Reviews on Recent Clinical Trials - Volume 15, Issue 3, 2020

Background: In accordance with the scientific literature heavy alcohol consumption (>50g per day) represents a risk factor for several diseases development, including cancer. However, the oncogenic role of light alcohol drinking (<12.5g per day) is still unknown. Objective: To assess the scientific knowledge about light alcohol consumption and the risk of malignancy onset. Methods: To collect the scientific evidences regarding this topic the keywords “light alcohol drinking”, “light alcohol consumption” and “cancer”, were used. Papers published during the last 15 years were analyzed, in order to select the most recent evidence. Meta-analyses with well-defined levels of alcohol intake were included in the present review. Other studies that focused on biochemical, molecular and genetic aspects, as well as duplicate articles, were excluded. Results: Twenty-nine large, meta-analyses were included in this review. Light alcohol drinking was not associated with an increased risk of cancer occurrence, with the exception of breast and prostate cancer and melanoma. Furthermore, a possible protective role of light alcohol consumption on the development of bladder, kidney and ovarian cancer and Non Hodgkin Lymphoma was observed. Conclusion: Light alcohol drinking was not associated with the development of several malignancies, except for a light increase of melanoma, breast cancer in women and prostate cancer in men.

Background: Digitization and automation are the buzzwords in clinical research and pharma companies are investigating heavily here. Right from drug discovery to personalized medicine, digital patients and patient engagement, there is great consideration of technology at each step. Methods: The published data and online information available is reviewed to give an overview of digitization in pharma, across the drug development cycle, industry collaborations and innovations. The regulatory guidelines, innovative collaborations across industry, academics and thought leadership are presented. Also included are some ideas, suggestions, way forwards while digitizing the pharma neurons, the regulatory stand, benefits and challenges. Results: The innovations range from discovering personalized medicine to conducting virtual clinical trials, and maximizing data collection from the real-world experience. To address the increasing demand for the real-world data and the needs of tech-savvy patients, the innovations are shaping up accordingly. Pharma companies are collaborating with academics and they are co-innovating the technology for example Massachusetts Institute of Technology’s program. This focuses on the modernization of clinical trials, strategic use of artificial intelligence and machine learning using real-world evidence, assess the risk-benefit ratio of deploying digital analytics in medicine, and proactively identifying the solutions. Conclusion: With unfolding data on the impact of science and technology amalgamation, we need shared mindset between data scientists and medical professionals to maximize the utility of enormous health and medical data. To tackle this efficiently, there is a need of cross-collaboration and education, and align with ethical and regulatory requirements. A perfect blend of industry, regulatory, and academia will ensure successful digitization of pharma neurons.

Background: Diabetic macular edema (DME) is a major cause of vision loss in diabetics worldwide. Anti-vascular endothelial growth factor (anti-VEGF) agents have become the mainstay of treatment of vision loss due to DME. Long-term effects of these agents on the macular perfusion (MP) are a current concern. Objective: To review recently published studies that evaluated the effect of intravitreal injection of anti-VEGF agents on the MP of diabetics with DME. Methods: Different databases were searched including PubMed, Medline, Ovid, Science Direct, and Google Scholar for relevant studies published between 2010 and 2019. All studies found were compared regarding methodology and results and included in this review. Some studies relating to retinal perfusion in general and not strictly MP were also included for comprehensiveness. Results: Several studies utilizing different anti-VEGF agents were identified. All the large randomized controlled clinical trials identified utilized primarily fluorescein angiography (FA) and human graders and found generally no worsening of MP associated with anti-VEGF agents use in diabetic patients with DME. Some of these studies, however, depended on post-hoc analysis. Several more recent, but smaller case series, have utilized the relatively new and non-invasive optical coherence tomography angiography (OCTA) in this evaluation and found more conflicting results. Conclusion: The large clinical trials recently performed depended mainly on FA in the analysis of MP changes following injections and generally found no worsening of MP. More recently, smaller case series have utilized OCTA in this analysis, yielding more conflicting results. Large randomized controlled trials using OCTA are thus needed.

Background: Infertility is a global social issue, and reproductive health is a priority in global health. This review aimed to study the relation between physical activity (PA) and infertility in non-obese or non-overweight women. Methods: We used search strategies in the National Library of Medicine database including the PubMed database to October 2019 to find articles related to women and fertility, infertility, exercise, PA, pregnancy rate, live births, fecundability, and conception. Only cohort studies or randomized controlled trials in English were chosen for review that included outcomes directly related to becoming pregnant. We selected studies in which the participants were categorized by low or high body mass index (BMI). Results: We found 6 papers meeting our criteria. In the association between PA and outcome, vigorous PA in women with low BMI resulted in both positive and negative effects that were weaker than those in women with high BMI. Among women with low BMI, moderate PA was weakly but positively associated with outcome whereas walking was not. Conclusion: We observed some trends and a slight difference between the outcomes of women with low versus high BMI. There are only a few studies on infertile women with low BMI, and further investigation is warranted.

