Digital approaches to reducing TB treatment loss to follow-up.

Poor adherence to TB treatment leads to adverse clinical outcomes. A range of digital technologies to support adherence have been developed and the COVID-19 pandemic considerably accelerated the implementation of digital interventions. Here, we review the current evidence on digital adherence support tools and update the findings of a previous review, with evidence published from 2018 to date. Interventional and observational studies, as well as primary and secondary analyses were included, and we summarised available evidence on effectiveness, cost-effectiveness and acceptability. The studies were heterogenous and varied in outcome measures and approaches used. Overall, our findings show that digital approaches, such as digital pillboxes and asynchronous video-observed treatment, are acceptable and have the potential to improve adherence and be cost-effective over time if implemented at scale. Digital tools should be part of multiple strategies to support adherence. Further research to integrate behavioural data on reasons for non-adherence will help to determine how to best implement these technologies in different settings.

Surveillance of congenital Zika syndrome in England and Wales: methods and results of laboratory, obstetric and paediatric surveillance.

The spread of the Zika virus (ZIKV) in the Americas led to large outbreaks across the region and most of the Southern hemisphere. Of greatest concern were complications following acute infection during pregnancy. At the beginning of the outbreak, the risk to unborn babies and their clinical presentation was unclear. This report describes the methods and results of the UK surveillance response to assess the risk of ZIKV to children born to returning travellers. Established surveillance systems operating within the UK - the paediatric and obstetric surveillance units for rare diseases, and national laboratory monitoring - enabled rapid assessment of this emerging public health threat. A combined total of 11 women experiencing adverse pregnancy outcomes after possible ZIKV exposure were reported by the three surveillance systems; five miscarriages, two intrauterine deaths and four children with clinical presentations potentially associated with ZIKV infection. Sixteen women were diagnosed with ZIKV during pregnancy in the UK. Amongst the offspring of these women, there was unequivocal laboratory evidence of infection in only one child. In the UK, the number and risk of congenital ZIKV infection for travellers returning from ZIKV-affected countries is very small.

The incubation period of hepatitis E genotype 1: insights from pooled analyses of travellers.

Hepatitis E virus genotype 1 (HEV G1) is an important cause of morbidity and mortality in Africa and Asia. HEV G1's natural history, including the incubation period, remains poorly understood, hindering surveillance efforts and effective control. Using individual-level data from 85 travel-related HEV G1 cases in England and Wales, we estimate the incubation period distribution using survival analysis methods, which allow for appropriate inference when only time ranges, rather than exact times are known for the exposure to HEV and symptom onset. We estimated a 29.8-day (95% confidence interval (CI) 24.1-36.0) median incubation period with 5% of people expected to develop symptoms within 14.3 days (95% CI 10.1-21.7) and 95% within 61.9 days (95% CI 47.4-74.4) of exposure. These estimates can help refine clinical case definitions and inform the design of disease burden and intervention studies.

Using data linkage to improve surveillance methods for acute hepatitis E infections in England and Wales 2010-2016.

Indigenous, foodborne transmission of hepatitis E has been increasing across industrialised countries. Public Health England has conducted enhanced surveillance in England and Wales since 2003.This report gives an account of acute infections from 2010 to 2016 and describes modification made to the methods of surveillance to account for changes in reporting behaviours and improve ascertainment.

Neonatal invasive fungal infection in England 2004-2010.

Rates of invasive fungal infection are highest among neonates, especially those of low birthweight. This study aimed to describe the current epidemiology of invasive neonatal fungal infections in a UK neonatal infection surveillance network. From 2004 to 2010 prospective multicentre surveillance was conducted by 14 neonatal units using a web-based database. Clinicians then completed a standardized pro forma for each positive fungal blood and/or cerebrospinal fluid culture. The overall incidence was 2.4/1000 neonatal unit admissions and was highest among babies <1000 g (extreme low birthweight, 18.8/1000). Only five infants (6%) were >1500 g. The majority of infections were caused by Candida albicans (59; 69%) and Candida parapsilosis (17; 20%); 33% of infants had received antifungal prophylaxis. Known risk factors (use of central venous catheter, parenteral nutrition, previous antibiotic use) were common among cases. The attributable case fatality rate was 21% (18/84). Extreme low birthweight infants remain at highest risk of invasive fungal infection and prophylaxis should be particularly considered for this group. The number needing to receive prophylaxis to prevent one case varies significantly among units, hence unit-specific decisions are required. Further research is still needed into the optimal empiric and therapeutic strategies.

