Background: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that presents with higher-order visual dysfunction with relative sparing of memory and other cognitive domains, and it is most commonly associated with Alzheimer's disease pathology. There is a lack of data regarding the presentation of PCA to non-cognitive specialists. Therefore, we collected clinical data from neuro-ophthalmologists regarding the presentation of PCA to their practices and compared data to published cohorts and a published survey of cognitive specialists.Methods: Members of the North American Neuro-Ophthalmology Society Listserv (NANOSnet) were invited to complete an online, retrospective, chart-review data-entry survey regarding their patients with PCA, and REDCap was used for data collection.Results: Data for 38 patients were entered by 12 neuro-ophthalmologists. Patient mean age at presentation was 67.8 years, and 74% of patients were women. Difficulty reading was reported at presentation by 91% of patients, and poor performance on color vision, stereopsis, and visual field testing (performed reliably by 36/38 patients) were common findings. Most patients who were treated were treated with donepezil and/or memantine.Conclusions: Compared to published data from cognitive specialists, patients presenting to neuro-ophthalmology with PCA were more likely to be older and female and have a reading complaint. Reliable visual field testing was the norm with homonymous defects in the majority of patients. The neuro-ophthalmologist plays an important role in diagnosing PCA in older adults with unexplained visual signs and symptoms, and future studies of PCA should involve multiple specialists in order to advance our understanding of PCA and develop effective treatments. Posterior cortical atrophy (PCA) is a progressive, neurodegenerative syndrome that is characterized by higher-order visual dysfunction with initial relative sparing of memory and other cognitive functions . The preInvestigations of disorders that are relatively rare and/or poorly recognized, such as PCA, face many challenges and require collaboration across institutions for true progress to be made in understanding clinical presentations, risk factors, and pathophysiology, as well as for the development of treatments . Many paThe recent consensus classification criteria for PCA for research purposes, set forth by an international, multidisciplinary working party as noted , have acA recent study of the longitudinal cognitive and imaging profiles from 117 patients with PCA, compared to typical AD, provided new insights into the PCA presentation and course within a tertiary dementia center in the United Kingdom and two other centers in Spain and the United States . NonetheThe utility of studying atypical presentations of AD should not be underestimated given that atypical AD represents ~25% of the more than 5 million people living with AD in the United States . ArguablGiven this background, we aimed to describe the clinical presentation of PCA to neuro-ophthalmologists using patient data collected across multiple institutions and community practices by a secure, online data registry, and compare findings to published studies of PCA and to survey data from the ISTAART Atypical AD PIA cognitive experts.Research Electronic Data Capture), which is a secure web application that is compliant with Health Insurance Portability and Accountability Act, 21CFR part 11, FISMA , and international ethical standards. Posterior cortical atrophy was defined using the criteria of Tang-Wai et al.  members. The survey was designed following a literature review to identify the salient signs and symptoms previously reported for the presentation of PCA, and participating neuro-ophthalmologists were instructed to gather patient data via retrospective chart reviews. The patient data were captured using the REDCap platform  or neurologists (six) with subspecialty training in neuro-ophthalmology. The patient cohort was 74% female with a mean age of 67.8 ± 9.70 years and a median age of 69 years with a range of 45–81 years. Mean and median age for men was 69.6 ± 9.2 years and 71 years, respectively , and mean and median age for women was 67.1 ± 7.5 years and 64 years, respectively . Twenty-one percent of patients reported a history of traumatic brain injury (TBI), and 19% reported a family history of dementia of the AD type.The frequency of symptoms at presentation is noted as percentages in The frequency of signs reported at presentation is noted as percentages in Thirty-five of 38 patients were reported as having magnetic resonance (MR) imaging of the brain, and two had computed tomography (CT) brain imaging. Of the reported findings on neuroimaging, generalized atrophy was most commonly found, and only one imaging report specifically noted the predominance of PCA. However, review of the brain imaging revealed that 34 of 38 CT brain scans by MR and CT had posterior atrophy . Five were normal. A total of 12 patients underwent fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging, and occipitoparietal hypometabolism was described in 50% (6/12), occipitoparietotemporal hypometabolism in 33% (4/12), and mesiotemporal hypometabolism in 17% (2/12). Cerebrospinal fluid (CSF) was collected on three patients, and two had testing for phosphorylated tau (p-tau) and amyloid beta 42 (Abeta42) levels, both of which are valid and sensitive markers for AD pathology. An abnormal CSF ratio of p-tau/Abeta42, in a manner consistent with AD pathology, was noted for both patients. One had slightly elevated CSF protein.subjective measures, and two of six reported response as unknown, one of six noted the medication was not tolerated (donepezil), one of six noted subjective improvement with donepezil, one of six reported subjective improvement with galantamine and memantine, and one of six noted no benefit with memantine.Twenty patients received treatment with medications that included one or more of the following: donepezil, rivastigmine, galantamine, and memantine. Ten patients were treated with donepezil (50%) and nine with memantine (45%). Rivastigmine and galantamine were less commonly used, and six patients were trialed on two or more of the medications noted. Only six respondents answered whether there was a response to medication treatment as determined by p < 0.05) negative correlations for limb apraxia (r = −0.47) and left–right disorientation (r = −0.44). Thus, with older age, patients were less likely at presentation to have limb apraxia and left–right disorientation, which represent functions that, in general, localize to the dominant posterior.Correlation analyses between age and signs and symptoms revealed statistically significant  or “common” (25–75%) 5% or “co, which iMemory complaints were commonly reported in our cohort (77%), while the survey of cognitive experts indicates that the frequency of anterograde memory deficit is similar to the frequency of alexia, either “rare” 0–25%) or “common” (25–75%) 5% or “co, and intIn regard to signs on examination, visual field defects 89%), color plate testing abnormalities (88%), and stereovision impairment (86%) were very common. Visual field defects were reported in the previously published expert survey as either “rare” 0–25%) or “common” (25–75%) at presentation . As noted, however, a history of amblyopia was not surveyed, and a recent population-based study found a prevalence of amblyopia is ~7% in people between 55 and 65 years old . Recent Brain imaging was most commonly reported as “generalized atrophy,” and it behooves the clinician to review the imaging for signs of posterior greater than anterior atrophy and consider PET-FDG imaging, as findings indicated posterior predominant atrophy in nearly all cases. In regard to treatment, although medications are commonly prescribed, there are no known effective pharmaceutical therapies for the PCA syndrome.The major limitation of this study is that it is a retrospective chart review of clinical data that were not collected using a standardized assessment protocol.The presentation of PCA to the neuro-ophthalmologist in this cohort is slightly different than the presentation reported in published cohorts and reported by cognitive specialists. Symptoms and signs at presentation are comparable, but patients presenting to the neuro-ophthalmologist with PCA are more likely to be older than 65 years, female, and with concerns about reading. Furthermore, visual field defects, pseudoisochromatic color vision test abnormalities, and abnormal stereopsis were very common, and visual field tests were performed reliably by nearly all patients. Consistent with other investigations of PCA, left-sided, homonymous visual field defects were the most common field abnormality. The frequency of these abnormal signs likely reflects the unique evaluation performed within a neuro-ophthalmology clinic and reveals potential to be useful markers of the PCA syndrome.Neuro-ophthalmologists play a critical role in diagnosing PCA and can contribute to a better understanding of the syndrome. Future investigations of PCA should focus on longitudinal, standardized data collection from multiple institutions and centers, with involvement of a wide spectrum of subspecialists, including those practicing in the community. Early recognition and a better understanding of progression of the PCA syndrome will benefit patients, families, and care partners and contribute to our understanding of disease mechanisms and development of new therapies.RRID:SCR_003445.REDCap, The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.The studies involving human participants were reviewed and approved by the OHSU Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JO and WH contributed to the conception or design of the work and oversaw the statistical analysis. VP, JO, and WH analyzed and interpreted the data, and wrote and revised the manuscript. JW, JF, LA, MM, RE, WC, AL, BF, RT, DK, and JC contributed to the acquisition of data for the work. All authors contributed to manuscript read and approved the submitted version.The views expressed are those of the author and do not reflect the official policy or position of the US Air Force, Department of Defense, Defense Health Agency, or the US Government. 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.


