Pn, 39.04%), and leaf area index . The overall effect of a waterlogging regime on crop yield is related to the crop type; the crop yield reduction varied between wheat (25.53%) and cotton (59.95%), with an overall average value of 36.81% under field conditions. In addition, we also found that compared with no waterlogging, waterlogging in the reproductive growth stage (41.90%) caused a greater yield reduction than in the vegetative growth stage (34.75%). Furthermore, decreases in crop yield were observed with an extension in the waterlogging duration; the greatest decreases in crop yield occurred at 15 < D ≤ 28 (53.19 and 55.96%) under field and potted conditions, respectively. Overall, the results of this meta-analysis showed that waterlogging can decrease crop yield and was mainly affected by crop type, growth stage, and experimental duration.Waterlogging, an abiotic stress, severely restricts crop yield in various parts of the world. Thus, we conducted a meta-analysis of 2,419 comparisons from 115 studies to comprehensively evaluate the overall change in crop yield induced by waterlogging in the global region. The results suggested that waterlogging obviously decreased crop yield by 32.9% on average, compared with no waterlogging, which was a result of a reduced 1,000-grain weight (13.67%), biomass (28.89%), plant height (10.68%), net photosynthetic rate ( Waterlogging is an identifiable phenomenon where free water overlays the soil surface of cropland . It is e2 and ethylene concentrations accumulate. This causes a severe decrease in the ATP synthesis of root cells and impacts multiple metabolic processes of plants , wheat (7.75–16.30%), and rice (7.48–57.42%) . Moreove1 and the China National Knowledge Infrastructure . The database for this meta-analysis was built based on keywords such as “waterlogging” OR “flooding stress” AND “plant height” OR “biomass” OR “dry weight” OR “net photosynthetic rate (Pn)” OR “leaf area index (LAI),” OR “yield.” Only publications that met the following predefined selection criteria were added to the database: (i) studies that involved plants that experienced waterlogging or flooding under field conditions and pot studies; greenhouse experiments were not included; (ii) the experimental research included a waterlogging treatment and a well-watered condition, without other treatments ; and (iii) the reported plants were field crops; vegetables and horticultural crops were excluded. Based on the above selection criteria, a total of 115 peer-reviewed publications (46 in English and 69 in Chinese) for inclusion with 920 data sets for crop yield, 329 for biomass, 737 for the thousand-grain weight, 242 for plant height, 125 for Pn, and 66 for LAI were collected in the global meta-analysis database (Appendix B). These articles originated from 16 different countries , standard deviations (SD), and sample sizes (n) of both waterlogging treatments and the well-watered control were extracted. If only the standard errors (SE) were given, SD was calculated by the following equation: SD = SE × For crop yield, agronomic traits, and photosynthetic index, the mean (lculated .R) as a measure of effect size (ES):To characterize the response of crop yield, agronomic traits, and photosynthetic index to waterlogging, a random-effects meta-analysis was used. We used the natural log of the response ratio  indicated the result had no publication bias  to examine the relationships of the responses of yield versus the various factors. The chi-square test was applied to determine significant differences between groups at resented . A fail-ion bias .Pn). The negative effects of the waterlogging regime on the agronomic traits and photosynthetic characteristics were in the order of Pn, biomass, leaf area index, 1,000-grain weight, and plant height. Categorical meta-analysis showed that the waterlogging regime obviously decreased Pn, biomass, leaf area index, 1,000-grain weight, and plant height by 39.04, 28.89, 22.89, 13.67, and 10.68%, respectively, compared with no waterlogging.As shown in P < 0.05; P < 0.05; The effect of the waterlogging regime on grain yield was significantly affected by the different crop types in the field and pot trials (P < 0.05). Waterlogging in the VS caused a smaller decline in grain yield than in the RS compared with no waterlogging under field culture . The meta-analysis results showed that the impact of waterlogging duration on wheat yield was smaller than that on maize and rice compared with no waterlogging. For maize, field waterlogging led to yield decreases of 22.43, 39.77, 52.72, and 76.33 in experiments with durations of 0–3, 3–6, 6–9, and 9–15 days, respectively, in comparison to no waterlogging (The effect of waterlogging duration on maize, rice, and wheat is shown in rlogging . For ricPn, and especially crop yield in the global region based on peer review research. Waterlogging was the main focus of our attention because waterlogging, an abiotic stress, severely limits crop yield in humid areas where continuous rain and poor water infiltration are frequent extreme climate events with global climate change (This meta-analysis provided a synthetic, quantitative, and systematic analysis of the effects of waterlogging on the 1,000-grain weight, biomass, plant height, LAI, e change .Pn were also reduced. Our Pearson results also indicated that the 1,000-grain weight has a significantly positive correlation with the yield reduction (In this study, approximately 2.9% of the database samples showed that waterlogging increased crop yield by 7.20% on average in comparison to no waterlogging. This phenomenon may be due to crop varieties that can tolerate longer periods of waterlogging duration or the texture of the experimental soil was relatively loose and the water infiltration was fast . Howevereduction , which ieduction . This caeduction .Numerous studies have confirmed that waterlogging at different phenological stages can decrease crop yield; the magnitude of the decrease in crop yield depends not only on the severity of waterlogging but also on the growth stages. Many studies have explored the vital stage associated with the effect of waterlogging on crop yield and showed that the vegetative growth stage was more tolerant to waterlogging than the RS . HoweverThis meta-analysis showed that crop yield after waterlogging was highly dependent on the crop type and experimental duration. The explanation of the effects of waterlogging on crop yield reduction must be prudent and should not ignore the various effects of waterlogging with different durations on different crops. Therefore, an appropriate assessment must be made in terms of the impacts of waterlogging on yield reduction.P < 0.001, In this study, we, for the first time, systematically and comprehensively confirmed that waterlogging significantly reduced the grain yield of rice, maize, wheat, cotton, and other crops. The lowest magnitude of reduction in crop yield was recorded for wheat under field waterlogged conditions. Waterlogging had a smaller impact on wheat under pot conditions. Our results also demonstrated that waterlogging led to the highest reduction in cotton and maize in field and pot trials . FurtherPn, and LAI. Moreover, waterlogging reduced crop yields most significantly in response to crop type, growth stage, and experimental duration. We found a lower sensitivity of wheat yield in response to waterlogging compared to other crops, such as maize, rice, and cotton, irrespective of field or potted conditions. More interestingly, our results also indicated that the reduction in crop yield was impacted by the growth stage subjected to waterlogging. The RS exhibited a greater yield reduction than the vegetative growth stage. Furthermore, the magnitude of the yield reduction caused by waterlogging increased with the experimental duration. In view of the importance of ensuring global crop yields, more attention should be paid to the overall effects of waterlogging on crop yields according to the factors identified in this meta-analysis.The responses of crop yield to waterlogging in a global region were identified based on a meta-analysis. The results indicated that crop yield decreased by an average of 32.9% under waterlogging compared to no waterlogging. The yield loss attributed to waterlogging was influenced significantly by the decrease in the 1,000-grain weight, biomass, plant height, B-LF and JL designed the experiment. F-FZ and P-LC contributed to collecting data. FY and YD performed the data analysis and prepared the manuscript. L-XT and Y-CZ wrote the manuscript. 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 of interest.


