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• TBE vaccination failures among those aged 50+ suggest declining immune response. • We studied the immunogenicity of the TBE vaccine FSME-Immun in various age groups. • Immune response to FSME-Immun declined with age. • We compared the immunogenicity of a three- and two different four-dose regimens. • For those aged 50+, the accelerated 0–7–21–360 regimen appeared most immunogenic. TBE vaccination failures among those past middle age have raised concern about immune response declining with age. We investigated immunogenicity of the TBE-vaccine FSME-Immun among those aged 50+ years using the standard three-dose primary series and alternative four-dose schedules. In this single-centre, open-label, randomized controlled trial, 200 TBE-naive Swedish adults were given primary TBE vaccination with FSME-Immun. Those aged 50+ years (n = 150) were randomized to receive the standard three-dose (days 0–30–360) or one of two four-dose series (0–7–21–360; 0–30–90–360). For participants < 50 years (n = 50) the standard three-dose schedule was used. Titres of neutralizing antibodies were determined on days 0, 60, 120, 360, and 400. The main outcome was the log titre of TBE virus-specific neutralizing antibodies on day 400. The three-dose schedule yielded lower antibody titres among those aged 50+ years than the younger participants on day 400 (geometric mean titre 41 versus 74, p < 0.05). The older group showed higher titres for the four-dose 0–7–21–360 than the standard three-dose schedule both on day 400 (103 versus 41, p < 0.01; primary end point) and at the other testing points (days 60, 120, 360). Using the other four-dose schedule (0–30–90–360), no such difference was observed on day 400 (63 versus 41, NS). Immune response to the TBE vaccine declined with age. A four-dose schedule (0–7–21–360) may benefit those aged 50 years or older. This study is registered at ClinicalTrials.gov, NCT01361776. [ABSTRACT FROM AUTHOR]

Research into persistent symptoms among SARS-CoV-2-positive i.e. CoV(+) patients mostly focuses on hospitalized individuals. Our prospective follow-up study compares long COVID-associated symptoms among laboratory-confirmed CoV(+) and SARS-CoV-2 negative [CoV(−)] individuals. SARS-CoV-2 RT-PCR-tested volunteers were recruited into four cohorts: 1) CoV(+) outpatients, 2) CoV(−) outpatients, 3) CoV(+) intensive care unit (ICU) inpatients, and 4) CoV(+) non-ICU inpatients. Neutralizing antibodies were assessed and questionnaires filled in at enrolment and days 90–120, 121–180, 181–270, 271–365, and 365–533. Of the 1326 participants, 1191 were CoV(+): 46 ICU, 123 non-ICU, and 1022 outpatients; 135 were CoV(−) outpatient controls. Both CoV(+) outpatients and CoV(−) controls showed high overall symptom rates at all time points. More prevalent among CoV(+) than CoV(−) outpatients were only impaired olfaction and taste; many others proved more frequent for CoV(−) participants. At ≥181 days, fatigue, dyspnoea, various neuropsychological symptoms and several others were recorded more often for CoV(+) inpatients than outpatients. Long COVID-associated symptoms were more frequent among hospitalized than non-hospitalized CoV(+) participants. As for outpatients, only impaired olfaction and taste showed higher rates in the CoV(+) group; some symptoms proved even more common among those CoV(−). Besides suggesting low long COVID prevalences for outpatients, our results highlight the weight of negative controls. • 'Long COVID-associated symptoms' were prevalent both among SARS-CoV-2 (+) and (−) participants. • Only two symptoms – impaired olfaction and taste – proved more common in the SARS-CoV-2 (+) than the SARS-CoV-2 (−) group. • Most of the others were more prevalent in the SARS-CoV-2 (−) than the SARS-CoV-2 (+) outpatient group. • SARS-CoV-2 (+) inpatients had higher symptom rates than SARS-CoV-2 (+) outpatients. [ABSTRACT FROM AUTHOR]

Abstract Background As antibiotics predispose travelers to acquiring multidrug-resistant intestinal bacteria, they should no longer be considered a mainstay for treating travelers' diarrhea. It has been claimed that stand-by antibiotics are justified as a means to avoid visits to local healthcare providers which often lead to polypharmacy. Method We revisited the traveler data of 316 prospectively recruited volunteers with travelers' diarrhea by retrieving from questionnaires and health diaries information on antibiotic use, stand-by antibiotic carriage, and visits with local healthcare. Multivariable analysis was applied to identify factors associated with antibiotic use. Results Among our 316 volunteers with travelers' diarrhea, however, carrying stand-by antibiotics seemed not to reduce the rate of healthcare-seeking; on the contrary, antibiotic use was more frequent among stand-by antibiotic carriers (34%) than non-carriers (11%). Antibiotics were equally taken for severe and incapacitating travelers' diarrhea, but compared to non-carriers, stand-by antibiotic carriers resorted to medication also for mild/moderate (38% vs. 4%) and non-incapacitating disease (29% vs. 5%). Antibiotic use was associated with stand-by antibiotic carriage (OR 7.2; 95%CI 2.8–18.8), vomiting (OR 3.5; 95%CI 1.3–9.5), incapacitating diarrhea (OR 3.6; 95%CI 1.3–9.8), age (OR 1.03; 95%CI 1.00–1.05), and healthcare visit for diarrhea (OR 465.3; 95%CI 22.5–9633.6). Conclusions Carriage of stand-by antibiotics encouraged less cautious use of antibiotics. Recommendations involving prescription of antibiotics for all travelers require urgent revision. [ABSTRACT FROM AUTHOR]

