Sensitivity, specificity, and accuracy of molecular profiling on circulating cell-free DNA in refractory or relapsed multiple myeloma patients, results of MM-EP1 study.

As a promising alternative to bone marrow aspiration (BMA), mutational profiling on blood-derived circulating cell-free tumor DNA (cfDNA) is a harmless and simple technique to monitor molecular response and treatment resistance of patients with refractory/relapsed multiple myeloma (R/R MM). We evaluated the sensitivity and specificity of cfDNA compared to BMA CD138 positive myeloma plasma cells (PCs) in a series of 45 R/R MM patients using the 29-gene targeted panel (AmpliSeq) NGS. KRAS, NRAS, FAM46C, DIS3, and TP53 were the most frequently mutated genes. The average sensitivity and specificity of cfDNA detection were 65% and 97%, respectively. The concordance per gene between the two samples was good to excellent according to Cohen's κ coefficients interpretation. An increased number of mutations detected in cfDNA were associated with a decreased overall survival. In conclusion, we demonstrated cfDNA NGS analysis feasibility and accuracy in R/R MM patients who may benefit from early phase clinical trial.

Exposure to ultraviolet radiation during pregnancy influences offspring immune and inflammatory responses in Wistar-strain rats.

OBJECTIVE: During pregnancy, maternal exposure to ultraviolet radiation (UVR) has been linked to altered offspring immune and health status. This study was therefore designed to investigate some markers of immune response in the offspring of pregnant Wistar rats exposed to UVR at various points of gestation. METHODS: Thirty pregnant rats were divided into 6 groups (n=5) as follows; group I, control, consisting of pregnant rats unexposed to UVR. Animals in groups II, III, IV, V and VI were exposed to UVR for one hour daily, on gestational days 1-7,8-14,15-21,1-14 and 1-21, respectively. Animals were allowed to come to term and offspring birth weight was taken. On postnatal Day 10, weight of each offspring was taken again. Thereafter, blood samples were collected from each offspring per group and evaluated for total protein, albumin, globulin, C-reactive protein, interleukin-1ß, and complement component protein-3 (C3). Offspring hepatic samples were evaluated using standard histological techniques. RESULTS: Offspring birthweight increased (p<0.05), while weight gain on postnatal day 10 reduced in all experimental groups compared to controls. No significant differences were observed for offspring total protein, albumin, and C3 levels across all groups. Globulin increased (p<0.05) only in group VI, while C-reactive protein increased (p<0.05) in all experimental groups, except group III, compared to controls. Interleukin-1ß in groups II, III, V and VI increased significantly compared to controls. Offspring hepatic samples exhibited hepatocellular degeneration and necrosis that was independent of gestational stage of maternal exposure to UVR. CONCLUSIONS: Maternal exposure to ultraviolet radiation during gestation in Wistar rats activates offspring immune and inflammatory responses.

Chitosan-Coated Halloysite Nanotubes As Vehicle for Controlled Drug Delivery to MCF-7 Cancer Cells In Vitro.

The aim of the work is to improve the release properties of curcumin onto human breast cancer cell lines using coated halloysite nanotubes (HNTs) with chitosan as a polycation. A loading efficiency of 70.2% (w/w) was attained for loading 4.9 mg of the drug into 0.204 g bed volume of HNTs using the vacuum suction method. Results acquired from Brunauer-Emmett-Teller (BET), Fourier-transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), scanning electron spectroscopy (SEM), zeta potential, and thermogravimetric analysis (TGA) indicated the presence of the drug and the biopolymer in and around the nanotubes. The release properties of drug-loaded HNTs (DLHNTs) and chitosan-coated drug-loaded HNTs (DLHNTs-CH) were evaluated. The release percentages of DLHNTs and DLHNTs-CH after 6 h were 50.7 and 37%, respectively. Based on the correlation coefficients obtained by fitting the release nature of curcumin from the two samples, the Korsmeyer-Peppas model was found to be the best-fitted model. In vitro cell viability studies were carried out on the human breast cancer cell line MCF-7, using the MTT and trypan blue exclusion assays. Prior to the Trypan blue assay, the IC50 of curcumin was determined to be ~30 µM. After 24 h of incubation, the recorded cell viability values were 94, 68, 57, and 51% for HNTs, DLHNTs-CH, DLHNTs, and curcumin, respectively. In comparison to the release studies, it could be deducted that sustained lethal doses of curcumin were released from the DLHNTs-CH within the same time. It is concluded from this work that the "burst release" of naked drugs could be slowly administered using chitosan-coated HNTs as potential drug carriers.

