Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia.

The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.

[Survey to know the perception of sexual education in adolescents]. / Encuesta para conocer la percepción sobre la educación sexual en adolescentes.

OBJECTIVE: Sex education is essential for an accurate approach of sexuality in adolescents, being more effective when it is carried out at early ages. This study aimed to estimate the sexual health knowledge and the information in this regard perceived by adolescents, as well as where it came from. METHODS: A cross-sectional observational study was performed in students from two public high schools in Castilla-La Mancha who were surveyed about sexual knowledge. Comparisons were made by using the Student's t test or Mann Whitney U test, the Chi-square test (or Fisher's exact test) depending on the variables. RESULTS: 248 students were included (68.1% from Madridejos and 31.9% from Herencia) with a mean age of 14.67±1.1 years. The 47.2% were women. Only 4.8% of the participants affirm to talk about sexuality with their parents. The 56% declared had consumed pornographic content, with a mean first access age of 12.8±1 years. Significant statistically differences were found between the information received in schools and in the familiar surroundings, being alcohol and drug intake, sexually transmitted infections (STI), and contraceptive methods more frequently treated at the educational centers. A 25% of the surveyed students who reported having performed sexual relations stated not having used condom. Approximately, half of the participants did not perceive a high risk of getting STIs (HIV, herpes and chlamydia) in the case of having sex without condom. CONCLUSIONS: There is a lack of sexual knowledge in adolescents, perceiving a noteworthy heterogeneity in the offered information depending on it is received in high school or in familiar surroundings.

OBJECTIVE: La educación sexual es un pilar fundamental para un correcto enfoque de la sexualidad en los adolescentes, siendo más efectiva si se realiza en edades tempranas. El objetivo de este trabajo se fundamentó en estimar los conocimientos de salud sexual y la información percibida por los adolescentes, así como de dónde provenía. METHODS: Se realizó un estudio observacional transversal en estudiantes de dos centros educativos públicos de Castilla-La Mancha a los que se les realizó una encuesta sobre conocimientos de sexualidad. Se hicieron comparaciones mediante t de student o U de Mann Whitney, o test de Chi-cuadrado (o test exacto de Fisher), según variables. RESULTS: Se incluyeron 248 encuestados/as (68,1% de Madridejos y 31,9% de Herencia) con una edad media de 14,67±1,1 años. El 47,2% fueron mujeres. Solo un 4,8% de los/as encuestados/as afirmaron hablar sobre sexualidad con sus progenitores. Un 56% afirmaron haber consumido contenido pornográfico, siendo la edad media de la primera visualización de 12,8±1 años. Se encontraron diferencias estadísticamente significativas entre la información recibida en los centros educativos y el ámbito familiar, tratándose más frecuentemente el consumo de alcohol y drogas, las infecciones de transmisión sexual (ITS) y los métodos anticonceptivos en los centros. Un cuarto de los/as encuestados/as que afirmaron haber tenido relaciones sexuales no habían utilizado preservativo. Aproximadamente, la mitad de los/as participantes no percibieron un riesgo alto de contraer ITS (VIH, herpes y clamidia) en el caso de mantener relaciones sexuales sin preservativo. CONCLUSIONS: Existe una falta de educación sexual en los/as adolescentes, percibiendo gran heterogeneidad en los conocimientos ofrecidos en los centros educativos y el ámbito familiar.

Biomarker-Driven Developments in the Context of the New Regulatory Framework for Companion Diagnostics in the European Union.

The new In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR) introduces important changes in the EU legal framework for companion diagnostics (CDx), including a new risk-based classification system for in vitro diagnostic tests (IVDs), a first legal definition for CDx and enhanced involvement of notified bodies in the conformity assessment and certification process of CDx. The IVDR also establishes an important link between the assessment of a CDx and the corresponding medicinal product by requiring the notified body to seek a scientific opinion from the medicines regulator on the suitability of the CDx for use with the concerned medicinal product(s) before issuing an IVD certificate. Whereas the IVDR aims at establishing a robust regulatory framework for IVDs, it is also associated with several challenges, such as insufficient capacity of notified bodies and readiness of manufacturers. To ensure timely access for patients to essential IVDs, a progressive roll-out for this new legislation has been introduced. In addition, the new consultation process for CDx requires increased collaboration and alignment of assessments performed by the different stakeholders involved in this process. The European Medicines Agency (EMA) and notified bodies are currently building experience based on the first CDx consultation procedures that have been submitted from January 2022 onward. In the current article, we describe the new European regulatory framework for certification of CDx and highlight several challenges for medicine and CDx co-development. In addition, we briefly touch upon the interplay between the Clinical Trial Regulation (EU) No. 536/2014 (CTR) and the IVDR.

Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells.

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.

Comparison of two different anti-infectious approaches after high-dose chemotherapy and autologous stem cell transplantation for hematologic malignancies in a 12-year period in British Hospital, Uruguay.

Autologous stem cell transplant (ASCT) is a widely used and safe procedure to treat mostly hematologic diseases. These patients are at risk of infectious complications, which represents a major cause of morbidity and it is the second cause of mortality. This retrospective 12-year analysis of the incidence, type, and severity of infections in 266 consecutive unselected ASCT patients at our institution provides novel information addressing this issue. We included 266 ASCT procedures. Patients included in the 2006-2013 period are referred to as group 1 (ciprofloxacin prophylaxis and ceftazidime-amikacin as empirical antibiotics), and those in the 2013-2017 period are group 2 (levofloxacin prophylaxis and meropenem as empirical antibiotics). The incidence of febrile neutropenia was 72% in group 1 and 86.2% in group 2 (p = 0.004). The majority of infectious episodes were associated with fever of unknown origin: 55% in group 1 and 59% in group 2. Febrile of unknown origin episodes were 82.6% in group 1 and 80% in group 2. Significant differences between both groups were found in age, hypogammaglobulinemia, and advanced disease at ASCT. No differences were found between groups regarding the most common agent documented in positive blood cultures (Gram+ were 66.6% in group 1 and 69% in group 2 (p = 0.68)). Mortality within 100 days of transplant was low, 1.87%. Regardless of the prophylactic regimen used, most patients experience febrile episodes in the ASCT setting, fever of unknown origin is the most common infection complication, and Gram+ agents are prevalent in both groups. Mortality rates were low. According to our results, ASCT is a safe procedure and there is no clear benefit in favor of levofloxacin versus ciprofloxacin prophylaxis. Both anti-infectious approaches are acceptable, yielding similar outcomes.

Mass Cytometry Enabling Absolute and Fast Quantification of Silver Nanoparticle Uptake at the Single Cell Level.

In the last decades, significant efforts have been made to investigate possible cytotoxic effects of metallic nanoparticles (NPs). Methodologies enabling precise information regarding uptake and intracellular distribution of NPs at the single cell level remain to be established. Mass cytometry (MC) has been developed for high-dimensional single cell analyses and is a promising tool to quantify NP-cell interactions. Here, we aim to establish a new MC-based quantification procedure to receive absolute numbers of NPs per single cell by using a calibration that considers the specific transmission efficiency (TE) of suspended NPs. The current MC-quantification strategy accept TE values of complementary metal solutions. In this study, we demonstrate the different transmission behavior of 50 nm silver NPs (AgNP) and silver nitrate solution. We have used identical AgNPs for calibration as for in vitro-differentiated macrophages (THP-1 cell line) in a time- and dose-dependent manner. Our quantification relies on silver intensities measuring AgNPs in the same detection mode as the cells. Results were comparable with the TE quantification strategy using AgNPs but differed when using ionic silver. Furthermore, intact and digested cell aliquots were measured to investigate the impact of MC sample processing on the amount of AgNPs/cell. Taken together, we have provided a MC-specific calibration procedure to precisely calculate absolute numbers of NPs per single cell. Combined with its unique feature of multiplexing up to 50 parameters, MC provides much more information on the single cell level than single cell-inductively coupled plasma mass spectrometry (SC-ICPMS) and, therefore, offers new opportunities in nanotoxicology.

Indoor radon in Spanish workplaces. A pilot study before the introduction of the European Directive 2013/59/Euratom.

OBJECTIVE: To explore whether there is a possible problem regarding indoor radon concentration surpassing the new European Directive 2013/59/Euratom threshold in Spanish workplaces. We also aim to find out whether radon concentration might be associated with certain characteristics of workplaces. METHOD: We performed a cross-sectional study to measure indoor radon concentrations in Spanish workplaces including five different sectors (education, public administration, the health sector, the tourist sector and the private sector). To be measured, the workplace should be occupied permanently by at least one worker. Alpha-track type radon detectors were placed for at least three months and read at the Galician Radon Laboratory at the University of Santiago de Compostela. A descriptive analysis was performed on radon distribution by sector, building characteristics and number of workers affected. RESULTS: We faced enormous difficulties in finding volunteers for this study. Galicia and Madrid had the highest number of measurements. Of a total of 248 measurements, 27% had concentrations above 300 Bq/m3. Median radon concentration was 251 Bq/m3 in Galicia, followed by Madrid, with 61.5 Bq/m3. Forty-six percent of the workplaces measured in Galicia had radon concentrations higher than 300 Bq/m3 followed by 10.6% in Madrid. Nineteen percent of all workers were exposed to more than 300 Bq/m3 and 6.3% were exposed to radon concentrations higher than 500 Bq/m3. CONCLUSION: Indoor radon exposure might be a relevant problem in Spanish workplaces and the number of affected workers could be high. The prevalence of workers exposed to high radon concentrations probably depends on the geographical area.

