Diagnosing Viral Infections Through T-Cell Receptor Sequencing of Activated CD8+ T Cells.

T-cell-based diagnostic tools identify pathogen exposure but lack differentiation between recent and historical exposures in acute infectious diseases. Here, T-cell receptor (TCR) RNA sequencing was performed on HLA-DR+/CD38+CD8+ T-cell subsets of hospitalized coronavirus disease 2019 (COVID-19) patients (n = 30) and healthy controls (n = 30; 10 of whom had previously been exposed to severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]). CDR3α and CDR3ß TCR regions were clustered separately before epitope specificity annotation using a database of SARS-CoV-2-associated CDR3α and CDR3ß sequences corresponding to >1000 SARS-CoV-2 epitopes. The depth of the SARS-CoV-2-associated CDR3α/ß sequences differentiated COVID-19 patients from the healthy controls with a receiver operating characteristic area under the curve of 0.84 ± 0.10. Hence, annotating TCR sequences of activated CD8+ T cells can be used to diagnose an acute viral infection and discriminate it from historical exposure. In essence, this work presents a new paradigm for applying the T-cell repertoire to accomplish TCR-based diagnostics.

Chronic high level parasitemia in HIV-infected individuals with or without visceral leishmaniasis in an endemic area in North-West Ethiopia: potential superspreaders?

BACKGROUND: HIV patients with recurrent visceral leishmaniasis (VL) could potentially drive Leishmania transmission in areas with anthroponotic transmission such as East-Africa, but studies are lacking. Leishmania parasitemia has been used as proxy for infectiousness. METHODS: This study is nested within the PreLeish prospective cohort study, following a total of 490 HIV infected individuals free of VL at enrollment for upto 24-37 months in North-West Ethiopia. Blood Leishmania PCR was done systematically. This case series reports on ten HIV-coinfected individuals with chronic VL (≥3 VL episodes during follow-up) for upto 37 months, and three individuals with asymptomatic Leishmania infection for upto 24 months. RESULTS: All ten chronic VL cases were male, on antiretroviral treatment, with 0-11 relapses before enrollment. Median baseline CD4 counts were 82 cells/µL. They displayed three to six VL treatment episodes over a period upto 37 months. Leishmania blood PCR levels were strongly positive for almost the entire follow-up time (median Ct value 26 (IQR 23-30), including during periods between VL treatment. Additionally, we describe three HIV-infected individuals with asymptomatic Leishmania infection and without VL history, with equally strong Leishmania parasitemia over a period of upto 24 months without developing VL. All were on antiretroviral treatment at enrollment, with baseline CD4 counts ranging from 78 to 350 cells/µL. CONCLUSION: These are the first data on chronic parasitemia in HIV-infected individuals from L donovani endemic areas. HIV patients with asymptomatic and symptomatic Leishmania infection could potentially be highly infectious and constitute Leishmania superspreaders. Xenodiagnosis studies are required to confirm infectiousness.

Malaria and other infections induce polyreactive antibodies that impact SARS-CoV-2 seropositivity estimations in endemic settings.

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence is used to estimate the proportion of individuals within a population previously infected, to track viral transmission, and to monitor naturally and vaccine-induced immune protection. However, in sub-Saharan African settings, antibodies induced by higher exposure to pathogens may increase unspecific seroreactivity to SARS-CoV-2 antigens, resulting in false positive responses. To investigate the level and type of unspecific seroreactivitiy to SARS-CoV-2 in Africa, we measured immunoglobulin G (IgG), IgA, and IgM to a broad panel of antigens from different pathogens by Luminex in 602 plasma samples from African and European subjects differing in coronavirus disease 2019, malaria, and other exposures. Seroreactivity to SARS-CoV-2 antigens was higher in prepandemic African than in European samples and positively correlated with antibodies against human coronaviruses, helminths, protozoa, and especially Plasmodium falciparum. African subjects presented higher levels of autoantibodies, a surrogate of polyreactivity, which correlated with P. falciparum and SARS-CoV-2 antibodies. Finally, we found an improved sensitivity in the IgG assay in African samples when using urea as a chaotropic agent. In conclusion, our data suggest that polyreactive antibodies induced mostly by malaria are important mediators of the unspecific anti-SARS-CoV-2 responses, and that the use of dissociating agents in immunoassays could be useful for more accurate estimates of SARS-CoV-2 seroprevalence in African settings.