Revision Laparoscopic Adjustable Gastric Band as a Successful Alternative Over Sleeve Gastrectomy After Failed Initial Weight Loss Therapies.

Bariatric surgery is one of the most successful treatment options for morbid obesity and related comorbidities that is reserved for patients when lifestyle modifications and medical treatments fail. Bariatric surgeries are proven to result in weight reduction and improve obesity-related complications; however, there still are some reported failures. We report the case of a 35-year-old woman with morbid obesity and diabetes mellitus who had failed laparoscopic adjustable gastric band (LAGB) and laparoscopic sleeve gastrectomy (LSG) when done individually. The patient finally had a successful weight loss after undergoing revision LAGB over LSG. Although the present literature reports LAGB being an unsuccessful weight loss procedure, this case highlights the significance of LAGB as an effective bariatric surgery compared to other procedures. Our patient not only lost her weight successfully but also resolved her comorbid conditions and mental illness following the LAGB.

Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers.

Diabetic ketoacidosis (DKA) is an acute and significant life-threatening complication of diabetes. The association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) with euglycemic diabetic ketoacidosis (EDKA) has been well reported. This literature review was conducted to understand the mechanism of EDKA and identify the potential risk factors and precipitants for patients taking SGLT2i. After reviewing the published literature between 2010 and 2020, 32 articles are included in the final review. The underlying mechanism is mainly enhanced lipolysis and ketone body reabsorption. SGLT2i also stimulates pancreatic alpha cells and inhibits beta cells, causing an imbalance in glucagon/insulin levels, further contributing to lipolysis and ketogenesis. Most patients were diagnosed with blood glucose less than 200 mg/dL, blood pH <7.3, increased anion gap, increased blood, or urine ketones. Perioperative fasting, pancreatic etiology, low carbohydrate or ketogenic diet, obesity, and malignancy are identified precipitants in this review. As normoglycemia can conceal the underlying acidosis, physicians should be cognizant of the EDKA diagnosis and initiate prompt treatment. Patient education on risk factors and triggers is recommended to avoid future events.

Evaluation of morbidity in Schistosoma mansoni-positive primary and secondary school children after four years of mass drug administration of praziquantel in western Kenya.

BACKGROUND: World Health Organization guidelines recommend preventive chemotherapy with praziquantel to control morbidity due to schistosomiasis. The primary aim of this cross-sectional study was to determine if 4 years of annual mass drug administration (MDA) in primary and secondary schools lowered potential markers of morbidity in infected children 1 year after the final MDA compared to infected children prior to initial MDA intervention. METHODS: Between 2012 and 2016 all students in two primary and three secondary schools within three kilometers of Lake Victoria in western Kenya received annual mass praziquantel administration. To evaluate potential changes in morbidity we measured height, weight, mid-upper arm circumference, hemoglobin levels, abdominal ultrasound, and quality of life in children in these schools. This study compared two cross-sectional samples of Schistosoma mansoni egg-positive children: one at baseline and one at year five, 1 year after the fourth annual MDA. Data were analyzed for all ages (6-18 years old) and stratified by primary (6-12 years old) and secondary (12-18 years old) school groups. RESULTS: The prevalence of multiple potential morbidity markers did not differ significantly between the egg-positive participants at baseline and those at 5 years by Mann Whitney nonparametric analysis and Fisher's exact test for continuous and categorical data, respectively. There was a small but significantly higher score in school-related quality of life assessment by year five compared to baseline by Mann Whitney analysis (P = 0.048) in 13-18 year olds where malaria-negative. However, anemia was not positively impacted by four annual rounds of MDA, but registered a significant negative outcome. CONCLUSIONS: We did not detect differences in morbidity markers measured in a population of those infected or re-infected after multiple MDA. This could have been due to their relative insensitivity or a failure of MDA to prevent morbidity among those who remain infected. High malaria transmission in this area and/or a lack of suitable methods to measure the more subtle functional morbidities caused by schistosomiasis could be a factor. Further research is needed to identify and develop well-defined, easily quantifiable S. mansoni morbidity markers for this age group.

Factors Influencing the Cost-Effectiveness Outcomes of HPV Vaccination and Screening Interventions in Low-to-Middle-Income Countries (LMICs): A Systematic Review.

