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An amendment to this paper has been published and can be accessed via the original article.…

Abstract Background Plasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite this, features contributing to such have not been exploited for anti-malarial drug design. Additionally, there are no anti-malarial drugs targeting PTKTs whereas the broad activity of these inhibitors against PTKTs from other Plasmodium spp. is yet to be reported. This study characterises different PTKTs [Plasmodium falciparum (PfTKT), Plasmodium vivax (PvTKT), Plasmodium ovale (PoTKT), Plasmodium malariae (PmTKT) and Plasmodium knowlesi (PkTKT) and the human homolog (HsTKT)] to identify key sequence and structural based differences as well as the identification of selective potential inhibitors against PTKTs. Methods A sequence-based study was carried out using multiple sequence alignment, phylogenetic tree calculations and motif discovery analysis. Additionally, TKT models of PfTKT, PmTKT, PoTKT, PmTKT and PkTKT were modelled using the Saccharomyces cerevisiae TKT structure as template. Based on the modelled structures, molecular docking using 623 South African natural compounds was done. The stability, conformational changes and detailed interactions of selected compounds were accessed viz all-atom molecular dynamics (MD) simulations and binding free energy (BFE) calculations. Results Sequence alignment, evolutionary and motif analyses revealed key differences between plasmodial and the human TKTs. High quality homodimeric three-dimensional PTKTs structures were constructed. Molecular docking results identified three compounds (SANC00107, SANC00411 and SANC00620) which selectively bind in the active site of all PTKTs with the lowest (better) binding affinity ≤ − 8.5 kcal/mol. MD simulations of ligand-bound systems showed stable fluctuations upon ligand binding. In all systems, ligands bind stably throughout the simulation and form crucial interactions with key active site residues. Simulations of selected compounds in complex with human TKT showed that ligands exited their binding sites at different time steps. BFE of protein–ligand complexes showed key residues involved in binding. Conclusions This study highlights significant differences between plasmodial and human TKTs and may provide valuable information for the development of novel anti-malarial inhibitors. Identified compounds may provide a starting point in the rational design of PTKT inhibitors and analogues based on these scaffolds.…

Abstract Background The analysis of single nucleotide polymorphism (SNPs) in drug-resistance associated genes is a commonly used strategy for the surveillance of anti-malarial drug resistance in populations of parasites. The present study was designed and performed to provide genetic epidemiological data of the prevalence of N86Y-Y184F-D1246Y SNPs in Plasmodium falciparum multidrug resistance 1 (pfmdr1) in the malaria hotspot of Northern Nigeria. Methods Plasmodium falciparum-positive blood samples on Whatman-3MM filter papers were collected from 750 symptomatic patients from four states (Kano, Kaduna, Yobe and Adamawa) in Northern Nigeria, and genotyped via BigDye (v3.1) terminator cycle sequencing for the presence of three SNPs in pfmdr1. SNPs in pfmdr1 were used to construct NYD, NYY, NFY, NFD, YYY, YYD, YFD and YFY haplotypes, and all data were analysed using Pearson Chi square and Fisher’s exact (FE) tests. Results The prevalence of the pfmdr1 86Y allele was highest in Kaduna (12.50%, 2 = 10.50, P = 0.02), whilst the 184F allele was highest in Kano (73.10%, 2 = 13.20, P = 0.00), and the pfmdr1 1246Y allele was highest in Yobe (5.26%, 2 = 9.20, P = 0.03). The NFD haplotype had the highest prevalence of 69.81% in Kano (2 = 36.10, P = 0.00), followed by NYD with a prevalence of 49.00% in Adamawa, then YFD with prevalence of 11.46% in Kaduna. The YYY haplotype was not observed in any of the studied states. Conclusion The present study suggests that strains of P. falciparum with reduced sensitivity to the lumefantrine component of AL exist in Northern Nigeria and predominate in the North-West region.…