Abstract Background Overnight international travels made by Finns more than doubled during 1995–2015. To estimate risks and observe trends of travel-related notifiable sexually transmitted and food- and water-borne infections (STIs and FWIs) among travellers, we analysed national reports of gonorrhoea, syphilis, hepatitis A, shigellosis, campylobacteriosis and salmonellosis cases and related them to travel statistics. Method Cases notified as travel-related to the Finnish infectious diseases register were used as numerators and overnight stays of Statistics Finland surveys as denominator. We calculated overall risks (per 100,000 travellers) and assessed trends (using regression model) in various geographic regions. Results Of all travel-related cases during 1995–2015, 2304 were STIs and 70,929 FWIs. During 2012–2015, Asia-Oceania showed highest risk estimates for gonorrhoea (11.0; 95%CI, 9.5–13), syphilis (1.4; 0.93–2.1), salmonellosis (157; 151–164), and campylobacteriosis (135; 129–141), and Africa for hepatitis A (4.5; 2.5–7.9), and shigellosis (35; 28–43). When evaluating at country level, the highest risks of infections was found in Thailand, except for hepatitis A ranking Hungary the first. During 2000–2011, significantly decreasing trends occurred for most FWIs particularly in the European regions and for STIs in Russia-Baltics. Conclusions Our findings can be used in targeting pre-travel advice, which should also cover those visiting Thailand or European hepatitis A risk areas. [ABSTRACT FROM AUTHOR]

Background Travellers' diarrhoea (TD) is a common health problem among visitors to the (sub)tropics. Much research deals with aetiology, prevention, and post-infection sequalae, yet the data may not allow comparisons due to incompatible definitions of TD and No TD control groups. Method The impact of defining TD and No TD control groups was explored by revisiting our recent data. We set up two TD groups: classical TD i.e. ≥3 loose or liquid stools/day and WHO TD (diarrhoea as defined by the WHO) i.e. any diarrhoea, and four No TD groups by TD definition and timing (no classical/WHO TD during travel, no ongoing classical/WHO TD). Results TD was recorded for 37% versus 65% of subjects when using classical versus WHO definitions, respectively; the proportions of the various pathogens proved similar. The strictest criterion for the No TD control group (no WHO TD during travel) yielded pathogens among 61% and the least strict (no ongoing classical TD) among 73% of the travellers; the differences were greatest for enteroaggregative Escherichia coli and Campylobacter. Conclusions Definition of TD and control group design substantially impact on TD study results. The WHO definition yields more cases, but the pathogen selection is similar by both definitions. Design of the No TD control group was found critical: only those remaining asymptomatic throughout the journey should be included. [ABSTRACT FROM AUTHOR]

Background Among visitors to the (sub)tropics, 20–50% contract travellers' diarrhoea (TD) and 5–30% take antibiotics. While shortening the duration of illness, antimicrobials predispose to acquisition of multi-drug resistant bacteria. Therefore, liberal use is no longer advocated. Although antibiotics kill pathogens, no data support the view that they could prevent post-infectious sequelae. We investigated how antibiotic use for TD abroad impacts the pathogen findings at return. Materials and methods We revisited 456 travellers' clinical data and stool pathogens examined by qPCR for Salmonella , Yersinia, Campylobacter, Shigella , Vibrio cholerae and enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enterohaemorrhagic (EHEC) and enteroinvasive (EIEC) Escherichia coli . Results Among travellers with TD, antibiotic users had pathogen-positive samples less frequently than non-users (50% versus 83%). The difference was significant for EPEC (23% versus 47%) and EAEC (27% versus 54%), but not ETEC (17% versus 26%) or the other pathogens. Shigella /EIEC was found more often among antibiotic users than non-users (4% versus 1%). Conclusion Despite antibiotic treatment of TD, half of the users still had stool pathogens at return, reflecting either antibiotic resistance of pathogens or recolonisation/reinfection while abroad. Treatment of TD with antibiotics during travel should not be interpreted to indicate eradication of pathogens. [ABSTRACT FROM AUTHOR]

Background One third of travellers to the poor regions of the (sub)tropics become colonized by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). Co-resistance to non-beta-lactam antibiotics complicates the treatment of potential ESBL-PE infections. Methods We analysed co-resistance to non-beta-lactams among travel-acquired ESBL-PE isolates of 90 visitors to the (sub)tropics with respect to major risk factors of colonization: destination, age, travellers' diarrhoea (TD) and antibiotic (AB) use. Results Of the ESBL-PE isolates, 53%, 52%, 73%, and 2% proved co-resistant to ciprofloxacin, tobramycin, co-trimoxazole, and nitrofurantoin, respectively. The rates were similar among those with (TD+) or without (TD-) travellers' diarrhoea. Among fluoroquinolone-users vs. AB non-users, the co-resistance rates for ciprofloxacin were 95% versus 37% (p = 0.001), for tobramycin 85% versus 43% (p = 0.005), co-trimoxazole 85% versus 68% (p = 0.146), and nitrofurantoin 5% versus 2% (p = 0.147). In multivariable analysis co-resistance to ciprofloxacin was associated with increasing age, fluoroquinolone use, and tobramycin resistance. Conlusions While TD predisposes to ESBL-PE non-selectively, antimicrobial use favours strains resistant to drug taken and, simultaneously, any drug with resistance genetically linked to the drug used. Antibiotics taken during travel predispose to ESBL-PE with a high co-resistance rate. [ABSTRACT FROM AUTHOR]

