Evaluating the Cost-Effectiveness of Changes to the Surveillance Intervals in the UK Abdominal Aortic Aneurysm Screening Programme.

OBJECTIVES: To investigate the safety and cost-effectiveness of lengthening the time between surveillance ultrasound scans in the UK Abdominal Aortic Aneurysm (AAA) Screening Programme. METHODS: A discrete event simulation model was used to evaluate the cost-effectiveness of AAA screening for men aged 65, comparing current surveillance intervals to 6 alternative surveillance interval strategies that lengthened the time between surveillance scans for 1 or more AAA size categories. The model considered clinical events and costs incurred over a 30-year time horizon and the cost per quality-adjusted life year (QALY). The model adopted the National Health Service perspective and discounted future costs and benefits at 3.5%. RESULTS: Compared with current practice, alternative surveillance strategies resulted in up to a 4% reduction in the number of elective AAA repairs but with an increase of up to 1.6% in the number of AAA ruptures and AAA-related deaths. Alternative strategies resulted in a small reduction in QALYs compared to current practice but with reduced costs. Two strategies that lengthened surveillance intervals in only very small AAAs (3.0-3.9 cm) provided, at a cost-effectiveness threshold of £20 000 per QALY, the highest positive incremental net benefit. There was negligible chance that current practice is the most cost-effective strategy at any threshold below £40 000 per QALY. CONCLUSIONS: Lengthening surveillance intervals in the UK Abdominal Aortic Aneurysm Screening Programme, especially for small AAA, can marginally reduce the incremental cost per QALY of the program. Nevertheless, whether the cost savings from refining surveillance strategies justifies a change in clinical practice is unclear.

Changing epidemiology of abdominal aortic aneurysms in England and Wales: older and more benign?

BACKGROUND: Recent studies from Australia, New Zealand, and Sweden have reported declines in abdominal aortic aneurysm (AAA) incidence, prevalence, and mortality. This finding may have important implications for screening programs. This study determined trends in AAA incidence and mortality in England and Wales. METHODS AND RESULTS: Cause-specific mortality data for England and Wales were obtained from UK Office for National Statistics, and hospital admissions and procedures data for England were obtained from Hospital Episode Statistics from 2001 to 2009. Poisson regression models were constructed to estimate the relative change over time. Age-standardized rates for AAA mortality in England and Wales fell significantly by 35.7% from 2001 to 2009, which was largely due to a 35.3% drop in age-standardized ruptured AAA deaths. During the same period, ruptured AAA admissions and emergency AAA repairs in England declined by 29.3% and 35.5%, respectively. In contrast, nonruptured AAA admissions remained static, and nonemergency AAA repairs increased by 17.2%. The average ages for hospital admissions for nonruptured AAAs and ruptured AAAs increased by 0.19 years of age per annum (P<0.001) and 0.09 years of age per annum (P<0.001), respectively. Nonruptured AAA admissions increased by 21.4% in age band 75 years or more but declined by 11.7% in ages <75 years. CONCLUSIONS: AAA mortality, ruptured AAA admission, and emergency AAA repair have declined in England and Wales. However, nonruptured AAA admission has remained steady, with an increasing rate in older population offsetting a decreasing rate in younger population. This suggests a shift in AAA presentation to the older population. Present screening strategies may need reassessment to include consideration for increasing the age at which to screen men for AAAs.

Analysis of localized immune responses reveals presence of Th17 and Treg cells in cutaneous leishmaniasis due to Leishmania tropica.

