Equitable inclusion of diverse populations in oncology clinical trials: deterrents and drivers.

The burden of cancer exerts a disproportionate impact across different regions and population subsets. Disease-specific attributes, coupled with genetic and socioeconomic factors, significantly influence cancer treatment outcomes. Precision oncology promises the development of safe and effective options for specific ethnic phenotypes and clinicodemographic profiles. Currently, clinical trials are concentrated in resource-rich geographies with younger, healthier, white, educated, and empowered populations. Vulnerable and marginalized people are often deprived of opportunities to participate in clinical trials. Despite consistent endeavors by regulators, industry, and other stakeholders, factors including diversity in trial regulations and patient and provider-related cultural, logistic, and operational barriers limit the inclusiveness of clinical trials. Understanding and addressing these constraints by collaborative actions involving regulatory initiatives, industry, patient advocacy groups, community engagement in a culturally sensitive manner, and designing and promoting decentralized clinical trials are vital to establishing a clinical research ecosystem that promotes equity in the representation of population subgroups.

Insulin Glargine in Type 1 Diabetes Mellitus: A Review of Clinical Trials and Real-world Evidence Across Two Decades.

BACKGROUND: Over the past two decades, insulin glargine 100 U/mL (Gla-100) has emerged as the "standard of care" basal insulin for the management of type 1 diabetes mellitus (T1DM). Both formulations, insulin glargine 100 U/mL (Gla-100) and glargine 300 U/mL (Gla- 300) have been extensively studied against various comparator basal insulins across various clinical and real-world studies. In this comprehensive article, we reviewed the evidence on both insulin glargine formulations in T1DM across clinical trials and real-world studies. METHODS: Evidence in T1DM for Gla-100 and Gla-300 since their approvals in 2000 and 2015, respectively, were reviewed. RESULTS: Gla-100 when compared to the second-generation basal insulins, Gla-300 and IDeg-100, demonstrated a comparable risk of overall hypoglycemia, but the risk of nocturnal hypoglycemia was higher with Gla-100. Additional benefits of Gla-300 over Gla-100 include a prolonged (>24- hours) duration of action, a more stable glucose-lowering profile, improved treatment satisfaction, and greater flexibility in the dose administration timing. CONCLUSION: Both glargine formulations are largely comparable to other basal insulins in terms of glucose-lowering properties in T1DM. Further, risk of hypoglycemia is lower with Gla-100 than Neutral Protamine Hagedorn but comparable to insulin detemir.

Legumes from the Paleocene sediments of India and their ecological significance.

During the early Paleogene, greenhouse gases created warm global climates. These warm climates redistributed the habitat of marine and terrestrial biota globally. Understanding the ecology of biotas under extremely warm climates is important to decipher their behavior in future climate warming. Here we report two new legume fossils (Leguminocarpum meghalayensis Bhatia, Srivastava et Mehrotra sp. nov., and Parvileguminophyllum damalgiriensis Bhatia, Srivastava et Mehrotra sp. nov.) from the late Paleocene sediments of Tura Formation of Meghalaya, northeast India. Globally, the Paleocene legume fossil records indicate that legumes most likely immigrated to India from Africa via the Ladakh-Kohistan Arc during the early Paleogene. Moreover, previously reconstructed climate data from the Tura Formation indicate that legumes were well adapted to a warm seasonal climate with monsoon rains.

Paleogene Ficus leaves from India and their implications for fig evolution and diversification.

PREMISE: Ficus is a scientifically and economically important genus with abundant fossil records from the Paleocene to Pleistocene, but with an intriguing early evolutionary history that remains unresolved. Here, the foliage of three well-preserved figs is described from the early Paleogene succession of the Gurha mine, Rajasthan, India. These fossils provide new morphological data that strengthens our understanding of the past occurrences of Ficus and, alongside all validly published records of fossil figs, helps to trace the evolutionary history of figs. METHODS: Fossils were identified and described by comparison with their closest modern analogs using the Nearest Living Relative (NLR) technique. Validated fig records are listed and categorized into six geological time frames. Modern precipitation data for the current distributions of NLRs were downloaded from the Climatic Research Unit Timeseries. RESULTS: Fossil leaves assigned to three new species Ficus paleodicranostyla, F. paleovariegata, and F. paleoauriculata closely resemble their modern analogs based on leaf morphology. Reliable fossil records were used to hypothesize historical fig distributions and paleodispersal pathways. Precipitation data suggest higher precipitations at the fossil locality during the early Paleogene than at present. CONCLUSIONS: The fossils described herein supplement fig fossil records known from other regions indicating that figs were widely diverse across low latitudes by the early Paleogene. These data support a Eurasian origin for figs, highlight a pivotal role for the Indian subcontinent during the early phase of fig diversification, and depict a perhumid-to-humid climate with high rainfall concordant with paleoclimate evidence from the Gurha mine.

