Podoconiosis is preventable if genetically susceptible people wear shoes starting from an early age and do so consistently. However, lack of routine use of footwear is one of the major risk factors for podoconiosis and several other foot-related Neglected Tropical Diseases (NTDs). This study is aimed at describing the extent of footwear use among school-age rural children susceptible to the disease and investigating associated socioeconomic factors.Cross sectional surveys were conducted in 330 randomly selected households in Wolaita zone, southern Ethiopia. A household head and a child aged between 9 and 15 years were recruited from each household. Household heads provided socioeconomic data while children were asked about their footwear ownership and footwear use.2 = 0.307). The interaction effect of adequate ownership of footwear and family socioeconomic status consistently predicted the protective use of footwear among children  though the main effect of adequacy of footwear ownership was stronger .Nearly half (49.5%) of the children reported either walking barefoot or wearing under-protective footwear in a range of situations. Girls, older children, those in higher school grades, who belonged to families with higher socio-economic status, and those who owned a larger number of pairs of footwear reported more protective use of footwear. The linear regression model constituting the adequacy of footwear ownership and interaction term (i.e. family socioeconomic status by adequacy of footwear ownership) variables explained 30% of variance in the protective use of footwear  participated in household surveys. Nearly half (49.5%) of the children were found to have less-protective use of footwear, either walking barefoot or wearing under-protective footwear in a range of situations. Girls, older children, those in higher school grades, those from families with higher socio-economic status, and those who owned a larger number of pairs of footwear reported more protective use of footwear. The protective footwear use among children is likely to increase with increase in family socioeconomic status and number of pairs of different types of footwear owned by the children. Increased adoption of protective footwear is needed to prevent school-age children living in endemic areas from developing podoconiosis and other neglected tropical diseases. Interventions aimed to encourage ownership of multiple pairs of footwear should use approaches that also increase the socio-economic capacity of podoconiosis-affected families. The health benefits of footwear have been well recognized in the context of neglected tropical diseases. Apart from providing protection and comfort to the feet, footwear reduces vulnerability to a range of foot-related diseases. Common examples of diseases associated with barefoot walking include Buruli ulcer, cutaneous larva migrans, tungiasis, hookworm infection, soil transmitted helminth infection, strongyloidiasis, and leptospirosis . These dA study conducted in Wolaita zone of Southern Ethiopia reported consistent  use of footwear among preschool children in podoconiosis-affected households to be only 31% . In anotThough these reports provide important evidence, biases may have led to under-ascertainment of inadequate footwear use. In one study  childrenAdditionally, there is a dearth of evidence regarding the influence of socioeconomic factors on footwear use among school-age rural children highly susceptible to podoconiosis. Previous qualitative studies have reported the role of financial constraints in limiting parents’ ability to provide adequate number of pairs of footwear for their children ,14. SociStudies into podoconiosis also have recognized the roles of socioeconomic circumstances of families in the practice of preventive behaviors. Studies among rural people in podoconiosis- endemic communities have observed a positive association of family socioeconomic status with adequacy of number of pairs of footwear owned and footwear use behavior ,14. Due Ethical approval was obtained from the ethics committees of the Armauer Hansen Research Institute (AHRI) (Project reg. No. P035/15) and the College of Health Sciences, Addis Ababa University (Protocol number 047/15/Ext). The Wolaita Zone Administrative Bureau gave written permission to work in the community. MFI allowed their outreach clinic site staff to help in the identification of study participants. Caregivers confirmed their permission for a child to participate in the study by signing or thumb-printing on the consent form. Children above age 12 expressed their assent verbally in the presence of their caregivers as a witness, to ensure the assent process was without any coercion. The use of verbal assent from children was approved by the ethics committees.kebeles (lowest administrative unit) in which outreach clinics were running. The outreach clinic staff identified affected families (households) eligible for the study using the last shoe distribution list that included information about children’s age and sex, the number of siblings in the family who received shoes, and kebele of residence. The list of households in the shoe distribution list served as a sampling frame. The total number of podoconiosis patients registered by MFI in the area at the time of the study is larger than this, as shoes were only distributed to households with school-age children.Cross-sectional surveys were conducted with children from households in Wolaita Zone, southern Ethiopia in March 2016. The study setting of this research has been described in an earlier publication . Househo(DEFF)d2 , where n(DEFF)d2 . Using tThe sampling frame was composed of a total of 261 households in Damot Pulasa district, 405 households in Ofa district and 297 households in Bolo Sore district. Due to the variation in number of households by district, a probability proportionate to size sampling technique was used to select 90 households from Damot Pulasa district, 139 households from Ofa district and 101 households from Boloso Sore district. We kept twenty percent of sample households in the sampling frame of each district in reserve list so that data collectors could easily replace if an eligible respondent was absent. A list of sampled households coded with random numbers was given to each data collector. In every sampled household, a household head and a child were recruited. In households with more than one child in the age range, data collectors used a lottery method to select one child to complete the survey. The eligibility criteria for children were a) being 9 to 15 years of age, and b) being free from podoconiosis. Household heads provided socio-economic data for their family.Composite indexes were used to measure footwear use, ownership of footwear and family socio-economic status variables. Indices are composite measures that summarize and rank several indicators to represent the general dimension of a given concept. The indicators used to form an index may not necessarily be related to each other and the inter-correlation of items within the index is not a prerequisite to combining them . A multifrequency of footwear use across situations and protectiveness of footwear used. Frequency was indicated by the use of footwear in a range of situations as recalled over the last seven days, and as observed by the data collector on the day of interview. The index constituted 13 indicators probing the use of footwear in a range of situations. The situations include looking after cattle, farming, fetching water from the river, collecting fuel wood, walking around the homestead, playing games or sports exercises and social occasions such as going to market, church or school. These indicators have been reported in previous qualitative and quantitative studies as important situations in which the use of footwear varied [We conceptualized footwear use as a function of both r varied –13. Protr varied ,27. ClosAdequacy of footwear ownership was defined as the number of pairs of footwear (of any type) owned by the school-aged child. Previous research has identified five general types of footwear including: open plastic/foam, closed plastic/foam, open leather, closed leather, and closed canvas/sneaker were included in the index as possible types of footwear owned –30. The The Family Socioeconomic Status index was developed to measure multidimensional aspects of household level socioeconomic inequality among families affected by podoconiosis. Three dimensions  have been widely used in the measurement of socioeconomic status ,32. Howekebele network leaders and other knowledgeable individuals in the village to link the sampled households with data collectors.Experienced data collectors certified with a college diploma or degree in a social or health sciences field were recruited and trained. The trained data collectors pretested the instruments in six households in the study area to ensure understandability, clarity and relevance of the questions. Two data collectors were deployed per study site: one surveyed a parent household head while the other surveyed the child. The data collection was conducted using a pretested instrument in a location that provided privacy for the respondent. Data collection was supervised daily by three assistant supervisors and every three days by the first author. In each study site, the MFI outreach clinic staff collaborated with the A trained data entry clerk entered the data into a SPSS spreadsheet as coded in the questionnaire. Statistical Package for Social Sciences version #20 (SPSS), was used for the analysis.Descriptive analysis was conducted using frequency distributions to describe socioeconomic status of households, adequacy of footwear ownership and extent of protective use of footwear among respondents. The independent samples T-test was employed to determine if the mean scores of protective use of footwear varied by gender , age , or educational attainment . Pearson product-moment correlation analysis was conducted to determine the association between socio-economic factors such as family socioeconomic status (standardized scores) and adequacy of footwear ownership (standardized scores). A linear regression analysis was conducted to test whether socioeconomic factors such as family socio-economic status (standardized scores) or adequacy of footwear ownership (standardized scores) had independent or interaction effect on the protective use of footwear (standardized scores). To determine the interaction effect, a new product term variable was created, family socioeconomic status variable multiplied by adequacy of footwear ownership. The effects of gender , age  and educational attainment  variables were controlled. All variables were entered into the linear regression model using a backward stepwise method. Collinearity between variables was checked through a correlation matrix, in which none of the independent variables were strongly correlated. An alpha value of 0.05 was considered to determine the statistical significance of associations. A list-wise deletion method was used to exclude cases with missing values during computation of index scores and test of associations.As indicated in As For descriptive purpose, we considered standard normal distribution of wealth index scores to classify households into five wealth quantiles: -2 to -1 = lowest, -1 to 0 = lower, 0 to 1 = middle, 1, 1 to 2 higher and 2 to 3 = highest. Households within 1 standard deviation were categorized into each category. Accordingly, as indicated in Adequacy of footwear ownership was measured by an index of types and number of pairs of footwear owned by children. To determine the adequacy of footwear ownership, weights were given to the number of pairs of each type of footwear children reported owning . As indicated in Patterns of footwear use varied across situations and activities . Going bAll 13 items representing various situations of footwear use were considered to determine the total scores for the footwear use index. As shown in As shown in As indicated in The exploratory regression analysis revealed the effects of family