Diseases, Volume 9, Issue 2 (June 2021) – 21 articles

Colistin is a last resort antibiotic medication for the treatment of infections caused by carbapenem-resistant Klebsiella pneumoniae. In recent years, various mechanisms have been reported to mediate colistin resistance in K. pneumoniae. This study reports a bibliometric analysis of published articles retrieved from the Scopus database relating to colistin resistance in K. pneumoniae. The research trends in colistin resistance and mechanisms of resistance were considered. A total of 1819 research articles published between 1995 and 2019 were retrieved, and the results indicated that 50.19% of the documents were published within 2017–2019. The USA had the highest participation with 340 (14.31%) articles and 14087 (17.61%) citations. Classification based on the WHO global epidemiological regions showed that the European Region contributed 42% of the articles while the American Region contributed 21%. The result further indicated that 45 countries had published at least 10 documents with strong international collaborations amounting to 272 links and a total linkage strength of 735. A total of 2282 keywords were retrieved; however, 57 keywords had ≥15 occurrences with 764 links and a total linkage strength of 2388. Furthermore, mcr-1, colistin resistance, NDM, mgrB, ceftazidime-avibactam, MDR, combination therapy, and carbapenem-resistant Enterobacteriaceae were the trending keywords. Concerning funders, the USA National Institute of Health funded 9.1% of the total research articles, topping the list. The analysis indicated poor research output, collaboration, and funding from Africa and South-East Asia and demands for improvement in international research collaboration. Full article

Burkitt lymphoma/leukemia (BL/L) is an aggressive oncohematological disease. This study evaluated the population-based prognosis and survival on BL/L as well as if BL/L behaved as a risk factor for the development of second primary cancers (SPCs) and if other first tumors behaved as risk factors for the occurrence of BL/L as an SPC. A retrospective cohort using the Surveillance, Epidemiology and End Results (SEER) Program (2008–2016) was performed. Kaplan–Meier, time-dependent covariate Cox regression and Poisson regression models were conducted. Overall, 3094 patients were included (median, 45 years; IQR, 22–62). The estimated overall survival was 65.4 months (95% CI, 63.6–67.3). Significantly more deaths occurred for older patients, black race, disease at an advanced stage, patients without chemotherapy/surgery and patients who underwent radiotherapy. Hodgkin lymphomas (nodal) (RR, 7.6 (3.9–15.0; p < 0.001)), Kaposi sarcomas (34.0 (16.8–68.9; p < 0.001)), liver tumors (3.4 (1.2–9.3; p = 0.020)) and trachea, mediastinum and other respiratory cancers (15.8 (2.2–113.9; p = 0.006)) behaved as risk factors for the occurrence of BL/L as an SPC. BL/L was a risk factor for the occurrence of SPCs as acute myeloid leukemias (4.6 (2.1–10.4; p < 0.001)), Hodgkin lymphomas (extranodal) (74.3 (10.0–549.8; p < 0.001)) and Kaposi sarcomas (35.1 (12.1–101.4; p < 0.001)). These results may assist the development of diagnostic and clinical recommendations for BL/L. Full article

The role of inflammation in neuroendocrine tumors is poorly known. The purpose of this study was to characterize the densities of CD3⁺, CD8⁺, CD4⁺ and FOXP3⁺ T cells in small bowel neuroendocrine tumors (SB-NETs), SB-NET lymph node metastases and gastric neuroendocrine tumors (G-NETs) to assess the prognostic role of immune cell infiltrates in SB-NETs. The final cohort included 113 SB-NETs, 75 SB-NET lymph node metastases and 19 G-NETs from two Finnish hospitals. CD3⁺- and CD8⁺-based immune cell score (ICS), and other T cell densities were evaluated. Survival analyses of SB-NETs and SB-NET lymph node metastases were performed with the Kaplan-Meier method and Cox regression adjusted for confounders. The primary outcome was disease-specific survival (DSS). No significant difference in DSS was seen between low and high ICS groups in SB-NETs at 5 years (92.6% vs. 87.8%) or 10 years (53.8% vs. 79.4%), p = 0.507, or in SB-NET lymph node metastases at 5 years (88.9% vs. 90.4%) or 10 years (71.1% vs. 59.8%), p = 0.466. Individual densities of the examined T cell types showed no correlation with prognosis either. SB-NETs and lymph node metastases had similar inflammatory cell profiles, whereas in G-NETs CD3⁺ and CD8⁺ T cells were particularly more abundant. In SB-NETs, ICS or T cell densities showed no correlation with prognosis. Full article

