Worldwide, 18.1 million new invasive cancers and 9.9 million cancer deaths occurred in 2020. Lung cancer is the second most frequent (11.4%) and, with 1.8 million deaths, remains the leading cause of cancer mortality. About 1.7 million of lung cancers are of the non-small cell lung cancer (NSCLC) subtype, and of these, 60%–70% are in advanced stage IV at the time of diagnosis. Thus, the annual worldwide number of new NSCLC stage IV patients is about 1 million, and they have a very poor prognosis. Indeed, 25%–30% die within 3 months of diagnosis. However, the survival duration of the remaining 700,000 new patients per year surviving >3 months varies enormously. Surprisingly, little research has been done to explain these survival differences, but recently it was found that classical patient, tumour and treatment features cannot accurately distinguish short- and very long-term survivors. What then are the causes of these bewildering survival variations amongst “the same cancers”? Clonality, proliferation differences, neovascularization, intra-tumour heterogeneity, genetic inhomogeneity and other cancer hallmarks play important roles. Considering each of these, single or combined, can greatly improve our understanding. Another technique is analysis of the survival curve of a seemingly homogeneous group of cancer patients. This can give valuable information about the existence of subgroups and their biological characteristics. Different basic survival curves and what their shapes tell about the biological properties of these invasive cancers are discussed. Application of this analysis technique to the survival curve of 690 stage IV NSCLC patients with a 3.2–120.0-month survival suggests that this seemingly homogeneously group of patients probably consists of 4–8 subgroups with a very different survival. A subsequent detailed mathematical analysis shows that a model of 8 subgroups gives a very good match with the original survival curve of the whole group. In conclusion, the survival curve of a seemingly homogeneous group of cancer patients can give valuable information about the existence of subgroups and their biological characteristics. Application of this technique to 690 NSCLC Stage IV patients makes it probable that 8 different subgroups with very different survival rates exist in this group of cancers. Worldwide, an estimated 18.1 million new invasive cancer cases and almost 9.9 million cancer deaths occurred in 2020. The average mortality rate of invasive cancers is therefore about 50%. Lung cancer, the second most frequently occurring cancer at 11.4%, with an estimated 1.8 million deaths, remains by far the leading cause of cancer mortality . The samWhat are the causes of these bewildering survival variations amongst “the same cancers”?clonality. Cancer is an evolutionary process, driven by stepwise, somatic cell mutations with sequential, sub-clonal selection , is less certain. From there to lethal metastases of 1,000 g (rough estimate), or 1012 cells, depends amongst other factors on intratumour heterogeneity (ITH)  to a clinically detectable proliferating invasive cancer, of approximately 10 (7.5–15.0) mm (10ty (ITH) . GenomicIt is of obvious clinical and therapeutic significance to understand why patients, with seemingly homogeneous cancers, have such different survival rates. Of course, often, age, gender, performance stage, histologic subtype, no/minimal versus heavy smoking and different treatment modalities are strongly prognostic. In pulmonary adenocarcinoma, the mean number of clonal and sub-clonal non-silent mutations in non-smokers is much smaller than in smokers . HoweverWe recently worked on an article on the survival prediction accuracy of prognostic factors in the seemingly homogeneous group of 690 stage IV NSCLC surviving patients between 3.2 and 120.0 months. In the original manuscript, we hypothesized that this group in fact consisted of several hypothetical subgroups with widely varying survival rates. This hypothesis was based on the interpretation of the survival curve of the patients . . The 60% deaths in the first 6 months have on average reached their lethal metastatic mass within 6 months. Of course, the original volume at diagnosis may have varied, but the most important feature of these 60% of the tumours, compared with the other 20% dying between 6 and 12 months, is their higher net growth . Likewise, the patients dying between 12 and 23 months again have a lower net growth rate. One can thus conclude that Group B tumours are both invasive, clonally expanding but also metastatic. One can further conclude from the survival curve of group B that it is not completely homogeneous but still consists of at least 3 subgroups with different proliferation rates (net growth speeds): very fast, fast and less fast.Cancers from Group B patients not only have invasive and clonal expansion properties, just like those from group A, but also all have A fourth type of survival curve is shown in Of course, such a linear curve can be found with different follow-up times, for example 10, 20 and 30 years. Examples are Hodgkin-type lymphomas and certain breast cancers.p = 0.04). Of these latter 690 patients, 42% were females, 58% males, median age 63 (range 27–85) years, 1-, 2-, 5- and 10-year survival rates 74%, 49%, 16% and 5%, respectively. 16% were alive with disease (AWD) at the last follow-up. Pathology subtype , performance score, TNM substage, the number of PBT cycles and TKI-TT had independent predictive value. However, with the multivariate combination of these features, identification results of short-term non-survivors and long-term survivors were poor.As described before, about 1.7 million of the lung cancers are NSCLC, and of these, 60%–70% are in advanced stage IV at the time of diagnosis. Thus, the annual worldwide number of new NSCLC stage IV patients is close to 1 million . 25%–30%The shape of the survival graph of the 690 patients . The slope of this third line again is less steep.Between 28% and 18% survival probability (follow-up at 45% and around 55–60 months), another nearly straight line can be discerned.Then, a somewhat less straight line from 18% to 10% can be observed from approximately 60 to 96 months of follow-up, respectively.Beyond the 96-month follow-up, the line is somewhat irregular, but roughly nearly horizontal from 10% to 5% (at the 120-month follow-up).The right part of The quantitative and graphical analyses described in the total group of 690 patients probably consists of different subgroups with different biological behaviour and survival rates.It is important to note that these 690 individuals had the same histological type (NSCLC) and stage (IV). Thus, all had metastases at the time of diagnosis and also at the entry in this study, at least 3 months after the diagnosis. Yet, some died very quickly, (within 12 months), and others survived very long (5–10 years). The 690 “homogeneous” group in retrospect was heterogeneous, i.e., consisted of subgroups with different survival rates.How many different subgroups exist in the 690 patients?The Actual Observed survival curve gives important clues. Remember that 261 stage IV NSCLC patients from the same observation period had already died before the 3-month survival and are not considered in the current study. This explains why the survival curve of the 690 patients in Closer observation shows that there are typical points in the graph, in which the slope of the survival curve shows a subtle change and becomes less steep. These points are shown in Q: 70% survival/14-month follow-up,R: 40%/30 months,S: 18%/54–60 monthsT: 10%-5%/90–108 months. Note that the number of patients becomes quite low after 90 months of follow-up, which could have caused the less smooth shape of the curve between 90 and 120 months of follow-up.Linear (straight) lines can be drawn between these points . These are shown in Of course, the subgroups which these lines represent did not start to exist at their respective starting points Q, R, S but were all present in the total group at the start of study . Consequently, the lines from From As the match of 4 hypothetical subgroups was not perfect, we then repeated the modelling study for 8 subgroups. 8 hypothetical subgroups are also determined by the linear tangent method used in In summary, the abovementioned shows that a combination of patients with linear non-curved survival curves with different survival rates can result in a curved survival line which is very close to the Actual Observed survival curve of the 690 patients. Secondly, it is highly probable that at least 4 and more likely 8 different subgroups with very different survival rates exist in the 690 NSCLC Stage IV patients.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.JB: concept of study and article, analysis, interpretation of results; drafting of the article and revising it critically for important intellectual content; final approval. HL: revising of the manuscript critically for important intellectual content; final approval. HG: conception and design of the study; analysis and analysis support; interpretation of data; drafting of the article or revising it critically for important intellectual content; final approval. All authors contributed to the article and approved the submitted version.This study was funded by a personal grant no. 2021-177 to JB from Medical Practice Dr. Jan Baak Inc., Tananger, Norway, to participate in this study and for the translation correction and publication costs.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The success of hypertension therapy is dependent on the healthcare systems and healthcare professionals in supplying enough medication, support of friends/family, and maintaining scheduled follow-ups. A combination of interventions using low-cost mobile technology led by healthcare professionals could be endorsed. To fully practice universal access to medication, public and private hospitals in Namibia should collaborate.In Namibia, the prevalence of hypertension among women and men aged 35–64 years is high, ranging from 44% to 57%. In this study, we aimed to determine adherence and predictors to antihypertensive therapy in Khomas region, Namibia. A cross-sectional study was performed to consecutively sample 400 patients from urban and peri-urban settings in Namibia. Results were validated using the Hill-Bone Compliance to High Blood Pressure Therapy Scale. Crude associations between predictors of adherence and compliance were tested using the Pearson chi-square test. A multivariable logistic regression analysis was then performed on adherence variables found to be significant to adjust for confounders, and the results are presented as adjusted odds ratios (aOR) with 95% confidence intervals. A total of 400 patients participated in this study. The participants’ mean age and standard deviation were Mean ± SD = 48.9 ± 12.5. In this study, 351 (87.7%) patients were estimated to have good adherence. Education, employment, and the presence of other chronic diseases were associated with adherence. Following multivariate adjustment, the following factors were significantly associated and are therefore predictors of adherence (95%CI,  Hypertension is the most important leading risk factor for cardiovascular diseases (CVDs), accounting for 17.3 million deaths annually, with 80% of these deaths occurring in low- and middle-income countries (LMICs) ,3. In NaIndirect measurements of hypertension include but are not restricted to patient interviews, adherence questionnaires, and pill count, whereas direct methods include drug measurement in body fluids and biomarker measurement in body fluids . AdherenWhereas it is substantial to understand the measurement of hypertension adherence, it is equally important to explore different interventions to improve BP medication adherence ,25,26. TThe World Health Organization recommends understanding BP determinants for adherence to reduce the high prevalence of hypertension complications . In chooWe employed a cross-sectional study to assess hypertension adherence among blood pressure patients receiving their BP medication from public and private health facilities in Windhoek district, Khomas region. Khomas region is the capital region of Namibia and, out of the 14 regions, is the most central region in the country . The popThis study included and recruited 400 hypertensive patients diagnosed with hypertension and completed at least one cycle (6 months) of antihypertensive medication refill at the public health center or private centers. Patients were aged 18 years and above and could recognize and tell apart their antihypertensive medicines from any other daily medicines. Blood pressure patients who were