Abstract Background Following a dramatic decline of malaria cases in Aceh province, geographically-based reactive case detection (RACD) was recently evaluated as a tool to improve surveillance with the goal of malaria elimination. While RACD detected few cases in households surrounding index cases, engaging in forest work was identified as a risk factor for malaria and infections from Plasmodium knowlesi—a non-human primate malaria parasite—were more common than expected. This qualitative formative assessment was conducted to improve understanding of malaria risk from forest work and identify strategies for targeted surveillance among forest workers, including adapting reactive case detection. Methods Between June and August, 2016, five focus groups and 18 in-depth interviews with forest workers and key informants were conducted in each of four subdistricts in Aceh Besar and Aceh Jaya districts. Themes included: types of forest activities, mobility of workers, interactions with non-human primates, malaria prevention and treatment-seeking behaviours, and willingness to participate in malaria surveys at forest work sites and using peer-referral. Results Reported forest activities included mining, logging, and agriculture in the deep forest and along the forest fringe. Forest workers, particularly miners and loggers, described often spending weeks to months at work sites in makeshift housing, rarely utilizing mosquito prevention and, upon fever, self-medicating and seeking care from traditional healers or pharmacies rather than health facilities. Non-human primates are frequently observed near work sites, and most forest work locations are within a day’s journey of health clinics. Employers and workers expressed interest in undertaking malaria testing and in participating in survey recruitment by peer-referral and at work sites. Conclusions Diverse groups of forest workers in Aceh are potentially exposed to malaria through forest work. Passive surveillance and household-based screening may under-estimate malaria burden due to extended stays in the forest and health-seeking behaviours. Adapting active surveillance to specifically target forest workers through work-site screening and/or peer-referral appears promising for addressing currently undetected infections.…

As we approach the end of 2020, and a year since the outbreak of COVID-19 began, cases are increasing again. We have learnt a lot about SARS-CoV-2 and our ability to test for and manage COVID-19 has improved, but ongoing debate remains about how SARS-CoV-2 is transmitted.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused more than 954 000 deaths worldwide to date,1 but the burden of morbidity and mortality has fallen unevenly on particular countries and population groups. Worldwide, COVID-19 has been recognised as a potential public health problem among people experiencing homelessness and other vulnerable cohorts such as prisoners.2–4 Broadly, reduced access to health care and basic sanitation, the potential for mobility between services and crowding within facilities, the greater sharing of resources between individuals, substance-seeking behaviours, economic need resulting in employment such as survival sex work,5 and underlying health conditions put such individuals theoretically more at risk of morbidity and mortality from COVID-19.

Testing for severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) remains a global issue of capacity, accuracy, and access. In their prospective, interventional, non-randomised, controlled trial published in The Lancet Respiratory Medicine, Nathan Brendish and colleagues1 move COVID-19 diagnostics forward, both by expanding the repertoire of in-situ evaluated molecular platforms, and also methodologically, with a diagnostic controlled trial using clinical impact as a primary outcome measure, analogous to their previous work on other respiratory viruses.

One of the most common causes of hospital admission and death in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is acute respiratory distress syndrome (ARDS), a clinical syndrome characterised by acute lung inflammation and increased-permeability pulmonary oedema due to injury to the alveolar capillary barrier. As clinicians care for a surge of patients with ARDS due to COVID-19, two questions arise. First, is COVID-19-associated ARDS intrinsically different from ARDS unrelated to COVID-19? The answer to this question has implications for the use of evidence-based therapies such as lung-protective mechanical ventilation, proning, and conservative fluid management in COVID-19-associated ARDS.

The first recorded autopsy was that of Julius Caesar in 44 BCE to establish which knife wound had caused his death; the wound that ruptured his aorta was the culprit. Autopsies have been the foundation of medical advancement over the subsequent centuries, and were done in 40–60% of all hospital deaths as recently as the 1950s.1,2 With increasingly sophisticated imaging and diagnostic advancements, autopsy rates have declined substantially to less than 1%.3 Despite these advancements, clinically missed diagnoses involving a primary cause of death are found at autopsy about 8–24% of the time.

RT-PCR tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA are the operational gold standard for detecting COVID-19 disease in clinical practice. RT-PCR assays in the UK have analytical sensitivity and specificity of greater than 95%, but no single gold standard assay exists.1,2 New assays are verified across panels of material, confirmed as COVID-19 by multiple testing with other assays, together with a consistent clinical and radiological picture. These new assays are often tested under idealised conditions with hospital samples containing higher viral loads than those from asymptomatic individuals living in the community.

As of Feb 18, 2020, a total of 2807 cases of e-cigarette, or vaping, product use-associated lung injury (EVALI) and 68 attributed deaths have been reported to the US Centers for Disease Control and Prevention.1 Diagnostic criteria for EVALI consists of a mixture of non-specific systemic symptoms (eg, fever, chills, and vomiting) and respiratory symptoms (eg, shortness of breath, cough, chest pain, pnoea, and hypoxia), along with detection of lung opacities on imaging. Diagnosis also depends on identifying a history of vaping and careful exclusion of alternative conditions.