Unravelling the utility of modern sulfonylureas from cardiovascular outcome trials and landmark trials: expert opinion from an international panel.

AIM: The primary objective of this review is to develop practice-based expert group opinions on the cardiovascular (CV) safety and utility of modern sulfonylureas (SUs) in cardiovascular outcome trials (CVOTs). BACKGROUND: The United States Food and Drug Administration issued new guidance to the pharmaceutical industry in 2008 regarding the development of new antihyperglycemic drugs. The guidance expanded the scope for the approval of novel antihyperglycemic drugs by mandating CVOTs for safety. A few long-term CVOTs on dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors have been completed, while others are ongoing. SUs, which constitute one of the key antihyperglycemic agents used for the management of type 2 diabetes mellitus (T2DM), have been used as comparator agents in several CVOTs. However, the need for CVOTs on modern SUs remains debatable. In this context, a multinational group of endocrinologists convened for a meeting and discussed the need for CVOTs of modern SUs to evaluate their utility in the management of patients with T2DM. At the meeting, CVOTs of modern SUs conducted to date and the hypotheses derived from the results of these trials were discussed. REVIEW RESULTS: The expert group analyzed the key trials emphasizing the CV safety of modern SUs and also reviewed the results of various CVOTs in which modern SUs were used as comparators. Based on literature evidence and individual clinical insights, the expert group opined that modern SUs are cardiosafe and that since they have been used as comparators in other CVOTs, CVOTs of SUs are not required. CONCLUSION: Modern SUs can be considered a cardiosafe option for the management of patients with diabetes mellitus and CV disease; thus CVOTs among individuals with T2DM are not required.

Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel.

AIM: The primary objective of this review is to develop a practice-based expert group opinion on the role of precision medicine with a specific focus on sulfonylureas (SUs) in diabetes management. BACKGROUND: The clinical etiology, presentation and complications of diabetes vary from one patient to another, making the management of the disease challenging. The pre-eminent feature of diabetes mellitus (DM) are chronically elevated blood glucose concentrations; however, in clinical practice, the exclusion of autoimmunity, pregnancy, pancreatic disease or injury and rare genetic forms of diabetes is crucial. Within this framework, precision medicine provides unique insights into the risk factors and natural history of DM. Precision medicine goes beyond genomics and encompasses patient-centered care, molecular technologies and data sharing. Precision medicine has evolved in the field of diabetology. It has helped improve the efficacy of SUs, a class of drugs, which have been effectively used in the management of diabetes mellitus for decades, and it has enabled the expansion of SUs use in diabetes patients with genetic mutations. REVIEW RESULTS: After due discussions, the expert group analyzed studies that focused on the use of SUs in diabetes patients with genomic variations and rare mutations. The expert group opined that SUs are important glucose-lowering drugs and that precision medicine helps in improving the efficacy of SUs by matching them to those patients who will benefit most. CONCLUSION: Precision medicine opens new vistas for the effective use of SUs in unexpected patient populations, such as those with genetic mutations.

Fixed-dose combination in management of type 2 diabetes mellitus: Expert opinion from an international panel.

