MS pathology is potentially orchestrated by autoreactive T cells, but the antigens recognized remain unknown. A novel APC/T‐cell platform was developed to determine intrathecal CD4+ and CD8+ T‐cell ...responses to candidate MS‐associated autoantigens (cMSAg) in clinically isolated syndrome (CIS, n = 7) and MS (n = 6) patients. Human cMSAg encoding open reading frames (n = 8) were cloned into an Epstein–Barr virus (EBV)‐based vector to express cMSAg at high levels in EBV‐transformed B‐cells (BLCLs). Human cMSAg cloned were myelin‐associated and ‐oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, ATP‐dependent potassium channel ATP‐dependent inwards rectifying potassium channel 4.1, S100 calcium‐binding protein B, contactin‐2, and neurofascin. Transduced BLCLs were used as autologous APC in functional T‐cell assays to determine cMSAg‐specific T‐cell frequencies in cerebrospinal fluid derived T‐cell lines (CSF‐TCLs) by intracellular IFN‐γ flow cytometry. Whereas all CSF‐TCL responded strongly to mitogenic stimulation, no substantial T‐cell reactivity to cMSAg was observed. Contrastingly, measles virus fusion protein‐specific CD4+ and CD8+ T‐cell clones, used as control of the APC/T‐cell platform, efficiently recognized transduced BLCL expressing their cognate antigen. The inability to detect substantial T‐cell reactivity to eight human endogenously synthesized cMSAg in autologous APC do not support their role as prominent intrathecal T‐cell target antigens in CIS and MS patients early after onset of disease.
Phylogenetic analysis can identify transmission networks by clustering genetically related HIV genotypes that are routinely collected. In this study, we will review phylogenetic insights gained on ...transmission of HIV and phylogenetically optimized HIV prevention strategies.
Phylogenetic analysis reports that HIV transmission varies by geographical region and by route of transmission. In high-income countries, HIV is predominantly transmitted between recently infected MSM who live in the same country. In rural Uganda, transmission of HIV is frequently between different communities. Age-discrepant transmission has been reported across the world. Four studies have used phylogenetic optimization of HIV prevention. Three studies predict that immediate treatment after diagnosis would have prevented 19-42% of infections, and that preexposure prophylaxis would have prevented 66% of infections. One phylogenetic study guided a public health response to an actively ongoing HIV outbreak. Phylogenetic clustering requires a dense sample of patients and small time-gaps between infection and diagnosis.
Phylogenetic analysis can be an important tool to identify a local strategy that prevents most infections. Future studies that use phylogenetic analysis for optimizing HIV prevention strategies should also include cost-effectiveness so that the most cost-effective prevention method is identified.
Zika virus and Guillain–Barré syndrome in Bangladesh GeurtsvanKessel, Corine H.; Islam, Zhahirul; Islam, Md. Badrul ...
Annals of clinical and translational neurology,
20/May , Letnik:
5, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Objective
Previous studies have associated Guillain–Barré syndrome (GBS) with Zika virus (ZIKV) outbreaks in South America and Oceania. In Asia, ZIKV is known to circulate widely, but the association ...with Guillain–Barré syndrome is unclear. We investigated whether endemic ZIKV infection is associated with the development of GBS.
Methods
A prospective study was conducted from 2011 to 2015 in Bangladesh. A total of 418 patients and 418 healthy family controls were included in the study. Patients were diagnosed with GBS prior to inclusion according to established criteria. Detailed information on the epidemiology, clinical presentation, electrophysiology, diagnosis, disease severity, and clinical course were obtained during a follow‐up of 1 year using a predefined protocol.
Results
ZIKV‐neutralizing antibodies were detected in our study from 2013 onwards. The prevalence of ZIKV‐neutralizing antibodies was not significantly higher in patients with GBS compared to healthy controls (OR 2.23, P = 0.14, 95% CI 0.77–6.53). Serological evidence for prior ZIKV infection in patients with GBS was associated with more frequent cranial, sensory, and autonomic nerve involvement compared to GBS patients with Campylobacter jejuni, the predominant preceding infection in GBS worldwide. Nerve‐conduction studies revealed that ZIKV antibodies were associated with a demyelinating subtype of GBS, while C. jejuni infections were related to an axonal subtype.
Interpretation
No significant association was found between ZIKV infection and GBS in Bangladesh, but GBS following ZIKV infection was characterized by a distinct clinical and electrophysiological subtype compared to C. jejuni infection. These findings indicate that ZIKV may precede a specific GBS subtype but the risk is low.