The impressive results of the RECOVERY trial established that a moderate dose of dexamethasone (6 mg daily for 10 days) reduced mortality in hospitalised patients with COVID-19 and respiratory failure who required therapy with supplemental oxygen or mechanical ventilation.1 The data also indicated that dexamethasone might increase mortality in hospitalised patients who were not receiving oxygen. This landmark trial and the subsequent practice guidelines from several academic and health organisations recommending dexamethasone use in patients with severe COVID-19 have changed clinical practice for hospitalised patients on supplemental oxygen or mechanical ventilation.

The current COVID-19 pandemic has challenged the continuity of health care and research. Health-care providers around the world are required to deal with social distancing and quarantine measures, while simultaneously ensuring quality of care for their patients. Consequently, eHealth applications, such as home monitoring, have gained increasing interest during the past months. For the vulnerable population of patients with interstitial lung diseases, home monitoring could be particularly relevant.

Matthieu Schmidt and colleagues1 aimed to establish the clinical characteristics and outcomes of patients with COVID-19 and respiratory failure treated with extracorporeal membrane oxygenation (ECMO). Among 83 patients, 30 (36%) died, 35 (42%) had major bleeding events, and four (5%) had a haemorrhagic stroke. When discussing the effectiveness of ECMO, an essential aspect is assessing whether the associated bleeding events are adverse incidents, or events resulting from abnormal coagulation.

We thank Hidesaku Asakura and Haruhiko Ogawa for their correspondence on our study on extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome related to COVID-19.1 They rightfully highlight that apart from heparin overdose, factors such as circuit-associated defibrination and thrombocytopenia, disseminated intravascular coagulation, acquired von Willebrand syndrome, and COVID-19-associated endotheliitis might cause bleeding in patients under ECMO support.

In a Spotlight in The Lancet Respiratory Medicine, the journal again invites spirited conversation in medicine.1 The Life of Breath project propelled the exploration of breathlessness through the humanities with research and therapeutic possibilities, such as the Dance Easy programme.1,2…

In the past few weeks, there has been a great deal of trepidation among the public about the impact of children returning to school on the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Children have greater difficulty adhering to physical distancing rules but are believed to transmit the virus less efficiently than adults.1 Rhinoviruses normally circulate year-round with seasonal peaks in spring and autumn and are transmitted in largely the same manner as SARS-CoV-2.

Marquette C-H, Boutros J, Benzaquen J, et al. Circulating tumour cells as a potential biomarker for lung cancer screening: a prospective cohort study. Lancet Respir Med 2020; 8: 709–16—In this Article, the spelling of the AIR project Study Group member Gilbert Ferretti's name (listed in the appendix) was incorrect. The appendix has been resupplied. This correction has been made to the online version as of Dec 1, 2020…

As societies around the world begin to reopen after many months of lockdown, a worrying shift is emerging in the demographic of COVID-19 cases towards individuals aged younger than 40 years. According to an analysis of 6 million cases between February and July, 2020, the number of infected people aged 15–24 years increased from 4·5% to 15%, possibly resulting from a combination of increased socialising in younger age groups and reversion to previous routines, including attending workplaces, schools, and universities, plus better surveillance.

The Human Challenge Consortium consists of UK Government representatives and experts from the National Health Service (NHS), academia, and the private sector. The group has come together to explore the feasibility and ethics of human challenge trials that could potentially accelerate the development of vaccines to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

At the time of publication, it looks like the second wave of COVID-19 is well underway in Europe. The weekly tally of new cases has been steadily rising for more than 2 months, but the past few weeks have seen accelerated transmission. Cases have also been trending upwards in the USA. Oct 14, 2020, saw the nation register the highest number of new cases of COVID-19 since Aug 7. In general, countries are much better prepared than they were when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first exploded onto the scene.

Multilevel upper airway surgery could be more effective in reducing the frequency of sleep apnoeas and daytime sleepiness in patients with moderate or severe obstructive sleep apnoea (OSA) compared with medical management (eg, weight loss) according to a study by Stuart MacKay and colleagues. The multicentre, randomised controlled trial is the first of its kind to assess multilevel airway surgery in this patient population. The study provides “arguably the highest quality evidence for surgical therapy of OSA”, according to Professor Atul Malhotra from The University of California San Diego (CA, USA).

