Cytomegalovirus (CMV) infection represents a vital complication after Hematopoietic Stem Cell Transplantation (HSCT). We screened the entire CMV proteome to visualize the humoral target epitope-focus ...profile in serum after HSCT. IgG profiling from four patient groups (donor and/or recipient +/- for CMV) was performed at 6, 12 and 24 months after HSCT using microarray slides containing 17174 of 15mer-peptides overlapping by 4 aa covering 214 proteins from CMV. Data were analyzed using maSigPro, PAM and the 'exclusive recognition analysis (ERA)' to identify unique CMV epitope responses for each patient group. The 'exclusive recognition analysis' of serum epitope patterns segregated best 12 months after HSCT for the D+/R+ group (versus D-/R-). Epitopes were derived from UL123 (IE1), UL99 (pp28), UL32 (pp150), this changed at 24 months to 2 strongly recognized peptides provided from UL123 and UL100. Strongly (IgG) recognized CMV targets elicited also robust cytokine production in T-cells from patients after HSCT defined by intracellular cytokine staining (IL-2, TNF, IFN and IL-17). High-content peptide microarrays allow epitope profiling of entire viral proteomes; this approach can be useful to map relevant targets for diagnostics and therapy in patients with well defined clinical endpoints. Peptide microarray analysis visualizes the breadth of B-cell immune reconstitution after HSCT and provides a useful tool to gauge immune reconstitution.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•‘Blue skies research’ refers to basic science or fundamental research•‘Blue skies research’ is essential new TB tools development for eradicating TB•Investments into fundamental TB research in LMICs ...is long overdue•COVID-19 advances bring hope for more holistic care for all RTIs
Investments into ‘Blue Skies’ fundamental TB research in low- and middle-income countries (LMICs) have not been forthcoming. We highlight why blue skies research will be essential for achieving global TB control and eradicating TB.
We review the historical background to early TB discovery research and give examples of where investments into basic science and fundamental ‘blue skies research’ are delivering novel data and approaches to advance diagnosis, management and holistic care for patients with active and latent TB infection.
The COVID-19 pandemic has shown that making available adequate funding for priority investments into ‘Blue skies research’ to delineate scientific understanding of a new infectious diseases threat to global health security can lead to rapid development and rollout of new diagnostic platforms, treatments, and vaccines. Several advances in new TB diagnostics, new treatments and vaccine development are underpinned by basic science research.
Blue Skies research is required to pave the way for a personalized medicine approach for management of TB and other Respiratory Tract Infections and preventing long-term functional disability. Transfer of skills and resources by wealthier nations is required to empower researchers in LMICs countries to engage in and lead Blue Skies research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract OBJECTIVE Nine out of ten tuberculosis deaths occur in tuberculosis-burdened countries, particularly Sub Saharan Africa. In these setting mortality has not been fully described. We describe ...the magnitude and pattern of TB mortality in Tanzania. METHODS A multicenter prospective cohort study was conducted among HIV infected and uninfected pulmonary tuberculosis patients from time of anti-TB treatment initiation to completion. Patients were censored at the time of treatment completion, or at their last visit for those who did not complete TB treatment. Kaplan-Meier curves were used to estimate time to death; cox proportional hazards model was used to examine risk factors for mortality. RESULTS A total of 58 deaths out of 1696 patients (3.4%) occurred, two thirds (n = 39) during the first two months of treatment. Compared to HIV un-infected TB patients, mortality risk for TB/HIV co-infected patients was least when antiretroviral therapy (ART) was initiated after 14 days of anti-TB (RR = 3.55; 95% CI: 1.44, 8.73 p < 0.0001) and highest when ART was initiated 90 days or less prior to anti-TB and within the first 14 days of anti-TB therapy (RR = 10; 95% CI: 3.28, 30.54; p < 0.0001). CONCLUSION Meticulously planned and supervised antiretroviral therapy reduces mortality among TB/HIV patients. Among patients with TB/HIV naïve of ART, withholding ART until the third week of anti-tuberculosis therapy will likely reduce TB mortality in Tanzania. Patients on ART and later develop tuberculosis should be closely monitored.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Development of novel vaccines has been slow, and tuberculosis (TB) remains a neglected disease.•Drug-resistant TB is rising in incidence because of the recent COVID-19 pandemic.•World Health ...Organization strategic targets for the reduction in TB mortality and incidence remain elusive.•Technological advances have led to a development pipeline of only 17 vaccines.•Newly introduced vaccines should be made widely available at scale and low cost.