Results. A high prevalence of Firmicutes and Bacteroidetes was found in all the fecal samples. Significant dissimilarities in the microbiota composition were found on the basis of MD adherence and PA levels (p = 0.001). At the genus level, Streptococcus and Dorea were highly abundant in overweight/obese individuals, Ruminococcus and Oscillospira in participants with lower adherence to MD, and Lachnobacterium in subjects with low levels of PA (p = 0.001). A significantly higher abundance of Paraprevotella was shown by individuals with lower BMI, lower MD adherence, and lower PA levels (p = 0.001). Conclusions. This study contributes to the characterization of the gut microbiome of healthy humans. The findings suggest the role of diet and PA in determining gut microbiota variability.Background. This cross-sectional study aimed to explore the microbial composition of the gut and its possible association with the Mediterranean diet (MD) after adjusting for demographic and anthropometric characteristics in a sample of healthy young Italian adults. Methods. Gut microbiota, demographic information, and data on adherence to MD and physical activity (PA) habits were collected in a sample of 140 university students  with a mean body mass index (BMI) of 22.4 ± 2.8 kg/m Firmicutes and the Gram-negative Bacteroidetes [Firmicutes/Bacteroidetes (F/B) ratio has been observed to change with the nutritional status, age, and gender [Recent evidence has shown that gut microbiota, depending on its composition, may influence human health and diseases ,2 and throidetes . Howeverd gender ,5,7,8,9.d gender ,11.Bifidobacterium and Lactobacobacillus, which are typically health-related [Diet and physical activity (PA) are likely to play a role—in particular, diet is a fundamental factor in determining which nutrients gut microbes can use for their biological processes, and the metabolic products of those processes may have important impacts on health and disease . In part-related . MD seem-related ,15,16. T-related ,18.A deeper understanding of the characteristics associated with gut microbiota composition in healthy people is necessary to improve knowledge about its role in physiological and pathological processes. Thus, the present study aimed to explore the bacterial composition of fecal samples and its possible association with dietary and PA habits in a sample of healthy young Italian adults. In particular, the BMI and adherence to MD patterns were used as indicators of diet, while weekly activities were used to assess the habitual levels of PA.The study protocol was approved by the institutional review board of the University of Rome “Foro Italico” (number CAR 10/2018) and tested in a previous pilot study . StudentParticipants were asked to report through a questionnaire their age, gender, weight, height, and particular diet regimens , which did not imply exclusion. Intercurrent chronic diseases, pregnancy, food intolerances, concomitant infections (and the associated use of antibiotics and probiotics), or gastrointestinal surgical procedures in the 3 previous months were also investigated and represented exclusion criteria. The 9-items questionnaire developed by Martínez-González et al. and the short version of the International Physical Activity Questionnaire (IPAQ) were used to assess the dietary habits and the habitual PA levels of the students, respectively ,21. The ® TC-PLUS thermocycler . Following amplification, 5 μL of PCR product from each reaction was used for agarose gel (1%) electrophoresis to confirm amplification. The final concentration of cleaned DNA amplicon was determined using the Qubit PicoGreen dsDNA BR assay kit  and validated on a Bioanalyzer DNA 1000 chip . Libraries were prepared using the MiSeq Reagent Kit Preparation Guide . Raw sequence data was processed using an in-house pipeline that was built on the Galaxy platform and incorporated various software tools to evaluate the quality of the raw sequence data . All datasets were rigorously screened to remove low-quality reads . Demultiplexing was performed to remove PhiX sequences and sort sequences; moreover, to minimize sequencing errors and ensure sequence quality, the reads were trimmed based on the sequence quality score using Btrim  [®): the taxonomic database used was the Illumina-curated version (May 2013 release of the Greengenes Consortium Database) [A fecal swab  was given to each participant, together with the instructions for the collection of a stool sample; participants were asked to deliver the swab on a planned day within two hours since collection. Samples were then stored at 4–8 °C in a refrigerated container and were taken within 24 h to the laboratory of the University of Rome “Foro Italico”, where they were processed with a previously validated protocol for DNA extraction from fecal traces . Feces wrimming) . OTUs (oatabase) . The rawA descriptive analysis was carried out on the collected information. Weight and height values were used to calculate the BMI. Age, BMI, adherence to MD, and levels of habitual PA were expressed as mean ± SD and ranges; numbers and percentages of participants for each gender and BMI category as defined by the World Health Organization standards  were alswww.mothur.org) and R ) with packages “ggplot2” and “vegan” (R Core team 2013). The R package was employed for comparative analyses of taxonomic and functional microbiota composition. Heatmaps and clustering analyses were based on the Pearson’s correlation as a measure of the distance and Ward’s method using the METAGENassist platform [Relative abundances of community members were determined with rarefied data and summarized at each taxonomic level. The proportion of the gut microbiome at each taxonomic rank, such as phylum, order, class, family, and genus, was determined using the RDP classifier and the Greengenes Database. The standard pipeline for 16S rDNA amplicon analysis revealed that the bacteria fell into 29 phylotypes (similarity level = 97%). Briefly, the relative abundance of the bacterial community was determined on 29 phylotypes  × 100). The subsequent mathematical analyses excluded the 24 rarest phyla—that is, those with a relative abundance below 0.1 % in all the samples. A total of 23,388,649 sequences were generated from 140 samples. The number of sequences for each sample ranged from 42,072 to 437,525, leading to the identification of 630 OTUs defined at 97% identity. Alpha and beta diversity were calculated using EstimateS software at a level of 97% sequence similarity. Regarding alpha diversity, the Shannon index and equitability index at the species level were computed . Principplatform .t-test was used to compare the bacterial diversity and relative abundance of the main bacterial phyla and genus  of samples from participants with different BMI  and levels of MD adherence. ANOVA with a Bonferroni post hoc test was employed to evaluate differences among participants grouped by habitual PA levels and to compare lifestyle subgroups obtained by merging MD adherence and PA. The statistical significance of factors potentially contributing to compositional differences among microbiota samples was tested also with the PRIMER software (version 7) by using the nonparametric permutation Analysis Of Similarity (ANOSIM) function and the default setting [p < 0.05 was considered statistically significant. Data were analyzed with IBM SPSS version 25 for Windows .Student’s  setting . In ordeAbout 450 undergraduates attending classes were invited to take part in the study. Of a total of 244 (54.2%) students who initially agreed to participate, 140 (57.3%) completed the questionnaire, consigned the fecal swab on the planned date, and fulfilled the inclusion criteria .Firmicutes (61.6 ± 14.6) and Bacteroidetes (30.7 ± 13.3)  .Firmicutes, and Bacteroidetes relative abundances and F/B ratios between the BMI and MD score groups and among the PA groups, with corresponding p-values. No significant differences in variability nor in the phyla relative abundance were found.R = −0.011, p = 0.5). In the regression analyses, only the male gender was significantly associated with the Shannon index  −0.08, confidence interval (CI) 95% −0.16–−0.01) and with the F/B ratio .In line with these results, also, the ANOSIM test yielded no significant dissimilarity for the BMI groups . The dissimilarity among the PA groups emerged from the principal component analysis, as shown in R value = 0.350, p = 0.001).The global structure of the gut microbiota composition, as well as grouping patterns based on the MD score or PA level, are shown in Merging declared lifestyles, we obtained subgroups defined by the MD score and PA level. In the comparison of the abovementioned parameters among these lifestyle subgroups, no significant differences were detected . The BonBacteroidetes and Prevotella genera are the most represented in all fecal samples . However, no significant difference was detected between the MD score groups.Plotting the correlation between the genera and adherence to the MD, an influence of the diet on the structure of the microbiota could be detected, although not strong in terms of absolute values . BacteroStreptococcus and Dorea genera were highly represented in overweight/obese individuals, while Ruminococcus and Oscillospira were abundant among participants with lower adherence to MD. The Lachnobacterium genus was more abundant in subjects with low levels of PA. Furthermore, it is possible to observe some overlapping in these profiles. In particular, significantly higher amounts of Megasphaera, Dialister, and Lachnobacterium were found in overweight/obese and low-active subjects; a significantly higher abundance of Paraprevotella was shown also by individuals with lower BMI, lower MD adherence, and lower PA levels. The post-hoc Bonferroni test showed significant differences in genera abundance between the low PA group and the others.This study provides data on the composition of the gut microbiota in a Mediterranean population of young adults with different habits regarding MD and PA.Firmicutes and Bacteroidetes as prevalent phyla in the gut microbiota of healthy humans and further support the a role for diet and PA in determining the variability of the gut microbiota. Indeed, significant dissimilarities in fecal microbiota compositions were found between the MD groups and among the PA groups.The results confirm the higher prevalence of Firmicutes and Bacteroidetes abundances were observed on the basis of the BMI classification, as reported by Peters et al. [No significant differences in s et al. . As for s et al. ,35,36. Is et al. , we did Streptococcus genus was highly abundant among