Type 2 diabetes mellitus (T2DM) is a progressive disease with multifactorial etiology. The first-line therapy includes monotherapy (with metformin), which often fails to provide effective glycemic control, necessitating the addition of add-on therapy. In this regard, multiple single-dose agents formulated as a single-dose form called fixed-dose combinations (FDCs) have been evaluated for their safety, efficacy, and tolerability. The primary objective of this review is to develop practice-based expert group opinion on the current status and the causes of concern regarding the irrational use of FDCs, in Indian settings. After due discussions, the expert group analyzed the results from several clinical evidence in which various fixed combinations were used in T2DM management. The panel opined that FDCs (double or triple) improve patient adherence, reduce cost, and provide effective glycemic control and, thereby, play an important role in the management of T2DM. The expert group strongly recommended that the irrational metformin FDC's, banned by Indian government, should be stopped and could be achieved through active participation from the government, regulatory bodies, and health ministry, and through continuous education of primary care physicians and pharmacists. In T2DM management, FDCs play a crucial role in achieving glycemic targets effectively. However, understanding the difference between rational and irrational FDC combinations is necessary from the safety, efficacy, and tolerability perspective. In this regard, primary care physicians will have to use a multistep approach so that they can take informed decisions.

Risk factors of breast cancer and breast self-examination in early detection: systematic review of awareness among Indian women in community and health care professionals.

BACKGROUND: This review aims at evaluating the awareness of risk factors for breast cancer (BC) and the knowledge of breast self-examination (BSE) among Indian women and health care professionals (HCPs). METHODS: Literature search was conducted on multiple bibliographic databases with restrictions applied to English peer-reviewed journals. RESULTS: We reviewed 37 published articles on this topic. The mean level of awareness for risk factors such as age at menarche (22.3%), age at menopause (27.1%) and late first pregnancy (34.6%) was low in community. The awareness was better among HCPs; however, there was still room for improvement.Knowledge of BSE varied from very poor (2%) to good (69.8%) in the community setting. The practice was similarly negligible (0%) to moderate (34.9%). Mean knowledge and practice of BSE in HCPs were 77.1 and 55.5%, respectively. A significant difference was noted in knowledge and practice of BSE between community and HCPs (P < 0.05). CONCLUSIONS: The present review highlights the low level of awareness regarding risk factors for BC and BSE in the community as well as HCPs. Though BSE is not the ideal modality, this seems to be the best alternative for resource-limited settings.

Association of smokeless tobacco and cerebrovascular accident: a systematic review and meta-analysis of global data.

BACKGROUND: The association of smokeless tobacco (SLT) with stroke has been dealt with in only a few reviews. The present meta-analysis aims to present the updated comprehensive summary risk of stroke in adult SLT users along with sub group analysis. METHODS: A systematic literature search for articles evaluating risk of stroke in SLT users was conducted. The study characteristics and risk estimates were extracted independently by two authors (RG and SG). Random-effect model was used to estimate the summary relative risks. RESULTS: The overall risk of stroke in SLT users was found to be significantly higher (1.17, 95% CI 1.04­1.30) compared to non-users, especially for users in Southeast Asian region. The results remained unchanged even after strict adjustment for smoking (1.18, 95% CI 1.04­1.32). SLT users had 1.34 times or 13.4% higher risk of fatal stroke, though risk of nonfatal stroke was not enhanced. Significantly higher risk of stroke was seen in users of chewing tobacco (1.35, 95% CI 1.20­1.50) in comparison to non-chewers. Gender-based analysis showed enhanced risk of fatal stroke in both male and female users. SLT-attributable fraction of fatal stroke was highest for India at 14.8%. CONCLUSION: The significant higher risk of stroke with SLT use, even after adjustment for smoking, emphasizes the imperative need to include SLT cessation advice for control and prevention of stroke.

Morphometric analysis of epithelial thickness and blood vessels in different grades of oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) is a common oral health problem in the Indian subcontinent. It is characterized by a juxtaepithelial inflammatory reaction followed by fibroelastic changes in the lamina propria. Traditionally, it is said to be associated with marked epidermal atrophy and decreased vasculature as the disease advances. OBJECTIVE: To assess the changes in epidermal thickness and mucosal vasculature in various stages of the disease. MATERIAL AND METHODS: Patients with histological diagnosis of OSF were included in the study. Demographic data and oral habits of each patient were collected. The severity of OSF was graded histologically according to Pindborg and Sirsat. Epithelial thickness and subepithelial blood vessel area, diameter and perimeter were measured and analysed using Image analysis software IMAGE PRO PLUS version 6.0. RESULTS: Thirty-five patients with OSF were studied. 25 (71.4%) were males and 10 (28.6%) were females with a male to female ratio of 1.3:1. Most patients were in the 31-40 yrs age group. The majority of patients (40%) chewed areca nut/dohra. Each grade of the disease was found to display either hyperplastic or atrophic epithelial changes. The mean blood vessel area, diameter and perimeter did not show any sustained change with the increasing severity (grade) of the disease. CONCLUSION: These findings question the role of ischaemia in the aetiopathogenesis of oral submucous fibrosis.