socioeconomic status and adequacy of footwear ownership on protective use of footwear when demographic attributes of respondents such as age , sex  and educational attainment  were controlled in all steps of the regression analysis. Regression analysis stopped at the fourth step. The final model, in which family socioeconomic status, adequacy of footwear ownership and product term variables remained, explained 31% of variance in the protective use footwear among respondents. The main effect of adequacy of footwear ownership on protective use of footwear remained consistent  while the main effect of family socioeconomic status was not consistent. Interestingly, the interaction between family socioeconomic status and adequacy of footwear ownership was statistically significant . This study aimed to measure the extent of protective footwear use among school-age rural children in Wolaita zone using a composite index of context-driven indicators. Efforts were made to systematically measure concepts such as socioeconomic status and adequacy of footwear ownership and to investigate their association with the protective use of footwear. Based on the wealth index scores, the proportion of households falling into the lowest socioeconomic status categories was 19%, while only 3.3% of the households belonged to the highest socioeconomic status. This may not be surprising as podoconiosis-affected families are known to face a double burden, being prevented from economic and social activities and impacted by the costs of treatment . StudiesAlmost all children participating in this study reported ownership of some form of footwear. This demonstrates a positive change in the lifestyle of rural people in Ethiopia, where a barefoot tradition has prevailed for a long period of time. Nevertheless, the types and numbers of pairs of footwear owned by rural children are very limited, with only two pairs owned on average. The most common types of footwear owned by children were open plastic shoes in contrast to adult members of the rural population in settings known for podoconiosis endemicity in Ethiopia. For example, a study reported ownership of open plastic footwear among only 18% of adults affected by podoconiosis and 29% of adults never affected by podoconiosis . On the Our assessment of protective footwear use among school-aged rural children provided important evidence on the vulnerability of rural children in the study area to podoconiosis. A range of previous studies have described footwear use in podoconiosis-endemic communities ,27,29,30Overall in this study, the extent of protective footwear use was low among school-age rural children in Wolaita zone. Nearly half (49.5%) of the children recruited from podoconiosis-affected families were found to use footwear in a way unlikely to afford them protection from the soil. This is congruent with Watanabe and colleagues’ study , that reThe association between gender and protective footwear use is another important finding. The protective use of footwear among girls was found to be better than used footwear more protectively than boys. This may be baffling considering the deeply entrenched privilege of men that stems from cultural and institutional bias against women in societies, particularly in low and middle income settings –45. HoweProtective footwear use tended to increase with children’s age and educational attainment–with age and progress to higher school grades, children are more likely to use more protective footwear regularly. This may be related to the parents’ tendency to provide footwear to children at the age they enroll in school . As age A positive association between family socio-economic status and protective use of footwear among school-age rural children suggests the need for interventions aimed to improve socioeconomic wellbeing of podoconiosis affected families. Family socio-economic status alone does not guarantee regular use of footwear—having adequate resources alone will not ensure optimal preventive actions against podoconiosis. Interventions aimed to address misconceptions and increase motivation to wear shoes are also needed. Health promotion research in behaviors such as physical activity showed that poorer households prioritize available resources for other purposes ,50. ThisA statistically significant association was also observed between adequacy of footwear ownership and protective use of footwear. Children owning few alternative pairs of footwear had less protective use of footwear. This is consistent with previous qualitative studies that reported shortage of alternative pairs of footwear to be an important determinant of footwear use ,14. It iThough the findings presented in this study are of significance, the study is not without limitations. One of the limitations relates to measuring protective use of footwear. These days, researchers use sophisticated technologies to accurately measure routinized behaviors such as physical activity using pedometers, portable electronic or electromechanical devices that count every step a person takes in a day . To dateThe low level of explained variance accounted for by the regression model consisting of family socioeconomic status, adequacy of footwear ownership and interaction term variables implies the importance of examining the role of other factors. In our previous qualitative study, misperception of risk for podoconiosis and perceived barriers to footwear use including uncomfortable footwear, shortage and poor adaptability of footwear for farm activities and sports were reported to negatively affect optimum use of footwear among school-age children . CulturaIncreased adoption of protective footwear is needed to effectively prevent school-age children living in endemic areas from developing podoconiosis and other neglected tropical diseases. Approaches aimed to encourage ownership of multiple pairs of footwear should also consider increasing the socio-economic capacity of families in podoconiosis endemic communities. Livelihood strengthening interventions that provide opportunities for skills development, self-employment, micro-credit and social protection services including educational support for children and access to free or subsidized health care may contribute to socio-economic empowerment of podoconiosis-affected families.S1 Text(DOCX)Click here for additional data file.


Melanoma is a type of skin cancer that often leads to poor prognostic responses and survival rates. Melanoma usually develops in the limbs, including in fingers, palms, and the margins of the nails. When melanoma is detected early, surgical treatment may achieve a higher cure rate. The early diagnosis of melanoma depends on the manual segmentation of suspected lesions. However, manual segmentation can lead to problems, including misclassification and low efficiency. Therefore, it is essential to devise a method for automatic image segmentation that overcomes the aforementioned issues. In this study, an improved algorithm is proposed, termed EfficientUNet++, which is developed from the U-Net model. In EfficientUNet++, the pretrained EfficientNet model is added to the UNet++ model to accelerate segmentation process, leading to more reliable and precise results in skin cancer image segmentation. Two skin lesion datasets were used to compare the performance of the proposed EfficientUNet++ algorithm with other common models. In the PH2 dataset, EfficientUNet++ achieved a better Dice coefficient (93% vs. 76%–91%), Intersection over Union , and loss value (30% vs. 44%–32%) compared with other models. In the International Skin Imaging Collaboration dataset, EfficientUNet++ obtained a similar Dice coefficient (96% vs. 94%–96%) but a better IoU (94% vs. 89%–93%) and loss value (11% vs. 13%–11%) than other models. In conclusion, the EfficientUNet++ model efficiently detects skin lesions by improving composite coefficients and structurally expanding the size of the convolution network. Moreover, the use of residual units deepens the network to further improve performance. Melanoma is a type of skin cancer with high spread characteristics and a mortality rate of approximately 75% . MachineConvolutional neural networks (CNNs) are the most commonly used algorithms in medical imaging –11 and aZhang et al. improved the accuracy of neural network image segmentation using a SENet module with a U-Net encoder . The SENThe research field of automatic prostate segmentation in 3D MR images presents challenges. The lack of exact edges between the prostate and other anatomical structures makes the challenge on accurate boundary extraction. The segmentation is further complicated by the complex background texture and the significant variation in the prostate's size, shape, and intensity distribution. Zhu et al.  proposedMelanoma is a type of skin cancer with high spread characteristics and a mortality rate of approximately 75% . MachineU-Net for segmentation is illustrated in Each upsampling adds a feature map of the corresponding encoding path, thereby reducing the number of feature channels by half. For transposed convolution, the general convolution is reversed, and the feature map obtained using convolution is restored to the pixel space through transposed convolution. The largest corresponding feature map can intuitively understand which features are selected through a convolution operation. The last layer of the network is a 1 × 1 convolutional layer, which can convert the 64-channel feature vector into the required number of classification results. U-Net can perform convolution operations on images of arbitrary shapes. The U-Net encoding path is upsampled four times and downsampled 16 times. Because of four upsampling operations, detailed information, such as that on the edge restoration of the segmentation map, can be obtained, enabling the decoder to determine target details, achieve point-level positioning, and devise decoding paths. The operations also correspond to four upsamplings.In U-Net, low-level and high-level information is combined. After multiple downsamplings of the low-level information, the low-resolution information can provide contextual semantic information of the segmentation target in the entire image, reflecting the characteristics of the target and its relationship with the environment. This feature determines the object category and uses skip connections between the encoder and decoder. The skip connection operation applied to high-level information involves directly passing information from the encoder to high-resolution information decoded at the same bandwidth, which provides more detailed features for segmentation. When low-level information is combined with high-level information, directly supervising semantic features and loss backpropagation is not necessary. The recovered feature map incorporates more low-level information features and features at different scales. Unlike other networks, U-Net uses feature fusion to perform stitching and stitches features together in channel dimensions to form thicker features.The U-Net model for medical image segmentation has the following advantages: (1) The boundaries of medical images are blurred, and gradients are complex. Moreover, more high-resolution information is required. High-resolution information is mainly used for accurate segmentation. (2) The internal structure of the human body is relatively fixed. The distribution of segmentation targets in human images is regular, and the semantics are simple and clear. Low-resolution information is suitable for target recognition. Such information is combined with high-resolution information in U-Net.The SegNet  architecAs depicted in U-Net , SegNet Transfer learning is a machine learning technique where for which the knowledge gained in training one problem is used in the training of another task or domain . In deepThis study proposed EfficientUNet++ that replaced the encoder in UNet++ with two backbone architectures: pretrained Xception  and EffiXception as depicted in As shown in EfficientNet++ was tested on two skin lesion segmentation datasets with a small number of