overweight/obese participants, so as the Dorea and Dialister, which were also mainly represented among low-active individuals [Dorea and Dialister were found to be related with insulin secretion and fasting blood glucose, suggesting their role in type 2 diabetes development in overweight-obese individuals [Oscillospira was higher in subjects with a low adherence to MD patterns [Lactobacillus and Lactococcus genera, were more represented in individuals who reported a higher adherence to the MD. This may be related to the dietary polyphenols, such as those present in olive oil, that represent substrates for Lactobacteria, mainly Lactobacillus strains, that are known to contributee in the healthy maintenance of the gut microbiota balance by modulating the oxidative status of the intestinal barrier, the inflammatory processes, and the immune response [Lachnospira was more represented among individuals with higher adherence to the MD, while Paraprevotella was more represented in those with lower MD scores. The literature reports that vegetable-based diets tend to correlate with the amount of short-chain fatty acids (SCFA), which are produced by gut bacteria through dietary fiber fermentation and have fundamental effects on the immunity, metabolism, and inflammation processes of the host [Lachnospira among Firmicutes, so as Prevotella among Bacteroidetes, seem to be involved in the fermentation of fibers, leading to a higher SCFA production. Even if the abundance of Firmicutes is generally associated with a higher intake of animal-associated foods, several members of this phylum were associated with SCFA production and were reported to be more abundant in individuals with higher adherence to the MD patterns and higher consumption of vegetables [Nevertheless, at the genus level, several important differences were highlighted in our sample. In particular, as previously reported, the ividuals ,38. Intepatterns . Lactic response . Lachnosgetables ,39,40,41Prevotella abundance and adherence to the MD pattern. Otherwise, the abundance of Paraprevotella genus was found to be significantly higher in the group with lower MD adherence, so as in less-active people, in accordance with previous studies [Ruminoccoccus was found to be higher in subjects with a lower level of adherence to MD, and this is in line with the work of Martinez-Medina et al., showing an association between this genus and the consumption of a diet rich in saturated fat and sugars [Megasphaera genus was found to be more abundant in low-active subjects, in accordance to the findings from Liang et al., who reported a higher abundance of this genus in lower-level athletes in comparison with higher-level ones [Lachnobacterium in low-active participants is a novel observation that needs to be explored in depth. Interestingly, indeed, we observed several significant differences in genera abundance in the inactive group respect to the others, underlining a possible influence of physical activity in the presence of Lachnobacterium within the microbiota composition.Our results did not show any correlation between  studies ,42. Diff studies . Furtherd sugars . The Megvel ones . The higThe analysis of biodiversity indexes and F/B ratio did not show any statistical significance among the different lifestyle subgroups. This could be due to the small sample size. Larger studies should be performed to verify these findings. In addition to the size of the sample, this study presents other limitations. First of all, the BMI, adherence to the MD, and the PA levels were calculated on the basis of self-reported information, and this could have led to inaccuracy or bias. Furthermore, we used a short and easy questionnaire to assess the MD adherence to facilitate the compliance of participants, but this did not allow us to perform a detailed analysis related to the quality and the quantity of nutrient intakes, e.g., fibers or animal proteins. However, our study offers an additional description of the microbiota composition in young adults from a Mediterranean population in association with their lifestyles and further studies are needed to characterize in depth the gut microbiota biodiversity in relation to several individual, social, and behavioral factors.This study is a contribution to the characterization of the gut microbiome of healthy young Italian adults. It provides a picture of the relative abundance of the main bacterial phyla in the human gut and suggests the influence of diet and PA on the gut microbiota composition. From the perspectives of preventive medicine and public health, the results of this study underline the importance of promoting healthy behaviors in the population.


The results show a significant, inverse relationship between breastfeeding rates and childhood obesity prevalence at the county level, p < 0.01. There is also a significant, inverse relationship between the number of CLCs and the number of all professional LSPs and childhood obesity rates at the county level, p < 0.01. Thus, the availability of breastfeeding support is significantly related to breastfeeding rates and inversely related to childhood obesity rates across Pennsylvania.Childhood obesity is a global public health issue. As the prevalence of childhood obesity continues to rise, identification of potential interventions by public health policy makers, and health care providers is imperative. Breastfeeding, the most optimal method of infant feeding, has been demonstrated to protect against childhood obesity. Lactation support providers (LSPs) play a key role in providing education, care, and support to families considering a feeding choice. Access to professional lactation care increases breastfeeding initiation, exclusivity, and duration rates, regardless of the credential that the LSP holds. The aims of the current study were to examine the relationship between childhood obesity and breastfeeding rates in Pennsylvania (PA) counties; to examine the relationship between geographic access to professional LSPs in PA counties and breastfeeding rates; and to examine the relationship between geographic access to professional LSPs and childhood obesity in PA counties. Data were collected on 617 professional LSPs in 67 PA counties. There are 608 Certified Lactation Counselors (CLCs) and 144 International Board Certified Lactation Consultants (IBCLCs) in PA. County-level breastfeeding rates, childhood obesity rates, and the number of CLCs and IBCLCs were tested for significance at the  Obesity is a global public health crisis and is strongly correlated with chronic health conditions such as diabetes, cardiovascular disease, and high blood pressure. Among children and adolescents aged 2–19 years, obesity rates are on the rise . The CenInterventions to reduce childhood obesity are multi-faceted and must include several components. Among these interventions, breastfeeding—a behavioral variable—has been shown to decrease the risk of childhood obesity and is inversely associated with weight gain velocity and BMI among infants –7. WhileDespite the evidence that breastfeeding is the optimal feeding method for infants, breastfeeding rates remain low across the U.S. According to the CDC's 2018 Breastfeeding Report Card, among infants born in 2015 in the United States, 4 out of 5 (83.2%) started to breastfeed, but just over half (57.6%) were breastfeeding at 6 months, and only about one-third (35.9%) continued breastfeeding to 12 months . When paThe United States Breastfeeding Committee (USBC), the American College of Obstetricians and Gynecologists (ACOG), and the CDC recognize Certified Lactation Counselors (CLCs) and International Board Certified Lactation Consultants (IBCLCs) as professional breastfeeding supporters –19. HoweInformed by this evidence, the aims of the current study were: to examine the relationship between childhood obesity and breastfeeding rates in PA counties; to examine the relationship between geographic access to professional LSPs in PA counties and breastfeeding rates; and to examine the relationship between geographic access to professional LSPs and childhood obesity in PA counties.This is a cross-sectional, observational study using retrospective data.PA is estimated to have a population of 12.81 million according to projections from the 2010 U.S. Census Bureau data. This makes PA the sixth most populous state in the country. 8.9 million residents live in urban areas of the state and 2.7 million residents live in the rural areas of the state. As of July 1, 2018, 81.8% of the population in PA identified as White, 12% identified as Black or African American, and 7.6% identified as Hispanic or Latino .According to the PA Department of Health, 16.8% of children in grades K-6 during the 2017–2018 school year were considered obese . Among cAccording to the most recent publicly available data, there are 608 CLCs and 144 IBCLCs in PA. With 137,682 live births in 2017, this indicates that there are 4.42 CLCs per 1,000 births and 1.05 IBCLCs per 1,000 births in the state –27.We measured the distribution of CLCs and IBCLCs, county level breastfeeding rates, and county level childhood obesity rates across PA. Data were collected from multiple sources. The obesity rates of children in grades K-6 were published by the Pennsylvania Department of Health in September 2019. The percent of live births to mothers who breastfed in PA was published in February 2018 by the PA Department of Health . The totThe number of CLCs in PA was obtained on December 2, 2019 from the Academy of Lactation Policy and Practice (ALPP) . CLCs weTo understand the relationship between childhood obesity and breastfeeding in PA counties, we ran a two-tailed significance test at the 0.01 level and a bivariate Pearson's correlation. We graphed the linear relationship on a scatter plot. To understand the relationship between geographic access to CLCs and childhood obesity by PA county, we ran a two-tailed significance test at the 0.01 level and a bivariate Pearson's correlation. We graphed the linear relationship on a scatter plot. Further, we examined the relationship between geographic access to CLCs and breastfeeding rates by PA county by running ANOVA tests to test for significant differences in the number of CLCs by PA county and the percentage of births to mothers who breastfed at the 0.05 level. This analysis was repeated to examine the relationship between all professional LSPs and breastfeeding rates by PA county. Results were mapped to demonstrate geographic access, or lack thereof, to LSPs across the state. To understand the relationship between professional lactation support and childhood obesity by PA county, we ran a two-tailed