Background: Under normal physiological conditions, endotoxin (ET) released during self-renewal of the colibacillus pool is an obligate stimulus for the formation of the immune system and homeostasis of the body. Violation of the barrier function of the intestinal wall and the mechanisms of neutralization of endotoxin lead to systemic endotoxemia of intestinal origin. Its development is facilitated by stress, intoxication, a decrease in nonspecific resistance of the body, as well as damage to the intestinal mucosa and dysbiosis, where the mucous membrane is more vulnerable and permeable to endotoxin. Purpose of the Research: The aim of this study is to compare and assess the severity and nature of hepatocyte damage from endotoxin exposure and the degree of manifestation of stress due to oxidation, to determine the characteristics of structural changes in hepatocytes and to assess the oxidation stress during endotoxin intoxication in the experiment with biochemical markers. Materials and Methods: The experiments were conducted on 40 non-linear rats, divided into two groups of 20 animals. Group 1 animals received intraperitoneal injections of ET of Escherichia coli drug (Sigma USA K-235) for seven days at a rate of 0.1 mg/kg of the body weight. Animals of the second group served as the control group. Character and stage of liver damage were studied using morphological methods, including electron and light microscopy. In studying oxidizing stress, biochemical methods were used to define the changes, such as conjugated dienes and dienketones, spontaneous oxidizing modification of proteins. Results and Conclusion: 1. The severity and depth of morphological changes in the liver during endotoxin intoxication were correlated with the dynamics of the content of lipid oxidation products (CD and DK, MDA) and proteins. There was a tendency for a more significant increase in the oxidative modification of proteins in serum. This confirms the data on the primary damage of proteins by free radicals. 2. When exposed to intestinal microflora endotoxin, pronounced dyscirculatory changes, fatty and hydropic degeneration of hepatocytes with signs of toxic damage to their nuclei were determined, but at the same time, the increased hyperplastic activity of sinusoidal cells remained associated with the effects of endotoxin. These changes are associated with both the direct toxic effect of endotoxin, and the effects of oxidative stress, in which endotoxin is a potent inducer.

Background: The purpose of the present study was to clarify the differences in social demographic factors and sedentary behavior by gender in Japanese living overseas in Malaysia. Methods: First, 130 subjects were surveyed by self-entry questionnaire for statistical factors related to social demographics and sedentary behavior. These factors were age (years), gender (man/woman), body mass index (BMI, kg/m2), educational history (>13 years, %), employment (full-time or part-time, yes, %), alcohol intake (a certain amount, yes, %), smoking behavior (yes, %), and marital status (yes, %). BMI, as obtained from the participants’ weight and height, was collected from the self-reported questionnaire and assessed. Sitting behavior time as an index of sedentary behavior on workdays, non-workdays, and total time was identified by questionnaire. Data were analyzed using the chi square-test and t-test, respectively. The criterion for a statistically significant difference was p < 0.05. Results: Finally, 107 subjects (68 men, 39 women) were analyzed. The ratios of social demographic factors of the men versus women group were age (58.5 ± 14.7 vs. 61.0 ± 12.1 years, p = 0.36), BMI (23.1 ± 2.6 vs. 21.8 ± 2.6 kg/m2, p = 0.01), educational history (86.7% vs. 56.4%, p < 0.001), employment (51.5% vs. 10.3%, p <0.001), alcohol intake (86.7% vs. 35.9%, p < 0.001), smoking behavior (30.9% vs. 10.3%, p = 0.01), and marital status (88.2% vs. 100%, p = 0.02). Sitting behavior time was 501.8 ± 254.6 vs. 346.0 ± 153.4 minutes (p < 0.001) on workdays, 415.1 ± 225.3 vs. 320.6 ± 178.7 minutes (p = 0.019) on non-workdays, and 458.5 ± 203.9 vs. 333.3 ± 132.1 minutes (p < 0.001) in total. Conclusion: These findings indicated that social demographic factors and sitting behavior time differed by gender. However, there are some limitations. This was a cross-sectional study conducted in only one city with a small number of participants who completed a self-entry questionnaire. In conclusion, assessment of the differences in social demographic factors and postponement of sedentary behavior for both genders may reduce sitting behavior time in overseas Japanese residents and may help in developing public health strategies.

