AVPR2) on the X chromosome. Herein, we reported clinical and biochemical parameters in four cases of three unrelated Japanese families and analyzed the status of the AVPR2. Two of the four patients had poor weight gain. However, in the male and female sibling cases, neither had poor weight gain while toddlers, but in the male sibling, episodes of recurrent fever, polyuria, and polydipsia led to the diagnosis of NDI at 4 years of age. Analysis of AVPR2 identified two nonsense mutations  and one missense mutation . These mutations were previously reported. The patient with c.316C > T; p.R106C had milder symptoms consistent with previous reports. Of the familial cases, the sister was diagnosed as having NDI, but a skewed X-inactivation pattern in her peripheral blood lymphocytes was not identified. In conclusion, our study expands the spectrum of phenotypes and characterized mutations in AVPR2 in NDI.Almost 90% of nephrogenic diabetes insipidus (NDI) is caused by mutations in the arginine vasopressin receptor 2 gene ( AVPR2) on the X chromosome [AVPR2 were classified into three types. Type-I mutants reach the cell surface but cannot bind its ligand, type-II mutant receptors have impaired intracellular transport and cannot reach the cell surface, and type-III mutants are inappropriately transcribed [Nephrogenic diabetes insipidus (NDI) is a rare disease that is characterized by resistance of the distal renal tubule and collecting ducts to arginine vasopressin , 2. Vastromosome . At presnscribed , 5.AVPR2 are related to partial NDI [Common symptoms in male patients are polyuria, polydipsia, fever of unknown etiology, convulsions, and vomiting, which usually develop soon after birth . On the tial NDI , 9.AVPR2 status in four NDI cases of three unrelated Japanese families.In this study, we assessed the clinical and biochemical parameters and Clinical symptoms, age at diagnosis, biochemical data, and current treatment are summarized in A 3-month-old Japanese boy was admitted because of poor body weight gain, vomiting, and fever that had persisted for one week. He was born as a full-term infant with no complications during pregnancy.At the time of admission, he had polyuria with a urine volume of 700–800 mL/d. Results of laboratory examinations are shown in In Case 2, poor weight gain was pointed out at the age of 4 months in this male Japanese infant. Polydipsia and polyuria were noted when he was 17 months of age. At that time, his water intake volume was approximately 3 L/d. Previously, he had experienced recurrent mild to moderate fevers of unknown etiology.+, plasma osmolality, and urine osmolality , he was diagnosed as having NDI. The laboratory data at the time of diagnosis are shown in AVPR2 exon was amplified by polymerase chain reaction (PCR) using the primers as reported previously [Genomic DNA was extracted from peripheral blood leukocytes of the cases and female carriers. The eviously , and PCReviously .AVPR2 were identified in all three male patients , 62.0% (Case 2 mother), and 58.0% (Case 3 and 4 mother), respectively . Skewed AVPR2 have been described as the cause of NDI [Currently, over 250 mutations in the e of NDI , 17. Thee of NDI , 15, 16.Although most cases of NDI are diagnosed within the first year of life, some are diagnosed later because of milder symptoms. Especially, several missense mutations have been related to mild phenotypes of NDI , 17, 19.in vitro study showed that p.R106C retained a slight capacity for production of cAMP in response to AVP, p.R106C is thought to cause less severe NDI [As a previous vere NDI . Two patvere NDI  had highvere NDI  also repIt is thought that the development of NDI in female carriers is due to skewed X-chromosome inactivation of the normal allele. In one Japanese study, 25% of female carriers developed NDI . A recenAVPR2 mutations . There are broad phenotypic differences among the patients with the same type of mutations. In female patients, skewed X-inactivation is not always detected in peripheral blood lymphocytes. As some NDI cases do not show severe dehydration, they should be checked not only electrolyte but also their urine and serum osmolality once they suspected NDI. Low-grade fever and poor body weight gain in infant can be the clue of diagnosing mild NDI.In conclusion, we report Japanese NDI patients with


FFR-guidedtreatment , used in the percutaneous coronaryintervention (PCI) with bare-metal stent (BMS) implantation in multi-arterial patientstreated in the Unified Health System (SUS) has been shown to be useful in decreasing theincidence of new revascularization of the target vessel , as wellas being cost-effective when compared to the angiography-guided treatment.The study by Quintella et al.2 study insingle-vessel patients, and the 5-year studies, FAME 1,3 and FAME 2,4 in multiarterial patients, showed consistent and unquestionableresults, with a better, or at least similar, clinical progression, in the FFR-guidedgroups, using less stents with fewer lesions and consequently lower costs, as well asevidenced the safety of leaving lesions whose FFR was not indicative of ischemia only ondrug treatment.The value of FFR to predict major adverse cardiovascular events (MCAEs) prior to PCIs hasbeen established for many years. Its ability to detect ischemia and, with this, to guidethe most appropriate treatment, has undergone the test of time, and passed. The 15-yearfollow-up of the DEFER5 showed a weak correlationbetween angiography, expressed as a percentage of stenosis diameter (SD), and FFR (rho =- 0.33), especially in intermediate lesions (between 40% and 70%). This disagreementbetween SD and physiology has already been documented in several other studies, such asthat by Toth et al.6 and Park etal.,7 which also showeddisagreement rates between FFR and angiography of 36% and 39% respectively. In a studypublished in 2007,8 in 250 patients(452 lesions) assessed by FFR before PCI, 32% of the lesions had their initially plannedtreatment strategy modified after FFR measurement, which is a major change because itwould imply inadequate treatment in more than one third of the patients. More recently,Ciccarelli et al.9 in a FAME 2substudy, analyzed the value of angiography compared to FFR to predict the naturalhistory of coronary lesions, correlating MCAE index with the angiographic andphysiological importance of these lesions in patients (n = 607) who were initially leftonly on drug treatment. In the subgroups in which FFR was discordant of angiography (FFR> 0.80 and SD ≥ 50% or FFR ≤ 0.80 and SD < 50%), clinicalprogression was worse in those in whom FFR was ≤ 0, 80, even if the lesion wasnot significant, and benign in those in whom FFR was > 0.80, regardless of SD.The limited value of angiography to predict ischemia has long been known. Sant'Anna etal.1 MCAEthat was reduced in the FFR group was due to the need for new revascularization of thetarget vessel, with no difference in mortality or infarction. Even with the limitednumber of patients involved in the study, this data is in agreement with what waspresented in the FAME studies, in which, after 5 years of progression, only the need fornew revascularization remains different in the groups. We call the attention to the lowrate of clinical restenosis in the FFR group (5.8%) of the study by Quintella etal.,1 because he used only BMS,which may be due to the fact that much less lesions were treated compared to the angiogroup (1.14 vs. 2.22 stents per patient), and with better selection criteria.In the study by Quintella et al.,1 was of R$ 21,156, 55, totally within theCE criteria, mainly if we consider that only BMS were used, that is, if DES were used,ICER would be even lower. Fearon et al.10 have published an interesting study on FFR CE in the population ofFAME 1,10 in which the author pointsout that the FFR-guided strategy has a lower cost compared to that guided by angiographyin 90.74%, and is cost-effective in 99.96% of cases, being one of those rare situationswhere a new technology not only improves outcomes, but also saves resources. Siebert etal.11 found similar findingsin the Australian population, where 1.776 USD would also be saved per patient over 1year with the use of FFR during PCI.Another interesting finding of the study is the cost-effectiveness (CE) relationship,measured by the incremental cost-effectiveness ratio (ICER), which represents the ratiobetween the costs of technologies under analysis, and their effectiveness. This ratio isusually adjusted for quality of life, and expressed as QALY . Costs below USD 20,000/QALY are accepted to be highly supportive of thetechnology tested. The ICER calculated for the study by Quintella et al.Although we cannot extrapolate these results from other countries to ours, because theprices practiced and the reimbursement system are different, we can still assume thatnow, when SUS begins to allow the use of drug-eluting stents at a more competitiveprice, the strategy of use of FFR becomes even more attractive.