Background Although infections represent the most common health problem of travellers abroad, data on morbidity and incidences of various infections are scarce. Method Data on infections of Finnish travellers during 2010–2012 were retrieved from the database of SOS International, an assistance organization covering 95% of Finns requiring aid abroad. The study included 30,086 cases. For incidence calculation, the data were linked to the numbers of Finns visiting these regions during the same period as recorded by the Official Statistics of Finland. Results The incidence of infections was particularly high in Africa, southern Europe plus the eastern Mediterranean, and Asia plus Oceania. The most frequent diagnoses were acute gastroenteritis (38.0%) and respiratory-tract infections (RTI) (34.5%), followed by infections of the ear (12.6%), skin or subcutaneous tissue (5.1%), urogenital tract (4.2%), eye (3.1%), and systemic febrile infections (2.2%). Vaccine-preventable diseases (VPD) accounted for 0.8% of cases, with varicella as most (49%) and influenza as second-most (27%) common. Conclusions Incidence of infections was higher in southern than in eastern and western Europe. Gastroenteritis and RTI proved the most frequent diagnoses, whereas systemic febrile infections were uncommon. Despite pre-travel immunizations, VPDs still occurred; pre-travel consultation should cover both varicella and influenza. [ABSTRACT FROM AUTHOR]

Summary Looking at the worldwide emergency of antimicrobial resistance, international travellers appear to have a central role in spreading the bacteria across the globe. Travellers' diarrhoea (TD) is the most common disease encountered by visitors to the (sub)tropics. Both TD and its treatment with antibiotics have proved significant independent risk factors of colonization by resistant intestinal bacteria while travelling. Travellers should therefore be given preventive advice regarding TD and cautioned about taking antibiotics: mild or moderate TD does not require antibiotics. Logical alternatives are medications with effects on gastrointestinal function, such as loperamide. The present review explores literature on loperamide in treating TD. Adhering to manufacturer's dosage recommendations, loperamide offers a safe and effective alternative for relieving mild and moderate symptoms. Moreover, loperamide taken singly does no predispose to contracting MDR bacteria. Most importantly, we found no proof that would show antibiotics to be significantly more effective than loperamide in treating mild/moderate TD. [ABSTRACT FROM AUTHOR]

Antibiotics predispose travellers to acquire multidrug-resistant bacteria, such as extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE). Although widely used in antimalarial prophylaxis, doxycycline has scarcely been studied in this respect. We explored the impact of doxycycline on rates of traveller's diarrhoea (TD), ESBL-PE acquisition and, particularly, doxycycline co-resistance among travel-acquired ESBL-PE in a sample of 412 visitors to low- and middle-income countries. We reviewed the literature on traveller studies of doxycycline/tetracycline resistance among stool pathogens and the impact of doxycycline on TD rates, ESBL-PE acquisition, and doxycycline/tetracycline resistance. The TD rates were similar for doxycycline users (32/46; 69.6%) and non-users (256/366; 69.9%). Of the 90 travel-acquired ESBL-PE isolates, 84.4% were co-resistant to doxycycline: 100% (11/11) among users and 82.3% (65/79) among non-users. The literature on doxycycline's effect on TD was not conclusive nor did it support a recent decline in doxycycline resistance. Although doxycycline did not increase ESBL-PE acquisition, doxycycline-resistance among stool pathogens proved more frequent for users than non-users. Our prospective data and the literature review together suggest the following: 1) doxycycline does not prevent TD; 2) doxycycline use favours acquisition of doxy/tetracycline-co-resistant intestinal bacteria; 3) although doxycycline does not predispose to travel-related ESBL-PE acquisition per se, it selects ESBL-PE strains co-resistant to doxycycline; 4) doxycycline resistance rates are high among stool bacteria in general with no evidence of any tendency to decrease. [ABSTRACT FROM AUTHOR]

Urinary tract infections (UTIs) rank among the most common infections encountered in health care, with an annual incidence of 12% for women. Despite the vast numbers of international travels (over 1.5 billion annually), no prospective studies have had primary focus on UTIs during travel. We recruited in 2008–17 international travelers who all filled out pre- and post-travel questionnaires. Incidence rates of UTI were calculated separately for both sexes. Multivariable analyses were conducted to identify risk factors for UTI during travel. In total 15/517 (2,9%) travelers acquired UTI during travel, yielding an annual incidence of 62% for female and 18% for male travelers. Travelers' diarrhea (TD) was identified as a factor predisposing to UTI (OR 9.2, 95% CI 1.5–+∞, p = 0.011); all UTI cases were recorded by travelers with TD. To our knowledge, this is the first prospective study with a primary focus on UTI during travel. Our data reveal that among travelers the incidence of UTI far exceeds that reported for the general population. TD was identified as a major risk factor for the infection. Our results suggest TD prevention as a means of also preventing UTI during travel. • Urinary tract infection are more common among travelers than in general population. • All UTI cases were identified among visitors to the tropics. • Travelers' diarrhea predisposes to urinary tract infections. [ABSTRACT FROM AUTHOR]