This retrospective cross-sectional database study used 2018 Medical Expenditure Panel Survey data to quantify and assess differences in healthcare expenditures between opioid users and non-users among a non-institutionalized sample of older (≥50 years) United States adults with pain in the past four weeks and a diagnosis of comorbid hypercholesterolemia (pain–hypercholesterolemia group) or hypertension (pain–hypertension group). Hierarchical multivariable linear regression models were constructed by using logarithmically transformed positive cost data and adjusting for relevant factors to assess cost differences between groups. Percent difference between opioid users and non-users was calculated by using semi-logarithmic equations. Healthcare costs included inpatient, outpatient, office-based, emergency room, prescription medication, other, and total costs. In adjusted analyses, compared to non-users, opioid users in the pain–hypercholesterolemia and pain–hypertension groups respectively had 66% and 60% greater inpatient expenditure, 46% and 55% greater outpatient expenditure, 67% and 72% greater office-based expenditure, 50% and 60% greater prescription medication expenditure, 24% and 22% greater other healthcare expenditure, and 85% and 93% greater total healthcare expenditure. In conclusion, adjusted total healthcare expenditures were 85–93% greater among opioid users versus non-users in older United States adults with pain and comorbid hypercholesterolemia or hypertension. Future research is needed to identify opioid use predictors among these populations and reduce expenditures. Full article

Light chain amyloidosis (AL) causes irreversible multi-organ damage if not diagnosed early in the disease process. Fat pad biopsy is thought to be a highly sensitive screening test in systemic AL cases, especially if greater than three organs are involved. We present a case of a 64-year-old female who was admitted to the hospital with worsening heart and kidney failure, anasarca, increased free serum lambda light chains, and a negative fat pad biopsy for amyloidosis. Later, she developed asystole, bradycardia, severe hypotension, and respiratory distress. Because X-rays of her calvarium showed multiple osteolytic lesions, a bone marrow biopsy was planned to assess for multiple myeloma. Due to her non-reassuring vitals, the biopsy was not attempted, and she passed away several weeks later. Autopsy findings identified the cause of death as multiple system organ failure due to systemic AL. Through microscopic examination, pathologists found amyloid deposits in her heart, kidneys, rectum, thyroid, adrenals, bone marrow, liver, and spleen. Postmortem fat pad biopsy was negative; however, bone marrow biopsy demonstrated clusters of CD138-positive cells, confirming plasma cell dyscrasia. In cases with a negative fat pad biopsy, an additional superficial or involved organ biopsy should be pursued to establish a diagnosis of amyloidosis if strong clinical suspicion exists. Full article

Very-low-carbohydrate diets or ketogenic diets are frequently used for weight loss in adults and as a therapy for epilepsy in children. The incidence and characteristics of kidney stones in patients on ketogenic diets are not well studied. Methods: A systematic literature search was performed, using MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews from the databases’ inception through April 2020. Observational studies or clinical trials that provide data on the incidence and/or types of kidney stones in patients on ketogenic diets were included. We applied a random-effects model to estimate the incidence of kidney stones. Results: A total of 36 studies with 2795 patients on ketogenic diets were enrolled. The estimated pooled incidence of kidney stones was 5.9% (95% CI, 4.6–7.6%, I2 = 47%) in patients on ketogenic diets at a mean follow-up time of 3.7 +/− 2.9 years. Subgroup analyses demonstrated the estimated pooled incidence of kidney stones of 5.8% (95% CI, 4.4–7.5%, I2 = 49%) in children and 7.9% (95% CI, 2.8–20.1%, I2 = 29%) in adults, respectively. Within reported studies, 48.7% (95% CI, 33.2–64.6%) of kidney stones were uric stones, 36.5% (95% CI, 10.6–73.6%) were calcium-based (CaOx/CaP) stones, and 27.8% (95% CI, 12.1–51.9%) were mixed uric acid and calcium-based stones, respectively. Conclusions: The estimated incidence of kidney stones in patients on ketogenic diets is 5.9%. Its incidence is approximately 5.8% in children and 7.9% in adults. Uric acid stones are the most prevalent kidney stones in patients on ketogenic diets followed by calcium-based stones. These findings may impact the prevention and clinical management of kidney stones in patients on ketogenic diets. Full article