Phytogeographical implication of Bridelia Will. (Phyllanthaceae) fossil leaf from the late Oligocene of India.

BACKGROUND: The family Phyllanthaceae has a predominantly pantropical distribution. Of its several genera, Bridelia Willd. is of a special interest because it has disjunct equally distributed species in Africa and tropical Asia i.e. 18-20 species in Africa-Madagascar (all endemic) and 18 species in tropical Asia (some shared with Australia). On the basis of molecular phylogenetic study on Bridelia, it has been suggested that the genus evolved in Southeast Asia around 33±5 Ma, while speciation and migration to other parts of the world occurred at 10±2 Ma. Fossil records of Bridelia are equally important to support the molecular phylogenetic studies and plate tectonic models. RESULTS: We describe a new fossil leaf of Bridelia from the late Oligocene (Chattian, 28.4-23 Ma) sediments of Assam, India. The detailed venation pattern of the fossil suggests its affinities with the extant B. ovata, B. retusa and B. stipularis. Based on the present fossil evidence and the known fossil records of Bridelia from the Tertiary sediments of Nepal and India, we infer that the genus evolved in India during the late Oligocene (Chattian, 28.4-23 Ma) and speciation occurred during the Miocene. The stem lineage of the genus migrated to Africa via "Iranian route" and again speciosed in Africa-Madagascar during the late Neogene resulting in the emergence of African endemic clades. Similarly, the genus also migrated to Southeast Asia via Myanmar after the complete suturing of Indian and Eurasian plates. The emergence and speciation of the genus in Asia and Africa is the result of climate change during the Cenozoic. CONCLUSIONS: On the basis of present and known fossil records of Bridelia, we have concluded that the genus evolved during the late Oligocene in northeast India. During the Neogene, the genus diversified and migrated to Southeast Asia via Myanmar and Africa via "Iranian Route".

Postmenopausal osteoporosis: Our experience.

INTRODUCTION: There is very little published literature about experience with osteoporosis treatment from our country. MATERIALS AND METHODS: It is a retrospective analysis of first 50 patients enrolled in our clinic for osteoporosis. Postmenopausal women with T score of less than -2.5 or history suggestive fragility fracture with supportive bone mineral density (BMD) were included. Patients having hypercalcemia, abnormal renal function, myeloma and on long-term steroids were also excluded. RESULTS: Nearly 34% subjects were below the age of 60 years, 47% of subjects were between 60 and 70 years, whereas 18% were above 70 years. Nearly 6% had family history of osteoporosis s or history of osteoporotic fractures. Nearly 20% subjects had fracture prior to starting of any treatment. A total of 86% (40/46) had evidence of Vitamin D (VD) deficiency. Nearly 80% of patients were treated with bisphosphonates, 12% were treated with injectable bisphosphonates, and 8% were treated with teriperatide. Nearly 16% patients had duration of more than 5 years of experience with bisphosphonates. Follow up BMD was available in 25 subjects. BMD had improved significantly in 68% of subjects. In 24% the BMD was stable (the change was less than least significant change (LSC)). In 8% BMD had shown a significant decline while being on treatment. CONCLUSION: Postmenopausal osteoporosis occurs in relatively younger women in our country. Majority of them are VD deficient. Oral bisphosphonates is the most common used drug; it is fairly well tolerated and effective.

Associations of pretransplant serum albumin with post-transplant outcomes in kidney transplant recipients.