dermatoscopic images in the training set compared with the number of network parameters. Therefore, to improve the performance of EfficientNet++ and overcome the possible overload problem due to the insufficient training set, the following three strategies were used for the segmentation of dermatoscopic images.A standard preprocessing step was performed on the images before delivering them to the network. Initially, an algorithm for grayscale world color constancy was applied to normalize the image's color, as suggested in . This prThe motivation of using the batch normalization layer, dropout layer, and regularisation term in the dense layers is to prevent overﬁtting to the limited training set . In our The Momentum Optimization  was propN is the size of the pixels, pi is the predicted pixels, and yi is the test pixels. The cross-entropy loss examines each pixel one by one and compares the predicted results (probability distribution vector) for each pixel category with the heat-coded label vector. When there are only two categories, a binary entropy loss, called BCE loss, is used and represented as equation  false positives (FP), true negatives (TN), and false negatives (FN). The confusion matrix of TP, FP, FN, and TN is presented in The Dice coefficient is a commonly used indicator for evaluating segmentation result quality. It is mainly used to calculate the Dice distance of the two intervals to segment the similarity of the interval. The range is between 0 and 1. Dice loss is proposed to solve problems arising when the foreground proportion is too small. When the overlapping part of two samples is measured, the indicator ranges from 0 to 1 (where 1 represents complete overlap), which is defined as follows:Intersection over Union (IoU) is a task outputting a prediction range. In order for IoU to be used to detect objects of any size and shape, it is necessary to mark the range of the detected object in the training set image and measure the correlation between the ground-truth and the prediction.The International Skin Imaging Collaboration (ISIC) has expert annotations on international datasets and is used to improve the automatic segmentation of melanoma diagnoses to help reduce mortality . The ISIPH2 is dataset of skin images obtained from the Pediatric Department of Pedro Hispano Hospital in Matosinhos, Portugal . Data arAblation studies are used to analyze the performance of an artificial intelligence system by removing certain components to obtain an understanding of the contribution of that component to the overall system. The term is used by analogy with biology  and, continuing the analogy, especially when analysing artificial neural nets, by analogy with brain ablation procedures . Meyes eThe activation functions were also explored for ablation study. The chosen comparators are mainly the following activation functions: Mish, Swish, SELU, and ReLU . For makAs shown in Figures Five models were trained, and then, tests were performed on 40 and 200 skin lesion images, respectively, after 100 epochs of training. The ISIC-2018 and PH2 datasets also showed that the IoU and Dice scores improve with further increases in datasets and training steps. The ability of the proposed model to learn through experiments with the two datasets was evaluated using the accuracy curve shown in Figures We compared the performance of our proposed method with that of other methods using the PH2 dataset. The results are listed in To verify the effectiveness of the proposed method, we compared the performance of various algorithms when applied to the ISIC-2018 dataset . The resManual segmentation of skin lesion images is time consuming and imprecise. The deep learning image segmentation UNet++ algorithm can be used for the automatic segmentation of medical images; however, because of the density of connections, the number of calculations required is high, so UNet++ cannot accurately segment the locations and boundaries of skin lesions. Automatic lesion segmentation remains a challenge due to the large variation in the appearance of dermoscopic images, and streaks on dermoscopy images usually are difficult to detect because they are not perfect linear structures b] lighting condition, and were subject to nonuniform vignetting . Sample The preprocessing of input images is very helpful in the task of segmentation, which consists of working with grayscale images and normalizing to improve image quality. In the UNet++ model, quality of encoding affects the final segmentation. Due to time and calculation limitations, it is unfeasible to train bespoke models from scratch. In this study, we proposed an improved UNet++ algorithm in which Xception and EfficientNet pretraining is implemented. Using pretrained image networks on the encoder can be useful because pretraining reduces the neural network model training time and can reduce errors. Pretrained models have learned to extract powerful and useful functions from images and use them as starting points for learning new tasks, and they can use pretraining as a benchmark from which to improve existing models. However, UNet++'s dense connection and the memory usage are efficient; meanwhile, the network can avoid vanishing gradient. However, this approach causes excessive irrelevant features passing on the network and the redundant use of computational resources. Therefore, to mitigate feature map explosion in the upsampling path, the dense connections of UNet++ are avoided in the network structure and improved the way to skip connection. The improved UNet++ algorithm can improve accuracy and efficiency in medical image segmentation. We used five deep learning algorithms for comparative experiments and performed image segmentation on the PH2 and ISIC-2018 datasets to verify the effectiveness of the improved method. The results show that the segmentation of the improved UNet++ is superior to that of other algorithms.An effective semantic segmentation model based on deep learning is proposed and validated with two skin lesion dataThe validity of the proposed method is compared with that of four classical models: SegNet , U-Net , UNet++ The proposed method exhibits the strengths from both of EfficientNet and UNet++ featuresThe experiments demonstrated that the robustness of EfficientUNet++ has outperformed other methodsThis work verified that the practicability of the integrated method of UNet ++ and EfficientNetFor modelling the features of melanoma skin lesion, EfficientUNet++ can exploit the advantages of EfficientNet and UNet++, and the performance of the method proposed in this study is verified in both ablation study and 5-fold cross validation. The primary contributions are concluded as follows:Although our model has achieved promising segmentation accuracy in two independent datasets, the lighter colors in lesion areas were not accurately segmented; therefore, our model requires further improvements. In the future, we will attempt to join residual blocks  and SE bManual image segmentation may result in errors and inefficiency. Therefore, an automatic image segmentation algorithm can help doctors to diagnose the size and location of melanoma lesions and reduce medical costs. To improve the UNet++ algorithm, we propose EfficientUNet++. This method combines UNet++ and EfficientNet networks and redesigns skip connections to aggregate features of varying semantic scales at the decoder subnetworks, leading to a highly flexible feature fusion scheme, thereby accelerating network convergence and retaining more edge information. The EfficientUNet++ algorithm structurally expands the size of the convolutional network by simply and efficiently compositing coefficients, and the introduction of residual units deepens the network and thereby improves performance. As a result, the outputs of EfficientUNet++'s PH2 and ISIC-2018 datasets are more accurate than those of other methods. Verification can prove that skin lesions can be well segmented using the improved UNet++. This research can play a vital role in reducing manual interventions and misdiagnoses, improving accuracy and solving related medical image segmentation problems. However, due to the dataset's limitation, the model's capacity to identify melanoma lesions was restricted, and the proposed method does not provide further insight into the prognosis of melanoma lesions that have received attention in recent studies , 70. Rec


Classical galactosaemia (CG) is a disorder of galactose metabolism which results from a deficiency of galactose-1 phosphate uridyltransferase  activity caused by mutations in the GALT gene (NM_000155.3). Patients have absent or barely detectable GALT enzyme activity and present in the first weeks of life with life threatening illness  after the ingestion of galactose from breast milk or infant formula. A lactose-free and galactose-restricted diet is life saving and the only available treatment at this time [Newborn screening for CG by measuring GALT enzyme activity  was intrNewborn screening has historically been implemented with consideration of the ten principles of Wilson and Junger . Some ofClassical galactosaemia is mostly screened by GALT enzyme measurement, often combined with total galactose (TGAL) measurement. Screening will result in the identification of false positive (FP) cases, as has been demonstrated in several reports ,13. It iThe only available treatment at this time is accepted and easily implemented: a life-long lactose-free and galactose restricted diet, which rapidly resolves the illness in the newborn period. It is advised to introduce this diet, which is in infants based on lactose free formula based on soy or a hydrolysate, as soon as the diagnosis is suspected, without awaiting results of diagnostic tests .Depending on the day of screening, most patients will be symptomatic and may already be hospitalized at the time of diagnosis by newborn screening . HoweverNewborn screening often results in the detection of individuals with previously unreported phenotypes and genotypes, for whom the need for treatment and the potential outcomes are unclear. Indeed, in the Netherlands, after the start of CG newborn screening, 14% of the diagnosed patients had a previously unreported phenotype and genotype. These individuals did not demonstrate any symptoms at the time of diagnosis while still being exposed to galactose, and some demonstrated normal metabolite levels after the start of dietary treatment. The recent international guideline for CG recommends dietary treatment in all patients with GALT enzyme activity <10%, and states that there is insuffcient evidence whether patients with 10-15% of GALT enzyme activity need to be treated. In the Netherlands, currently all the patients with enzyme activity below 15% are treated. Future studies on the need for treatment and the outcome of these patients are warranted , 16.A small number of studies evaluating cost benefits with different methods provide contradictory results , 20, 21.Currently newborn screening is performed in 9 European countries: Austria, Estonia (on a research basis), Germany, Greece, Italy, the Netherlands, Spain, Switzerland and Ireland. Two recent papers discussed the appropriateness of galactosaemia newborn screening. Varela Lema et al. (2016) concluded from their systematic review that there was insufficient evidence to establish the appropriateness of CG newborn screening, but that health benefIts could be expected if early diagnosis and treatment is achieved . A CochrThe striking effects of early diagnosis on the morbidity and mortality of patients in the first weeks of life strongly confirm the appropriateness of CG newborn screening, even when taking into consideration the fact that early diagnosis does not prevent long-term complications and the lack of insight into the cost-benefit ratios. However, with the implementation of CG newborn screening, It is of utmost importance to minimize the number of FP referrals and to educate the professionals involved in the treatment that if TGAL is one of the screening parameters newborns on low lactose diets may not be detected by the screening.