not hypertensive or hypertensive but did not complete at least 6 months, patients with mental health diagnoses, and pregnant women were excluded. The primary outcome was the proportion of patients with adherence levels to antihypertensive therapy ≥80% on the Hill-Bone blood pressure scale, and the secondary outcome was the predictors of adherence to hypertensive medication.The following formula was applied to estimate the sample size:where:n= 328 (public facilities) and n = 72 (private centers). The attendance catchment population of 2019 for each public health facility and their estimated hypertension prevalence during that year was used to estimate the specific sample size for each public facility. As there was no estimated BP (blood pressure) prevalence data from private centers, an equal number of 18 patients was sampled from each private center, namely Roman Catholic, Wanahenda Medical Center, Windhoek West Medical Center, and Pionierspark Medical Centre. A consecutive sampling method was used to recruit participants for this study. Refer to services ; the estData were collected from 19 January 2021 to 31 June 2021 in Windhoek, Khomas region, using a semi-structured questionnaire. The questionnaire included three (3) sections (A–C). Section A assessed socio—demographic characteristics and anthropometric measurements, section B assessed patient medical history, and section C was the piloted HBCHTS questionnaire . The HBCThe HBCHTS reliability  coefficient was conducted to measure the consistency of the 14 questions/items. The scale assesses patient behaviors for three important behavioral domains of high blood pressure treatment: reducing sodium intake, appointment keeping, and medication adherence. The higher the Cronbach’s alpha, the better the reliability. The item–rest correlation indicates the correlation between an item and the scale. The items were excluded if the results had a low alpha value and the lowest item–rest correlation. Principal component analysis (PCA) was used to assess construct validity of the entire questionnaire. The Hill-Bone scale was previously validated in Namibia but only for peri-urban areas . TherefoData were analyzed descriptively and analytically using STATA-17 software. The responses to the 14 original items of the Hill-Bone HBP Compliance to High Blood Pressure Therapy Scale (HB-HBP) were coded as follows: 1 = all the time, 2 = most of the time, 3 = some of the time, and 4 = none of the time, where high values are better. The coding for one variable (item 6) had to be reversed. From the reliability analysis, three (3) variables were dropped. The remaining 11 variables were then summed to give scores on a resulting scale of 11–44, where 11 is the worst score, and 44 is the best. The total scores were then converted to the percentage scale using the following formula:p-value < 0.1) from these bivariate comparisons were inputted into a multivariable logistic regression analysis to determine the unadjusted and adjusted relative odds of having good adherence (≥80%) as opposed to poor adherence.The resulting percentage scores were then categorized as good adherence (≥80%) and poor adherence (<80%). This categorized adherence variable was then used in comparisons with respondents’ characteristics and experiences with hypertension using the Pearson chi-square test (or Fisher’s exact test if expected frequency <5 observations). Variables that were significantly associated at 10% level  mmHg was significantly lower compared to those with poor adherence (97.2 ± 19.6) mmHg; t = 4.68, p < 0.001. Hypertension adherence across the following items was statistically significant (p< 0.001): age, employment, patients receiving adequate medication until the next visit, encouragement of family and friends to take medication, and consistency in attending follow-ups on schedule . At least 50% of the participants were employed, and the rest were either retired, unemployed, or were still students. The majority of the participants received a monthly income between N$500–1999. Less than 23% had an income of between N$5000 and N$10,000 or more. Body mass index (BMI) indicates that most patients were overweight and obese, and a few were underweight (Mean ± SD = 28.4 ± 6.7). Fifty-nine (59%) of the patients included in this study had been diagnosed with hypertension for more than five years, and 29% of the total participants had been diagnosed with other chronic diseases and conditions, namely HIV, diabetes, asthma, epilepsy, heart diseases, allergies, high cholesterol level, gastritis, gout, and Hypothyroidism. The patients’ experiences with hypertension and adherence show that more than 80% had an adequate supply of medication to last them until the next visit and had knowledge of the importance of taking medication and the consequences if medication is not taken. Support from family and friends to take medication was more than 70%. Most patients reported that their family and friends did not accompany them during follow-ups (68%). Of the 19% of patients who did not always attend follow-ups, the main reasons were forgetting, transport and financial constraints, distance, laziness, and work commitments. At bivariate analysis, mean systolic blood pressure for those with good adherence (137.0 ± 21.0) mmHg was significantly lower than that for those with poor adherence (149.1 ± 28.0) mmHg; t = 3.61, dule see p < 0.005): receiving enough medication at the last check-up until the next one , encouragement of family and friends (OR = 0.11 (0.03–0.42)), and attendance of follow-ups on schedule  . The following factors were significantly associated with good adherence  .In this study, we aimed to determine the levels of adherence and predictors in antihypertensive therapy in public and private health facilities of a high-burden region in Namibia. In this study, 351 (87.7%) of the patients were estimated to have good BP adherence levels (adherence > 80%). Overall, most of the Hill-Bone items performed well; however, forgetting to take hypertension medication, adherence to dietary advice, missing scheduled appointments, and running out of hypertension medication still raised concerns. The adherence findings of the current study were measured by a modified 11-item validated Hill-Bone compliance (HBCHTS) scale. Sociodemographic characteristics, such as education and employment, were associated with adherence. The presence of other chronic diseases was also associated with adherence. The present study’s findings show that having received enough medication at the last check-up until the next one, family and friends’ encouragement to take medication, and always attending follow-up schedules on time were significantly associated with good adherence and are therefore predictors of BP adherence. High adherence levels are not only good for the control of blood pressure but will also help Namibia achieve the WHO global target of a 25% relative reduction in the risk of premature mortality from NCDs by 2025. Our findings show a need to continue promoting adherence and further strengthening existing policies. This way, Namibia can reach the Sustainable Development Goals (SDG) target of a one-third reduction in premature deaths from NCDs by 2030.n = 521, 80.4%), hypertensive patients were adherent using according to the HBCHTS compliance scale [Adherence can vary from region to region depending on the population and the measurement scale ,35. It wce scale . One of ce scale . This coce scale . We usedce scale ,18. HoweStudies have shown that some progress has been made to improve adherence by modifying the medication type, dosing, and regimen, with simplified regimens including once-a-day medication promoting best adherence ,40,41,42The World Health Organization has recommended that a strong focus be directed on understanding the variety of factors that may influence antihypertensive medication adherence . In partWhen implementing the correct intervention for the right setting, it is equally important to continuously evaluate interventions to constantly improve adherence to treatment regimens ,51. We rOverall, adherence to antihypertensive medication was good in patients with a diagnosis of hypertension in Khomas region. Although adherence was good, certain individuals were non-adherent despite universal access to medication in Namibia. The success of hypertension therapy depends on the healthcare system and healthcare professionals in supplying enough medication, support of friends/family, and maintaining scheduled follow-ups. A combination of interventions using low-cost mobile technology led by healthcare professionals could be helpful to further improve adherence. To practice universal access to medication, it may be essential that public and private hospitals in Namibia collaborate.


Melanocytic neuroectodermal tumor of infancy (MNTI) is a rare benign pigmented neoplasm that arises from the neural crest and has an aggressive growth pattern. It is predominantly seen in infants under 1 year of age, and the most common site of involvement is the maxilla. The currently accepted treatment is removal by surgical resection. Herein, we report a case of MNTI that involved the anterior alveolar ridge of the mandible in a 6-month-old infant.A case of a 6-month-old male child with a huge mass in the anterior alveolar ridge of the mandible.The tumor was diagnosed using histopathological and immunohistochemical techniques on the biopsy specimen obtained following incisional biopsy. Based on the findings, a final diagnosis of MNTI was established.Radical resection of the tumor was performed, after determining the extent of resection by referring to the mandibular 3D model created using the pre-operative CT data.The postoperative course was uneventful, and no recurrence has been observed to date for more than 4 years after surgery.This case emphasizes that early diagnosis and radical surgery are critical to the effective treatment, as MNTI exhibits rapid and destructive growth. It also requires careful and close follow-up because of high recurrence rates. The most common site of occurrence is the maxilla, with approximately two-thirds of lesions occurring there. However, there are reports that MNTI can also involve the mandible, skull, brain, epididymis, and mediastinum. Surgical resection is the conventional definitive treatment for this tumor. Due to the relatively high recurrence rate, MNTI should be followed carefully after surgery. In this paper, we describe a case of MNTI involving the mandibular anterior alveolar ridge of a 6-month-old infant.Melanocytic neuroectodermal tumor of infancy (MNTI) is a rare benign pigmented neoplasm of neural crest origin, which was first described by Krombecher as congenital melanocarcinoma in 1918.This study was approved by ethics committee review board of Niigata University . Written informed consent was obtained from the patient's family for publication of the case details and accompanying images.2A 6-month-old male child was referred to our hospital with a mass on the anterior alveolar ridge of the mandible. The patient's parents noticed this mass at the age of 4 months, which rapidly increased in size thereafter.At his first visit to our hospital, his face was symmetrical, but the lower lip was protruded. A relatively well-defined spherical mass (30 × 20 × 20 mm) was located on the mandibular alveolar ridge extending from the right mandibular deciduous canine to the left mandibular first deciduous molar Fig. . The masComputed tomography (CT) showed a relatively uniform multicentric osteolytic lesion extending from the right mandibular deciduous central incisor to the left mandibular deciduous canine with expansion of the surrounding bone and numerous displaced tooth germs. The density of the lesion mass was lower than that of the muscle, and the boundary with cancellous bone was irregular Fig. . HistopaThe tumor continued to grow rapidly, and marginal mandibulectomy was performed under general anesthesia 28 days after the first visit to our hospital. The extent of resection was determined by referring to the mandibular 3D model which was created based on the CT data obtained before the surgery. Marginal mandibulectomy, approximately 5 mm lateral to the tumor, was successful in preserving the inferior margin of the mandible , which identified the neural crest origin of the disease. They also reported that the tumor is biphasic, consisting of epithelioid melanogenic cells and neuroblast-like cells. However, this case did not match any of the histopathological findings. Histopathologically, all MNTIs have biphasic morphology characterized by small primordial neuroblast-like cells and larger peripheral epithelioid cells containing melanin granules. Immunohistochemistry can be used as a diagnostic aid, where biopsy specimens reveal a neuroblast-like morphology and expression of neuronal markers such as neuron-specific enolase, synaptophysin, and chromogranin A can confirm the neuroblastic origin of the small cells. The large cells have a lightly eosinophilic or vacuolated cytoplasm, an oval bright nucleus with small nucleoli, and are of ectodermal origin, which can be confirmed by epithelial membrane antigen, cytokeratin, and HMB-45 positivity. This heterogeneity of cellular phenotypes is probably explained by the morphological features of the mesoderm and ectoderm displayed by neural crest cells at different stages of their ontogeny.The histological diagnosis of MNTI is relatively simple and rarely poses a diagnostic challenge if an appropriate tissue specimen is available for histopathological examination. The differential diagnosis of MNTI includes other neoplasms of infancy, especially neuroblastoma, Ewing sarcoma, and alveolar rhabdomyosarcoma. we found 49 cases reported between January 2014 and June 2021 by searching PubMed.