Aetiologies of acute undifferentiated febrile illness at the emergency ward of the University of Gondar Hospital, Ethiopia.

OBJECTIVE: Causes of acute febrile illness (AFI) often remain undetermined in developing countries, due to overlap of symptoms and limited available diagnostics. We aimed to assess the aetiology of AFI in adults in a referral hospital in northwest Ethiopia. METHODS: While all participants were tested for malaria by rapid diagnostic test (RDT), microscopy was only done on physician's request. Dengue virus (DENV) infections were detected using an RDT and ELISAs and dengue, yellow fever and chikungunya cases were identified by PCR. Bacterial aetiologies were investigated using blood culture and PCR. RESULTS: The aetiology of acute infection was identified for 20.5% of 200 patients enrolled. Eleven percent tested positive for Plasmodium, while microscopy was only requested for half of the identified malaria cases. For 4.0% of the Plasmodium-infected patients, an acute or past DENV (co-)infection was detected. We found 7.5% acute and 13.0% past DENV - all serotype 3 - infections. Bacterial infections were observed in 4.5% of the patients. CONCLUSION: Malaria is still a considerable aetiology of AFI and dengue is underrecognised. There are areas where both diseases occur concomitantly, and the DENV-3 serotype presumably spreads from Sudan to northern Ethiopia. As only 20.5% of the aetiologies were identified, a broader testing platform is required.

Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial.

Background: We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian human immunodeficiency virus-infected patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of up to 2.5 years after initiating PSP, including 1-year follow-up after PSP discontinuation. Methods: The trial had 3 phases: (1) 12 months of PSP; (2) a 6-month PSP extension period if CD4 count was ≤200 cells/µL at month 12; and (3) 12-month follow-up after stopping PSP. The probability of relapse and risk factors were calculated using Kaplan-Meier methods and Cox regression analysis. Results: For the 74 patients included, final study outcomes were as follows: 39 (53%) relapse-free, 20 (27%) relapsed, 5 (7%) deaths, 10 (14%) lost to follow-up. The 2-year risk of relapse was 36.9% (95% confidence interval, 23.4%-55.0%) and was highest for those with a history of VL relapse and low baseline CD4 count. Forty-five patients were relapse-free and in follow-up at month 12 of PSP. This included 28 patients with month 12 CD4 counts >200 cells/µL, remaining relapse-free after PSP discontinuation. Among the 17 with month 12 CD4 count <200 cells/µL, 1 relapsed and 3 were lost during the PSP extension period. During 1-year post-PSP follow-up, 2 patients relapsed and 1 was lost to follow-up. No PSP-related serious adverse events were reported during the PSP-extension/post-PSP follow-up period. Conclusions: It seems safe to discontinue PSP at month 12 CD4 counts of >200 cells/µL. The management of those failing to reach this level remains to be defined. Clinical Trials Registration: NCT01360762.

The clinical impact of valvular heart disease in a population-based cohort of subjects aged 80 and older.

BACKGROUND: In our ageing society, valvular heart diseases (VHD) have become an increasing public health problem. However, the lack of studies describing the impact of these diseases on the outcome of very old subjects makes it difficult to appreciate their real clinical burden. METHODS: Prospective, observational, population-based cohort study in Belgium. Five hundred fifty six subjects aged 80 years and older were followed up for 5.1 ± 0.25 years for mortality and 3.0 ± 0.25 years for hospitalization. Echocardiograms were performed at baseline. The Cumulative Illness Rating Scale (CIRS) was calculated for each subject. RESULTS: The prevalence of moderate-to-severe VHD was 17% (n = 97). Mitral stenosis was more prevalent in women and an age-dependent increase of the prevalence of severe aortic stenosis was seen. The overall disease burden was higher in participants with VHD (median CIRS 3 [IQR 3-5] vs 4 [IQR 3-6] (P = 0.008)). Moderate-to-severe VHD, and more specifically mitral stenosis and aortic stenosis, was found to be an independent predictor of both all-cause (HR 1.42 (95% CI 1.04-1.95)) and cardiovascular mortality (HR 2.13 (95% CI 1.38-3.29)). Moderate-to-severe VHD was also found to be an independent predictor of the need for a first unplanned hospitalization (HR 1.43 (95% CI 1.06-1.94)). CONCLUSIONS: A high prevalence of moderate-to-severe VHD was found in the very old. Moderate-to-severe VHD was identified as an independent risk factor for all-cause and cardiovascular mortality and as well for unplanned hospitalizations, independent of other structural cardiac abnormalities, ventricular function and major co-morbidities.