BACKGROUND: Cervical cancer ranks fourth amongst the commonest malignancies worldwide and the second most prevalent cancer afflicting women in low-to-middle income countries (LMICs), hence, of great public health importance. LMICs are the most affected regions as evidenced by their high prevalence of the disease. Mortality associated with cervical neoplasms is preventable through the implementation of recommended preventive approaches. AIMS: This review aimed to appraise evidence on the cost effectiveness of cervical cancer prevention interventions in LMICs involving cervical screening and human papilloma virus (HPV) vaccination programmes. METHODS: A search of CINAHL, MEDLINE, PubMed, and Web of Science was elicited and studies published between 1st January 2008 and 31st December 2018 were retrieved. Two authors independently undertook the screening, review, selection of studies, and data extraction with disagreements being resolved through discussion and consensus. RESULTS: Twelve studies were selected. The cost-effectiveness outcomes of HPV vaccination and screening interventions are dependent on age, screening method used, intervention coverage, and the number of doses or visits required for vaccination and screening, respectively. A combination of visual inspection with acetic acid (VIA) screening and HPV vaccination appears to be the most cost-effective approach in reducing the lifetime risk for HPV-linked cervical neoplasms. Similarly, vaccination as a stand-alone intervention is potentially cost effective provided the coverage is maintained between 70 and 100%. CONCLUSIONS: HPV vaccination and screening interventions may be cost effective in LMICs and potentially reduce the lifetime risk, economic burden, and associated mortality. However, it is important to consider the factors that influence the cost effectiveness of cervical cancer prevention interventions for better outcomes to be realised.

Impact of Four Years of Annual Mass Drug Administration on Prevalence and Intensity of Schistosomiasis among Primary and High School Children in Western Kenya: A Repeated Cross-Sectional Study.

Schistosomiasis remains a major public health problem in Kenya. The World Health Organization recommends preventive chemotherapy with praziquantel (PZQ) to control morbidity due to schistosomiasis. Morbidity is considered linked to intensity of infection, which along with prevalence is used to determine the frequency of mass drug administration (MDA) to school-age children. We determined the impact of annual school-based MDA on children across all primary and high school years using a repeated cross-sectional study design in five schools near Lake Victoria in western Kenya, an area endemic for Schistosoma mansoni. At baseline and for the following four consecutive years, between 897 and 1,440 school children in Grades 1-12 were enrolled and evaluated by Kato-Katz for S. mansoni and soil-transmitted helminths (STH), followed by annual MDA with PZQ and albendazole. Four annual rounds of MDA with PZQ were associated with reduced S. mansoni prevalence in all school children (44.7-14.0%; P < 0.001) and mean intensity of infection by 91% (90.4 to 8.1 eggs per gram [epg] of stool; P < 0.001). Prevalence of high-intensity infection (≥ 400 epg) decreased from 6.8% at baseline to 0.3% by the end of the study. Soil-transmitted helminth infections, already low at baseline, also decreased significantly over the years. In this high prevalence area, annual school-based MDA with high coverage across all Grades (1-12) resulted in rapid and progressive declines in overall prevalence and intensity of infection. This decrease was dramatic in regard to heavy infections in older school-attending children.

Long-term outcome of liver transplantation in childhood: A study of 20-year survivors.

We report the results of a study of survival, liver and kidney functions, and growth with a median follow-up of 24 years following liver transplantation in childhood. From 1988 to 1993, 128 children underwent deceased donor liver transplantation (median age: 2.5 years). Twenty-year patient and graft survival rates were 79% and 64%, respectively. Raised serum aminotransferase and/or γ-glutamyl transferase activities were present in 42% of survivors after a single transplantation. Graft histology (35 patients) showed signs of chronic rejection in 11 and biliary obstruction in 5. Mean total fibrosis scores were 4.5/9 and 3/9 in patients with abnormal and normal serum liver tests, respectively. Glomerular filtration rate was <90 mL·min-1 in 35 survivors, including 4 in end-stage renal disease who were undergoing dialysis or had undergone renal transplantation. Median final heights were 159 cm for women and 172 cm for men; final height was below the target height in 37 patients. Twenty-year survival after childhood liver transplantation may be close to 80%, and final height is within the normal range for most patients. However, chronic kidney disease or altered liver biochemistries are present in over one third of patients, which is a matter of concern for the future.

Cluster randomized trial comparing school-based mass drug administration schedules in areas of western Kenya with moderate initial prevalence of Schistosoma mansoni infections.