Background Central compartment lymph node dissection (CLND) is a part of the surgical management of differentiated thyroid cancer (DTC). Therapeutic CLND is done to address clinically significant central compartment nodes in patients with DTC, while prophylactic CLND is performed in the presence of high-risk features in the absence of clinically significant neck nodes. Removal of thymus—unilateral or bilateral—during CLND to achieve complete clearance of level VI and VII lymph node stations and address thymic metastasis is debatable.Objective The present systematic review was conducted to summarize the evidence, delineating the role of thymectomy during CLND in patients with DTC.Methods Electronic databases of PubMed, Embase, and Cochrane were searched from their inception to July 2020 using keywords—thyroid neoplasms or tumors, thyroidectomy, and thymectomy—to identify the articles describing the role of thymectomy during CLND in DTC. A pooled analysis of surgicopathological outcomes was performed using metaprop command in STATA software version 16.Result A total of three studies and 347 patients—total thyroidectomy (TT) with bilateral thymectomy in 154, TT with unilateral thymectomy in 166, and TT alone in 27 patients with DTC—were included in the systematic review. The pooled frequency of thymic metastasis was a mere 2% in patients undergoing either unilateral or bilateral thymectomy. The routine addition of thymectomy does not result in better lymph node clearance. Unilateral and bilateral thymectomy were associated with high chances of transient hypocalcemia .Conclusion Routine thymectomy is not warranted during CLND, considering minimal oncological benefit and high risk of postoperative hypocalcemia. Thyroid cancer is a leading endocrine malignancy with differentiated thyroid cancers accounting for 90% of cases. GLOBOCAN 2018 documented 567,233 new cases of thyroid cancer and 41,071 deaths annually.There are several inconsistencies among the international guidelines regarding the inferior limit for CLND in thyroid cancer. The American Thyroid Association (ATA) management guidelines, published in 2015, specify CLND to target level VI station lymph nodes.The thymus is anatomically located in the superior mediastinum and is encountered during level VII lymph node dissection. Should thymectomy be done routinely as a part of CLND to achieve good level VII clearance has not been addressed properly in the literature. The rationale of performing thymectomy in CLND is as follows: (a) it permits better lymph node clearance, as the thymus gland, especially its superior horns, lies within the anatomical confines of the central compartment, and (b) it entails extirpation of thymic metastasis if any. However, thymectomy performed as a part of CLND poses a significantly high risk of postoperative hypocalcemia, as the upper poles of the thymus as well as the inferior parathyroid glands share a common embryological origin from the endoderm of III pharyngeal pouch and lie close to each other in the paratracheal area within the domains of surgical boundaries.The present systematic review aimed to analyze the risk-benefit of the routine thymectomy in CLND for DTC. A pooled analysis of previously conducted studies comparing morbidity associated with bilateral versus unilateral versus no thymectomy to determine the optimal extent of CLND was also performed.The systematic review of the literature was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines. The protocol of this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42020186741.A thorough literature search was conducted using the electronic databases of MEDLINE (PubMed), Embase (Ovid), and Cochrane Library (Wiley) of the systematic review. A complete search strategy was developed following a consensus among the coauthors in collaboration with an external expert. The search strategy used variations in keywords—thyroid neoplasms or tumors, thyroidectomy, and thymectomy—found in the title, abstract, or keyword fields to retrieve articles referring to the role of thymectomy during CLND in DTC. Filters (humans and English) were applied to refine the search, and the articles published since the inception until July 2020 were included in the analysis. Single case reports/editorials/commentaries were not included in the review. The abstracts of the articles retrieved were screened for their relevance to our topic of study. The full text of the pertinent articles was obtained and evaluated. The references of these articles were also evaluated to look for any relevant studies. EndNote, version 8  was used to facilitate the search process.Two authors (P.K. and P.K.G.) searched the electronic databases and screened all the titles and abstracts from the selected articles. Any disagreement was resolved by the consensus among the authors. The full texts of the selected articles were analyzed by the three authors . The relevant information was extracted using a predefined data extraction sheet. The information collected included study location, year of publication, study design, sample size, clinicopathological details, and treatment outcomes of the patients included in the study.All the relevant data was entered on the Microsoft Excel sheet and analyzed. A pooled analysis of surgicopathological outcomes was performed using metaprop command in the STATA software version 16.An initial database search of PubMed, Embase, and Cochrane using the stated keywords yielded 74, 127, and 301 articles, respectively. A total of 321 articles were identified after the removal of the duplicates. The search results were narrowed down to 26 after screening the titles. The abstracts of these articles were reviewed and a total of 10 full-text articles were assessed for eligibility after removing all the studies not addressing both the procedures simultaneously. After a thorough evaluation, we found three articlesThe studies included were heterogeneous, concerning the inclusion and exclusion criteria and patient population. A formal assessment of the quality of the studies and publication bias could not be undertaken due to the presence of a few studies. Three studies satisfying the inclusion criteria were included in the present review and have been enlisted inThe average age of presentation of the patients in either of the subgroups of all the three studies was the fourth decade of life. The mean and median ages have been enumerated inThe average tumor size of various subgroups in the three studies analyzed has been enumerated inp = 0.657). Similar results with no statistically significant difference were reported by Khatib et alp = 0.038).p = 0.704). Permanent vocal cord palsy was reported in one patient in the bilateral thymectomy group due to the violation of the recurrent laryngeal nerve. With regard to131I treatment, there was no significant difference in preablation serum thyroglobulin levels between the thymus preservation and bilateral thymectomy groups .The pooled frequency of transient hypocalcemia in unilateral and bilateral thymectomy was 12%  and 51% (95% CI 43%–59%), respectively. The pooled frequency of permanent hypocalcemia in bilateral thymectomy was 5% (95% CI 1%–12%) . Li et The thymus is a specialized lymphoid organ located in the anterior superior mediastinum associated with T-cell maturation and is critical to the adaptive immune system. The presence of a blood thymic barrier restrains a direct contact of unwanted antigens and tumor cells with the thymus and thereby prevents metastasis. However, on precise analysis, structural variation in the cortex and medulla of the organ explains the variable robustness of this barrier, which provides a possibility for metastasis.Moreover, the present review also highlights that routine thymectomy  does not improve lymph node yield in patients undergoing CLND. However, a cervical extension of the thymus is frequently encountered in about two-thirds of children and young adults as a direct continuation of mediastinal thymic tissue.The results of our pooled analysis show that unilateral and bilateral thymectomy was associated with high chances of transient hypocalcemia, albeit the pooled frequency of permanent hypocalcemia was low. Lin et alThyroidectomy performed for carcinoma is a high-risk operation, as the posterior capsule is radically dissected with the gland, placing the parathyroid glands as well as the recurrent laryngeal nerve at higher risk of injury.Therapeutic CLND for nodal metastases in DTC is well-accepted for cN1 disease. However, controversy surrounds its role in cN0 neck, although acceptable results can be achieved with low morbidity by an experienced thyroid surgeon.The main limitation of this systematic review was the limited number of studies addressing the issue of routine thymectomy during the clearance of the central compartment in DTC. Moreover, two of the three studies included in the review were retrospective observational studies generating low-level evidence. One of them included 20 patients with medullary thyroid cancer in their study.This systematic review elucidates that the literature on the role of thymectomy during CLND in patients with DTC is sparse. As the thymectomy during CLND does not confer any additional oncological benefit and is associated with a high risk of postoperative hypocalcemia, thymic preservation must be considered by the operating surgeons, barring the situations involving multiple metastatic nodes close to the thymus and warranting selective thymectomy.


The Yale New Haven Hospital Adler Geriatric Assessment Center is an outpatient consultative service that provides comprehensive assessment of older adults. As elsewhere, at Adler the COVID crisis necessitated a rapid shift in mode of care following a total cessation of in-person visits from late March 2020 to the end of May 2020. While our patients initially preferred telephone visits, video visits as a proportion of total scheduled increased from an average of 6% in the last full week of March to 24% in the last week in May possibly indicating increasing familiarity and comfort with the technology during that time. In addition, while video appointments as a proportion of total scheduled dropped rapidly in June 2020 as face-to-face appointments were reintroduced, we found a steady increase in the proportion of video visits from 3% in the first week of July 2020 to 7% in the second week of February 2021. To test for significance, we ran logistic regression models modelling the dichotomous video-appointment variable as the outcome and week and day of week as continuous variables. We found there was a significant increase in the proportion of appointments delivered over video both during the time when no face-to-face video appointments were allowed  and later in the pandemic . Durbin-Watson statistics were run to ensure that autocorrelation could be ignored. Sensitivity analyses limiting the sample to those with non-cancelled appointments gave similar results. Future analyses will examine patient clinical and demographic characteristics that might influence these trends.