significance test at the 0.01 level and a bivariate Pearson's correlation. We graphed the linear relationship on a scatter plot. All data analysis was conducted using IBM SPSS Statistics version 26.0 .r(66) = −0.395, p < 0.01  = −0.526, p < 0.01  = 0.277, p < 0.05 (r(66) = 0.307, p < 0.05  = −0.567, p < 0.01  requires insurers to provide coverage of breastfeeding supplies and support services . As someStructural barriers, such as a lack of Baby-Friendly designated hospitals, may also have an effect on breastfeeding initiation and continuation rates , 41. TheSeveral limitations to this study exist. First, the current study only examines geographic access to CLCs and IBCLCs and breastfeeding rates in PA. There is no data included to analyze access to La Leche League Leaders, WIC peer counselors, breastfeeding educators, doulas, lactation educators, or any other LSP in the community. The influence of breastfeeding support of any kind on breastfeeding rates should not be understated.The IBCLC data were collected using publicly available data from the ILCA and USLCA online search databases, which are membership organizations. If an IBCLC is not listed as a provider in their county on the ILCA or the USLCA websites, they were not included in the total number of IBCLCs per county. A preferred data source using per county counts from the International Board Certified Lactation Consultant Examiners (IBLCE) was not made available for this research.The current study utilizes retrospective data to assess the relationship between childhood obesity prevalence, breastfeeding rates, and geographic access to professional lactation support. Due to the nature of the available data, potential confounding variables were not controlled for. The strength of the current study and its results validate the need for a future, prospective study on this subject where potential confounding variables can be controlled.Finally, many LSPs may hold their LSP credential, but may not be actively working in that role. These individuals were counted as a LSP in PA, but may be working in a different role, with limited interaction between themselves and breastfeeding families.The facilitation of breastfeeding and assisting families in reaching their breastfeeding goals often requires support beyond the immediate postnatal period. Lactation support, counseling, and education provided by a CLC or an IBCLC is just one of many factors contributing to a successful breastfeeding experience.We examined the relationship between breastfeeding rates, childhood obesity, and breastfeeding support from a CLC and from all professional LSPs in PA counties. Clearly, available breastfeeding support is significantly related to an increase in breastfeeding rates and a decrease in childhood obesity rates across PA. This analysis can be replicated in other states to increase equitable access to lactation support and counties in PA can use this blueprint as a strategy to increase breastfeeding rates and decrease rates of childhood obesity.All datasets generated for this study are included in the article/supplementary material.Ethical approval for this study was not required in accordance with local legislation and national guidelines. No human studies are presented in this manuscript. This retrospective study involved the counts of individuals in the public arena using only publicly available or accessible records without contact with the individual/s. The current research is based on a review of published/publicly reported literature.AB and EM: conceptualization. AB, EM, and NL: data curation, methodology, and writing—review and editing. EM: formal analysis and software and writing—original draft.The authors declare the following areas of interest: the authors hold the professional LSP credentials, CLC, and IBCLC. One author was employed by the Academy of Lactation Policy and Practice , one author was employed by the Healthy Children Project, Inc. (an organization that provides training for both the CLC and IBCLC examination preparation), and one author holds the credential ANLC and is a lactation consultant in private practice in PA.


Background: Different antinuclear antibody (ANA) patterns have been associated with the presence of cancer, while other are typically seen in autoimmune diseases. This study aims to investigate the association between ANA and cancer, focusing on patients with ANA with a nucleolar indirect immunofluorescence (IIF) pattern.Materials and Methods: ANA patterns and positivity of antibodies against nuclear antigens (NA), in particular those responsible for a nucleolar ANA pattern and/or associated with systemic sclerosis  were analyzed and correlated to an internal database of patients with cancer.Results: The study included 15,728 patients who had an ANA analysis, 386 patients who had immunodot analysis for antibody/ies against/to specific NA and 15,701 patients diagnosed with cancer. The presence of ANA with a nucleolar pattern showed an increased relative risk  for an associated cancer. Anti-Scl70 and anti-RNAP-III were associated with cancer in 15 and 14%, respectively. The presence of ANA with a homogeneous & speckled (HS) pattern was significantly associated with the absence of cancer (p < 0.01). Patients with a HS pattern were found to have a lower relative risk  of having cancer compared to those with other patterns.Conclusions: Larger studies are needed to investigate which particular antibody/ies against/to specific NA is responsible for the association between nucleolar ANA and cancer, but anti-Scl70 and anti-RNAP-III, which is frequently associated with the presence of anti-RNAP-I, are good candidates to explain this association. Patients with a nucleolar pattern might be considered for cancer screening, in particular if they have anti-Scl70 and anti-RNAP-III antibodies. Autoantibodies against proteins located in the nucleus are called antinuclear antibodies (ANA). ANA can be detected efficiently and sensitively by indirect immunofluorescence (IIF) when suspecting an autoimmune disease (AID). Antigen specific tests usually follow positive ANA tests to give more information on the specific targeted nuclear antigens (NA) .In IIF, ANA can display different nuclear patterns depending on the targeted antigen. These patterns were recently defined by the International Consensus on ANA Patterns (ICAP) . Anti-nuIn clinical practice, the presence of high titers of ANA raises the suspicion of an underlying AID. Additionally, several studies have shown the association of ANoA, historically linked to SSc and myositis, with malignant disease –8. OtherDespite the association of ANA with malignant disease, different studies have shown that patients with ANA had a more favorable cancer outcome when compared to patients negative for ANA, possibly explained by more vigorous activation of the immune system fighting against the malignant cells –20.This retrospective study aims to investigate the relationship between the presence of different ANA patterns, antibody/ies against/to specific NA and the presence or outcome of cancer.Patients tested for ANA by IIF and for antibody/ies against/to specific NA by immunodot in the University Hospital of Geneva's immunology and clinical allergology laboratory were analyzed and compared to a database of all patients who presented at the same center diagnosed with cancer according to the ICD-10 code, between 2010 and 2016. Patients tested for ANA or by immunoblot but not included in the latter database were considered to not have cancer.Patients who had positive ANA exhibiting different IIF aspects in two separate analyses  or have been tested once positive and once negative during this time, were subsequently excluded in order to obtain a cohort without ambiguous IIF pattern.Immunodot results of 10 specific antigens , known to possibly elicit a nucleolar ANA pattern or to be positive in SSc, were further analyzed.For patients with a nucleolar pattern, as well as those with a HS pattern, medical charts were studied in order to confirm the cancer diagnosis and analyze the survival rate. Ethical approval was obtained from swissethics (study no. 2017-02046) in accordance with the World Medical Association's Declaration of Helsinki.Our laboratory has accreditation by the Swiss Accreditation Service on the basis of the relevant international standards: ISO/CEI 15189. ANA detection was performed by IIF technique using HEp-2  substrate slides and FITC anti-human IgG conjugate . Serums were tittered from 1/80 to endpoint and results were expressed as the last positive dilution. ANA titer ≥1/160 were considered positive. The ICAP classification was gradually introduced in our laboratory only in 2016. The term HS, which still sometimes is seen without an association with anti-DFS70/LEDGF antibodies, was used in our study to describe both the dense fine speckled (AC-2) and other patterns with a speckled nuclear staining associated with a stained metaphase plate.According to an internal algorithm, antigen specificity was tested in the presence of ANA with nucleolar pattern at a titer ≥1/320 and in patients suspected to have SSc by the treating physician with the EUROLINE SSC Profile (Nucleoli) immunodot  and scanned with CanoScan Lide 100. Antibodies against Scl-70, CENP A, CENP B, RP11 (RNAP-III), RP155 (RNAP-III), fibrillarin, NOR-90, Th/To, PM/Scl-100, PM/Scl-75, Ku, Ro52/TRIM21 were tested and analyzed with EUROLineScan software. Intensity values above 50 were considered positive.Table 2. For age, the Kolmogorov-Smirnov test of normality showed a D value of 0.13, p-value was 0.74, indicating likely normal distribution. The Shapiro–Wilk test gave a similar result when excluding outliners. A value of p < 0.05 was considered statistically significant. The free available internet version of GraphPad QuickCalcs and MedCalc were used.Two statistical approaches were used in order to increase the reliability of the results: First we tested whether the rate of positivity of a particular ANA pattern among patient who had cancer was significantly different from those who did not have cancer, i.e., if there was an association. In a different approach, we tested if the risk to have cancer with a given pattern was significantly different than the risk to have cancer with any other pattern, i.e., the relative risk. Fisher test and two-tailed Chi-square with Yate's correction were used depending on the number of patients. Two-tailed unpaired student t-test was used to compare two means, that is the age and delay in Among 15,728 patients tested by IIF during the study period, 2,903 had ANA titers ≥ 1/160, after the exclusion of 577 patients who had inconsistent duplicate results, as outlined in the methods. in situ neoplasms .Among 23,195 patients diagnosed with neoplasm, 15,701 patients had malignant disease  and 7,494 patients had either benign disease or p = 0.2). Similarly, other patterns analyzed  were not statistically associated with the presence of malignant disease, except for the HS aspect that was found to be significantly associated with the absence of malignant neoplastic disease (p < 0.01).Association analysis of each ANA pattern with the presence of malignant disease showed that 10.4% of patients with the nucleolar pattern had malignant disease compared to 8.0% without this pattern, the difference not reaching statistical significance (p = 0.02) compared to patients with other ANA patterns. On the contrary, the nucleolar pattern showed an increased relative risk .A total of 1,217 patients had both an ANA analysis and a malignant cancer. 