Acute Stroke Elizabeth Boaden, PhD, Jane Burnell, MSc, Lucy Hives, MSc, Paola Dey, MD, Andrew Clegg, PhD, Mary W. Lyons, MPH, C. Elizabeth Lightbody, PhD, Margaret A. Hurley, PhD, Hazel Roddam, PhD, Elizabeth McInnes, PhD, Anne W. Alexandrov, PhD and Caroline L. Watkins, PhD Elizabeth BoadenElizabeth Boaden Correspondence to: Elizabeth Boaden, PhD, Senior Research Fellow, Stroke Research Team, Brook Building 247, University of Central Lancashire, Preston, PR1 2HE. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4647-6392 Faculty of Health and Care (E.B., J.B., L.H., A.C., C.E.L., M.A.H., C.L.W.), University of Central Lancashire, Preston, United Kingdom. Search for more papers by this author , Jane BurnellJane Burnell https://orcid.org/0000-0002-4601-1632 Faculty of Health and Care (E.B., J.B., L.H., A.C., C.E.L., M.A.H., C.L.W.), University of Central Lancashire, Preston, United Kingdom. Search for more papers by this author , Lucy HivesLucy Hives https://orcid.org/0000-0003-4125-4034 Faculty of Health and Care (E.B., J.B., L.H., A.C., C.E.L., M.A.H., C.L.W.), University of Central Lancashire, Preston, United Kingdom. Search for more papers by this author , Paola DeyPaola Dey https://orcid.org/0000-0003-4555-1917 Faculty of Health, Social Care and Medicine, Edge Hill University, Ormskirk, United Kingdom (P.D.). Search for more papers by this author , Andrew CleggAndrew Clegg https://orcid.org/0000-0001-8938-7819 Faculty of Health and Care (E.B., J.B., L.H., A.C., C.E.L., M.A.H., C.L.W.), University of Central Lancashire, Preston, United Kingdom. Search for more papers by this author , Mary W. LyonsMary W. Lyons https://orcid.org/0000-0001-7532-2301 Liverpool School of Tropical Medicine, United Kingdom (M.W.L.). Search for more papers by this author , C. Elizabeth LightbodyC. Elizabeth Lightbody https://orcid.org/0000-0001-5016-3471 Faculty of Health and Care (E.B., J.B., L.H., A.C., C.E.L., M.A.H., C.L.W.), University of Central Lancashire, Preston, United Kingdom. Lancashire Teaching Hospitals NHS Foundation Trust, United Kingdom (C.E.L.). Search for more papers by this author , Margaret A. HurleyMargaret A. Hurley https://orcid.org/0000-0002-2502-432X Faculty of Health and Care (E.B., J.B., L.H., A.C., C.E.L., M.A.H., C.L.W.), University of Central Lancashire, Preston, United Kingdom. Search for more papers by this author , Hazel RoddamHazel Roddam https://orcid.org/0000-0002-0637-1801 Faculty of Allied Health and Well-being (H.R.), University of Central Lancashire, Preston, United Kingdom. Search for more papers by this author , Elizabeth McInnesElizabeth McInnes https://orcid.org/0000-0002-0567-9679 Nursing Research Institute, Australian Catholic University, Sydney, Australia (E.M.). Search for more papers by this author , Anne W. AlexandrovAnne W. Alexandrov https://orcid.org/0000-0002-4060-6766 Department of Acute and Tertiary Care, University of Tennessee Health Science Center (UTHSC), Memphis (A.W.A.). Search for more papers by this author and Caroline L. WatkinsCaroline L. Watkins https://orcid.org/0000-0002-9403-3772 Faculty of Health and Care (E.B., J.B., L.H., A.C., C.E.L., M.A.H., C.L.W.), University of Central Lancashire, Preston, United Kingdom. Search for more papers by this author Originally published22 Aug 2022https://doi.org/10.1161/STROKEAHA.122.037998Stroke. 2022;53:e424–e425"Screening for Aspiration Risk Associated With Dysphagia in Acute Stroke." Stroke, 53(9), pp. e424–e425FootnotesFor Sources of Funding and Disclosures, see page e425.Correspondence to: Elizabeth Boaden, PhD, Senior Research Fellow, Stroke Research Team, Brook Building 247, University of Central Lancashire, Preston, PR1 2HE. Email [email protected]ac.uk

Risk Factors for Nonattendance in Delusional Infestation: A Multicenter Observational Study

Background: Nonattendance is common among patients suffering from delusional infestation (DI) with a risk factor for poorer patient outcomes. Objective: The aim of this study was to determine the incidence rate and predictors of nonattendance among patients presenting to a psychodermatology department with DI and the subsequent effect on the success of prescribing new antipsychotics. Methods: Data of 265 patients were reviewed of the Amsterdam UMC, the Erasmus University Medical Center, the Royal London Hospital, and the Liverpool School of Tropical Medicine between January 2008 and October 2019. Results: We observed that among the patients who attended the first consultation, 57% (n = 144) did not attend their second visit. Recreational drug use was significantly higher in the nonattendance group compared to the attendance group (25% against 18%). Patients who had a history of previously prescribed antipsychotics at the time of the first consultation were less likely to get prescribed antipsychotics from the psychodermatology departments for DI; however, prescribing antipsychotic drugs by the psychodermatology department did not influence nonattendance significantly. Conclusions: People suffering from DI are at high risk of nonattendance, even in specialist settings. Patients with current illicit drug use and younger patients are particularly at risk of this.