Airflow limitation by the Global Lungs Initiative equations in a cohort of very old adults.

The cut-off for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) defining airflow limitation for chronic obstructive pulmonary disease (COPD) is still contested. We assessed airflow limitation prevalence by the lower limit of normal (LLN) of Global Lungs Initiative (GLI) 2012 reference values and its predictive ability for all-cause mortality and hospitalisation in very old adults (aged ≥80 years) compared with the fixed cut-off. In a Belgian population-based prospective cohort of 411 very old adults, airflow limitation prevalence by the 5th percentile of GLI 2012 z-scores (GLI-LLN) and fixed cut-off (0.70) were compared with COPD reported by general practitioners (GPs). Survival and Cox regression multivariable analysis assessed the association of airflow limitation by both cut-offs with 5-year all-cause mortality and first hospitalisation at 3 years. 9.2% had airflow limitation by GLI-LLN and 27% by fixed cut-off, without good agreement (kappa coefficient ≤0.40) with GP-reported COPD (9%). Only airflow limitation by GLI-LLN was independently associated with mortality (adjusted hazard ratio 2.10, 95% CI 1.30-3.38). FEV1/FVC <0.70 but ≥GLI-LLN (17.8%) had no significantly higher risk for mortality or hospitalisation. In a cohort of very old adults, airflow limitation by GLI-LLN has lower prevalence than by fixed cut-off, independently predicts all-cause mortality and does not miss individuals with significantly higher all-cause mortality and hospitalisation.

No relation between CMV infection and mortality in the oldest old: results from the Belfrail study.

OBJECTIVE: previous studies have demonstrated an association between cytomegalovirus (CMV) infection and mortality in adults. In this prospective study, it was investigated whether these findings could be confirmed in the oldest old. METHODOLOGY: data obtained from a prospective observational cohort study (2008-2012) of 549 community-dwelling persons in Belgium aged 80 and older. RESULTS: seventy-six percent were anti-CMV seropositive of whom 37.5% had an anti-CMV IgG titre in the highest tertile (>250 IU/ml). After a median time of follow-up of 1,049 days, 127 deaths occurred. Cox proportional hazard models failed to show an association between CMV serostatus and all-cause mortality. Among persons seropositive for CMV, after adjusting for multiple confounders an anti-CMV in the highest tertile was statistically significantly associated with all-cause mortality (hazard ratio: 1.64, 95% confidence interval: 1.08, 2.48). CONCLUSION: in contrast to previous findings, a positive CMV serostatus was not associated with an increased risk for all-cause mortality in this cohort of very old people. This is probably the result of a survival effect. CMV seropositive subjects with high anti-CMV titres were at higher risk for all-cause mortality compared with other individuals. This may reflect CMV infection reactivation to be more common in the end stages of life.

Short-term prognostic value of forced expiratory volume in 1 second divided by height cubed in a prospective cohort of people 80 years and older.

