Biological and functional multimorbidity-from mechanisms to management.

Globally, the number of people with multiple co-occurring diseases will increase substantially over the coming decades, with important consequences for patients, carers, healthcare systems and society. Addressing this challenge requires a shift in the prevailing clinical, educational and scientific thinking and organization-with a strong emphasis on the maintenance of generalist skills to balance the specialization trends of medical education and research. Multimorbidity is not a single entity but differs quantitively and qualitatively across life stages, ethnicities, sexes, socioeconomic groups and geographies. Data-driven science that quantifies the impact of disease co-occurrence-beyond the small number of currently well-studied long-term conditions (such as cardiometabolic diseases)-can help illuminate the pathological diversity of multimorbidity and identify common, mechanistically related, and prognostically relevant clusters. Broader access to data opportunities across modalities and disciplines will catalyze vertical and horizontal integration of multimorbidity research, to enable reconfiguring of medical services, clinical trials, guidelines and research in a way that accounts for the complexity of multimorbidity-and provides efficient, joined-up services for patients.

Formal and informal science advice in emergencies: COVID-19 in the UK.

The importance of scientific advice to government gains greater recognition in emergencies but inevitably has to be done in an environment of uncertainty, with limited data and at high speed. Adapting existing structures is more effective than creating new ones in an emergency. Between emergencies, the UK has a structured scientific advice system, including Chief Scientific Advisers, scientists in government, regulatory bodies and independent expert committees, which were adapted to COVID-19 under the umbrella of the Scientific Advisory Group for Emergencies. These worked alongside networks of informal scientific advice, including internationally. Multiple sciences were needed, including from the social sciences and engineering in addition to clinical science and epidemiology, and these had to be integrated. A centrally directed clinical research programme helped provide practitioners robust evidence, with observational and interventional trials providing data for policy and testing treatments and vaccines. The scale of the emergency meant unavoidable tension between detailed work and speed, and between an integrated scientific view usable in decision-making and constructive challenge. While a final judgement of the UK scientific response will take time, everyone should be grateful to the thousands of scientists involved for the research, synthesis and advice, which improved outcomes for the public.

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

High Prevalence of Strongyloides among South Asian Migrants in Primary Care-Associations with Eosinophilia and Gastrointestinal Symptoms.

Gastrointestinal (GI) symptoms are a frequent reason for primary care consultation, and common amongst patients with strongyloidiasis. We conducted a prospective cohort and nested case control study in East London to examine the predictive value of a raised eosinophil count or of GI symptoms, for Strongyloides infection in South Asian migrants. We included 503 patients in the final analyses and all underwent a standardised GI symptom questionnaire, eosinophil count and Strongyloides serology testing. Positive Strongyloides serology was found in 33.6% in the eosinophilia cohort against 12.5% in the phlebotomy controls, with adjusted odds ratio of 3.54 (95% CI 1.88-6.67). In the GI symptoms cohort, 16.4% were seropositive but this was not significantly different compared with controls, nor were there associations between particular symptoms and Strongyloidiasis. Almost a third (35/115) of patients with a positive Strongyloides serology did not have eosinophilia at time of testing. Median eosinophil count declined post-treatment from 0.5 cells × 109/L (IQR 0.3-0.7) to 0.3 (0.1-0.5), p < 0.001. We conclude Strongyloides infection is common in this setting, and the true symptom burden remains unclear. Availability of ivermectin in primary care would improve access to treatment. Further work should clarify cost-effectiveness of screening strategies for Strongyloides infection in UK migrant populations.

Patients with positive malaria tests not given artemisinin-based combination therapies: a research synthesis describing under-prescription of antimalarial medicines in Africa.

BACKGROUND: There has been a successful push towards parasitological diagnosis of malaria in Africa, mainly with rapid diagnostic tests (mRDTs), which has reduced over-prescribing of artemisinin-based combination therapies (ACT) to malaria test-negative patients. The effect on prescribing for test-positive patients has received much less attention. Malaria infection in endemic Africa is often most dangerous for young children and those in low-transmission settings. This study examined non-prescription of antimalarials for patients with malaria infection demonstrated by positive mRDT results, and in particular these groups who are most vulnerable to poor outcomes if antimalarials are not given. METHODS: Analysis of data from 562,762 patients in 8 studies co-designed as part of the ACT Consortium, conducted 2007-2013 in children and adults, in Cameroon, Ghana, Nigeria, Tanzania, and Uganda, in a variety of public and private health care sector settings, and across a range of malaria endemic zones. RESULTS: Of 106,039 patients with positive mRDT results (median age 6 years), 7426 (7.0%) were not prescribed an ACT antimalarial. The proportion of mRDT-positive patients not prescribed ACT ranged across sites from 1.3 to 37.1%. For patients under age 5 years, 3473/44,539 (7.8%) were not prescribed an ACT, compared with 3833/60,043 (6.4%) of those aged ≥ 5 years. The proportion of < 5-year-olds not prescribed ACT ranged up to 41.8% across sites. The odds of not being prescribed an ACT were 2-32 times higher for patients in settings with lower-transmission intensity (using test positivity as a proxy) compared to areas of higher transmission. mRDT-positive children in low-transmission settings were especially likely not to be prescribed ACT, with proportions untreated up to 70%. Of the 7426 mRDT-positive patients not prescribed an ACT, 4121 (55.5%) were prescribed other, non-recommended non-ACT antimalarial medications, and the remainder (44.5%) were prescribed no antimalarial. CONCLUSIONS: In eight studies of mRDT implementation in five African countries, substantial proportions of patients testing mRDT-positive were not prescribed an ACT antimalarial, and many were not prescribed an antimalarial at all. Patients most vulnerable to serious outcomes, children < 5 years and those in low-transmission settings, were most likely to not be prescribed antimalarials, and young children in low-transmission settings were least likely to be treated for malaria. This major public health risk must be addressed in training and practice. TRIAL REGISTRATION: Reported in individual primary studies.

UK vaccines network: Mapping priority pathogens of epidemic potential and vaccine pipeline developments.

During the 2013-2016 Ebola outbreak in West Africa an expert panel was established on the instructions of the UK Prime Minister to identify priority pathogens for outbreak diseases that had the potential to cause future epidemics. A total of 13 priority pathogens were identified, which led to the prioritisation of spending in emerging diseases vaccine research and development from the UK. This meeting report summarises the process used to develop the UK pathogen priority list, compares it to lists generated by other organisations (World Health Organisation, National Institutes of Allergy and Infectious Diseases) and summarises clinical progress towards the development of vaccines against priority diseases. There is clear technical progress towards the development of vaccines. However, the availability of these vaccines will be dependent on sustained funding for clinical trials and the preparation of clinically acceptable manufactured material during inter-epidemic periods.

Clinical and Diagnostic Features of 413 Patients Treated for Imported Strongyloidiasis at the Hospital for Tropical Diseases, London.

This study describes the clinical features of a cohort of imported cases of strongyloidiasis and the performance of standard diagnostic techniques for this condition. A total of 413 cases were identified, of whom 86 had microscopically proven infection. In proven cases, 23% had normal eosinophil counts, 19% had negative Strongyloides-specific serology, and 9.3% had normal blood counts and were seronegative. Serological testing was less sensitive for returning travelers (46.2%) than for migrants (89.7%). Immunosuppression, including human T-cell lymphotropic virus 1, was significantly associated with proven infection after controlling for age, presence of symptoms, duration of infection, and eosinophilia (OR 5.60, 95% CI 1.54-20.4). Patients with proven infection had lower serology values than those diagnosed with strongyloidiasis on the basis of positive serology and eosinophilia alone (P = 0.016). Symptomatic patients were significantly younger, had a shorter presumed duration of infection, and lower serology values. These data suggest a correlation between immunologic control of strongyloidiasis and the amplitude of the humoral response.

Imported malaria: key messages in an era of elimination.

Despite concerted efforts to eliminate malaria, it remains a major global cause of morbidity and mortality with over 200 million annual cases. Significant gains have been made, with the annual global malaria incidence and mortality halving over the past twenty years, using tools such as long-lasting insecticide-treated bed nets and artemisinin-based therapies. Malaria is also a significant cause of life-threatening imported infection in the UK. It is vital for front line clinical staff involved in the assessment of acutely ill patients to be aware of the need for early diagnostic testing, malaria epidemiology, markers of severe infection and developments in antimalarial treatments to optimise patient management. The difference between a good and poor outcome is early diagnosis and treatment. Many of the challenges faced in the quest for global eradication, such as availability of appropriate diagnostic tests, and drug and insecticide resistance could also have future implications for imported malaria.

Geographical and temporal trends and seasonal relapse in Plasmodium ovale spp. and Plasmodium malariae infections imported to the UK between 1987 and 2015.

BACKGROUND: Plasmodium ovale spp. and P. malariae cause illness in endemic regions and returning travellers. Far less is known about these species than P. falciparum and P. vivax. METHODS: The UK national surveillance data, collected 1987 to 2015, were collated with the International Passenger Survey and climatic data to determine geographical, temporal and seasonal trends of imported P. ovale spp. and P. malariae infection. RESULTS: Of 52,242 notified cases of malaria, 6.04% (3157) were caused by P. ovale spp. and 1.61% (841) by P. malariae; mortality was 0.03% (1) and 0.12% (1), respectively. Almost all travellers acquired infection in West or East Africa. Infection rate per travel episode fell fivefold during the study period. The median latency of P. malariae and P. ovale spp. was 18 and 76 days, respectively; delayed presentation occurred with both species. The latency of P. ovale spp. infection imported from West Africa was significantly shorter in those arriving in the UK during the West African peak malarial season compared to those arriving outside it (44 days vs 94 days, p < 0.0001), implying that relapse synchronises with the period of high malarial transmission. This trend was not seen in P. ovale spp. imported from East Africa nor in P. malariae. CONCLUSION: In West Africa, where malaria transmission is highly seasonal, P. ovale spp. may have evolved to relapse during the malarial high transmission season. This has public health implications. Deaths are very rare, supporting current guidelines emphasising outpatient treatment. However, late presentations do occur.