Explore the vast range of titles available.

IntroductionAlthough there are many studies on the use of convalescent plasma (CP) for treatment of COVID-19, it is not clear (1) which groups of patients may benefit, (2) what dose of plasma to give, or (3) which antibody levels the plasma should contain. Previous phase I/II studies and literature review suggest that CP should only be given to patients with viraemia, that a daily infusion should be given until the patient becomes virus free and that the neutralising antibody titre should preferably be >1:640Methods and analysisAn open randomised controlled trial enrolling patients with COVID-19, who must be SARS-CoV-2 positive in both airway and blood samples and admitted to a study hospital. Block randomisation 2:1 is to either 200 mL CP (preferably titre ≥1/640) daily for up to 10 days (until virus negative in blood) plus standard care or standard care only (control arm). The primary endpoint is mortality by day 28 after study inclusion. Secondary endpoints include mortality by day 60 and doses of plasma needed to clear viraemia. Assuming a reduced mortality of approximately 30% by the CP therapy and 85%–88% survival in the control arm, approximately 600 participants will be enrolled to the CP therapy arm and 300 participants to the control arm.Ethics and disseminationEthical approval has been granted by the Swedish Ethical Review Authority (reference: 2020-06277). Results from this trial will be compiled in a clinical study report, disseminated via journal articles and communicated to stakeholders.Trial registration numberNCT04649879.

Background Recurrent Clostridioides difficile infection is most effectively treated with faecal microbiota transplantation. Swedish and European guidelines suggest faecal microbiota transplantation after a first or second recurrence, respectively. The aims of this study were to evaluate risk factors for further relapses at the first and second recurrence, related to treatment recommendations. Methods Patients aged ≥ 18 years with two positive tests for C. difficile within eight weeks and treated at the study hospitals during 2014–2022 were eligible for inclusion. Retrospectively collected data included age, sex, treatment, and clinical characteristics for each episode. Risk factors for further recurrences at the first and second recurrence were identified using multivariable logistic regression analysis. Results The median age in the total cohort ( n  = 231) was 76 (IQR 67–84) years, 52% were females and 15% were healthy without comorbidities. One recurrence only occurred in 110 patients (48%), however, no clinically significant risk factors predicting more than one recurrence were identified. Two or more recurrences occurred in 110 patients, of whom, 44 (40%) had further recurrences. Frailty (Clinical Frailty Scale ≥ 4) was significantly associated with more than two recurrences ( p  = 0.03). The respective median times between the first and the second recurrences were 12 and 17 days in patients with more than two recurrences compared to two recurrences only ( p  = 0.02). Conclusions Patients experiencing a second recurrence of C. difficile infection who were frail and relapsed in a shorter time span after the first recurrence had a significantly increased risk of further recurrences.

Faecal microbiota transplantation (FMT) is recommended treatment for recurrent Clostridioides difficile infection and is studied as a potential modifier of other gastrointestinal and systemic disorders. Autologous FMT limits the potential risks of donor transplant material and enables prophylactic treatment. Capsulized FMT is convenient and accessible, but safety data are lacking. To describe safety and tolerability of capsules containing autologous FMT, compared to placebo, in healthy volunteers treated with antibiotics. Healthy volunteers without antibiotic exposure during the past three months, that had a negative Clostridioides difficile stool sample, were recruited. Study persons donated faeces for production of capsules containing autologous microbiota. They were then given Clindamycin for seven days to disrupt the intestinal microbiota, which was followed by a two-day washout. Study persons were then randomized (1:1) to unsupervised treatment with autologous faecal matter or placebo, with two capsules twice daily for five days. A standardized questionnaire about side effects and tolerability, daily until day 28, and on days 60 and 180, was completed. Twenty-four study persons were included, all completed the treatment. One person from the placebo and FMT groups each, were lost to follow up from days 21 and 60, respectively. No study person experienced serious side effects, but severe fatigue was reported during the antibiotic period (n = 2). Reported side effects were mild to moderate and there were no significant differences between the groups. Reported general and intestinal health improved significantly and similarly in both groups after the antibiotic treatment. Time to normalized intestinal habits were 17 and 19 days from study start in the placebo group and the FMT group, respectively (p = 0.8). Capsulized frozen autologous faecal microbiota transplantation was safe and well tolerated but did not affect time to normalized intestinal habits compared to placebo.