The COVID-19 pandemic continues to pose extraordinary challenges to clinicians, patients, and health-care services worldwide. Anticipating substantial burdens of multisystem and psychological morbidity, many organisations have instituted post-COVID-19 clinical services. Exponential increases in case numbers at the peak of the pandemic necessitated rapid implementation of follow-up pathways that evolved in response to clinical need and, in the absence of robust COVID-19-specific data, through extrapolation of post-critical illness evidence and observations made during previous coronavirus outbreaks.

Perhaps the strangest thing about Jessi Gutch's condition is that she is currently feeling no symptoms, is pain free, and is showing no outward signs of a person facing incurable cancer. Yet this is the situation that this 28-year-old film producer from London, UK, finds herself. She has a very rare ovarian cancer called Sertoli-Leydig cell tumour, which has metastasised. Sertoli-Leydig represents roughly just 0·5% of all ovarian cancers, and of these, 90% are found at stage 1 and resolved, while just 10% metastasise.

Over the past few months, more than 80 000 Americans with COVID-19 have been treated with convalescent plasma, under an expanded access programme. The programme was discontinued on Aug 23, 2020, after the US Food and Drug Administration (FDA) authorised the emergency use of convalescent plasma in hospitalised patients with COVID-19. “This product may be effective in treating COVID-19”, stated the FDA. “The known and potential benefits...outweigh the known and potential risks.” The agency had good reason to sound so cautious.

Outbreaks of SARS-CoV-2 in homeless settings can lead to a high attack rate among people experiencing homelessness, even if incidence remains low in the general population. Avoidance of deaths depends on prevention of transmission within settings such as hostels and night shelters.

Point-of-care testing is associated with large reductions in time to results and could lead to improvements in infection control measures and patient flow compared with centralised laboratory PCR testing.

Patients with COVID-19-associated ARDS have a form of injury that, in many aspects, is similar to that of those with ARDS unrelated to COVID-19. Notably, patients with COVID-19-related ARDS who have a reduction in respiratory system compliance together with increased D-dimer concentrations have high mortality rates.

In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model.

Acute to subacute lung injury patterns were seen in all ten biopsies and most autopsy lung tissues from individuals with suspected EVALI. Acute to subacute lung injury can have numerous causes; however, if it is identified in an individual with a history of e-cigarette, or vaping, product use, and no alternative cause is apparent, a diagnosis of EVALI should be strongly considered. A review of autopsy tissue pathology in suspected EVALI deaths can also identify alternative diagnoses, which can enhance the specificity of public health surveillance efforts.

The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded.

The new IDSA guidelines for HIV primary care providers emphasise the importance of targeting mental health and comorbidities. Farooq Kazi and Ammara Mushtaq report.

The UNAIDS target to reduce HIV-related death to fewer than 500 000 deaths per year by 2020 will not be met.1 This statement might not be headline grabbing as this target was never as prominent as the 90-90-90 targets,2 the achievement of which is a necessary but not sufficient step towards ending AIDS mortality.

Schistosomiasis is a parasitic helminth disease that can cause organ lesions leading to health damage. During a schistosome infection, schistosome eggs can flow into the liver along the portal vein. Numerous inflammatory cells gather around the eggs, causing granulomas and fibrosis in the liver. In this process, many molecules are involved in the initiation and regulation of the fibrous scar formation. However, the precise molecular mechanisms that explain the progression of granuloma formation and fibrosis initiation caused by schistosome infection have not been extensively studied. In this study, C57BL/6 wild-type mice and signal transducer and activator of transcription 3 (Stat3)flox/flox Alb-Cre mice were infected with cercariae of Schistosoma japonicum. Liver injury, effector molecule levels and RNA transcriptome resequencing of liver were detected at 4, 5, and 6 weeks postinfection. We investigated the role of STAT3 in Schistosoma-induced liver injury in mice. After 6 weeks postinfection, there has obvious liver fibrosis. A sustained pathological process such as inflammation, oxidative stress, proliferation and apoptosis occurred in S. japonicum-induced liver fibrosis initiation. Meanwhile, we found the activation of the STAT3 pathway in hepatic injury during S. japonicum infection by RNA transcriptome resequencing. Liver p-STAT3 deficiency alleviated infection-induced liver dysfunction, hepatic granuloma formation and fibrosis initiation. It also promoted STAT3-dependent apoptosis and reduced liver inflammation, oxidative stress and proliferation. Our results suggest that STAT3 signal pathway and its mediating inflammation, oxidative stress, proliferation and apoptosis are involved in S. japonicum-induced liver injury and may be a new potential guideline for the treatment of schistosomiasis.…