[Magnetic resonance as initial screening diagnosis of secondary involvement of central nervous system in NHL diffuse large B cell lymphoma] / Resonancia magnética como screening inicial de diagnóstico de compromiso secundario del sistema nervioso central en LNH difuso de grandes Células B.

Background: Background: Central Nervous System (CNS) relapse in Diffuse Large B-cell Lymphoma occurs mostly 6-8 months after disease onset. This has led to propose that CNS infiltration is an early event in the evolution of the disease. We intend to evaluate the role of magnetic resonance imaging (MR) at diagnosis to detect early SNC compromise. Methods: Prospective longitudinal cohort's study in DGCB patients treated at Hospital de Clínicas between 2013 and 2015. Skull MRI was performed in all patients at diagnosis and lumbar puncture was done according to predefined risk factors. Results: 35 patients were analyzed. Median age: 68 years (24-85 years). Stage III-IV: 62%, 57% good prognosis according to RIPI score and 43% poor prognosis. MRI was performed in all patients, with no pathological findings in any of them. Twenty-one patients fullfilled criteria for cerebrospinal fluid study. Twenty-two patients were studied and received intrathecal methotrexate prophylaxis. Meningeal relapse was observed in a single patient who had negative studies at diagnosis and had received complete prophylaxis at the end of the 6 R-CHOP series. Conclusions: Only one of the 35 patients relapsed in the CNS. This patient had a noral MRI and CSF study at diagnosis and had received prophylaxis with intrathecal chemotherapy. This results lead us to believe that the value of MRI to detect early infiltration in asymptomatic patients at diagnosis is low.

Antecedentes: la recaída en el Sistema Nervioso Central (SNC) del Linfoma No Hodgkin Difuso de Grandes Células B ocurre más frecuentemente 6-8 meses del debut de la enfermedad. Esto ha levado a plantear que la infiltración en SNC es un evento temprano en esta enfermedad. Nos proponemos evaluar el valor de la realización de estudio imagenológico por Resonancia Magnética (RM) al debut para detectar compromiso precoz. Materiales y métodos: Estudio longitudinal prospectivo de cohortes en LNH DGCB tratados en el Hospital de Clínicas entre 2013 y 2015. A todos los pacientes se les realizó RM de cráneo al debut y estudio de líquido cefaloraquídeo (LCR) según factores de riesgo predefinidos. Resultados: Se analizaron 35 pacientes. Mediana de edad: 68 años (24-85 años). Estadío III-IV: 62%; 57% presentaron buen pronóstico según score RIPI al debut y 43% mal pronóstico. Se realizó RM a todos los pacientes, no habiéndose encontrado hallazgos patológicos en ninguno de ellos. Veintitres pacientes tuvieron criterio de estudio del LCR de los cuales veintidós se estudiaron y recibieron profilaxis con metotrexate intratecal. Se observó recaída meníngea en una única paciente con estudios negativos al debut y profilaxis completa al mes de finalizadas las 6 series de R-CHOP. Conclusiones: De 35 pacientes uno sólo recayó en el SNC; el mismo había recibido profilaxis con quimioterapia intratecal y presentó una RM normal al debut de su enfermedad. Los resultados nos conducen a pensar que el valor de la RM para detectar precozmente infiltración en pacientes asintomáticos al debut es bajo.

Quantification of silver nanoparticle uptake and distribution within individual human macrophages by FIB/SEM slice and view.