The association between pretransplant serum albumin concentration and post-transplant outcomes in kidney transplant recipients is unclear. We hypothesized that in transplant-waitlisted hemodialysis patients, lower serum albumin concentrations are associated with worse post-transplant outcomes. Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 8961 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (Odds ratio [OR]), respectively. Patients were 48 ± 13 years old and included 37% women and 27% diabetics. The higher pretransplant serum albumin was associated with lower mortality, graft failure and DGF risk even after multivariate adjustment for case-mix, malnutrition-inflammation complex and transplant related variable. Every 0.2 g/dL higher pretransplant serum albumin concentration was associated with 13% lower all-cause mortality (HR = 0.87 [95% confidence interval: 0.82-0.93]), 17% lower cardiovascular mortality (HR = 0.83[0.74-0.93]), 7% lower combined risk of death or graft failure (HR = 0.93[0.89-0.97]) and 4% lower DGF risk (OR = 0.96[0.93-0.99]). Hence, lower pretransplant serum albumin level is associated with worse post-transplant outcomes. Clinical trials to examine interventions to improve nutritional status in transplant-waitlisted hemodialysis patients and their impacts on post-transplant outcomes are indicated.

Hypovitaminosis D, neighborhood poverty, and progression of chronic kidney disease in disadvantaged populations.

In the United States, there are significant racial disparities in the incidence and prevalence of end-stage renal disease. The disparities are greatest for the Blacks and the magnitude of disparity is significantly greater than is evident from the incidence and prevalence data of end-stage renal disease - early stage chronic kidney disease is less common in Blacks and during that stage, mortality rate is significantly higher for that racial group. Recent studies have identified a genetic predisposition for non-diabetic renal disease among Blacks. However, genetic factors explain only part of the higher risk and the racial disparities are a result of a complex interplay of biology and sociology. Herein we focus on two factors and their role in explaining the higher risk for progression of chronic kidney disease among Blacks - one biologic (vitamin D deficiency) and one sociologic (neighborhood poverty). A greater Understanding of these factors is important in order to reduce the racial disparities in the United States.

Can we reduce the cardiovascular risk in peritoneal dialysis patients?

Patients with end-stage renal disease (ESRD), including those treated with peritoneal dialysis (PD), have a high risk for death, particularly from cardiovascular (CV) causes. Traditional risk factors for CV disease - like hypertension, diabetes, and dyslipidemia - are highly prevalent, often severe, and more difficult to treat in dialysis patients. Development of strategies for CV risk reduction in dialysis patients is complicated by epidemiologic studies that demonstrate paradoxical associations of some of the traditional risk factors with mortality. The difficulty is enhanced by either a paucity or negative findings of studies that have tested risk modification by targeting traditional CV risk factors. It is also clear that neither the prevalence nor the severity of traditional risk factors explains the substantial increase in risk for death associated with ESRD; this has led to identification of several nontraditional risk factors. Among these, systemic inflammation, disordered mineral metabolism, and long-term CV risk from infectious complications appear the most promising. However, the evidence in favor of the importance of these risk factors is largely limited to observational studies. In this review, we present a critical analysis of the literature to assist the clinician to reduce the CV risk of ESRD patients treated with PD.

Tobacco control legislation in India: past and present.

Beginning with the Cigarettes Act, 1975, a number of legislative strategies and programs to curb tobacco use have been implemented in India, with limited success. Currently, the Cigarettes and Other Tobacco Products Act, 2003, is designed to curb the use of tobacco in order to protect and promote public health. This review presents a critical appraisal of the current situation in its historical context.

Low Framingham risk score despite high prevalence of metabolic syndrome in asymptomatic North-Indian population.

BACKGROUND: Conflicting data exists regarding relationship between the Framingham risk score (FRS) and presence of metabolic syndrome (MS). Strong influence of age on FRS may further modify this relationship as prevalence of MS at younger age increases in South-Asian countries including India. However, only limited information is available about the prevalence of MS and its relationship with FRS in such populations at present. METHODS: Clinical examination and biochemical investigations were performed in 1905 asymptomatic office executives who underwent routine health check-up at a tertiary care centre in India during the year 2005. Diagnosis of MS and FRS were based on the modified National Cholesterol Education Program-Adult Treatment Panel III guidelines. RESULTS: Mean age of the subjects was 45.2 +/- 10.3 years and 71.8% were males. MS was present in 47.5% (905 of 1905) subjects. Overall, 76.8% patients with MS had 10-year cardiovascular (CV) risk < 10%, 20.6% had 10-20% risk and only 2.7% had > 20% risk according to FRS. In the lowest age-quartile, 95.9% patients had 10-year risk < 10%, 4.1% patients had 10-20% risk and none had > 20% risk. In contrast, in the highest age-quartile, less than half of the patients had 10-year risk <10% and nearly half had 10-20% risk of CV events. CONCLUSIONS: Although the prevalence of MS is markedly high in young asymptomatic Indians, majority have low 10-year risk of CV events as estimated by FRS. These findings necessitate continued emphasis on detection of MS in these populations as reliance on FRS alone may result in underestimation of CV risk in them.