In the wake of the COVID-19 pandemic, it is crucial to assess the application of a multitude of effective diagnostic specimens for conducting mass testing, for accurate diagnosis and to formulate strategies for its prevention and control. As one of the most versatile and amenable specimen options, saliva offers great advantages for widespread screening strategies due to its non-invasive properties, cost-effectiveness, excellent stability and minimal risk of cross-infection. This review attempts to outline the scientific rationale for detection of SARS-COV-2 in saliva specimens. By combining the data obtained from ten chosen published clinical studies, we calculated the pooled sensitivity and specificity using an online calculator. Through evidence, we established that SARS-COV-2 is detectable in saliva with a high degree of diagnostic sensitivity (87%) and specificity (98%). We also presented a review of emerging technologies approved by the FDA for detection of SARS-COV-2 in oral fluids (saliva and sputum) using polymerase chain reaction methods. Given the challenges involved in obtaining invasive specimens from the naso- and oropharynx, saliva can serve as an easy to collect diagnostic specimen for screening in the work environment, schools and for home testing. Furthermore, saliva offers the opportunity to screen early cases that can be missed by invasive sampling. Full article

Human granulocytic Anaplasmosis (HGA), is a tick-borne infectious disease transmitted by ticks, resulting in acute feverish episodes. The etiological agent is the bacteria Anaplasma phagocytophilum; which is spread by ticks of the genus Ixodes spp. to complete its life cycle. In Mexico, there is only one case report. The primary challenge is understanding how other bacteria affect or overlap with the clinical manifestation of the disease. Sample collection occurred over the period September 2017 through October 2019. Blood samples from human subjects were obtained immediately after they signed consent forms. We analyzed for the presence for A. phagocytophilum by serological (IFA IgG two times) and PCR targeting 16SrRNA and groEL genes, followed by DNA sequencing. All patients with a history of travel abroad were dismissed for this project. In total, 1924 patients participated and of these, 1014 samples across the country were analyzed. Of these, 85 (8.38%) had IFA results that ranged from 1:384 to 1:896. Of the positive samples, 7.10% were used for PCR. Significant clinical manifestations included: dizziness, nausea, petechial, epistaxis, enlarged liver and/or spleen and thrombocytopenia. Hospitalization of at least 1.5 days was necessary for 3.2% of patients. None of the cases analyzed were lethal. This is the first clinical manifestations along with serological test results and molecular analysis confirmed the presence of A. phagocytophilum resulting in HGA in patients from Mexico. Health institutions and medical practitioners in general should include diagnostic testing for HGA among high risk populations and should recognize it as a vector-borne emerging infectious disease in Mexico. Full article

Background: The COVID-19 pandemic has been characterized by wide variations in mortality across nations. Some of this variability may be explained by medical comorbidities such as obesity and depression, both of which are strongly correlated with dietary practices such as levels of sugar and seafood consumption. Methods: COVID-19 mortality indices for 156 countries were obtained from the Johns Hopkins University’s data aggregator. Correlations between these variables and (a) per capita consumption of sugar and seafood, and (b) country-wise prevalence of depression and obesity were examined. Results: Sugar consumption (r = 0.51, p < 0.001) and prevalence of obesity (r = 0.66, p < 0.001) and depression (r = 0.56, p < 0.001) were positively correlated with crude mortality rates, while seafood consumption was negatively correlated with the infection fatality rate (r = −0.28, p = 0.015). These effects were significant even after correcting for potential confounders. The associations with depression and obesity remained significant upon multivariate regression. Conclusions: Both obesity and depression, which are associated with inflammatory dysregulation, may be related to cross-national variations in COVID-19 mortality, while seafood consumption may be protective. These findings have implications in terms of protecting vulnerable individuals during the current pandemic. Full article