–32,36–38 In a systematic review of 472 MNTI cases, most cases developed within 1 year of age, with more than 90% of cases occurring in the craniofacial region, such as the maxilla (60.3%), skull (18.1%), and mandible (10.3%). On the other hand, to summarize the reported cases since 2014, 27 (87.1%) cases of MNTI developed within 1 year of age, and 32 (65.3%) cases occurred in the maxilla, 4 (8.2%) in the mandible, and 1 (2%) in the hard palate, while 12 (24.5%) cases occurred outside the oral cavity, such as the cranial bone, middle ear, upper arm, fibula, and ovary.More than 500 cases of MNTI have been reported worldwide by Rachidi et al. In addition to the 472 cases reported between 1918 and 2013 as a part of the largest retrospective study,,38 The definitive treatment for MNTI is usually surgical resection. Complete resection of the lesion is a particularly important factor for determining disease-free survival time. Chemotherapy may be effective in cases where complete resection of the lesion is difficult or where the tumor remains or metastasizes.,29,38 To reduce the possibility of recurrence, it is necessary to include the adjacent teeth, bones, and soft tissues within the resection margin according to the extent of the tumor. Some authors argue that the surgically resected area should include a margin of 5 mm in healthy tissue.–35 There is no obvious treatment strategy for metastatic and/or recurrent MNTI that is unresectable. In these cases, chemotherapy may be effective for treating large tumors and residual tumors.,38 In a previous study, only 3 out of 249 cases of MNTI were treated with chemotherapy without surgery. However, the combination of surgery, chemotherapy, and radiotherapy can cause serious acute and late radiation injury in infant patients and requires careful consideration and restricted use. Recurrence rates for MNTI have been reported to be 15% to 27% for multiple reasons, including incomplete resection and the occurrence of multicentric tumors.,5,8 In addition, cases of MNTI diagnosed before 2 months of age have the highest risk of recurrence and all cases of relapse occur within 6 months of surgery. We have also encountered a previous case in which a segmental mandibulectomy had to be performed because of recurrence, 1 month after the first surgery.MNTI is typically a benign lesion and presents as an enlarging, painless, and firm mass, often underlying an intact epithelial surface; however, it has a relatively high risk of recurrence, and peripheral lymph nodes may be involved. Metastasis to distant organs occurs in approximately 6.5% of patients. In the present patient, marginal mandibulectomy based on appropriate early diagnosis was performed, including almost all deciduous and permanent tooth germs ranging from the mandibular anterior teeth to premolars, and no recurrence has been observed to date more than 4 years after surgery. In the future, occlusal reconstruction and recovery of masticatory function following surgery will be the crucial therapeutic goals.Although definitive MNTI treatment guidelines have not been established, radical surgery with safety margins is the accepted current gold standard because of the rapid and destructive growth of the tumor into the surrounding tissues and the high propensity for recurrence. In addition, early diagnosis and regular follow-up are important. On the other hand, in the case of a large MNTI and extensive tissue loss, reconstruction of the maxillofacial region is essential, which can be very challenging in infants.Conceptualization: Ryoko Takeuchi, Akinori Funayama, Takafumi Hayashi, Jun-Ichi Tanuma, Tadaharu Kobayashi.Data curation: Ryoko Takeuchi.Formal analysis: Ryoko Takeuchi, Akinori Funayama, Tatsuya Abé, Takafumi Hayashi, Tadaharu Kobayashi.Investigation: Ryoko Takeuchi, Akinori Funayama, Yohei Oda, Tatsuya Abé, Manabu Yamazaki, Satoshi Maruyama, Takafumi Hayashi, Tadaharu Kobayashi.Methodology: Ryoko Takeuchi, Akinori Funayama, Yohei Oda, Tatsuya Abé, Manabu Yamazaki, Satoshi Maruyama, Takafumi Hayashi, Jun-ichi Tanuma, Tadaharu Kobayashi.Project administration: Tadaharu Kobayashi.Supervision: Akinori Funayama, Jun-ichi Tanuma, Tadaharu Kobayashi.Validation: Ryoko Takeuchi, Akinori Funayama, Yohei Oda, Tatsuya Abé, Manabu Yamazaki, Satoshi Maruyama, Takafumi Hayashi, Jun-ichi Tanuma, Tadaharu Kobayashi.Visualization: Ryoko Takeuchi, Tatsuya Abé, Jun-ichi Tanuma, Tadaharu Kobayashi.Writing – original draft: Ryoko Takeuchi.Writing – review & editing: Ryoko Takeuchi, Akinori Funayama, Tadaharu Kobayashi.


Elevated serum cholesterol levels, either associated or not with increased triglycerides, represent a risk of developing vascular injury, mostly leading to atherothrombosis-related diseases including myocardial infarction and stroke. Natural products have been investigated in the last few decades as they are seen to offer an alternative solution to counteract cardiometabolic risk, due to the occurrence of side effects with the use of statins, the leading drugs for treating hyperlipidemias. Red yeast rice (RYR), a monacolin K-rich natural extract, has been found to be effective in counteracting high cholesterol, being its use accompanied by consistent warnings by regulatory authorities based on the potential detrimental responses accompanying its statin-like chemical charcateristics. Here we compared the effects of RYR with those produced by bergamot polyphenolic fraction (BPF), a well-known natural extract proven to be effective in lowering both serum cholesterol and triglycerides in animals fed a hyperlipidemic diet. In particular, BPF at doses of 10 mg/Kg given orally for 30 consecutive days, counteracted the elevation of both serum LDL cholesterol (LDL-C) and triglycerides induced by the hyperlipidemic diet, an effect which was accompanied by significant reductions of malondialdehyde (MDA) and glutathione peroxidase serum levels, two biomarkers of oxidative stress. Furthermore, the activity of BPF was associated to increased HDL cholesterol (HDL-C) levels and to strong reduction of Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels which were found increased in hyperlipidemic rats. In contrast, RYR at doses of 1 and 3 mg/Kg, produced only significant reduction of LDL-C with very poor effects on triglycerides, HDL-C, glutathione peroxidase, MDA and PCSK9 expression. This indicates that while BPF and RYR both produce serum cholesterol-lowering benefits, BPF produces additional effects on triglycerides and HDL cholesterol compared to RYR at the doses used throughout the study. These additional effects of BPF appear to be related to the reduction of PCSK9 expression and to the antioxidant properties of this extract compared to RYR, thereby suggesting a more complete protection from cardiometabolic risk. Hypercholesterolemia, either associated or not to increased triglyceride serum levels, has been clearly shown to represent one of the key players in the development of atherosclerosis-associated vascular disorders including coronary artery disease and stroke ,2. On thIn the last decades, this was achieved by means of extensive use of very effective drugs such as the statins, which reduce endogenous biosynthesis of cholesterol, via inhibition of hydroxy-3-methylglutaryl-CoA reductase (HMGCoA reductase), the key enzyme of the pathway generating cholesterol from acetyl-CoA ,7,8.This class of drugs, due to their widespread activities in protecting vascular tissues, , has also been found able to reduce hospitalization and mortality in high-risk atherosclerotic patients ,7.Alongside their beneficial effect in the prevention and treatment of cardiovascular disorders, the use of statins is however associated to several side effects that include muscular pain, rhabdomyolysis and subsequent elevation of serum creatine phosphokinase (CPK) ,10,11. TMonascus purpureus mold that has widely been used to reduce serum cholesterol in patients [to be unable to identify a dietary intake of monacolins from RYR, not giving rise to concerns about potentially harmful effects to health for the general population, and as appropriate, for vulnerable subgroups of the population” [Red yeast rice (RYR) is a natural extract obtained via fermentation of white rice with the yeast patients ,18. The patients . To datepatients ,20. Howeulation” .Thus, based on this conclusion, it is necessary to identify better nutraceutical solutions to attenuate the potential risk of using RYR as a first line nutraceutical approach and to counteract potential side effects and uncertainties deriving from elevated amounts of monacolin K in final preparations.Based on this preliminary evidence, the present study was addressed to evaluate the potential synergistic response in a formulation containing lower concentration of RYR either associated or not to bergamot polyphenolic fraction (BPF) a well characterized natural extract deriving from bergamot juice which has been found to produce consistent hypolipidemic response both in animal settings and in patients ,24,25,26RyR extract (NLT 3% Monacolin K) was purchased from Giellepi S.p.A .C. bergamia Risso & Poiteau fruits were collected in the Calabrian region, from plantations that cover 90 km long costal area located between Reggio Calabria and Bianco. Bergamot juice (BJ) was obtained from peeled-off fruits by industrial pressing and squeezing. The depletion of oil fraction from juice was obtained through the stripping and the clarification by ultra-filtration; the subsequent loading on suitable polystyrene resin columns  that absorbed polyphenol compounds of MW between 300 and 600 Da [d 600 Da . The elud 600 Da . StandarHigh-pressure liquid chromatography (HPLC) analysis was performed on Fast 1200 HPLC system  equipped with DAD detector and ZORBAX Eclipse XDB-C18 column—50 mm. Two μL of sample (BPF diluted in 50% ethanol and filtered through a 0.2 μm filter) was injected eluting with a two solvent gradient of water and acetonitrile. Different gradients were used for the determination of flavonoid content or possible fumocumarin contaminants. The flow-rate was 3 mL/min and the column was maintained at 35 °C. The detector was monitored at 280 nm. Flavonoid and furocumarin pure standards were purchased from Sigma-Aldrich . Brutieridin and melitidin were identified according to Di Donna ,23. The Male Wistar rats , weighing 180–200 g, were used for the experiments. The animals were kept under stable and controlled conditions  with water ad libitum. Animal care was in accordance with Italian regulations on protection of animals used for experimental and other scientific purposes (D.M. 116192), as well as with the European Community guidelines .The effects of BPF, or RYR on total cholesterol, LDL-C, high density lipoprotein cholesterol (HDL-C), triglycerides, malondialdehyde (expressing peroxidative damage) and paraoxonase were evaluated in Wistar rats fed a hypercholesterolemic diet composed of a standard diet , supplemented with cholesterol 2% , 0.2% cholic acid  and 4.8% palm oil. Moreover, the effect of these treatments on proprotein convertase subtilisin/kexin type 9 (PCSK9) levels were also studied.The rats were divided into five groups of 10 animals each:Group 1 (normolipidemic controls) was kept on a standard diet (Harlan) for 30 days.Group 2 (hyperlipidemic controls) received the hypercholesterolemic diet for 30 days.Group 3 received the hypercholesterolemic diet for 30 days; from the 1st to the 30th day, each rat was administered by gavage with BPF .Groups 4 and 5 received the hypercholesterolemic diet for 30 days; from the 1st to the 30th day, each rat was administered by gavage with RYR