The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol.

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement, and demonstrate reduced effectiveness against mucosal colonisation. For Malawi, nasopharyngeal carriage of vaccine-type pneumococci is common in vaccinated children despite national roll-out of 13-valent pneumococcal conjugate vaccine (PCV13) since 2011. Our team has safely transferred an established experimental human pneumococcal carriage method from Liverpool School of Tropical Medicine to the Malawi-Liverpool Wellcome Trust Clinical Research Programme, Malawi. This study will determine potential immunological mechanisms for the differential effects of PCV13 on nasal carriage between healthy Malawian and UK populations. We will conduct a double-blinded randomised controlled trial to vaccinate (1:1) participants with either PCV13 or control (normal saline). After a period of one month, participants will be inoculated with S. pneumoniae serotype 6B to experimentally induce nasal carriage using the EHPC method. Subsequently, participants will be invited for a second inoculation after one year to determine longer-term vaccine-induced immunological effects. Primary endpoint: detection of inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: local and systemic innate, humoral and cellular responses to PCV-13 with and without pneumococcal nasal carriage The primary objective of this controlled human infection model study is to determine if PCV-13 vaccination is protective against pneumococcal carriage in healthy adult Malawian volunteers. This study will help us to understand the observed differences in PCV-13 efficacy between populations and inform the design of future vaccines relevant to the Malawian population. Trial Registration: Pan African Clinical Trial Registry (REF: PACTR202008503507113).

The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement, and demonstrate reduced effectiveness against mucosal colonisation.  For Malawi, nasopharyngeal carriage of vaccine-type pneumococci is common in vaccinated children despite national roll-out of 13-valent pneumococcal conjugate vaccine (PCV13) since 2011. Our team has safely transferred an established experimental human pneumococcal carriage method from Liverpool School of Tropical Medicine to the Malawi-Liverpool Wellcome Trust Clinical Research Programme, Malawi. This study will determine potential immunological mechanisms for the differential effects of PCV13 on nasal carriage between healthy Malawian and UK populations. We will conduct a double-blinded randomised controlled trial to vaccinate (1:1) participants with either PCV13 or control (normal saline). After a period of one month, participants will be inoculated with S. pneumoniae serotype 6B to experimentally induce nasal carriage using the EHPC method. Subsequently, participants will be invited for a second inoculation after one year to determine longer-term vaccine-induced immunological effects. Primary endpoint: detection of inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: local and systemic innate, humoral and cellular responses to PCV-13 with and without pneumococcal nasal carriage The primary objective of this controlled human infection model study is to determine if PCV-13 vaccination is protective against pneumococcal carriage in healthy adult Malawian volunteers. This study will help us to understand the observed differences in PCV-13 efficacy between populations and inform the design of future vaccines relevant to the Malawian population. Trial Registration: Pan African Clinical Trial Registry (REF: PACTR202008503507113)

Racism in two UK global health institutions

Many people have been shocked by the racism evidenced in the February, 2022 independent review 1 Arday J Equity and inclusion at LSTM: improving racial equity in global medicine—an independent report. https://www.lstmed.ac.uk/sites/default/files/LSTM%20Race%20Equality%20Review%20-%20Arday%20%28February%202022%29%20FINAL.pdfDate: February, 2022 Date accessed: February 24, 2022 Google Scholar , 2 Wolfe-Robinson M Race report delivers damning verdict on Liverpool School of Tropical Medicine. The Guardian. Feb 17, 2022; Google Scholar of the Liverpool School of Tropical Medicine (LSTM), Liverpool, UK, the oldest institute of global health in the world. The LSTM findings are strikingly similar to those of a 2021 independent review 3 Nous GroupIndependent review to address discrimination and advance anti-racism: London School of Hygiene and Tropical Medicine. https://www.lshtm.ac.uk/media/56316Date: Dec 8, 2021 Date accessed: February 24, 2022 Google Scholar , 4 Weale S Structural racism at London School of Hygiene & Tropical Medicine, finds report. The Guardian. Dec 13, 2021; Google Scholar of the London School of Hygiene & Tropical Medicine (LSHTM), London, UK, a marginally younger, but substantially larger institute of global health. Dedicated almost exclusively to research in low-income and middle-income countries and related teaching, the institutes annually receive about £115 million (LSTM) and £180 million (LSHTM) in research grant income from various funding bodies, including UK Research and Innovation (UKRI), the Bill & Melinda Gates Foundation, and the Wellcome Trust. 5 Liverpool School of Tropical MedicineThe Liverpool School of Tropical Medicine 2020/21 annual report. Liverpool School of Tropical Medicine, Liverpool2021 Google Scholar , 6 Liverpool School of Tropical MedicineFinancial statements 2020/2021. Liverpool School of Tropical Medicine, Liverpool2021 Google Scholar , 7 London School of Hygiene & Tropical MedicineAnnual report 2020: the London School of Hygiene & Tropical Medicine. London School of Hygiene & Tropical Medicine, London2020 Google Scholar

Household food insecurity, maternal nutrition, environmental risks and infants’ health outcomes: protocol of the IMPALA birth cohort study in Uganda

IntroductionIn low- and middle-income countries (LMICs), food insecurity and undernutrition disproportionately affect women of reproductive age, infants and young children. The disease burden from undernutrition in these vulnerable sections of...

