Application of T cell receptor (TCR) repertoire analysis for the advancement of cancer immunotherapy

T cell receptor (TCR) sequencing has emerged as a powerful new technology in analysis of the host–tumour interaction. The advances in NextGen sequencing technologies, coupled with powerful novel bioinformatic tools, allow quantitative and reproducible characterisation of repertoires from tumour and blood samples from an increasing number of patients with a variety of solid cancers. In this review, we consider how global metrics such as T cell clonality and diversity can be extracted from these repertoires and used to give insight into the mechanism of action of immune checkpoint blockade. Furthermore, we explore how the analysis of TCR overlap between repertories can help define spatial and temporal heterogeneity of the anti-tumoural immune response. Finally, we review how analysis of TCR sequence and structure, either of individual TCRs or from sets of related TCRs can be used to annotate the antigenic specificity, with important implications for the development of personalised adoptive cellular immunotherapies

Role of extracorporeal shockwave therapy and injectable corticosteroids in the treatment of lateral epicondylitis: a comparative study of 100 patients

Background: Even though considered to be self-limiting, lateral epicondylitis (tennis elbow) can cause significant impediment in professional and activities of daily living. A safe and minimally invasive procedure that will enable patients to return to their daily activities as soon as possible should be advocated in the management of this condition. The aim of the present study was to investigate the role of extracorporeal shock wave therapy (ESWT) and injectable corticosteroids in the treatment of lateral epicondylitis with the secondary objective of comparing the difference in pain relief and functional improvement in patients treated with both modalities.Methods: A cross sectional analytical study was conducted over an 18 month period.100 patients were randomized into two groups, A (51 patients) who received three sessions of ESWT on weekly intervals and B (49 patients) who received two intra-lesional injections of 1ml of methylprednisolone and 2% lignocaine on weekly intervals. The patients were followed up at 3 weeks, 6 weeks and 6 months after the interventions. Subjective and objective improvements were measured using visual analogue score (VAS) and Patient Rated Tennis Elbow Evaluation Score (PRTEE).Results: The mean VAS in both groups reduced from 8.47 and 8.53 to 2.51 and 1.67 respectively at the end of the follow up (p <0.001) .The mean PRTEE score in Group A reduced from 80.59 to 26.53 (p<0.001) and Group B from 82.76 to 13.59 (p<0.05). In Group A (ESWT), the average reduction In PRTEE Score at the end of follow up was 54.06 and Group B (steroids) was 69.16. The difference was found to be statistically significant (p<0.001) favouring steroid injections.Conclusions: Both ESWT and steroid injections were found to be effective in producing symptomatic pain relief and improving the functional disability in the management of lateral epicondylitis. The comparison of both modalities showed a statistically significant improvement in pain and functional disability in favour of steroids at a short duration of follow up i.e., 03 weeks, 06 weeks and 06 months.

Interposition arthroplasty: an epochal event in a case of bilateral post burn contracture of elbow

A 21 year old female, suffered accidental burns in April 2008 resulting in severe soft tissue contractures and bony ankylosis of both elbows. She was disabled with both nonfunctional upper extremities and reported to our center with deformity and dysfunction of both elbows for past 02 years. On evaluation her elbows were fixed in 40° flexion on right side and 30° flexion on left side. She was completely dependent on her mother for her daily activities like feeding and hygiene care, though she had acceptable wrist and hand function. She was managed with interposition arthroplasty with ipsilateral autogenous tensor fascia lata graft on both elbows. At 5 year follow-up, she has pain free elbows with functional range of motion and no neurovascular deficits. She is able to use both upper extremities for all activities of daily living. Most importantly she is independent and has taken up a job for her livelihood

Correlation between hematological parameters, blood urea level and mortality of COVID-19 patients.