extract .During the experiment, animals were weighed weekly, and 24 h food consumption was recorded daily. On day 29, rats were individually housed in metabolic cages. At the end of the study, the animals were fasted overnight; blood samples were collected from the penile vein of the rats and serum was separated and stored at −20 °C until analyzed. The analysis of serum T-CHOL, LDL-C and HDL-C, triglycerides, MDA and paraoxonase was performed as described below.At the baseline and after 4 weeks of the experimental protocol, a 12 h fasting morning blood sample was collected, processed and stored at −80 °C. All serum marker concentrations or activities were measured using classical methods and commercial assay kits, according to the manufacturers’ instructions. Assay kits for total cholesterol, LDL-C, HDL-C, triglycerides, malondialdehyde (MDA), paraoxonase and glutathione peroxidase were purchased from Novamedical S.R.L. . All the laboratory tests were performed in a blinded manner in respect to the assigned treatment.For proprotein convertase subtilisin/kexin type 9 (PCSK9) assay one serum aliquot from each rat was tested by colorimetric enzyme-linked immunosorbent assay from R&D Systems . The minimal limit of detection was 125 pg/mL, the mean intra- and inter-assay coefficient of variation was at the accepted threshold of less than 8%.t tests, as appropriate. The analysis was performed by the Statistical analysis add-in component of Microsoft Excel 2007.In case of homogenous set of data ANOVA was performed to determine the treatment effects, and Dunnett’s test was employed as appropriate. In case of heterogeneous data, F test was carried out to determine which pairs of groups are heterogeneous. This was followed by Cochran’s or Student’s Administration of hyperlipidemic diet in rats (Group 2) produced, compared to control group (Group 1) an elevation of serum levels of total cholesterol, LDL-C  and an eTreatment of rats with RYR  reduced total cholesterol, LDL-C and paraoxonase . HoweverOur data show, for the first time, that BPF leads to a better hypolipidemic response when compared to RYR in rats fed a hyperlipidemic diet. In particular, our data demonstrate that BPF reduces both LDL-C and triglycerides, alongside with an elevation of HDL-C, as previously found in animal settings and patients with hyperlipidemia ,25,26,27The reason for a better performance of BPF when compared to RYR still remains to be better clarified. However, antioxidant properties of BPF and its subsequent activity against overexpression of PCSK9 seem to play a role.Accumulated evidence has shown that BPF, a polyphenolic rich extract obtained from bergamot juice, produces consistent activities in regulating serum levels of cholesterol and triglycerides acting at different levels in the lipid metabolism ,25,26,27The effect of BPF was also associated to reduced expression of PCSK9 in animals fed an hyperlipidemic diet, thus suggesting that this effect may significantly contribute in the better reduction produced by this extract when compared to RYR.The role of PCSK9 in the regulation of cholesterol metabolism and the relative cardioprotective action has been widely studied in the last few years ,29,30. IOur data show that BPF produces consistent benefits in reducing serum cholesterol and triglycerides compared to RYR in animals fed a hyperlipidemic diet. This better performance seems to results from a better antioxidant profile, an effect associated to reduced expression of PCSK9, and this may represent a new perspective in nutraceutical supplementation in hyperlipidemic states. Obviously, the study takes into account the potential bias and imprecision of data collected in animal models that need to be confirmed in clinical studies to be carried out in patients.


Despite demonstrated benefits, most countries fall short of meeting international targets for breastfeeding patterns, optimal complementary feeding, mother-children's quality diet, and malnutrition among under-five children.Since mothers usually play the most vital role in the healthcare of their children, research is needed to illuminate maternal factors that might promote a child's health and nutritional status.The purpose of this study is to retrospectively (1) examine the under-five children's (0–59 months) feeding habits including exclusive breastfeeding, exclusive bottle feeding, continued breastfeeding, and complementary feedings, (2) investigate the mother-child's dietary diversity, and (3) identify any factors that cause less optimal nutrition due to a lack of food diversity in children aged 6 to 59 months. Moreover, (4) the prevalence of wasting, stunting, underweight, and overweight in the under-five offspring living in households located in the main two provinces in Lebanon (Beirut and Mount Lebanon) was determined.The data for this analysis were collected from a representative sample of 384 households [384 mothers (21–49 years old) and children (0–59 months)] between February 2019 and June 2019. A questionnaire was used to inquire mothers of children ages 0–23 months about exclusive breastfeeding (EBF), continuous breastfeeding (CBF), exclusive bottle feeding (EBOT), mixed feeding (MF), and complementary feeding patterns. Moreover, additional questions regarding dietary diversity were asked to mothers of children aged 6 to 59 months. This score was calculated based on the 24 h recall of the mother and her child's consumption of 7 food groups, during the 24 h prior to the survey. Moreover, stunting, wasting, overweight, and underweight were calculated using the z-score for height-for-age (HAZ), weight-for-height (WHZ), and weight-for-age (WAZ), respectively. Binary logistic regression was used to explore the dietary diversity among children (ages 6–59 months) adjusting for covariates at maternal and household levels.p-value = 0.034). Regression analysis showed that children's DD increased around 2 times  in context of high maternal DDS, and about 12 times  when a member of the highest-income households.Around 44% of children (0–59 months) had normal body weight. In addition, 9.3% were underweight (WAZ < -2SD to −3SD), 6.5% were at risk of being overweight, 24.45% were overweight, 9.3% were stunted (HAZ < -2SD to −3SD), and 6.25% (WHZ < -2SD to −3SD) were wasted. In total, among under-five children, the prevalence of EBF at 40 d and 6 months was 27 and 30%, respectively. The prevalence of CBF was 23%. Around 60% of mothers breastfed their offspring between 0 and 6 months and half of them introduced infant formula at earlier stages between 0–6 months. Furthermore, 78.4% of mothers introduced food to their children between 4 and 6 months (of which 40% before 6 months) and 62.5% of them introduced sugary drinks before 6 months. As for dietary diversity (DD), one out of two mothers and one out of three children (ages 6–59 months) had a low DD score (DDS) . The children's and mother's DD were strongly found to be correlated (Our findings demonstrated low rates of EBF and CBF, high prevalence of EBOT, and early introduction of complementary foods among children ages 0–59 months. Furthermore, for children ages 6–59 months, there was poor mother-child dietary diversity and a high prevalence of overweight and stunted children in the main two Lebanese provinces. This suggests the alarming need for continuous nutrition intervention to improve infant feeding patterns and dietary diversity to reduce the malnutrition rates. Moreover, the prevalence of wasting, stunting, underweight, and overweight in the under-five offspring living in households located in the main two provinces in Lebanon (Beirut and Mount Lebanon) was determined.n = [p (1-p)] * [(Z∝/2)2 / (e)2], where n denotes the sample size, Z∝/2 is the reliability coefficient of the standard error at 5% level of significance = 1.96, p represents the probability of under-five children who were unable to practice preventive measures against the diseases , and e refers to the level of standard error tolerated (5%) as stated by Hosmer and Lemeshow. Based on this formula, it was determined that the minimum acceptable sample size of 300 respondents would be sufficient to identify differences by respondent's characteristics.A total of 400 mothers and children were included in the sample. Of these, 384 were included in the analyses. Thus, the data for this analysis were collected from a representative sample of 384 households located in the two main Lebanese provinces—Beirut and Mount Lebanon—and using a stratified cluster sampling design. Within each district, households were selected following a probability proportional to size approach. Housing units constituted the primary sampling unit in the two districts. A single population formula was used to determine the sample size. Accordingly, the formula for sample size determination used was A total of 384 mothers (21–49 years old) and children (0–59 months) were included in this study between February 2019 and June 2019. Trained nutritionists administered the survey through face-to-face interviews with the mothers. A questionnaire was used to inquire mothers of children ages between 0 and 23 months about EBF, CBF (duration exceeding 6 months), EBOT, MF, and complementary feeding patterns. Moreover, additional questions regarding DD were asked to mothers of children ages 6 to 59 months. This score was calculated according to the WHO guidelines and based on the 24 h recall of the mother and her child's consumption of 7 food groups, during the 24 h prior to the survey , and had no chronic medical conditions, inborn errors of metabolism, or physical malformations that interfered with feeding patterns and body composition.Infant feeding practices were defined as follows:Exclusive breastfeeding (EBF): The infant received breast milk from their mother or expressed breast milk and no other fluids or solids.Mixed feeding: The infant received breast milk with formula milk and/or other fluids and/or solid food.Exclusive bottle feeding (EBOT): The infant received formula milk with or without other fluids.p < 0.05. Frequencies and descriptive statistics were performed for the general variables. Chi-square test was used to compare the categorical variables in the study as well as determine the prevalence of obesity, overweight, underweight, stunting, and wasting according to the child's age category. Chi-square was also used to assess the association between the mother's DDS and the child's DDS. In addition to that, independent t-test was conducted to compare the means between two unrelated groups (low child's DDS and high child's DDS) on the same continuous, dependent variable (mother's age). Binary logistic regression was used to explore the association between mothers' and children's DD adjusting for covariates at maternal and household levels with analyses represented as odds ratios and 95% confidence intervals.The statistical analysis of this study was performed using the Statistical Analysis Package for Social Science  and the significance level was set at Ethical approval was obtained from the Ethical Committee at the Lebanese University (#CU201907). The mother of the child signed a consent form, and the questionnaires were administered after the families agreed to participate in the study.A total of 400 mothers and children were included in the sample. Of these, 384 were included in the analyses. The remaining 16 were excluded from the analysis because of missing data. Socio-demographic details are shown in Most of the children aged under 5 in this study had a normal body weight (44%). In addition, 9.3% were underweight (WAZ < -2SD to −3SD), 6.5% were at risk of being overweight, 24.45% were overweight, 9.3% were stunted (HAZ < -2SD to −3SD), and 6.25% (WHZ < -2SD to −3SD) were wasted. The prevalence of stunting, wasting, and overweight among under 2 children was 12.5, 37.5, and 62.5%, respectively .The prevalence of EBF, EBOT, MF, and complementary feeding among children ages 0–23 months is shown in The prevalence of EBF, EBOT, MF, and complementary feeding among children ages 0–59 months is shown in p-value = 0.003). Most children with high DDS (75%) had employed mothers . Moreover, the children's DDS was related to the mother's education. Mothers holding a university degree had children who were eating an adequate diversified diet .The association between a child's DDS, socio-demographic characteristics, mother's nutritional status, and child's nutritional status is shown in The DD among children (6–59 months) adjusting for covariates at maternal and household levels is described in The current study examines the feeding patterns including breastfeeding, formula-feeding, complementary feeding, and the prevalence of malnutrition in