Background: Hepatitis A vaccine is the most frequently used travel vaccine, yet data are scarce about its ability to induce protection in patients with concurrent immunosuppressive treatment. We assessed the immunogenicity of this vaccine in rheumatoid arthritis (RA) patients treated with tumour necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX). Methods: Hepatitis A vaccine was administered to non-immune RA patients at 0 and 6 months. Hepatitis A virus (HAV) antibodies were assessed at 0, 1, 6, 7, 12, and 24 months with a quantitative Chemiluminescent Microparticle Immuno Assay (CMIA) for HAV-IgG. Samples from month 1, 6, and 7 were, in addition, analysed with a microparticle EIA (MEIA) for anti-HAV IgM + IgG. Results: The final study population consisted of 53 patients treated with TNFi (n = 15), TNFi + MTX (n = 21) or MTX (n = 17). One and six months after the first dose, 10% and 33% of the patients had attained seroprotection. One and six months after the second dose 83% and 72% were seroprotected. At month 24, 86% of the vaccinees showed protective levels. Conclusions: Two doses of hepatitis A vaccine at a 6-month interval provided protection for most immunosuppressed RA patients. A single dose does not seem to afford sufficient protection to this group of patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Non-typhoid Salmonella (NTS) is a leading cause of food-borne illness with more than 90 million annual cases and an emerging antimicrobial resistance among the strains worldwide. Paradoxically, no vaccines are available against these pathogens. Numerous NTS strains share surface O-antigens with Salmonella enterica serotype Typhi. As intestinal antibodies against O-antigens have proven protective against NTS in animal experiments, it appears conceivable that the oral whole-cell typhoid vaccine, Salmonella Typhi Ty21a (Vivotif®), which effectively elicits intestinal antibodies against O-antigens, could exhibit cross-protective efficacy against NTS. We sought immunological evidence in support of cross-protective efficacy of Ty21a against NTS. Materials and methods: 35 volunteers receiving Ty21a vaccine and five patients with enteric fever were investigated with ELISPOT for circulating plasmablasts secreting antibodies reactive with Salmonella Typhi and six different NTS serotypes. These plasmablasts were also analysed for homing receptor expressions. Results: In all vaccinees and patients, a strong gut-directed cross-reactive plasmablast response was found against serotypes sharing the two O-antigens with Salmonella Typhi (O-9,12) (in vaccinees, mean: 95%CI 268: 228–508 and 363: 234–493 plasmablasts/106PBMC against Salmonella Typhi and Enteritidis). Responses against strains sharing one O-antigen (O-12) were weaker (222: 105–338 against Salmonella Typhimurium), while no significant reactivity was detected against strains without typhoidal O-antigens. Conclusions: Intestinal antibodies against O-antigens protect against NTS in animal experiments. Ty21a was found to elicit intestinal immune responses cross-reactive with NTS strains sharing O-antigens with Ty21a. These include the most common NTS, Salmonella Enteritidis and Typhimurium. The data suggest that Ty21a may have cross-protective efficacy against numerous NTS strains. [Copyright &y& Elsevier]

The worldwide population of forcibly displaced people has increased over the past decade, approaching 80 million and encompassing more than 30 million refugees and asylum seekers. Research into refugee and migrant health has remained scarce, however. To investigate the reasons for hospital admissions of refugees, asylum seekers and undocumented migrants, we collected medical data from Helsinki University Hospital (HUH) records 2010–20. The study population consisted of 647 patients originally from 54 different countries, mainly Iraq, Syria, and Afghanistan. Among adults, 40.9% of the admissions were related to pregnancy. For minors, the group comprising congenital malformations, deformations, and chromosomal abnormalities accounted for most hospitalizations, followed by diseases of the digestive or nervous system. Every fifth patient (19.3%) was admitted because of an infection: adults mostly for urinary tract infection (16.3%), pneumonia (14.1%), and tuberculosis (9.8%), and minors for acute gastroenteritis (15.2%). Infectious reason was more frequent within two months after immigration than later. Our data reveal a unique admission profile for forced migrants: in addition to infectious diseases, a particularly high rate of obstetric diagnoses was recorded, the two ranking as the most common reasons for hospitalization. [ABSTRACT FROM AUTHOR]

The diagnostics of travellers' diarrhoea (TD) has been revolutionised by multiplex qPCR assays. While mostly of bacterial aetiology, viruses and parasites account for the disease among 10–20% of travellers. Despite this, prospective studies applying qPCR assays remain scarce that cover not only bacteria, such as the various diarrhoeagenic Escherichia coli (DEC), but also viral and parasitic pathogens. We analysed by qPCR pre- and post-travel stool samples of 146 Finnish travellers for bacterial, viral and parasitic pathogens: enteropathogenic (EPEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enterohaemorrhagic (EHEC), and enteroinvasive (EIEC) E. coli; Shigella , Campylobacter , Salmonella , Yersinia and Vibrio cholerae ; norovirus G1 and G2, rotavirus, enteroviruses, and sapovirus; and Giardia lamblia , Entamoeba histolytica , and Cryptosporidium. Symptoms and medication data during travel were collected by questionnaires. We detected bacterial pathogens in 102/146 samples (69.9%; EAEC, EPEC, ETEC most common), viral ones in 13 (8.9%; norovirus most common), and parasitic ones in one (0.7%; Giardia). Noroviruses were associated with severe symptoms (23.5% versus non-severe 4.9%). In the TD group, 41.7% (5/12) of those with viral pathogens (vs. 13.3%; 11/83 without) took antibiotics. Viral pathogens, particularly noroviruses, prevail in severe TD. The symptoms of viral disease are often severe and lead to unwarranted use of antibiotics. • Prospectively collected stool specimens were tested by qPCR for bacteria, viruses and parasites. • Viruses were associated with severe TD. • Viral TD was associated with particularly high rate of antibiotic use. [ABSTRACT FROM AUTHOR]