Ferroptosis is a new form of regulatory cell death characterized by iron-dependent and intracellular lipid peroxidation. Ferroptosis can be divided into two stages. The first stage is iron overload in the cell, which generates a large amount of reactive oxygen species through the Fenton reaction, and the second stage results from an imbalance of the intracellular antioxidant system. Excessive phospholipid hydroperoxides cannot be removed by reduction reactions, as this could destroy the cell membrane structure and interfere with mitochondrial function, eventually leading to ferroptosis of the cell. Cardiovascular diseases have gradually become the leading cause of death in modern society. The relationship between ferroptosis and the occurrence and progression of cardiovascular disease has become a research hotspot in recent years. In this review, we summarize the mechanism of ferroptosis and its specific role in cardiovascular disease. Cell death is an important cornerstone for maintaining the balance of development and homeostasis of the body. There are two main types of cell death: regulatory cell death (RCD) and non-regulatory cell death . NonreguCardiovascular disease is one of the most threatening diseases to human health today. Cardiovascular diseases mainly include coronary atherosclerotic heart disease, myocardial ischemia/reperfusion injury (IRI), and heart failure (HF). Severe coronary artery stenosis can lead to IRI after recanalization, HF after myocardial injury, and even ischemic cardiomyopathy . TherefoIron is an essential trace element for the human body; it participates in the formation of a variety of proteins, including hemoglobin, myoglobin, and ferritin, and various redox reactions in cells. It is not only involved in the above-mentioned biological processes but is also the most important initiation and promotion factor for ferroptosis. Under physiological conditions, the complex and precise mechanism of iron homeostasis regulation ensures that iron concentration in the cell remains stable and prevents intracellular iron overload from triggering the Fenton reaction, which in turn leads to ferroptosis . The regFerroportin (Fpn), also known as SLC40A1, is the only protein known to export nonheme iron to the outside of the cell. Fpn is widely distributed on the surface of duodenal epithelial cells, macrophages, and hepatocytes. The main source of iron in the human body is hemoglobin iron recovered by macrophages phagocytosing senescent red blood cells. The macrophages then transport the iron into plasma through Fpn. Simultaneously, the duodenum absorbs iron ions from food into the human body through Fpn  Ganz, 2. The lacUnder physiological conditions, ferric iron exported from cells binds to transferrin, which is a protein secreted primarily by the liver and transports iron to the bone marrow and other tissues. Conversely, if transferrin in plasma decreases, iron binds to albumin and anions to form non-transferrin-bound iron (NTBI), which can be absorbed by tissue cells, causing iron overload . Yu et aFerritin is an intracellular protein that oxidizes ferrous iron to ferric iron to avoid the occurrence of Fenton reaction, composed of light subunits (Ftl) and heavy subunits (Fth1). Ferritin is an inhibitor of ferroptosis, knockdown of Fth1 expression significantly increases the occurrence of ferroptosis . FerritiNovel regulators of iron homeostasis have been described. Sun et al. found that phosphorylated heat shock protein beta-1(HSPB1) acted as a negative regulator of ferroptosis by reducing iron uptake by cells and the production of lipids. Transphosphorylation of HSPB1 increases ferritin expression and reduces TfR1 expression. HSPB1 is expressed in a heat shock factor 1(HSF1) dependent manner. Protein kinase C (PKC) regulates the phosphorylation of HSPB1 and indirectly regulates ferroptosis . The HSFNot only does abnormal iron homeostasis regulation play an important role in ferroptosis but ferroptosis also requires the dysregulation of the intracellular antioxidant system. Yang et al. found that in ferroptosis cells, reduced glutathione (GSH), one of the most important endogenous antioxidants, was depleted, leading to the inactivation of glutathione peroxidase 4 (GPX4) . GSH-depSelenoproteins are unique and rare proteins among a large protein family with unique physiological functions. Selenocysteine, which is not one of the 20 proteinogenic amino acids, is involved in the synthesis of GPX4. Selenocysteine ensures the need for unexpected antioxidant capacity . Moreove− is an amino acid reverse transporter located on the surface of the cell membrane, which can transport cystine outside the cell and glutamate inside the cell in a 1:1 ratio across the membrane. Therefore, System Xc− activity is closely related to intracellular GSH content and GPX4 function. Ferroptosis is induced if system Xc− activity is inhibited by erastin treatment  and activating transcription factor 4 (ATF4), which have been confirmed to be related to the function of the system Xc− . In the − . Interesroptosis . There atosis   .−. High extracellular glutamate concentrations inhibit the activity of system Xc−, whereas elevated intracellular glutamate concentrations have the opposite effect. If cells are treated with erastin or sorafenib, the intracellular labile iron level will increase and subsequently induce ferritinophagy  that downregulated the expression of SLC7A11 and SLC3A2 expression  . DHODH iThe Fenton reaction triggered by abnormal iron metabolism leads to an increase in ROS, and an antioxidant system represented by GPX4 can eliminate ROS toxicity to cells, but the link between the two is lipid metabolism within the cell. Phospholipids are a component of cell membranes. ROS generated by the Fenton reaction tends to react with phospholipids (PL) to form hydroperoxy-phospholipids (PLOOH), which are the main elimination target of GPX4 . PhosphoThe preferred substrate for oxidation is phosphatidylethanolamine containing arachidonic acid (AA) and adrenal acid (AdA), and ACSL4 has a strong selectivity for AA-CoA and AdA-CoA . ACSL4 pMDM2 and MDMX are negative regulatory proteins of the P53 gene. However, their role in ferroptosis has nothing to do with P53, but with lipid metabolism . During Coronary artery disease refers to a series of diseases with angina pectoris as the main symptom caused by the inability of the coronary blood supply to meet the metabolic needs of the myocardium. Coronary artery disease is a general term for a series of diseases that include coronary atherosclerotic heart disease, coronary artery spasm, and myocardial bridge—of which coronary atherosclerotic heart disease accounts for the vast majority. Coronary atherosclerotic heart disease is a disease characterized by hyperplasia of atherosclerotic plaques. In the early stage of atherosclerosis, endothelial cell ability to resist blood cell attachment is reduced under stimulation of high levels of low-density lipoprotein (LDL) , hyperteEndothelial dysfunction also causes the lipid composition of the blood to gradually accumulate under the inner membrane. To remove deposited lipids, especially LDL, monocytes, macrophages, and smooth muscle cells will phagocytose lipids to form foam cells. As lipids and foam cells accumulate and lipid deposition under the inner membrane, a fatty streak gradually forms in the intima, which are the early lesions of atherosclerosis . HoweverAs plaque size increases, coronary lumen stenosis reduces blood supply to cardiomyocytes and presents as angina pectoris. A potentially more lethal process may occur if the plaque thrombus suddenly occludes the coronary arteries and blood flow is drastically reduced. The produces a lack of collateral circulation compensation and can cause acute coronary syndromes (ACS), including unstable angina (UA) and acute myocardial infarction (AMI) . AccordiAnother vital pathogen that causes the occurrence of ACS is plaque erosion, which is responsible for up to about a third of ACS incidence. Compared to plaque rupture, plaque erosion has smaller necrotic cores, a higher number of smooth muscle cells, and thicker fibrous caps . In factAs early as 30 years ago, Sullivan proposed the iron hypothesis, which pointed out that iron accumulation in atherosclerosis increases the risk of cardiovascular disease . The iroThe discovery of ferroptosis may explain the biological effects of iron accumulation. A recent study found that the SIRT1 autophagy axis in foam cells can inhibit ferroptosis induced by excessive iron . By addiRegulating macrophage ferroptosis and foam cells derived from macrophages has become a novel target for the treatment of coronary atherosclerotic heart disease. Iron is a necessary condition for macrophage ferroptosis, and the most important pathway for macrophage iron regulation is the hepcidin-FPN axis . HepcidiSmooth muscle cells are the cellular components of the fatty streak and the most important source of extracellular matrix secretion in plaques. Unlike macrophages, smooth muscle cell death interferes mainly with plaque vulnerability by affecting the components of the fibrous cap on the surface of the plaque . Smooth in vitro model of oxidative stress, and found that smooth muscle cells produce ferroptosis and promote calcification deposition -induced endothelial cell dysfunction . When endisorder . Zinc oxdisorder . FerroptCoronary artery subtotal occlusion or complete thrombosis-induced occlusion is likely to cause the onset of AMI. When AMI occurs, the blood supply to myocardial cells is interrupted and the cells are in a state of severe hypoxia. Unfortunately, the rapid improvement in blood supply in the ischemic myocardium can aggravate the degree of myocardial injury. Ischemia-reperfusion is one of the main mechanisms of myocardial injury (IRI) caused by AMI, and can be responsible for up to 50% of the infracted myocardial area . The preDiabetes is one of the most important risk factors for AMI. The incidence of myocardial ischemia in patients with diabetes is significantly higher than in the normal population . If diab2+ to mitochondria, which inhibits cardiomyocyte apoptosis. Moreover, Lip-1 can strongly eliminate ROS and significantly reduces the ferroptosis of myocardial cells (Existing studies have confirmed the important role of ferroptosis in myocardial ischemia-reperfusion. Therefore, suppressing ferroptosis during ischemia-reperfusion may become a new therapeutic strategy to protect the myocardium. Before reperfusion, Feng et al. administered Lip-1 to mice, a potent specific inhibitor of ferroptosis, which reduced the level of VDAC1 and increased the activity of GPX4 . Lip-1 aal cells . TherefoSubsequent to insufficient blood supply and myocardial IRI caused by coronary atherosclerotic heart disease, a considerable number of patients exhibit a reduction in the number of myocardial cells and present severely damaged cardiac contractile function . HF is aThe noncoding RNA circSnx12 can up-regulate the downstream target miR224-5p, and can combine with the 3′UTR region of FTH1 to down-regulate its expression . In addiWith the development of basic research related to ferroptosis, combining ferroptosis with clinical applications has gradually become the next important research direction. The clinical application of ferroptosis-related targets is currently in its infancy. The current clinical research results may enlighten us several potential intervention targets in clinical applications. Since it is difficult to collect ferroptosis indicators in clinical practice, most studies focus on iron metabolity-related indicators, such as serum iron, serum ferritin, transferrin and soluble transferrin receptors. These targets with translational medicine potential could be key to controlling the progression of cardiovascular disease in the future.Since Sullivan’s hypothesis, people have focused on the relationship between serum iron and atherosclerotic diseases . The incElevated levels of ferritin and hepcidin were highly associated with a higher risk of new-onset heart failure in women but not in men . AlternaIn recent years, research on the occurrence of ferroptosis and disease has gradually improved. More and more mechanisms related to the regulation of ferroptosis have been discovered, such as the FSP1-CoQ10-NADPH axis and DHODH antioxidant system. But there are still many unsolved mysteries. To date, the major research directions have focused on ferroptosis and tumors. By studying the regulatory pathways that promote tumor cell ferroptosis, we can provide new directions to prolong the survival of tumor patients. In addition, degenerative diseases of the nervous system, liver disease, and kidney disease are also hotspots in ferroptosis research. Due to the high incidence and mortality of cardiovascular diseases, these have gradually become the number one killer of human health. However, our understanding of the pathogenesis and treatment of cardiovascular disease is limited. After the discovery of apoptosis, researchers have confirmed its important role in cardiovascular disease. With the improved understanding of regulatory cell death, other modalities of regulatory cell death, such as necroptosis and pyrolysis, are believed to occur in cardiovascular diseases. Research on ferroptosis and cardiovascular disease is still in its infancy, and most existing studies have confirmed the existence of ferroptosis in cardiovascular disease. As we gradually deepen our understanding of the role of ferroptosis, this mechanism will become a potential breakthrough point in the treatment of cardiovascular disease.Research on the mechanism of ferroptosis is a prerequisite for clinical treatment and application. The iron hypothesis has been a controversial issue for many years since it was put forward. The recent discovery that iron metabolism disorder is the first step in ferroptosis may be a strategy to quell the controversial issue of iron hypothesis. According to previous theories, the antioxidant system with GPX4 at the core is the only anti-ferroptosis mechanism. The FSP1-CoQ10-NADPH axis and the DHODH antioxidant system suggest that ferroptosis may be regulated by a variety of independent antioxidant mechanisms. The chemical structure of phospholipids is also a target for regulating ferroptosis. The structure of the phospholipid bilayer membrane of different ratios of fatty acid composition gives cells different degrees of vulnerability to ferroptosis. The discovery that conjugated and nonconjugated fatty acids have different ferroptosis characteristics has provided a novel insight for a strategies for intervention, that is, in the future, it is possible to alter the proportion of fatty acids by optimizing dietary intake by the population as a strategy to achieve the goals of prevention and treatment.in vitro cell-based experiments and animal studies, and there is almost no verification of the pathological development process mentioned above in human samples. Further verification of the role of ferroptosis in human specimens will be the goal of the next stage of research. Arrhythmia-related diseases have so far been the blind spot in ferroptosis studies. In the future, exploring whether ferroptosis is related to arrhythmia may be part of the research prospects.In terms of basic research, ferroptosis has been investigated in terms of coronary atherosclerotic heart disease progression to IRI and even HF. Existing research is limited to In clinical application, iron metabolism indicators can only predict the risk of AMI or initial heart failure in a limited manner. Since iron metabolism-related indicators are interfered by many other factors in the human body, more independent predictors of ferroptosis need to be discovered in the future.In summary, current research has preliminarily shown that ferroptosis is closely related to a variety of cardiovascular diseases. Regulating ferroptosis will be one of the most promising emerging targets to improve the prognosis and the survival rate of cardiovascular diseases.