Background: In the past, most people sought medical information by consulting health care professionals. Nowadays, many people started to use online resources to access medical information. Objective: The study aims to investigate whether YouTube videos on hemorrhoids and hemorrhoid surgery can be a useful e-learning source for the general population, surgical trainees and specialists. Methods: A YouTube search was performed in October 2019 using the keywords “hemorrhoids” and “hemorrhoid surgery”, and the videos were divided into 2 groups according to the keywords. Three independent researchers assessed the metadata and classified them according to the level of accuracy (hemorrhoid group) and the level of usefulness (hemorrhoid surgery group). Cohen’s test and Kappa (K) value were used to evaluate the inter-investigators agreement. Results: A total of 200 videos were analyzed, 100 for each keyword. Regarding the hemorrhoid group, 43 videos (48.3%) were misleading, 9 were accurate (10.1%), 18 were approximate (20.2%), and 19 were considered a personal experience (21.4%). Regarding the hemorrhoid surgery group, around 60% of the videos were lacking a clear explanation, while about 16% were inaccurate. Only the remaining 24% were considered useful for teaching. Conclusion: Around half of the YouTube videos regarding hemorrhoids topic were found to be misleading or inaccurate and present a risk of harmful consequences. Credible videos with accurate information need to be uploaded by medical professionals and medical institutions and some sort of filtering, using categories by the staff of YouTube, appears to be necessary. Care must be taken to produce clear, high-quality operative clips with proper scientific commentary.

Background: Pre-eclampsia poses a significant potential risk of hypertensive disorders during pregnancy, a leading cause of maternal deaths. Hyperuricemia is associated with adverse effects on endothelial function, normal cellular metabolism, and platelet aggregation and adhesion. This study was designed to compare serum urate levels in normotensive pregnant women to those with pregnancy-induced hypertension, and to evaluate its value as a potential predictive marker of hypertension severity during pregnancy. Methods: A prospective, observational, case-control study conducted on 100 pregnant women in their third trimester. Pregnant women were classified into two groups (n=50) according to arterial blood pressure measurements: group I had normal blood pressure, and group II had a blood pressure of ≥ 140/90, which was further subdivided according to hypertension severity into IIa (pregnancy- induced hypertension, IIb (mild pre-eclampsia), and IIc (severe pre-eclampsia). Blood samples were obtained on admission. Serum urate, high sensitive C-reactive protein, and interleukin-1β levels, and lipid profile were compared among the groups. Results: A significant increase in the mean values of serum urate, C-reactive protein, and interleukin- 1β levels was detected in gestational hypertensives. In addition, there was a positive correlation between serum urate levels and C-reactive protein and interleukin-1β, as well as between serum urate levels and hypertension severity. Conclusion: Hyperuricemia and increased C-reactive protein and interleukin-1β serum levels correlate with the severity of pregnancy-induced hypertension, and these biomarkers may play a role in the pathogenesis of pre-eclampsia. Serum urate measurement is sensitive, reliable markers that correlate well with the severity of hypertension in pregnant females with pre-eclampsia.

Background: Autoimmune diseases are multifactorial with environmental and heritable factors. Autoimmunity reflects an altered immune status, therefore the presence of more than one disorder is not uncommon. The coexistence of three or more autoimmune diseases in a patient constitutes multiple autoimmune syndrome (MAS). This is an interesting case of a middle-aged female who had celiac disease, primary biliary cholangitis, autoimmune hepatitis and evolving CREST (Calcinosis, Rhaynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia) syndrome. Case Report: Fifty years old female patient presented with generalized fatigue, fever, weight loss, vertigo and constipation. She was a diagnosed case of celiac disease, and responded well to glutenfree diet. Family history was unremarkable for any autoimmune disorder. Laboratory workup showed normal complete blood counts, markedly elevated transaminases and alkaline phosphates. Her antinuclear antibodies (ANA) test was strongly positive (>1:320) and showed an anti-centromere pattern. Anti-extractable nuclear antibody(ENA) assay showed anti-mitochondrial and anti- CENP B antibodies. Liver biopsy revealed overlap syndrome (primary biliary cholangitis and autoimmune hepatitis). This patient had celiac disease, primary biliary cholangitis and autoimmune hepatitis. Extensive immunological workup unexpectedly revealed the presence of anti-centromere protein B (anti-CENP B) antibodies which are strongly associated with CREST syndrome. Clinical re-evaluation of the patient gave clues of the evolving CREST syndrome. This case report highlights the importance of adequate immunological investigations in conjunction with clinical information for adequate patient management to achieve favorable consequences in the future. Conclusion: Patients suffering from an autoimmune disease need special attention as multiple immune- mediated disorders may be present simultaneously or sequentially during the course of the disease process. MAS patients are at a higher risk of acquiring infections and tumor development due to prolonged use of immunosuppressants. These patients need close surveillance for the development of another autoimmune disease, so as to control the current disease and to prevent future complications. This case report emphasizes the importance of a multidisciplinary team approach including an immunologist who may facilitate a better understanding of disorders related to the breakdown of immune tolerance.