BACKGROUND: Quantification of nanoparticle (NP) uptake in cells or tissues is very important for safety assessment. Often, electron microscopy based approaches are used for this purpose, which allow imaging at very high resolution. However, precise quantification of NP numbers in cells and tissues remains challenging. The aim of this study was to present a novel approach, that combines precise quantification of NPs in individual cells together with high resolution imaging of their intracellular distribution based on focused ion beam/ scanning electron microscopy (FIB/SEM) slice and view approaches. RESULTS: We quantified cellular uptake of 75 nm diameter citrate stabilized silver NPs (Ag 75 Cit) into an individual human macrophage derived from monocytic THP-1 cells using a FIB/SEM slice and view approach. Cells were treated with 10 µg/ml for 24 h. We investigated a single cell and found in total 3138 ± 722 silver NPs inside this cell. Most of the silver NPs were located in large agglomerates, only a few were found in clusters of fewer than five NPs. Furthermore, we cross-checked our results by using inductively coupled plasma mass spectrometry and could confirm the FIB/SEM results. CONCLUSIONS: Our approach based on FIB/SEM slice and view is currently the only one that allows the quantification of the absolute dose of silver NPs in individual cells and at the same time to assess their intracellular distribution at high resolution. We therefore propose to use FIB/SEM slice and view to systematically analyse the cellular uptake of various NPs as a function of size, concentration and incubation time.

Bioaccumulation of ionic titanium and titanium dioxide nanoparticles in zebrafish eleutheroembryos.

The production of titanium dioxide nanoparticles (TiO(2) NPs) for commercial applications has greatly increased over the last years and consequently the potential risk for human health. There is a growing awareness of the need to understand the behavior and influence these nanoparticles exert on the environment. Bioaccumulation serves as a good integrator to assess chemical exposure in aquatic systems and is dependent on factors, such as the exposure routes, diet and the aqueous medium. We analyzed the experimental bioaccumulation capability of ionic titanium and TiO(2) NPs by zebrafish (Danio rerio) eleutheroembryos through bioconcentration factors (BCFs), after 48 or 72 h of exposure. The stability of both chemical forms in an aquatic medium was fully characterized for further bioaccumulation studies. Several stabilizing agents (humic acids, soluble starch, polyethylene glycol, Na(4)P(2)O(7) and Na(2)HPO(4)) for anatase and rutile, the two allotrophs of TiO(2) NPs, were evaluated to check the evolution of the aggregation process. Around 60% of TiO(2) NPs remained disaggregated under simulated environmental conditions with the addition of 50 mg L(-1) of humic acids. However, the presence of eleutheroembryos in the exposure medium increased TiO(2) NPs aggregation in the experimental tests. The BCFs values obtained in all cases were <100, which classifies ionic titanium and TiO(2) NPs as non-bioaccumulative substances, under the REACH regulations.

Transformation of tributyltin in zebrafish eleutheroembryos (Danio rerio).

Organotin compounds are highly versatile group of organometallic chemicals used in industrial and agricultural applications. Their endocrine-disrupting effects are well known and their extensive uses as biocide materials, e.g., in antifouling paints, for many years have led to serious environmental problems. So far, attention has mainly been given to tributyltin pollution in water, sediments, and marine organisms because of its highly toxic effects and high accumulation levels at very low concentrations. In this study, we will focus on the conversion of tributyltin after it is absorbed by zebrafish eleutheroembryos, presented here as an alternative model to adult fish for describing bioconcentration. A simplified analytical extraction procedure based on the use of an assisted ultrasonic probe and derivatization by ethylation, followed by gas chromatography with a flame photometric detector (GC-FPD) is proposed. This classical methodology for organotin determination has been validated by inductively coupled plasma mass spectrometry (ICP-MS) and Zeeman graphite furnace atomic absorption spectrometry (ZGF-AAS) in terms of total tin content. The speciation analysis results show that zebrafish eleutheroembryos absorb high amounts of tributyltin and convert it into monobutyltin and likely in inorganic tin.

Does water chemistry affect the dietary uptake and toxicity of silver nanoparticles by the freshwater snail Lymnaea stagnalis?

Silver nanoparticles (AgNPs) are widely used in many applications and likely released into the aquatic environment. There is increasing evidence that Ag is efficiently delivered to aquatic organisms from AgNPs after aqueous and dietary exposures. Accumulation of AgNPs through the diet can damage digestion and adversely affect growth. It is well recognized that aspects of water quality, such as hardness, affect the bioavailability and toxicity of waterborne Ag. However, the influence of water chemistry on the bioavailability and toxicity of dietborne AgNPs to aquatic invertebrates is largely unknown. Here we characterize for the first time the effects of water hardness and humic acids on the bioaccumulation and toxicity of AgNPs coated with polyvinyl pyrrolidone (PVP) to the freshwater snail Lymnaea stagnalis after dietary exposures. Our results indicate that bioaccumulation and toxicity of Ag from PVP-AgNPs ingested with food are not affected by water hardness and by humic acids, although both could affect interactions with the biological membrane and trigger nanoparticle transformations. Snails efficiently assimilated Ag from the PVP-AgNPs mixed with diatoms (Ag assimilation efficiencies ranged from 82 to 93%). Rate constants of Ag uptake from food were similar across the entire range of water hardness and humic acid concentrations. These results suggest that correcting regulations for water quality could be irrelevant and ineffective where dietary exposure is important.