Clinical findings and management of imported cutaneous leishmaniasis: report of 14 cases from Austria.

BACKGROUND: The management of cutaneous leishmaniasis in non-endemic countries is challenging due to the wide variety of clinical manifestations and little information available on treatment modalities for travellers. METHODS: Retrospective analysis and follow-up investigation in patients with imported cutaneous leishmaniasis managed at the General Hospital Vienna from 2004 to 2010. RESULTS: In total, 14 patients with cutaneous leishmaniasis were analyzed. The time to diagnosis ranged between weeks and several months and up to four consultations were necessary before diagnosis was accomplished. Histological investigations performed in all patients were diagnostic for CL in 8 (57%) patients. PCR analyses were performed in 12 patients and were positive in 10 (83%) patients. All six patients with negative histological results for CL tested positive in the PCR analysis. Treatment regimens applied included systemic therapy with liposomal amphotericin B, miltefosine, or fluconazole, and local therapy with cryotherapy, paromomycin ointment, photodynamic therapy, surgery, and various combinations. CONCLUSIONS: The present analysis strongly suggests that awareness of CL among physicians and travellers remains low and highlights the need to harmonize diagnostic and treatment guidelines for cutaneous and mucosal leishmaniasis in European travellers. Diagnostic outcome can be improved by combining histology and PCR in patients with suspected cutaneous leishmaniasis.

[Smelling diseases? A short review on electronic noses]. / Krankheiten erriechen? Eine kurze Übersicht über elektronische Nasen.

Non-invasive pulmonary diagnostics is a promising and interesting field in respiratory medicine. Beside exhaled breath condensate, there is an increasing interest in alternative and faster techniques such as electronic noses (EN). EN aim to mimic or improve the sense of smelling. Different types of EN have been employed in research so far. In addition to ion mobility spectrometry and mass spectrometry, ENs that consist of various biopolymer sensors for the sensing of volatile organic compounds (VOCs) have been tested. VOCs bind to the sensors depending on size, structure, hydrogen binding and polarity. This leads to physical alterations, e. g., swelling resulting in a change of resistance. The smell print represents composite patterns in contrast to single compounds, and the distinction between different categories is achieved by pattern recognition algorithms. Other types of EN like mass spectrometry and ion mobility spectrometry are capable of identifying even single analyte fractions provided that their characteristics have been saved in data repositories. The non-invasive nature, onsite availability and relatively cheap sampling are advantages of ENs that underly the increasing interest in their use for medical purposes. Some promising results have already been published. This review aims to describe the state of the art in brief form.

[Comparison of four identical electronic noses and three measurement set-ups]. / Vergleich von vier baugleichen elektronischen Nasen und drei Messaufbauten.

BACKGROUND: Volatile organic compounds (VOCs) can be used as biomarkers in exhaled air. VOC profiles can be detected by an array of nanosensors of an electronic nose. These profiles can be analysed using bioinformatics. It is, however, not known whether different devices of the same model measure identically and to which extent different set-ups and the humidity of the inhaled air influence the VOC profile. METHODS: Three different measuring set-ups were designed and three healthy control subjects were measured with each of them, using four devices of the same model (Cyranose 320™, Smiths Detection). The exhaled air was collected in a plastic bag. Either ambient air was used as reference (set-up Leipzig), or the reference air was humidified (100% relative humidity) (set-up Marburg and set-up Munich). In the set-up Marburg the subjects inhaled standardised medical air (Aer medicinalis Linde, AGA AB) out of a compressed air bottle through a demand valve; this air (after humidification) was also used as reference. In the set-up Leipzig the subjects inhaled VOC-filtered ambient air, in the set-up Munich unfiltered room air. The data were evaluated using either the real-time data or the changes in resistance as calculated by the device. RESULTS: The results were clearly dependent on the set-up. Apparently, humidification of the reference air could reduce the variance between devices, but this result was also dependent on the evaluation method used. When comparing the three subjects, the set-ups Munich and Marburg mapped these in a similar way, whereas not only the signals but also the variance of the set-up Leipzig were larger. CONCLUSION: Measuring VOCs with an electronic nose has not yet been standardised and the set-up significantly affects the results. As other researchers use further methods, it is currently not possible to draw generally accepted conclusions. More systematic tests are required to find the most sensitive and reliable but still feasible set-up so that comparability is improved.