BACKGROUND: Spirometry-based parameters of pulmonary function such as forced expiratory volume in 1 second (FEV1) have prognostic value beyond respiratory morbidity and mortality. FEV1 divided by height cubed (FEV1/Ht(3)) has been found to be better at predicting all-cause mortality than the usual standardization as percentage of predicted "normal values" (FEV1%) and its use is independent of reference equations. Yet, limited data are available on the very old adults (80 years and older) and in association to other adverse health outcomes relevant for this age group. This study aims to investigate the short-term prognostic value of FEV1/Ht(3) for all-cause mortality, hospitalization, physical and mental decline in a cohort of very old adults. METHODS: In a population-based prospective cohort study of 501 very old adults in Belgium, comprehensive geriatric assessment and spirometry were performed at baseline and after 1.7 ± 0.21 years. Kaplan-Meier curves for 3-year all-cause mortality and hospitalization rates and multivariable analysis adjusted for age, sex, smoking status, co-morbidities, anemia, high C reactive protein and creatinine levels examined the association of FEV1/Ht(3) with all-cause mortality, unplanned hospitalization and decline in mental and physical functioning. Physical functioning was assessed by activities of daily living, a battery of physical performance tests and grip strength. Mental functioning was assessed with mini mental state examination and 15 items geriatric depression scale. RESULTS: Individuals in the lowest quartile of FEV1/Ht(3) had a statistically significant increased adjusted risk for all-cause mortality (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.10-2.60) and unplanned hospitalization (HR 1.65, 95% CI 1.21-2.25), as well as decline in physical (odds ratio [OR] 1.89, 95% CI 1.05-3.39) and mental functioning (OR 2.39, 95% CI 1.30-4.40) compared to the rest of the study population. CONCLUSIONS: In a cohort of very old adults, low FEV1 expressed as FEV1/Ht(3) was found to be a short-term predictor of all-cause mortality, hospitalization and decline in physical and mental functioning independently of age, smoking status, chronic lung disease and other co-morbidities. Further research is needed on FEV1/Ht(3) as a potential risk marker for frailty and adverse health outcomes in this age group.

The glomerular filtration rate estimated by new and old equations as a predictor of important outcomes in elderly patients.

BACKGROUND: The prevalence of chronic kidney disease (CKD) increases with age, and new glomerular filtration rate-estimating equations have recently been validated. The epidemiology of CKD in older individuals and the relationship between a low estimated glomerular filtration rate as calculated by these equations and adverse outcomes remains unknown. METHODS: Data from the BELFRAIL study, a prospective, population-based cohort study of 539 individuals aged 80 years and older, were used. For every participant, five equations were used to calculate estimated glomerular filtration rate based on serum creatinine and/or cystatin C values: MDRD, CKD-EPIcreat, CKD-EPIcyst, CKD-EPIcreatcyst, and BIS equations. The outcomes analyzed included mortality combined with the necessity of new renal replacement therapy, severe cardiovascular events, and hospitalization. RESULTS: During the follow-up period, which was an average of 2.9 years, 124 participants died, 7 required renal replacement therapy, 271 were hospitalized, and 73 had a severe cardiovascular event. The prevalence of estimated glomerular filtration rate values <60 mL/min/1.73 m2 differed depending on the equation used as follows: 44% (MDRD), 45% (CKD-EPIcreat), 75% (CKD-EPIcyst), 65% (CKD-EPIcreatcyst), and 80% (BIS). All of the glomerular filtration rate-estimating equations revealed that higher cardiovascular mortality was associated with lower estimated glomerular filtration rates and that higher probabilities of hospitalization were associated with estimated glomerular filtration rates <30 mL/min/1.73 m2. A lower estimated glomerular filtration rate did not predict a higher probability of severe cardiovascular events, except when using the CKD-EPIcyst equation. By calculating the net reclassification improvement, CKD-EPIcyst and CKD-EPIcreatcyst were shown to predict mortality (+25% and +18%) and severe cardiovascular events (+7% and +9%) with the highest accuracy. The BIS equation was less accurate in predicting mortality (-12%). CONCLUSION: Higher prevalence of CKD were found using the CKD-EPIcyst, CKD-EPIcreatcyst, and BIS equations compared with the MDRD and CKD-EPIcreat equations. The new CKD-EPIcreatcyst and CKD-EPIcyst equations appear to be better predictors of mortality and severe cardiovascular events.

Urgent considerations for booster vaccination strategies against Ebola virus disease.