205 patients had positive ANA and had a malignant neoplastic disease . The HS p < 0.01) compared to the patients with the HS aspect (5%).10.4% of patients who were positive for ANoA had malignant cancers, which was significantly higher (n = 8. However it is worth noting that two (15.4%) of the patients with anti-Scl-70 and 1 (14.3%) of the patients with anti-RNAP-III had malignant disease . No statistical analysis was performed with  disease .The medical charts of patients with a HS or nucleolar aspects were analyzed to confirm the diagnosis of malignant disease and investigate the clinical characteristic, including the survival.The average age of patients with ANoA was 60 years at cancer diagnosis. During the study period, 12 died (48%), at an average age of 66.9 years. Four patients had a concomitant AID or paraneoplastic disease.p = 0.02). 10 patients had either an AID or a paraneoplastic disease. Mortality cause was not always available from medical charts, so that the all-cause mortality was assessed and is shown in For patients with a HS pattern, the average age was 66.7 years at the time of cancer diagnosis. 16 patients died (47%), with an average of 75 years at the time of death, this being statistically higher than for the nucleolar pattern (The recent discoveries on the mechanism of CTLA-4 and PD-1 inhibition led to the development of several drugs that have increased the treatment options for a large number of malignant diseases . HoweverANA were found to be positive in ~40% of patients with malignant tumors in two previous studies , 23. ConDifferently than most studies investigating the prevalence of cancer in selected cohorts , 29, 30,Interestingly, numerous studies linked specific NA, showing a nucleolar pattern in IIF, to cancer, such as PM/Scl , 8, 30, The second main result of our study is that the HS pattern is significantly associated with the absence of cancer and has a lower relative risk than other ANA patterns. Although this pattern has not been previously described as protective, the study of Blaes et al. support our results. These authors found the presence of ANA as an indicator of a protective immune response in a cohort of 61 patients with non-small cell lung carcinoma . In thisIn our study, only the HS pattern was associated with a decreased relative risk of concomitant neoplastic disease. Recent studies have shown that in some cases the HS pattern might be related to ANA targeting the DFS70/LEDGF antigen . These ain vivo, neither to predict the development of AID in cancer patients, for which prospective studies are urgently needed.In our study, data from medical charts revealed a lower average age at death for ANoA positive patients compared those with the HS pattern. However, this is probably biased by the increased age of patients with a HS pattern compared to patients with an ANoA pattern. Our study therefore does not allow to speculate on the role of antibodies eliciting a HS or nucleolar pattern In conclusion, ANA with a HS pattern were associated with a significantly lower prevalence of neoplastic malignant disease and a decreased relative risk of having cancer compared to other ANA patterns. On the other hand, the nucleolar pattern was associated with a significantly increased relative risk of malignant neoplastic disease. Further studies are needed to investigate which particular antibody/ies against/to NA is responsible for these associations. While anti-DFS70/LEDGF antibodies could be involved in association of the HS pattern with the lower prevalence of cancer, anti-Scl70 and anti-RNAP-III antibodies, the latter being frequently associated with the presence of anti-RNAP-I, are good candidates for the association between ANoA and the presence of cancer, because these antibodies are well known to be associated with cancer and possibly give rise to a nucleolar pattern.david.spoerl@hcuge.ch.The datasets generated for this study will not be made publicly available. Despite encrypted crypted, database contain patients numbers that could potentially be used to identify patients. However, database can be provided to the editor to prove the results. Requests to access the datasets should be sent to David Spoerl, DS contributed conception and design of the study. DS and AG organized the database, performed the statistical analysis. AG wrote the first draft of the manuscript. PR-L collected the data and wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pineoblastoma (PB) is a rare neoplasm of the central nervous system. This analysis aimed to identify factors and establish a predictive model for the prognosis of adult patients with PB. Data for 213 adult patients with PB  were randomly divided into primary and validation cohorts. A predictive model was established and optimized based on the Akaike Information Criterion and visualized by a nomogram. Its predictive performance (concordance index and receiver operating characteristic curve) and clinical utility  were evaluated. We internally and externally validated the model using calibration curves. Multivariate Cox regression analysis identified age, year of diagnosis, therapy, tumor size, and tumor extension as independent predictors of PB. The model exhibited great discriminative ability . Calibration plots  showed good consistency between the actual observation and the nomogram prediction in both cohorts, and the decision curve analyses demonstrated great clinical utility of the nomogram. The nomogram is a useful and practical tool for evaluating prognosis and determining appropriate therapy strategies. The pineal gland is an endocrine gland in the midline of the brain that secretes melatonin to modulate circadian rhythms. Primary tumors arising from the pineal gland are termed pineal parenchymal tumors (PPTs). These tumors are rare, comprising <1% of all primary central nervous system neoplasms  of all iDefined as a highly malignant embryonal tumor of the pineal gland, PB is a type of primary supratentorial middle primitive neuroectodermal tumor of the central nervous system . SimilarFor the above reasons, we used the data of 213 adult patients with PB from the Surveillance, Epidemiology, and End Results (SEER) database to identify independent prognostic factors of adult patients with PB through Cox proportional hazards regression analysis. Moreover, we compared survival outcomes according to patient and tumor characteristics, as well as treatments received. Additionally, we attempted to establish a nomogram model based on the identified independent prognostic factors to provide a more accurate prediction of patient survival.*Sat version 8.3.6 (https://seer.cancer.gov/), which contained the SEER 18 registries research data.We acquired the data of patients with PB from the SEER database of the American National Cancer Institute using the latest SEERThe aim of this study is to analyze the prognostic factors of adult patients with PB in a large sample dataset. In order to meet the research needs, inclusion and exclusion criteria were set up as follows. Inclusion criteria: (1)patients were diagnosed as PB between 1975 and 2016 ; (2) adult patients with PB who were older than 20 years old and younger than 80 at diagnosis; (3) cases with clear treatment information. Exclusion criteria: (1) other types of cancer were excluded according to the ICD-O-3 and Conversion of Neoplasms by Topography and Morphology from the ICD-O-2 to ICD-O-3 edited by the SEER Program National Cancer Institute; (2) patients aged <20 years; (3) patients without clear treatment information (unknown); (4) dead of other causes; (5) there was only one case in some treatment regimens . Finally, 213 adult patients with PB were identified and selected for this analysis .http://web2.facs.org/cstage0205/intracranialgland/IntracranialGland_bfy.html), and tumor size. The time from diagnosis to death or last follow-up was defined as survival time, and those cases lost to follow-up were censored by the SEER. Non-survival included death caused by PB. Furthermore, there were some missing data regarding variable tumor extension and size. Multiple imputation of missing data was performed using the R software  to ensure a sufficient sample size and boost statistical power , therapy ; surgical treatment; only biopsy; RT and CT, sequence unknown; RT after surgery; RT after surgery and CT, sequence unknown; and RT after non-primary surgical procedure and CT, sequence unknown], tumor extension  and the time-dependent receiver operating characteristic (ROC) curve were applied to evaluate the accuracy and discriminative ability , 26. TheThe X-title software  was used to explore the best cutoff point of the continuous variables , based on the log-rank test statistics . The opthttp://www.r-project.org/), X-title software , and SPSS . A p < 0.1 was chosen as the criterion for excluding a variable from the multivariate Cox proportional hazards model, and a p < 0.05 denoted statistical significance for all other tests.All statistics analyses were performed using the R software  and aged 20–50 years . In addition, a large proportion of the patients had laterality characteristics without a paired site , and tumor extension characteristics confined to the gland of origin and localized, not otherwise specified . About 80% of patients were diagnosed in the period from 2001 to 2016 . Importantly, the ratio of cases with confirmed diagnosis by the positive histology were up to 97% .A total of 213 patients with PB were finally selected and analyzed in this study. The primary and validation cohorts consisted of 152 and 61 patients, respectively. Baseline information on the patients included in this study is shown in As shown in P < 0.01], therapy strategies , the scope of tumor extension , tumor size , and year of diagnosis . Sex , race , and laterality  were not identified as independent prognostic factors.The results from the multivariate analysis are shown in In addition, the effects of all dependent prognostic factors on survival of patients were assessed by survival analysis and shown by the Kaplan–Meier curves .The prognostic nomogram, shown in Based on the data of 61 patients in the validation cohort, the C-index of the nomogram for predicting overall survival was 0.802 (95% CI: 0.78–0.83). Additionally, calibration plots of the nomogram showed good consistency between observation and prediction both in the primary  and valiP < 0.01).The weights of extension and year of diagnosis for survival, shown in Identification of risk factors affecting patient survival and the effectiveness of currently applied treatments in rare diseases, such as PB, is of vital importance. Therefore, an abundance of high-quality clinical data is critical to achieving this goal. However, the rarity of PB renders the possibility of conducting prospective clinical trials a difficult task. In this study, the information on 213 adult patients with PB, collected by the SEER database from 1975 to 2016, was retrospectively analyzed. To our knowledge, thus far, this study analyzed the largest series of data regarding PB in adults. The results confirmed the predominant impact of the extent of tumor extension, tumor size, year of diagnosis, age, and different treatment regiments  on the outcome of adult patients with PB. Young patients, especially those not receiving RT during their initial treatment, are often associated with extremely poor outcome , which revealed that for every 1 mm increase in tumor size, the risk of death is reduced by 4%.As for the effect of tumor size on the prognosis of patients, to date, there is still some controversy in the published literature. Dittmar et al.  found thNumerous studies demonstrated that the clinical outcome of patients with PB, irrespective of treatment regimens, is worse than that of patients with infratentorial primitive neuro-ectodermal tumors –41. It iParikh et al.  suggesteThe role of CT in PB remains controversial. According to studies , 47, PB Interestingly, there is also a lack of consensus concerning the effectiveness of RT against PB. Several studies reported that PB was sensitive to RT , 48, 49.Similar to other studies , 52, theSeveral limitations of this study must be acknowledged. First, heterogeneity in the workup, diagnosis, and treatment modalities was unavoidable due to the long period  required to collect the data regarding diagnosis and treatment. Second, data on some critical items reflecting tumor characteristics, such as tumor size and extension, were not available. Although multiple imputations were conducted for missing data during the statistical analysis, the difference between the imputation data and real data was also unavoidable. Third, in the treatment regimens, it was still not known whether the CT regimens were performed before or after surgery. Despite its shortcomings, this analysis has perceptible strengths. Compared with some previous case reports and small-sample analyses, this analysis provided richer information regarding prognostic factors. In addition, inherent biases and heterogeneity were greatly limited, and statistical power was significantly increased. More importantly, the risk factors included in the model are those that are significantly related to PB and markedly easier to acquire than those determined by costly and time-consuming approaches.In conclusion, five risk factors  were identified in this analysis. Moreover, a nomogram which provided a precise and objective prediction of the prognosis for patients with PB was developed and validated using large-sample data from the SEER database. Importantly, this nomogram is a functional and practical tool that can assist clinicians in evaluating the prognosis of patients and determining appropriate therapeutic strategies. Additional studies are warranted to confirm the clinical value of this model.https://seer.cancer.gov/data/.Publicly available datasets were analyzed in this study. This data can be found here: All authors signed the SEER Research Data Agreement to protect the privacy of the patients, which is consistent with ethical principles.All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Hypopharyngeal squamous cell carcinoma (HSCC) is a rare type of head and neck cancer with poor prognosis. However, till now, there is still no model predicting the survival outcomes for HSCC patients. We aim to develop a novel nomogram predicting the long-term cancer-specific survival (CSS) for patients with HSCC and establish a prognostic classification system.Data of 2021 eligible HSCC patients were retrieved from the Surveillance, Epidemiology and End Results database between 2010 and 2015. We randomly split the whole cases (ratio: 7:3) into the training and the validation cohort. Cox regression as well as the Least absolute shrinkage and selection operator (LASSO) COX were used to select significant predictors of CSS. Based on the beta-value of these predictors, a novel nomogram was built. The concordance index (C-index), the calibration curve and the decision curve analysis (DCA) were utilized for the model validation and evaluation using the validation cohort.p < 0.001).In total, cancer-specific death occurred in 974/2021 (48.2%) patients. LASSO COX indicated that age, race, T stage, N stage, M stage, surgery, radiotherapy and chemotherapy are significant prognosticators of CSS. A prognostic model based on these factors was constructed and visually presented as nomogram. The C-index of the model was 0.764, indicating great predictive accuracy. Additionally, DCA and calibration curves also demonstrated that the nomogram had good clinical effect and satisfactory consistency between the predictive CSS and actual observation. Furthermore, we developed a prognostic classification system that divides HSCC patients into three groups with different prognosis. The median CSS for HSCC patients in the favorable, intermediate and poor prognosis group was not reached, 39.0-Mo and 10.0-Mo, respectively (In this study, we constructed the first nomogram as well as a relevant prognostic classification system that predicts CSS for HSCC patients. We believe these tools would be helpful for clinical practice in patients’ consultation and risk group stratification. Hypopharyngeal carcinoma is a rare type of cancer accounting for approximately only 2–6% of head and neck neoplasms , 2. HoweDue to its low incidence, only very few studies had investigated the prognostic factors of HSCC. By now, tumor-node-metastasis (TNM) staging system is still the most commonly used method for prognostic evaluation for HSCC patients. Other reported adverse indicators of HSCC included age, performance status, advanced clinical stage –9. HowevIt is well acknowledged that, because of the heterogeneity of tumor, the prognosis of patients with cancer is affected by various factors. Thus, to more accurately predict the prognosis of HSCC patients, it is essential to evaluate the survival outcomes of patients by integrating multiple risk factors. A nomogram is an ideal tool to achieve this goal. In general, nomograms are the visualization of prognostic models. One of the biggest advantages of nomograms is that, they can conveniently calculate and present the survival probability of a certain time-point for a certain patient based on risk factors included. Hence, nomograms are useful in the prognostic evaluation and are widely used in the real clinical practice in various cancer types .The purpose of this study is to develop a novel nomogram predicting the long-term cancer-specific survival (CSS) for patients with HSCC. In addition, we also established a prognostic classification system which can divide patients into different prognostic subgroups.Patients’ clinical and prognostic information were all retrieved from the Surveillance, Epidemiology and End Results (SEER) database. The SEER database is a population-based cancer database that collects data from 18 registries among 14 states and covers around 28% population across the USA . Cases iThe primary endpoint and the predicted target of this study is CSS which is the interval from the initial diagnosis of HSCC to death caused by it. Overall survival (OS) was the secondary endpoint which was duration from the initial diagnosis to death of any cause.The specific processes of prognostic model building and nomogram construction were as follow: Firstly, the total cohort was randomly split (splitting ratio: 7:3) into the training and validation cohort. The development of the prognostic model and the corresponding nomogram was carried out using the training cohort, whereas the validation cohort was responsible for the validation of the model. Secondly, Cox regression was conducted to test factors’ value in predicting CSS. Thirdly, the variable selection process was performed by the least absolute shrinkage and selection operator (LASSO) COX. Fourthly, the beta-value of predictors was calculated by the traditional Cox regression. Finally, based on the beta-value of these factors, the CSS-predicting model was visually presented in the way of nomogram.The validation of the novel nomogram was conducted in three distinct aspects using the validation cohort, i.e. the discrimination power, the calibration and the clinical effect. The discrimination power was assessed by the C-index. Calibration curves were carried out to evaluate the calibration of the model in diverse time-points with 500 bootstrap resamples. In addition, decision curve analyses (DCAs) were utilized to examine if the prognostic model was useful in clinical decision making.We also developed a CSS prognostic classification system in corresponding to the nomogram. According to the total score of each patient calculated by the nomogram from low to high, all cases could be classified into three groups. Each with roughly the same number of patients and then all cases could be classified into the favorable, intermediate and poor prognostic group.p value < 0.05 was considered statistically significant for all the tests.The chi-square test or the Mann–Whitney rank-sum test was conducted to compare the baseline factors between cases in the training and the validation cohort. Survival outcomes were compared by the log-rank test and were exhibited by Kaplan-Meier curves. Data retrieving was conducted by using SEER*Stat (version 8.3.5). R software (version 3.6.1) and MedCalc statistical software 15 were used for data analyses. All tests were two-sided. A p = 0.215; Median OS: 23.0 vs. 22.0-Mo, p = 0.951).In