Aim: Present study was aimed to analyze difference of hematological parameters and blood urea level between Recovered and Dead cases of COVID-19. Material & Methods: A hospital based study was undertaken wherein hematological parameters and blood urea level of 65 cases were analyzed. Results: Recovered patients, 16 (42.1%) showed higher levels of neutrophils with corresponding 22 (57.9%) patients showing normal level of lymphocytes, 25 (65.7%) with normal hemoglobin and 35 (92%) with normal blood urea. On other hand, among 27 Died cases, 26 (96.2%) showed higher counts of neutrophils, 1 patient showed normal lymphocytes (3.8%) and 26 (96.2%) with low count of lymphocytes. Conclusion: In majority of cases, recovered patients showed normal range of lymphocytes (20-45%), hemoglobin and blood urea levels, whereas mortality was observed associated with deficiency of lymphocytes (except one patient all belo

Binaries and Globular Cluster Dynamics

We summarize the results of recent theoretical work on the dynamical evolution of globular clusters containing primordial binaries. Even a very small initial binary fraction (e.g., 10%) can play a key role in supporting a cluster against gravothermal collapse for many relaxation times. Inelastic encounters between binaries and single stars or other binaries provide a very significant energy source for the cluster. These dynamical interactions also lead to the production of large numbers of exotic systems such as ultracompact X-ray binaries, recycled radio pulsars, double degenerate systems, and blue stragglers. Our work is based on a new parallel supercomputer code implementing Henon's Monte Carlo method for simulating the dynamical evolution of dense stellar systems in the Fokker-Planck approximation. This new code allows us to calculate very accurately the evolution of a cluster containing a realistic number of stars (N ~ 10^5 - 10^6) in typically a few hours to a few days of computing time. The discrete, star-by-star representation of the cluster in the simulation makes it possible to treat naturally a number of important processes, including single and binary star evolution, all dynamical interactions of single stars and binaries, and tidal interactions with the Galaxy.Comment: 15 pages, to appear in `The Influence of Binaries on Stellar Population Studies', ed. D. Vanbeveren (Kluwer

Conceptualizing pathways linking women's empowerment and prematurity in developing countries.

BackgroundGlobally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity.MethodsThe key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors.ResultsThere is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving access to and receipt of recommended health services during pregnancy and delivery to help prevent prematurity and improve survival of premature babies.ConclusionsWomen's empowerment is an important distal factor that affects prematurity through several intervening factors. Improving women's empowerment will help prevent prematurity and improve survival of preterm babies. Research to empirically show the links between women's empowerment and prematurity is however needed

Evaluation of Diagnostic Accuracy, Feasibility and Client Preference for Rapid Oral Fluid-Based Diagnosis of HIV Infection in Rural India

BACKGROUND: Oral fluid-based rapid tests are promising for improving HIV diagnosis and screening. However, recent reports from the United States of false-positive results with the oral OraQuick® ADVANCE HIV1/2 test have raised concerns about their performance in routine practice. We report a field evaluation of the diagnostic accuracy, client preference, and feasibility for the oral fluid-based OraQuick® Rapid HIV1/2 test in a rural hospital in India. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional, hospital-based study was conducted in 450 consenting participants with suspected HIV infection in rural India. The objectives were to evaluate performance, client preference and feasibility of the OraQuick® Rapid HIV-1/2 tests. Two Oraquick® Rapid HIV1/2 tests (oral fluid and finger stick) were administered in parallel with confirmatory ELISA/Western Blot (reference standard). Pre- and post-test counseling and face to face interviews were conducted to determine client preference. Of the 450 participants, 146 were deemed to be HIV sero-positive using the reference standard (seropositivity rate of 32% (95% confidence interval [CI] 28%, 37%)). The OraQuick test on oral fluid specimens had better performance with a sensitivity of 100% (95% CI 98, 100) and a specificity of 100% (95% CI 99, 100), as compared to the OraQuick test on finger stick specimens with a sensitivity of 100% (95% CI 98, 100), and a specificity of 99.7% (95% CI 98.4, 99.9). The OraQuick oral fluid-based test was preferred by 87% of the participants for first time testing and 60% of the participants for repeat testing. CONCLUSION/SIGNIFICANCE: In a rural Indian hospital setting, the OraQuick® Rapid- HIV1/2 test was found to be highly accurate. The oral fluid-based test performed marginally better than the finger stick test. The oral OraQuick test was highly preferred by participants. In the context of global efforts to scale-up HIV testing, our data suggest that oral fluid-based rapid HIV testing may work well in rural, resource-limited settings