This study investigated differences in the body composition of police officers from different occupational groups and the moderation effects of leisure time physical activity (LTPA). A sample of 237 police officers  participated in the study. Body mass index (BMI), percent of body fat (%BF), percent of skeletal muscle mass (%SMM), and index of hypokinesia (IH) were assessed using a multichannel bioelectric impedance analyzer and officers reported the amount of LTPA using an international physical activity questionnaire. The sample was divided in three groups relative to LTPA, sedentary (0–149 min/week), moderately active (150–299 min/week), and very active (300+ min/week). Multiple analysis of variance (4 × 3) was used to analyze if occupational groups differed based solely on occupation, if officers from the same occupation differed in muscularity and fatness based on LTPA, and if any differences in body composition occurred between officers from different occupations with the same level of LTPA. Police officers from more physically demanding occupations demonstrated lower %BF and IH, while having higher %SMM. This was also observed among the officers of the same occupation who reported a higher LTPA, while officers who reported very high LTPA had similar body composition. The tasks performed differ across police occupations, some of which are physically demanding , while others are more sedentary  ,2,3. To 2)), increases due to lack of physical activity, sedentary work, and shift work in police officers [Body fatness, indicated through measures such as percent body fat (%BF), waist circumference, and body mass index (BMI—body mass (kg) divided by body height , and body mass ((BM), average increase of 7 kg, p < 0.001 or 0.5 kg/year of service) in Finnish police officers after 15 years of service. These health-related factors may contribute to the significantly shorter life expectancy for police officers compared to the general population [p < 0.05) decrease of approximately 5.60% in %BF and an increase of approximately 3% in percent of lean mass. Furthermore, significant (p < 0.001) reductions in BM (7.50%), BMI (7.48%), waist circumference (8.26%) and waist-to-height ratio (9.26%) occurred after a 12-week exercise and diet programme in overweight police trainees [Evidence shows that age plays a role in body composition changes for police officers. Sorrensen et al.  found nepulation . In contpulation  found thtrainees . Vukovićtrainees  investigPolice officers’ daily duties influence their body composition as well as the frequency and volume of their physical activity at work and during leisure time. The sedentary activities an officer is required to do on a daily basis  can leave little available time for physical activity and/or exercise due to operational work overload ,20,21. OConsideration of these factors in police agencies is important from the perspective of occupational health as it could help to determine how officers’ body composition and physical activity levels differ between police occupations and whether LTPA could be a significant moderator of body composition. Therefore, the aims of this study were to investigate differences in body composition and levels of LTPA between various police occupations, and whether LTPA, more so than occupation, moderates the relationship between occupation and body composition. We hypothesized that police officers from more physically demanding occupations will have lower levels of body fat, greater %SMM, and that they will report higher levels of physical activity. We also hypothesized that LTPA could be a significant moderator of body composition.n = 54), Gendarmerie (n = 55), firefighters (n = 68), and general police officers (n = 60). The main characteristics of groups were: SAU  = 181.63 ± 5.30 cm, BM = 89.13 ± 9.57 kg, and BMI = 26.99 ± 2.17 kg/m2); Gendarmerie ; firefighters ; and general police . All participants were informed about the purpose of the study and were assessed after providing informed consent. Data for this study were collected in a de-identified format without obtaining names or any personal identification. To match the different types of data collected, participants were coded using an alpha numeric coding system . The ethical board of the Faculty of Sport and Physical Education, University of Belgrade, Serbia provided the ethical approval (no. 484-2) for this study. The study was conducted in accordance with the Declaration of Helsinki [The sample consisted of 237 male police officers recruited randomly from four different occupations: Special Anti-Terrorist Unit ((SAU), The organizational structure of the police of the Republic of Serbia is based on the responsibilities covered by the Ministry of Interior and occupational processes within the Ministry . OrganizThe SAU is the most elite police tactical unit in Serbia specializing in weapons and tactics, preventing complex anti-terrorist tasks, hostage crises interdiction, VIP protection, high-risk arrests, and other complex security tasks . The phyGendarmerie of the Republic of Serbia is another police tactical unit who specialize in crowd and riot control, search and rescue, weapons and tactics training, border control, some general police duties, and support of the SAU in case of terrorist attack . They maFirefighters of the Republic of Serbia are the part of the civil defence specialized for fire and rescue operations and operating in case of man-caused or natural disasters. Their physical fitness at recruitment and during their career needs to be high, given that tasks conducted during operations are often very physically demanding. Moreover, the protective clothing, self-contained breathing apparatus, and other tools needed for certain tasks constitute a heavy external load which they are required to wear and carry. Therefore, physical fitness and specific skills are assessed on a regular basis and in order to attain the expected levels, they may need to implement general and specific strength and conditioning programs ,31.Police officers of general jurisdiction perform preventive and operative tasks aimed to establish public security and safety. Furthermore, they patrol the streets and inter-city roads, conduct investigative tasks, complete administrative work, and respond to reported offences, homicides, traffic accidents, and more. Although physical fitness assessment is part of the recruitment and initial training at the academy, once they enter the force, it is not as rigorously or frequently checked as in the tactical units such as SAU and Gendarmerie.A multichannel bioelectric impendence analyser InBody 720  was used for the assessment of body composition. This device has been found to be valid and reliable ,33. The Immediately after they completed the body composition assessment, participants were provided with an international physical activity questionnaire (IPAQ) that assessed their levels of physical activity . The quep < 0.05. Cohen’s effect sizes (d) were calculated as the ratio of the difference in mean scores to standard deviation, following the formula: ES = (M2 − M1)/SD, where M1 and M2 were the means of the groups investigated and the SD was a pooled standard deviation of compared groups. Relative differences (%) and d showed the sizes of differences obtained in the aforementioned comparisons.All data were collected and entered into Microsoft Excel and transferred to the Statistical Package for Social Sciences  for statistical analyses. Descriptive statistics for mean, standard deviation, minimum and maximum values were calculated for each occupation group relative to V-LTPA. Pearson’s correlation analysis was conducted to establish associations between age, occupation, V-LTPA, BMI, %BF, %SMM, and IH. For this purpose, occupations were coded as: 1—SAU, 2—Gendarmerie, 3—firefighters, and 4—general police, with 1 being the most demanding and 4 being the least physically demanding occupation. The magnitude of the effects was defined as follows: small = 0.2, moderate = 0.6, large = 1.2 and very large = 2.0 . Multivan = 8), 47.3% for Gendarmerie (n = 26), 76.5% for firefighters (n = 52), and 73.3% for general police (n = 44). Moderately active officers comprised 42.6% of SAU (n = 23), 29.1% of Gendarmerie (n = 16), 14.7% of firefighters (n = 10), and 21.7% of general police (n = 13). Finally, the percentage of very active officers was 42.6% for SAU (n = 23), 23.6% for Gendarmerie (n = 13), 8.8% for firefighters (n = 6), and 5% for general police (n = 3).Descriptive statistics for age, BH, BMI, %BF, %SMM, and IH for each occupation group and relative to LTPA level are shown in p < 0.01) of V-LTPA with age and occupation, while age, occupation and V-LTPA were negatively correlated with BMI, %BF, and IH, and positively with %SMM , %SMM , IH , and V-LTPA , but not in age  or BMI . Post hoc analysis , but found no significant difference between very active officers from different occupations. Thus, as hypothesized, physical activity moderated the relationship between occupation and body composition. However, physical activity only partially moderated the relationship since, among moderately active participants, SAU had significantly lower body fat and IH than firefighters, while in sedentary participants, SAU had significantly lower body fat and IH and higher muscle mass than general police. Accordingly, our results suggest that as the V-LTPA reduces, occupational demands may play a larger role in body composition. The lower body fatness of sedentary SAU officers may lie in the recruitment and service  requirements as well as more frequent fitness assessments that officers must meet in order to remain in service. This demonstrates importance, as studies suggest that police officer LTPA tends to decrease, while BMI and body fatness tend to increase, with the time spent in service ,15,42,43Due to the cross-sectional nature of this study, we cannot determine whether time in occupation resulted in the significant differences found or whether more fit and physically active officers with better body composition were recruited into more demanding occupations in the first place. This study lacked an objective prospective measure of physical activity and did not account for differences in physical fitness training on the job versus in personal leisure time. The results of this study may differ from those found in other countries and additional research should be conducted with female officers. In addition, information on family tasks and their association with age could be considered in the future, and whether older police officers were also higher ranked in police organizations so their duties were more organizational and supervision-based rather than in the field.This was the first study to investigate the differences in body composition and LTPA across several police occupations and whether LTPA moderated that relationship. Our results suggest that both occupation and V-LTPA were significantly related to the body composition of police officers, with officers from more physically demanding occupations with higher V-LTPA demonstrating better body composition. However, V-LTPA partially moderated the relationship between occupation and body composition, thereby showing its viability as a potential intervention target. This relationship seemed to have a protective effect, as body composition was similar between police officers from different occupations if they reported to be physically very active. Thereby, higher volumes of LTPA  seem to be sufficient for a good body composition of police officers, as none of the participants from this group were obese . Moreover, moderately active officers had lower %BF and IH  than those who reported to be sedentary. Therefore, officers should aim to be at least moderately physically active during leisure time  for some improvements, while, for greater improvements, they may need to aim for a higher volume of activity.


Nevus sebaceous (NS) is a lesion caused by congenital hyperplastic disorder of the sebaceous glands. It commonly noted in the scalp and face and rarely in the trunk, neck, or oral mucosa. We present a rare case of a lesion arising in the genital region.A 47-year-old woman complained of a gradual increase in the size of her bilateral labia minora over 2 years, which affected her sexual life and caused walking difficulty. She was admitted to the Department of Obstetrics and Gynecology. On physical examination, no ulcer, discharge, and vulval or vaginal bleeding were found. The bilateral inguinal lymph nodes were not palpable, bilateral labia minora were asymmetric, and the right side was evidently bigger than the left. The labia minora had serrated edges and numerous papillae with a maximum diameter of 0.5 cm. The vagina, cervix, and uterus with its attachments were normal. Blood samples tested negative for human immunodeficiency virus, human papilloma virus, hepatitis B virus, and hepatitis C virus.A diagnosis of NS of the bilateral labia minora was made following histopathological examination of the resected specimen.The bilateral labia minora lesions were resected general anesthesia on August 29, 2016. The operation was successful, and intraoperative blood loss was about 10 ml.After 40 months of postoperative follow-up, no recurrence or appearance of other tumors were noted.We recommend surgical removal of lesions in the genital area during adolescence or before adulthood. Adolescence may be the best period for surgical intervention owing to a greater risk of malignant change in adulthood. On the other hand, surgical risk should be avoided in children considering the low incidence of malignant transformation. It is also called a sebaceous gland hamartoma and was first reported by Jadassohn in 1895. The onset of NS typically occurs at birth, and occasionally, in adulthood. In childhood, NS presents as an elevated hairless patch, that is pale yellow with a smooth surface and waxy luster. In adolescent patients, because the sebaceous gland can be fully developed by then, the nevus presents as nodular, petaloid or verrucous lesions. In elderly patients, NS presents as a brown, hard verrucous lesion. It rarely occurs in other locations such as the eyelid and the oral mucosa, where it presents as plaques or nodules; multiple lesions are also a possibility.–5 NS occurring in the genital organs is extremely rare, with only 5 cases reported in the literature to-date, out of which only 3 have been reported in detail.,7 Since the specific morphological characteristics of genital organ NS are scarcely reported in the literature, clinical diagnosis is difficult, and cases can be easily misdiagnosed. This paper, with relevant literature review, elucidates the morphologic characteristics of labia minora lesions, that can aid plastic surgeons, dermatologists, and gynecologists to arrive at a suitable differential diagnosis and treatment strategy.NS most frequently occurs on the head and neck, and usually involves the scalp (87%–95% of cases) resulting in alopecia.22.1A 47-year-old woman of Han ethnicity with obstetric history G2P0L1A1, who complained of gradually enlarging labia minora over 2 years, was admitted to the hospital on August 26, 2016.2.2Two years prior to admission, she found the right labia minora to have gradually enlarged; it was soft to touch and deep in color. There were no symptoms of swelling, erosion, or pain in the right labia minora. Subsequently, she found that the left labia minora was gradually enlarging too. The bilateral labia minora were asymmetrical, with the right side being larger than the left. Three months before admission, the labia minora enlarged rapidly, accompanied by mild tenderness that affected sexual life and walking to a certain extent. There were, however, no complaints of ulcer, discharge, and vulval or vaginal bleeding.2.3The patient had a 2-year history of hypertension and regularly took telmisartan 40 mg/d to maintain a blood pressure of 120 to 130/80 mm Hg.2.4The patient maintained a normal diet, had no significant change in weight recently, and had no history of bowel or bladder dysfunction. Her menstrual cycles were normal; there was no history of radiation or poison exposure, previous surgeries, or relevant illnesses in the family.2.5Systemic examination was found to be normal. On local examination, the bilateral inguinal lymph nodes were not palpable. The bilateral labia minora were asymmetric, with the right side being evidently bigger than the left. The labia minora had serrated edges and numerous papillae with a maximum diameter of 0.5 cm Fig. A–C. The 2.6Blood test results showed that the blood type was O (+). Moreover, tests for human immunodeficiency virus, human papilloma virus, syphilis, hepatitis B virus, and hepatitis C virus were all negative; serum cancer antigen 125 level was 13.35 U/ml and carbohydrate antigen 19-9 level was 7.41 U/ml. The cervical pap smear showed normal results.2.7A transvaginal color Doppler ultrasound was suggestive of a uterine adenomyoma. The results of electrocardiogram, chest X ray, and abdominal ultrasonography for liver and spleen were normal.2.8Before surgery, the dermatological consultant suggested removing the lesions, but did not provide a clear diagnosis. The postoperative pathological diagnosis was NS.2.9The resection of bilateral labia minora lesions was performed under general anesthesia on August 29, 2016. The operation was successfully completed, and intraoperative blood loss was about 10 ml.2.10Pathological examination showed that the right-sided lesion was 2.5 × 1.0 cm in size, while the left was 2.5 × 0.8 cm. The surface of the bilateral labia minora lesions was partially covered with proliferative squamous epithelium and displayed papillary hyperplasia. A large number of proliferative sebaceous glands were found under the skin and deep dermis; they were well-differentiated but lacked hair follicles. Immunohistochemical analysis was positive for P63 in the basal layer, vessels positive for cluster of differentiation (CD) 34 and CD31, and negative for S-100 and Sox; 10% of Ki-67 was positive. Thus, the diagnosis was confirmed as NS  and unusual location” and 6 additional records were found, of which only 1 was ultimately relevant. After reading the above-mentioned articles, we found 2 other related articles,,10 though neither had a detailed description of NS. Herein, we list the information we retrieved and sorted , and Web of Science databases and retrieved only 2 related reports.–10 retrieved by us were diagnosed as NS, and they were all located in the genital area. Kavak et al first reported a case of bilateral labia minora NS, for which the patient went to the Department of Dermatology and Plastic, Reconstructive and Esthetic Surgery. The patient sought help due to slight enlargement of the lesion with occasional pruritus. Lesion removal was planned for aesthetic reasons. After excluding the possibility of neurological or ophthalmologic disease and syphilis, the lesion was partially excised and primary repair was achieved. There was no recurrence or development of other tumors at follow-up (postoperative year 1). Ugras et al published the second paper on lesions of NS in the genital region, but the manuscript did not provide accurate details on tumor location. The vulvar biopsy was initially performed in another institution and reported as squamous hyperplasia, whereas a repeat biopsy performed in the author's institution was suggestive of NS. The surgery was performed consequently and the patient was followed up regularly for 10 months without recurrence. Feito et al recently reported a case of NS in 2018. The patient was a 13-year-old girl with hypertrophy and asymmetry of the left labia, but no pain or abnormal sensation. The lesion was surgically removed, and the patient was discharged 2 days later without further follow-up information.All the cases NS is a benign disease with a detection rate of 0.5% to 1% in all dermatologic patients, but it may lead to benign or malignant secondary tumors. Aslam et al noted in a meta-analysis of 4900 NS cases that secondary tumors developed in around 25% of cases. The most common benign tumor was trichoblastoma, while basal cell carcinoma (BCC) was the most common malignant tumor. Hsu et al published a research report on 450 cases, which pointed out that syringocystadenoma papilliferum was the most common benign tumor, accounting for 2.7% of all cases, trichoblastoma occurred in 1.6%, and BCC in about 0.9% of cases. What is worthy of our attention is that this article listed 8 large studies on NS, dated from 2000 to 2016. By analyzing the data reported by Hsu et al, we found that there were 3847 NS cases in total, and 36 cases of BCC accounting for about 0.94%, consistent with other studies. Kamyab-Hesari et al studied the histopathological features of 168 patients with NS in order to determine the proportion of different histological features and incidence of secondary tumors. The results pointed out 9 cases of neoplastic change, including 4 cases of trichoblastoma, 3 of tricholemmoma, and 2 of syringocystadenoma papilliferum. Neither BCC nor other malignant tumors was found. Hence, Kamyab-Hesari holds the view that unnecessary surgical intervention should be avoided, and recommends regular follow-up for children. A prophylactic excision, however, would need thorough evaluation and individualized therapy. Further, Santibanez-Gallerani et al assessed 658 NS pediatric patients under 16 years of age and found no malignancy, but deemed that the risk of NS-induced tumors increased over time. As a supplement, Cribier study of 596 NS subjects recorded 5 cases of BCC, but only in individuals over 22 years of age. Bernard Cribier et al noted that the incidence of BCC may be overestimated because of the similarity between BCC and trichoblastoma, and proposed that when clinical signs indicating malignant transformation were absent, children should not receive preventive surgery. Hsu research results strongly support that malignant transformation of NS mainly occurs in adulthood. When performing prophylactic excision in children, it is an elective procedure and the risks of general anesthesia and surgical complications should be considered. However, resection is strongly advocated during adolescence due to the significantly increased risks. In our opinion, NS is a congenital hyperplastic disease of sebaceous glands, and its treatment should be surgical removal during puberty. The definitive treatment for NS is full-thickness dermal and epidermal excision, and lesions should be excised with 2 to 3 mm margins since it extends at least as deep as the subcutaneous tissue with involvement of adnexal structures. In cases with incomplete clearance, close follow-up is necessary.As it is unclear whether the surgical resection was appropriate, we studied the relevant literature further. According to reports,HRAS and NRAS is responsible for the occurrence of sebaceous nevus, which can activate mitogen-activated protein kinase and phosphoinositide 3-kinase pathways and stimulate cellular proliferation causing so-called “RASopathy” in NS lesional keratinocytes.,12 Taking into account that benign and malignant secondary tumors of NS often occur in adulthood, Hsu et al and Idriss et al endorsed the idea that age may be a critical risk factor. Furthermore, Person et al were the first to propose the hypothesis that NS was related to hormonal hyperresponsiveness. They speculated that since sebaceous and apocrine glands are androgen-target organs, androgen receptors may increase in these lesions. To prove this hypothesis, they performed androgen receptor assays in 4 specimens of 3 NS cases, and unsurprisingly, the results showed a significant increase in androgen receptors. NS seems to be directly regulated by hormones, and the level of androgen receptors tends to be up-regulated at all ages, thus being particularly hypersensitive to the effects of hematological androgens.As for the pathogenesis of NS, Hsu viewpoint deserves our careful consideration. Mosaic mutation of HRAS and NRAS and is accompanied by an increased expression of androgen receptors. According to previous studies, genital NS lesions are usually located on either unilateral or bilateral labia minora, and can present as a slightly pigmented plaque with verrucous lesions or as a yellowish-tan-colored lobulated growth. All cases of NS in the genital area have been reported in female patients so far, with no other skin malignancies and the age of onset ranging from puberty to perimenopausal period concerning treatment strategies, full-thickness skin resection is an effective method, requiring at least 2 to 3 mm margin and close follow-up postoperatively. Whether for aesthetic reasons or for concerns of malignant transformation, with the consent of the patient, we recommend surgical removal of the genital lesion within the period of adolescence or before adulthood. Adolescence may be the best period for surgical intervention owing to a greater risk of malignant change in adulthood. On the other hand, the risk of surgery can be avoided in children, considering the low incidence of malignant transformation in the pediatric age-group. At present, the reported follow-up duration of patients is around 1 year, while we found no recurrence after 40 months of observation. Thus, we strongly believe that if patients with lesion-free margins have no recurrence after 1 year of follow-up, the possibility of recurrence in the future is lower. In addition, differential diagnosis is also very important, by virtue of the fact that patients may visit different departments under different circumstances. Although the diagnosis can be confirmed mainly by pathological examination, detailed history-taking and medical tests should be done to distinguish NS from neurological diseases, syphilis, and other potential diseases.Briefly, NS in genital or other parts is associated with mosaic mutations of In conclusion, we recommend full-thickness skin resection of NS lesions with at least 2 to 3 mm margin in the genital area during adolescence or before adulthood, and close follow-up postoperatively. Adolescence may be the best period for surgical intervention owing to a greater risk of malignant change in adulthood. On the other hand, surgical risks can be avoided in children considering the low incidence of malignant transformation in the pediatric age group. In addition, we strongly believe that if patients with lesion-free margins have no recurrence after 1 year of follow-up, the possibility of recurrence in the future is lower. Lastly, we hope that our report can provide some important references to other dermatologists, gynecologists, or plastic surgeons, and remind them to attach enough importance to the long-term follow-up of patients with NS.Conceptualization: Zhiwei Zhao, Jiang Wu, Yali Miao.Data curation: Qiao Wen, Yanlin Yang, Fengnian Zhao.Funding acquisition: Jiang Wu, Yali Miao.Investigation: Qiao Wen, Ling Wang, Juan Cheng.Methodology: Zhiwei Zhao, Jiang Wu, Yali Miao.Project administration: Zhiwei Zhao, Jiang Wu, Yali Miao.Writing – original draft: Qiao Wen, Zhiwei Zhao.Writing – review & editing: Jiang Wu, Yali Miao.


Our study provides important information pertaining to the dissemination of scientific knowledge about COVID-19 in online media.The novel coronavirus disease 2019 (COVID-19) is a global pandemic. This study’s aim was to identify and characterize the top 100 COVID-19-related scientific publications, which had received the highest Altmetric Attention Scores (AASs). Hence, we searched Altmetric Explorer using search terms such as “COVID” or “COVID-19” or “Coronavirus” or “SARS-CoV-2” or “nCoV” and then selected the top 100 articles with the highest AASs. For each article identified, we extracted the following information: the overall AAS, publishing journal, journal impact factor (IF), date of publication, language, country of origin, document type, main topic, and accessibility. The top 100 articles most frequently were published in journals with high (>10.0) IF ( The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV), which caused coronavirus disease 2019 (COVID-19)—a new infectious disease—was first detected in December 2019 in Wuhan, China , and theWith the spread of the pandemic, a remarkably high number of scientific articles on COVID-19 have been published. Therefore, evaluating the impact of an article is particularly important, especially for readers who lack the time to read all relevant papers. Since the development of citation indexing in the 1960s, the number of citations has been widely used to measure the impact of articles. However, citations take a long time to accumulate and fail to reflect the impact of an article outside the academic community ,5.With the recent advent of social media, the concept of “altmetrics”—referring to non-traditional alternative article-level metrics—was introduced in the early 2010s. In comparison to traditional citation metrics, altmetrics measure the impact of an article after publication, based on its number of mentions across various online sources. This new metric can evaluate the instantaneous influence of published work on broad audiences in comparison to citation counts, thereby indicating the articles’ dissemination to the general public ,7.To date, several studies have been conducted to identify the top altmetric articles in specific medical fields ,10,11,12The present study did not involve human subjects and thus did not require approval from the institutional review board.We conducted a search for scientific publications on COVID-19 using “Advanced Search” in Altmetric Explorer . To identify the closest matching publication, the search terms applied included “COVID” or “COVID-19” or “Coronavirus” or “SARS-CoV-2” or “nCoV”, which were used as keywords in the title. No restrictions were applied regarding journal, language, date of publication, output title, output type, or scholarly identifiers.Altmetric.com, one of the main providers of alternative indicators, was chosen for this study because it is the most comprehensive source covering the vast majority of online media activities associated with scientific papers. We obtained permission to access the Altmetric database, which contains almost 31 million research articles from more than 36,000 journals and captures real-time mentions in public policy documents, blogs, mainstream media, online reference managers, such as Mendeley, research highlights, post-publication peer review platforms, Open Syllabus, YouTube, and social media networks, including Facebook and Twitter. Altmetric.com provides Altmetric Attention Scores (AASs) to measure the overall level of online impact arising from a particular research output, which is presented as a whole number. The AAS is a weighted score of total mentions of an article across various online media, reflecting the anticipated relative degrees of influence of sources on potential readers  .The AASs of all articles were recorded and then compiled into a single database. Then, these articles were ranked in descending order, based on their AASs for selecting the top 100 articles with the highest AAS. To determine if the articles were mainly focused on COVID-19, two authors (J.Y.M. and D.Y.Y.) independently reviewed each article’s title and abstract  and generated the final lists of the top 100 articles with the highest AAS. There was no disagreement between the two reviewers in the selection of top 100 articles on COVID-19. Both reviewers excluded three articles among 103 articles with the highest AAS because two original articles mainly focused on other coronavirus family outbreaks rather than COVID-19, and one news report could not be discovered with the Internet search for the title on 29 December 2020.The abstract and full text for each article identified were independently reviewed by the same two authors, who extracted the following information: (1) overall AAS, (2) publishing journal, (3) its journal impact factor (IF) based on the Journal Citation Reports (JCR) 2019 edition , (4) month and year of publication, (5) language, (6) country of origin, (7) document type , reviews, case reports, letters, news, editorials, etc.), (8) main topics ); and (9) accessibility (open-access or pay-for-access).The Altmetric Explorer search was conducted on a specific day (29 December 2020) to avoid changes in the scores of articles. In only two cases in which disagreement occurred between two reviewers regarding the main topic of articles, the articles were reviewed jointly and discussed with a third reviewer (E.J.Y.) until consensus was reached. The country of origin was defined by the address provided for the authors. If the authors were affiliated with more than one country, it was classified as an international collaboration.This study adopted descriptive statistics using counts and proportions to describe the articles included.The top 100 articles on COVID-19 with the highest AAS were listed in n = 17), followed by the Lancet (n = 11)  . If jourA total of 67 articles were published in journals with an IF > 10.0, whereas 12 papers appeared in preprint online databases, such as MedRxiv and BioRxiv. All the articles were published in 2020, with 19 and 15 articles being published in April and March, respectively .n = 45), followed by China (n = 18), and the United Kingdom (n = 10). Seven were conducted through international collaborations (The United States published the most articles (orations .n = 59), of which 28 were clinical observational studies. For the remaining articles, the most common document types were letters (n = 20) and case reports (n = 15). The most common topics were treatment (n = 18), clinical manifestations (n = 15), transmission (n = 14), epidemiology (n = 13), and virology (n = 11). All the publications were in English and 98 papers had open-access . A total of 67 articles were published during the early pandemic, whereas 24 were published later in the pandemic (between August and December 2020). This could be attributed to the public’s greater interest and need to receive information regarding the novel infectious disease during the pandemic’s early phase.In our study, the United States was the country with the most articles in the top 100, distantly followed by China. The dominance of the United States in the altmetric top 100 articles is in line with previous studies in other fields ,10,11,12With regard to the document type of articles, although original articles accounted for 59 of the altmetric top 100, there were various document types such as original articles, letters, case reports, editorials, as well as news in our list of the altmetric top 100 COVID-19 articles. This reflects the public’s diverse and broad interests in COVID-19. In particular, scientific publications providing information that is newer and easier to understand are the ones that attract the greater audiences in online media. This is in contrast to the results of the majority of classic citation studies, which reported that the most top-cited articles were typically original articles and reviews ,17. AlthIn the case of the COVID-19 outbreak, social media could be an increasingly important part of public health . People However, during the COVID-19 pandemic, social media also had a dark side―rumors, stigma, conspiracy theories, etc. Such misinformation can have potentially serious implications on individuals and communities in dealing with the pandemic crisis .PredictaIn addition, there are several public key players, who play a pivotal role with regard to COVID-19 information in social networks. For example, the number 4 ranked article, “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: A multinational registry analysis” was published in the 22 May 2020, issue of the Lancet . The newDespite these negative aspects, social media represents a uniquely powerful tool for the widespread dissemination of scholarly publications Thus, our list of the altmetric top 100 COVID-19 articles provides an insight into the dissemination of scientific knowledge through online media during a defined short period of time, following the emergence of the novel infectious disease.Altmetric.com. We selected it because of its wide use and inclusion of a comprehensive range of online platforms. Our results might have been slightly different if we had used other altmetric tools that aggregate and provide article-level metrics, such as PlumX, ImpactStory, and PLoS Impact Explorer [Our study has some limitations. First, for assessing alternative metrics, we solely used data supplied by Explorer . Second,Explorer ,28,29.In conclusion, our study presents a detailed list and analysis of the altmetric top 100 articles on COVID-19 research, thereby providing important information pertaining to the dissemination of scientific knowledge during the pandemic caused by a novel virus.


The aim of this study was to evaluate a series of blood count inflammation indexes in predicting anastomotic leakage (AL) in elective colorectal surgery.Demographic, pathologic, and clinical data of 1432 consecutive patients submitted to colorectal surgery in eight surgical centers were retrospectively evaluated. The neutrophil to lymphocyte (NLR), derived neutrophil to lymphocyte (dNLR), lymphocyte to monocyte (LMR), and platelet to lymphocyte (PLR) ratios were calculated before surgery and on the 1st and 4th postoperative days, in patients with or without AL.There were 106 patients with AL . The NLR, dNLR, and PLR were significantly higher in patients with AL in comparison to those without, on both the 1st and 4th postoperative days, but significance was greater on the 4th postoperative day. An NLR cutoff value of 7.1 on this day showed the best area under the curve  in predicting AL.Among the blood cell indexes of inflammation evaluated, NLR on the 4th postoperative day showed the best ability to predict AL. NLR is a low cost, easy to perform, and widely available index, which might be potentially used in clinical practice as a predictor of AL in patients undergoing elective colorectal surgery. Anastomotic leakage (AL) is one of the most severe complications in modern colorectal surgery. It has been reported to occur in 3 to 27% of patients in relation to specific risk factors, despite recent improvements in the preoperative selection and preparation of the patients, the evolution of minimally invasive surgical techniques, the stapling devices used to fashion the anastomoses, and the postoperative management of the patients , 2. AnasAnastomotic leakage can manifest clinically in several ways, in relation to the grade of the anastomotic breakdown, the anatomical site (colon or rectum) and the type of the surgical procedure, the general condition of the patient, and the presence of a protective stoma. Generally, early AL is caused by technical errors or defects, has a major clinical impact, and reoperation is often needed to treat it. Most commonly, AL occurs between the 5th and 8th postoperative days, and has a variable clinical presentation; minor leaks can be treated conservatively using drains to evacuate possible infectious collections, while major defects require re-intervention to clean the abdomen and restore the intestinal integrity or exteriorize the bowel . In all +, tissue plasminogen activator, and soluble fibrin have been evaluated in blood samples, as well as indexes including the cells participating in the inflammatory process, like the neutrophil to lymphocyte ratio (NLR) [To this regard, several biomarkers have been evaluated so far, most of them related to the inflammatory response to surgical manipulation, and the consequent reparative events in resected tissues. Factors like interleukins, C-reactive protein (CRP), procalcitonin (PCT), Naio (NLR) , 10. Theio (NLR) –14. Furtio (NLR) –19. HoweData of consecutive patients with histologically proven colorectal cancer, and undergoing elective surgery at the surgical units involved in the study from January 1, 2013 through December 31, 2017 were collected in an electronic database. Demographic and clinical data, including sex, age, body mass index (BMI), American Society of Anesthesiologists (ASA) score, Charlson comorbidity index, localization and histology of the disease, as well as the stage of the disease according to the American Joint Committee on Cancer (AJCC) staging system (7th edition), were registered. Tumor distance from the anocutaneous line was included for patients with rectal cancer. Furthermore, details regarding the surgical procedure, postoperative course, morbidity, and 30-day mortality were collected.The inclusion criteria were as follows: (a) patients with histologically proven colorectal cancer; (b) patients undergoing elective surgical procedure with an open or laparoscopic approach; (c) patients with available clinical, surgical, and pathological data; (d) patients with available blood cell counts before surgery, and at the 1st and 4th postoperative days; and (e) patients who signed an informed consent for each procedure performed. The exclusion criteria were the following: (a) patients younger than 18, (b) those operated on an emergency setting, and (c) those who did not have an anastomosis. Patients who had a clinically manifested anastomotic leakage (Extended Clavien-Dindo classification stage III through V)  within 3Regarding laboratory tests, fasting blood samples were obtained with standard procedures and methodologies dictated by the current international and national guidelines, adopted by the institutions involved in the study; the samples were processed and analyzed in certified laboratories. Complete blood counts before the operation, on the 1st postoperative day, and on the 4th postoperative day were retrieved, and the NLR, dNLR (neutrophils/white blood cells—neutrophils), LMR, and PLR were calculated.t test or Mann-Whitney rank sum test, as appropriate. Correlations between variables were assessed by Pearson’s correlation or Spearman’s correlation, as appropriate. Multiple comparisons were performed by one-way ANOVA, student-Newman-Keuls test or Kruskal-Wallis test, as appropriate. Levene’s test for equality of error variances was employed. Logistic regression analysis was employed to investigate the association of NLR and other risk factors with AL.All results were expressed as mean (mean ± SD) or median values (median and IQR). Variable distribution was assessed by the Shapiro-Wilcoxon test. Statistical differences between groups were compared using unpaired Student’s The ability of the studied parameters to predict AL was analyzed using receiver operating characteristic (ROC) curve analysis. Optimal cutoff maximizing sensitivity and specificity was selected. Sensitivity and specificity were reported using the optimal ROC curve value according to the Youden index. The results of the area under the curve (AUC) represented the global accuracy of the tests performed, 0.91–1.00 (excellent), 0.81–0.90 (good), 0.71–0.80 (fair), 0.61–0.70 (poor), and 0.51–0.60 (fail). Statistical analyses were performed using MedCalc for Windows, version 15.4 64 bit  and SPSS for Windows, version 14.0 32 bit .p = 0.0002) and a significantly higher mean Charlson comorbidity index . Furthermore, there was a significantly higher percentage of TNM stage III patients  in the group of patients with AL in comparison to those without; the latter had significantly more patients of TNM stage II  and significantly less pathological grade 3 tumors . AL was treated with a surgical operation in most cases (72.6%) and without surgery in the remaining cases. AL patients had significantly higher percentage of concomitant complications , a greater length of stay , and significantly worse 30-day postoperative mortality .The global number of patients enrolled in the study was 1432; among them, 817 (57%) were male, and the mean age was 65.8 (± 13.7). Globally, 106 (7.4%) patients with AL fulfilling the selection criteria were registered; among them, 59 (55.7%) were affected by rectal or sigmoid cancer. The demographic, anthropometric, and clinical data of patients with and without AL are summarized in Table p = 0.038) which showed a limited but statistically significant difference. On the first postoperative day, some further differences in blood cell populations and indexes were observed, but the greatest statistical differences were registered on the 4th postoperative day. On that day, patients with AL had significantly greater mean WBC  and neutrophil  values, but lower mean lymphocyte  values. In addition, the mean NLR , dNLR , and PLR  values were consistently greater in patients who developed an AL (Table p < 0.001), Charlson comorbidity index , and 4th postoperative day NLR  were shown to be independent factors associated with AL.As shown by Table We performed ROC curve analysis for the indexes which showed statistically significant differences between the two groups of patients on the 4th postoperative day Table , Fig. 1.Anastomotic leakage is one of the most serious postoperative adverse events in colorectal surgery –6. This To our knowledge, this is the first study to evaluate the role of the dNLR, LMR, and PLR in predicting AL. These simple blood count indexes, together with the NLR and RDW, have been demonstrated to have a prognostic potential in several chronic pathological conditions, including colorectal cancer and colorectal liver metastases –26, and p = 0.0089, odds ratio = 8.24) and that the sensitivity and specificity of the test at this cutoff point was 83% and 47%, respectively [Miyakita et al. published a study on 260 patients with rectal cancer who underwent radical surgery to examine the relations between complications and 5 types of risk scores, including the preoperative NLR . Complicectively . This cup = 0.0012). The ROC analysis showed a sensitivity of 69% , and a specificity of 78%  at a cutoff point of 6.5, with an AUC of 0.68 [Another study recently published by Mik et al. included 724 patients who underwent elective open colorectal surgery, and (among them) the rate of AL was 4.6% . In this of 0.68 . In our More recently, Walker et al. published their results on the predictive roles of CRP, PCT, and NLR on 136 patients retrospectively enrolled  . Median The RDW and the LMR did not show any predictive ability for the early detection of AL in our study. To this regard, a retrospective pilot study by Paliogiannis et al. investigated the role of the preoperative RDW and mean platelet volume (MPV) in 42 case-matched patients who underwent oncological colorectal surgery . The autOur study has some limitations, mainly the retrospective design, the lack of information about treatments that may alter the indexes under evaluation (like steroids), as well as potential variability in the perioperative management of the patients and laboratory testing. On the other hand, it includes the largest cohort employed so far for the study of the role of specific inflammatory indexes in predicting AL, some of them tested for the first time. Further prospectively designed trials are necessary to investigate the prognostic effect and the clinical applicability of NLR in patients who develop AL following colorectal resection.Among the blood cell indexes of systemic inflammation investigated in this study, NLR evaluated on the 4th postoperative day showed the better results in predicting AL. Therefore, NLR which is a simple, inexpensive, and widely available index, might be a useful tool in clinical practice in predicting the occurrence of AL in patients undergoing elective colorectal surgery. Nevertheless, its potential usefulness in daily practice needs to be further evaluated in future prospective studies.


The nuclear hormone activates the transcription factor vitamin D receptor that affects, via fine-tuning of the epigenome, the transcription of >1000 human genes. In this review, we discuss that changes in the epigenome, in particular in immune cells, may be central for the clinical manifestation of FA. These epigenetic changes can be modulated by vitamin D suggesting that the individual FA patient’s vitamin D status and responsiveness are of critical importance for disease progression.Fanconi anemia (FA) is a rare disorder with the clinical characteristics of (i) specific malformations at birth, (ii) progressive bone marrow failure already during early childhood and (iii) dramatically increased risk of developing cancer in early age, such as acute myeloid leukemia and squamous cell carcinoma. Patients with FA show DNA fragility due to a defect in the DNA repair machinery based on predominately recessive mutations in 23 genes. Interestingly, patients originating from the same family and sharing an identical mutation, frequently show significant differences in their clinical presentation. This implies that epigenetics plays an important role in the manifestation of the disease. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D Fanconi anemia (FA) is a rare 1:300,000) inherited disease that is one of the leading causes of bone marrow failure and inherited bone marrow failure syndromes :300,000 . FA resuEpigenetics covers all changes of the genome that are functionally relevant but do not involve any alteration in the nucleotide sequence . This in3 2D3), that directly activate transcription factors like peroxisome proliferator-activated receptors (PPARs) or vitamin D receptor (VDR), respectively. In addition, the signals can work via intermediary metabolites, such as α-ketoglutarate, being an essential co-substrate of chromatin modifying enzymes like lysine demethylases and DNA demethylating TET proteins [3, can prevent or at least delay the onset of cancer and other disorders [In contrast to the static genome, the epigenome is very dynamic and responds to intra- and extracellular signal transduction cascades, which are induced, e.g., by peptide hormones, cytokines and growth factors . Importaproteins . Both typroteins . This hiisorders ,19.Although, in principle, the genome can be edited by methods like CRISPR-Cas9, efficient genome editing is very difficult to achieve for the trillions of cells of an adult body and may lead to undesired off-target effects, i.e., genome changes at sites other than the targeted ones . In cont3 is an unique molecule, since its most biologically active metabolite, 1,25(OH)2D3, acts as a high affinity ligand of the transcription factor VDR [3 is inexpensive, readily accessible and has a favorable side effect profile [2D3 is an epigenome modulating signaling molecule [Vitamin Dctor VDR . Moreove profile . Vitamin profile   carry a heterozygous mutation in the RAD51 recombinase (RAD51) gene [FANCB gene is located on the X chromosome [FANCD1 = BRCA2, FANCS = BRCA1, FANCN = PABLB2, FANCJ = BRIP1, FANCO = RAD51C). Impairment in the FA pathway leads to increased spontaneous and inducible chromosomal fragility [Until now, 23 genes have been identified that associate with FA, in the majority of which the mode of inheritance is autosomal recessive . Patient51) gene ,70, wherromosome . The mairomosome , which pragility  and cellragility , which aIn recent years, the molecular understanding of the role of FA proteins has rapidly grown in addition to functions in genomic maintenance and homeostasis mainly during replication. For example, FA proteins are linked to aldehyde detoxification ,76 and aTaken together, the understanding of FA as a pure DNA damage repair disease shifts towards a more holistic view, shedding light on energy metabolism. Thus, the cellular and the clinical phenotype of FA can also be subsumed as a premature aging syndrome ,86.Based on its clinical and cellular phenotype FA can also serve as a cellular model for the study of general molecular functions and physiological aspects like aging as well as other non-communicable diseases occurring in the general population. In that respect, the study of FA had a considerable impact on the molecular understanding of breast/ovarian cancer . MoreoveCandida albicans. Additionally, carcinogens at low concentrations can tip the scale. Another example is hematopoietic stem cell transplant: FA patients exhibit an up to 700-fold increased risk for the development of squamous cell carcinomas compared to the general population [versus-host disease, i.e., a dysregulation of the transplanted immune system of the donor, as the underlying factor [The different clinical presentations of FA patients point out that a number of extrinsic modifiers have a significant modulatory impact on the course of the disease. Like in tumorigenesis, the disease modifiers do not need to be disease causing by themselves. Typical examples of such extrinsic factors can be oxygen, inflammation or infections like by human papillomavirus or pulation  but in Fpulation ,90. Riskg factor . In balaMECOM (MDS1 and EVI1 complex locus)), and deletions of chromosome 7 during the aplastic phase of the disease display the origin of the respective clones [MECOM plays a crucial role as it encodes for a transcriptional regulator with an essential role in hematopoiesis and mediating epigenetic modifications by interacting with DNA, proteins and protein complexes [MECOM provides the cell with growth advantages and disturbs the epigenetic landscape. Moreover, at the stage of myelodysplasia, de-regulations of the RUNX1 gene are frequently found [Despite its rareness, the hematopoietic clonal disease and expansion in FA are intensely studied. Somatic amplifications at chromosomes 1q, 3q  and Roadmap Epigenomics (www.roadmapepigenomics.org), for the epigenome-wide characterization of more than one hundred human cell lines [Next-generation sequencing techniques, which had been developed after the sequencing of the human genome, such as chromatin immunoprecipitation sequencing (ChIP-seq) and formaldehyde-assisted isolation of regulatory elements sequencing (FAIRE-seq), allow the genome-wide assessment of the transcription factor binding, histone modifications and chromatin accessibility . These all lines  and a coll lines , respectFANCE [FANCE gene encodes for a critical protein of the FA core complex mediating FANCD2/FANCI mono-ubiquitination, which is the essential activation step of the FA/breast cancer DNA-repair pathway [FANCE gene. Within this enhancer region 1,25(OH)2D3 not only significantly increased the binding of VDR but also of its pioneer factor CEBPA. In parallel, at this genomic region the amount of accessible chromatin as well as the histone marker of active chromatin, H3K27ac, raised after treatment of the cells with the VDR ligand. Looping of this enhancer to the transcription start site of the FANCE gene results in 1,25(OH)2D3-triggered changes of accessible chromatin, H3K27ac markers and markers of active transcription start sites, H3K4me3. Taken together, vitamin D changes specifically on the level of VDR and CEBPA binding, chromatin markers and accessible chromatin of the epigenome at the region of the FANCE gene.The genomic region of the vitamin D target gene FANCE  serves a pathway . In the  pathway , ChIP-seIn general, epigenetics associates with lifestyle and environmental conditions of healthy as well as of diseased individuals, such as FA patients . The dyn3 is produced from 7-dehydrocholesterol in a non-enzymatic reaction that requires the energy of UV-B (290–315 nm) radiation [3 production, since they stay most of the day indoors, cover their skin by textiles outdoors and/or use sunscreen in order to prevent sunburn. Since average human diet is low in vitamin D3 sources, such as the fatty fish tuna, sardines, salmon and mackerel, worldwide more than a billion persons are vitamin D deficient [3 is recommended [Vitamin Dadiation . Humans eficient . Thus, dommended .3 is converted to 25-hydroxyvitamin D3 (25(OH)D3), the serum concentration of which is used as a marker for the vitamin D status of an individual [3 serum levels should be in the range of 75–150 nM, i.e., 30–60 ng/mL, in order to achieve benefits form vitamin D [3 is hydroxylated further to 1,25(OH)2D3, which acts as the high-affinity (KD = 0.1 nM) VDR ligand [2D3 at sub-nanomolar concentrations [In the liver, vitamin Ddividual  ess fish ,121. In ess fish ,123, theess fish . VDR obtess fish . Importaess fish . When soess fish . The latess fish . For thiess fish .CDKN1A encoding for a cyclin-dependent kinase inhibitor [versus-host disease, in the context of hematopoietic stem cell transplants [The most important extra-skeletal function of vitamin D is the modulation of the immune system, such as stimulating the innate immune system in its fight against bacterial infections  and prevnhibitor ,136. Addnhibitor . Vitaminnsplants . Moreovensplants . Thus, vH (T helper) 1 cells of adaptive immunity and increases the number of TH2 cells and Treg (T regulatory) cells. It is important to note, that rapidly growing immune and cancer cells use the same signal transduction pathways and genes for controlling their proliferation, differentiation and apoptosis [+ cytolytic T cells with an active effector memory phenotype into the tumor site [Vitamin D potentiates the activity of cells of innate immunity, such as monocytes, macrophages and natural killer cells, while it represses Tpoptosis . Thus, tpoptosis ,141. Nevpoptosis . Thus, vmor site . This im3 concentration of 50 nM, while at least 75 nM are suggested by the US Endocrine Society [3 supplementation ranging from 800 to 4000 IU/day (20–100 µg). However, probably not all individuals have the same needs for vitamin D3, i.e., it is questionable, whether a threshold level of the vitamin D status is an optimal reference. Nevertheless, patients with hematological diseases often have a low vitamin D status, which is associated with an unfavorable prognosis [Seasonal changes of sun exposure at higher latitudes, such as in Europe, cause over the year variations in the vitamin D status of non-supplemented individuals . This le Society . Accordirognosis ,148,149.We analyzed the vitamin D status of newly diagnosed FA patients in a single center and observed that the majority of them were vitamin D deficient . FA cohoTherefore, the general recommendation for FA patients is an annual measurement of their vitamin D status and an appropriate supplementation . Moreove3 supplementation, which depends on the relation of vitamin D status and response index. The index is based on the molecular response to vitamin D and is determined via the change in the expression of vitamin D target genes after a significant change in the vitamin D status [3 production, such as during European winters. Accordingly, they should be less affected by infections [3 supplementation studies VitDmet  [Based on the concept of the vitamin D response index, persons are distinguished into high, mid and low responders to vitamin D . Thus, eD status . Thus, tfections , autoimmfections  and cancfections , againstals.gov)  and VitDals.gov)  some 25%3/kg body weight especially during winter is needed for achieving normal vitamin D levels, i.e., a 50 kg person should take 2000 IU per day .In summary, the vitamin D response index may be more suited for tailoring the daily vitamin D supplementation needs of healthy and diseased individuals than referring exclusively to the vitamin D status. FA patients need special attention and mostly a daily supplementation of 1 µg (40 IU) vitamin D3 for FA patients. Because FA is a rare disease, large randomized controlled trials are not feasible. Nevertheless, smaller scale vitamin D intervention studies with FA patients will be very instructive, in particular, if they involve transcriptome- and epigenome-wide analysis. This may widen the perspective on FA in regard to its epigenetic component, which is essential for the personalized treatment of the disorder.This review aimed to bring together two different fields, FA and vitamin D, that had not been jointly presented before. We used epigenetics and the immune system as a bridge between both fields, but we admit that far more research needs to be done before we can fully appreciate the impact of vitamin DFA is well understood as a collection of at least 23 different monogenetic diseases affecting the DNA double-strand repair system. However, the onset of the outbreak of severe consequences of the disease are very individual and seem to depend on the lifestyle and environment of the FA patient. Lifestyle decisions, such as composition of diet and the exposure to carcinogens like tobacco smoke, as well as environmental encounters, such as virus and bacterial infections, trigger signal transduction cascades that often result in transient and persistent changes of the epigenome. The nature of its function makes the immune system a special target of epigenetic changes. Thus, the dynamic epigenome can have beneficial as well as detrimental effects on the progression of FA.3 supplementation, ideally being personalized based on individual’s vitamin D response index, is assumed to enable proper epigenetic programing of immune cells throughout hematopoiesis as well as during antigen encounter. In this way, sufficient vitamin D levels should contribute to the maintenance of wellbeing and the prevention of the onset of diseases and disease progression, especially in genetic disorders like FA.Vitamin D is a safe natural compound with an epigenome modulating function . The epi


The sample presented high functionality and a nutritional status with a predominance of overweight and obesity. Factors associated with frailty (R2 = 0.43) were age over 75 years , female gender , anemia , falls  and the fear of falling . Performing more than 3 weekly hours of physical activity was found to be a protective factor . Conclusions: The relationship between frailty and malnutrition in functionally independent community-dwelling older people is unclear. More studies are needed to know what nutritional markers are related to frailty, cognition, and functionality in order to discriminate the risk factors for community-dwelling older people at risk of malnutrition and dependency.Objective: This study aims to assess the relationship that frailty has with nutritional status and functional risk factors in community-dwelling older adults. Methods: Cross-sectional study in community-dwelling older people, independent for walking and without impaired cognition. Frailty was assessed by Fried criteria. Nutritional status was analyzed by the Mini Nutritional Assessment Short Form (MNA-SF), biochemical markers ; and anthropometric parameters . A comprehensive geriatric assessment analyzed other risk factors: functionality, cognition, falls, comorbidity, polypharmacy, physical activity, and quality of life (QoL). Results: We included 564 elderly people with a mean age of 76.05 (standard deviation 3.97) years; 63.1% ( Life expectancy is increasing in most countries globally. Currently, 9% of the world’s population is over 65 years old, and this figure is expected to increase to 16% by 2050 [Frailty is a syndrome characterized by diminished physiological reserves, and its prevalence is aggravated by age . While tIn clinical practice, people over 80 years of age with high comorbidity or disability have often been misidentified as frail . AlthougThe phenotype proposed by Fried  Figure  frames sInternational guidelines agree on the need to carry out a correct nutritional assessment, although the subsequent intervention strategies are not really defined due to difficulties in implementation ,21,22. TA recent systematic review  reportedThe aim of the study was to determine the factors associated with frailty in community-dwelling older people with functional independence and no cognitive impairment, and to analyze their relationship with nutritional status.A cross-sectional study was carried out from 1 December 2014 to 31 May 2015. The inclusion criteria were as follows: participants aged 70 years or older; independent for walking ; and living within the catchment area of La Ribera Health Department . Exclusion criteria were: refusal to participate in the study, the existence of associated disease conditions resulting in a life expectancy of under 6 months, blindness and deafness, serious psychiatric problems (severe depression subjected to treatment or acute psychosis), or moderate to severe cognitive impairment (diagnosed previously by a physician) and/or after cognitive evaluation with the Mini Mental State Examination (MMSE) with Cronbach’s alpha 0.90 and a score of 24 points or less, indicating cognitive impairment . Loss ofThe sample size was calculated based on the population census of 2013. The region of La Ribera  has a population of about 253,330 inhabitants (15.8% over 70 years of age). A sample of 401 participants was required to estimate a 12% incidence of older adults with frailty, with an alpha error of 5% and a statistical power of 95%. In order to control for dropouts, oversampling of 15% was performed, resulting in a final minimum sample of 471 participants. In order to use an adequate sampling frame, we decided to recruit participants during the months of highest attendance at primary care centers and contact all the centers of La Ribera Health Department. Meetings were held with the nurses and doctors to explain the study objective, as they are the reference professionals for community-dwelling older adults and could inform potential participants to take part in the study. In addition, posters were made and placed in the waiting rooms of the primary health care centers and community social centers, to inform both the older adults who attended the center and their relatives about the study objectives. Volunteers signed up on a list in each health center, and their data were recorded using alphanumeric codes identifying the center and the individual. Open group discussions were scheduled at the different health centers so that potential participants could ask questions about the study; these information sessions were held in the morning and in the afternoon to facilitate access to all those interested. Finally, all people who showed their willingness to participate and who met the inclusion criteria were included. It was necessary to review the participants’ electronic medical records and conduct personalized interviews with each to obtain their comprehensive geriatric assessments along with functional and anthropometric variables. This task was performed by four nurses with at least 10 years of experience in primary health care centers. 