Adolescent mental health research in Tanzania: a study protocol for a priority setting exercise and the development of an interinstitutional capacity strengthening programme

IntroductionPoor adolescent mental health is a barrier to achieving several sustainable development goals in Tanzania, where adolescent mental health infrastructure is weak. This is compounded by a lack of community...

Prisoner of War Medical Ingenuity in Far East Captivity.

Research into British perspectives of the medical history of Far East prisoners of war (FEPOWs) has been conducted by the Liverpool School of Tropical Medicine (United Kingdom), resulting from decades of treating FEPOW veterans that began after their repatriation in late 1945. This paper examines some of the ingenious ways that British medical officers, medical orderlies, and volunteers fought to save the lives of thousands of FEPOWs during captivity in the Second World War. It highlights some of the key medical challenges, together with the resourcefulness of a "citizen's army" of conscripts and volunteers who used their civilian knowledge, skills, and ingenuity in many ways to support Allied medical staff. Using the most basic of materials, they were able to produce a vast array of medical support equipment and even drugs, undoubtedly saving many lives.

The noble mission of Nobel Laureate Sir Ronald Ross

INTRODUCTION July 25 is a Historic Day. On that day in the year 1603, James VI of Scotland was crowned by James of England Uniting Kingdom of England and Scotland. Malaria and Yellow fever, The deadly Mosquito borne diseases, compelled England and Scotland to form the Kingdom of Great Britain through Union Act 1707, to conquer these diseases to set up and spread their Colonies’ business. MALARIA HUNTERS Two legendary Scots, Sir Ronald Ross [Figure 1] (13.05.1857-16.09.1932), inspired and guided by his mentor Sir Patrick Manson (03.10.1894-09.04.1922), made the breakthrough to combat Malaria and Mosquito-borne diseases and thus saving the humanity from this veritable scourge. A French Army Physician and Scientist (Father of Protozoa) Charles Louis Alphonse Laveran (18.06.1845-18.05.1924) discovered “oscillaria Malariae” (Plasmodium) on November 6, 1880 responsible for Malaria at Constantine, Algeria proving the “Germ Theory” of disease propounded by Louis Pasteur (27.12.1822-28.09.1885), in 1870. Thus, it was proved that Malaria (mal aria-bad air in Italian) or Paludism (“means Marshy” in French) is due to parasite, not due to bad air or marshy, i.e., Miasmatic origin. Sir Patrick Manson (Father of Tropical medicine) was the author of “Mosquito Malaria theory.”Figure 1: Sir Ronald Ross (1857–1932)EPIC STUDY Sir Ronald Ross made the landmark discovery that female Anopheles mosquito is the Vector of Malarial Parasite in Secundrabad (August 20, 1897, calling MOSQUITO DAY) and the lifecycle of Malarial Parasite (Bird to mosquito to the bird cycle of malaria) at the Presidency General Hospital, Calcutta (established on April 22, 1770) now, known as SSKM Hospital, Kolkata, at the present Sir Ronald Ross Laboratory on July 4, 1898 (MALARIA DAY). Calcutta (Once Mecca of Medicine in India) is the BIRTH PLACE OF MALARIA LOGY (Covell, 1932). Sir Ronald Ross is revered as FATHER OF MALARIALOGY for his “Great and Epoch making Discovery.” Sir Ronald Ross was awarded the Nobel Prize in physiology and Medicine on December 10, 1902 and he was recognized as “One of Greatest benefactors of mankind.” In Nobel Citation, it was mentioned “for his work on Malaria by which he has shown how it enters the organism and thereby he laid the foundation for successful research on this disease and methods of combating it.” BIOGRAPHY Sir Ronald Ross was born at Almora, India. He was the eldest son of the ten children of Sir Campbell Claye Grant Ross, a General in British Indian Army (Bengal Staff Corps) and Matilda Charlotte Elderton. At the age of 8 years, he was sent to England to study. He completed primary school and secondary education. During school life, he developed intense interest in poetry, literature, music, painting and mathematics and devoted to pursue his passion. He was not very much attentive to his academic study or playing. His father was very tough to his son to be a medical doctor. Hence, he was enrolled at St. Bartholomew’s Hospital Medical Collage in London on October 29, 1874 and passed in 1881. As a Medical Student, he did not show any brightness and also failed in examinations because he devoted to his Passions-not to be a Medical Doctor. INDIA - HIS DREAM Ronald Ross joined Indian Medical Service (IMS) on April 2, 1881, and worked from 25 years at different places such as Madras, Burma, Baluchistan, Andaman Islands, Bangalore, Secunderabad, Calcutta, and Assam. Wherever he went, two things – one iron frame upright