With two endorsed and prophylactic vaccines against Zaire ebolavirus (referred to hereafter as EBOV), the number of individuals vaccinated against EBOV worldwide is estimated to range between 500 000 and 1 000 000 individuals, increasing with every renewed EBOV threat and vaccination campaign. Therefore, re-exposure of previously vaccinated health-care workers, and possibly community members, could become more frequent. In the absence of long-term data on vaccine efficacy and duration of protection, we urgently need to understand revaccination strategies that could maximise the level of protection. In this Personal View, we highlight the scarcity of available evidence to guide revaccination recommendations for the accumulating groups of previously vaccinated communities or front-line health-care workers that could be redeployed or re-exposed in the next EBOV outbreak(s). This evidence base is crucial to identify optimal target populations and the frequency of booster doses, and guide vaccine interchangeability (especially in settings with limited or unpredictable vaccine supplies), while preventing vaccine mistrust, equity concerns, and exclusion of vulnerable populations. We discuss five priority gaps (to whom, when, and how frequently, to provide booster doses; long-term correlates and thresholds of protection; the effect of vector-directed immunity and viral variant protection; comparative research in mix-and-match schedules; and implementation concerns) that should be urgently tackled to adapt the initial EBOV prophylactic vaccination strategies considering potential booster dose vaccinations.

Persistent T cell unresponsiveness associated with chronic visceral leishmaniasis in HIV-coinfected patients.

A large proportion of HIV-coinfected visceral leishmaniasis (VL-HIV) patients exhibit chronic disease with frequent VL recurrence. However, knowledge on immunological determinants underlying the disease course is scarce. We longitudinally profiled the circulatory cellular immunity of an Ethiopian HIV cohort that included VL developers. We show that chronic VL-HIV patients exhibit high and persistent levels of TIGIT and PD-1 on CD8+/CD8- T cells, in addition to a lower frequency of IFN-γ+ TIGIT- CD8+/CD8- T cells, suggestive of impaired T cell functionality. At single T cell transcriptome and clonal resolution, the patients show CD4+ T cell anergy, characterised by a lack of T cell activation and lymphoproliferative response. These findings suggest that PD-1 and TIGIT play a pivotal role in VL-HIV chronicity, and may be further explored for patient risk stratification. Our findings provide a strong rationale for adjunctive immunotherapy for the treatment of chronic VL-HIV patients to break the recurrent disease cycle.

Lack of functional TCR-epitope interaction is associated with herpes zoster through reduced downstream T cell activation.

The role of T cell receptor (TCR) diversity in infectious disease susceptibility is not well understood. We use a systems immunology approach on three cohorts of herpes zoster (HZ) patients and controls to investigate whether TCR diversity against varicella-zoster virus (VZV) influences the risk of HZ. We show that CD4+ T cell TCR diversity against VZV glycoprotein E (gE) and immediate early 63 protein (IE63) after 1-week culture is more restricted in HZ patients. Single-cell RNA and TCR sequencing of VZV-specific T cells shows that T cell activation pathways are significantly decreased after stimulation with VZV peptides in convalescent HZ patients. TCR clustering indicates that TCRs from HZ patients co-cluster more often together than TCRs from controls. Collectively, our results suggest that not only lower VZV-specific TCR diversity but also reduced functional TCR affinity for VZV-specific proteins in HZ patients leads to lower T cell activation and consequently affects the susceptibility for viral reactivation.

No relation between vitamin D status and physical performance in the oldest old: results from the Belfrail study.

BACKGROUND: vitamin D deficiency is a well-known cause of bone loss and fractures but its association, especially among the oldest old, with muscle weakness is less obvious. OBJECTIVE: to investigate the relationship between 25-hydroxyvitamin D (25-OHD) and muscle performance in persons aged 80 years and older. METHODS: baseline results of the Belfrail study, a prospective, population-based cohort study were used to study balance, grip strength and gait speed in relation to 25-OHD serum levels in 367 subjects. RESULTS: a sufficient 25-OHD serum level of 30 ng/ml or more was found in 12.8% of the population. The prevalence of vitamin deficiency (20-29 ng/ml), insufficiency (10-19 ng/ml) and severe insufficiency (<10 ng/ml) was 21.5, 33 and 32.7%, respectively. No significant relation between balance, gait speed and grip strength, and serum 25-OHD was detected neither in bivariate analysis nor after adjustment for age, gender, level of education, institutionalisation, smoking status, body mass index, co-morbidity, level of activity, season, CRP, renal function, serum calcium parathyroid hormone levels, vitamin D intake and use of loop or thiazide diuretics. CONCLUSION: in this cohort of octogenarians vitamin D deficiency was highly prevalent. We could not confirm the findings of previous studies showing an association between serum 25-OHD and physical performance in elderly.