BACKGROUND: Mass drug administration (MDA) using praziquantel is the WHO-recommended approach for control of schistosomiasis. However, few studies have compared the impact of different schedules of MDA on the resultant infection levels. We wished to evaluate whether annual MDA was more effective than less frequent treatments for reducing community-level prevalence and intensity of Schistosoma mansoni infections. METHODS: We performed a cluster randomized trial (ISRCTN 14849830) of 3 different MDA frequencies over a 5 year period in 75 villages with moderate (10%-24%) initial prevalence of S. mansoni in school children in western Kenya. Praziquantel was distributed by school teachers to students either annually, the first 2 years, or every other year over a 4 year period. Prevalence and intensity of infection were measured by stool examination in 9-12 year old students using the Kato-Katz method at baseline, each treatment year, and for the final evaluation at year 5. S. mansoni prevalence and intensity were also measured in first year students at baseline and year 5. RESULTS: Twenty-five schools were randomly assigned to each arm. S. mansoni prevalence and infection intensity in 9-12 year old students significantly decreased within each arm from baseline to year 5 but there were no differences between arms. There were no differences in infection levels in first year students either within or between arms. CONCLUSIONS: Strategies employing 2 or 4 rounds of MDA had a similar impact in schools with moderate initial prevalence, suggesting that schistosomiasis control can be sustained by school-based MDA, even if provided only every other year.

Bacteriological safety assessment, hygienic habits and cross-contamination risks in a Nigerian urban sample of household kitchen environment.

Urban household kitchen environment was assessed for safety by determining their levels of indicator bacteria, hygienic habits and risk of cross-contamination. Household kitchens (60) were selected in Warri Town, Nigeria, by the multi-stage sampling technique. Contact surfaces, water and indoor kitchen air were analysed for aerobic plate counts, total and faecal coliforms using Nutrient and McConkey media by swab/rinse method, membrane filtration and sedimentation methods, respectively. Hygienic habits and risk of cross-contamination were assessed with structured questionnaire which included socio-demographic variables. On the basis of median counts, the prevalence of high counts (log cfu/cm2/m3/100 mL) of aerobic plate counts (>3.0), total coliforms (>1.0) and faecal coliforms (>0) on contact surfaces and air was high (58.0-92.0%), but low in water (30.0-40.0%). Pots, plates and cutleries were the contact surfaces with low counts. Prevalence of poor hygienic habits and high risk of cross-contamination was 38.6 and 67.5%, respectively. Education, occupation and kitchen type were associated with cross-contamination risk (P = 0.002-0.022), while only education was associated with hygienic habits (P = 0.03). Cross-contamination risk was related (P = 0.01-0.05) to aerobic plate counts (OR 2.30; CL 1.30-3.17), total coliforms (OR 5.63; CL 2.76-8.25) and faecal coliforms (OR 4.24; CL 2.87-6.24), while hygienic habit was not. It can be concluded that urban household kitchens in the Nigerian setting are vulnerable to pathogens likely to cause food-borne infections.

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia.

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

DNMT3A(R882H) mutant and Tet2 inactivation cooperate in the deregulation of DNA methylation control to induce lymphoid malignancies in mice.

TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3A(R882H)) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.

Assessment of the physicochemical and microbiological status of western Niger Delta soil for crude oil pollution bioremediation potential.

The physical, chemical and microbiological characteristics of the soil across the western Niger Delta area of Nigeria were determined to assess its potential for natural remediation of crude oil pollution. The pH (oil-producing area, 6.1 ± 1.1; non-oil producing, 5.9 ± 0.9) and temperature (28-35 °C in both areas) were favourable to natural remediation, while the fluctuating moisture (7.7-45.6 %) and the dominant sandy soil textural classes (70 %) were limitations. The carbon nitrogen phosphorus (CNP) ratio markedly exceeded recommended 100:10:1, while the cation exchange capacity was below acceptable range. Counts of heterotrophic bacteria, fungi and hydrocarbon-utilising and nitrogen-fixing bacteria (mean range log10 3.8 ± 1.5-6.52 ± 0.9 cfu/g) were favourable having markedly exceeded the minimum counts required. Crude oil loss was highest in loam soil, but significantly (P = 0.00) increased in all soil textural classes including sandy soils after amendment with cow dung/poultry dropping and manual aeration in laboratory and 8-month field tests as indicated by two-way ANOVA. Thus, the overall assessment is that while CNP can be viewed as the major limiting factor to natural oil pollution remediation in the western Niger Delta soil, its influence can be minimised by the amendment indicated in the study.

The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases.

Ten-Eleven Translocation-2 (TET2) inactivation through loss-of-function mutation, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2 gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate with age in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET (Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNA demethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietic tissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteins recruit the O-linked ß-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, which promotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level is regulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by the microRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal, lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which are viable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiency initiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2 physiological and pathological functions and discusses how this knowledge influences our therapeutic approaches in hematological malignancies and possibly other tumor types.