Piano and one microscope – always were essential items of his luggage. STUDY ON MALARIA Ronald Ross used to suffer as a child seeing the malaria attack of his grandfather Lt. Col. Hugh Ross. Ross was determined to find a cure of the disease. During course of his Medical School, he saw a female patient presenting with muscle ache and high fever with chill and headache. That lady came from Essex marshes. Ronald Ross thoroughly examined her and provisionally diagnosed as a case of Malaria. However, malaria was very common in south America and India. The patient became frightened to see the exhaustive examination of Ronald Ross. She was lost to follow-up. Hence, Ross could not prove the diagnosis. Ronald Ross’s interest in Malaria began in 1892. He got a Laveran’s masterpiece on Malaria (translated from French to English). It was a great inspiration to him. From 1892 to 1894, he could not find Laveran’s “Oscillaria malariae” (Malarial Parasite). He met Sir Patrick Manson on April 10, 1894, at Cavendish Square, London, who taught him how to see the malarial parasite under microscope. During his leave from June 1888 to May 1889, he obtained D.P.H. (Diploma in Public Health) in London. He was first recipient of D.P.H. in the world. He was trained by Prof. Emanuel Edward Klein (Father of British Microbiology) on Bacteriology for 2 months. He married to Rosa Bessi Bloxam on 1889. From 1894 to 1898, Ronald Ross was under the constant guidance of his mentor Sir Patrick Manson. 173 letters were exchanged between them from 1895 to 1899. Ross observed early stages of Malarial Parasite in the stomach of a mosquito in May 1895. His total devotion was focused on mosquito and Malarial Parasite. It was interrupted when he was deputed to Bangalore as a Sanitary Officer to investigate the outbreak of Cholera. At Bangalore, there was no mosquito. Hence, Ronald Ross was very unhappy, but he worked hard to check cholera through proper massive sanitization (Drainages, Cleanliness, etc). Ross was an adroit environmentalist. Between 1895 and 1897, he made Bangalore in a clean and healthy city by dint of his meticulous planning and leadership. At Sigur Ghat, near Ooty, he saw “dappled winged” brown mosquitoes with peculiar posture. These dappled winged mosquitoes were species of the genus Anopheles. On August 20, 1897, he discovered that female anopheles mosquitoes were the vectors of Malarial Parasite at Secunderabad. He declared August 20, as Mosquito Day. He wrote a poem and sent to his wife Rosa Bessi Bloxam and Sir Patrick Manson On August 22: “This day relenting God Hath Placed Within My Hand A Wondrous thing, and God Be praised. At His command Seeking his secret deeds With tears and toiling breath, I find Thy cunning seeds 0 Million – murdering Death I know this little thing A myriad men will save 0 Death, where is Thy sting? Thy Victory, 0 Grave? This discovery was published in the Indian Medical Gazette on August 27, 1897, and subsequently on the December 18, 1897, Issue of British Medical Journal titled – ”on some peculiar pigmented cells found in two Mosquitoes fed on Malarial blood.” AGAIN INTERRUPTION IN RESEARCH WORK In September 1897, Ross was transferred to Malaria-free Kherwara in Rajputana (Rajasthan). He became angry and deeply frustrated. He threatened to resign from service, but due to Patrick Manson’s (Medical Advisor to Colonial Office) intervention, the Government arranged for his continued service and transferred to Calcutta “On a special duty” for 6 months under the Director General of IMS to investigate Malaria and Kala-azar (Visceral leishmaniasis). He joined the Presidency General Hospital (now SSKM Hospital) Calcutta on February 17, 1898. He was transferred to Calcutta on January 29, 1898. DISCOVERY OF LIFE CYCLE OF MALARIAL PARASITE At Presidency General Hospital, Calcutta Ross did his research on bird (purchased at his own cost) by grey Mosquitoes (Infected Culex Pipiens). His very obedient servant Mohammad Bux helped him a lot. His Laboratory Assistant was Dr. Kishori Mohan Bandhopadhyay. Due to plague in Calcutta at that time, human volunteers were not available; female Anopheles stephensi Mosquitoes do not cause Malaria in birds. Ross knew Danielewski’s studies on bird Malaria. Ross used birds as experimental model. ON July 4, 1898, he made the landmark discovery at D.D. Cunnigham’s Laboratory (at present Sir Ronald Ross Laboratory) of life cycle of Malarial Parasite proving the hypothesis of Laveran and Manson. RETIREMENT FROM INDIAN MEDICAL SERVICE Ronald Ross left Calcutta on August 13, 1898, to get rid of “Administrative Barbarism.” He submitted a report to the Government giving details of “Anti-Malarial weapons” including rational interventional strategies, as he thought to prevent, control, and eradicate malaria. WORK ON KALA-AZAR (VISCERAL