Childhood diarrhoea, a major cause of morbidity and mortality in low-income regions, remains scarcely studied in many countries, such as Guinea-Bissau. Stool sample drying enables later qPCR analyses of pathogens without concern about electricity shortages. Dried stool samples of children under five years treated at the Bandim Health Centre in Bissau, Guinea-Bissau were screened by qPCR for nine enteric bacteria, five viruses, and four parasites. The findings of children having and not having diarrhoea were compared in age groups 0-11 and 12-59 months. Of the 429 children- 228 with and 201 without diarrhoea- 96.9% and 93.5% had bacterial, 62.7% and 44.3% viral, and 52.6% and 48.3% parasitic pathogen findings, respectively. Enteroaggregarive Escherichia coli (EAEC; 60.5% versus 66.7%), enteropathogenic E. coli (EPEC; 61.4% versus 62.7%), Campylobacter (53.2% versus 51.8%), and enterotoxigenic E. coli (ETEC; 54.4% versus 44.3%) were the most common bacterial pathogens. Diarrhoea was associated with enteroinvasive E. coli (EIEC)/Shigella (63.3%), ETEC (54.4%), astrovirus (75.0%), norovirus GII (72.6%) and Cryptosporidium (71.2%). The only pathogen associated with severe diarrhoea was EIEC/Shigella (p<0.001). EAEC was found more frequent among the infants, and EIEC/Shigella, Giardia duodenalis and Dientamoeba fragilis among the older children. Stool pathogens proved common among all the children regardless of them having diarrhoea or not.

Diarrhoea remains a major cause of childhood morbidity and mortality in low-income countries (LICs). The frequency of diarrhoeal episodes may vary by season, yet few prospective cohort studies have examined seasonal variation among various diarrhoeal pathogens using multiplex qPCR to analyse bacterial, viral and parasitic pathogens. We combined our recent qPCR data of diarrhoeal pathogens (nine bacterial, five viral and four parasitic) among Guinea-Bissauan children under five years old with individual background data, dividing by season. The associations of season (dry winter and rainy summer) and the various pathogens were explored among infants (0-11 months) and young children (12-59 months) and those with and without diarrhoea. Many bacterial pathogens, especially EAEC, ETEC and Campylobacter, and parasitic Cryptosporidium, prevailed in the rainy season, whereas many viruses, particularly the adenovirus, astrovirus and rotavirus proved common in the dry season. Noroviruses were found constantly throughout the year. Seasonal variation was observed in both age groups. In childhood diarrhoea in a West African LIC, seasonal variation appears to favour EAEC, ETEC, and Cryptosporidium in the rainy and viral pathogens in the dry season.