A 1-year follow-on study from a randomised, head-to-head, multicentre, open-label study of two pandemic influenza vaccines in children.

INTRODUCTION: Pandemic influenza A H1N1 infections occurred worldwide from 2009. Children were particularly vulnerable. Novel vaccines were used during the pandemic. OBJECTIVE: To assess the persistence of antibody to H1N1 influenza 1 year after children aged 6 months to 12 years had been immunised with two doses of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine; and also to assess the immunogenicity and reactogenicity in this population of a single dose of 2010-11 trivalent seasonal influenza vaccine. DESIGN: Multicentre, open-label, follow-on from randomised, head-to-head trial. SETTING: Five UK sites (Southampton, Oxford, Bristol, London and Exeter). PARTICIPANTS: Children who completed last year's head-to-head randomised study were invited to participate. Children who had subsequently received a further dose of H1N1 vaccine, or who had already received a dose of 2010-11 trivalent seasonal influenza vaccine, were excluded. INTERVENTIONS: In the previous study, children were randomised (in a 1 : 1 ratio) to receive two doses, 21 days apart, of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine. In this follow-on study, a blood sample was taken to assess the persistence of antibody 1 year later, followed by administration of one 0.5 ml-dose of trivalent seasonal influenza vaccine. A second blood sample was taken 3 weeks later. MAIN OUTCOME MEASURES: Comparison between vaccines of the percentage of participants with a microneutralisation (MN) titre ≥ 1 : 40 and a haemagglutination titre ≥ 1 : 32, 1 year after vaccination. Immunogenicity of the trivalent seasonal influenza vaccine was assessed 3 weeks after vaccination by both the MN and the haemagglutination inhibition (HI) titres. Reactogenicity data were recorded for 7 days after vaccination. RESULTS: A total of 323 children were enrolled and 318 were included in the analysis of the persistence of antibody. One year after receipt of whole-virion vaccine, the MN titre was ≥ 1 : 40 in 32.4% of those vaccinated when < 3 years old and in 65.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 63.2% and 79.1% of children in the respective age groups. One year after receipt of the adjuvanted vaccine, the MN titre was ≥ 1 : 40 in 100% of those vaccinated when < 3 years old and in 96.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 98.4% and 96.9% of children in the respective age groups. Three hundred and two children were given trivalent seasonal influenza vaccination. Three weeks later, sera were obtained from 282 children; 100% had an MN titre ≥ 1 : 40 and HI titre ≥ 1 : 32. Trivalent seasonal influenza vaccine was well tolerated, although in children < 5 years old, fever ≥ 38 °C was reported in 13.6% of those who had previously received whole-virion vaccine, and in 18.3% of those who had received adjuvanted vaccine. CONCLUSIONS: Nearly all children who received two doses of AS03B-adjuvanted split-virion pandemic H1N1 influenza vaccine had titres of antibody deemed protective (HI titre ≥ 1 : 32, MN titre ≥ 1 : 40) 1 year later. Children who received two doses of whole-virion vaccine had lower titres, although many were above the putative protective thresholds. One year after either pandemic vaccine, the 2010-11 trivalent seasonal influenza vaccine produced a marked serological response to the H1N1 component of the vaccine and was well tolerated. We propose to investigate whether or not previous receipt of monovalent influenza vaccines affected serological response to the H3N2 and B components of the 2010-11 seasonal influenza vaccine, using stored sera. TRIAL REGISTRATION: ClinicalTrials.gov NCT01239537. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age.