Significance: Longitudinal tracking of hemodynamic changes in the breast has shown potential for neoadjuvant chemotherapy (NAC) outcome prediction. Spatial frequency domain imaging (SFDI) could be suitable for frequent monitoring of shallow breast tumors, but strong sensitivity to superficial absorbers presents a challenge.Aim: We investigated the efficacy of a two-layer SFDI inverse model that accounts for varying melanin concentration in the skin to improve discrimination of optical properties of deep tissue of the breast.Approach: Hemodynamic changes in response to localized breast compression were measured in 13 healthy volunteers using a handheld SFDI device. Epidermis optical thickness was determined based on spectral fitting of the model output and used to calculate subcutaneous optical properties.Results: Optical properties from a homogeneous model yielded physiologically unreasonable absorption and scattering coefficients for highly pigmented volunteers. The two-layer model compensated for the effect of melanin and yielded properties in the expected range for healthy breast. Extracted epidermal optical thickness was higher for higher Fitzpatrick types. Compression induced a decrease in total hemoglobin consistent with tissue blanching.Conclusions: The handheld SFDI device and two-layer model show potential for imaging hemodynamic responses that potentially could help predict efficacy of NAC in patients of varying skin tones. Breast tumor vasculature tends to be disorganized and exhibit abnormal flow,,,Due to the significant cost and large footprint of DOT instrumentation, various less expensive and more portable approaches have also been developed. The DOSI technology consists of combined frequency domain and broadband continuous-wave NIRS and utilizes a handheld probe that is moved across the breast to create a 2D image. However, the need to acquire multiple point measurements prevents imaging of hemodynamic responses to perturbations. Portable approaches to dynamic breast imaging include the P-scan handheld continuous-wave NIRS device,We have chosen to pursue a handheld breast imaging method based on spatial frequency domain imaging (SFDI). Because SFDI can be built inexpensively at small form-factor, we envision this device to be suitable for frequent measurement during therapy, including in the patient’s home. SFDI is a wide-field diffuse optical imaging method capable of quantifying absorption and reduced scattering coefficients. Reflectance of spatially modulated illumination is used to characterize the spatial frequency dependent attenuation of light by the tissue, from which optical properties can be obtained by fitting to a theoretical model of light propagation within the tissue. In the simplest implementations, this light propagation model includes the assumption of tissue homogeneity, based either on the standard diffusion approximation,A known drawback of SFDI is limited penetration depth, on the order of Various approaches have been developed to account for the presence of skin pigmentation. Spatial frequency domain spectroscopy (SFDS) utilizes broadband spatially modulated illumination detected by fiber coupled spectrometer rather than a camera, trading spatial information for spectral resolution. SFDS leverages the differential penetration depth of the visible and NIR wavelength ranges to provide estimates of layer-specific chromophore concentrationsA different approach introduced by Tabassum et al.2An SFDI-based handheld breast imaging device was used to record hemodynamic response to localized breast compression in 13 healthy subjects of varying skin tone. A two-layer inverse model was employed in which the product of top layer (epidermis) absorption coefficient and epidermal thickness was estimated based on goodness of fit of calculated subcutaneous absorption with hemoglobin extinction coefficients.2.1We previously developed a handheld SFDI device for breast imaging, described previously.Sinusoidal illumination at spatial frequency Calibration images were taken from a polydimethylsiloxane reference phantom of known optical properties, to obtain 2.2Human subject testing was approved by the Carnegie Mellon Institutional Review Board under protocol STUDY2015_00000046. Thirteen healthy volunteers were recruited through the Pitt+Me online portal.The experimental setup is shown in 2.32.3.1,,To simulate human skin, a two-layer model was developed in which the top layer mimicked the non-perfused epidermis, and the bottom layer represented the subcutaneous tissue. The chromophores contributing to absorption are melanin in the epidermis layer, and HbO and Hb in the subcutaneous layer. The thickness and scattering coefficient, 2.3.2Optical properties from SFDI were extracted based on a two-layer look up table, which was created using MC simulations using the virtual tissue simulator (VTS) software . VTS utilizes the method described by Gardner and VenugopalanFor a specific Additionally, a conventional homogenous SFDI LUT was generated for comparison purposes. Using a homogeneous one-layer geometry, all other properties were maintained, with 2.3.3a priori knowledge of the participant-specific epidermal thickness, direct estimation of The purpose of this optimization procedure is to produce the values of Additionally, this optimization procedure does not attempt to fit for To determine MI for each human subject volunteer, Using the two-layer LUT described in Sec. 2.3.4To test this optimization algorithm, several MC forward simulations were performed representing eight skin pigmentation levels, In addition to the above simulations, in which 2.4After optimizing the value of MI for each subject from their baseline measurement, the hemodynamic changes induced by compression of the breast tissue were calculated. This was achieved by calculating 33.1in vivo data and the optimization procedure described in Sec. To demonstrate the effect of the epidermis layer absorption on diffuse reflectance, four Monte Carlo LUTs at varying values of 3.2The forward simulation inputs are summarized in in vivo data, detailed below. For simulated data, adjusted MSE yields the same estimate of MI as unadjusted MSE for all cases.These results illustrate that the point of minimum MSE slightly over-estimates the ground truth value of MI. This overestimation is reflected in the computation of underlying tHb and Error quantification for simulations where 3.3in vivo breast data. This trend, along with the effect on estimated tHb and The effect of varying assumed MI on the goodness of fit of hemoglobin concentrations to Similar to the trend observed in the simulated data, increasing assumed MI produced lower estimates of tHb and higher estimates of Based on the apparent bias against high values of Hb, an adjusted MSE was introduced, in which MSE is divided by the corresponding percentage of Hb at that MI,  is used to calculate baseline optical properties for all of that subject’s measurements. Baseline optical properties are also calculated for every measurement using the homogeneous LUT. Box plots of tHb, Optical properties derived from the homogenous model reveal separation between groups not only for tHb and tissue saturation but also for scattering power and amplitude. Adjusted MSE-based correction brings the two groups closer together for each property considered. For the layered model results, the mean and standard deviation of tHb concentration was found to be 3.4Supplementary Material. The red lines in The tHb response to localized tissue compression with our handheld SFDI device was found to be consistent with tissue blanching and reperfusion, with tHb decreasing upon initiation of compression onset and recovering quickly after compression release. The response in The overall variability of the slope of the To illustrate the range of The ROIs were further analyzed in terms of the Fitzpatrick score of the subject they were obtained from. Again splitting the group into Fitzpatrick scale I, II, III, IV and V and VI, we found the ROIs trending down in 4,,Here, we presented the application of a two-layer LUT inverse model to measurements of hemodynamics in the healthy breast, using a handheld SFDI instrument. The value of MI  was estimated by an optimization procedure based on examining the fitting error obtained when calculating hemoglobin concentrations from measured optical properties. This model requires the assumption of the thickness of the epidermis layer, however we demonstrate reasonable accuracy in quantifying subcutaneous properties in simulations with epidermal thickness differing significantly from the model assumption. This is the case because diffuse reflectance was primarily influenced by the product of thickness and An additional weakness of this model is the simplicity of the two-layer design. The bulk layer was termed “subcutaneous” though it includes both dermal and subcutaneous tissues. When used to measure breast tumors, compression can be used to reduce the depth of the lesion from the surface, but significant partial volume effects will still be present from healthy tissue covering the tumor, including the microvasculature of the dermis.In simulated data for which the ground truth bulk-layer absorption is derived from only two chromophores, the error in fitting simulated When MI was optimized by this method, higher Fitzpatrick scores resulted in higher estimates of MI. All subjects Fitzpatrick IV and lower received an optimal MI value of 0 or near-zero, indicating the absence of any light-absorbing pigment in the epidermis, which is unrealistic. Our results indicate that the method has low sensitivity to low levels of absorption in the epidermis. However, all participants in these group exhibited physiologically reasonable baseline values of tHb and While some measurements exhibited a steadily decreasing trend in 5The two-layer inverse model and inexpensive SFDI setup reported here show potential for imaging hemodynamic responses for the prediction of NAC in patients of a variety of skin tones. More work is needed to further validate the estimation of epidermal absorption using our introduced method of optimization based on hemoglobin fitting error.Click here for additional data file.