total, 2021 patients were included in this study. Finally, cancer-specific death and all-cause death occurred in 974/2021 (48.2%) and 1236/2021 (61.2%) patients, respectively. The median CSS and OS of the total patients were 32.0-Mo (95%CI: 26.9–37.1 Mo) and 23.0-Mo (95%CI: 20.7–25.3 Mo), respectively. The total cases were randomly split into the training cohort  and validation  cohort as is shown in Table The prognostic significance of each factor in predicting CSS is evaluated using the training cohort. Statistically significant predictive value was achieved among factors including age, race, AJCC Stage, T stage, N stage, M stage, surgical treatment, radiotherapy treatment and chemotherapy in univariate analyses Table . These fThe validation and evaluation of the nomogram was carried out using the validation cohort. The C-index of the prognostic model was 0.764 (95%CI: 0.735–0.793) which was significantly higher than any factor alone or the TNM staging system (C-index: 0.669), indicating that the novel model has a great discrimination ability. Besides, the potential clinical effect of the nomogram was tested using DCA , intermediate prognosis group  and poor prognosis group   and the treatment-related part . The old age and black race were found to be adversely associated with short CSS in HSCC patients, which was in accordance with other studies , 22, 23.The nomogram also revealed that treatment is essential to prolong the survival time of HSCC patients. Total laryngectomy used to be the standard way of treatment for patients with HSCC. However, with the development of new therapeutic agents, there was a shift from surgery to the laryngeal preservation therapy after the introduction of chemoradiotherapy , 25. ForIt is well acknowledged that the pathogenesis of head and neck cancers is associated with virus infection. For example, Epstein-Barr virus (EBV) and human papilloma virus (HPV) has been identified to be related with the occurrence of oropharyngeal cancer and nasopharyngeal carcinoma, respectively , 27. HowOur study still owns many limitations. First of all, this is a retrospective study with weakness related to its study type. Secondly, although the novel nomogram was generated based on a quite big sample size and a split validation of the model was performed, no external validation using data from other centers was carried out. However, due to the low incidence of HSCC, designing an external validation study is faced with great difficulties. Thirdly, since SEER database does not provide detailed chemotherapy regimens and radiotherapy doses, the prognostic value of these factors could not be assessed. Finally, since all patients included in this study were diagnosed with HSCC between 2010 and 2015, only cTNM stage based on the 7th edition of the AJCC staging system was available in the SEER database, because the AJCC 8th edition was released in late 2017. Therefore, the 7th instead of the latest 8th edition of the AJCC staging system was used for cTNM staging in the current study. However, there are only very little changes in the 8th edition of AJCC clinical staging criteria against the 7th, i.e. in the 8th edition extranodal extension was included in the N stage evaluation, while the T and M stage criteria remained unchanged.We constructed the first nomogram that predicts the CSS for HSCC patients in the current study. The validation of the prognostic model using a split cohort showed that the nomogram had high discrimination ability, great calibration and satisfactory clinical effect. We also built a prognostic classification system corresponding to the nomogram which could conveniently classify all HSCC patients into three prognostic groups. We believe these tools would be useful in the real clinical practice for patients’ consultation and risk group stratification.


Hospital workers have been the most frequently and severely affected professional group during the COVID-19 pandemic, and have a big impact on transmission. In this context, innovative tools are required to measure the symptoms compatible with COVID-19, the spread of infection, and testing capabilities within hospitals in real time.We aimed to develop and test an effective and user-friendly tool to identify and track symptoms compatible with COVID-19 in hospital workers.We developed and pilot tested Hospital Epidemics Tracker (HEpiTracker), a newly designed app to track the spread of COVID-19 among hospital workers. Hospital staff in 9 hospital centers across 5 Spanish regions  were invited to download the app on their phones and to register their daily body temperature, COVID-19–compatible symptoms, and general health score, as well as any polymerase chain reaction and serological test results.A total of 477 hospital staff participated in the study between April 8 and June 2, 2020. Of note, both health-related (n=329) and non–health-related (n=148) professionals participated in the study; over two-thirds of participants (68.8%) were health workers (43.4% physicians and 25.4% nurses), while the proportion of non–health-related workers by center ranged from 40% to 85%. Most participants were female , with a mean age of 45.4 years (SD 10.6). Regarding smoking habits, 13.0% and 34.2% of participants were current or former smokers, respectively. The daily reporting of symptoms was highly variable across participating hospitals; although we observed a decline in adherence after an initial participation peak in some hospitals, other sites were characterized by low participation rates throughout the study period.HEpiTracker is an already available tool to monitor COVID-19 and other infectious diseases in hospital workers. This tool has already been tested in real conditions. HEpiTracker is available in Spanish, Portuguese, and English. It has the potential to become a customized asset to be used in future COVID-19 pandemic waves and other environments.ClinicalTrials.gov NCT04326400; https://clinicaltrials.gov/ct2/show/NCT04326400 The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, requires an urgent, collaborative, and multidisciplinary response supported by innovative methods . Indeed,In August 2020, the World Health Organization (WHO) declared that the COVID-19 pandemic is far from controlled. The cumulative number of confirmed COVID-19 cases across 216 countries, areas, or territories worldwide amounts to over 21,989,366, and 775,893 confirmed deaths have been reported to date . Record COVID-19–related symptoms are nonspecific, resembling common cold symptoms in immunocompetent individuals. According to the Centers for Disease Control and Prevention (CDC) , the lisThe real-time assessment of COVID-19–related symptoms, their spread, and testing capabilities in hospital settings requires the use of innovative tools. In this context, digital health technologies have great potential to improve surveillance and epidemic control, primarily through increased information coverage, faster acquisition and distribution of information, rapid case tracking, and improved proximity tracing . ConsequHere, we summarize the development of Hospital Epidemics Tracker (HEpiTracker) , a newlyOn March 14, 2020, a multidisciplinary group of individuals with varied backgrounds held the first of many daily meetings to discuss, by means of a “think tank” approach, research avenues aimed at mitigating the impact of the COVID-19 crisis. As part of the Active Monitoring And Determinants of Incident Infection of COVID-19 in a Hospital population (AMADIICH) initiative, this multidisciplinary group created a framework designed to collect large amounts of heterogeneous data regarding COVID-19 in hospital staff, from shoe-leather epidemiology to big data and biosensors . One of The standard process of reporting COVID-19–related symptoms differs by area and center, but typically starts with a phone call from the employee to the occupational health unit (OHU) of the center. The employee is then advised to self-isolate at home, where he/she receives a polymerase chain reaction (PCR) test. If the test is positive, he/she remains in home isolation. If the test is negative but there are symptoms, the employee remains in isolation and the test is repeated during the following days. Therefore, workers can only return to work once they do not have symptoms and have returned two consecutive negative PCR tests. The OHU should always have access to the status of all employees and is typically responsible for escalating the data. The purpose of the HEpiTracker app is to provide an easier, homogenous, and transparent way of tracking positive PCR results and symptoms. The tracking happens automatically and relieves the health manager from manually updating the aggregated information and calculating statistics. It can also provide the updated information to the workers themselves in a transparent manner.We provide descriptive data obtained in the pilot study that illustrate the applicability of the app in practical settings. We would like to clarify that we do not intend to study the factors behind app adoption or the effect these types of tools have on infection rates. These, and other related issues, are beyond the scope of this article. What we do present is a working app that can help already overwhelmed hospital staff to actively monitor and assess COVID-19 infections and compatible symptoms in the hospital worker population.As mentioned above, a mobile app to help monitor the spread of COVID-19 within hospitals was conceived after a state of emergency and full lockdown were declared in Spain on March 14, 2020. Following initial discussions and ethical approval, a stepwise approach was carried out by ASELCIS software developers  to creatThere was a feedback process from users within our scientific committee, which includes doctors, nurses, computer science specialists, mathematicians, physicists, and statisticians, but not patients themselves, although during the development of the app several authors became infected or were quarantined due to COVID-19. The app also included a self-assessment of overall health status based on an ordinal Likert scale from 0 to 10. HEpiTracker was made available for both Android and iOS operating systems at Google and Apple stores, respectively.Once HEpiTracker was up and running, we designed a pilot study in real-world conditions to test the feasibility of the app. Specifically, we tested the app in several hospitals across regions with different incidence rates and undergoing different phases of the COVID-19 pandemic: Hospital Can Misses (Eivissa) from April 9, 2020; Hospital Lucus Augusti (Lugo) from April 10, 2020; Hospital Álvaro Cunqueiro (Vigo) from April 