Exposure, risks and immunity of healthcare workers (HCWs), a vital resource during the SARS-CoV-2 pandemic, warrant special attention. HCWs at Helsinki University Hospital, Finland, filled in questionnaires and provided serum samples for SARS-CoV-2-specific antibody screening by Euroimmun IgG assay in March–April 2020. Positive/equivocal findings were confirmed by Abbott and microneutralization tests. Positivity by two of the three assays or RT-PCR indicated a Covid-19 case (CoV+). The rate of CoV(+) was 3.3% (36/1095) and seropositivity 3.0% (33/1095). CoV(+) was associated with contact with a known Covid-19 case, and working on a Covid-19-dedicated ward or one with cases among staff. The rate in the Covid-19-dedicated ICU was negligible. Smoking and age <55 years were associated with decreased risk. CoV(+) was strongly associated with ageusia, anosmia, myalgia, fatigue, fever, and chest pressure. Seropositivity was recorded for 89.3% of those with prior documented RT-PCR-positivity and 2.4% of those RT-PCR-negative. The rate of previously unidentified cases was 0.7% (8/1067) and asymptomatic ones 0% (0/36). Undiagnosed and asymptomatic cases among HCWs proved rare. An increased risk was associated with Covid-19-dedicated wards. Particularly high rates were seen for wards with liberal HCW-HCW contacts, highlighting the importance of social distancing also among HCWs. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC) is a major pathogen causing travellers' diarrhoea (TD) among visitors to low- and middle-income countries (LMIC). Scant data are available on rates of travel-acquired ETEC producing heat-labile (LT) and/or heat-stable (ST) toxin or its subtypes, STh (human) and STp (porcine) in various geographic regions, and on clinical pictures associated with each toxin. Using qPCR, we analysed LT, STh, and STp in stools positive for ETEC in a prospective study among 103 Finnish travellers visiting LMIC. They filled in questionnaires and provided stool samples before and after travel. We scrutinized geographic distribution of LT, STh, and STp ETEC findings, and association between these different ETEC subtypes and moderate/severe TD. Among the 103 stool samples positive for ETEC toxins, the rate for LT was 76%, for STh 26%, and STp 41%. The rate for LT-only was 44%, for STh-only 6%, STp-only 16%, LT + STh 10%, LT + STp 15%, STh + STp 3%, and LT + STh + STp 8%. Findings varied by destination; the rates of LT, STh, and STp were 79%, 21%, and 57%, respectively, in Southern Asia (n = 14); 85%, 10%, and 20% in South-eastern Asia (n = 20); 84%, 13%, and 29% in Eastern Africa (n = 31); and 56%, 50%, and 63% in Western Africa (n = 32), respectively. Of travellers positive for LT, STh, and STp, 83%, 100%, and 88%, encountered TD; 35%, 55%, and 41% reported moderate/severe TD. STh was associated with moderate/severe TD. Toxin findings varied by destination; multiple toxins were commonly detected. Moderate/severe TD was reported most frequently by subjects with STh-ETEC. • ETEC is a major cause of childhood diarrhoea in LMICs and travellers' diarrhoea among visitors to these destinations. • The diarrhoeal symptoms of ETEC are mediated by its LT and ST toxins. ST-toxin is divided into the subtypes STh and STp. • This prospective study explored the distribution of ETEC toxins among travellers to various geographic destinations. • Toxin findings varied by geographic location. Multiple toxin types proved common. • STh was associated with moderate/severe diarrhoea. [ABSTRACT FROM AUTHOR]

We explored the influence of coadministration on safety and immunogenicity of the most common travellers' vaccine hepatitis A (HepA) and the pneumococcal conjugate vaccine (PCV) increasingly used both at home and before travel. Volunteers aged ≥18 years (n = 305) were randomly assigned 1:1:1 into three groups receiving: 13-valent PCV (PCV13) + HepA, PCV13, or HepA. Anti-pneumococcal IgG concentrations, opsonophagocytic activity (OPA) titres, and total hepatitis A antibody (anti-HAV) concentrations were measured before and 28 ± 3 days after vaccination. Adverse events (AEs) were recorded over 4 weeks. After vaccination, the anti-HAV geometric mean concentration was significantly lower in the PCV13+HepA than the HepA group: 34.47 mIU/mL (95% CI: 26.42–44.97 mIU/mL) versus 72.94 mIU/mL (95% CI: 55.01–96.72 mIU/mL), p < 0.001. Anti-HAV ≥10 mIU/mL considered protective was reached by 71 of 85 (83.5%) in the PCV13+HepA group versus 76 of 79 (96.2%) in the HepA group, p 0.008. The increases in anti-pneumococcal IgG and OPA levels were comparable in the PCV13+HepA and PCV13 groups, apart from a bigger rise in the PCV13+HepA group for serotype 3 (one-way ANOVA: serotype 3 IgG p 0.010, OPA p 0.002). AEs proved more frequent among those receiving PCV13 than HepA, but simultaneous administration did not increase the rates: ≥one AE was reported by 45 of 56 (80.4%) PCV13, 43 of 54 (79.6%) PCV13+HepA, and 25 of 53 (47.2%) HepA recipients providing structured AE data. Coadministration of HepA and PCV13 did not cause safety concerns, nor did it impact the patients' response to PCV13, apart from serotype 3. However, coadministered PCV13 significantly impaired antibody responses to HepA. [ABSTRACT FROM AUTHOR]