Spatial accessibility to medical resources is an integral component of universal health coverage. However, research evaluating the spatial accessibility of healthcare services at the community level in China remains limited. We assessed the community-level spatial access to beds, doctors, and nurses at general hospitals and identified the shortage areas in Shenzhen, one of the fastest growing cities in China. Based on hospital and population data from 2016, spatial accessibility was analyzed using several methods: shortest path analysis, Gini coefficient, and enhanced 2-step floating catchment area (E2SFCA). The study found that 99.9% of the residents in Shenzhen could get to the nearest general hospital within 30 min. Healthcare supply was much more equitable between populations than across communities in the city. E2SFCA scores showed that the communities with the best and worst hospital accessibility were found in the southwest and southeast of the city, respectively. State-owned public hospitals still dominated the medical resources supply market and there was a clear spatial accessibility disparity between private and public healthcare resources. The E2SFCA scores supplement more details about resource disparity over space than do crude provider-to-population ratios (PPR) and can help improve the efficiency of the distribution of medical resources. The United Nations established goals for the achievement of universal health coverage, which include access to quality essential healthcare services, access to safe, effective, quality, and affordable essential medicines, and financial risk protection for all . SpecifiIt has been proved that spatial access plays an important role in health outcomes ,5,6,7,8.Most past studies on spatial accessibility in China have been conducted at either the district or street level; thus, there is a great need to further the analysis at a finer spatial scale, such as the community level, so that spatial accessibility may be more accurately quantified ,14,15,16In China, healthcare is provided almost exclusively by state-owned public general hospitals at the primary, secondary, and tertiary levels . In 2009Shenzhen is highly urbanized and became the most crowded first-tier city in mainland China with a natural population growth rate of 21% in 2016 . However2 (density: 5962/km2). Being the first special economic zone (SEZ) in China in 1980, Shenzhen contains 10 administrative districts , 60 streets, and 648 communities. There are three levels of administration under the Shenzhen city municipal government: district, street, and community. The community is at the lowest level of the hierarchy with a population ranging from 10,000 to 20,000, and is the smallest geographic unit that we used in our accessibility analysis [Shenzhen is located in the south of Guangdong province, linking Hong Kong and mainland China, with a total population of 19,150,155 in 2016 and an area of 1997.27 kmanalysis .The data on all general hospitals  and population of all communities in 2016 were obtained from Shenzhen Health Information Center. In that year, there were 41 public and 41 private general hospitals in Shenzhen . Data onFirst, we conducted a shortest path analysis to examine the geographical potential of hospital utilization. This measure indicates whether individuals can have a timely access to the nearest hospital. Second, we calculated Gini coefficients to measure the equality of medical resources considering both the supply and demand factors. Additionally, we used Lorenz curves to display the inequality. Third, we used the E2SFCA to compute the spatial accessibility of hospitals by combining geographical, supply, and demand factors.To estimate the travel time of urban residents to the nearest general hospital, we conducted a shortest path analysis based on road network distance. The analysis involves three general steps using ArcGIS  software ,27. FirsIn this study, travel time thresholds were set as 15, 30, and 60 min. The longest time threshold was set according to the golden hour theory which implies that health outcomes are affected if care is not accessed within the first hour immediately after traumatic injury ,29. SubsWe used Gini coefficients and Lorenz curves to measure the inequalities in distribution of beds, doctors, and nurses by population and administrative district area. Both tools were initially used to measure income/wealth inequality but have been widely applied in the healthcare field in recent decades ,35. It iiX represents the cumulative proportion of i population or area and iY represents the corresponding cumulative proportion of medical resources. Gini coefficients were calculated using the formula below; a Gini coefficient of 0 expresses perfect equality, while a value of 1 indicates maximal inequality [Lorenz curves were drawn using ranked quantities of medical resources in the 10 districts. equality .(1)G=1−The enhanced two-step floating catchment area (E2SFCA) method was implemented to assess spatial accessibility ,28,37,38j. Searching all population locations (k) within a threshold travel time subzone (rD) from hospital j, the weighted bed/doctor/nurse-to-population ratio jR, were computed using the equation bellow:kP is the population of community k with its centroid falling within the catchment r (kjd∈rD), jS is the beds/doctors/nurses capacity at hospital j, kjd is the travel time between k and j, and rD is the r-th travel time zone. We used minimum travel time across the road network considering the speed limitations. rW (r = 1–3) is the distance decay weight for the r-th travel time zone. We applied Gaussian-based weights to differentiate three travel time thresholds to model the distance decay effect [rW) of 0.890, 0.316, and 0.010 for three subzones , respectively, were calculated using the Gaussian function listed below, where parameter β was set as 440 based on previous sensitivity analysis studies [Step 1 involves the calculation of the weighted beds/doctors/nurses and population ratio within each travel time zone centered at hospital y effect . Weights studies ,39:(3)w, and ijd is the travel time between i and j. rW  is the distance decay weight for the r-th travel time zone.Step 2 involved summing up the values obtained for three weighted subzone supply and demand ratios within each travel time zone centered at the community centroid location In terms of software packages, ArcGIS10.2  was used to conduct the E2SFCA and shortest path analysis, while Excel 2016  and R 3.4.4 were used to generate and plot Gini coefficients and Lorenz curves.The final results showed the proportion of the population that could find at least one general hospital within 60 min of travel time . In termDescriptive statistics of the calculated spatial accessibilities are presented in In terms of accessibility to beds (beds per thousand population) in the 648 communities, 255  had scores higher than 2, and 154 (23.77%) had scores lower than 1; for accessibility to doctors, 47 (7.41%) communities had scores higher than 1.5, and 297 (45.83%) lower than 1; for accessibility to nurses, 253 (39.04%) communities had scores higher than 1.5, and 208 (32.10%) lower than 1.p < 0.0001). More specifically, spatial accessibility of public beds was generally higher in the south-southwest communities and lower in the peripheral communities.In terms of accessibility to beds in public hospitals (beds per thousand population) in the 648 communities, 173 communities (26.70%) had scores higher than 2, while 201 (31.01%) had scores lower than 1, and 45 (6.94%) lower than 0.5. Regarding bed accessibility in private hospitals, only communities in Longgang district had relatively higher accessibility scores, and overall scores were much lower than those found in the public hospitals in the remaining communities. The scores in 606 communities (93.52%) were lower than 0.5, and no community had values higher than 1. In this study, we assessed the community-level spatial access to medical resources in Shenzhen, China. We conducted a shortest path analysis to measure travel time between the centroids of communities to hospitals. We then calculated Gini coefficients and applied the E2SFCA model to understand inequalities and spatial accessibility. Our analytical results indicate that spatial inaccessibility to medical resources existed in Shenzhen. In addition, the spatial access to public hospitals was much better than to private ones.Our study found that the existing general hospitals across the city were relatively accessible to most residents in the travel time dimension. In terms of beds and staff supply, the Gini coefficients  showed that medical resources were more equably distributed between populations than district areas. Results from the E2SFCA analysis showed more detailed spatial accessibility disparities in the 648 communities. There were obvious spatial accessibility disparities between the communities. More specifically, communities in southeastern Shenzhen  had the lowest accessibility, while communities in the southwestern region of central Shenzhen  had the highest accessibility. The median accessibility scores for beds, doctors, and nurses were 1.74, 1.04, and 1.31, respectively. As a reference, the crude PPR values released by Shenzhen municipal government were 3.59, 2.57, and 2.86, respectively. Although the order of the relative accessibility of beds, doctors, and nurses is the same for the two sources, the median E2SFCA scores are much lower than the crude PPR values due to the nature of the E2SFCA method. Unlike the PPR, the E2SFCA method is a relative measure, so the focus should be placed on a relative comparison rather than the absolute values .The spatial accessibility showed a central-outward gradient decreasing trend from the original SEZ to the east and west of the city. A previous study indicated that this is partly because the original SEZ included only four districts  before 2010, where market-oriented economy has been developed for a longer time, which is related to an unbalanced development of the healthcare service system between the original SEZ and other districts .Public hospitals have been the main suppliers in the current healthcare market conditions. Being the leading pioneer city in market reform in China, Shenzhen private general hospitals were promoted by the government with several favorable policies, such as no restriction on the location of new hospitals or quotas on hospital beds . HoweverCompared with the situation in the other regions in China, residents in Shenzhen can access general hospitals timelier, but beds and staff  are less accessible. For example, Pan et al. 2015) computed the county-level spatial accessibility in Sichuan province using the E2SFCA method. It was found that only 39.4% of the population in the province had access to a hospital within a 30-min drive. However, the average spatial accessibility of doctors in Sichuan was generally above 2, which was almost the highest accessibility value in Shenzhen  computed. MoreoveMethodologically, the shortest path analysis and Gini coefficients measure accessibility from only one dimension ; thus, the E2SFCA method has so far been one of the best tools to evaluate the spatial accessibility of health services using multiple dimensions ,43,44. TTo the best of our knowledge, previous research has focused on the accessibility issue in rural areas, but uneven distribution of health services in urban areas does also exist and could result in serious consequences such as inefficient and inequitable resource location and allocation . One majSeveral limitations of this study need to be addressed. First, the quality of the assessment was restricted by the unavailability of key non-spatial data such as socioeconomic and demographic variables ,48,49. SThis study measured spatial accessibility of beds, doctors, and nurses at both public and private general hospitals at the community level in Shenzhen, China. We found that urban residents could access general hospitals timely, but inaccessibility to medical resources among communities existed in this first-tier Chinese city. While the PPR values provided by the government provide only an overall description without any details about spatial accessibility, the E2SFCA scores supplement a relative measure of the disparity in spatial accessibility. A wide application of the E2SFCA method will help to directly improve the allocation of medical resources.


Introduction Breast sarcomas are tumors of a mesenchymal origin, with an incidence of less than 1% of the total breast tumors. The diagnosis of this disease is a challenge for pathologists, radiologists, and breast surgeons. AimTo describe the diagnostic, therapeutic, and outcomes approach of patients with breast sarcoma treated at the National Cancer Institute (NCI) in Bogota, Colombia. Materials and methodsIt is a descriptive and retrospective case series study of patients diagnosed with breast sarcoma treated at the NCI during the period between August 1, 2016 and March 30, 2019. Results We identified 14 patients diagnosed with breast sarcoma, 10 (71.4%) patients with primary breast sarcomas, and four (28.6%) with sarcomas associated with radiotherapy. The most frequent histological subtype in both, primary and secondary sarcomas, was angiosarcoma . 100% (n = 14) of patients received surgical management as primary treatment. Eight (57.1%) patients presented recurrence  follow-up of 5.95 months). A total of five deaths were recorded, representing 35.7% of patients  follow-up of 23.5 months).ConclusionBreast sarcomas are characterized by aggressive clinical behavior, which is why it is important to make a precise histological diagnosis and thus provide patients with radical surgical procedures that ensure local control of the disease and improve DFS.  Breast sarcomas are tumors of a mesenchymal origin, corresponding to less than 1% of all breast tumors and to less than 5% of all sarcomas -7. Breast sarcomas originate from the periductal stromal and are named according to the type of associated cells. Different histological subtypes have been described, the most frequent is angiosarcoma, representing 0.002% to 0.05% of breast tumors, and a relationship has been identified with radiotherapy received by patients for the treatment of breast cancer, with an adjusted relative risk of 59 times (IC 95% 22-153) ; followiRisk factors for the development of primary sarcomas are not yet established, unlike secondary sarcomas, which are caused by conditions that cause chronic lymphoedema and by exposure to radiotherapy. Secondary sarcoma to chronic lymphoedema, was described by Stewart and Treves, this sarcoma occurs in patients who required axillary lymph node dissection or who received radiotherapy at the axillary lymph node chain .Regarding sarcomas associated with radiotherapy, it must be taken into account that the risk of having this disease is directly proportional to the dose of radiation received, and is higher if it was administered during childhood. This risk persists for 20 to 30 years after treatment, with an average appearance at 10 years. The criteria for the diagnosis of sarcomas associated with radiotherapy were established by Cahan, and are the following: first, having a history of malignant tumor of different histology; second, sarcoma developed in irradiated fields; and third, appearing within a latency period greater than four years .Similarly, exposure to certain environmental and biological factors, such as arsenic, vinyl chloride, herbicides, immunosuppressive agents, Kaposi's sarcoma, human immunodeficiency virus (HIV), and human herpes virus type 8, can promote the development of sarcomas ,5. Clinically, sarcomas are described as a unilateral mass, of variable size (average of 5 to 6 cm), well defined, not painful, solitary, with rapid progression and expansive growth, and in the case of angiosarcomas an involvement of the skin can be evidenced, which appears with papular skin lesions or macules with ecchymosis -12. RegiAs for diagnosis, findings, and approach, these are performed in the same way as with other diseases of the breast. In mammography, these tumors are described as masses of an oval, defined or irregular margins, and may be reported as distortions of the architecture, not associated with calcifications; likewise, in breast ultrasound, irregular, hypoechoic masses can be observed, with spiculated or indefinite margins. Magnetic resonance imaging (MRI) can help to assess the extent of the disease, showing a mass with indistinct margins and with heterogeneous enhancement, with low signal intensity in T1, but with high intensity in T2, suggesting the presence of vascular channels with slow flow -18.The gold standard of diagnosis in breast sarcomas is the histopathological study, this must always include immunohistochemical markers (IHC) for cytokeratins and myoepithelial cells . SarcomaThe degree of differentiation is the most important prognostic factor; it is for this reason that the pathology study should evaluate cell differentiation, mitotic counting, the presence or absence of necrosis, cellularity and nuclear pleomorphism ,9. These tumors have the ability to spread by hematogenous dissemination, and the main sites of localization of metastases occur at the lungs, bone, and liver ,12.Given its low incidence, there are information gaps when describing its clinical course. Regarding approach and treatment, these have been based on the results obtained through retrospective studies and clinical experience for the treatment of soft tissue sarcomas of the extremities. Surgery is the mainstay of treatment; the type of procedure will depend on the size of the tumor and its relationship with the breast. Section margins greater than 1 cm should be obtained and in angiosarcoma should be 3 cm, since the status of the resection margins is directly related to the survival of patients ,20-21. AReferring to adjuvant treatment, according to data from a meta-analysis conducted in 1997, it was shown that adjuvant chemotherapy based on Doxorubicin and Ifosfamide may have a benefit in disease-free survival (DFS), without finding a statistically significant difference in overall survival (OS) . An updaAbout adjuvant radiotherapy, its benefit in DFS is not clear, some studies conclude that locoregional recurrence rate decreases and DFS increases, as was evident in the analysis conducted by Johnstone et al., which included 10 patients with non-metastatic primary breast sarcomas who received treatment with mastectomy and adjuvant radiotherapy . Other sThe prognosis of patients depends on clinical stage of the disease, on a tumor size greater than 5 cm, the histological grade, the margins (which is the most important factor in determining recurrence) and on the histological subtype (being angiosarcoma the worst prognosis). DFS of patients with breast sarcoma varies between 44% and 66%, while OS varies between 49% and 67% ,29-30. A search on the SAP®electronic medical records system  of patients with a diagnosis of breast sarcoma, was carried out. We found 14 patients who were treated at the National Cancer Institute (NCI) in Bogota, Colombia during the period between August 1, 2016 and March 31, 2019. Survival functions were estimated for each of the two outcomes (OS and DFS) using the Kaplan-Meier method. This study was approved by the institutional ethics committee and was classified as a risk-free study. The median age of patients was 51.2 years (19-86 years). Of these patients, 10 (71.4%) had primary breast sarcomas. The most frequent histological subtype, both in primary and secondary sarcomas, was angiosarcoma . Regarding the diagnosis of secondary sarcoma associated with radiation for adjuvant treatment of breast cancer, the latency period varied between 5 and 9 years, with a mean occurrence of 6.7 years. The most frequent clinical stage found was IIIA ; and only one patient (7.1%) presented axillary lymph node involvement. 78.6% (n = 11) of tumors had a high grade of differentiation  of patients received surgical management as a primary treatment, with simple mastectomy the mostly performed procedure . For adjuvant therapy, only 14.3% n = 2) of the patients received chemotherapy, while six patients (42.9%) received radiotherapy. Of the total of 14 patients, five (35.7%) required intervention by the Plastic Surgery service for breast reconstruction or covering the surgical defect (Table  of the pEight 57.1%) patients relapsed, representing 75.0% (n = 6) of patients at a local recurrence (DFS follow-up of 5.95 months)  and mortality (OS: 49%-67% at 5 years) ,29-30, tThe prognosis of this disease is poor, due to its difficult diagnosis, surgical management, adjuvant treatment and high risk of recurrence ,29-30. Breast sarcomas are very low incidence tumors so it is important to recognize their clinical and biological behavior. This case series study shows that this disease has a very aggressive behavior; therefore, it is important to make an adequate histological diagnosis for being able to offer priority treatment to patients, having surgical management as a pillar thereof. Regarding adjuvant treatment, current clinical practice guidelines do not recommend offering routine chemotherapy or radiotherapy, and in many cases, these therapeutic options are relegated to the management of tumor recurrences.


However, in contrast with nutritional targets, it had lower concentrations of omega-3 PUFA, vaccenic acid, lignans, Ca, S and Zn. The extent of these differences was strongly influenced by season and may demonstrate a combination of differences on intrinsic species metabolism, and farm breeding/husbandry practices.Goat milk is globally consumed but nutritional profiling at retail level is scarce. This study compared the nutrient composition of retail cow and goat milk  throughout the year and quantified the potential implications on the consumers’ nutrient intakes. When compared to cow milk, goat milk demonstrated nutritionally desirable traits, such as lower concentrations of C12:0, C14:0, C16:0 and Na: K ratio, and the higher concentrations of  Dairy goats have been traditionally used for milk production across the globe, and in particular Asia, Africa and Europe, which produce 58.4%, 24.1% and 14.2% of world’s goat milk, respectively . In the Potential health benefits from the consumption of goat milk were recently reviewed, including hypoallergenicity, and improvements in gastro-intestinal disorders, Fe and Cu absorption, growth rates, bone density, and blood levels of vitamin A, Ca, thiamine, riboflavin, niacin, and cholesterol, however, claims around human health still mostly rely on anecdotal evidence, which is also used in industry promotional material and within the media ,5. Givenn-3) c9c12c15 C18:3 , c5c8c11c14c17 C20:5 , c7c10c13c16c19 C22:5  and c4c7c10c13c16c19 C22:6 . Minerals are essential to the human body and play numerous vital roles, including (but not restricted to) enzyme co-factor activity, metallo-proteins, vitamin and bone formation, osmolarity, nutrient absorption and oxygen transport, as previously presented in multiple books and publications [The discussion in the present work focuses on milk FA profiles, minerals and phytoestrogens. Milk and dairy products are the main source of saturated FA (SFA) in human nutrition, also including those deemed responsible for increased risk of cardiovascular disease  ,12. Totaications . Phytoesications ,24,25,26n = 84) from four brands of conventional retail cow milk (n = 48) and three brands of conventional retail goat milk (n = 36) were collected at the second week of each month between March 2016 and February 2017. Retail outlets (supermarkets) were located within an 8 km radius from the University of Reading. Cow milk brands were collected from the four supermarkets with the highest market share in the UK while goat milk brands were the three brands available in the survey area during the study. All samples were whole, pasteurized and homogenized milk. The commercial containers  with the furthest “best before” date, at the day of collection, were sampled, aiming to represent the bottles with the freshest milk available. The commercial containers were immediately transferred in cool-boxes to the laboratories of the University of Reading, where they were aliquoted in 30 mL sterile, screw-top, polypropylene containers and stored at −20 °C. Milk composition is influenced by several factors, the most influential of which are considered to be the animal species, breed and diet [Milk samples n = 4 from foand diet ,28,29. Tand diet . In contand diet ,33. Notaand diet ,33. Theiand diet ,33. TherMilk was processed by aliquoting each collected milk sample into four 30 mL containers for separate analysis at multiple laboratories, prior to freezing. The first set of 30 mL aliquots was sent as fresh milk (not frozen) for basic composition analysis to National Milk Laboratories . Milk concentrations of fat, protein, casein and lactose were measured by Fourier Transform InfraRed spectroscopy , while somatic cell count (SCC) were measured by flow cytometry . The second, frozen, 30 mL milk sample was thawed overnight at 0–4 °C for FA profiling. The combination of techniques used to analyse milk FA profile were previously reported .p < 0.05, while tendencies were considered at 0.05 < p < 0.10. The residual diagnostics relied on normality plots and data did not deviate from normality, except for SCC, which required logarithmic transformation prior to analysis. Pairwise comparison of means (p < 0.05) was carried out when the effect of the species × month interaction was significant, using Fisher’s Least Significant Difference test. Desaturase activity indices were calculated as previously described [Analysis of variance (ANOVA) was performed by linear mixed effects models and the residual maximum likelihood analysis algorithm in GenStat 17th Edition . Specieescribed .In order to model the impact of switching from cow to goat milk consumption, the present study relied on the average milk and dairy fat intakes reported in the National Diet and Nutrition Survey (NDNS) rolling programme, from Years 1–4 combined . These dThe effect of species was significant on the concentrations of protein, casein, lactose, and SCC . When coIn addition, the effect of the species × month interaction was significant for all basic composition parameters . Goat mitrans MUFA, cis PUFA, trans PUFA, cis/trans + trans/cis PUFA, n-3, omega-6 (n-6), and trans FA, as well as for the ratio n-3/n-6 and the desaturase activity indices C14:1/C14:0, C16:1/C16:0 and RA/VA (cis PUFA (+29.5%), n-6 (+40.7%) and RA/VA ratio. In contrast, it had lower concentrations of C14:0 (−6.8%), C16:0 (−8.5%), VA (−41.2%), EPA (−26.8%), trans MUFA (−20.9%), trans PUFA (−82.6%), cis/trans + trans/cis PUFA (−24.0%), n-3 (−32.2%), trans FA (−21.6%), and ratios of n-3/n-6, C14:1/C14:0, and C16:1/C16:0 , EPA, DHA, SFA, nd RA/VA . In comp:1/C16:0 . The detcis MUFA, trans MUFA, PUFA, cis PUFA, trans PUFA, cis/trans + trans/cis PUFA, n-3, n-6, trans, and trans excluding VA  typically between April and October, although some of the differences at the beginning and end of this period were not statistically significant. For EPA and n-3, the difference was also significant in November. Concentrations of LA  and this may explain the lower lactose concentrations in goat milk in the present work.The similar fat content between goat and cow milk is partly in line with previous work  but alsoFASN , which demonstrate a higher de novo synthesis of fat in goats than in cows [Although previous studies reported similar SFA concentrations between goat and cow milk ,50, the  in cows . The act in cows . Given t in cows ,44, it i in cows ,49,50. I in cows ,29,31,53 in cows ,31,33. Atrans MUFA and total trans FA were also higher in cow milk (mainly during the grazing season), this is down to VA’s contribution to these two parameters (around 39%). When VA was excluded from the sum of total trans FA, there was no significant overall effect of species, although cow milk still contained more trans during the grazing season, potentially because of the higher intakes of ALNA from pasture and its subsequent rumen biohydrogenation to trans FA [Goat milk has been previously reported to contain less OA under control diets , containtrans FA ,53. n-3 during the grazing season. This is expected because the higher grazing intake of cows during the grazing season will increase the supply of n-3, and in particular ALNA [9-desaturase, and (iii) the production of EPA under the effect of Δ6-desaturase [The higher LA concentrations in goat milk in the current study are in line with Fougere et al.  and Potilar ALNA . Increassaturase . The higher concentrations of DHA in goat milk are in contrast with previous work, which showed either no significant effect of species, or higher concentrations of DHA in cow milk and/or higher DHA transfer efficiencies from diet to milk when DHA-rich diets were fed ,45. Pote9-desaturase in the mammary gland of goats may have a higher affinity for VA, rather than for C14:0 and C16:0 [The lower ratios of C14:1/C14:0 and C16:1/C16:0, the higher ratios of RA/VA and the similar ratio of OA/C18:0 are in line with previous work ,45. Thesnd C16:0 . The major milk cations are associated within casein micelles, accounting for 70% Ca and 35% Mg, whilst 50% inorganic phosphate (P) are also found within the milk solid fraction ,55. MilkK and Na are the main solely diffusible (liquid milk) cation macro minerals in milk and they exist mainly as free ions, with the rest being associated with citrate, inorganic phosphate and chloride . The conSe, I, and Zn  are all Few studies report I in goat milk with the concentrations reported by Park et al.  for bothFor the remaining micro minerals, B, Cu and Mn were higher in goat than cow milk, whereas no difference was found for Co, Fe, Mo and Ni. Previous work ,56 reporUnlike the other potentially toxic heavy metals, Cd and Pb, ruminants have been shown to have a requirement for As at levels between 350 and 500 μg/kg DM, with levels <50 μg/kg DM reducing mineralisation of bone . TrancosThe concentration of isoflavones, lignans and coumestants in milk from cows and goats is influenced mainly by (i) animal diet, which determines the amounts of plant lignans, isoflavones and coumestants entering the digestive tract, and (ii) rumen microbial activity, which determines the extent of synthesis of mammalian lignans and isoflavones using the dietary phytoestrogens as substrates ,69,70,71The concentrations of equol, its precursors formononetin and daidzein, in goat milk are substantially higher than in cow milk, whereas the opposite was seen for enterolactone and its precursors secoisolariciresinol, lariciresinol and matairesinol. These differences may be attributed to contrasting dietary supply and/or microbial composition in the rumen. There are several studies investigating the effect of equol synthesis from rumen bacteria by using dietary isoflavones as precursors ,72,73. YGlycine max L.) and clover (Trifolium spp. L.) are known as major sources of these isoflavones in animal diets [The higher concentrations of the dietary origin daidzein, genistein and formononetin in goat milk indicate a higher dietary supply of these in goat diets. Soybean , oat (Avena sativa) and barley (Hordeum vulgare), which are the main constituents of concentrate diets in the UK. However, the contribution of these concentrates into the diets of dairy cows and goats in the supply chains of the brands that were sampled in the present study is not known. It is possible that a higher contribution of soybean meal in the concentrate part of the diet of the dairy goats may have resulted in lower contribution of these cereals than in dairy cow diets. This potentially lower intake would reduce the amounts of plant lignans transferred in goat milk, as well as the substrate for enterodiol synthesis in the rumen [Prevotella spp., the main bacteria responsible for the conversion of plant lignans to mammalian lignans [Opposite to isoflavones, the concentration of lignans were lower in goat milk than in cow milk. The major source of lignans, such as secoisolariciresinol, matairesinol, lariciresinol and hydroxymatairesinol, are grains such as wheat  and VA , and (iii) increase the intakes of the essential, but oversupplied in Western diets [n-6 PUFA . On the contrary, beneficial changes will also be observed. A switch to goat milk for children (years 1–18) and adults (>19 years) would reduce the intakes of the nutritionally undesirable C12:0, C14:0 and C16:0 , and trans FA  and increase the intakes of nutritionally beneficial cis PUFA  and EPA + DHA .A switch from cow milk to goat milk for children (years 1–18) and adults (>19 years) would (i) increase the intakes of nutritionally undesirable ,12,40 SFrn diets , LA (by n-3 (from 20.0% to 13.6%). Although a reduction to the contribution of milk to the upper recommended intakes for trans FA by consuming goat milk (from 8.3% to 6.5%) may be considered desirable, this has been observed mainly to the reduction of VA, which is a beneficial FA [trans FA content in cow and goat milk are similar. A switch to goat milk would also increase the contribution of milk to the dietary requirements for cis PUFA, n-6 and EPA + DHA but the extent of these differences is biologically small .Interestingly, when compared with cow milk, consumption of goat milk would increase the contribution to the upper recommended limit  for SFAicial FA . When VAA switch from cow milk to goat milk for children years 1–18) and adults (>19 years) would increase the intakes of Cu , I , Mg , P , K , Mn , and B . These are nutrients highly relevant to human health  and adul.The most striking difference in the mineral content between cow and goat milk was for I, an essential co-factor in thyroid hormone formation controlling metabolic rate. A switch to goat milk will increase the contribution of milk to I dietary requirements for children  and adults . For adults, this is beneficial because I deficiency is among the most widely documented deficiencies globally (including the UK), and the world’s greatest single cause of preventable brain damage, impaired intellectual ability, low IQ scores, and poor school and work performance, with such problems being documented even in populations classified as mildly I deficient ,82. An eA switch from cow milk to goat milk for children years 1–18) and adults (>19 years) would reduce the intakes of Ca , Na , Zn , and S . This switch to goat milk would therefore reduce the contribution of milk to the dietary requirements for Ca, Na and Zn, but the extent of these differences is small . These nutrients are also highly relevant to human health  and adul.Cow and goat milk had similar concentrations of Co (responsible for the formation of vitamin B12 in the rumen), Fe (demonstrating enzyme and protein functions and participating in the formation of haemoglobin), Mo , Ni  and Se  . TherefoDespite the high variation in phytoestrogen concentrations among the goat milk samples, a switch from cow milk to goat milk for children (years 1–18) and adults (>19 years) would potentially increase the intakes of daidzein , glycitein , naringenin , and equol . The most striking anticipated effect on isoflavones intakes, by switching to goat milk, was therefore estimated to be the potentially higher intakes of equol, as differences in the other isoflavones were numerically small. Potential health benefits from an increased consumption of equol include decreased risks of breast, prostate and colon cancers, osteoporosis, cardiovascular diseases and hormone-dependent conditions . On the However, it is not possible to draw any conclusion about the potential effect of the differences between cow and goat milk on the phytoestrogen concentrations. This is partly due to the relatively low numerical differences for most of them  but, most importantly, because of limited research on their effect on health and the consequent absence of relevant nutritional recommendations .This is the first study to present the nutrient composition of goat milk in the UK and model the subsequent effect of nutrient intake in UK consumers, by switching from cow to goat milk. This information can be used by health organisations and nutritionists when public nutritional advice is developed. The impact of goat milk consumption on nutrients intake has been assessed for the different age groups and revealed that characteristics which are considered desirable in adults  may pose an area of concern for children. The present work covered a 12-month period, thus capturing and investigating the seasonal variation in milk composition, a process that revealed that nutritional advice should also account for temporal milk composition changes. The main limitation of the current study is that it relies on milk samples collected solely in the UK. Given that production system influences milk composition, and goat husbandry practices are highly variant across the world, the comparative analysis between cow and goat milk may differ between countries. Therefore, the application of the results in other countries may require further investigation in the future. In addition, in the present study, there was an absence of background information on animal breed and husbandry practices for the produced milk (as this is a retail survey). Although the potential explanations for the observed differences rely on data around husbandry practices from UK studies and producers’ organisations, these speculations should be further investigated in the future with studies at the farm or animal level.In comparison to retail cow milk, goat milk showed a number of nutritionally desirable characteristics, including lower concentrations of individual SFA which are associated with increased risk of cardiovascular diseases , an improved Na:K ratio, higher concentrations of fatty acids with positive effect on human health, including cis PUFA, EPA, DHA, and contained isoflavones, B, Cu, Mg, Mn, P. The higher contents of I in goat milk may be desirable in adults , but care should be taken in children 1–3 years old as consumption of reasonable amounts of goat milk can reach upper tolerable limits of I supply. Furthermore, goat milk had lower concentrations of beneficial omega-3 PUFA, VA, and lignans, and the minerals Ca, S and Zn which play major metabolic roles in the human body. The compositional differences between cow and goat milk may be potentially explained by husbandry practices between cow and goat dairy production systems in the UK, and in particular the lower grazing intake and forage: concentrate ratio and the higher concentrate and mineral supplementation of the dairy goat diets. However, intrinsic metabolic differences between species may have also contributed to this difference. Although a number of compositional differences have been identified which also influence the nutrient intake of consumers, the implication of these differences on human health are not known.


Bone mineral density (BMD) and lean and fat tissue were measured by Lunar iDXA. Serum and urinary markers of bone turnover were analyzed. Diet and physical activity were assessed with 3-day records. Participants on average lost ~4%, ~3%, and ~2% of body weight, fat, and lean tissue, respectively. The significantly better outcomes were noticed in participants in the D group regarding body composition (fat loss/lean tissue preservation) and in participants in the S group regarding the BMD outcomes, compared to those in the C group. Therefore, increasing low-fat dairy foods to 4–5 servings/day and/or increasing Ca & vitamin D intake by supplements (in those who are at the borderline dietary intake) may be beneficial for weight loss/maintenance and may lead to more favorable bone and body composition outcomes in postmenopausal women during moderate weight loss.Several studies have investigated the possibility of dairy foods and calcium (Ca) mediating weight and body composition, but a consensus has not been reached. We aimed to investigate weight-loss-related outcomes during intervention with low-fat dairy foods or Ca + vitamin D supplements, both as complements to hypocaloric diets. Overweight/obese Caucasian, early-postmenopausal women ( At particularly high risk of becoming overweight are women in the early postmenopausal years, due to a combination of factors, including cessation of estrogen, decreased activity, and decreased resting metabolic rate ,2. OverwAnother important aspect that needs to be addressed in aging population, especially in women, is that aging itself leads to reduction in bone mass/quality (osteopenia/osteoporosis) and muscle mass and strength (sarcopenia/dynapenia) and increase in, or redistribution of, body fat . The coeVarious foods and nutrients have been implicated to improve or worsen body weight and/or body fat accretion. Besides the energy and fat/carbohydrate intake, of the frequently studied foods and nutrients, dairy foods and calcium (Ca) have received considerable attention, yet their roles have not been elucidated. Various research groups agreed that Ca (with or without vitamin D) improved weight and body fat outcomes in overweight/obese individuals ,25,26,27Therefore, our objective was to conduct a weight loss study and investigate whether weight loss and/or improvement in body composition, as well as the preservation of bone mass could be achieved easier with Ca + vitamin D supplements or low-fat dairy foods as complements to hypocaloric diets. We opted for a 6-month intervention study, a period long enough to detect changes in bone and body composition measured by dual energy x-ray absorptiometry (DXA), but not too long to cause diminished compliance and increased attrition rate among participants. We hypothesized that the hypocaloric diets with increased low-fat dairy foods or with Ca + vitamin D supplements, will be associated with greater weight reduction toward a healthier body composition and preservation of bone mass, in comparison to the control group , with the best outcomes in the low-fat dairy group. This was a randomized, placebo-controlled clinical trial of three weight reduction protocols in overweight and obese Caucasian early postmenopausal women. The protocol involved moderate energy restriction (~85% of energy needs) for all participants divided in three groups: 1) Dairy group ; 2) Supplement group ; and 3) Control group . After the baseline screening, participants were randomly assigned to one of the three groups, following a simple randomization procedure. The codes A, B, and D were assigned indicating two pill groups  and dairy group (D) and connected with the computer-generated random numbers for each participant. Further, A and B codes were double blinded and the allocator at Bayer, HealthCare LLC (pill manufacturer) concealed the codes until the end of the study. A dietitian reviewed participants’ diets to learn about each participant’s eating patterns and food preferences and subsequently design appropriate meal plan. Therefore, each woman received a tailored menu plan, which included her own food preferences. The intervention also included behavioral modification  to help with dietary compliance and achieve possible long-term behavioral changes. All participants went through a run-in period lasting 3 months, when they were seen every 2 weeks and given advice about their food choices and behavioral modification principles. During the run-in period, participants attended the biweekly 2-hour group sessions, with 5–8 members (of the same intervention group) and the multimodal cognitive-behavioral intervention, as well as nutritional education, as described previously . This inMeal plans were self-selected (based on self-preference) from the suitable and appropriate exchange lists based on the Dietary Guidelines for Americans . The eneParticipants in the D group were instructed to consume low- or reduced-fat dairy foods (4–5 servings/day) such as cheeses, skim or 1% milk, yogurt, pudding, low-fat ice cream and frozen yogurt. It was estimated that total diet provided ~1500 mg of Ca/day and ~600 IU (10 μg) of vitamin D. Participants in the S group received Ca citrate + vitamin D tablets  and the C group received placebo . The participants in the latter two groups were instructed to consume no more than two servings of dairy food/day. The compliance with Ca supplements/placebo was monitored by pill count, while that of dairy food intake by dietary records. In all cases, 24-h urine (see below) was analyzed for Ca excretion and bone resorption markers.The inclusion/exclusion criteria have been described previously ,21,46. BWeight and height were measured in normal indoor clothing without shoes using a digital scale  and a wall-mounted stadiometer , respectively, every 1–2 weeks in the run-in period, and then at 3 and 6 months, but only the measurements at baseline and six months are presented here. Waist and hip circumferences were measured to a nearest 0.1 cm with a plastic measuring tape  as the participant exhaled while standing straight. Waist circumference was measured at the smallest portion of the midsection, and hip at the maximum circumference around the buttocks on a horizontal level plain parallel to floor. The coefficient of variation (CV) for each measure was determined by measuring 10 participants at three separate times with the resulting CV% for weight, height, hip and waist circumference of <0.1%, 0.3%, 0.5%, and 0.5%, respectively, as described previously ,21,46.2). The iDXA has a wider scan field and higher precision that can accommodate individuals up to 181 kg, avoiding the errors typically encountered when measuring overweight/obese individuals, and therefore providing a more accurate assessment of body composition [Body composition measurements were performed by dual energy x-ray absorptiometry using the iDXA instrument  with Encore 2006 software (version 13.11.016), as described previously [position . The lea2, ranging from 1.241–1.263 g/cm2. The %CV for different skeletal sites in-vivo was calculated from the repeated measurements (3 times each) on 10 overweight/obese women, comparable to the study participants. The %CV for the BMD of various skeletal sites was as follows: lumbar spine (L2–L4), 1.3%; femoral neck, 0.6%; whole femur, 0.7%; forearm (radius and ulna pooled together at 1/3 distance from styloid process) 0.9%. The CV% from the total body scans were: BMD (g/cm2), fat (kg), fat (%) and lean mass (kg) 0.6%, 0.8%, 0.8%, and 0.7%, respectively.The quality assurance of the densitometer was performed weekly by measuring the aluminum spine phantom  with the resulting CV of 0.45% for the entire study period. The measurements did not show drift during the study period, with an average BMD of 1.248 ± 0.01 g/cmOvernight fasting blood samples were obtained at the baseline and 6 months screening. Serum was separated from red blood cells and analyzed for routine tests, including serum Ca, protein, and creatinine, by the contracting laboratory , as described previously . RemainiEach participant received written instructions and was individually trained on how to collect a 24-hour urine sample, as described previously ,54. The ® , and the mean daily intake was calculated, including energy and all other macro- and micronutrients. The intakes of vitamin and mineral supplements were carefully recorded and included in the total nutrient analysis. The participants who qualified for the study but were taking Ca supplements were asked to stop taking them and if they agreed, their enrollment was delayed for 1 month after which time they were randomly assigned in one of the three groups, as described previously [The participants were instructed by a dietitian on how to complete detailed 3-day dietary record (2 week and 1 weekend day) upon entering the study. Subsequently, they completed the records on a biweekly basis in the first 3-month run-in period and then at the end of the study (6 months). The nutrient intake from the records was analyzed with Food Processoreviously ,46,55.Physical activity was assessed using interview format with a modified version of the Allied Dunbar National Fitness Survey ,57,58. SUnderlying factors such as education level, marital status, current smoking status, perceived health status, and medication intake were collected using a self-administered questionnaire at data collection sessions, as described previously , and usen = 189 subjects participated in the baseline measurements, there was an attrition of about 30% in 6-month follow-up. There were also missing data in some variables even among the subjects who completed the study as seen in Most of the exploratory longitudinal analyses were performed via standard statistical methods such as repeated outcome measures using SAS and SPSS. P of ≤0.05 was considered significant. After checking for normal distribution of variables, the descriptive characteristics were calculated. Specifically, difference among three treatment groups (inter) or difference between baseline and 6 months within the same group (intra) were computed. Although, Additionally, although missing sample adjustments are widely criticized , we usedn = 44 is utilized for each of three groups for which to test the null hypotheses. Since covariates are of interest, an additional one subject per each df would be required for the repeated measures analysis of covariance, totaling n = (44 x 3) + 10 = 142 subjects. We recruited n=189 and ended with n = 135 at 6 months, Power analysis was calculated based on the results from the Chao et al. study examining the effects of weight loss on BMD of older women . These pn = 189 women was recruited and n = 135 completed the 6-month follow-up (28.6% drop-out rate), as shown in flow-chart, A total of p < 0.05) compared to those in other two groups. The participants in the C group were significantly heavier and had higher BMI compared to those in the S group, but not to those in the D group. Likewise, total body fat (kg) was significantly higher in the C group participants, compared to the S group only, while there was no difference in the total % body fat among the groups. Other variables (as listed in Regarding the baseline characteristics of the continuing participants stratified in groups (not presented), although there was no difference in the age among the groups, the participants in the S group were longer in menopause  compared to those in the S group but not compared to the D group. On the contrary, CTx, the marker of bone resorption, was significantly higher in C and S groups’ participants, compared to those in the D group. There was no difference at baseline among the groups regarding the NTx, another bone resorption marker, and osteocalcin, typically referred to as the marker of bone formation , but not from those in the C group (4.3 ± 1.9). The compliance with placebo/supplements and low-fat dairy food consumption, assessed at 6-month point showed 82.7% and 73.0% compliance with placebo and Ca supplements in C and S groups, respectively, while participants in D group consumed an average of 4.6 servings of low-fat dairy foods.The attendance to the group meetings was different among groups: participants in the S group had significantly higher attendance (4.7 ± 1.5) at group meetings than those in the D group  for one-tailed t-tests . Therefore, we conducted other statistical analyses, e.g., repeated measures ANOVA, MANOVA, autoregression models, etc. We present here the change-score-regression results in  t-tests . In simi t-tests , interven = 5 (12.2%), n = 2 (4.4%) and n = 0 participants in the C, S, and D groups, respectively, smoked (1 pack of cigarettes/day or less). As far as the number of weight loss attempts in adult life (since high school), participants in C, S, and D had on average 1.8, 1.2, and 1.6 weight loss attempts (during which they lost ≥10 lbs), respectively. As far as the educational level, there were no differences (by Chi-square tests) in higher education levels among the groups, with over 50% and 20% participants completing college and/or graduate degrees, respectively. The rest of the participants completed either high school or some other vocational schools, equally spread among groups.Regarding other lifestyle variables captured by questionnaires, only Our data show that participants in both Ca + vitamin D supplements (S) group and low-fat dairy (D) group presented with better bone and body composition outcomes compared with participants in control (C) group after 6 months of moderate weight loss intervention. In general, the participants in S group tended to have better bone outcomes; lower decrease or slight increase in BMD in measured skeletal sites, while those in D group tended to have better body composition outcomes; higher decrease in fat and lower decrease in lean mass . All parThe overall weight loss in our study was moderate and lower than what was achieved in some other studies with similar design. For example, in Zemel et al.’s study , the decIn our study participants, markers of bone turnover, serum osteocalcin (formation) and NTx (resorption), remained unchanged. However, urinary CTx  significantly increased in the C group’s participants and decreased in the S group’s participants, indicating higher bone resorption in C and lower in S group’s participants . While CIt is interesting to note that PTH decreased significantly only in the S group’s participants, while 25(OH)D significantly increased in participants of both the S and D groups after 6 months. Although the changes were small, and participants had normal values to begin with, they may indicate an improvement in bone metabolism, as well as compliance with the prescribed diets. Other studies have also shown a reduction in PTH from Ca supplementation ,71. AddiIn the obesity epidemic era, numerous attempts for weight loss by millions of individuals became a health concern because of the bone and muscle loss during and/or after the weight loss. It is important to emphasize that bone, muscle and adipose tissues are interrelated organs, which are involved in secreting several biomarkers that can affect each tissue ,80,81. W++ induced muscle force production and strength [The reviews by Radak and Ilich discuss the studies of weight loss with Ca and/or dairy foods and their effects on bone ,65; howestrength . The revstrength  in burn strength ,90,91.Overall, keeping in mind that adipose tissue is a major endocrine organ, secreting and/or metabolizing hormones , adipokines , and numerous cytokines, it affects both bone and muscle, often in a dual manner (positively and/or negatively) ,17. Ther++, stimulating PTH and calcitriol secretion, which both promote Ca influx into adipocytes. This increased intracellular Ca in adipocytes stimulates lipogenesis and suppresses lipolysis resulting in conservation of fat. High Ca intake (resulting in higher serum ionized Ca++) on the other hand, suppresses PTH and calcitriol response, stimulating lipolysis. This is also referred to as “calcium paradox”; paradoxical in that high cytosolic Ca caused by low dietary Ca will promote high lipogenesis and conservation of fat [As proposed by Zemel ,93 the mn of fat .Regarding the mechanism of dairy foods possibly mediating weight/adiposity, besides Ca, several other components have been introduced. Another study by Zemel et al., comparing the effects of dairy foods and supplemental Ca on weight loss showed that women on reduced energy intake lost about 70% more weight on dairy foods and 26% more on Ca supplements  compared to controls who had similar energy intake . This efDespite the recent criticism of the role of dairy foods, particularly milk, in health, the available evidence supports the notion that adequate intake of dairy foods may protect against or improve many chronic conditions of modern time . It is oThere are several limitations, as well as strengths to our study. This study was conducted in Caucasian overweight/obese early postmenopausal women (as per inclusion criteria) which limits the generalizability but increases the homogeneity of the study, particularly regarding the bone outcomes. Bone metabolism and BMD are different in Caucasian women compared to other ethnic groups  and particularly to those of men. Therefore, the results of our study are limited to the population studied. It is important to keep in mind that DXA does not measure muscle directly, but the lean tissue which includes muscle and organs. During each weight loss, there is a loss of water, the highest occurring in the first couple of weeks. Since muscle contains much higher amount of water than body fat, it is likely that the proportion of water lost is higher from lean tissue. Over time however, the water loss stabilizes. During the 6-month duration of our study, it is likely that participants reached equilibrium in homeostatic regulation and the continued fat and lean mass loss occurred with a substantially smaller loss of water.The extensive data collection  enabled the most comprehensive analyses and release of wide-ranging findings. Although we tried to limit the attrition rate and make the participation in the study as easy and pleasurable as possible (by conducting group meetings and counseling and having frequent contact with participants), the attrition rate still reached some 30%. Furthermore, the subsequent missing data-points were high . We counteracted this by conducting the extensive analyses of the direct changes among the groups and differences between baseline and 6-month intervention, as well as the regression analyses using the FIML to offset the missing sample difficulties. Both types of analyses showed similar trends.Our results show that hypocaloric diets with increased Ca + vitamin D intake and/or low-fat dairy foods during the 6-month intervention resulted in better weight and fat tissue loss, as well as in preservation of bone and lean tissue, compared to the hypocaloric diets only. The best outcomes were noticed in the participants in the low-fat dairy group, regarding the body composition outcomes and in those on Ca + vitamin D supplement group regarding the BMD outcomes. Therefore, increasing low-fat dairy foods to 4–5 servings per day and/or increasing Ca and vitamin D intake by supplements (in those who are at the borderline dietary intake) may be beneficial for weight loss/maintenance and may lead to more favorable bone and body composition outcomes. This is particularly important in view of the newly identified OSO syndrome , which s


Objectives: To assess maternal and neonatal risk factors for intraventricular hemorrhage (IVH). To examine the association of patent ductus arteriosus (PDA) and its treatment, with IVH and its severity.Study design: In this retrospective cohort study, we included preterm neonates born at <29 weeks, admitted to a tertiary level III Neonatal Intensive Care Unit in Calgary, Canada, between 2013 and 2016, who had a head ultrasound in the first 7 days of life. A subset analysis included neonates who also had cardiac ultrasound in the first 3 days of life.Results: Of the 495 neonates, 121 (24.4%) had IVH of any grade and 48 (9.7%) had severe IVH. Identified risk factors were small birth gestation and weight, lack of antenatal corticosteroids, maternal chorioamnionitis, Apgar score <5 at 5 min, umbilical cord pH < 7, respiratory distress syndrome, early onset sepsis, hypercapnia, pCO2 fluctuations, prolonged intubation, inhaled nitric oxide, inotropes or normal saline boluses, metabolic derangements, opioids infusions, and bicarbonate/THAM therapy. In a primary analysis of the total cohort, when the decision to treat a PDA was used as a surrogate marker of its clinical significance, a PDA requiring treatment was associated with a higher risk of IVH. There was no significant difference in the incidence of IVH between neonates with early treatment of a clinically significant PDA compared to late, however early indomethacin treatment was associated with reduced severity of IVH. In the subset analysis, the presence of a hemodynamically significant PDA (hs-PDA) was not associated with a higher probability of IVH. Of those with severe IVH, 18 (55%) had a hs-PDA; this is clinically but not statistically significant.Conclusions: Identified risk factors should be the target of IVH reduction bundles. Early indomethacin treatment for a clinically significant PDA may reduce IVH severity. Extremely preterm neonates <29 weeks) have an increased risk of intraventricular hemorrhage (IVH) which is a multifactorial medical complication. A hemodynamically significant PDA (hs-PDA) can cause fluctuations in cerebral blood flow –3, which9 weeks hIn the neonatal literature, the severity of IVH is graded from I to IV, depending on its ultrasound imaging appearance. Severe IVH refers to equal or greater than Papile's or Volpe's Grade III. Papile  defines The incidence of all grades of IVH in the extremely preterm population varies between 31 and 36% –13, whilThe patent ductus arteriosus (PDA), a shunt between the pulmonary artery and the aorta, is essential for fetal circulation. It normally constricts shortly after birth in term neonates. However, spontaneous ductal closure by the seventh day of life occurs in only 13–36% of preterm neonates born at less 29 weeks; the younger the gestation, the higher the risk of ductal persistence . After bSignificant controversy remains surrounding the optimal management of a hs-PDA; there is a lack of consensus regarding which PDA to treat, when and how. Treatment options include conservative treatment, non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and ibuprofen, acetaminophen, or surgical ligation.Literature review regarding the impact of PDA treatment on the incidence of IVH is contradicting. An analysis of neonates not recruited into the PDA-TOLERATE trial (a randomized control study) does bring into focus that the more immature and unwell neonates are more likely to be excluded from such studies, which could affect the results . A CochrThis was a retrospective analysis of a prospectively collected cohort of all neonates born at a gestational age of <29 weeks, admitted to the Neonatal Intensive Care Unit (NICU) at Foothills Medical Center in Calgary, Canada, between January 1, 2013 and December 31, 2016, who had a head ultrasound in the first 7 days of life. We excluded neonates with major congenital or chromosomal anomalies, antenatally diagnosed IVH, incomplete dataset, or who died prior to obtaining a head ultrasound. A secondary analysis examined the subset of neonates who had a Targeted Neonatal Echocardiogram (TNE) in the first 72 h of life.This study was approved by the Conjoint Health Research Ethics Board (CHREB) at the University of Calgary and the consent was waived. Data was collected prospectively, using predefined variables, as part of a local quality improvement project aiming at IVH prevention (“Drive to Zero”), also approved by CHREB (REB14-1466). Data collected included demographic characteristics, head and cardiac imaging, as well as other morbidities. The database analysis allowed us to determine the incidence and severity of IVH, as well as the incidence of untreated and treated PDA in our cohort. We were then able to examine the incidence and severity of IVH between neonates treated for PDA and those without PDA treatment.+6 weeks gestation in the first 72 h of age. This bundle consists of recommendations on respiratory and hemodynamic management, lighting, noise, thermoregulation, skin care, minimal handling, positioning, and obtaining vascular access. This document is available under “Drive to Zero” is a Calgary-based project that aims to reduce IVH in the preterm population. The “Intraventricular Hemorrhage and Brain Injury Prevention Package” (IVH-BIPP) is a care bundle that targets premature neonates of ≤ 30According to local guidelines, neonates born at <32 weeks of gestation, or with a birth weight of <1,500 g, have a head ultrasound between days 5–7 of life, or earlier, if clinically indicated, to assess for IVH. All images are reviewed and scored blindly by an independent neuroradiologist (JNS), who is unaware of the neonate's clinical course using a standard template .The IVH-BIPP guided clinical decisions such as the administration of normal saline boluses and/or inotropes, extubation, and reintubation. The use of iNO was directed by the requirement of a high FiOThe “IVH window” refers to the first 72 h of life, during which there is the highest risk of IVH. For this study, we defined “Mild IVH” as IVH grades I or II, and “severe IVH” as IVH grades III or IV, moderate to severe post-hemorrhagic ventricular dilation, and/or periventricular leukomalacia.For this study, a hs-PDA was defined as a PDA of 1.5 mm or more in diameter at its narrowest point with complete or predominantly left to right shunting, and showing a low velocity flow on Doppler interrogation, defined as <1.5 m/s, or the presence of signs of left volume loading with a LA:Ao ratio of >1.5. Echocardiographic findings were further classified into four phenotypes: (a) moderate to large shunt volume—if the PDA size was >1.5 mm, the flow pattern was growing or pulsatile, and the shunt direction was left to right or mostly left to right with evidence of volume overloading of the left side; (b) small shunt volume—if the size was ≤1.5 mm, the flow pattern was restricted, and the shunt direction was left to right; (c) non-PDA physiology—PDA with complete left to right shunt or bidirectional with a pulsatile pattern; and (d) no PDA. The echocardiographic data was reviewed by neonatologists trained in performing and reading TNE who were blinded to the head imaging findings.The timing of PDA treatment was considered early if it was given within the first 72 h of life, and late if it was given between 72 h and 14 days. Surgical ligation was considered for infants with a hs-PDA, which failed to close after 2–3 courses of medical treatment or contraindication to medical treatment.2 fluctuation was defined as the recording of at least one hypocapnea  and at least one hypercapnea , hypoglycemia as any blood glucose level <2.6 mmol/L, hyperglycemia as any blood glucose level >10 mmol/L, hypothermia as any temperature <36 C, hyperthermia as any temperature higher than 37.5 C, acidosis as any arterial or capillary blood pH < 7.20, and alkalosis as any arterial or capillary pH > 7.45. Early onset sepsis was defined as a positive blood culture in the first 48 h. At our center, the most common agents used for sedation are morphine or fentanyl infusions.In the first 72 h of life, any infant requiring reintubation was counted as an extubation failure, pCOp < 0.05.Statistical analysis was performed with Stata 14. Descriptive statistical analysis was performed. We compared the maternal and neonatal characteristics between infants with no IVH, mild IVH and severe IVH. We used Chi Square test or Fisher exact test for comparing the categorical variables and analysis of variance for comparing the continuous variables. The tests used were two-sided and significance was defined as Of the 500 eligible neonates admitted during the study period, 495 neonates were included. Five infants were excluded due to incomplete data or death prior to head ultrasound. Of the 495 neonates, 121 (24.4%) had IVH of any grade, and 48 (9.7%) had severe IVH. Grade I and Grade II accounted for 34 (28%) and 39 (32%) cases, respectively, while Grade III and Grade IV accounted for 6 (5%) and 42 (35%) cases, respectively. The incidence of IVH was reduced with increasing gestational age. The incidence of IVH (any grade) at 23, 24, 25, 26, 27, and 28 weeks was 30.4, 48.6, 30.8, 25, 18.7, and 11.9%, respectively. The incidence of severe IVH followed a similar trend. At 23, 24, 25, 26, 27, and 28 weeks, 8.7, 21.6, 13.8, 6.5, 7.3, and 5.2% had severe IVH, respectively.2 fluctuations, as well as the use of normal saline boluses and inotropes, were more common in the mild and severe IVH groups, as compared to the no IVH group. Neonates in the IVH group had more hyperglycemia, hypothermia and early onset sepsis. The early neonatal mortality rate was significantly higher in the mild and severe IVH groups, as compared to the no IVH group  were more immature, had smaller birth weights, and had a lower 5-min Apgar score compared to those without IVH . FurtherVH group .In our total cohort of 495 neonates, 198 neonates (40%) had at least one intervention for PDA treatment during their NICU stay. Medical treatment was received by 195 neonates (39%), of whom 18 (9%) received early ibuprofen and 35 (18%) received early indomethacin. Surgical ligation was performed in 43 (9%) neonates .p < 0.001) and birth weight , as compared to infants who did not have early cardiac ultrasound. Of the 258 neonates, 142 (55%) had a hs-PDA, however only 32 (22.5%) of these received early medical treatment with either ibuprofen or indomethacin, and 93 (65.5%) received early and/or late medical treatment for a PDA. A number of these neonates had concomitant pulmonary hypertension, which makes PDA closure inadvisable. Interestingly, 17 neonates with a non hs-PDA and two with no PDA on initial cardiac ultrasound also received early medical treatment. These infants were likely treated based on significant clinical findings that developed after the initial cardiac imaging had already been done or based on a subsequent cardiac ultrasound that showed a hs-PDA. Seven infants received early and/or late treatment for PDA despite not having a PDA on early TNE. Of these, four had their PDA spontaneously reopen and become hemodynamically significant on later echocardiography, one was treated with indomethacin prophylactically, one had severe PPHN with decreased right ventricular contractility on a later echocardiogram , and finally, one had pulmonary hemorrhage with no documented echocardiography prior to treatment. Five out of the seven infants had an abnormal head ultrasound prior to treatment (four infants with Grade I and one with Grade II); the other two had normal head ultrasounds.Of the 495 neonates, 258 (52%) had a cardiac ultrasound in the first 72 h . The medp < 0.001), but there was no statistically significant difference with the early treatment of PDA , or treatment using ibuprofen vs. indomethacin (p = 0.02). In the subset analysis, 142 neonates (55%) had a hs-PDA, of whom 18 (12.7%) had severe IVH. However, of those with severe IVH, 55% had a hs-PDA. Although this is clinically significant, no statistical significance was detected , but no other statistically significant association was found.When IVH and PDA are analyzed within the total cohort  and the early imaging group  , the likp = 0.005) , there was no significant difference seen in the incidence of IVH, however, the composite outcome of death/severe IVH was higher in the non-PDA physiology group (= 0.005) .in utero growth (both in gestation and weight), and antenatal corticosteroids. Postnatally, tight pH control, maintaining normocapnea, normothermia, and normoglycemia, as well as avoiding the use of inotropes or saline boluses may be protective. In our cohort of 495 extremely preterm neonates, our rates of any IVH (24.4%) and severe IVH (9.7%) are comparatively low  is lower than the Canadian average of 51% , whereasIn our total cohort, when PDA treatment was used as a surrogate marker for its clinical significance, we observed that a PDA requiring treatment was associated with a higher risk of IVH. Early treatment of a clinically significant PDA did not seem to affect the incidence of IVH, but early treatment with indomethacin was associated with decreased severity of IVH. However, this finding did not reach statistical significance in our secondary analysis, in which we used cardiac imaging in the first 72 h of life to determine clinical significance, as opposed to treatment decisions. This dissonance between our primary and secondary analysis may be because the criteria we used to determine hemodynamic significance on cardiac imaging did not in fact adequately capture clinically significant PDAs. It could also perhaps be argued that the use of the clinical judgment to treat or not to treat a PDA as a marker of its significance , which would be based on a bedside analysis of the neonate's entire clinical situation and not just one snapshot in time as offered by cardiac imaging , provides a more accurate portrayal of PDA significance.Our findings are consistent with the 2010 and 2011 Cochrane reviews, which showed that the use of early indomethacin was associated with a decreased severity of IVH, and that early ibuprofen did not cause a statistically significant reduction in IVH , 25. HowThis analysis, which spans 4 years of data from our level III center, raises multiples practical questions that can influence our care for this fragile population. Apart from assessments for pulmonary hypertension, and cardiac contractility or filling, early cardiac imaging is usually used to assess the status of a PDA, in order to provide guidance for a treatment decision. However, if the use of early indomethacin decreases IVH, regardless of PDA status, routinely assessing the PDA in the first 72 h may be of little clinical benefit and may lead to overtreatment. The limitation of PDA assessments to only when clinically indicated will have an added benefit of minimizing handling of the baby in the IVH window. Early treatment of PDA does not seem to confer added protection to the preterm neonate. As for the use of early indomethacin, early prophylactic indomethacin decreases the incidence of IVH among extremely low birth weight neonates, whether or not they were exposed to antenatal steroids . The incThe mechanism by which indomethacin affects IVH is unclear. Animal studies have suggested that it may prevent surges in cerebral blood flow, as seen in animal models with asphyxia or hypercapnia –34, and The main strengths of our study are the prospective completeness of our data collection into the database, which captured 495 of 500 admissions during the period of study, as well as the independent review of cardiac and head ultrasounds images. We were able to retrospectively analyze early cardiac imaging obtained in 52% of participants, which provided additional clinical context. The main limitations of this study relate to our imaging: (1) we do not have early head imaging (in the first 72 h) to delineate the timing of the IVH occurrence with the PDA significance; and (2) we did not have a protocol for serial cardiac ultrasounds at standard time points, so it is possible that some PDAs that were classified as “non-PDA physiology” or “no PDA” actually became hemodynamically significant later within the IVH critical window. Additionally, the definition of PDA significance remains controversial in the neonatal community, and so our definition has its limitations, which may have contributed to the differences seen between our primary and secondary analysis. Finally, this was a prospectively collected and retrospectively analyzed, single-center study, which cannot infer causality, as opposed to a randomized control study.Risk factors for IVH were identified and should be the target of IVH reduction bundles. A PDA requiring treatment was associated with a higher risk of IVH. There was no difference in the incidence of IVH in neonates who received medical treatment for PDA closure in the first 72 h of life or had a hs-PDA on imaging in the first 72 h of life, however, early indomethacin treatment for a clinically significant PDA reduced the severity of IVH.Individual de-identified participant data can be shared.The raw data supporting the conclusions of this manuscript will be made available by the corresponding author on request.This study was approved by the University of Calgary Conjoint Health Research Ethics Board (CHREB). Data was collected prospectively, using predefined variables, as part of a local quality improvement project aiming at IVH prevention (Drive to Zero), also approved by the CHREB (REB14-1466).Some of the information included in this manuscript was previously presented in a poster at the Pediatric Academic Societies Meeting in Toronto, Ontario, Canada .IK-L and KM contributed conception, design of the study, and wrote the first draft of the manuscript. KM organized the database and supervised the study. KM and ASo performed the statistical analysis. ASo, ASt, EA, ST, PM, MK, JS, and KM contributed to the acquisition and analysis of imaging data. All authors contributed to manuscript revision, read, 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.


Dietary oxidized olive oil, alone or in combination with different doses of α-tocopherol, were given to Swiss albino rats for 30 days; in order to determine its role in oxidative stress and fatty liver, induced by the oxidized olive oils. Serum biochemical parameters and hematological indices of blood were analyzed. The liver was analyzed for histopathological changes, lipid peroxidation, and polar triacylglycerols composition. Results revealed that there was a significant decline in the serum total cholesterol, triglycerides, LDL, glucose and ALT; while a significant increase occurred in the serum HDL levels through the supplementation of α-tocopherol in male and female rats. Hematological parameters were almost in the normal reference range in the groups that were fed α-tocopherol, alone or in combination with oxidized oil, while being significantly altered by the oxidized olive oil. There were acute hepatitis and necrosis in the liver with no fatty changes after feeding with oxidized olive oil, along with varying doses of α-tocopherol. Higher amounts of polar compounds were present in female rats (15.2–93.1 μg/g) compared to male rats (12.2–82.3%) that correspond to the supplementation of α-tocopherol in combination with oxidized oil. Lipid oxidation in liver was minimized by tocopherol, while an increase occurred in the accumulation of oxidized lipids in the liver. These findings revealed that tocopherol is beneficial against the oxidized oil induced biochemical and hematological changes and lipid peroxidation but causes fatty accumulation in the liver. Therefore, the role of tocopherol in patients with fatty liver disease may be considered, as tocopherol may increase the chance of survival. Thermally oxidized lipids are considered one of the crucial components in modern-day food preparation. Oils and fats, when thermally oxidized, produce primary oxidized triacylglycerols , which aAlpha-tocopherol is a natural antioxidant present in the cells of plants and animals. When rats were supplemented with diets containing α-tocopherol, it was found to maintain the cellular redox status, especially, by preserving the activities of important enzymes; such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, as well as, glutathione and vitamin E levels. The levels of peroxides, hydroxyl radical and hydrogen peroxides of lipids significantly decreased . In combFresh olive oil was purchased from the local market in Chakdara, Lower Dir, Khyber Pakhtunkhwa, Pakistan. The olive oil was selected based on its high contents of oleic acid  and highOlive oil was heated for 5 h at 100°C on a hot plate, and soon after, was stored in the refrigerator at −20°C to avoid any further alteration till its use. The oleic acid composition of the control and oxidized olive oils were 77.9 and 81.4 mg/100 g, respectively. The characteristics of normal and oxidized olive oil have been reported in our recent work  were selected after rearing in a bio-park of the University of Malakand. The experiments were approved by the ethical committee, the graduate studies committee, and the advanced studies and research board of the University of Malakand for proper care and experimentation. The composition of the basal casein diet given to rats consisted of casein (22%), sucrose (69.5%), corn oil (4.5%) and a salt mixture IV (4.0%). Rats were divided into 16 groups; 8 males and 8 female groups. Each group consisted of three animals. Two groups  were fed a normal diet without any treatment. The dosing scheme is given as under with F, M, T, and O representing female, male, tocopherol, and oxidized oil, respectively.FC group was fed a normal diet; FO group was fed oxidized oil (2 g/kg body weight); FT1 group was fed tocopherol (100 mg/kg body weight); FT2 group was fed tocopherol (200 mg/kg body weight); FT3 group was fed tocopherol (300 mg/kg body weight); FTO1 group was fed oxidized oil (2 g/kg body weight) and tocopherol (100 mg/kg body weight); FTO2 group was fed oxidized oil (2 g/kg body weight) and tocopherol (200 mg/kg body weight) and FTO3 group was fed oxidized oil (2 g/kg body weight) and tocopherol (300 mg/kg body weight). The male rats were fed a similar dosing scheme. Feeding was carried out regularly for 1 month and at the end of the period, the rats were humanely killed, and blood samples collected.The serum was used for the analyses of biochemical parameters, such as total cholesterol, total triglycerides assay kits , while HDL-c, LDL-c, ALT, and glucose assay kits were of Human .Three milliliters of whole blood samples were transferred to heparinized tubes. Whole blood was used for the analyses of total red blood cells, hemoglobin concentration, hematocrit value, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, total leukocyte count, neutrophils, eosinophil, lymphocytes, and platelets count by employing a fully automated blood hematology analyzer .After killing the rats, their liver was isolated and preserved in a formalin solution. Tissues sectioning were made, stained and histopathological examination was done as described earlier . MicroscLipids were extracted using the method of Folch et al. . BrieflyPolar or oxidized compounds in the liver lipids were determined using the HPLC-DAD method reported previously . Twenty Lipid peroxidation was studied in the extracted liver lipids using a sensitive spectrophotometric method, as thiobarbituric acid reactive substances (TBARS). The method uses the reaction of malondialdehyde (MDA) and thiobarbituric acid (TBA) in the glacial acetic acid. The extracted lipids 200 mg) were mixed with 5 mL of glacial acetic acid-water  and shaken for 1 h. The samples were then centrifuged at 4,000 rpm for 10 min and absorbance was measured at 532 nm  of replicate measurements using GraphPad Prism version 7.01 . The analysis of variance (ANOVA) was performed for significant differences between mean values vs. control at different P < 0.001) reduced the total cholesterol amounts in both male and female rats  with the increasing dose amount. There was the relatively double the amount of lipid peroxidation as TBARS of 2.48 μmol/g of the tissue compared to its corresponding control male rats (1.48 μmol/g). The increase of tocopherol at 300 mg significantly decreased the amount of TBARS level equivalent to the amount of control samples. In female rats, the amount of TBARS was higher in control than its corresponding doses in male rats. There was a significant increase in the amount at the dose of 200 mg in control female rats, which was found to decline by increasing further tocopherol to 300 mg. The supplementation of thermally oxidized olive oil and tocopherol increased the levels of TBARS to 2.47 μmol/g at the dose rate of 100 mg. A further increase in the tocopherol showed a decrease of TBARS values.The TBARS value is one of the key parameters for the determination of total lipid peroxidation in the tissue and is different than the polar triacylglycerol (TAGs) analyzed by HPLC. Figure Thermal oxidation of olive oils produces significant amounts of polar TAGs . The heaOxidized oil was given to male rats at a dose rate of 2 g/kg along with α-tocopherol at the dose rate of 100–300 mg; RBC, Hb level, HCT value, MCV, MCH, MCHC, granulocytes, and platelets count were low, when oxidized olive oil was given along with α-tocopherol in small dose. As the dose of α-tocopherol was raised, these values were normalized. Hemoglobin level, RBC, and MCV were decreased after feeding rats with different fresh and fried oils . After aThe histological studies revealed that thermally oxidized olive oils caused significant negative changes in the structure and functions of the liver, which was enhanced by supplementation of tocopherol. Tocopherol alone has no significant effects on the liver, with the exception of causing inflammation. The literature showed that thermally oxidized edible oils lead to the histological alteration in liver , 34. OurR2 = 0.8691 & R2 = 0.9999 between the tocopherol amount and the lipid peroxidation in female and male rats, respectively. This shows that tocopherol may hinder the production of secondary lipid peroxidation in the liver but cause the fatty accumulation in the liver. Previous studies showed that vitamin E reduces oxidative stress and improve insulin action (It has been found that supplementation of tocopherol and oxidized lipids, in combination or alone, increased the polar compounds in the liver in all treated rats. In the earlier experiments , it was n action . The tocn action . Thus, iFrom these results, it has been concluded that oxidized olive oil leads to liver toxicity and also causes an alteration in biochemical parameters and hematological indices. Alpha-tocopherol, when co-administered alone or in combination with oxidized olive oil, lead to a decrease in toxic effects. However, tocopherol has been found to increase polar compounds in the liver, while hindering the formation of secondary lipid peroxidation. Thus, the use of tocopherol may be thoroughly monitored in patients with non-alcoholic fatty liver diseases.AZ designed the experiments, analyzed the characteristics, performed the biochemical analysis, and wrote the manuscript. AK collected the samples and animals, performed the feeding of animals, and analyzed hematology and histology.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.