under-five children living in two main Lebanese provinces (Beirut and Mount Lebanon). This study also investigates the mother-child's DD and identifies the factors that cause less optimal nutrition due to a lack of food diversity in children aged 6 to 59 months. Our findings demonstrated that in the main two Lebanese provinces, there are low rates of EBF, high rates of EBOT, early initiation of complementary feeding, and early introduction of infant formula among under-two children. These results were reported retrospectively also by mothers of under-five children. Furthermore, for children aged 6–59 months, there was poor mother-child DD, and a high prevalence of overweight and stunted children. In Lebanon, based on a recent report published by UNICEF , the earRegarding complementary feeding, our data found that more than 60% of the mothers introduced complementary foods before the age of 6 months from which 40% started introducing solid foods and 53.5% introduced sugary juices. In our study, only 31% of mothers adhered to the WHO recommendations to introduce foods at 6 months. This finding was below the complementary feeding prevalence reported by UNICEF for the EMR which is 68% and at global level which is 73% . Howeverp = 0.03). This is to mean that the more food groups the mothers consumed, the more likely their children achieved their DD and vice versa. As the mothers' DD increased, the percentage of children (0–59 months) meeting this criterion increased dramatically. Even though there is a dearth of literature on concordance between maternal and child dietary diversity in the EMR and in Lebanon, a related study on maternal and child DD associations in Bangladesh, Vietnam, and Ethiopia showed a fair association between the two . In addition, 9.3% were underweight (WAZ < -2SD to −3SD), 6.5% were at risk of being overweight, 24.45% were overweight, 9.3% were stunted (HAZ < -2SD to −3SD), and 6.25% (WHZ < -2 SD to −3SD) were wasted. The prevalence of stunting, wasting, and overweight among under-two children was 12.5, 37.5, and 62.5%, respectively. According to WHO, in 2020, globally, 149.2 million children under the age of 5 years were stunted (22%), 45.4 million wasting (13.6%), and 38.9 million overweight (5.7%), respectively . MoreoveThe study offers a unique lens into infant feeding practices related to under-five children in Lebanon. However, it has several limitations. First, it is a cross-sectional study with unclear chronology of the factors associated with infant feeding patterns. Second, mothers reported infant feeding practices of their children, with potential for more recall bias among mothers of older children due to a longer time since delivery; however, almost half of the children were younger than 5 years of age.Our findings demonstrated low rates of EBF and continuous BF, high use of IF, and early introduction of complementary feeding among children aged 0–23 months. Furthermore, for children 6–59 months, there was poor mother/child DD, and a high prevalence of overweight and stunted children in the main two Lebanese provinces. This suggests the alarming need for continuous nutrition intervention to improve the DD and to reduce the malnutrition rates. Future research should investigate the factors associated with EBF, complementary feeding practices, and DD in prospective cohort studies and help to better understand the cultural factors limiting the adherence to international guidelines. Such research can guide effective planning for interventions to improve infant feeding practices and ultimately children's health status.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethical Committee Lebanese University. The patients/participants provided their written informed consent to participate in this study.MHo: conceptualization, methodology, supervision, and writing—reviewing and editing. HA and MHa: data curation, writing—original draft preparation, visualization, and investigation. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict ofinterest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


What is the prevalence of moderate to severe vision impairment (VI) and blindness among individuals 85 years and older in Russia, and what are the factors associated with moderate to severe VI and blindness?In this cohort study of 1526 Russian adults 85 years and older, the prevalence of moderate to severe VI and blindness was 49% and 6%, respectively; moderate to severe VI and blindness were associated with cataracts, age-related macular degeneration, glaucoma, and myopic maculopathy. A higher prevalence of moderate to severe VI and blindness was significantly associated with lower physical strength (measured by hand grip force) and lower cognitive function .This study found a relatively high prevalence of VI and blindness among adults 85 years and older, with cataracts as the primary reversible condition associated with vision loss; these findings suggest that increases in cataract surgery may be helpful to address the lower cognitive function and physical strength associated with VI and blindness. Visual performance is important for quality of life. However, vision impairment among adults 85 years and older has not been intensively examined.To assess the prevalence of mild vision impairment (VI), moderate to severe vision impairment, and blindness and the factors associated with these conditions among a population 85 years and older.The Ural Very Old Study was a population-based cohort study conducted in rural and urban areas in Bashkortostan, Russia from 2017 to 2020. Among 1882 eligible individuals 85 years and older, 1526 participants (81.1%) were enrolled.Ophthalmologic, physical, and mental examinations.Prevalence of vision impairment and blindness based on best-corrected visual acuity  in the better eye or both eyes. Mild vision impairment was defined as BCVA worse than 6/12 to 6/18, and moderate to severe VI was defined as BCVA worse than 6/18 but equal to or better than 3/60. Blindness was defined as BCVA worse than 3/60.P < .001), higher blood pressure , lower hand grip force , lower score on the Mini-Mental State Examination , lower prothrombin index , lower refractive error , and lower prevalence of previous cataract surgery .Among 1526 participants, 1149 individuals  had available BCVA measurements and were included in the present analysis. Mild vision impairment was present in 114 individuals , moderate to severe VI in 562 individuals , and blindness in 68 individuals . Factors associated with moderate to severe VI were cataracts , secondary cataracts , age-related macular degeneration , glaucoma , corneal opacifications , myopic maculopathy , and nonglaucomatous optic nerve damage . Factors associated with blindness were cataracts , age-related macular degeneration , glaucoma , myopic maculopathy , and corneal opacifications . Higher moderate to severe VI prevalence was associated with older age (odds ratio [OR], 1.19; 95% CI, 1.11-1.28; In this cohort study of individuals 85 years and older, the prevalence of moderate to severe VI and blindness was relatively high. Cataracts were the main reversible condition associated with vision loss, and age-related macular degeneration, glaucoma, and myopic maculopathy were the main irreversible conditions. Because a higher prevalence of moderate to severe VI was associated with lower cognitive function and physical strength, improvement of vision through increases in cataract surgery and measures to prevent and treat irreversible conditions may help to improve cognitive function and physical strength. This cohort study assesses the prevalence of mild vision impairment, moderate to severe vision impairment, and blindness among individuals 85 years and older in Russia and examines the factors associated with moderate to severe vision impairment and blindness. The most common factors associated with blindness in individuals 85 years and older were cataracts, glaucoma, undercorrected refractive error, age-related macular degeneration (AMD), and diabetic retinopathy.4 These and other meta-analyses were limited by a scarcity of population-based studies focusing on adults 85 years and older. Most available studies had an age-related inclusion criterion of 40 years and older, with fewer than 5% of study participants 85 years and older. Our hypothesis was that the prevalence of vision impairment and blindness and their associated factors may differ in a population of individuals 85 years and older compared with younger populations. Therefore, we conducted the Ural Very Old Study (UVOS) to examine the prevalence of vision impairment and blindness and the factors associated with these conditions in a population 85 years and older, to explore the association of vision impairment and blindness with other demographic and clinical variables, and to compare these data with findings obtained among a younger population in the same study regions.Visual performance is important for an individual’s quality of life and public health in general.STROBE) reporting guideline for cohort studies and the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).6The UVOS was a population-based study performed in Kirovskii, a rural region that is 65 km from the capital of Ufa, and the Republic of Bashkortostan, Russia, an urban region of Ufa that is approximately 1300 km east of Moscow. The study was conducted between November 2017 and December 2020 and was approved by the ethics committee of the Academic Council of the Ufa Eye Research Institute. Written informed consent was obtained from all participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  were enrolled in the study. Participants in the urban study region included the inhabitants of 3 small private retirement homes; there were no retirement homes in the rural study region. The participation rate did not substantially vary between the urban group  and the rural group . According to the 2010 Russian census, the sex and age composition of the study population was consistent with that of the Russian population who were 85 years and older, with a preponderance of women.14 Physical and clinical examinations included measurement of anthropomorphic parameters, arterial blood pressure and pulse rate, dynamometric assessment of handgrip strength, and biochemical examination of blood samples obtained under fasting conditions. Arterial hypertension was defined based on recommendations from the American College of Cardiology and the American Heart Association in 2017.15 Diabetes was characterized as a fasting glucose concentration of ≥126 mg/dL  or a self-reported history of physician diagnosis of diabetes or drug treatment for diabetes. Cognitive function was assessed using the Mini-Mental State Examination (MMSE),11 anxiety was measured using the State-Trait Anxiety Inventory,16 and depression was assessed using the Center for Epidemiologic Studies–Depression scale.9 The estimated glomerular filtration rate was calculated using the equation developed by the Chronic Kidney Disease Epidemiology Collaboration.17 The design of the UVOS was similar to that of the Ural Eye and Medical Study (UEMS), which has been described in detail previously.19All participants received a standardized interview conducted by trained social workers; this interview comprised almost 300 questions on socioeconomic background, self-reported ethnic background, diet, smoking, physical activity, quality of life, quality of vision, history of any type of injury or injury associated with interpersonal violence, health assessment, medical history, previous neurologic events, cognitive function, and hearing loss.20 were applied for the definition of AMD . Glaucoma was defined using morphological criteria described by Foster et al.21 Based on criteria from the World Health Organization,22 we defined mild vision impairment as BCVA worse than 6/12 to 6/18 in the better eye or both eyes, moderate to severe VI as BCVA worse than 6/18 but equal to or better than 3/60 in the better eye or both eyes, and blindness as BCVA worse than 3/60 in the better eye or both eyes.The ophthalmologic examinations comprised the measurement of presenting, uncorrected, and best-corrected visual acuity (BCVA) using modified Early Treatment of Diabetic Retinopathy Study charts; automated refractometry; static perimetry; anterior segment imaging using a Scheimflug camera ; sonographic biometric measurement of axial length; slit lamp biomicroscopy of the anterior and posterior ocular segment; noncontact tonometry; photography of the cornea and lens ; photography of the optic disc  and macula ; and spectral-domain optical coherence tomography of the optic nerve head  and macula . The guidelines published by the Beckman Initiative