West Nile virus (WNV) has caused outbreaks and sporadic infections in Central, Eastern and Mediterranean Europe for over 45 years. Most strains responsible for the European and Mediterranean basin ...outbreaks are classified as lineage 1. In recent years, WNV strains belonging to lineage 1 and 2 have been causing outbreaks of neuroinvasive disease in humans in countries such as Italy, Hungary and Greece, while mass mortality among birds was not reported. This study characterizes three European strains of WNV isolated in Italy (FIN and Ita09) and Hungary (578/10) in terms of in vitro replication kinetics on neuroblastoma cells, LD50 values in C57BL/6 mice, median day mortality, cumulative mortality, concentration of virus in the brain and spinal cord, and the response to infection in the brain. Overall, the results indicate that strains circulating in Europe belonging to both lineage 1 and 2 are highly virulent and that Ita09 and 578/10 are more neurovirulent compared to the FIN strain.
Earlier antiretroviral therapy initiation and pre-exposure prophylaxis (PrEP) prevent HIV, although at a substantial cost. We use mathematical modeling to compare the cost-effectiveness and economic ...affordability of antiretroviral-based prevention strategies in rural Macha, Zambia.
We compare the epidemiological impact and cost-effectiveness over 40 years of a baseline scenario (treatment initiation at CD4 <350 cells/μL) with treatment initiation at CD4 <500 cells per microliter, and PrEP (prioritized to the most sexually active, or nonprioritized). A strategy is cost effective when the incremental cost-effectiveness ratio (ICER) is <$3480 (<3 times Zambian per capita GDP). Stochastic league tables then predict the optimal intervention per budget level.
All scenarios will reduce the prevalence from 6.2% (interquartile range, 5.8%-6.6%) in 2014 to about 1% after 40 years. Compared with the baseline, 16% of infections will be averted with prioritized PrEP plus treatment at CD4 <350, 34% with treatment at CD4 <500, and 59% with nonprioritized PrEP plus treatment at CD4 <500. Only treating at CD4 <500 is cost effective: ICER of $62 ($46-$75). Nonprioritized PrEP plus treating at CD4 <500 is borderline cost effective: ICER of $5861 ($3959-$8483). Initiating treatment at CD4 <500 requires a budget increase from $20 million to $25 million over 40 years, with a 96.7% probability of being the optimal intervention. PrEP should only be considered when the budget exceeds $180 million.
Treatment initiation at CD4 <500 is a cost-effective HIV prevention approach that will require a modest increase in budget. Although adding PrEP will avert more infections, it is not economically feasible, as it requires a 10-fold increase in budget.
BackgroundFollowing the 2022-2023 mpox outbreak, crucial knowledge gaps exist regarding orthopoxvirus-specific immunity in risk groups and its impact on future outbreaks.AimWe combined ...cross-sectional seroprevalence studies in two cities in the Netherlands with mathematical modelling to evaluate scenarios of future mpox outbreaks among men who have sex with men (MSM).MethodsSerum samples were obtained from 1,065 MSM attending Centres for Sexual Health (CSH) in Rotterdam or Amsterdam following the peak of the Dutch mpox outbreak and the introduction of vaccination. For MSM visiting the Rotterdam CSH, sera were linked to epidemiological and vaccination data. An in-house developed ELISA was used to detect vaccinia virus (VACV)-specific IgG. These observations were combined with published data on serial interval and vaccine effectiveness to inform a stochastic transmission model that estimates the risk of future mpox outbreaks.ResultsThe seroprevalence of VACV-specific antibodies was 45.4% and 47.1% in Rotterdam and Amsterdam, respectively. Transmission modelling showed that the impact of risk group vaccination on the original outbreak was likely small. However, assuming different scenarios, the number of mpox cases in a future outbreak would be markedly reduced because of vaccination. Simultaneously, the current level of immunity alone may not prevent future outbreaks. Maintaining a short time-to-diagnosis is a key component of any strategy to prevent new outbreaks.ConclusionOur findings indicate a reduced likelihood of large future mpox outbreaks among MSM in the Netherlands under current conditions, but emphasise the importance of maintaining population immunity, diagnostic capacities and disease awareness.
Introduction
Earlier antiretroviral therapy (ART) initiation reduces HIV‐1 incidence. This benefit may be offset by increased transmitted drug resistance (TDR), which could limit future HIV treatment ...options. We analyze the epidemiological impact and cost‐effectiveness of strategies to reduce TDR.
Methods
We develop a deterministic mathematical model representing Kampala, Uganda, to predict the prevalence of TDR over a 10‐year period. We then compare the impact on TDR and cost‐effectiveness of: (1) introduction of pre‐therapy genotyping; (2) doubling use of second‐line treatment to 80% (50–90%) of patients with confirmed virological failure on first‐line ART; and (3) increasing viral load monitoring from yearly to twice yearly. An intervention can be considered cost‐effective if it costs less than three times the gross domestic product per capita per quality adjusted life year (QALY) gained, or less than $3420 in Uganda.