LEISHMANIASIS) Ronald Ross submitted his report on the nature Kala-azar on January 30,1899, to the Director General of IMS. Ross named “Leishman-donovan bodies” as parasite of Kalaazar discovered by W. B. Leishman (06.11.1865-02.06.1926) and Charles Donovan (September 19, 1863–October, 29, 1951). Leishman discovered in 1903 but could not definitely identify; Donovan in 1903 in his research found the same but called it a parasite. Ronald Ross solved this dispute and named this parasite as “Leishman-Donovan Bodies.” ROSS JOINED LIVERPOOL SCHOOL OF TROPICAL MEDICINE, UK Returning from Calcutta, Ronald Ross joined as Lecturer with a very poor pay. He worked from 1899 to 1926 at different positions. He retired as Alfred Jones’ Professor and Director of Tropical Medicine. HEROIC EXPEDITIONS During his service at LSTM, he made expedition to Freetown, capital of Sierra Leona (1899 and 1901), Mian mir Lahore (1901), Lagos (1901), Ismailia at Egypt (1902), Panama (1904), Greece (1906), Mauritius (1907–1908), Alexandria (1914–18) to control, prevent, and eradicate Malaria. AWARDED NOBEL PRIZE IN PHYSIOLOGY AND MEDICINE (DECEMBER 10, 1902) Ronald Ross was the First Indian to get the Nobel Prize in Physiology and Medicine. Malaria known as Modern Plague or Deadly Fever (Mrityujwar by Sushruta, 800 BC-700 BCE) is now defeated by Ronald Ross. Sir Ronald Ross was a man of immense versatility; even within malaria, at least three streams of subsequent work flow from his original contribution; in parasitology-work on the life cycle, best known but perhaps not his greatest work, although crucial to all the rest; in epidemiological models which was 20 years ahead of his time and in sanitation or hygiene, in promoting the prevention of Malaria and other diseases by Environmental means. -David J Bradley Director, Ross Institute, London ROSS INSTITUTE AND HOSPITAL FOR TROPICAL DISEASES This institute was inaugurated in 1926 in Putney Heath by the Prince of Wales as a memorial to and in recognition of Ronald Ross’s work. It was dedicated to study of the nature and treatment, propagation and prevention of tropical diseases. In 1926, Ronald Ross became the Director-in-Chief of this institute till his death in 1932. After his death, it was incorporated by the London School of Hygiene and Tropical Medicine. HONOR TO SIR RONALD ROSS After his death on September 16, 1932, The Times, London, paid tribute to him “He slew the Dragon and delivered mankind from immortal bondage.” Dr. W. C. Gorgas said “Dr. Ronald Ross had dug the Panama canal with the help of microscope.” Calcutta honors Sir Ronald Ross. Barkley Bronze Medal by the Asiatic society of Calcutta on May 20, 1903 Gate of Commemoration unveiled by Lord Lytton, in the presence of Sir Ronald Ross at PG Hospital Campus on January 7, 1927. Ronald Ross Building was established at PG (SSKM) Hospital Kolkata in 1954. Ronald Ross oration (yearly) was established at IPGM and R (Institute of Post Graduate Medical Education and Research) in 1956. PG (SSKM) hospital was declared as a Heritage precinct and Sir Ronald Ross Laboratory Building as a Heritage Building by Calcutta Municipal Corporation on January 6,1991 due to appeal of Dr. Ranen Dasgupta. Sir Ronald Ross Sarani (Erstwhile Hospital Road) was declared by the Calcutta Municipal Corporation on the 09.01.2001, in response to appeal of Dr. Ranen Dasgupta Sir Ronald Ross Memorial Malaria Clinic (24 h) at Sir Ronald Ross Laboratory at SSKM Hospital was sanctioned by Government of West Bengal and Kolkata Municipal Corporation in response to appeal of Dr. Ranen Dasgupta, which was inaugurated on February 05, 2004. Sir Ronald Ross Park was established at SSKM Hospital on January 16, 2006. due to my endeavor. CONCLUSION Sir Ronald Ross was a remarkable man who contributed immensely not only in Malaria Research but also as a Mathematician, Epidemiologist, Sanitarian, Editor of Science Progress, Dramatist, Poet, Musician, Composer, Artist, and Author. He was a Polymath. Above all, he was a Medical Missionary. Earnest appeal To Commemorate his glorious attachment to PG SSKM Hospital Calcutta, The IPGME and R (Institute of Post Graduate Medical Education and Research) should be renamed as SIR RONALD ROSS INSTITUTE OF POST GRADUATE MEDICAL EDUCATION and RESEARCH. A MEDICAL MUSEUM should be established at the allotted land for the second campus of PG (SSKM) HOSPITAL at New Town, Kolkata, where foundation stone was laid on 11th November, 2010, to Showcase Calcutta, as MECCA OF MEDICINE and PG HOSPITAL AS PRIDE and GLORY OF BENGAL. The History of Malaria contains a good lesson for humanity. We should be more scientific in our habits of thought and more practical in our habits of Government. -Sir Ronald Ross Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Chemistry that delighted us in 2021