Gynecological and breast cancers still remain a significant health problem worldwide. Diagnostic methods are not sensitive and specific enough to detect the disease at an early stage. During carcinogenesis and tumor progression, the cellular need for DNA and protein synthesis increases leading to changes in the levels of amino acids. An important role of amino acids in many biological pathways, including biosynthesis of proteins, nucleic acids, enzymes, etc., which serve as an energy source and maintain redox balance, has been highlighted in many research articles. The aim of this review is a detailed analysis of the literature on metabolomic studies of gynecology and breast cancers with particular emphasis on alterations in free amino acid profiles. The work includes a brief overview of the metabolomic methodology and types of biological samples used in the studies. Special attention was paid to the possible role of selected amino acids in the carcinogenesis, especially proline and amino acids related to its metabolism. There is a clear need for further research and multiple external validation studies to establish the role of amino acid profiling in diagnosing gynecological and breast cancers. Carcinogenesis is a complex process that affects many pathological pathways. These changes can be investigated on different levels: genes (genome), gene expression (transcriptome), products of mRNA translation (proteome) as well as effects of action of those products (metabolome), as illustrated in Gynecological cancers and breast cancer constitute four out of the eight most common cancers in women globally a and greoriginal studies;studies focused on changes in amino acid profiles in patients with gynecological cancers  and breast cancerarticles in English.The authors conducted a systematic, comprehensive literature search using the PubMed database of the studies published from January 2010 to May 2021 with the Medical Subject Headings (MeSH) search terms. The search was conducted using the terms presented in reviewsmeta-analysesletterscommentsarticles unrelated to the topicstudies on cell lines or animalsThe excluded articles were:We screened the titles from the search results for eligibility. Then, each abstract was screened if eligibility was not clear from the title. The last selection was performed on the full text of the selected papers on which a decision could not be made based on the abstract. When studies did not report all the required information but cited relevant studies instead, the related articles were manually screened to check if the additional articles met the eligibility criteria. Finally, additional articles were added to refine this review. The characteristics of the retrieved articles were summarized in 1H-NMR) was used in seven studies  and nuclear magnetic resonance (NMR) . Mass sp studies . Other aThe analyses in metabolomic studies can be targeted or untargeted. Targeted approaches aim to identify and measure a pre-defined metabolite group, while untargeted metabolomics focus on the identification and relative quantitation of measurable small molecules in a sample with no prior hypothesis . In receThe technological progress in metabolomic profiling opens opportunities to discover new cancer biomarkers and elucidate cancer-driven alterations at the metabolomic level. In biomarker research, three key definitions can be distinguished: analytical validity, clinical validity and clinical utility . AnalytiValidation of the proposed cancer markers is undoubtedly a crucial step in metabolomics studies. Validation of a biomarker candidate on an independent patient cohort or a subset of the first set of samples  increases the reliability of the study results. Among the articles discussed in this review, 14 studies included the external validation step and proved the performance of the proposed markers . The majIn metabolomic studies, we can distinguish two alternate approaches: the top-down and the bottom-up approach . The firOver the years there has been a number of studies attempting to (1) investigate the human metabolome, (2) find cancer biomarkers, and (3) describe the molecular background of carcinogenesis, that focused on amino acids within various biological matrices. The two most popular matrices used for metabolomic analyses in the reviewed studies were serum (18 studies) ,42,43,47Among the reviewed papers concerning amino acids, a few studies have been conducted using urine ,51,69 asThe role of amino acids in cancer growth and progression is well-established in scientific literature. The analysis of tumor tissue allows observation of the target alteration directly at the tumor site and enables the detection of molecules that could be elusive after secretion into biofluids, the same evaluation of amino acids directly in the tissue emerge as promising matrix for studies on cancer. Seven out of 44 reviewed studies investigated amino acids in tissue samples ,38,43,49The need to search for new clinically useful methods of early detection of gynecological cancers prompts scientists to investigate more unconventional matrices. The most important cause of this trend is looking for matrices with non-invasive sample collection, independent of confounding factors but providing relevant information about the metabolome complementary to serum, plasma, or urine.In one study included in the review, research was conducted using cervicovaginal fluid in the search of biomarkers of inflammation, precancerous lesions, or EC . It was The most surprising matrix used in the reviewed studies on amino acids were the nails of breast cancer patients . This maThe goal of this review was to summarize relevant studies on metabolite-based markers of gynecological and breast cancers. The most widely analyzed cancers in terms of changes in amino acid profiles are BC, EC and OC . The avaAmino acids are an important group of metabolites. Their potential as biomarkers has been highlighted in many studies ,74,75,76The research conducted so far has pointed at various amino acids potentially indicative of cancer, but the evidence is inconclusive. This may be due to using different biological matrices for research, the use of different analytical techniques, or differences in patient groups between studies. Moreover, the diagnostic methods are very often based on the panels of biomarkers consisting of various compounds rather than a single biomarker. Thus, it seems that the biomarker research should not focus on one specific compound but rather take into consideration changes in metabolic pathways involving many different compounds often linked by various relationships.Glutamine is one of the most frequently mentioned amino acids among the proposed biomarkers of breast cancer, as it was previously known that cancer cells consume glutamine to support self-sustained growth and aggressiveness. In the study by Yang et al. , the decAmino acids are promising biomarkers of cervical cancer as they have a critical role in cancer growth and are identified among the most differentiating compounds in many metabolomic studies on this tumor. According to Khan et al.  aspartatOne of the most frequently proposed differentiating amino acids in EC studies was asparagine ,59,102. Methionine was identified by Ihata et al. , Bahado-In the study by Troisi et al. , one of According to the study by Ihata et al. , in EC pWhat is interesting in the study of Audet-Delage et al.  is that Tryptophan mentioned in a couple of studies ,13,17 isAlanine ,22,24,31Among 20 DNA-encoded amino acids, proline appears to be unique due to its chemical structure. It is a cyclic and nonessential amino acid containing a pyrrolidine ring which provides its chemical stability . CurrentProline anabolism and catabolism are mainly regulated by the enzymes D1-pyrroline-5-carboxylate (P5C) reductase (P5CR) and proline dehydrogenase/proline oxidase (PRODH/POX) being transferred between mitochondria and cytoplasm. The relationship P5C-proline is known as a proline cycle discovered by Phang and colleagues  serving Of critical importance in cancer research could be the collagen-prolidase-proline axis since recent studies demonstrated several reports for a regulatory role of proline in apoptosis . In termIn the context of cancer cells, the demand for sucbstrates for DNA biosynthesis is increased since cells proliferate rapidly and in an uncontrolled way. It demands a remarkable quantity of building blocks for protein and DNA synthesis. Therefore, cancer cell reprograms its function to decrease the rate of collagen biosynthesis and make proline available for PRODH/POX activity . ProlineIt is a well-documented fact that the conversion of proline to P5C generates reactive oxygen species (ROS) or ATP . The proSince cancer cells exhibit an unlimited capacity for invading adjacent tissues, blood vessels, and distant organs, there is a need to inhibit metastases formation. Recently, it has been found that proline metabolism is involved in this process through the upregulation of PRODH/POX expression . AnotherThe presented review summarizes the available literature on changes in amino acid profiles in gynecological and breast cancers. It is evident that cancer growth and progression affect various metabolic pathways and thus alter the levels of certain amino acids in biological fluids and/or tissue. The studies of the metabolome of cancer patients explain the process of carcinogenesis and enable researchers to understand certain mechanisms of cancer progression. As amino acids are crucial for nucleotide synthesis, they could be promising cancer biomarkers. However, due to the complexity of metabolomics alterations it is most probable that a whole panel of substances, rather than a single compound, could serve as a discriminating tool. The potential applications of these markers or panels of markers are innumerable: from screening and early detection, through pre-treatment assessment of the disease type and risk-group stratification, predicting the response to chemotherapeutic agents, to monitoring the effects of treatment. Effective models based on the novel biomarkers could become powerful tools in the hand of clinicians and could contribute to early disease detection and individualization of treatment, hopefully positively affecting the prognosis of patients in the long term. Unfortunately, the results of various studies are sometimes inconclusive, and this is probably due to the dynamic and complex changes of amino acid levels in the body as well as many confounding factors. In should be noted that the studies discussed in the review employed different inclusion criteria for cancer patients and different control groups. Moreover, the research involved the analysis of various biological matrices that implemented various metabolomic methods and strategies offering different specificity and sensitivity. Further research in the field and multiple external validation studies are needed to establish the role of amino acid profiling in diagnosing gynecological and breast cancers. One of the crucial gaps that needs to be filled is elucidating proline anabolism and catabolism to better understand mechanism underlying reprogrammed metabolism in cancer cells and propose new cancer markers and targets for therapies.