Travel is important in the acquisition and dissemination of infection. We aimed to assess European surveillance data for travel-related illness to profile imported infections, track trends, identify risk groups, and assess the usefulness of pre-travel advice. We analysed travel-associated morbidity in ill travellers presenting at EuroTravNet sites during the 5-year period of 2008–12. We calculated proportionate morbidity per 1000 ill travellers and made comparisons over time and between subgroups. We did 5-year trend analyses (2008–12) by testing differences in proportions between subgroups using Pearson's χ2 test. We assessed the effect of the pre-travel consultation on infection acquisition and outcome by use of proportionate morbidity ratios. The top diagnoses in 32 136 patients, ranked by proportionate morbidity, were malaria and acute diarrhoea, both with high proportionate morbidity (>60). Dengue, giardiasis, and insect bites had high proportionate morbidity (>30) as well. 5-year analyses showed increases in vector borne infections with significant peaks in 2010; examples were increased Plasmodium falciparum malaria (χ2=37·57, p<0·001); increased dengue fever (χ2=135·9, p<0·001); and a widening geographic range of acquisition of chikungunya fever. The proportionate morbidity of dengue increased from 22 in 2008 to 36 in 2012. Five dengue cases acquired in Europe contributed to this increase. Dermatological diagnoses increased from 851 in 2008 to 1102 in 2012, especially insect bites and animal-related injuries. Respiratory infection trends were dominated by the influenza H1N1 pandemic in 2009. Illness acquired in Europe accounted for 1794 (6%) of all 32 136 cases—mainly, gastrointestinal (634) and respiratory (357) infections. Migration within Europe was associated with more serious infection such as hepatitis C, tuberculosis, hepatitis B, and HIV/AIDS. Pre-travel consultation was associated with significantly lower proportionate morbidity ratios for P falciparum malaria and also for acute hepatitis and HIV/AIDS. The pattern of travel-related infections presenting in Europe is complex. Trend analyses can inform on emerging infection threats. Pre-travel consultation is associated with reduced malaria proportionate morbidity ratios and less severe illness. These findings support the importance and effectiveness of pre-travel advice on malaria prevention, but cast doubt on the effectiveness of current strategies to prevent travel-related diarrhoea. European Centre for Disease Prevention and Control, University Hospital Institute Méditerranée Infection, US Centers for Disease Control and Prevention, and the International Society of Travel Medicine.

Genetic polymorphisms in P. falciparum can be used to indicate the parasite’s susceptibility to antimalarial drugs as well as its geographical origin. Both of these factors are key to monitoring development and spread of antimalarial drug resistance. In this study, we combine multiplex PCR, custom designed dual indexing and Miseq sequencing for high throughput SNP-profiling of 457 malaria infections from Guinea-Bissau, at the cost of 10 USD per sample. By amplifying and sequencing 15 genetic fragments, we cover 20 resistance-conferring SNPs occurring in pfcrt , pfmdr1 , pfdhfr , pfdhps , as well as the entire length of pfK13 , and the mitochondrial barcode for parasite origin. SNPs of interest were sequenced with an average depth of 2,043 reads, and bases were called for the various SNP-positions with a p-value below 0.05, for 89.8–100% of samples. The SNP data indicates that artemisinin resistance-conferring SNPs in pfK13 are absent from the studied area of Guinea-Bissau, while the pfmdr1 86 N allele is found at a high prevalence. The mitochondrial barcodes are unanimous and accommodate a West African origin of the parasites. With this method, very reliable high throughput surveillance of antimalarial drug resistance becomes more affordable than ever before.

Artemether-lumefantrine (AL) was introduced for treatment of uncomplicated malaria in Guinea-Bissau in 2008. Malaria then resurged and recurrent malaria after treatment with AL and stock-outs of AL were common. This study therefore aimed to assess the efficacy of AL and identify an alternative second line antimalarial. Dihydroartemisinin-piperaquine (DP) was chosen as it has been shown to be safe and efficacious and to reduce the incidence of recurrent malaria. In a multicentre randomised open-label non-inferiority clinical trial, AL or DP were given over 3 days to children aged 6 months-15 years with uncomplicated P. falciparum mono-infection. Intake was observed and AL was given with milk. Children were seen on days 0, 1, 2 and 3 and then weekly days 7-42. Recurring P. falciparum were classified as recrudescence or new infections by genotyping. Between November 2012 and July 2015, 312 children were randomised to AL (n = 155) or DP (n = 157). The day 42 PCR adjusted per protocol adequate clinical and parasitological responses were 95% and 100% in the AL and DP groups respectively, Mantel-Haenszel weighted odds ratio (OR) 0.22 (95% CI 0-0.68), p = 0.022. In a modified intention to treat analysis in which treatment failures day 0 and reinfections were also considered as treatment failures adequate clinical and parasitological responses were 94% and 97% (OR 0.42 [95% CI, 0.13-1.38], p = 0.15). Parasite clearance and symptom resolution were similar with both treatments. Both treatments achieved the WHO recommended efficacy for antimalarials about to be adopted as policy. DP was not inferior to AL for treatment of uncomplicated P. falciparum malaria in Guinea-Bissau. ClinicalTrials.gov NTC01704508.