Snakes spitting pain Most of the venomous snakes in the Liverpool School of Tropical Medicine’s collection immobilize and kill prey by injecting venom through their fangs. But some snakes protect themselves from predators by spitting venom —potentially causing pain, inflammation, and blindness. This year, a team of researchers at the school’s Centre for Snakebite Research and Interventions uncovered how the venom packs such a punch: the molecular cocktail in spitting snakes’ venom contains high levels of proteins that increase the sensation of pain ( Science 2021, DOI: 10.1126/science.abb9303 ). The team found that, while each snake’s venom had a unique concoction of toxins, all the spitting snakes had higher levels of phospholipase A 2 (PLA 2 ) enzymes in their venom than nonspitting snakes. In tests on mouse nerve cells, mixtures of venom components including PLA 2 triggered more cell activity than cocktails without it, a sign of a greater

Protocol for a prospective cohort study of open tibia fractures in Malawi with a nested implementation of open fracture guidelines

Background: Road traffic injury (RTI) is the largest cause of death amongst 15–39-year-old people worldwide, and the burden of injuries such as open tibia fractures are rapidly increasing in Malawi. This study aims to investigate disability and economic outcomes of people with open tibia fractures in Malawi and improve these with locally delivered implementation of open fracture guidelines. Methods: This is a prospective cohort study describing function, quality of life and economic burden of open tibia fractures in Malawi. In total, 160 participants will be recruited across six centres and will be followed-up with face-to-face interviews at six weeks, three months, six months and one year following injury. The primary outcome will be function at one year measured by the short musculoskeletal functional assessment (SMFA) score. Secondary outcomes will include quality of life measured by EuroQol EQ-5D-3L, catastrophic loss of income and implementation outcomes (acceptability, adoption, appropriateness, costs, feasibility, fidelity, penetration, and sustainability) at one year. A nested pilot pre-post implementation study of an interventional bundle for all open fractures will be developed based on other implementation studies from low- and middle-income countries (LMICs). Regression analysis will be used to model and investigate associations between SMFA score and fracture severity, infection and the pre- and post-training course period. Outcome: This prospective cohort study will report patient reported outcomes from open tibia fractures in low-resource settings. Subsequent detailed evaluation of both the clinical and implementation components of the study will promote sustainability of improved open fractures management in the study sites and further scale-up of open fracture management guidelines. Ethics: Ethics approval has been obtained from the Liverpool School of Tropical Medicine and College of Medicine Research and Ethics committee.

The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol.

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement, and demonstrate reduced effectiveness against mucosal colonisation. For Malawi, nasopharyngeal carriage of vaccine-type pneumococci is common in vaccinated children despite national roll-out of 13-valent pneumococcal conjugate vaccine (PCV13) since 2011. Our team has safely transferred an established experimental human pneumococcal carriage method from Liverpool School of Tropical Medicine to the Malawi-Liverpool Wellcome Trust Clinical Research Programme, Malawi. This study will determine potential immunological mechanisms for the differential effects of PCV13 on nasal carriage between healthy Malawian and UK populations. We will conduct a double-blinded randomised controlled trial to vaccinate (1:1) participants with either PCV13 or control (normal saline). After a period of one month, participants will be inoculated with S. pneumoniae serotype 6B to experimentally induce nasal carriage using the EHPC method. Subsequently, participants will be invited for a second inoculation after one year to determine longer-term vaccine-induced immunological effects. Primary endpoint: detection of inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: local and systemic innate, humoral and cellular responses to PCV-13 with and without pneumococcal nasal carriage The primary objective of this controlled human infection model study is to determine if PCV-13 vaccination is protective against pneumococcal carriage in healthy adult Malawian volunteers. This study will help us to understand the observed differences in PCV-13 efficacy between populations and inform the design of future vaccines relevant to the Malawian population. Trial Registration: Pan African Clinical Trial Registry (REF: PACTR202008503507113).

Protocol for a prospective cohort study of open tibia fractures in Malawi with a nested implementation of open fracture guidelines

Background: Road traffic injury (RTI) is the largest cause of death amongst 15-39-year-old people worldwide, and the burden of injuries such as open tibia fractures are rapidly increasing in Malawi. This study aims to investigate disability and economic outcomes of people with open tibia fractures in Malawi and improve these with locally delivered implementation of open fracture guidelines. Methods: This is a prospective cohort study describing function, quality of life and economic burden of open tibia fractures in Malawi. In total, 160 participants will be recruited across six centres and will be followed-up with face-to-face interviews at six weeks, three months, six months and one year following injury. The primary outcome will be function at one year measured by the short musculoskeletal functional assessment (SMFA) score. Secondary outcomes will include quality of life measured by EuroQol EQ-5D-3L, catastrophic loss of income and implementation outcomes (acceptability, adoption, appropriateness, costs, feasibility, fidelity, penetration, and sustainability) at one year. A nested pilot pre-post implementation study of an interventional bundle for all open fractures will be developed based on other implementation studies from low- and middle-income countries (LMICs). Regression analysis will be used to model and investigate associations between SMFA score and fracture severity, infection and the pre- and post-training course period. Outcome: This prospective cohort study will report patient reported outcomes from open tibia fractures in low-resource settings. Subsequent detailed evaluation of both the clinical and implementation components of the study will promote sustainability of improved open fractures management in the study sites and further scale-up of open fracture management guidelines. Ethics: Ethics approval has been obtained from the Liverpool School of Tropical Medicine and College of Medicine Research and Ethics committee.