Leveraging T-cell receptor - epitope recognition models to disentangle unique and cross-reactive T-cell response to SARS-CoV-2 during COVID-19 progression/resolution.

Despite the general agreement on the significance of T cells during SARS-CoV-2 infection, the clinical impact of specific and cross-reactive T-cell responses remains uncertain. Understanding this aspect could provide insights for adjusting vaccines and maintaining robust long-term protection against continuously emerging variants. To characterize CD8+ T-cell response to SARS-CoV-2 epitopes unique to the virus (SC2-unique) or shared with other coronaviruses (CoV-common), we trained a large number of T-cell receptor (TCR) - epitope recognition models for MHC-I-presented SARS-CoV-2 epitopes from publicly available data. These models were then applied to longitudinal CD8+ TCR repertoires from critical and non-critical COVID-19 patients. In spite of comparable initial CoV-common TCR repertoire depth and CD8+ T-cell depletion, the temporal dynamics of SC2-unique TCRs differed depending on the disease severity. Specifically, while non-critical patients demonstrated a large and diverse SC2-unique TCR repertoire by the second week of the disease, critical patients did not. Furthermore, only non-critical patients exhibited redundancy in the CD8+ T-cell response to both groups of epitopes, SC2-unique and CoV-common. These findings indicate a valuable contribution of the SC2-unique CD8+ TCR repertoires. Therefore, a combination of specific and cross-reactive CD8+ T-cell responses may offer a stronger clinical advantage. Besides tracking the specific and cross-reactive SARS-CoV-2 CD8+ T cells in any TCR repertoire, our analytical framework can be expanded to more epitopes and assist in the assessment and monitoring of CD8+ T-cell response to other infections.

Comparison of serum cytokine levels in symptomatic and asymptomatic HIV-Leishmania coinfected individuals from a Brazilian visceral leishmaniasis endemic area.

BACKGROUND: Visceral leishmaniasis (VL) remains an important infectious disease worldwide. VL-HIV coinfected individuals can present with atypical clinical forms of VL and have a high risk of VL relapse. Some cytokines have been described as potential markers to diagnose active VL and to predict the severity of the cases. However, few studies have included VL-HIV coinfected patients. We aimed to characterize the levels of several cytokines among VL-HIV coinfected individuals living in a VL-endemic area in Northeast Brazil. METHODS: This was a retrospective, cross-sectional study, aiming to estimate the levels of various cytokines in symptomatic and asymptomatic VL-HIV coinfected individuals. There were 134 study participants (35 symptomatic VL-HIV, 75 asymptomatic VL-HIV, and 24 healthy controls), all ≥ 18 years-old. Serum cytokine levels (interferon-γ, tumor necrosis factor, and interleukins 2, 4, 6, 10, and 17A) were quantified using the Becton Dickinson-BD's Cytometric Bead Array (CBA) system. RESULTS: The population mainly consisted of men (64.9%), with a median age of 35 (27-41) years. Asymptomatic individuals were younger (p = 0.013), with more years of education (p < 0.001), and were more often on antiretroviral therapy (p < 0.001) than those in the symptomatic group. Hemoglobin levels (p < 0.001), lymphocytes (p < 0.001) and CD4 count (p < 0.001) were lower in symptomatic individuals, while HIV viral loads were higher (p < 0.001). In the symptomatic VL-HIV coinfected group, we observed increased serum levels of IL-17A, IL-6, and IL-10 compared to asymptomatic patients and the healthy controls. There were no differences in the levels of all cytokines between asymptomatic VL-HIV coinfected individuals and the healthy controls. CONCLUSIONS: Higher serum levels of IL-17A, IL-6, and IL-10 cytokines were observed in symptomatic coinfected individuals but not in asymptomatically infected individuals. More studies among HIV-positive persons are needed to better understand the role of serum cytokines for prognosis, to define cure and predict VL relapses in VL-HIV coinfected individuals.