PURPOSE: The interaction between the Leishmania parasite and the host cell involves complex, multifaceted processes. The disease severity in cutaneous leishmaniasis (CL) is largely dependent on the causative species. Most of the information on immune responses in human CL is available with respect to L. major infection and is lacking for L. tropica species. In this study, we employed cytokine/chemokine/receptor membrane cDNA array to capture comprehensive picture of immuno-determinants in localized human tissue during L. tropica infection. Expression of selected molecules was evaluated by real time PCR in dermal lesion tissues at pre- and post treatment stages. Plasma IL-17 level was estimated by sandwich ELISA. RESULTS: The cDNA array analysis identified several immuno-determinants in tissue lesions of Indian CL including cytokines (IFN-γ, TNF-α, IL-1ß, IL-10, IL-13), chemokines (IL-8, CCL2, CCL3, CCL4) and apoptotic molecules (Fas, TRAIL, IRF-1). Elevated mRNA levels of Th17 (IL-17, IL-23 and RORγt) and Treg (CD25, CTLA-4 and Foxp3) markers were observed in lesion tissues of CL patients compared to the control group, which subsided post treatment. Plasma IL-17 levels were found to be significantly higher in CL samples compared to controls. CONCLUSIONS: In addition to defining comprehensive immunological responses inside lesion tissues of CL patients, our study demonstrated the presence of Th17 and Treg cells in CL caused by L. tropica.

IL-27 and IL-21 are associated with T cell IL-10 responses in human visceral leishmaniasis.

IL-10 is believed to underlie many of the immunologic defects in human visceral leishmaniasis (VL). We have identified CD4(+)CD25(-)Foxp3(-) T cells as the major source of IL-10 in the VL spleen. IL-27, a member of the IL-6/IL-12 cytokine family, has been shown to promote development of IL-10-producing T cells, in part by upregulating their production of autocrine IL-21. We investigated whether IL-27 and IL-21 are associated with human VL. IL-27 was elevated in VL plasma, and at pretreatment, spleen cells showed significantly elevated mRNA levels of both IL-27 subunits, IL-27p28 and EBI-3, as well as IL-21, compared with posttreatment biopsies. CD14(+) spleen cells were the main source of IL-27 mRNA, whereas CD3(+) T cells were the main source of IL-21. IL-27 mRNA could be strongly upregulated in normal donor macrophages with IFN-γ and IL-1ß, conditions consistent with those in the VL spleen. Last, a whole-blood assay revealed that most VL patients could produce Ag-specific IFN-γ and IL-10 and that the IL-10 could be augmented with recombinant human IL-21. Thus, proinflammatory cytokines acting on macrophages in the VL spleen have the potential to upregulate IL-27, which in turn can induce IL-21 to expand IL-10-producing T cells as a mechanism of feedback control.

Combined emergency abdominal aortic aneurysm repair and valve replacement in a patient with severe aortic stenosis.

Simultaneous open surgery has been advocated in the elective management of abdominal aortic aneurysm patients with significant ischemic heart disease, as staged procedures risk worsening myocardial ischemia or aortic rupture, depending on which is the first intervention. The argument for combined aneurysm and valve repair is less established. We describe the case of a 70-year-old female who while awaiting aortic valve replacement suffered rupture of an abdominal aortic aneurysm. The patient was successfully managed with emergency combined open abdominal aortic aneurysm repair and open aortic valve replacement. We would advocate that such a strategy be considered as a salvage technique in similarly difficult management dilemmas.

BdSLW-11: Dataset of Bangladeshi sign language words for recognizing 11 daily useful BdSL words.

The dataset of Bangladeshi sign language words (BdSLW) is rare. Though there are lots of datasets of BdSL sign alphabets, numbers, or characters, there are not enough datasets of sign words. This is the first dataset about sign words of BdSL according to the author(s) knowledge. So, this dataset is developed by collecting data from people. This is an image dataset. This dataset is a collection of 1105 images of sign words. A total of 11 sign word categories are selected which are important and daily use in our life. As this is an image dataset, so the images of sign words are taken by camera from the sign users of Bangladesh. Authors have gone to the individuals of sign users and captured images from them with their permission. Then the images are analyzed and segmented into the images which have quality such as no background, clear, bright, etc. This dataset is used for recognizing BdSL sign words.

Modelling the impact of changes to abdominal aortic aneurysm screening and treatment services in England during the COVID-19 pandemic.