Tuberculosis (TB) remains a leading cause of death worldwide and is estimated to have caused 1.3 million deaths worldwide in 2022. Approximately one quarter of the world's population are infected with Mycobacterium tuberculosis, of whom up to 10% will progress to developing active TB disease. Achieving the World Health Organization End TB Strategy targets of a 95% reduction in TB mortality and a 90% reduction in TB incidence worldwide by 2035 remains a daunting task. The continuing spread of multidrug-resistant TB adds another obstacle to achieving global TB control. Larger funding pledges coupled with technological advances have recently enabled the enhancement of TB vaccine development efforts. These are yielding a pipeline of over 17 products currently in different stages of clinical trials. Emerging promising phase I and II trial results and advancement to phase III trials have necessitated “vaccine preparedness” in parallel so that a smooth transition from any positive clinical trial result to phase IV evaluation and implementation into policy and practice can follow. Promotion of a human rights–based approach, which recognizes and upholds the fundamental rights of all affected by the disease, is essential to ensure universal access to quality TB vaccines, regardless of their background or personal circumstances.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
KRAS is a driver mutation for malignant transformation. It is found in 30% of all cancers and in 90% of pancreatic cancers. The identification of small molecules selectively inhibiting KRAS mutants ...has been challenging, yet mutant KRAS has recently been shown to be targeted by tumor-infiltrating lymphocyte (TIL)-derived T cells that confer tumor regression upon adoptive transfer. Furthermore, a human IgG1 monoclonal antibody interfering with mutant KRAS function inside the cell has been described to inhibit growth of KRAS-mutant xenografts in tumor-bearing mice. B cells have been described to infiltrate pancreatic cancer and may be associated with tertiary lymphoid structures associated with good prognosis, or, in contrast, promote tumor growth. However, their function, nor their antigen-specificity has been clearly defined. We discuss here the presence of tumor-infiltrating B cells (TIB) in patients with pancreatic cancer that produce KRAS-mutant specific IgG, underlining that intratumoral T and B cells may exclusively target mutant KRAS. KRAS-specific IgG may, therefore, serve as a readout of the activation of both arms of the anti-tumor adaptive immune armament although some B-cell populations may promote tumor progression.
Background & Aims:
Confocal laser endomicroscopy enables subsurface microscopic imaging of living tissue during ongoing endoscopy. This case report describes the in vivo detection of
Helicobacter ...pylori by endomicroscopy.
Methods:
Endomicroscopy (Pentax, Tokyo, EC-3870CIFK) was performed by using two different contrast stains: Topical Acriflavine in addition to intravenously applied fluorescein netted the surface and allowed identification of focal accumulation of
Helicobacter pylori at the surface and in deeper layer of the gastric epithelium. Biopsies were performed at the antrum and corpus for urease testing and histology. In addition, biopsies were cultured for
Helicobacter pylori. Cultured bacteria were re-assessed ex vivo using confocal microscopy with and without acriflavine staining.
Results: Helicobacter pylori
infection could be detected in a 70-year-old male by endomicroscopy. Accumulated, as well as single bacteria, could be observed and the distinct shape and flagella of
Helicobacter pylori could be identified.
Helicobacter pylori infection was proved by histology. Furthermore, ex vivo examination of cultures proved the presence of
Helicobacter pylori and the active uptake of acriflavine into the bacteria.
Conclusions:
Endomicroscopy is a new diagnostic approach, which enables the immediate diagnosis of
Helicobacter pylori in vivo during standard video endoscopy.
•The holistic management of tuberculosis (TB) patients can improve life-expectancy.•Pulmonary rehabilitation after TB treatment shows good effects for selected TB patients.•Disease-related ...malnutrition may lead to treatment failure in TB patients.•Nutritional status plays a key role in shaping immune responses.
The holistic management of tuberculosis (TB) patients can improve life expectancy and lost organ function.
Chronic sequelae are very common among patients who survive TB, which can lead to a further decline in lung function. There is still no guidance for ‘cured’ patients with impaired lung function who need pulmonary rehabilitation. Additional tests for evaluation should be given after the end of treatment, as recent studies have shown the good effect of pulmonary rehabilitation for TB patients.
Malnutrition is very common among TB patients and is related to malabsorption. The latter can cause lower drug exposure, which may result in treatment failure, increasing the risk of death, and can lead to acquired drug resistance. Malnutrition should be assessed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and the diagnosis should lead to an individualized treatment plan, including sufficient proteins and preferably in combination with adequate training.