• Antibody titers of the HI and MN assays correlated strongly positively. • A HI titer of 40 was considered to be equivalent to a MN titer of 160. • (day 21) GMTs were higher in the Fluarix group as compared to the Vaxigrip group. • Pre-existing SR values were higher in 2012 compared to those seen in the 2010. • Both vaccinations induced very high SRs. Influenza A(H1N1)pdm09 viruses have been circulating throughout the world since the 2009 pandemic. A/California/07/2009 (H1N1) virus was included in seasonal influenza vaccines for seven years altogether, providing a great opportunity to analyse vaccine-induced immunity in relation to the postpandemic evolution of the A(H1N1)pdm09 virus. Serum antibodies against various epidemic strains of influenza A(H1N1)pdm09 viruses were measured among health care workers (HCWs) by haemagglutination inhibition and microneutralization tests before and after 2010 and 2012 seasonal influenza vaccinations. We detected high responses of vaccine-induced neutralizing antibodies to six distinct genetic groups. Our results indicate antigenic similarity between vaccine and circulating A(H1N1)pdm09 strains, and substantial vaccine-induced immunity against circulating epidemic viruses. [ABSTRACT FROM AUTHOR]

Background & Aims: Every year, 80 million tourists traveling to tropical and subtropical areas contract traveler's diarrhea (TD). Forty percent to 80% of cases are caused by bacteria, yet clinical diagnostic tests are available to identify only a few of the strains that cause TD. We aimed to develop a quantitative polymerase chain reaction (qPCR) assay to identify all major pathogens in stool samples. Methods: We developed a low-cost, high-throughput, multiplex qPCR assay for simultaneous detection of 9 bacterial pathogens in stool samples: Salmonella, Yersinia, Campylobacter, and Vibrio cholerae, as well as Shigella or enteroinvasive Escherichia coli, enterohemorrhagic E coli, enterotoxigenic E coli (ETEC), enteroaggregative E coli (EAEC), and enteropathogenic E coli (EPEC). The assay was validated using positive (n = 245) and negative (n = 243) control strains, as well as preselected positive and negative stool samples. In addition, stool samples were collected from 96 returning travelers with TD. The findings were compared with those from routine diagnostic tests. Results: The assay detected the bacterial strains with 100% sensitivity and specificity, compared with results from the reference tests. Of all stool samples collected from travelers with TD, EPEC was found in 47%, EAEC in 46%, ETEC in 22%, enterohemorrhagic E coli in 7%, Campylobacter in 6%, Shigella or enteroinvasive E coli in 2%, and Salmonella in 2%. Multiple pathogens were found in 37% of all samples. Conclusions: We developed a low-cost, high-throughput qPCR assay for use in routine diagnostic analysis and research. It detects the pathogenic bacteria most commonly associated with TD in stool samples with 100% sensitivity and specificity, compared with reference methods. The assay requires 4 hours, whereas current detection methods require 1 to 7 days. At least 1 TD pathogen was identified in stool samples from 76% of returning travelers, whereas conventional methods found a pathogen in only 17%. The most commonly detected bacteria were EPEC, EAEC, and ETEC. [Copyright &y& Elsevier]

Abstract: Background: There are no vaccines against paratyphoid fever in clinical use. The disease has become more wide-spread and there is a growing problem of antibiotic resistance among the strains. Previous reports suggest that the oral live Salmonella Typhi Ty21a-vaccine confers protection against paratyphoid B fever. Data on efficacy against paratyphoid A fever are somewhat contentious. The present study investigated the immunological basis for such efficacy reports at a single-cell level: plasmablasts (identified as antibody-secreting cells, ASC) were studied for secretion of antibodies cross-reactive with Salmonella Paratyphi in the circulation of patients with enteric fever and of volunteers vaccinated with Ty21a. Materials and methods: Thirty volunteers immunized with Ty21a and five patients with enteric fever were investigated for Salmonella Typhi and Salmonella Paratyphi A/B/C-specific circulating plasmablasts. PBMC were sorted by their expression of homing receptors (HR) for the intestine (α4β7), peripheral lymph node (l-selectin) and skin (CLA) and typhoid- and paratyphoid-specific plasmablasts were enumerated with ELISPOT. Results: Before vaccination, no cross-reactive ASC were found in the volunteers. In addition to the Salmonella Typhi-specific response, a significant cross-reactive immune response was mounted against Salmonella Paratyphi A and B both in the patients and the vaccinees. The magnitude of the response increased in the order Salmonella Paratyphi A (median 30 ASC/106 PBMC)→ Salmonella Paratyphi B (median 81)→ Salmonella Typhi (median 301) in the vaccinees. Both in patients and in vaccinees, the homing receptor (HR) selection favored homing to the gut, indicating a humoral intestinal immune response. Conclusions: These immunological data provide evidence consistent with previous reports describing certain levels of cross-protective efficacy of Ty21a against paratyphoid fever. Controlled studies are needed to evaluate cross-protective efficacy. In the current situation where paratyphoid fever is emerging and no vaccines are available, any level of cross-protective capacity is valuable. [Copyright &y& Elsevier]