Surgical output within the Fast Track Initiative against trachoma in Amhara region, Ethiopia.

INTRODUCTION: Trachomatous trichiasis (TT) is the advanced stage of trachoma where lashes touch the globe of the eye causing permanent damage. Without eyelid surgery, TT can lead to irreversible blindness. In 2015 the Ethiopian Ministry of Health launched the Fast Track Initiative with the aim of enhancing the provision of surgical services for TT. The aims of this study were to determine the productivity of individual surgeons during the 2017 Initiative, to compare this productivity with the Ministry's annual target indicator of ≥ 200 surgeries, and to assess the factors associated with surgical output. METHODOLOGY: This retrospective cross-sectional study utilized programmatic data on surgical output from 140 surgeons active from January 2017 through December 2017 in the eastern half of Amhara region, Ethiopia. Data were collected from a surgery monitoring dataset, analyzed, and compared to the performance targets set by the Ministry. RESULTS: The mean annual number of surgeries carried out per surgeon was 169 (standard deviation: 111) for a total of 23,616 surgeries. Among the 140 surgeons, 38% achieved the target set by the Ministry. Location of surgical training site and estimated surgical backlog were signficantly associated with a higher surgery output. CONCLUSIONS: An increase in surgical output was observed compared to productivity prior to the Initiative, although the average annual output during the 2017 Fast Track Initiative was lower than the Ministry's target. Using data driven approaches to setting annual productivity goals should be considered, particularly in light of fewer remaining TT cases as a result of the successful Initiative.

HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires.

Susceptibility for leishmaniasis is largely dependent on host genetic and immune factors. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors for leishmaniasis, little is known regarding the mechanisms that underpin these associations. To better understand this underlying functionality, we first collected all known leishmaniasis-associated HLA variants in a thorough literature review. Next, we aligned and compared the protection- and risk-associated HLA-DRB1 allele sequences. This identified several amino acid polymorphisms that distinguish protection- from risk-associated HLA-DRB1 alleles. Subsequently, T cell epitope binding predictions were carried out across these alleles to map the impact of these polymorphisms on the epitope binding repertoires. For these predictions, we used epitopes derived from entire proteomes of multiple Leishmania species. Epitopes binding to protection-associated HLA-DRB1 alleles shared common binding core motifs, mapping to the identified HLA-DRB1 amino acid polymorphisms. These results strongly suggest that HLA polymorphism, resulting in differential antigen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes. A set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, was prioritized for further epitope discovery in the search for novel subunit-based vaccines.

Cellular Immune Phenotypes and Worsening Scores of Frailty-Associated Parameters Over an 18-Month Period in the Very Old.

Frailty has been related to inflammaging and certain immune parameters. In previous analyses of participants older than 80 years of age in the longitudinal BELFRAIL cohort study, the main focus was on T-cell phenotypes and the association with cytomegalovirus (CMV) serostatus and survival, finding that a CD4:CD8 ratio greater than 5 was associated with frailty, impaired activities of daily living (ADLs), and mortality (but only in women). Here, we phenotyped peripheral blood immune cells via multicolor flow cytometry and correlated these with the dynamics of changes in ADL, geriatric depression score, Mini-Mental State Examination, and Short Physical Performance Battery from baseline values over 18 months follow-up. We found that higher frequencies of B cells and late-differentiated CD8+ T cells at 18 months from baseline were associated with ADL impairment that had worsened over the preceding 18 months. There were no significant associations with monocyte, dendritic cell, or natural killer (NK) cell phenotypes. No associations with the Geriatric Depression Scale, the Mini-Mental State Examination, or the Short Physical Performance Battery were found. Thus, while these results do not establish causality, they suggest that certain adaptive immune, but not innate immune, parameters are associated with a worsened ADL in the very old.

Sexual Transmission of Visceral Leishmaniasis: A Neglected Story.

For visceral leishmaniasis (VL), a major vector-borne parasitic disease, an alternative sexual transmission route is well documented in dogs but evidence is lacking in humans. Here, we discuss the current knowledge and key questions to be answered as it may be an additional obstacle in ongoing VL elimination programs.