Towards Intermittent Preventive Therapy in Pregnancy with Dihydroartemisinin-Piperaquine?

Malaria is a major cause of adverse pregnancy outcomes in sub-Saharan Africa, but resistance to sulfadoxine-pyrimethamine, the only antimalarial recommended by the World Health Organisation for intermittent preventive therapy, is threatening the gains made in the last two decades. In this issue, Mlugu and colleagues present the results of a trial of dihydroartemisinin-piperaquine as an alternative to sulfadoxine-pyrimethamine. The results are impressive but raise the question why they differ so much from three previous trials.

Establishment of CORONET: COVID-19 Risk in Oncology Evaluation Tool to Identify Cancer Patients at Low Versus High Risk of Severe Complications of COVID-19 Infection Upon Presentation to Hospital

Background: Patients with cancer are at increased risk of severe COVID-19, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 in cancer patients predicting severe disease and build a decision-support online tool; COVID-19 Risk in Oncology Evaluation Tool (CORONET).Methods: Patients with active cancer (stage I-IV) and laboratory confirmed COVID-19 presenting to hospitals worldwide were included. Discharge (within 24hrs), admission (≥24hrs inpatient), oxygen requirement (O2) and death were combined in a 0-3 point severity scale. Association of features with outcome were investigated using Lasso regression and Random Forest (RF) combined with SHapley Additive exPlanations (SHAP). RF was further validated in 4 cohorts, split by geography. The CORONET model was then examined in the entire cohort to build an online CORONET decision-support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions.Findings: The dataset comprised 920 patients; median age 70 (range 5-99), 56% males, 44% females, 81% solid vs. 19% haematological cancers. In derivation, RF demonstrated superior performance over Lasso with lower mean squared error (0.801 vs. 0.807) and was selected for development. During validation, RF achieved mean AUROC 0.77, 0.80 and 0.75 for prediction of admission, O 2 and death, respectively. Using the entire cohort, CORONET cut-offs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died. SHAP explanations revealed National-Early-Warning-Score-2, C-reactive protein and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation.Interpretation: CORONET, a decision-support tool validated in healthcare systems worldwide can aid admission decisions and predict COVID-19 severity in patients with cancer.Funding Information: R. Lee and T. Robinson and J. Weaver are supported by the National Institute for Health Research as Clinical Lecturers. T. Bhogal is supported by the National Institute for Health Research as an academic clinical fellow. U. Khan is an MRC Clinical Training Fellow based at the University of Liverpool supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Award Ref. MR/N025989/1). The Liverpool Experimental Cancer Medicine Centre for providing infrastructure support (Grant Reference: C18616/A25153) and The Clatterbridge Cancer charity (North West Cancer Research). C. Dive is funded by CRUK Core funding to Manchester Institute (C5757/A27412) and is supported by the CRUK Manchester Centre Award (C5759/A25254), and by the NIHR Manchester Biomedical Research Centre. C. Zhou is funded by the CRUK Manchester Centre Award (C5759/A25254), J. Stevenson and P. Fitzpatrick are funded by the CRUK Accelerator Award (29374). This research was funded in part, by the Wellcome Trust [205228/Z/16/Z]. LT is also supported by the National Institute for Health Research Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. LT is based at University of Liverpool. MS is supported by a grant from the Ministry of Science and Higher Education of the Russian Federation for the state support for the creation and development of World Class Research Centers "Digital biodesign and personalized healthcare” N.075-15-2020-926.Declaration of Interests: R Lee research funding (institution) BMS and speaker fees Astrazeneca. A. Croitoru Consulting or Advisory Role: Lilly, Merck, Roche, Bayer, Novartis, Ipsen, Research Funding me and my hospital: Gilead Sciences, Pfizer, Canfite, NanoCarrier, Bristol-Myers Squibb, Merck, Amgen, Servier, Five Prime Therapeutics, Travel Accommodations: Pfizer, Genekor, and oz, Merck, Pfizer, Servier, Roche. O. Michielin reports personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Roche, personal fees from Amgen, personal fees from NeraCare GmbH, outside the submitted work. E. Romano institutional research grants from Amgen, Astra Zeneca, Bristol-Myers Squibb. G. Pentheroudakis advisory board for Amgen, Astra Zeneca, Bristol-Myers Squibb, Lilly, Merck, MSD, Roche, Abbvie, institutional research grants from Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Debbio, Enorasis, Genekor, Ipsen, Janssen, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, Servier. Solange Peters reports consultation/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody, talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda, receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. M Rowe honoraria from Astellas Pharma, speaker fees MSD and Servier. C. Wilson consultancy and speaker fees Pfizer, Amgen, Novartis, A Armstrong conference fee Merck, spouse shares in Astrazeneca. T Robinson financial support to attend educational workshops from Amgen and Daiichi-Sankyo. C Dive, outside of this scope of work, has received research funding from AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, Clearbridge Biomedics, Angle PLC, Menarini Diagnostics, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Thermofisher. C Dive is on advisory boards for, and has received consultancy fees/honoraria from, AstraZeneca, Biocartis and Merck KGaA.No other authors have nothing to declare. Ethics Approval Statement: Approval (reference 20/WA/0269) was granted from the UK Research Ethics Committee for the study. Information regarding governance/regulatory approvals for each international cohort are available in the Supp. Methods.