In recent years, the digital polymerase chain reaction has received increasing interest as it has emerged as a tool to provide more sensitive and accurate detection of minimal residual disease. In order to start the process of data alignment, we assessed the consistency of the BCR-ABL1 quantification results of the analysis of 16 RNA samples at different levels of disease. The results were obtained by two different laboratories that relied on The Qx100/Qx200 Droplet Digital PCR System (Bio-Rad) and Quant Studio 3D dPCR System (Thermofisher) platforms. We assessed the compatibility between the estimated values by linear regression, Bland–Altman bias-plot, and Mann–Whitney nonparametric test. The results confirmed the compatibility of the measures, allowing us tocompute an ‘alignment factor’ (AF), equal to 1.41, which was further validated by a different series of experiments. We conclude that the performed measurements by the two laboratories are comparable, and also equalized through the introduction of an alignment factor. Full article

Cancer-associated thrombosis (CAT) is a rising and significant phenomenon, becoming the second leading cause of death in cancer patients. Pathophysiology of CAT differs from thrombosis in the non-cancer population. There are additional risk factors for thrombosis specific to cancer including cancer type, histology, and treatment, such as chemotherapy. Recently developed scoring systems use these risk factors to stratify the degree of risk and encourage thromboprophylaxis in intermediate- to high-risk patients. Anticoagulation is safely used for prophylaxis and treatment of CAT. Both of these have largely been with low-molecular-weight heparin (LMWH), rather than the vitamin K antagonist (VKA); however, there has been increasing evidence for direct oral anticoagulant (DOAC) use. Consequently, international guidelines have also adapted to recommend the role of DOACs in CAT. Using DOACs is a turning point for CAT, but further research is warranted for their long-term risk profile. This review will discuss mechanisms, risk factors, prophylaxis and management of CAT, including both LMWH and DOACs. There will also be a comparison of current international guidelines and how they reflect the growing evidence base. Full article

The incidence of multiple pregnancies has increased in the last decades, mostly explained by the more frequent use of ovulation induction drugs and assisted reproduction techniques. Although single fetal death in the first trimester of twin pregnancy is not an uncommon event nor does it have serious consequences on the survival fetus, the death of one fetus in the second or third trimester of pregnancy is associated with a serious increase in morbidity and mortality for the surviving co-twin. Preterm labor, preeclampsia, intrauterine growth restriction (IUGR), neurological complications or even the death of the surviving twin have been associated with single fetal demise after mid gestation. We present a very rare case of twin pregnancy with single fetal demise at 26 weeks of gestation successfully managed to term. Full article

The novel coronavirus can cause a severe respiratory disease with impact on the central nervous system, as has been reported by several medical health services. In the COVID-19 pandemic caused by the SARS-CoV-2 neurotrophic virus, neurologists have focused their attention on the early identification of suggestive manifestations of the neurological impact of the disease. In this context, they are exploring related chronic disease and the possibility of achieving a more effective understanding of symptoms derived from COVID-19 infection and those derived from the course of preexisting neurological disease. The present review summarizes evidence from the infection with SARS-CoV-2 and the management of the risks of multiple sclerosis and how it is related to the risks of general comorbidities associated with COVID-19. In addition, we reviewed other factors characteristic of MS, such as relapses, and the maximum tolerated dose of treatment medications from clinical and experimental evidence. Full article

Background: Ranolazine has the potential to prevent atrial fibrillation (AF) and plays a role in rhythm control strategy for atrial fibrillation in various clinical settings. However, data on the use of ranolazine in patients with left ventricular (LV) systolic dysfunction are limited. The aims of this meta-analysis of randomized clinical trials are to investigate the efficacy and safety of ranolazine in AF patients with LV systolic dysfunction. PubMed and the Cochrane Database of Systematic Reviews were searched until July 2020. The efficacy outcomes included the incidence of new-onset AF, the rate of sinus rhythm restoration, and the time until sinus rhythm restoration. Safety endpoints were at death, and any adverse events were reported in the enrolled studies. We initially identified 204 studies and finally retrieved 5 RCTs. Three studies were analyzed in the meta-analysis. Among AF patients with LV systolic dysfunction, our meta-analysis showed that the combination of ranolazine to amiodarone significantly increased the sinus rhythm restoration rate compared to amiodarone alone (risk ratio (RR) 2.87, 95% confidence interval (CI) 2.48–3.32). Moreover, the time to sinus rhythm restoration was 2.46 h shorter in the ranolazine added to amiodarone group (95% CI: 2.27–2.64). No significant adverse events and proarrhythmias in the ranolazine group were identified. In conclusion, in AF patients with LV systolic dysfunction, ranolazine as an add-on therapy to amiodarone potentiates and accelerates the conversion of AF to sinus rhythm. Moreover, ranolazine shows good safety profiles. Further studies to investigate the effectiveness of ranolazine in the prevention of new-onset AF among patients with LV systolic dysfunction are needed. Full article

