A rare case of sirenomelia with total bilateral cleft lip palate and kyphoscoliosis

Sirenomelia, a rare congenital deformity, has fused lower limbs with variable combination of visceral anomalies. This condition is fatal within a day or two of birth so early antenatal detection and pregnancy termination is advocated. Antenatally it can be diagnosed by ultrasonography showing oligohydramnios, renal agenesis and fibulae positioned between the tibiae. A 24 years old Muslim primigravida came for first antenatal check up at 18 weeks of pregnancy. She didn’t turn up and came directly in emergency at 37 weeks in active labor and delivered a baby weighing 1.8 kg with a small sized placenta, complete bilateral cleft lip palate, Kyphoscoliosis and fused lower limbs upto ankles. Baby expired after 25 minutes of birth. Till now around 300 cases of Sirenomelia have been reported worldwide. All human cases of Sirenomelia have been found to be associated with variable degree of renal and urethral dysplasia or renal agenesis. External genitalia are affected, whereas gonads remain unaffected. In rare cases Sirenomelia is associated with upper body defects including cleft palate, cervical and upper thoracic vertebral abnormalities, pulmonary hypoplasia and cardiac defects

Evaluation of NS1, IgM ELISA and RT-PCR in diagnosis of dengue fever

Background: Dengue fever is a mosquito borne disease caused by flavivirus. Its cases are increasing in India with increasing mortality rate year by year hence, prompt and accurate diagnosis is necessary to prevent morbidity and mortality.Methods: In this study we enrolled 125 clinically suspected cases of dengue. All the collected samples were processed for RT-PCR, NS1 and IgM ELISA. We evaluated NS1 antigen ELISA alone, and combination of NS1 and IgM ELISA against RT-PCR.Results: Among 125 clinically suspected case 67 were positive by RT-PCR and 58 were negative. Sensitivity and Specificity of NS1 ELISA and NS1 with IgM ELISA (in combination) against RT-PCR were 83.58%, 94.82% and 95.55%, 79.31% respectively. (p<0.001).Conclusions: The NS1 ELISA alone was sufficient to detect acute phase of dengue fever, although, combination of NS1 and IgM proved to be most appropriate method for detection of acute as well as late phase of dengue fever

A study to know the prevalence of genital tuberculosis in female’s pulmonary tuberculosis patients and role of cartridge based nucleic acid amplification test in genital tuberculosis from North India

Background: Mycobacterium tuberculosis, most commonly, infects the lungs (pulmonary TB). Most cases of female genital TB (FGTB) are found in premenopausal women, theoretically because an atrophic endometrium provides a poor milieu for mycobacterial growth. Female genital TB generally occurs secondary to pulmonary (commonest) and more common in women with reproductive age group. The present study was designed to know the prevalence of genital tuberculosis in female’s pulmonary tuberculosis patients and role of cartridge based nucleic acid amplification test (CBNAAT) in genital tuberculosis.Methods: The patients of female’s pulmonary tuberculosis were picked up from out-patient and in patients’ section of the hospital at random. After ruling out pregnancy, the endometrial samples were collected from premenstrual endometrium (approximately 2-3 days before menstruation) and were subjected to histopathological examination and CBNAAT. Day 1 or 2 menstrual blood of unmarried females and patients not giving consent for biopsy were taken.Results: Seventy married and 20 unmarried patients of female pulmonary tuberculosis patients were evaluated for genital tuberculosis. The mean age of married population was 29±7.68 years. Cough with expectoration was most common respiratory symptoms and seen in 94% cases. In present study 89% cases were sputum positive and 11% were sputum negative. The percentage of non MDR and MDR TB cases were respectively 95.7 and 4.2% respectively. Among the gynecological symptom’s irregular menstruation, vaginal discharge and pelvic pain were present in 68, 60 and 52% of the study patients respectively. The diagnosis of FGTB by histopathology examination and CBNAAT were 28.6 and 17.1% respectively.Conclusions: In present study FGTB diagnosed by histopathology examination and CBNAAT were 28.6 and 17.1% respectively and which was statistically significant (c2=28.25 and p value=0.00001)

CHEMICAL PENETRATION ENHANCERS FOR TRANSDERMAL DRUG DELIVERY SYSTEM

In present scenario more than 70% of the drugs that are taken by oral route are found to be less effective as desired, to overcome this constraint Transdermal drug delivery system has emerged as an innovative area of research, this system helps in delivering the drugs and macromolecules through skin into systemic circulation. At present, the worldwide market of Transdermal patch has reached 2 billion pounds. Many drugs like Estrogen, Progestrone, Nitroglycerine, Clonodine etc. are fabricated in form of Transdermal patches due to its ability to deliver the drug in non-invasive manner and also to overcome the problems associated with oral route. Although the Transdermal patches deliver the drug at predetermined rate1, the partitioning of drug from the system to the skin and then penetration through different layers of skin can be altered by adding penetration enhancers that can be physical or chemical in nature. This article deals with the role of different chemicals that can be used as penetration enhancer. Keywords: Penetration enhancer, Layer of skin, Fatty alcohol and glyco

Impact of promoter region mutations of Pim-1 on c-Myc expression as well as survival in patients with breast cancer

Purpose: Breast cancer accounts for most cancer-related deaths in women with over 2.3 million new breast cancer cases diagnosed every year worldwide. Pim kinases are oncogenic proteins that play important role in various cancers. Pim-1 contains 1.7 kb promoter region without any transcriptional regulation, which is a characteristic feature of a housekeeping or constitutive promoter. This study was carried out to ascertain potential mutations in the promoter region of Pim-1 in breast cancer and also to comprehend the effect of mutations on c-Myc expression as well as on patients’ survival. Methods: Ninety-six Indian subjects with a first diagnosis of breast cancer who underwent surgery at our hospital were recruited in this study. Genomic DNA was isolated from whole blood, amplified and sequenced to identify potential mutations at the promoter region of Pim-1. FFPE sections were used to determine the c-Mycexpression in all the studied groups. Results: We observed a transversion (C>A at –502) and a deletion (–754Cdel) mutation in the promoter region with negligible association with tumor biology and c-Myc expression. Positive c-Myc expression was noted in almost 50% of the studied population with absolute nuclear staining or both cytoplasmic/nuclear staining. As per survival analysis, promoter region mutations did not modulate the patients’ survival, but patients with negative c-Myc expression had better disease-free survival compared with positive c-Myc expression. Conclusion: Our findings identified the presence of mutation in the promoter region of Pim-1 with negligible impact on c-Myc expression in patients with breast cance

Use of thiopurines in inflammatory bowel disease : an update

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.Peer reviewe

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. Results and Conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival