Category: Nevin Manimala

Hum Reprod. 2023 Apr 19:dead069. doi: 10.1093/humrep/dead069. Online ahead of print.

ABSTRACT

STUDY QUESTION: How does an altered maternal hormonal environment, such as that seen during superovulation with gonadotropins in ART, impact human uterine immune cell distribution and function during the window of implantation?

SUMMARY ANSWER: Hormonal stimulation with gonadotropins alters abundance of maternal immune cells including uterine natural killer (uNK) cells and reduces uNK cell ability to promote extravillous trophoblast (EVT) invasion.

WHAT IS KNOWN ALREADY: An altered maternal hormonal environment, seen following ART, can lead to increased risk for adverse perinatal outcomes associated with disordered placentation. Maternal immune cells play an essential role in invasion of EVTs, a process required for proper establishment of the placenta, and adverse perinatal outcomes have been associated with altered immune cell populations. How ART impacts maternal immune cells and whether this can in turn affect implantation and placentation in humans remain unknown.

STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out between 2018 and 2021 on 51 subjects: 20 from natural cycles 8 days after LH surge; and 31 from stimulated IVF cycles 7 days after egg retrieval.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial biopsies and peripheral blood samples were collected during the window of implantation in subjects with regular menstrual cycles or undergoing superovulation. Serum estradiol and progesterone levels were measured by chemiluminescent competitive immunoassay. Immune cell populations in blood and endometrium were analyzed using flow cytometry. uNK cells were purified using fluorescence-activated cell sorting and were subjected to RNA sequencing (RNA-seq). Functional changes in uNK cells due to hormonal stimulation were evaluated using the implantation-on-a-chip (IOC) device, a novel bioengineered platform using human primary cells that mimics early processes that occur during pregnancy in a physiologically relevant manner. Unpaired t-tests, one-way ANOVA, and pairwise multiple comparison tests were used to statistically evaluate differences.

MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were comparable for both groups. As expected, serum estradiol levels on the day of biopsy were significantly higher in stimulated (superovulated) patients (P = 0.0005). In the setting of superovulation, we found an endometrium-specific reduction in the density of bulk CD56+ uNK cells (P < 0.05), as well as in the uNK3 subpopulation (P = 0.025) specifically (CD103+ NK cells). In stimulated samples, we also found that the proportion of endometrial B cells was increased (P < 0.0001). Our findings were specific to the endometrium and not seen in peripheral blood. On the IOC device, uNK cells from naturally cycling secretory endometrium promote EVT invasion (P = 0.03). However, uNK cells from hormonally stimulated endometrium were unable to significantly promote EVT invasion, as measured by area of invasion, depth of invasion, and number of invaded EVTs by area. Bulk RNA-seq of sorted uNK cells from stimulated and unstimulated endometrium revealed changes in signaling pathways associated with immune cell trafficking/movement and inflammation.

LIMITATIONS, REASONS FOR CAUTION: Patient numbers utilized for the study were low but were enough to identify significant overall population differences in select immune cell types. With additional power and deeper immune phenotyping, we may detect additional differences in immune cell composition of blood and endometrium in the setting of hormonal stimulation. Flow cytometry was performed on targeted immune cell populations that have shown involvement in early pregnancy. A more unbiased approach might identify changes in novel maternal immune cells not investigated in this study. We performed RNA-seq only on uNK cells, which demonstrated differences in gene expression. Ovarian stimulation may also impact gene expression and function of other subsets of immune cells, as well as other cell types within the endometrium. Finally, the IOC device, while a major improvement over existing in vitro methods to study early pregnancy, does not include all possible maternal cells present during early pregnancy, which could impact functional effects seen. Immune cells other than uNK cells may impact invasion of EVTs in vitro and in vivo, though these remain to be tested.

WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate that hormonal stimulation affects the distribution of uNK cells during the implantation window and reduces the proinvasive effects of uNK cells during early pregnancy. Our results provide a potential mechanism by which fresh IVF cycles may increase risk of disorders of placentation, previously linked to adverse perinatal outcomes.

STUDY FUNDING/COMPETING INTEREST(S): Research reported in this publication was supported by the University of Pennsylvania University Research Funding (to M.M.), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD068157 to M.M., S.S., and S.M.), National Center for Advancing Translational Sciences of the National Institutes of Health (TL1TR001880 to J.K.), the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the Children’s Hospital of Philadelphia Research Institute (to S.M.G.), and the National Institute of Allergy and Infectious Diseases (K08AI151265 to S.M.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All authors declare no conflict of interest.

TRIAL REGISTRATION NUMBER: N/A.

PMID:37075311 | DOI:10.1093/humrep/dead069

J Neuroophthalmol. 2023 Apr 19. doi: 10.1097/WNO.0000000000001836. Online ahead of print.

ABSTRACT

BACKGROUND: There is modest literature regarding fellowship applicant factors that may predict future career achievement. We aim to characterize neuro-ophthalmology fellows and identify and analyze characteristics that may predict future career trajectory.

METHODS: Data, including demographic information, academic background, scholarly activities, and practice information, were collected using publicly available sources, on individuals who completed neuro-ophthalmology fellowships from 2015 to 2021. Summary statistics describing the cohort were calculated. Prefellowship characteristics were compared with postfellowship characteristics to evaluate which prefellowship characteristics may predict postfellowship academic productivity and career achievement.

RESULTS: Data were collected on 174 individuals (41.6% men, 58.4% women). Sixty-five percent were residency-trained in ophthalmology, 31% neurology, 1.7% both, and 1.7% pediatric neurology. Fifty-eight percent completed residency in the US, 8% in Canada, 32% internationally, and 2% in multiple locations. Among those practicing in the US/Canada, 63.8% practice at academic centers, 35.3% private practice, and 0.9% at both. Thirty-one percent completed additional subspecialty training and 17.8% additional graduate degrees. Completion of additional fellowship training or graduate degrees, and publication of more papers before fellowship, correlated with later academic productivity. There were no significant correlations between completion of an additional fellowship or graduate degree with current practice environment or attainment of leadership roles. There were no significant correlations between total publishing productivity prefellowship and practice environment or leadership roles postfellowship.

CONCLUSIONS: Additional graduate degrees/subspecialty training, and prefellowship academic productivity, correlated with later academic productivity among neuro-ophthalmologists, suggesting that these metrics may be helpful in predicting future academic performance among fellowship applicants.

PMID:37075283 | DOI:10.1097/WNO.0000000000001836

J Clin Oncol. 2023 Apr 19:JCO2201740. doi: 10.1200/JCO.22.01740. Online ahead of print.

ABSTRACT

PURPOSE: Although the incidence of young-onset digestive tract cancers is increasing worldwide, their risk factors remain largely unknown. We investigated the association between nonalcoholic fatty liver disease (NAFLD) and young-onset digestive tract cancers.

PATIENTS AND METHODS: This nationwide cohort study included 5,265,590 individuals age 20-39 years who underwent national health screening under the Korean National Health Insurance Service between 2009 and 2012. The fatty liver index was used as a diagnostic biomarker for NAFLD. The participants were followed up until December 2018 to determine the incidence of young-onset digestive tract cancers (ie, esophageal, stomach, colorectal, liver, pancreatic, biliary tract, and gallbladder). Multivariable Cox proportional hazards models were conducted to estimate the risk after adjusting for potential confounders.

RESULTS: During the 38.8 million person-years of follow-up, 14,565 patients were newly diagnosed with young-onset digestive tract cancers. The cumulative incidence probability of each cancer type was consistently higher in individuals with NAFLD than in those without NAFLD (all log-rank P < .05). NAFLD was associated with an increased risk of overall digestive tract (adjusted hazard ratio [aHR], 1.16; 95% CI, 1.10 to 1.22), stomach (aHR, 1.14; 95% CI, 1.06 to 1.24), colorectal (aHR, 1.14; 95% CI, 1.06 to 1.22), liver (aHR, 1.13; 95% CI, 1.12 to 1.52), pancreatic (aHR, 1.23; 95% CI, 1.09 to 1.40), biliary tract (aHR, 1.29; 95% CI, 1.00 to 1.66), and gallbladder (aHR, 1.53; 95% CI, 1.01 to 2.31) cancer. These associations remained significant regardless of age, sex, smoking status, alcohol consumption, and obesity status (all P < .05; P for interaction >.05). The aHR for esophageal cancer was 1.67 (95% CI, 0.92 to 3.03).

CONCLUSION: NAFLD may be an independent, modifiable risk factor for young-onset digestive tract cancers. Our findings suggest a crucial opportunity to reduce premature morbidity and mortality associated with young-onset digestive tract cancers in the next generation.

PMID:37075279 | DOI:10.1200/JCO.22.01740

J Chem Theory Comput. 2023 Apr 19. doi: 10.1021/acs.jctc.2c01018. Online ahead of print.

ABSTRACT

Interdependence across time and length scales is common in biology, where atomic interactions can impact larger-scale phenomenon. Such dependence is especially true for a well-known cancer signaling pathway, where the membrane-bound RAS protein binds an effector protein called RAF. To capture the driving forces that bring RAS and RAF (represented as two domains, RBD and CRD) together on the plasma membrane, simulations with the ability to calculate atomic detail while having long time and large length- scales are needed. The Multiscale Machine-Learned Modeling Infrastructure (MuMMI) is able to resolve RAS/RAF protein-membrane interactions that identify specific lipid-protein fingerprints that enhance protein orientations viable for effector binding. MuMMI is a fully automated, ensemble-based multiscale approach connecting three resolution scales: (1) the coarsest scale is a continuum model able to simulate milliseconds of time for a 1 μm² membrane, (2) the middle scale is a coarse-grained (CG) Martini bead model to explore protein-lipid interactions, and (3) the finest scale is an all-atom (AA) model capturing specific interactions between lipids and proteins. MuMMI dynamically couples adjacent scales in a pairwise manner using machine learning (ML). The dynamic coupling allows for better sampling of the refined scale from the adjacent coarse scale (forward) and on-the-fly feedback to improve the fidelity of the coarser scale from the adjacent refined scale (backward). MuMMI operates efficiently at any scale, from a few compute nodes to the largest supercomputers in the world, and is generalizable to simulate different systems. As computing resources continue to increase and multiscale methods continue to advance, fully automated multiscale simulations (like MuMMI) will be commonly used to address complex science questions.

PMID:37075065 | DOI:10.1021/acs.jctc.2c01018

PLoS One. 2023 Apr 19;18(4):e0284712. doi: 10.1371/journal.pone.0284712. eCollection 2023.

ABSTRACT

INTRODUCTION: Increasing use of CT examinations has led to concerns of possible negative cognitive effects for children. The objective of this study is to examine if the ionizing radiation dose from a CT head scan at the age of 6-16 years affects academic performance and high school eligibility at the end of compulsory school.

MATERIALS AND METHODS: A total of 832 children, 535 boys and 297 girls, from a previous trial where CT head scan was randomized on patients presenting with mild traumatic brain injury, were followed. Age at inclusion was 6-16 years (mean of 12.1), age at follow up 15-18 years (mean of 16.0), and time between injury and follow up one week up to 10 years (mean of 3.9). Participants’ radiation exposure status was linked with the total grade score, grades in mathematics and the Swedish language, eligibility for high school at the end of compulsory school, previously measured GOSE-score, and their mothers’ education level. The Chi-Square Test, Student’s t-Test and factorial logistics were used to analyze data.

RESULTS: Although estimates of school grades and high school eligibility were generally higher for the unexposed, the results showed no statistically significant differences between the exposed and unexposed participants in any of the aforementioned variables.

CONCLUSIONS: Any effect on high school eligibility and school grades from a CT head scan at the age of 6-16 years is too small to be detected in a study of more than 800 patients, half of whom were randomly assigned to CT head scan exposure.

PMID:37075051 | DOI:10.1371/journal.pone.0284712

PLoS One. 2023 Apr 19;18(4):e0283851. doi: 10.1371/journal.pone.0283851. eCollection 2023.

ABSTRACT

The Boston Marathon is one of the most prestigious running races in the world. From its inception in 1897, popularity grew to a point in 1970 where qualifying times were implemented to cap the number of participants. Currently, women’s qualifying times in each age group are thirty minutes slower than the men’s qualifying times equating to a 16.7% adjustment for the 18-34 age group, decreasing with age to a 10.4% adjustment for the 80+ age group. This setup somewhat counter-intuitively implies that women become faster with age relative to men. We present a data-driven approach to determine qualifying standards that lead to an equal proportion of qualifiers in each age category and gender. We had to exclude the 75-79 and 80+ age groups from analysis due to limited data. When minimizing the difference in proportion of men and women qualifying, the women’s times for the 65-69 and 70-74 age groups are 4-5 minutes slower than the current qualifying standard, while they are 0 to 3 minutes faster for all other age groups.

PMID:37075050 | DOI:10.1371/journal.pone.0283851

PLoS One. 2023 Apr 19;18(4):e0284382. doi: 10.1371/journal.pone.0284382. eCollection 2023.

ABSTRACT

BACKGROUND: Childhood stunting is still a global public health challenge, including in Ethiopia. Over the past decade, in developing countries, stunting has been characterized by large rural and urban disparities. To design an effective intervention, it is necessary to understand the urban and rural disparities in stunting.

OBJECTIVE: To assess the urban-rural disparities in stunting among Ethiopian children aged 6-59 months.

METHODS: This study was done based on the data obtained from the 2019 mini-Ethiopian Demographic and Health Survey, conducted by the Central Statistical Agency of Ethiopia and ICF international. The result of descriptive statistics was reported using the mean with standard deviation, frequency, percentages, graphs, and tables. A multivariate decomposition analysis was used to decompose the urban-rural disparity in stunting into two components: one that is explained by residence differences in the level of the determinants (covariate effects), and the other component is explained by differences in the effect of the covariates on the outcome (coefficient effects). The results were robust to the different decomposition weighting schemes.

RESULT: The prevalence of stunting among Ethiopian children aged 6-59 months was 37.8% (95% CI: 36.8%, 39.6%). The difference in stunting prevalence between urban and rural residences was high (rural prevalence was 41.5%, while in urban areas it was 25.5%). Endowment and coefficient factors explained the urban-rural disparity in stunting with magnitudes of 35.26% and 64.74%, respectively. Maternal educational status, sex, and age of children were the determinants of the urban-rural disparity in stunting.

CONCLUSION AND RECOMMENDATION: There is a significant stunting disparity among urban and rural children in Ethiopia. A larger portion of the urban-rural stunting disparity was explained by coefficient effects (differences in behaviour). Maternal educational status, sex, and age of children were the determinants of the disparity. So, to narrow this disparity, emphasis should be given to both resource distribution and the appropriate utilization of available interventions, including improvement of maternal education and consideration of sex and age differences during child feeding practices.

PMID:37075042 | DOI:10.1371/journal.pone.0284382

PLoS One. 2023 Apr 19;18(4):e0283251. doi: 10.1371/journal.pone.0283251. eCollection 2023.

ABSTRACT

The utilization or secondary use of technogenic waste is a relevant problem for the current economy. To assess the environmental influence and economic potential, it is necessary to study the elemental content of technogenic objects and to reveal the tendencies of the spatial distribution of elements, components, and indices such as the pollution coefficient. In this study, we performed elemental analysis, and calculation of indicators: average gross content, hazard quotients, concentration coefficients of metals, and total pollution coefficients of ground samples taken from the ash-slag storage of the Aksu ferroalloy plant [Aksu, Pavlodar region, Kazakhstan]. Maps of the spatial distribution of concentrations of elements and total pollution coefficients were created. The territory of the studied ash-slag storage by the level of soil contamination should be considered as an environmental disaster zone. The given statistical data on the number of oncological and respiratory diseases indirectly indicated the negative influence of open storage of ash-slag waste. The studied ground was of chromium-manganese geochemical specialization. The calculated volume of the accumulated waste mass by the approximating method was 1 054 638.0 m3. The calculated approximate weight of the accumulated waste was 23 679 576.0864 tons, including 1 822 972.2 tons of chromium, 1 727 354.0 tons of manganese, and 953 813.3 tons of iron. The large amounts of valuable components retained in the waste mass led us to conclude that the studied technogenic object can be considered as a secondary field to produce various technological products. Moreover, valuable metals can be extracted as metal concentrates.

PMID:37074997 | DOI:10.1371/journal.pone.0283251

PLoS One. 2023 Apr 19;18(4):e0283848. doi: 10.1371/journal.pone.0283848. eCollection 2023.

ABSTRACT

Soundscape ecology provides a long-term, noninvasive approach to track animal behavior, habitat quality, and community structure over temporal and spatial scales. Using soniferous species as an indicator, biological soundscapes provide information about species and ecosystem health as well as their response and resiliency to potential stressors such as noise pollution. Charleston Harbor, South Carolina, USA provides important estuarine habitat for an abundance of marine life and is one of the busiest and fastest growing container ports in the southeast USA. Six passive acoustic recorders were deployed in the Charleston Harbor from December 2017 to June 2019 to determine biological patterns and human-associated influences on the soundscape. Anthropogenic noise was detected frequently across the estuary, especially along the shipping channel. Despite this anthropogenic noise, biological sound patterns were identified including snapping shrimp snaps (Alpheus spp. and Synalpheus spp.), fish calling and chorusing (Sciaenidae and Batrachoididae families), and bottlenose dolphin vocalizations. Biological response to anthropogenic activity varied among trophic levels, with decreased detection of fish calling when anthropogenic noise occurred and increased dolphin vocalizations in the presence of anthropogenic noise. Statistically, fine-scale, temporal patterns in biological sound were not clearly identified by sound pressure levels (SPLs), until files with anthropogenic noise presence were removed. These findings indicate that SPL patterns may be limited in their interpretation of biological activity for noisy regions and that the overall acoustic signature that we find in more pristine estuaries is lost in Charleston Harbor.

PMID:37074986 | DOI:10.1371/journal.pone.0283848

J Natl Cancer Inst. 2023 Apr 19:djad069. doi: 10.1093/jnci/djad069. Online ahead of print.

ABSTRACT

BACKGROUND: Starting in 2018, national death certificates included a new racial classification system that accounts for multiple-race decedents and separates Native Hawaiian and Pacific Islander (NHPI) individuals from Asian individuals. We estimated cancer death rates across updated racial/ethnic categories, sex, and age.

METHODS: Age-standardized U.S. cancer mortality rates and rate ratios from 2018-2020 among ≥20-year-olds were estimated with national death certificate data by race/ethnicity, sex, age, and cancer site.

RESULTS: In 2018, there were approximately 597,000 cancer deaths, 598,000 in 2019, and 601,000 in 2020. Among men, cancer death rates were highest in Black men (298.2/100,000; n = 105,632), followed by White (250.8; n = 736,319), American Indian/Alaska Native (AI/AN) (249.2; n = 3,376), NHPI (205.6; n = 1,080), Latino (177.2; n = 66,167), and Asian (147.9; n = 26,591) men. Among women, Black women had the highest cancer death rates (206.5/100,000; n = 104,437), followed by NHPI (192.1; n = 1,141), AI/AN (189.9; n = 3,239), White (183.0; n = 646,865), Latina (128.4; n = 61,579), and Asian women (111.4; n = 26,396). The highest death rates by age group occurred among NHPI individuals aged 20-49 years, and Black individuals aged 50-69 and ≥70 years. Asian individuals had the lowest cancer death rates across age groups. Compared to Asian individuals, total cancer death rates were 39% higher in NHPI men and 73% higher in NHPI women.

CONCLUSIONS: There were striking racial/ethnic disparities in cancer death rates during 2018-2020. Separating NHPI and Asian individuals revealed large differences in cancer mortality between two groups that were previously combined in vital statistics data.

PMID:37074947 | DOI:10.1093/jnci/djad069