Results
The prevalence of TDR is predicted to rise from 6.7% (interquartile range IQR 6.2–7.2%) in 2014, to 6.8% (IQR 6.1–7.6%), 10.0% (IQR 8.9–11.5%) and 11.1% (IQR 9.7–13.0%) in 2024 if treatment is initiated at a CD4 <350, <500, or immediately, respectively. The absolute number of TDR cases is predicted to decrease 4.4–8.1% when treating earlier compared to treating at CD4 <350 due to the preventative effects of earlier treatment. Most cases of TDR can be averted by increasing second‐line treatment (additional 7.1–10.2% reduction), followed by increased viral load monitoring (<2.7%) and pre‐therapy genotyping (<1.0%). Only increasing second‐line treatment is cost‐effective, ranging from $1612 to $2234 (IQR $450‐dominated) per QALY gained.
Conclusions
While earlier treatment initiation will result in a predicted increase in the proportion of patients infected with drug‐resistant HIV, the absolute numbers of patients infected with drug‐resistant HIV is predicted to decrease. Increasing use of second‐line treatment to all patients with confirmed failure on first‐line therapy is a cost‐effective approach to reduce TDR. Improving access to second‐line ART is therefore a major priority.
BackgroundPreexposure prophylaxis (PrEP) with antiretroviral drugs may prevent transmission of human immunodeficiency virus (HIV). Our objective was to predict whether PrEP, in the presence of ...circulating drug resistance, will reduce the risk of infection with HIV MethodsWe used risk equations to calculate the monthly risk of infection with HIV before and after the introduction of PrEP. Uncertainty and sensitivity analyses were performed for 2 ranges of PrEP effectiveness (40%–60% and 60%–80%). Circulating drug resistance was assumed to reduce the effectiveness of PrEP by 50%–90% and the transmissibility of HIV by 0%–30%. Parameter ranges were chosen for women 17–29 years of age from publications on HIV in Manicaland in Zimbabwe ResultsPrEP would decrease the median risk of HIV transmission by 21%–33% (effectiveness of PrEP, 40%–60% and 60%–80%). If 50% of HIV strains are drug resistant, then the median risk reduction would be 19%–26% if drug-resistant strains were less transmissible than wild-type HIV and 12%–19% if they were equally transmissible. The risk would increase if condoms were frequently replaced with PrEP. Use of PrEP for sexual acts for which no protection is currently used would be beneficial ConclusionThe public health impact of PrEP will depend on its effectiveness and on risk behavior. Circulating drug resistance will have only a small impact on the effectiveness of PrEP
Understanding HIV-1 subtype distribution and epidemiology can assist preventive measures and clinical decisions. Sequence variation may affect antiviral drug resistance development, disease ...progression, evolutionary rates and transmission routes.
We investigated the subtype distribution of HIV-1 in Europe and Israel in a representative sample of patients diagnosed between 2002 and 2005 and related it to the demographic data available. 2793 PRO-RT sequences were subtyped either with the REGA Subtyping tool or by a manual procedure that included phylogenetic tree and recombination analysis. The most prevalent subtypes/CRFs in our dataset were subtype B (66.1%), followed by sub-subtype A1 (6.9%), subtype C (6.8%) and CRF02_AG (4.7%). Substantial differences in the proportion of new diagnoses with distinct subtypes were found between European countries: the lowest proportion of subtype B was found in Israel (27.9%) and Portugal (39.2%), while the highest was observed in Poland (96.2%) and Slovenia (93.6%). Other subtypes were significantly more diagnosed in immigrant populations. Subtype B was significantly more diagnosed in men than in women and in MSM > IDUs > heterosexuals. Furthermore, the subtype distribution according to continent of origin of the patients suggests they acquired their infection there or in Europe from compatriots.
The association of subtype with demographic parameters suggests highly compartmentalized epidemics, determined by social and behavioural characteristics of the patients.
Diabetes triples the risk for active tuberculosis, thus the increasing burden of type 2 diabetes will help to sustain the present tuberculosis epidemic. Recommendations have been made for ...bidirectional screening, but evidence is scarce about the performance of specific tuberculosis tests in individuals with diabetes, specific diabetes tests in patients with tuberculosis, and screening and preventive therapy for latent tuberculosis infections in individuals with diabetes. Clinical management of patients with both diseases can be difficult. Tuberculosis patients with diabetes have a lower concentration of tuberculosis drugs and a higher risk of drug toxicity than tuberculosis patients without diabetes. Good glycaemic control, which reduces long-term diabetes complications and could also improve tuberculosis treatment outcomes, is hampered by chronic inflammation, drug-drug interactions, suboptimum adherence to drug treatments, and other factors. Besides drug treatments for tuberculosis and diabetes, other interventions, such as education, intensive monitoring, and lifestyle interventions, might be needed, especially for patients with newly diagnosed diabetes or those who need insulin. From a health systems point of view, delivery of optimum care and integration of services for tuberculosis and diabetes is a huge challenge in many countries. Experience from the combined tuberculosis and HIV/AIDS epidemic could serve as an example, but more studies are needed that include economic assessments of recommended screening and systems to manage concurrent tuberculosis and diabetes.
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