Jak-2 positive myeloproliferative neoplasms.

Originally described by Dameshek in 1951, myeloproliferative disorders are today classified as myeloproliferative Neoplasms (MPNs) in WHO's Classification of Tumors of Hematopoietic and Lymphoid Tissues. The term includes a range of conditions, [ie, BCR-ABL-positive chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), polycythemia vera (PV), primary myelofibrosis (PMF), essential thromobocythemia (ET), chronic eosinophilic leukemia not otherwise specified (CEL-NOS), mastocytosis, and unclassifiable myeloproliferative neoplasm]. In the specific case of CML, a better understanding of the pathogenesis and pathophysiology of the disease has led to a targeted therapy. The presence of chromosome Philadelphia, t(9;22)(q34;11) results in the oncogene BCR-ABL, which characterizes the disease; this molecular rearrangement gives rise to a tyrosine-kinase, which in turn triggers the proliferation of the myeloid line through the activation of the signaling pathways downstream. Tyrosine-kinase inhibitors (TKIs) have altered the therapy and monitoring of CML patients and improved both their prognosis and quality of life. In 2005, various groups of investigators described a new point mutation of the gene JAK2 associated to MPNs. Although the presence of this mutation has led to a modification in the diagnostic criteria of these conditions, the impact of the use of JAK2 inhibitors on the prognosis and course of the disease continues to be controversial.

Response to arsenate treatment in Schizosaccharomyces pombe and the role of its arsenate reductase activity.

Arsenic toxicity has been studied for a long time due to its effects in humans. Although epidemiological studies have demonstrated multiple effects in human physiology, there are many open questions about the cellular targets and the mechanisms of response to arsenic. Using the fission yeast Schizosaccharomyces pombe as model system, we have been able to demonstrate a strong activation of the MAPK Spc1/Sty1 in response to arsenate. This activation is dependent on Wis1 activation and Pyp2 phosphatase inactivation. Using arsenic speciation analysis we have also demonstrated the previously unknown capacity of S. pombe cells to reduce As (V) to As (III). Genetic analysis of several fission yeast mutants point towards the cell cycle phosphatase Cdc25 as a possible candidate to carry out this arsenate reductase activity. We propose that arsenate reduction and intracellular accumulation of arsenite are the key mechanisms of arsenate tolerance in fission yeast.

[Effects of a revision program on the control of type 2 diabetics followed at the primary care level. Diabetes First program]. / Efectos de un programa de revisión en el control de los diabéticos tipo 2 seguidos en atención primaria. Programa Diabetes First.

BACKGROUND AND OBJECTIVE: To analyze the evolution of the glycosylated hemoglobin and other parameters after performing a control program and follow-up by nurses to improve the control of the patients with type 2 diabetes mellitus (Diabetes First). PATIENTS AND METHOD: Intervention study in type 2 diabetes mellitus patients from Murcia. The inclusion criterium was to be a type 2 diabetes mellitus patient badly controlled on diabetes parameters (glycosylated haemoglobin > or = 7%). We included 831 patients from 8 primary care centers. The program consisted of three visits (first one, after three months and after six months), where the patients received diabetic education. RESULTS: The mean initial glycosylated haemoglobin value was 8.1% +/- 1.3%, after 3 months it decreased to 7.5% +/- 1.1%, and after 6 months from the first visit its value was 7.5% +/- 2.6%. There was a statistically significant (p < 0.001) difference between the initial glycosylated haemoglobin and the values three months later. There was not such a difference between the second and third visit. Total and low-density liporpotein cholesterol decreased significantly after 3 months (p < 0.05). High-density lipoprotein cholesterol and triglycerides showed no difference. Systolic and diastolic blood pressure significantly decreased after three months (p < 0.0001 and p < 0.005). CONCLUSIONS: A simple nursing intervention program performed in primary care centers has a very positive impact on the control and treatment of patients with type 2 diabetes mellitus.