Exaggerated oxidative stress and hyper-inflammation are essential features of oxidative/inflammatory diseases. Simultaneously, both processes may be the cause or consequence of mitochondrial dysfunction, thus establishing a vicious cycle among these three factors. However, several natural substances, including melatonin and micronutrients, may prevent or attenuate mitochondrial damage and may preserve an optimal state of health by managing the general oxidative and inflammatory status. This review aims to describe the crucial role of mitochondria in the development and progression of multiple diseases as well as the close relationship among mitochondrial dysfunction, oxidative stress, and cytokine storm. Likewise, it attempts to summarize the main findings related to the powerful effects of melatonin and some micronutrients (vitamins and minerals), which may be useful (alone or in combination) as therapeutic agents in the treatment of several examples of oxidative/inflammatory pathologies, including sepsis, as well as cardiovascular, renal, neurodegenerative, and metabolic disorders. Full article

Frequent diseases of the CNS, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and psychiatric disorders (e.g., schizophrenia), elicit a neuroinflammatory response that contributes to the neurodegenerative disease process itself. The immune and nervous systems use the same mediators, receptors, and cells to regulate the immune and nervous systems as well as neuro-immune interactions. In various neurodegenerative diseases, peripheral inflammatory mediators and infiltrating immune cells from the periphery cause exacerbation to current injury in the brain. Acetylcholine (ACh) plays a crucial role in the peripheral and central nervous systems, in fact, other than cells of the CNS, the peripheral immune cells also possess a cholinergic system. The findings on peripheral cholinergic signaling, and the activation of the “cholinergic anti-inflammatory pathway” mediated by ACh binding to α7 nAChR as one of the possible mechanisms for controlling inflammation, have restarted interest in cholinergic-mediated pathological processes and in the new potential therapeutic target for neuro-inflammatory-degenerative diseases. Herein, we focus on recent progress in the modulatory mechanisms of the cholinergic anti-inflammatory pathway in neuroinflammatory diseases. Full article

Anti-angiogenics currently used in cancer therapy target angiogenesis by two major mechanisms: (i) neutralizing angiogenic factors or their receptors by using macromolecule anti-angiogenic drugs (e.g., therapeutic antibodies), and (ii) blocking intracellularly the activity of receptor tyrosine kinases with small molecule (M_r < 1 kDa) inhibitors. Anti-angiogenics halt the growth and spread of cancer, and significantly prolong the disease-free survival of the patients. However, resistance to treatment, insufficient efficacy, and toxicity limit the success of this antivascular therapy. Published evidence suggests that four albumin-binding proteins (ABPs) (gp18, gp30, gp60/albondin, and secreted protein acidic and cysteine-rich (SPARC)) could be responsible for the accumulation of small molecule receptor tyrosine kinase inhibitors (RTKIs) in normal organs and tissues and therefore responsible for the side effects and toxicity associated with this type of cancer therapy. Drawing attention to these studies, this review discusses the possible negative role of albumin as a drug carrier and the rationale for a new strategy for cancer therapy based on follicle-stimulating hormone receptor (FSHR) expressed on the luminal endothelial cell surface of peritumoral blood vessels associated with the major human cancers. This review should be relevant to the audience and the field of cancer therapeutics and angiogenesis/microvascular modulation-based interventions. Full article