for Macular Research Classification Committee23 This analysis was followed by a multivariable regression analysis, with the prevalence of blindness or moderate to severe VI as the dependent variable and all factors that were significantly associated with prevalence as independent variables in the univariate analyses. We then removed, in a step-by-step manner, those factors from the list of independent variables that had collinearity with other factors and that were no longer significantly associated with the prevalence of moderate to severe VI or blindness. We calculated the odds ratios (ORs) and their 95% CIs. The significance threshold was 2-sided P < .05.We assessed the prevalence of blindness, moderate to severe VI, and mild VI (reported as means with 95% CIs) using SPSS for Windows, version 25.0 (SPSS Institute), and we performed a binary regression analysis of the association between the prevalence of moderate to severe VI or blindness and other demographic, clinical, and ocular factors.P = .001), whereas those with vs without BCVA assessments did not differ significantly in educational level  and sex .Among 1526 participants in the UVOS, 1149 individuals  with available BCVA measurements who received examinations in the hospital were included in the present analysis. A total of 408 individuals (35.5%) were Russian, 504 (43.9%) were Tatar, 135 (11.7%) were Bashkir, 44 (3.8%) were Chuvash, 7 (0.6%) were Mari, and 51 (4.4%) were of other ethnicities. The mean (SD) axial length was 23.1 (1.1) mm . The prevalence of moderate myopia  was 47 of 717 individuals , and the prevalence of high myopia  was 10 of 717 individuals . Those who received BCVA assessments were significantly younger than those who did not  were illiterate. A total of 236 individuals (20.5%) completed fifth grade, 249 (21.7%) completed eighth grade, 48 (4.2%) completed tenth grade, and 35 (3.0%) completed eleventh grade; 241 individuals (21.0%) had some specialized secondary education, 285 (24.8%) were college graduates, and 4 (0.3%) were postgraduates. A total of 199 individuals (17.3%) were living in a joint family , 95 (8.3%) were living with nuclear family, 441 (38.4%) were living alone, and 405 (35.2%) were living with 1 family member; 250 individuals (21.8%) were married, 22 (81.9%) were unmarried, 21 (1.8%) were divorced, and 847 (73.7%) were widowed. Almost all of the participants owned a home or apartment  and a television and/or telephone . The mean (SD) body height was 157 (9) cm, and the mean (SD) body mass index  was 26.6 (4.5). Of 1149 participants, 114 individuals  met the criteria for having mild VI, 562 individuals  met the criteria for having moderate to severe VI in the better eye or both eyes, and 68 individuals  met the criteria for having blindness in the better eye or both eyes .P < .001) and rural region of residence  (P < .001), higher mean blood pressure , lower score on the Mini-Mental State Examination , more substantial cylindrical refractive error , lower prevalence of previous cataract surgery , lower prothrombin index , and lower hand grip force  (P = .006). When refractive error was replaced by axial length, the latter was significantly associated with moderate to severe VI prevalence . When MMSE score was removed, higher moderate to severe VI prevalence was associated with a higher depression score .In the univariate analysis, the prevalence of moderate to severe VI increased with various demographic, clinical, and ocular factors, including older age  ; Table 2 < .001) . When thP < .001) and rural region of residence  (P = .01) and lower MMSE score  (P < .001), higher mean blood pressure , lower MMSE score , lower prevalence of previous cataract surgery , and more substantial cylindrical refractive error  (P < .001), higher educational level , urban region of residence , lower prevalence of moderate to severe VI and blindness , and lower hearing loss score .In the univariate analysis, the prevalence of blindness increased with demographic, clinical, and ocular factors, such as older age  . In the  = .001) . The pre < .001) . In contThe factors associated with moderate to severe VI were cataracts , secondary cataracts , AMD , glaucoma , corneal opacifications , myopic maculopathy , nonglaucomatous optic nerve damage , macular edema of unknown origin , macular holes , and unclear reason  . DiffereThe factors associated with blindness were cataracts , AMD , glaucoma , myopic maculopathy , corneal opacifications , and unclear reason  . Among aIn this cohort study of an ethnically mixed population 85 years and older from Bashkortostan, Russia, the prevalence of blindness, moderate to severe VI, and mild VI was 5.9%, 48.9%, and 9.9%, respectively. The most common factors associated with blindness and moderate to severe VI were cataracts , AMD (22.1% and 13.9%), and glaucoma (10.3% and 8.0%).19 The marked difference in prevalence was mainly because of the substantial difference in participant age. Among participants in the oldest age category in the UEMS , the prevalence of moderate to severe VI was 19.2%  among men and 27.6%  among women23; this finding was substantially lower than the prevalence of 48.9%  found in the older population in the present study . In the ALIENOR study24 of individuals 75 years and older, which used the oldest age inclusion criterion among ophthalmologically related population-based studies to date, the prevalence of blindness and moderate to severe VI has not yet been reported. In other population-based studies of younger populations in high-income countries,26 the age-standardized prevalence of blindness and moderate to severe VI in 2015 was 0.15%  and 1.27% , respectively,25 whereas in rural central India, among a population 30 years and older, the prevalence of blindness and moderate to severe VI from 2008 to 2009 was 0.5%  and 7.0% , respectively.26 In the latter study, the prevalence of moderate to severe VI and blindness increased to 39.0% and 5.4%, respectively, among individuals 80 years and older.26The findings of the present study cannot be directly compared with observations made in other studies because previous investigations typically did not include a sufficient number of participants who were 85 years and older. In the UEMS, which was performed using a similar study design in the same study regions among a population 40 years and older , the prevalence of blindness, moderate to severe VI, and mild VI was 0.19%, 3.1%, and 3.1%, respectively.29 the presence of cataracts was the most common reversible condition associated with moderate to severe VI and blindness, followed by irreversible conditions associated with vision loss, including AMD, glaucoma, myopic maculopathy, and corneal opacifications. None of the individuals with vision impairment or blindness had diabetic retinopathy as the main condition associated with vision loss , glaucoma , undercorrected refractive error , AMD , and diabetic retinopathy , whereas the most common factors associated with moderate to severe VI were undercorrected refractive error  and cataracts . Differentiated into global regions, the lists of the most common factors associated with blindness and moderate to severe VI29 do not differ markedly from those reported in the present study. The relatively high prevalence of cataracts as factors associated with blindness  and moderate to severe VI  suggests the need to increase the rate of cataract surgery in the study regions.In our study, as in other previous investigations,ion loss . In a re4 myopic maculopathy was not separately assessed regarding its frequency as a factor associated with moderate to severe VI and blindness. In our study, myopic maculopathy was associated with blindness in 4.4% of all participants with blindness (12.0% of participants with irreversible blindness) and with moderate to severe VI in 2.3% of all participants with moderate to severe VI (9.3% of participants with irreversible moderate to severe VI)  . The pre23 The prevalence of myopic maculopathy as a factor associated with blindness (0.3% in our study vs 0.03% in the UEMS) and moderate to severe VI (1.1% in our study vs 0.2% in the UEMS) was thus higher in our older population compared with the younger population of the UEMS. Even if one assumes a further age-related increase in the prevalence of myopic maculopathy, the 5- to 10-fold higher prevalence of myopic maculopathy as a factor associated with blindness or moderate to severe VI in our older study population compared with the middle-aged population of the UEMS suggests that, in the UEMS and UVOS study regions, the prevalence of myopic maculopathy as a factor associated with moderate to severe VI or blindness (in the middle-aged population) may not have substantially increased compared with previous periods.30 The importance of myopic maculopathy as a factor associated with moderate to severe VI and blindness has also been reported in population-based studies conducted in East Asia,29 such as the Beijing Eye Study,27 in which myopic maculopathy was the most common factor associated with irreversible vision impairment and blindness in a population 40 years and older who were examined in 2001.Myopic maculopathy was the third most common factor associated with irreversible blindness and moderate to severe VI. In the UEMS population, which included participants with substantially younger ages, myopic maculopathy was the second most common factor associated with irreversible blindness  and the second most common factor associated with irreversible moderate to severe VI .29 the association between a higher prevalence of moderate to severe VI and blindness and lower cognitive function (as measured by MMSE score) is of interest because another study31 found an association between the prevalence of Alzheimer disease and hearing loss. This finding suggests that cataract surgery (and the provision of best-correcting glasses), in particular, may be a means of reducing the risk of cognitive dysfunction. The finding is also consistent with the observation of lower hand grip force among participants with visual disabilities in our study. Hand grip strength has been regarded as a biomarker of concurrent overall strength, upper limb function, bone mineral density, depression, multimorbidity, and quality of life.32Factors associated with moderate to severe VI and blindness were older age, lower MMSE score, lower dynamometric hand grip force, lower prothrombin index, lower prevalence of previous cataract surgery, and more substantial cylindrical refractive error . AlthougThis study has strengths. To our knowledge, the study is the first population-based investigation of the prevalence of moderate to severe VI and blindness among individuals 85 years and older to include a relatively large sample and many demographic, clinical, and ocular factors.This study also has limitations. First, the presenting visual acuity of participants was not assessed, so we could not determine the prevalence of undercorrection of refractive error as a factor associated with vision impairment and blindness. Second, dense cataracts prevented examination of the fundus; thus, any additional disorders of the optic nerve and macula were not detected. This limitation might have produced an underestimation of the prevalence of macular and optic nerve diseases. Third, difficulty with access to medical services may have been the primary factor associated with the relatively high prevalence of moderate to severe VI and blindness in the study population. We did not, however, assess the interval between the participants’ last ophthalmologic examinations and the start of the study.Among a population 85 years and older from Bashkortostan, Russia, the prevalence of moderate to severe VI and blindness was 48.9% and 5.9%, respectively, with 28.2% and 2.9% of the total study population experiencing moderate to severe VI or blindness associated with cataracts. Because cataracts were the main reversible condition associated with vision loss, increases in cataract surgery may be helpful to address blindness and VI among participants in the study region. Age-related macular degeneration was associated with moderate to severe VI and blindness in 3.9% and 0.6% of the population, respectively, and myopic maculopathy was the third most common factor associated with irreversible blindness and moderate to severe VI. Efforts may be intensified for the prevention and treatment of these conditions. Blindness and moderate to severe VI were associated with lower cognitive function and physical strength (as measured by hand grip force); thus, addressing vision impairment through measures such as cataract surgery may also help to improve cognitive function and physical strength.