BACKGROUND: The National Health Service (NHS) abdominal aortic aneurysm (AAA) screening programme (NAAASP) in England screens 65-year-old men. The programme monitors those with an aneurysm, and early intervention for large aneurysms reduces ruptures and AAA-related mortality. AAA screening services have been disrupted following COVID-19 but it is not known how this may impact AAA-related mortality, or where efforts should be focussed as services resume. METHODS: We repurposed a previously validated discrete event simulation model to investigate the impact of COVID-19-related service disruption on key outcomes. This model was used to explore the impact of delayed invitation and reduced attendance in men invited to screening. Additionally, we investigated the impact of temporarily suspending scans, increasing the threshold for elective surgery to 7cm and increasing drop-out in the AAA cohort under surveillance, using data from NAAASP to inform the population. FINDINGS: Delaying invitation to primary screening up to two years had little impact on key outcomes whereas a 10% reduction in attendance could lead to a 2% lifetime increase in AAA-related deaths. In surveillance patients, a 1-year suspension of surveillance or increase in the elective threshold resulted in a 0.4% increase in excess AAA-related deaths (8% in those 5-5.4cm at the start). Longer suspensions or a doubling of drop-out from surveillance would have a pronounced impact on outcomes. INTERPRETATION: Efforts should be directed towards encouraging men to attend AAA screening service appointments post-COVID-19. Those with AAAs on surveillance should be prioritised as the screening programme resumes, as changes to these services beyond one year are likely to have a larger impact on surgical burden and AAA-related mortality.

Osmolytes in vaccine production, flocculation and storage: a critical review.

Small molecule osmolytes, responsible for protecting stresses have long been known to rescue proteins and enzymes from loss of function. In addition to protecting macromolecules integrity, many osmolytes also act as potential antioxidant and also help to prevent protein aggregation, amyloid formation or misfolding, and therefore are considered promising molecules for neurodegenerative and many other genetic diseases. Osmolytes are also known to be involved in the regulation of several key immunological processes. In the present review we discuss in detail the effect of these compounds on important aspects of vaccines i.e., increasing the efficiency, production and purification steps. The present review therefore will help researchers to make a better strategy in vaccine production to formulation by incorporating specific and appropriate osmolytes in the processes.

Analysis of dengue specific memory B cells, neutralizing antibodies and binding antibodies in healthy adults from India.

BACKGROUND: The Indian population is facing highest dengue burden worldwide supporting an urgent need for vaccines. For vaccine introduction, evaluation and interpretation it is important to gain a critical understanding of immune memory induced by natural exposure. However, immune memory to dengue remains poorly characterized in this region. METHODS: We enumerated levels of dengue specific memory B cells (MBC), neutralizing (NT) and binding antibodies in healthy adults (n=70) from New Delhi. RESULTS: NT-antibodies, binding antibodies and MBC were detectable in 86%, 86.56% and 81.63% of the subjects respectively. Among the neutralizing positive subjects, 58%, 27%, 5% and 10% neutralized all four, any three, any two and any one dengue serotypes respectively. The presence of the neutralizing antibodies was associated with the presence of the MBC and binding antibodies. However, a massive interindividual variation was observed in the levels of the neutralizing antibodies (range, <1:50-1:30,264), binding antibodies (range, 1:3,000-1:134,000,) as well as the MBC (range=0.006%-5.05%). CONCLUSION: These results indicate that a vast majority of the adults are immune to multiple dengue serotypes and show massive interindividual variation in neutralizing/binding antibodies and MBCs - emphasizing the importance of monitoring multiple parameters of immune memory in order to properly plan, evaluate and interpret dengue vaccines.

Cutaneous leishmaniasis in Nepal: Leishmania major as a cause.

Nepal is endemic for visceral leishmaniasis; however, recently a solitary report of cutaneous leishmaniasis (CL) was recorded. The present report describes a CL case in a Nepalese woman, initially referred as a case of basal cell carcinoma. Histopathological examination, culture and PCR analysis of lesions revealed it to be a case of CL. Molecular methods, including kDNA PCR, ITS-1 PCR-RFLP and sequence analysis, revealed the species as Leishmania major. The patient was cured with sodium stibogluconate. This report suggests that the extent to which L. major causes CL in the Indian subcontinent needs to be monitored.

Evidence for involvement of Th17 type responses in post kala azar dermal leishmaniasis (PKDL).

BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis, caused by Leishmania donovani, constitutes an important reservoir for the parasite. Parallel functioning of counter acting immune responses (Th1/Th2) reflects a complex immunological scenario, suggesting the involvement of additional regulatory molecules in the disease pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, human cytokine/chemokine/receptor specific cDNA array technique was employed to identify modulations in gene expression of host immuno-determinants during PKDL, followed by evaluation of Th17 type responses by analyzing mRNA and protein expression of Th17 markers (IL-23, IL-17, RORγt) and performing functional assays using Leishmania antigen (TSLA) or recombinant (rec)IL-17. Array analysis identified key immuno-regulatory molecules including cytokines (TNF-α, IFN-γ, IL-10, IL-17), chemokines (MCP-1, MIP-1α), apoptotic molecules (FasL, TRAIL, IRF-1) and receptors (CD40, Fas). Up regulation in lesional expression of Th17 markers was observed during PKDL compared to control (IL-17 and IL-23, P = 0.0008; RORγt, P = 0.02). In follow-up samples, chemotherapy significantly down regulated expression of all markers. In addition, lesional expression of IL-17 was confirmed at protein level by Immuno-histochemistry. Further, systemic presence of Th17 responses (IL-17 and IL-23) was observed in plasma samples from PKDL patients. In functional assays, TSLA stimulated the secretion of IL-17 and IL-23 from PBMCs of PKDL patients, while recIL-17 enhanced the production of TNF-α as well as nitric oxide (NO) in PKDL compared to control (TNF-α, P = 0.0002; NO, P = 0.0013). Further, a positive correlation was evident between lesional mRNA expression of IL-17 and TNF-α during PKDL. CONCLUSION/SIGNIFICANCE: The results highlight key immune modulators in PKDL and provide evidence for the involvement of Th17 type responses in the disease pathogenesis.

Foxp3 and IL-10 expression correlates with parasite burden in lesional tissues of post kala azar dermal leishmaniasis (PKDL) patients.

BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL), a sequel to visceral leishamaniasis (VL) in 5-15% cases, constitutes a parasite reservoir important in disease transmission. The precise immunological cause of PKDL outcome remains obscure. However, overlapping counter regulatory responses with elevated IFN-γ and IL-10 are reported. METHODOLOGY/PRINCIPAL FINDINGS: Present study deals with ex-vivo mRNA and protein analysis of natural regulatory T cells (nTreg) markers (Foxp3, CD25 and CTLA-4) and IL-10 levels in lesion tissues of PKDL patients at pre and post treatment stages. In addition, correlation of nTreg markers and IL-10 with parasite load in tissue lesions was investigated. mRNA levels of nTreg markers and IL-10 were found significantly elevated in pre-treatment PKDL cases compared to controls (Foxp3, P = 0.0009; CD25 & CTLA-4, P<0.0001; IL-10, P<0.0001), and were restored after treatment. Analysis of nTreg cell markers and IL-10 in different clinical manifestations of disease revealed elevated levels in nodular lesions compared to macules/papules. Further, Foxp3, CD25 and IL-10 mRNA levels directly correlated with parasite load in lesions tissues. CONCLUSION/SIGNIFICANCE: Data demonstrated accumulation of nTreg cells in infected tissue and a correlation of both IL-10 and nTreg levels with parasite burden suggesting their role in disease severity in PKDL.

Immune response following miltefosine therapy in a patient with post-kala-azar dermal leishmaniasis.

We report a case of post-kala-azar dermal leishmaniasis in which real-time PCR was exploited to measure changes in cytokine transcripts in lesion tissue before and after oral miltefosine treatment. Unlike antimonial therapy elevated levels of IFNgamma transcripts were noted, whereas TNFalpha, IL-10 and transforming growth factor-beta declined similar to that observed after therapy with antimonials. A significant increase in IFNgamma and CD40 levels seen after miltefosine therapy could enhance parasite clearance. The patient remained normal after 18 months of follow-up.

Circulating nitric oxide and C-reactive protein levels in Indian kala azar patients: correlation with clinical outcome.