Blister or vesicant chemical warfare agents (CWAs) have been widely used in different military conflicts, including World War I and the Iran-Iraq War. However, their mechanism of action is not fully understood. Sulfur and nitrogen mustard exert toxic effects not only through the alkylation of thiol-bearing macromolecules, such as DNA and proteins, but also produce free radicals that can develop direct toxic effects in target organs such as the eyes, skin, and respiratory system. The lack of effective treatments against vesicant CWAs-induced injury makes us consider, in this complex scenario, the use and development of melatonin-based therapeutic strategies. This multifunctional indoleamine could facilitate neutralization of the oxidative stress, modulate the inflammatory response, and prevent the DNA damage, as well as the long-term health consequences mediated by vesicant CWAs-induced epigenetic mechanisms. In this context, it would be essential to develop new galenic formulations for the use of orally and/or topically applied melatonin for the prophylaxis against vesicant CWAs, as well as the development of post-exposure treatments in the near future. Full article

Cleft lip and palate are common congenital pathologies that affect the human population worldwide. The formation of cleft lip is associated with multiple genes and their coded proteins, which regulate the development of craniofacial region, but the exact role of these factors is not always clear. The use of morphological studies for evaluation of human cleft-affected tissue has been limited because of insufficiency of available pathological material. The aim of this study was to detect and compare the immunohistochemical expression of cleft candidate gene coded proteins (DLX4, MSX2, HOXB3, SHH, PAX7, SOX3, WNT3A, and FOXE1) in the non-syndromic unilateral cleft lip patient tissue and control group tissue. A semiquantitative counting method was used to evaluate the tissue in biotin-streptavidin-stained slides. Statistically significant differences between the patient and control groups were found for the number of immunoreactive structures for SHH (p = 0.019) and FOXE1 (p = 0.011) in the connective tissue and SOX3 (p = 0.012) in the epithelium. Multiple statistically significant very strong and strong correlations were found between the immunoreactives in cleft-affected tissue. These significant differences and various correlations indicate that multiple morphopathogenetic pathways are possibly involved in unilateral cleft lip pathogenesis. Therefore, we further discuss these possible interactions. Full article

(1) Background: Adolescence is a period of increased autonomy and independent decision making; it determines health behaviors that can persist into the future. Individual factors like food choices and unhealthy lifestyle have an essential role in the development and prevention of obesity among adolescents and are associated with the nutrition literacy of parents and other adults. While the association of parents’ nutrition literacy with adolescent BMI has been addressed, there is still a scarcity of studies that examine the effect of adolescents’ nutrition literacy on their eating habits and body mass index (BMI) status. (2) Methods: A cross-sectional study was conducted that included 189 adolescents (68 with overweight and obesity and 121 with normal weight) aged between 14–19 years from four private schools in Tripoli, Lebanon. A self-administered questionnaire that included the Nutrition Literacy Assessment Instrument (NLAI) and the Adolescent Food Habits Checklist (AFHC) was used. Anthropometrics were measured using standardized procedures. The association between nutrition literacy, food habits and BMI was assessed using a chi squared test for independence and Poisson regression analysis where suitable. (3) Results: Results indicated no association between all five components of nutrition literacy and body mass index categories. Furthermore, there was no association between the Adolescent Food Habits Checklist and overweight or obese BMI status (RR = 0.947, 95%CI: 0.629–1.426) (p = 0.796). No association was observed between nutrition literacy and food habits, except for an inverse association with macronutrients literacy. (4) Conclusions: In conclusion, the study indicated that there was no association between the components of nutrition literacy with body mass index or with food habits, except for macronutrient literacy. Full article

Catabacter hongkongensis is a Gram-positive rod, isolated in 2007 in blood culture. Fewer than 15 infections have been reported. Herein, we present a lethal case of bacteremia due to C. hongkongensis identified through phylogenetic analyses. A woman was found unconscious in a context of chronic diarrhea. An abdominal abscess with a hydroaeric level was discovered, associated with sigmoid adenocarcinoma and peritoneal carcinomatosis. Despite hospitalization in an ICU and the adaptation of antibiotic therapy, the patient died. Blood cultures were positive in the final stage of the disease (>60 h). Identification of C. hongkongensis was performed using 16S rDNA sequencing. Phylogenetic analyses did not enable classification of these strains according to clinical outcome or the antibiotic sensitivity to treatment. In this case, bacteria were difficult to isolate and MALDI-TOF remained non-contributive. As strains are resistant to probabilistic treatments, addition of metronidazole or vancomycin could optimize clinical management, highlighting the benefit of rapid molecular identification by sequencing. Full article