Under normal circumstances, most immune cells use a glucose-based mechanism to generate energy. Therefore the patient’s nutritional status is a key factor in shaping immune responses. Disease-related malnutrition leads to proteolysis and lipolysis. In the end, the identification of individuals who will benefit from immune-modulatory strategies may lead to clinically relevant markers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • The appearance, disappearance, and re-emergence of pathogens of humans with epidemic potential and high mortality rates have threatened global health security for centuries. • Global ...public health authorities should have been better prepared for the recent Ebola virus disease (EVD) epidemic in West Africa. • The current Zika virus outbreak is diverting the attention of public authorities and governments from other important infectious diseases that continue to threaten global public health security; one such disease lurking in the background is the Middle East respiratory syndrome (MERS). • The emergence of the MERS coronavirus (MERS-CoV) in 2012 was the second time (after severe acute respiratory syndrome coronavirus (SARS-CoV)) that a new coronavirus, highly pathogenic for humans, emerged in the 21st century. Whilst most MERS cases have been reported from the Middle East, MERS cases have been reported from 27 countries in all continents. • MERS-CoV has been found in camel populations of Eastern Africa and the Middle East, and with millions of pilgrims visiting Saudi Arabia and returning home every year, the movement of MERS-CoV to new locations presents a real threat to global health security. • With animal, human, and environmental factors playing a critical role in its evolution, MERS-CoV represents a classical zoonosis. • A serious and more collaborative and coordinated MERS-CoV response plan is required to better define MERS-CoV epidemiology, transmission dynamics, molecular evolution, optimal treatment and prevention measures, and development of vaccines for humans and camels. • The ‘One Health’ concept focuses on the relationship and interconnectedness between humans, animals, and the environment, and recognizes that the health and wellbeing of humans is intimately connected to the health of animals and their environment (and vice versa). • A ‘One Health’ approach is ideally suited to the MERS-CoV situation and requires close cooperation between those who provide human health, animal health, and promote environmental and ecosystems health. • Critical to the establishment of a ‘One Health’ platform is the creation of a multidisciplinary team with a range of expertise to learn more about zoonotic spread between animals, humans, and the environment, and to monitor, respond to, and prevent major outbreaks conductive sociopolitical and economic framework for action. • The persistence of MERS-CoV 4 years since its first discovery has created major opportunities for Saudi Arabia or one of the other Middle Eastern countries to take leadership of the ‘One Health’ approach to tackling new emerging and re-emerging infectious diseases with epidemic potential in their region. • Parallel initiatives across Africa and the tropics could be harmonized to create regional networks that can serve as a repository for expert ‘One Health’ advice on safe and sustainable agricultural systems, especially for livestock, in support of human development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Recurrent pulmonary tuberculosis (RPTB) is a growing, neglected problem worldwide.•We performed a case-controlled study to ascertain main clinical features of RPTB.•Hemoptysis was significantly more ...common in patients with RPTB than controls.•A higher proportion of RPTB presented with cavitation and lung tissue damage.•Patients being older than 45 years of age are significant features of RPTB.
Recurrent pulmonary tuberculosis (RPTB) is a growing, important and neglected problem affecting treated TB patients and TB health services across the world, particularly in sub-Saharan Africa. Analyses and identification of differences in clinical features between recurrent PTB and newly diagnosed PTB may lead to improved management recommendations.
Between September 1st 2019 and January 31st 2020, we performed a prospective case controlled study of clinical and imaging features of patients with recurrent pulmonary tuberculosis and compared them with those of newly diagnosed PTB cases. Recurrent PTB was defined as a patient with bacteriologically confirmed active PTB who was previously successfully treated for PTB and was cured. A control was defined as a patient who presents for the first time with bacteriologically confirmed PTB. Clinical and radiological features were assessed and documented. Chi-square and t-test were used to test the difference between proportion and continuous data, respectively. Logistic regression analysis was done to determine factors associated with RPTB using SPSS version 23 software.
A total of 312 patients with PTB were enrolled (104 RPTB cases and 208 newly diagnosed controls). Clinically hemoptysis was more common in RPTB compared to controls 28/104 (26.9%) vs 35/208 (16.8%), P = 0.036. Chest pain was significantly less common among patients with RPTB compared to controls 33 (31.7%) vs 92 (44.2%), P = 0.034. A higher proportion of RPTB presented with cavitation 34/104 (32.7%) compared to control 44/208 (21.2%) P = 0.027. The median score for lung pathology was higher among patients with RPTB (50) compared to controls (30); P = 0.001. Lung function of patients with RPTB at diagnosis of index TB were more likely to show mixed restrictive and obstructive pattern 36/104 (34.6%) compared to controls 31/208 (14.9%). p<0.001. Multivariate analysis showed that patients older than 45 years of age (adjusted odds ratio aOR: 3.59, 95% CI: 1.38 – 9.32), those with hemoptysis (aOR 1.96, 95% CI: 1.04 – 3.69) p=0.04) and fibrosis on chest x rays (aOR 2.18, 95% CI: 1.16 – 4.10) were significantly associated with recurrent PTB.
Hemoptysis, lung parenchymal damage, and patients being older than 45 years of age are significant features of RPTB. Management should focus on risk factors for recurrence, and a more holistic model of care to prevent long term lung injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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