Motivated by reports of increased risk of coronavirus disease 2019 (COVID-19) in ethnic minorities of high-income countries, we explored whether patients with a foreign first language are at an increased risk of COVID-19 infections, more serious presentations, or worse outcomes. In a retrospective observational population-based quality registry study covering a population of 1.7 million, we studied the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), admissions to specialist healthcare and the intensive care unit (ICU), and all-cause case fatality in different language groups between 27th February and 3rd August 2020 in Southern Finland. A first language other than Finnish, Swedish or Sámi served as a surrogate marker for a foreign ethnic background. In total, 124 240 individuals were tested, and among the 118 300 (95%) whose first language could be determined, 4005 (3.4%) were COVID-19-positive, 623 (0.5%) were admitted to specialized hospitals, and 147 (0.1%) were admitted to the ICU; 254 (0.2%) died. Those with a foreign first language had lower testing rates (348, 95%CI 340–355 versus 758, 95%CI 753–762 per 10 000, p < 0.0001), higher incidence (36, 95%CI 33–38 versus 22, 95%CI 21–23 per 10 000, p < 0.0001), and higher positivity rates (103, 95%CI 96–109 versus 29, 95%CI 28–30 per 1000, p < 0.0001). There was no significant difference in ICU admissions, disease severity at ICU admission, or ICU outcomes. Case fatality by 90 days was 7.7% in domestic cases and 1.2% in those with a foreign first language, explained by demographics (age- and sex-adjusted HR 0.49, 95%CI 0.21–1.15). The population with a foreign first language was at an increased risk for testing positive for SARS-CoV-2, but when hospitalized they had outcomes similar to those in the native, domestic language population. This suggests that special attention should be paid to the prevention and control of infectious diseases among language minorities. [ABSTRACT FROM AUTHOR]

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare coagulation disorder reported after administration of COVID-19 adenovirus-vectored vaccines. VITT is mediated by anti-platelet factor 4 (PF4) antibodies activating platelets through the Fcγ-receptor II (FcγRII), and it is associated with strong fibrin turnover. The complement system is involved in several other immunothrombotic entities, but its impact on VITT is not established. To assess antibodies in interaction with the activation of platelets and complement triggered by VITT. Antibodies against adenovirus type 2 hexon protein, ChAdOx1 adenoviral vector-specific IgG and PF4 were analyzed by enzyme immunoassays from VITT patients (n = 5). The EDTA plasma samples of the patients and controls were used to measure both terminal complement complexes (TCC) by ELISA and aggregation of healthy donor platelets. We studied the effects of human immunoglobulin (IVIG) and glycoprotein IIb/IIIa inhibitor (GPIIb/IIIa) on spontaneous and collagen-induced platelet aggregation supplemented with VITT plasma. None of the patients had experienced a COVID-19 infection. Antibody analyses confirmed the immunogenicity of the adenovirus-vectored ChAdOx1 vaccine. Moreover, VITT plasma had anti-PF4 antibodies and elevated TCC levels as a sign of complement activation. In isolated healthy donor platelets, VITT patient plasma caused marked, spontaneous aggregation of platelets, which was abolished by eptifibatide and high-dose therapeutic IVIG. Our findings suggest that VITT is triggered by antibodies against adenovirus vector and PF4-polyanion complexes which strongly co-activate complement and platelets. The spontaneous platelet aggregation was suppressed by IVIG or eptifibatide, indicating that besides FcγRII, also GPIIb/IIIa receptor exerts platelet procoagulant role in VITT. [Display omitted] [ABSTRACT FROM AUTHOR]

• We reviewed the discovery and development process of broad-spectrum antiviral agents. • We summarized the information on 120 safe-in-man agents in a freely accessible database. • Further studies will increase the number of broad-spectrum antivirals, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections. Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections. [ABSTRACT FROM AUTHOR]

Dientamoeba fragilis (DF), the most common intestinal protozoal pathogen in affluent countries, causes asymptomatic or symptomatic infections with severity ranging from mild to disabling. Currently, many studies of treatment options only have small sample sizes and report results that are partly contradictory. Investigating data retrieved from Helsinki University Hospital and Helsinki City patient records, we searched for the most effective antiprotozoal in treating DF infections. To study microbiological clearance of DF , we collected laboratory results of control samples from patients given one of four commonly used antiprotozoals: doxycycline, metronidazole, paromomycin, or secnidazole. For patients symptomatic prior to antiprotozoal treatment, we also retrieved data on clinical outcomes. Furthermore, we explored factors associated with faecal clearance and clinical cure. A total of 369 patients (median age 38) and 492 treatment episodes were included. Paromomycin (n ​= ​297) proved effective (clearance rate 83%), showing strong association with faecal clearance (aOR 18.08 [7.24–45.16], p ​< ​0.001). For metronidazole the rate was 42% (n ​= ​84), for secnidazole 37% (n ​= ​79), and doxycycline 22% (n ​= ​32). In pairwise comparisons, paromomycin outdid the three other regimens (p ​< ​0.001, χ 2 test). Faecal clearance was associated with clinical cure (aOR 5.85 [3.02–11.32], p ​< ​0.001). Faecal clearance, strongly associated with clinical cure, is most effectively achieved with a course of paromomycin, followed by metronidazole, secnidazole and doxycycline. Our findings will be useful in devising treatment guidelines for adults with symptomatic D. fragilis infection. • In Dientamoeba fragilis infection, faecal clearance is associated with clinical cure. • Faecal clearance is best achieved with paromomycin. • Paromomycin is superior over metronidazole, doxycycline and secnidazole. • Doxycycline is not a drug of choice in treatment of Dientamoeba fragilis infection. • Paromomycin is preferable as first-line medication in eradicating D. fragilis. [ABSTRACT FROM AUTHOR]