10, 2020; Hospital Institut Català d'Oncologia  from April 8, 2020; Hospital de Alta Resolución Loja (Granada) from April 13, 2020; and Hospital Universitario de La Princesa (Madrid) from April 9, 2020.Hospital staff in 5 Spanish autonomous communities  were invited to download the app on their smartphones , and to In addition to answering Yes/No for the presence of daily symptoms, participants self-assessed their overall health by means of a visual analog scale (VAS), and they disclosed whether they had a history (either of diagnosis or treatment) of rhinitis, allergy, or chronic obstructive pulmonary disease (COPD)/chronic bronchitis, as well as their smoking status. Further, participants manually entered their body temperature in degrees Celsius to one decimal. They were also invited to register the outcome and the date of any COVID-19 laboratory test ; these could have been performed routinely at their center, throughout the study by risk exposure, or as a result of the presence of symptoms or suspicion of having the disease .A participant could withdraw from the study at any time (by simply not filling in their own information or by removing the app from their smartphone). However, given the ongoing public health emergency during this COVID-19 outbreak, it was agreed that any data already obtained would be kept for analysis and grouped tabulation. In addition, participants would be withdrawn at the discretion of the investigators if they failed to comply with the protocol procedures .The first data entry was made by a user of the mobile app. The coding language is based on Ionic, which allows developers to create native apps with web coding such as HTML, CSS, and JavaScript. Users’ initial data and subsequent symptom records are automatically transferred to an Odoo V11 Enterprise Edition server application . The codThe storage of data is done in a PostgreSQL database in an encrypted way. In addition, user data is stored anonymously with an internal code assigned to each participant. In this way, the user's identification number is related to the internal code, and all data entered is linked to it, preventing the end user  from having access to the user's personal data.To guarantee the storage of data and avoid its loss or modification, a backup is made daily that is kept in three data centers (DCs) on three different continents, thus ensuring the integrity of the data in the event of any serious problem or inconvenience in any of the three DCs.All individual participants’ collected data were stored on secure ASELCIS servers. Data were anonymized with a unique identifier by user and hospital. Statistics were performed by ISGlobal and IdIsBa with databases already anonymized over a PostgreSQL connection under a user and password requirement.Study reports were sent to the participating hospitals. These reports included descriptive information regarding changes in the symptoms and incidence of COVID-19 infection by age group, sex, job category, and department/section. We followed the STROBE  guidelines for reporting observational studies [A total of 477 hospital staff participated in the study between April 8 and June 2, 2020 .Of note, both health-related (n=329) and non–health-related (n=148) professionals participated in the study. Overall participation by center was low; the highest participation rate of potential participants was 5.06% at Hospital Álvaro Cunqueiro , followed by a participation rate of 2.97% at ICO L'Hospitalet . Most participants were female (67.7%), with a mean age of 45.4 years (SD 10.6). Regarding smoking habits, 13.0% and 34.2% of participants were current or former smokers, respectively . Over twThe daily report of symptoms was highly variable across participants; overall, 2% to 6% of the source population in each hospital engaged with the app. Although we observed a decline in adherence after an initial participation peak in some hospitals, other sites were characterized by poor participation rates since inception and throughout the study period .There were no major differences across hospitals in the distribution of respiratory comorbidities , smoking status, or symptoms, namely cough, shortness of breath, malaise, or anosmia .However, for temperature and overall health status scored from 0 to 10, there were subtle but not clinically significant differences. Finally, the percentage of positive PCR tests was highly variable, from 39% of participants at La Princesa (16/41 participants), to 20% at ICO Girona (2/10), 9.5% (16/169) at Álvaro Cunqueiro, 8.8% (6/68) at ICO L’Hospitalet, and 3.6% (4/116) at Lucus Augusti.A daily summary display of these results was made available for circulation at all participating sites each morning during the study period .HEpiTracker is a newly designed mobile app aimed at monitoring the spread of COVID-19 symptoms and testing among professionals in hospital settings. Although the first wave of the pandemic in Spain and other countries is thought to be over, many experts warn that lockdown lifts might be premature . In the We tested the HEpiTracker app in a sample of 477 hospital staff including both health-related and non–health-related professionals from 9 centers in 5 regions of Spain experiencing different stages of the COVID-19 pandemic. The daily report of COVID-19–related symptoms was highly variable across participating hospitals, as well as the reported infection testing rates. We observed a decline in adherence after an initial participation peak in some hospitals, while other sites were characterized by low participation rates throughout the study period. It is worth noting that our pilot study aimed to test the technical aspects of the app in different real-world hospital settings, all in different stages of the COVID-19 pandemic, but not its deployment or coverage. In general, an acceptable response rate for any epidemiological study is 80% or higher for usability ,22. HaviIn future analyses, techniques and tools used in artificial intelligence and machine learning will be explored. For instance, machine learning can be used to forecast new cases or to identify relevant phenotypes .Mobile apps are effective, valid tools for monitoring very diverse patterns in real-life conditions . HoweverIt should be stressed that the present study did not intend to study the factors that determine app adoption or the impact of the app on infection rates. These, along with other relevant issues, are outside the scope of this paper and would only be addressed by a larger-scale study that would be complex in its design and execution. However, this pilot study allowed us to identify some strengths and limitations of the app that will be addressed in the following sections.Some strengths of HEpiTracker include novelty, flexibility, and the ability to quickly modify it and include new updates and information. Notably, the app is now available in several languages  and is accepted by both health care professionals and non–health care professionals in hospital settings. In the near future, we plan to design customized versions to be used in primary care, by security forces, and even in universities once in-class teaching is resumed.However, our results must be interpreted in light of the following limitations. Despite fulfilling all European Union regulations and disclaimers on data protection, concerns with data privacy were raised by legal departments or individual managers in several nonparticipating hospitals, so clarity among leadership should be ensured. When evaluating usability and user experience of mobile health  solutions, there are standardized questionnaires such as The Standardized User Experience Percentile Rank Questionnaire (SUPR-Qm)  for userUnfortunately, the inclusion of alarm reminders for the daily recording of symptoms and temperature was not effective. Indeed, a proper communication and marketing strategy for wider implementation will be critical for its future use. We have already developed QR codes and templates of posters to pin in hospital entrances, elevators, and notice boards, which serve as a way to download HEpiTracker directly on any platform.This lack of adherence, however inspired the next evolution of the app, consisting of an activity wristband that will incorporate HEpiTracker plus a number of other utilities. This evolution of HEpiTracker, named Epiwrist (an “epidemiologist on your wrist”), could passively monitor all HEpiTracker variables, as well as others. Epiwrist would include a gyroscope to assess hand-washing behavior (duration and frequency), synchronized with a cough sensor to identify if the cough is directed to your sleeve (good) or your hand (bad), and a continuous heart rate monitor, oxygen saturation meter, and built-in thermometer. It is envisaged that Epiwrist will also measure physical activity, sleep duration and patterns, blood pressure, and respiratory rate. The development of this software and hardware started in May 2020; it was designed by engineers at Softlution . AlthougDuring the COVID-19 epidemic, OHUs in hospitals were in charge of diagnosing health care workers with symptoms of the disease, and applying and changing protocols from their respective public health institutions, which included the study of contacts within the hospital, affecting both hospitalized patients and staff. OHUs also reported the cases to the local epidemiological surveillance systems. Moreover, OHUs participated in the constant updating and implementation of internal protocols for COVID-19 prevention in collaboration with the preventive medicine units. In our study, some hospitals showed an unwillingness to participate because they believed that HEpiTracker would interfere with established tracking of health care providers and surveillance. Moreover, they claimed that it could affect the privacy rights of participants. In general, public health interventions during infectious outbreaks can be divided into those consisting of personal actions , case and contact identification , regulatory actions , and international border measures .A key priority during the ongoing COVID-19 pandemic is to identify the combination of measures that minimizes societal and economic disruption while adequately controlling infection . Our aimHEpiTracker is an already available tool to monitor COVID-19 and other epidemics in hospital workers. It has been tested in real conditions and might represent a stepping stone toward effective health policies in response to future waves of the pandemic. HEpiTracker is available in Spanish, Portuguese, and English and holds the potential to become a customized asset to be used in future COVID-19 pandemic waves and other environments.