Oral cytology revisited.

During the last decade, oral cytology has once again become the focus of scientific research. This new interest is due to the introduction of a cytobrush for cell collection as well as a computer-assisted analysis (Oral CDx). Although promising, the sensitivity and specificity of conventional oral brush cytology remains limited. To circumvent the problems and improve the accuracy, various adjunctive analytical methods have been attempted. DNA analysis, immunocytochemical and molecular analysis are suggested methodological cytology approaches to improve the validity of oral brush cytology. An increase in sensitivity (up to 100%) and specificity (up to 100%) of oral brush biopsy has been reported on localized pre-malignant and malignant lesions. Oral brush biopsy probably will not replace histopathology in the definitive diagnosis of oral cancer, but it might be valuable for the prevention of misdiagnosis of clinically doubtful oral lesions and for the monitoring of lesions that might proceed on to oral cancer.

Efficacy of teriparatide in increasing bone mineral density in postmenopausal women with osteoporosis--an Indian experience.

BACKGROUND AND OBJECTIVE: Osteoporosis is emerging as a leading cause of substantial morbidity in India, particularly in postmenopausal women. Teriparatide (recombinant human parathyroid hormone [1-34]) increases bone formation and improves bone microarchitecture, thereby reducing the risk of fractures. This study was conducted to evaluate the efficacy of teriparatide in increasing bone mineral density (BMD) in postmenopausal women with osteoporosis. MATERIAL AND METHODS: A randomised, prospective, multicentre, open-label, controlled study was conducted on 82 postmenopausal women with established osteoporosis. Patients were randomly divided into control and teriparatide groups, each group consisting of 41 patients. All the patients were supplemented with 1000 mg of elemental calcium and 500 IU of vitamin D throughout the study period of 180 days. Besides, teriparatide group patients were administered teriparatide 20 microg daily subcutaneously. Lumbar spine, femoral neck and total hip BMD, bone mineral content (BMC) and bone area were measured by dual energy x-ray absorptiometry (DXA) at baseline and at the end of 6 months of treatment. Bone biomarkers, such as serum bone specific alkaline phosphatase (BSAP) and serum osteocalcin (OC), representing bone formation, and urinary deoxypyridinoline (DPD), representing bone resorption were assessed at baseline, and at 3 and 6 months of treatment. RESULTS: During the study period, 9 patients (11%) were lost to follow-up--6 in control group (7.3%) and 3 in teriparatide group (3.7%). There was an excellent compliance to both oral and injectable medication. The investigational product teriparatide was well tolerated and there were no serious adverse events. In addition, there were no significant differences between the groups in the incidence of adverse events. The percentage of increase in lumbar spine BMD, which is the primary endpoint, was significantly (P < 0.001) higher in teriparatide group compared to that in control group (6.58% vs. 1.06%). Further, teriparatide significantly increased percentage of change in lumbar spine T-score (P < 0.001), BMC (P < 0.001) and bone area (P < 0.028) compared to control group at 6 months. Administration of teriparatide resulted in a significant percentage of increase in all the bone biomarkers in teriparatide group compared to control group patients at 3 and 6 months over baseline, thereby showing that there was a significant increase in bone turnover in teriparatide group of patients. CONCLUSION: These results show that teriparatide is an effective and safe drug in increasing the BMD and therefore, teriparatide provides yet another new therapeutic option for reducing the risk management of osteoporosis in postmenopausal women (clinicaltrials.gov number, NCT00500409).