Background Artesunate plus sulfadoxine–pyrimethamine (ASP) is first-line treatment for uncomplicated Plasmodium falciparum malaria in most of India, except for six North-eastern provinces where treatment failure rates were high. In Ujjain, central India, the frequency of mutations associated with increased drug tolerance, but not overt resistance to sulfadoxine and pyrimethamine were 9% and > 80%, respectively, in 2009 and 2010, just prior to the introduction of ASP. The frequency of drug resistance associated mutations in Ujjain in 2015–2016 after 3–4 years of ASP use, are reported. Methods Blood samples from patients with P. falciparum mono-infection verified by microscopy were collected on filter-paper at all nine major pathology laboratories in Ujjain city. Codons pfdhfr 16–185, pfdhps 436–632 and K13 407–689 were identified by sequencing. Pfcrt K76T and pfmdr1 N86Y were identified by restriction fragment length polymorphism. Results Sulfadoxine–pyrimethamine resistance-associated pfdhfr 108 N and 59R alleles were found in 100/104 (96%) and 87/91 (96%) samples, respectively. Pfdhps 437G was found in 10/105 (10%) samples. Double mutant pfdhfr 59R + 108 N were found in 75/81 (93%) samples. Triple mutant pfdhfr 59R + 108 N and pfdhps 437G were found in 6/78 (8%) samples. Chloroquine-resistance-associated pfcrt 76T was found in 102/102 (100%). Pfmdr1 N86 and 86Y were identified in 83/115 (72%) and 32/115 (28%) samples, respectively. Conclusion The frequency of P. falciparum with reduced susceptibility to sulfadoxine–pyrimethamine remained high, but did not appear to have increased significantly since the introduction of ASP. No polymorphisms in K13 associated with decreased artemisinin susceptibility were found. ASP probably remained effective, supporting continued ASP use.

Background Large-scale surveillance of molecular markers of anti-malarial drug resistance is an attractive method of resistance monitoring, to complement therapeutic efficacy studies in settings where the latter are logistically challenging. Methods Between 2014 and 2017, this study sampled malaria rapid diagnostic tests (RDTs), used in routine clinical care, from two health centres in Bissau, Guinea-Bissau. In order to obtain epidemiological insights, RDTs were collected together with patient data on age and sex. A subset of positive RDTs from one of the two sites (n = 2184) were tested for Plasmodium DNA content. Those testing positive for Plasmodium DNA by PCR (n = 1390) were used for library preparation, custom designed dual indexing and next generation Miseq targeted sequencing of Plasmodium falciparum genes pfcrt , pfmdr1 , pfdhfr , pfdhps and pfk13 . Results The study found a high frequency of the pfmdr1 codon 86N at 88–97%, a significant decrease of the pfcrt wildtype CVMNK haplotype and elevated levels of the pfdhfr/pfdhps quadruple mutant ranging from 33 to 51% between 2014 and 2017. No polymorphisms indicating artemisinin tolerance were discovered. The demographic data indicate a large proportion of young adults (66%, interquartile range 11–28 years) presenting with P. falciparum infections. While a total of 5532 gene fragments were successfully analysed on a single Illumina Miseq flow cell, PCR-positivity from the library preparation varied considerably from 13 to 87% for different amplicons. Furthermore, pre-screening of samples for Plasmodium DNA content proved necessary prior to library preparation. Conclusions This study serves as a proof of concept for using leftover clinical material (used RDTs) for large-scale molecular surveillance, encompassing the inherent complications regarding to methodology and analysis when doing so. Factors such as RDT storage prior to DNA extraction and parasitaemia of the infection are likely to have an effect on whether or not parasite DNA can be successfully analysed, and are considered part of the reason the data yield is suboptimal. However, given the necessity of molecular surveillance of anti-malarial resistance in settings where poor infrastructure, poor economy, lack of educated staff and even surges of political instability remain major obstacles to performing clinical studies, obtaining the necessary data from used RDTs, despite suboptimal output, becomes a feasible, affordable and hence a justifiable method.