Interferon gamma (IFN-gamma) and nitric oxide (NO) are the major players of the host defense against Leishmania. In the present study circulating levels of IFN-gamma, NO, interleukin (IL)-6 and C-reactive protein (CRP) were compared in kala azar (KA), post-kala azar dermal leishmaniasis (PKDL) and healthy controls. A significantly elevated level of these parameters was evident in KA compared to PKDL or control. Further, significantly elevated levels of IFN-gamma, NO and CRP were observed in sodium antimony gluconate (SAG) unresponsive cases compared to responsive cases. In PKDL cases, NO was significantly elevated while other parameters were comparable to control. At post-treatment stage, KA patients showed a significant decrement in all the parameters, however, IL-6 and CRP remained above control level. Hence, data implies that the parasites survive in spite of the presence of effector molecules, and the excessive release of IFN-gamma and NO could be associated with the progression of the disease.

Successful endovascular repair of a ruptured abdominal aortic aneurysm in a patient with unfavorable anatomy.

Endovascular repair of an abdominal aortic aneurysm (AAA) offers hope of improved outcomes in patients presenting with acute rupture. However, a high proportion of such patients have unfavorable proximal neck anatomy and are not suitable for treatment with conventional endografts. Fenestrated endografts overcome the problem of a short proximal neck, but at present their deployment is time consuming and therefore not easily applicable to a ruptured AAA. In this case report, the authors describe a hybrid device (a composite thoracic and infrarenal stent graft) that was able to overcome the problem of a short wide proximal neck in a patient with a ruptured AAA.

CT-guided embolization of an isolated internal iliac artery aneurysm 8 years after AAA repair.

PURPOSE: To report the use of computed tomographic (CT) guidance for percutaneous treatment of an isolated internal iliac artery (IIA) aneurysm after open aortic aneurysm repair. CASE REPORT: A 74-year-old man presented with an isolated IIA aneurysm 8 years after an open repair of his abdominal aortic aneurysm. In view of his diabetes, hypertension, and chronic renal impairment, an endovascular technique was selected. However, because of previous ligation of the internal iliac origin, a transarterial approach could not be used. The proximity of the aneurysm to the anterior abdominal wall allowed us to gain access to it percutaneously using CT guidance to perform embolization. CONCLUSION: CT-guided direct puncture of isolated IIA aneurysms adds to the current armamentarium of minimally invasive modalities. It is a technique that can be applied to isolated IIA aneurysms that develop subsequent to AAA repair or appear in cases where intra-arterial access is not possible.

Elevated levels of interferon-gamma, interleukin-10, and interleukin-6 during active disease in Indian kala azar.

We have evaluated levels of 6 cytokines in sera of 35 patients of kala azar (KA), 29 post kala azar dermal leishmaniasis (PKDL), and 18 healthy controls using cytometric bead array technology. Results indicated significantly high levels of interferon gamma (IFN-gamma), interleukin (IL)-10, and IL-6 during active KA, while tumor necrosis factor alpha (TNF-alpha), IL-2, and IL-4 were minimal. Serum level of cytokines in PKDL was comparable to the controls while TNF-alpha was significantly elevated compared to KA or control. At post-treatment stage, KA patients showed a significant decrement in the levels of IFN-gamma, IL-10, and IL-6; however, IL-6 remained significantly elevated above control levels. Further, comparison of cytokine levels in children and adults revealed elevated level of IL-10 in pediatric cases. SAG unresponsive cases showed significantly elevated levels of IFN-gamma in comparison with the responsive cases. The results depict that type1 response is not depressed during active KA and suggest the possibility that unresponsiveness to type1 stimuli may prevail.

Extra-adrenal pheochromocytoma: an unusual cause of deep vein thrombosis.

We report a case of extra-adrenal pheochromocytoma within the organ of Zuckerkandl that presented initially with a left iliofemoral deep venous thrombosis (DVT). At the time of presentation, the DVT was thought to be idiopathic as no underlying cause was detected. Subsequently, because of a series of medical events, the patient was further investigated. This led to a diagnosis of extra-adrenal pheochromocytoma. We discuss the management of patients presenting with DVT, the nature of pheochromocytoma within the organ of Zuckerkandl, and problems relating to its diagnosis.