3/mm3), total cholesterol (mg/dL), total proteins (mg/dL) and albumin (mg/dL). Participants self-reported their home living situation.The variables collected from the clinical history were as follows: age; sex; diagnosed comorbidity ; number of daily active ingredients prescribed; and number of falls recorded in the last 12 months. Other variables were biochemical values within the month preceding the comprehensive geriatric assessment: creatinine (mg/dL), hemoglobin (g/dL), total lymphocytes . Slowness was assessed based on the time taken to walk 4.5 m with a cut-off value of < 0.8 m/s. Unintentional weight loss was defined as a loss of 4.5 kg or 5% of body weight in the last year (determined by direct measurement of weight). Low physical activity was defined based on the weighted score of kilocalories expended per week . Lastly, poor endurance and energy were documented from self-reported exhaustion: (a) “I felt that everything I did was an effort”; (b) “I could not get going”. The presence of one or two criteria was considered to indicate prefrailty, and three or more, frailty. The absence of all criteria was considered to indicate robustness. Functional parameters were assessed based on the Barthel index with Cronbach’s alpha 0.70 [The following five frailty criteria were assessed by nurses in the primary health care centers : weaknesFor the nutritional assessment, anthropometric data comprised BMI, hand grip strength determined using a KernMap-40 kg  dynamometer, body fat percentage determined by bioelectrical impedance analysis , and the MNA-SF  with Cronbach’s alpha 0.670 . AbdominAll participants gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Clinical Research Ethics Committee of Hospital Universitario de la Ribera , (Project identification cod HULR_2013/45).t-test for independent samples was used to compare means. The chi-squared test was used to compare categorical variables .The variables were reported as proportions and/or means and standard deviations (SD). The Kolmogorov-Smirnov test was used to assess normality, and the Levene test was applied to explore homogeneity of variances for continuous variables . There were no significant outliers. The data met the main assumptions of normality, so the 2), and fear of falling syndrome (FES-I ≥ 20). We analyzed the association between frailty and different risk factors, expressing results as odds ratios (ORs) with their 95% confidence intervals (CIs). Risk factors considered were gender, age > 75 years, living at home alone, arterial hypertension, diabetes mellitus, hyperlipidemia and metabolic syndrome, comorbidity (≥ three diseases), history of falls, polypharmacy (≥ 5 drugs per day), central obesity (waist circumference for women ≥ 88 cm and for men ≥ 102 cm), dependence in the basic activities of daily living (Barthel < 90 points), the instrumental activities of daily living (Lawton ≤ 4) and walking (Tinnetti < 25), obesity , including those which did not result in an improved standard error when omitted. In cases where two or more subsets of variables with the same degree of fit were obtained, consensus was sought among the investigators. In order to introduce continuous variables in the regression model, these were categorized according to the cut-offs admitted in the literature. The values were: for hemoglobin, low < 13.5 g/dL in men and < 12.5 g/dL in women, normal ≥ 13.5 g/dL in men and ≥ 12.5 g/dL in women; for total lymphocytes count, low < 1×10n = 168) were excluded: 95.6% (n = 162) declined to participate, and 3.5%, (n = 6) did not meet the selection criteria. The final study sample thus comprised 564 participants (77.1%). According to the Fried Frailty Phenotype criteria, the prevalence of frailty was 10.99% (n = 62), and the prevalence of prefrailty was 72.89% (n = 411), so altogether 83.86% (n = 473) of the participants were assigned to the prefrail/frail group (1 to 5 frailty criteria), and 16.13% (n = 91) to the robust group (no frailty criteria).Of the 732 people initially evaluated for eligibility, 22.9% . In the functional assessment, the Barthel and Lawton indices showed no differences in the performance of basic and instrumental activities of daily living, respectively, nor were there any differences in walking (assessed by Tinetti) or in cognitive ability (assessed using the MMSE). On the other hand, the prefrail/frail group did present a significantly higher number of falls in the previous 12 months and a significantly higher fear of falling, as assessed by the FES-I (p < 0.001). Quality of life was comparably good in both groups (Age was higher in the prefrail/frail group (h groups .p = 0.019). In the biochemical markers, only hemoglobin differed between groups, with the prefrail/frail group showing lower values (p < 0.001). For anthropometric variables, the prefrail/frail group showed a significantly higher BMI and body fat percentage, and a significantly weaker handgrip . Albumin values were normal in most of the sample. In both groups, there was a high percentage with hypercholesterolemia (robust 55.1% vs. frail 59.2%), central obesity (robust 75.8% vs. frail 83.3%) and obesity (robust 60.4% vs. frail 50.1%). However, the percentage of participants with high body fat was lower in the prefrail/frail group (60.4% vs. 35%), and the percentage with low palm grip strength was higher (7.7% vs. 88.6%). Nutritional status, as assessed by the MNA-SF, was adequate in 2.7% of the frail elderly.For the nutritional assessment, we compared participants based on BMI . LymphocComparing risk factors between groups, the prefrail/frail participants showed higher odds of presenting, in order of magnitude: a fear of falling, a recent history of falls, anemia (hemoglobin < 13.5 g/dL in men and < 12.5 g/dL in women), age over 75, living at home alone, polypharmacy, and female gender .p < 0.001; R2 = 0.43), correctly classifying 83.9% of cases, with a sensitivity of 94.4% and a specificity of 39.2%.A binary logistic regression was performed to identify predictors of frailty. The following variables were entered into the model: age group, female gender, living at home alone, diabetes mellitus, polypharmacy, Barthel < 90, previous falls, FES-I ≥ 20, anemia (hemoglobin < 13.5 g/dL in men and < 12.5 g/dL in women), central obesity, obesity, and physical activity. Handgrip was not introduced because it is a criterion of the frailty phenotype. The model was statistically significant  on the MNA-SF, although in the prefrail/frail elderly the figures were lower than in the robust group. Recent studies indicate that the MNA-SF, a tool for screening for malnutrition or risk of malnutrition , is a goBiochemical markers also indicated good nutritional status in terms of lymphocytes, total protein, albumin, and creatinine, but there was also a large proportion of cholesterolemia in both groups. In contrast, the prevalence of anemia was higher in the prefrail/frail group. There is evidence that deficits in the daily amount of ingested energy or in macro and micronutrients like total proteins, albumin, creatinine, essential amino acids, vitamin D or hemoglobin, could be predictors of frailty , but morAfter including the risk factors in the regression model, female sex and age over 75 years were both predictors for frailty, in consonance with the literature . Anemia Living alone at home, despite being an independent factor related to frailty, was not included in the final predictive model. This can be explained by the likelihood that cooking for oneself, eating alone, and losing the chance to use meals as a source of play and family communication decreases people’s interest in buying and cooking certain foods, which is in itself a risk factor . SimilarThis study has a number of limitations, the first being that it is a cross-sectional study. It was not possible to include data on daily caloric intake nor to analyze the macro or micronutrients ingested. We were similarly unable to analyze all the parameters recommended in the nutritional assessment due to the difficulty of obtaining them from the community population. Although the population analyzed is considered to have a middle to high income, we did not specifically analyze socioeconomic level. In addition, there is a difference in sample size between the groups analyzed according to different prevalence of frail phenotype in the sample and this, coupled to the study’s inclusion criteria, could difficult the generalizability of the findings. Finally, it was not possible to analyze the type of physical exercise the participants engaged in, as the research team did not witness these activities.The studies with the highest prevalence of malnutrition are carried out in hospitalized and institutionalized older people ,14. TherFunctionally independent community-dwelling older people are at risk for frailty, falls, and other geriatric syndromes. The prevalence of frailty and prefrailty in community populations with excess malnutrition was 10.99% and 72.89%, respectively. Female sex, advanced age, anemia, a recent history of falling, fear of falling, and level of sedentary or light physical activity should be considered risk factors for frailty in functionally independent older people.