Diabetic kidney disease (DKD) is the most frequent cause of kidney failure (KF). There are large variations in the incidence rates of kidney replacement therapy (KRT). Late referral to nephrology services has been associated with an increased risk of adverse outcomes. In many countries, when patients reach severely reduced glomerular filtration rate (GFR), they are managed by multidisciplinary teams led by nephrologists. In these clinics, efforts will continue to halt chronic kidney disease (CKD) progression and to prevent cardiovascular mortality and morbidity. In patients with diabetes and severely reduced GFR and KF, treating hyperglycemia is a challenge, since some drugs are contraindicated and most of them require dose adjustments. Even more, a decision-making process will help in deciding whether the patient would prefer comprehensive conservative care or KRT. On many occasions, this decision will be conditioned by diabetes mellitus itself. Effective education should cover the necessary information for the patient and family to answer these questions: 1. Should I go for KRT or not? 2. If the answer is KRT, dialysis and/or transplantation? 3. Dialysis at home or in center? 4. If dialysis at home, peritoneal dialysis or home hemodialysis? 5. If transplantation is desired, discuss the options of whether the donation would be from a living or deceased donor. This review addresses the determinant factors with an impact on DKD, aiming to shed light on the specific needs that arise in the management and recommendations on how to achieve a comprehensive approach to the diabetic patient with chronic kidney disease. Kidney replacement therapy (KRT) may consist of either the realization of a renal transplant or the initiation of dialysis therapy.Patients with DKD have an eight-fold increased risk of cardiovascular and all-cause mortality compared to those without DM and CKD ,3,4. FurFor the evaluation of those patients who are candidates to receive a renal transplant, there are guidelines to guide the decision making process regarding the convenience of transplantation and the appropriate time to perform it . On the Based on the above, it is important to educate the healthcare community about the benefits of a referral protocol for patients with progressive kidney function decline, since late referral to nephrology services has been associated with an increased risk of adverse outcomes . For insIn this review we will address the factors that influence CKD in the patient with DM, including those that predict the occurrence of cardiovascular events and progression to kidney failure in DKD. The aim is to shed light on the specific needs that arise in the management of DKD and recommendations on how to achieve a comprehensive approach, either conservatively or through KRT. For this, the role of the nursing team as well as the collaboration between nephrologists, endocrinologists, vascular surgeons, general surgeons, interventional radiologists, nutritionists, psychologists and physical exercise specialists, among others, will be of great importance.2 per year) in DM than in healthy individuals, particularly in patients with a long duration of diabetes (more than 10 years), severely increased albuminuria, or low baseline eGFR [2 ≤ annual decline < 0 mL/min/1.73 m2) and 15% of them presented severe decline  [Due to its complex pathogenesis, DKD presents a wide clinical variability. The incidence rate of KF in type 2 DM (T2DM) is 0.29% at 10 years and 0.74% at 20 years from the diagnosis of diabetes . Howeverine eGFR . Still, 1.73 m2) .2 independently of albuminuria [Unfortunately, the traditionally employed clinical biomarkers, although very useful in the diagnosis and long-term follow-up of the disease, are usually not sensitive enough to detect early kidney injury. To illustrate, the absence of albuminuria does not exclude the presence of diabetic kidney injury or subclinical renal damage . On the uminuria . Moreoveuminuria .Numerous risk factors  have beeAs mentioned above, one of the most determinant factors in CKD progression is the time course of diabetes. Cumulative risk of KFRT was 0.29% at 10 years and 0.74% at 20 years from diagnosis of T2DM .The risk of developing DKD has a polygenetic component ,21,22. D2, the shortening of erythrocyte life biases the measurement of low HbA1c, especially in patients receiving erythropoietin-stimulating agents.Hyperglycemia is an important risk factor for the progression of albuminuria in diabetic subjects; however, its influence is more modest in the progression to kidney failure than the effect exerted by hypertension, hypercholesterolemia and genetic factors . Among p2), regardless of the presence or absence of diabetes, when comparing dapaglifozin with placebo (hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.51 to 0.72; p < 0.001). Dapagliflozin has proven to be effective as a cardiovascular and renal protective treatment, showing a significant decrease in mortality, in the incidence of KFRT and in suffering a decline of at least 50% in the estimated GFR . Previously, the CREDENCE study [p < 0.001) at a median follow-up of 2.62 years. These findings show that SGLT2 inhibitors can be an effective therapy option for renal and cardiovascular protection in patients with type 2 diabetes with chronic kidney disease. Additionally, a subgroup analysis of the CREDENCE trial [2 , whose effects were maintained in those subjects with an eGFR < 30 mL/min/1.73 m2 . There was also no difference in the rate of kidney-related adverse events or AKI, associated with canagliflozin, between participants with eGFR < 30 and ≥30 mL/min/1.73 m2. The results support the use and continuation of SGLT2 inhibitors until initiation of dialysis or kidney transplantation (KT).The goals and treatments for the management of diabetes in CKD are described in the new KDIGO guidelines . CardiovCE study  analyzedCE trial  showed t2 [2, either in combination with metformin or when metformin cannot be used [2; however, in accordance with the approach followed in the CREDENCE trial [2, the SGLT2 inhibitor can be continued until initiation of kidney replacement therapy. Furthermore, when diabetic patients with CKD require additional treatment for glycemic control, or cannot use metformin and/or SGLT2 inhibitors, the KDIGO guidelines recommend glucagon-like peptide-1 receptor agonists (GLP-1 RA) as the preferred option, due to the cardiovascular and renal benefit they have proven in the recent trials [2 [2 are DPP-4 inhibitors, insulin, and thiazolidinediones [In summary, for adequate glycemic control in the diabetic patient with CKD, it is important to take into account the need for lifestyle therapy through physical exercise, nutritional intervention and weight loss. The KDIGO guidelines recommend as first-line antihyperglycemic therapy the use of metformin, as long as the GFR ≥ 30 mL/min/1.73 m2 . Metform2 ,37,38. I be used . Differe be used ,39,40,41CE trial , in thost trials ,44,45,46t trials , ADA [48rials [2 . Optionsnediones . It is i2; G2: GFR 60-89 mL/min per 1.73 m2, G3a: GFR 45–59 mL/min per 1.73 m2; G3b: GFR 30–44 mL/min per 1.73 m2; G4: GFR 15–29 mL/min per 1.73 m2; G5: GFR <15 mL/min per 1.73 m2 or treated by dialysis. (1) A. S. Levey et al., “Nomenclature for kidney function and disease: executive summary and glossary from a Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference,” Journal of Nephrology, vol. 33, no. 4. pp. 639–648, 2020. (2) I. H. de Boer et al., “Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment,” Kidney Int., vol. 98, no. 4, pp. 839–848, Octorber 2020.First-line antiglycemic medications (green) are metformin and SGLT2 inhibitor. As second-line therapy (purple) it is recommended to prioritize GLP-1 AR over other antiglycemic medications due to its cardiovascular and renal benefits. Other drugs that can be used are iDPP4, insulin, thiazolidinedione, sulfonylureas and alpha-glucosidase inhibitor. In patients with KF, iDPP4, insulin and thiazolidinedione are more suitable options. CKD, Chronic kidney disease; GFR, Glomerular filtration rate; SGLT2, Sodium-glucose cotransporter-2; GLP-1 RA, Glucagon-like peptide-1 receptor agonists; DPP-4, Dipeptidyl peptidase-4; KF, Kidney failure; KRT, Kidney replacement therapy; G1: GFR ≥90 mL/min per 1.73 mMany authors recommend a blood pressure (BP) target of 140/90 mmHg for patients with DM, regardless of CKD . In pati2, the European guidelines advise starting treatment with ACEi if there is a cardiac indication, but also advise to stop it if there are side effects. If renal function progresses to an eGFR < 15 mL/min/1.73 m2, due to the risk of a cardiovascular event or the initiation of dialysis, it is advisable to evaluate its interruption in an attempt to delay the start of dialysis [Finally, and in reference to the RAAS axis blockade, in patients with an eGFR < 30 mL/min/1.73 mp = 0.034), as well as a decreased in kidney events  in patients with GFR 25–75 mL/min/1.73 m2 [Another drug of interest is finerenone . In the FIDELIO-DKD study, it shows a decrease in the incidence of cardiovascular events  found that the association of statin plus ezetimibe significantly reduced major atherosclerotic events. The relative effect was similar when diabetes was present (23% of 9438 patients had diabetes). This study did not detect any effect of lipid-lowering therapy on the frequency of doubling of baseline serum creatinine concentration or progression to KFRT [People with diabetes and severely reduced GFR typically have significant hypertriglyceridemia, high LDL and low HDL cholesterol levels . These a to KFRT . The rol to KFRT . No effe to KFRT .Long-term high protein intake accelerates structural and functional injury in models of DKD, whereas low protein provides kidney protection . NeverthAdequate salt intake has been associated with reduced BP and improved control of albuminuria. In fact, sodium intake is the single most important factor in CKD progression and the control of hypertension. Dietary sodium is known to significantly modulate the nephroprotective response to RAAS blockade, while a persistent proteinuria is found in those subjects with high dietary sodium intake . The inc2, 95% CI, 24.42 to 22.14), along with a reduced risk of progression to KF .A recent meta-analysis including 14 trials and 1394 participants  found thEfforts to prevent and treat DKD progression factors with the available measures have not reduced the morbidity and mortality of these patients to the desired level.2. Typically, in these situations the histological injury is at the vascular and interstitial compartments rather than in the glomerular area. This presentation does not seem to depend on glycemic control and is associated with higher CV risk [Different epidemiological studies have