This study examined the impact of the age-friendly environment on the association between cognitive ability and the attitude towards gerontechnology. The participants were 277 Korean young-old age 65 through 74. The data were collected by an online survey conducted in February 2021. The dependent variable was the attitude towards gerontechnology sum of perceived usefulness, perceived ease of use, and perceived adaptability . The independent variable was the cognitive ability of participants to report on their own. The moderating variable was the age-friendly environment sum of physical, service-side, and cultural conditions. Multiple regression analysis was conducted to determine the relation between cognitive ability and the attitude towards gerontechnology. The moderating effect was then analyzed using PROCESS macro and bootstrapping. Results show that cognitive ability has a positive effect on the attitude towards gerontechnology, and the age-friendly environment has softened its effectiveness. When participants were living in a more age-friendly environment, their attitude toward gerontechnology was less affected by their cognitive ability. However, when age-friendly environmental condition scores above 62 (out of 75), the environmental aspect did not affect the association between cognitive ability and attitudes to gerontechnology. This study suggests that the age-friendly environment can narrow the disparity of the attitude towards gerontechnology depending on the cognitive capability levels under certain conditions. Regarding the attitude towards technology may affect the actual use, the possibility of environmental help is meaningful.


Kidney disease is a health condition affecting a high number of patients with an estimated worldwide prevalence of 10% .The close relationship between the kidneys and the cardiovascular system has long been recognized. While the main cause of death in chronic kidney disease (CKD) patients is related to major cardiovascular events, acute or chronic heart failure may also result in kidney damage  play in the cardiorenal syndrome pathology through modulating inflammation and oxidative stress. Though more studies are required, the current evidence points out for a role of CaMKs in CKD-associated cardiac injury. Finally, Lowenstein and Nigam, present an integrative view of the multi-organ effects of uremic toxin accumulation when kidney function is compromised with special focus on the role of uremic toxins and drug transporters in inter-organ communication (intestine-liver-kidney-brain) and inter organismal communication, for example the host with the microbiome.Three review papers addressed the mechanisms linking CKD and cardiovascular complications. Xiao et al. studied the effect of the treatment with oxymatrine (OMT) in renal fibrosis induced by type 2 diabetes in mice. Following 8 weeks of treatment with OMT, diabetic mice presented decreased renal expression of fibrotic markers and increased expression of E-cadherin as an epithelial marker. This protective effect was mediated via upregulation of the inhibitor of differentiation-2 which would bind and inhibit Twist-mediated epithelial to mesenchymal transition. This mechanism was corroborated in tubular epithelial cells cultured in high glucose. Another strategy to target renal fibrosis was tested in the article by Rui-Zhi et al. who showed that the Astragalus mongholicus Bunge and Panax notoginseng formula and Bifidobacterium administration has functional and structural renal protective effects in a mouse model of CKD induced by 5/6th nephrectomy through the inhibition of inflammatory M1 macrophages via Mincle/NfkB pathway inhibition in the kidney. Similarly, mincle/NFkB pathway was also inhibited in the intestine, leading to the restoration of the intestinal barrier in CKD mice and a recovery of the intestinal flora similar to the one present in normal mice. Thus, by inhibiting inflammation in both, the kidney and the gut this treatment reduced renal and intestine injury induced by CKD, highlighting the role of inflammation in intestine changes observed during CKD.A major complication of diabetes is diabetic kidney disease, for which the therapeutic options are limited  at dialysis initiation was found to be a predictor for chronic leukopenia and thrombocytopenia, while chronic liver disease and high serum ferritin levels (>800 mg/dL) were risk factors for chronic thrombocytopenia. In patients in maintenance HD, Zhang Y. et al. showed that moderate to severe tricuspid regurgitation occurs in 62.6% of the patients and that sodium, decreased fractional shortening and increased right atrium diameter were independently associated to moderate to severe tricuspid regurgitation. Zhang Q. et al. showed that increased arterial stiffness determined by pulse wave velocity together with high plasma galectin-3 levels predicted mortality and cerebral and cardiovascular events in stable HD patients. These studies are important as proof of concept that these parameters might be used to predict adverse cardiovascular events in CKD patients and further confirmation is required in larger cohorts.Hematological alterations other than anemia are a less explored complication observed in hemodialysis (HD) patients for which the risk factors need to be known by healthcare providers to deliver an accurate management. In a single-center study, Lu H. et al. present an observational retrospective single-center study to assess the prevalence of hyponatremia in hospitalized patients and its related adverse outcomes. The authors found a prevalence of hyponatremia of 32.5% and was associated with higher hospital costs and length of stay and in-hospital and 30-day mortality.Burek et al. the authors created an in vitro model to gain insights into the kidney-brain crosstalk during disease. They showed that hypoxic and glucose starved tubular cells co-cultured with brain microvascular endothelial cells (BMEC) on a transwell system and with the addition of uremic toxins induced changes in the expression of blood brain barrier (BBB) transporters, receptors and tight junction proteins in BMEC. This changes in BBB efflux and influx transporter expression were validated in brain capillaries isolated from mice after 24 h of ischemic AKI induction.Kidney disease is often associated to neurological disorders. While the mechanisms remain elusive, ischemic AKI has been associated with a long-term risk of stroke and dementia  (Vijayan and Humphreys, The contributions to this Research Topic illustrate the complexity of the communication between the kidneys and other organs in health and disease conditions, providing new therapeutic and diagnosis tools, and contributing to mechanistic insights into the connection of kidney disease and distant organ disorders. The review articles also highlight that further efforts are needed in order to gain complete understanding of the molecular processes involved in these pathological connections, which will help to propose novel therapeutic avenues for kidney disease and its associated distant organ injuries.All authors contributed to the editorial, approved the submitted version, and performed editorial assignments for this Research Topic.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.


We have reported herein the data to understand the nature and number of non-covalent interactions that stabilize the structures of the thiophene clusters. In addition, we have also provided the optimized Cartesian coordinates of all the structures of the investigated thiophene clusters. Initially, the geometries have been generated using the ABCluster code which performs a global optimization to locate local and global minima structures of molecular clusters. The located geometries have been optimized at the MP2/aug-cc-pVDZ level of theory using Gaussian 16 suite of programs. To understand the nature of non-covalent interactions, we have performed a quantum theory of atoms in molecules (QTAIM) analysis on all the structures of the thiophene dimer. Furthermore, the QTAIM analysis has been performed also on the most stable structure of the thiophene trimer and tetramer. We have used the AIMAll program to perform the QTAIM analysis. The data reported in this paper contains the critical points, the bonds paths and their related properties, for each investigated structures. Besides, the data contains the optimized Cartesian coordinates of all the investigated structures of the thiophene clusters. This can be use for any further investigations involving thiophene clusters. For further information and analysis, the reader is referred to the original related research article . Specifications Table•We have reported the critical points, bond paths and their related properties for the structures of the thiophene dimer. These data will be useful to understand the nature and number of non-covalent interactions that stabilize the structures of the thiophene clusters.•The optimized Cartesian coordinates of the thiophene clusters will save computational time for all further investigations involving thiophene clusters.•Using this data one would be able to determine all non-covalent bonds in thiophene clusters and therefore, will provide proper understanding of non-covalent bonds in aromatic and heterocyclic molecular clusters.•The optimized Cartesian coordinates of the structures of the thiophene clusters will be useful for investigations involving solvation processes and/or ions transfer in thiophene solvent.•The data provided in this paper will be of great interest for investigations using quantum cluster equilibrium theory to compute the thermodynamics properties of the liquid thiophene.1name), the two atoms involved in the bond critical point (Atoms), the electron density at the bond critical point (Ellipticity), the electron kinetic energy density at the bond critical point (K) and the difference between the bond path length with a corresponding geometric bond length (BPL-GBL_I). In the supplementary material, we have also reported the Cartesian coordinates of all the investigated structures of the thiophene dimer, trimer and tetramer as optimized at the MP2/aug-cc-pVDZ level of theory.We have reported in 2tight option of the optimization for high accuracy. To ensure accurate location of stable minima, frequencies calculations have been also performed at the same level of theory. All the located structures have positive frequencies highlighting their stability. After optimizations, some structures have been optimized to the same isomer. The redundant structures have been eliminated from the final structures reported in the supplementary material.The most important task in exploring the potential energy surfaces (PESs) of molecular clusters is the location of possible stable structures. Thus, to obtain the Cartesian coordinates of the structures reported in the supplementary material, we explored thoroughly the PESs of thiophene clusters from dimer to tetramer using classical molecular dynamics as implemented in ABCluster After locating the structures, we used their Gaussian formatted checkpoint files to perform (to generate the data related to) the quantum theory of atoms in molecule (QTAIM) analysis. The QTAIM analysis is performed to provide data necessary to understand the nature of non-covalent bondings in thiophene clusters. QTAIM analyses the topology of the electron density, Alhadji Malloum: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Visualization. Jeanet Conradie: Resources, Visualization, Writing – review & editing, Supervision, Funding acquisition, Project administration.The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article.