Building supply chain capacity for neglected tropical diseases: experience from the Ascend West and Central Africa programme.

The Ascend West and Central Africa programme, funded by the UK Foreign, Commonwealth and Development Office (FCDO) is supporting integrated preventative chemotherapy for up to five neglected tropical diseases (NTDs), including intestinal worms, lymphatic filariasis, river blindness, trachoma and schistosomiasis. The programme is implemented across 13 countries by a consortium of four leading international development partners: Sightsavers, Liverpool School of Tropical Medicine, Schistosomiasis Control Initiative Foundation and Mott Macdonald. This paper presents messages learnt from country assessments that took place prior to the global outbreak of coronavirus disease 2019 (COVID-19). These messages remain relevant post-COVID-19, with greater priority being given to the challenges for national NTD programmes in continuing to deliver mass drug administration (MDA) during the pandemic. Stakeholder coordination from the earliest stages of the pandemic has occurred at two levels: in the first mile with global partners of the NTD Supply Chain Forum and in the last mile with implementing partners in each country. This has been instrumental to manage delayed MDA, including the impact delays have on the shipment of NTD donated drugs and the distribution of stock held in country. The Ascend West and Central Africa programme is supporting countries with the resumption of MDA through a risk assessment and mitigation action (RAMA) process.

Spitting cobras keep constant venom viscosity

Sometimes a bite just isn't good enough. Turning your teeth on a predator won't always be sufficient warning to back off, so some species throw in a dash of venom to get the message across. But one group of snakes take their toxic warning a stage further. They don't wait until a threat is within fang reach; spitting cobras eject their venom, sometimes over several metres, aiming at their victim's face and eyes. To ensure that their venom hits the spot, spitters have evolved specialised fangs that eject the venom forward at high pressure, but Arie van der Meijden and Ignazio Avella from the Research Center in Biodiversity and Genetic Resources (CIBIO), Porto, Portugal, wondered whether the snakes’ alternative lifestyle may also have affected the venom itself. Previous research had suggested that the venom of spitters might be a specialised fluid – known as a non-Newtonian fluid – which becomes less viscous as it flows through the fine channel connecting the venom gland to the fangs before increasing in viscosity as the venom sprays out to extend the range of the jet. But no one had thoroughly tested the theory on a variety of venoms, so Avella travelled to the Liverpool School of Tropical Medicine (LSTM), UK, home to some of the most venomous species on the planet.‘LSTM houses one of the richest collections of venomous snakes in Europe. Nicholas Casewell and Robert Harrison, the heads of LSTM's Centre for Snakebite Research and Interventions, allowed us to analyse the venoms of 13 different cobra species including spitters and non-spitters. I don't know of many other places that would be able to provide such a nice sample!’ exclaims Avella. During Avella's visit, Paul Rowley and Edouard Crittenden carefully collected venom samples by gently holding each snake behind the head and allowing it to bite a Parafilm-covered Petri dish, to catch the venom as it flowed from the fangs. ‘It doesn't matter how many venomous snakes you have dealt with, when a cobra raises its head and inflates its hood at you, it always sends a shiver down your spine’, Avella chuckles. Then he transported the lethal samples – ranging from 0.13 g from a Naja atra to 1.4 g from a Naja nigricollis – to Edgar Barajas-Ledesma and Chris Holland at the University of Sheffield, UK, where they took tiny droplets of each venom to measure the fluid's viscosity and how that altered as the liquids flowed.However, when the team compared the cobra venoms, they were surprised that the viscosity of the spitters’ venom didn't alter at different flow speeds and was remarkably similar to the viscosity of the venom collected from non-spitting snakes. ‘When our measurements disproved something that we considered a given based on previous studies, it was both surprising and exhilarating’, says Van der Meijden. In addition, Barajas-Ledesma calculated the impact of venom viscosity and fang shape on the fluid pressure inside the fang and found that the pressure in the non-spitting Naja nivea fangs was higher than the pressure in the spitting N. nigricollis fangs. However, Barajas-Ledesma adds ‘Spitting and non-spitting cobras still use the same pressure as a firehose to eject their venom, so perhaps it's not so surprising they need it to flow as consistently as possible’.Given that spitting cobras only do so for defence, Van der Meijden is puzzled as to why more of the fearsome serpents haven't opted for this fangs-off approach to self-defence. He suspects that spitters may have evolved the strategy to keep fast-moving predators at bay, especially out in the open.