revealed the heterogenicity of DKD features within different rates of CKD progression. Between 19% and 31% of patients may have a non-linear GFR decline . In addi CV risk .The use of predictive models of KF such as the kidney failure risk equation (KFRE), or those associated with the histological classification of diabetic nephropathy score (D-Score) can be useful. However, in DKD these tools present a lower predictive value than in the general cohort of CKD (c-statistic: 0.80 (0.74–0.86)) .In the prediction of CV events, screening for coronary disease in asymptomatic patients is not indicated. Nonetheless, the indication for coronary arteriography should not be restricted, when necessary, despite the risk of kidney injury exacerbation. A carotid and/or femoral ultrasound should be considered to assess the presence of atheromatous disease in patients without cardiovascular disease, as it predicts CV events ,68,69.The prediction of CV events and CKD progression can be interfered with by different factors. The incorporation of new drugs to CKD G4, which go beyond glycemic control, with a double objective (cardio and nephro-protection), opens up hope for the future of patients with DKD, in whom the risk of suffering from any of the two events is very high.The transition from CKD G4 to KF (G5) represents a vulnerable period for the patient with elevated risk of adverse events and multiple physiologic and psychosocial changes. It is also a period in which nephrologists must make decisions together with the patient and family members . In patiPatient education and involvement make this transition easier. A meta-analysis found that self-management support interventions may improve self-management activities . These iEffective education should cover the necessary information for the patient and family members to answer the following questions : 1. ShouWhen kidney function is failing, discussion of the different KRT modalities and selection of a specific therapy should be started promptly . There iIf there are no contraindications for KRT (patient candidacy or eligibility profile), it is not clear in subjects with diabetes whether the KRT modality  or peritoneal dialysis (PD)) selected as first-choice has a major impact on outcomes, metabolic profile, diabetes complications and technique survival of the KRT. Therefore, the patient’s preference in selecting KRT should be the driving force for kidney replacement modality. Obviously, patients should be provided with unbiased information . EducatiPhysicians have the responsibility for initiating and guiding through the advance care planning process. Information needs to be personalized, integrating how their medical and interventions would affect their life and relationships most .Kidney transplantation (KT) is the treatment of choice for the diabetic patient with KFRT, as it increases quality of life and prolongs long-term patient survival . In spit2 [2. Living donor KT has the added advantage of the reduced waiting time, thus increasing the possibilities to avoid dialysis initiation [The timing for KT is a relevant aspect to consider. Many studies demonstrate that transplantation in the predialysis phase (preemptive transplantation) is associated with an increased patient survival, both in diabetic and non-diabetic patients ,84,85,86itiation .Combined kidney-pancreas transplantation in patients with T1DM and KF brings an additional benefit associated with the normalization of glucose metabolism, the slowing down of progression of organ damage induced by diabetes , as well as a significant improvement in quality of life .Patients with diabetes have an increased surgical risk related to the severity of CV disease. As a consequence, they have a reduced survival rate compared with patients without diabetes ,91. ThisIn 2001, the NKF-KDOQI guidelines published their recommendations, indications and contraindications of peritoneal dialysis (PD)   . An obseThe associated multi-comorbidity that affects diabetic and non-diabetic patients alike may be present from the beginning of treatment, and the numerous barriers that may arise over time  must be There are no specific contraindications for performing HD in patients with DKD. However, patients with diabetes may present important complications to be taken into account. These complications are related to atherosclerosis and cardiomyopathy, which cause most morbidity and mortality, as well as problems with the vascular access . The excIn 1972, Chavanian wrote: “…there is little prospect of improving the quality of life for patients with diabetic nephropathy and renal failure, and survival is likely to be short. Dialysis for such patients may be considered as a palliative measure with little prospect of long-term survival” . Since tThere is a series of specific problems in patients with diabetes, such as intradialytic hypotension , anemia,In patients with diabetes on hemodialysis, blood glucose levels are associated not only with factors related to KF but also with HD. In patients on HD, predialysis glucose levels are used instead of fasting glucose. Glycosylated hemoglobin (HbA1c) values tend to be lower in HD patients, indicating a glycemic control apparently better than what they actually have ,124. TheSince a considerable number of hemodialysis patients are diabetic and elderly, the vascular access issue is one of the major challenges for nephrologists and vascular surgeons. Both the creation and proper development of the vascular access are crucial for adequate dialysis treatment, while ensuring adequate longevity of use, sufficient blood flow to achieve the necessary dialysis dose, and a minimal complication rate . Howevern = 166) did atherosclerosis pose a significant obstacle to AVF creation, despite requiring additional procedures. Regarding the site of AVF creation, the authors agree that the preferred site is the wrist region; however, in patients with diabetes, due to atherosclerotic changes, the elbow area is frequently used.A study by Gołębiowski et al.  analyzedAnother important study  analyzinAs a recommendation, it is important to bear in mind that a detailed and systematic preoperative study helps in the choice of the anatomical area to be preferred for the first AVF, since adequate maturation of the AVF requires a healthy vascular tree, free of calcifications. If the arteries are calcified, the elbow should be the first choice for AVF creation, as calcification at this level is less pronounced than in the wrist arteries. However, these present an increased risk of steal syndrome, as involvement of arteries distal to the elbow results in increased peripheral resistance, diverting most of the flow into the fistula, leading to hand ischemia . JenningThe EUDIAL group  reminds The increased incidence and prevalence of patients with diabetes and CKD G5 who require dialysis is a challenge to optimizing accessibility to the current available kidney replacement therapy (KRT).Home HD offers the possibility of increasing the frequency, duration of the session, tolerance, and efficacy of substitution treatment since it directly affects not only a series of very prevalent factors in patients with advanced and elderly DKD, such as BP control, ventricular hypertrophy, anemia, mineral metabolism, peripheral vascular disease, autonomic dysfunction, hemodynamic instability and nutrition but also their quality of life, with a favorable impact on survival ,139,140.International  clinicalIn patients with diabetes and CKD G5 on home HD, due to its comorbidities, special attention is required to its stability during medical follow-up. Also, is important to avoid major clinical or hemodynamic incidences during HD sessions, to have an adequate vascular access and commitment to self-care, as well as socio-family support that, on occasions, includes a caregiver committed to performing the Home HD and/or assisting it .For patients with DKD, the absolute and relative contraindications for performing home HD  are the Whilst KRT offers better results, it is our obligation to offer patients with DKD the option of home HD in the informed decision-making process. We must offer them the best adequate dialysis possible, individualized and respecting their autonomy wherever their preferences are located and their lifestyle at the center of choice.For people with diabetes, KF is a potentially devastating condition, markedly increasing cardiovascular risk and potentially leading to premature death . PatientComprehensive conservative kidney care is understood as a holistic patient-centered care that not only includes interventions to delay CKD progression and minimize complications but also provides detailed communication, shared decision-making, advance care planning, and psychological and family support; however, it does not include dialysis . Older pKnowledge of the main etiologies of CKD and the metabolic alterations and associated symptoms is an important element in providing patients with good palliative care. It should be noted that excessive decreases in blood pressure and glucose levels may be linked with severe complications in CKD G5. Approaches to managing diabetes vary. Individuals previously on insulin therapy are often required to decrease dosages, since insulin is metabolized in the renal tubular cells and has its half-life prolonged in CKD G5 . A recenIn the absence of robust evidence in favor of comprehensive conservative care in patients with diabetes, nephrologists may consider this option in older patients or in those who have higher levels of comorbidity and poorer functional status, independent of the age.When patients with DKD progress to severely reduced GFR (CKD G4), they are in a vulnerable situation in which it will be necessary to continue efforts to delay the progression to KF (CKD G5), while controlling CV risk factors and/or vascular complications associated with diabetes. It should also be borne in mind that in the situation of advanced kidney injury, less scientific evidence is available and the use of certain pharmacological tools is restricted. At the same time, it is important to recall that when the progression of kidney disease cannot be delayed, other possibilities to improve the patient’s quality of life, such as dialysis, renal transplantation or conservative management, should be explored. Therefore, a shared decision-making process between health care agents, patients and family members should be initiated at this point. In this process, the clinical circumstances and preferences of the patient should be taken into account. In certain cases, it should be considered whether comprehensive conservative care is appropriate. For all this, it is essential to have an adequate multidisciplinary team and sufficient time to devote to the patient and his or her family.