The Challenges of Institutionalizing Community-Level Social Accountability Mechanisms for Health and Nutrition: a Qualitative Study in Odisha, India

Background: India has been at the forefront of innovations around social accountability mechanisms in improving the delivery of public services, including health and nutrition. Yet little is known about how such initiatives are faring now that they are incorporated formally into government programmes and implemented at scale. This brings greater impetus to understand their effectiveness. This formative qualitative study focuses on how such mechanisms have sought to strengthen community-level nutrition and health services (the Integrated Child Development Services and the National Rural Health Mission) in the state of Odisha. It fills a gap in the literature on considering how such initiatives are running when institutionalised at scale. The primary research questions were ‘what kinds of community level mechanisms are functioning in randomly selected villages in 3 districts of state of Odisha' and 'how are they perceived to function by their members and frontline workers’

Comparison of Human Memory CD8 T Cell Responses to Adenoviral Early and Late Proteins in Peripheral Blood and Lymphoid Tissue

Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs) targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977) and late protein hexon (H-892) were compared in peripheral blood (PB) and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly higher frequency of P-977+CD8+ T cells compared to H-892+CD8+ T cells; this trend was reversed in PB. Tonsil epitope-specific CD8+ T cells expressed IFN-γ and IL-2 but not perforin or TNF-α, whereas PB T cells were positive for IFN-γ, TNF-α, and perforin. Tonsil epitope-specific T cells expressed lymphoid homing marker CCR7 and exhibited lower levels of the activation marker CD25 but higher proliferative potential than PB T cells. Finally, in parallel with the kinetics of mRNA expression, P-977-specific CTLs lysed targets as early as 8 hrs post infection. In contrast, H-892-specific CTLs did not kill unless infected fibroblasts were pretreated with IFN-γ to up regulate HLA class I antigens, and cytotoxicity was delayed until 16–24 hours. These data show that, in contrast to hexon CTLs, central memory type DNA polymerase CTLs dominate the lymphoid compartment and kill fibroblasts earlier after infection without requiring exogenous IFN-γ. Thus, use of CTLs targeted to both early and late Ad proteins may improve the efficacy of immunotherapy for life-threatening Ad disease in SCT recipients

Mortality profiles in a country facing epidemiological transition: An analysis of registered data

BACKGROUND: Sub-national analyses of causes of death and time-trends help to define public health policy priorities. They are particularly important in countries undergoing epidemiological transition like Peru. There are no studies exploring Peruvian national and regional characteristics of such epidemiological transition. We aimed to describe Peru's national and regional mortality profiles between 1996 and 2000. METHODS: Registered mortality data for the study period were corrected for under-registration following standardized methods. Main causes of death by age group and by geographical region were determined. Departmental mortality profiles were constructed to evaluate mortality transition, using 1996 data as baseline. Annual cumulative slopes for the period 1996-2000 were estimated for each department and region. RESULTS: For the study period non-communicable diseases explained more than half of all causes of death, communicable diseases more than one third, and injuries 10.8% of all deaths. Lima accounted for 32% of total population and 20% of total deaths. The Andean region, with 38% of Peru's population, accounted for half of all country deaths. Departmental mortality predominance shifted from communicable diseases in 1996 towards non-communicable diseases and injuries in 2000. Maternal and perinatal conditions, and nutritional deficiencies and nutritional anaemia declined markedly in all departments and regions. Infectious diseases decreased in all regions except Lima. In all regions acute respiratory infections are a leading cause of death, but their proportion ranged from 9.3% in Lima and Callao to 15.3% in the Andean region. Tuberculosis and injuries ranked high in Lima and the Andean region. CONCLUSION: Peruvian mortality shows a double burden of communicable and non-communicable, with increasing importance of non-communicable diseases and injuries. This challenges national and sub-national health system performance and policy making