According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases. [ABSTRACT FROM AUTHOR]

Background Since protective efficacy of the current typhoid vaccines—oral whole-cell S almonella Typhi Ty21a and parenteral Vi-capsular polysaccharide preparation—is not optimal, and no vaccines are available against paratyphoid or non-typhoidal Salmonella (NTS) serotypes, new approaches deserve to be explored. The immunological mechanisms elicited by the two typhoid vaccines are mainly targeted against different structures. We studied whether these vaccines would enhance S. Typhi-specific immune response and cross-reactivity against other Salmonellae , if administered concomitantly. Materials and methods Volunteers were immunized simultaneously with Ty21a and Vi vaccines (Ty21a + Vi group) or with either of the two singly (Ty21a and Vi groups). All volunteers were investigated for circulating specific and cross-reactive plasmablasts, identified by ELISPOT as IgA, IgG or IgM antibody-secreting cells (ASC) reactive with S . Typhi, S . Paratyphi A/B/C, or selected NTS serotypes ( S . Enteritidis, S . Typhimurium). Results In the Ty21a + Vi group, no specific or cross-reactive plasmablasts were detected before vaccination. After vaccination, the number of S . Typhi-specific plasmablasts (878 ASC/10 6 PBMC, 95%CI 554–1201) proved higher than in the Ty21a (339 ASC/10 6 PBMC; p < 0.001) and Vi (149 ASC/10 6 PBMC; p < 0.001) groups. Likewise, cross-reactive responses in the Ty21a + Vi group were higher than in the Ty21a and Vi groups (Ty21a + Vi vs Ty21a: ASC against S . Paratyphi A/B, S . Enteritidis and S . Typhimurium p < 0.05, against S . Paratyphi C p < 0.01; Ty21a + Vi vs Vi: against S . Paratyphi C not significant, others p < 0.0001). A gut-directed homing profile was seen among O antigen-specific and a systemic one among Vi antigen-specific plasmablasts. Conclusions Concomitant administration of Ty21a and Vi vaccines is well tolerated and induces an additive immune response to the two vaccines. Thus it enhances the magnitude of both typhoid-specific plasmablast responses and those cross-reacting with paratyphoid and most important NTS serotypes. The data encourage concomitant use of Ty21 and Vi vaccines for those at risk. [ABSTRACT FROM AUTHOR]

Highlights: [•] There are no vaccines available against non-typhoid Salmonellae (NTS). [•] Typhoid vaccine Ty21a elicits antibodies to NTS strains with typhoidal O-antigens. [•] Vi vaccine elicits a response to typhoidal O-antigens. [•] Vi vaccine elicits cross-reactive response to NTS strains with typhoidal O-antigens. [•] The response with Vi is lower than with Ty21a. [ABSTRACT FROM AUTHOR]

Highlights: [•] Seroprotection was studied two years after vaccination against Japanese encephalitis. [•] After Ixiaro primary series, protection appeared to wane first against GI-genotype. [•] The first Ixiaro booster dose should not be delayed beyond two years. [•] A single Ixiaro dose gives protection to JE-MB primed subjects for at least two years. [ABSTRACT FROM AUTHOR]

Influenza A viruses (IAVs) infect humans and cause significant morbidity and mortality. Different treatment options have been developed; however, these were insufficient during recent IAV outbreaks. Here, we conducted a targeted chemical screen in human nonmalignant cells to validate known and search for novel host-directed antivirals. The screen validated saliphenylhalamide (SaliPhe) and identified two novel anti-IAV agents, obatoclax and gemcitabine. Further experiments demonstrated that Mcl-1 (target of obatoclax) provides a novel host target for IAV treatment. Moreover, we showed that obatoclax and SaliPhe inhibited IAV uptake and gemcitabine suppressed viral RNA transcription and replication. These compounds possess broad spectrum antiviral activity, although their antiviral efficacies were virus-, cell type-, and species-specific. Altogether, our results suggest that phase II obatoclax, investigational SaliPhe, and FDA/EMEA-approved gemcitabine represent potent antiviral agents. [ABSTRACT FROM AUTHOR]

Abstract: Background: The increased traveling to dengue endemic regions and the numerous epidemics have led to a rise in imported dengue. The laboratory diagnosis of acute dengue requires several types of tests and often paired samples are needed for obtaining reliable results. Although several diagnostic methods are available, proper comparative data on their performance are lacking. Objectives: To compare the performance of novel methods including a novel pan-DENV real-time RT-PCR and a commercially available NS1 capture-EIA in regard to IgM detection for optimizing the early diagnosis of DENV in travelers. Study design: A panel of 99 selected early phase serum samples of dengue patients was studied by real-time RT-PCR, NS1 antigen ELISA, IgM-EIA, IgG-IFA and cell culture virus isolation. Results: The novel real-time RT-PCR was shown specific and sensitive for detection of DENV-1-4 RNA and suitable for diagnostic use. The diagnostic rate using combination of RNA and IgM detection was 99% and using NS1 and IgM detection 95.9%. The results of RNA and NS1 antigen detection disagreed in 15.5% of samples that had only RNA or NS1 antigen detected. Conclusions: The diagnostic rates of early samples are higher when either RNA or NS1 antigen detection is combined with IgM detection. Besides the differences in the RNA and NS1 detection assays, the observed discrepancy of results could suggest individual variation or differences in timing of these markers in patient serum. [Copyright &y& Elsevier]