OBJECTIVE: To evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children aged 6 months to 12 years. DESIGN: Multicentre, randomised, head-to-head, open-label trial. SETTING: Five UK sites (Oxford, Bristol, Southampton, Exeter and London). PARTICIPANTS: Children aged 6 months to < 13 years, for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures, were eligible for inclusion. INTERVENTIONS: A tocopherol/oil-in-water emulsion-adjuvanted (AS03(B)) egg culture-derived split-virion H1N1 vaccine and a non-adjuvanted cell culture-derived whole-virion vaccine, given as a two-dose schedule, 21 days apart, were compared. Participants were grouped into those aged 6 months to < 3 years (younger group) and 3 years to < 13 years of age (older group) and were randomised by study investigators (1 : 1 ratio) to receive one of the two vaccines. Vaccines were administered by intramuscular injection (deltoid or anterior-lateral thigh, depending on age and muscle bulk). Local reactions and systemic symptoms were collected for 1 week post immunisation, and serum was collected at baseline and after the second dose. To assess safety and tolerability, parents or guardians recorded the following information in diary cards from days 0-7 post vaccination: axillary temperature, injection site reactions, solicited and unsolicited systemic symptoms, and medications. MAIN OUTCOME MEASURE: Comparison between vaccines of the percentage of participants demonstrating seroconversion by microneutralisation assay. RESULTS: Among 937 children receiving vaccine, per-protocol seroconversion rates were higher after the AS03(B)-adjuvanted vaccine than after the whole-virion vaccine (98.2% vs 80.1% in children < 3 years, 99.1% vs 95.9% among those aged 3-12 years), as were severe local reactions (3.6% vs 0.0% in those under 5 years, 7.8% vs 1.1% in those aged 5-12 years), irritability in children < 5 years (46.7% vs 32.0%), and muscle pain in older children (28.9% vs 13.2%). The second dose of the adjuvanted vaccine was more reactogenic than the first, especially for fever > 38.0°C in those under 5 years of age (8.9% vs 22.4%). CONCLUSION: The adjuvanted vaccine, although reactogenic, was more immunogenic, especially in younger children, indicating the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION NUMBER: ISRCTN89141709.

Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study.

OBJECTIVES: To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. DESIGN: Open label, randomised, parallel group, phase II study. SETTING: Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). PARTICIPANTS: Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. INTERVENTIONS: Participants were randomised 1:1 to receive AS03(B) (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. MAIN OUTCOME MEASURES: Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of >or=1:40 from before vaccination to three weeks after the second dose). RESULTS: Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever >or=38 masculineC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001). CONCLUSIONS: In this first direct comparison of an AS03(B) adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION: Clinical trials.gov NCT00980850; ISRCTN89141709.

Clinical role of anti-granulocyte MoAb versus radiolabeled white blood cells.

Scintigraphy with white blood cells (WBC), labeled with ¹¹¹In-oxine or (99m)Tc-hexamethylpropyleneamine oxime (HMPAO), and anti-granulocyte scintigraphy using (99m)Tc-labeled monoclonal antibodies (MoAb), or fragments thereof, are established procedures for the diagnostic workup of infectious or inflammatory disease processes. Clinically severe afflictions such as fever of unknown origin (FUO), infectious joint replacements, osteomyelitis, vascular graft infections or cardiovascular infections often present where noninvasive proof of granulocytic inflammatory activity is more useful than mere morphology-based radiological diagnostic approaches. The labeling differences between WBC and antigranulocyte antibodies produce different pharmacokinetics and patterns of tracer accumulation and distribution. Together with the physical imaging properties of the respective isotope used for imaging, the diagnostic value of a tracer depends on the clinical setting. Thus, despite the easier and safer handling of antibody-based in-vivo labeling, indications for in-vivo labeled WBC remain. As a consequence there is as yet no ideal inflammation tracer, also bearing in mind that neither WBCs nor antibody-diagnostics can reliably differentiate sterile inflammation from infection. Although positron emission tomography (PET) using e.g. FDG-PET is replacing conventional scintigraphies in some indications, both in vivo and in vitro labelled leukocytes will remain an important clinical pillar in the diagnosis of infection and inflammation.