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In this report, we describe a 6-year-old girl with a medical history of pallor, mild icterus, anemia, blood transfusion and abnormal hemoglobin variant analysis on capillary electrophoresis. She was referred for further analysis. DNA sequencing of the proband revealed a de novo mutation in Codon 88 (CTG > CCG) of the β-globin gene ( HBB : c.266T > C) in a heterozygous state compatible with hemoglobin Santa Ana, an unstable hemoglobin. This is the first case of Hb Santa Ana from Iran associated with moderate to severe anemia who underwent splenectomy with clinical improvement.

Computational Pathology (CPath) is an interdisciplinary science that augments developments of computational approaches to analyze and model medical histopathology images. The main objective for CPath is to develop infrastructure and workflows of digital diagnostics as an assistive CAD system for clinical pathology, facilitating transformational changes in the diagnosis and treatment of cancer that are mainly address by CPath tools. With evergrowing developments in deep learning and computer vision algorithms, and the ease of the data flow from digital pathology, currently CPath is witnessing a paradigm shift. Despite the sheer volume of engineering and scientific works being introduced for cancer image analysis, there is still a considerable gap of adopting and integrating these algorithms in clinical practice. This raises a significant question regarding the direction and trends that are undertaken in CPath. In this article we provide a comprehensive review of more than 800 papers to address the challenges faced in problem design all-the-way to the application and implementation viewpoints. We have catalogued each paper into a model-card by examining the key works and challenges faced to layout the current landscape in CPath. We hope this helps the community to locate relevant works and facilitate understanding of the field's future directions. In a nutshell, we oversee the CPath developments in cycle of stages which are required to be cohesively linked together to address the challenges associated with such multidisciplinary science. We overview this cycle from different perspectives of data-centric, model-centric, and application-centric problems. We finally sketch remaining challenges and provide directions for future technical developments and clinical integration of CPath. For updated information on this survey review paper and accessing to the original model cards repository, please refer to GitHub. Updated version of this draft can also be found from arXiv., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Objective: A classification model based on preterm birth clinical presentations (phenotypes) was proposed at the International Conference on Prematurity and Stillbirth, with calls for validation. This study sought to determine the distribution of clinical phenotypes of preterm birth among nulliparous women, their corresponding associations with maternal characteristics, and the odds ratios (ORs) of preterm Caesarean section and other adverse outcomes., Methods: A population-based cohort study was performed of all nulliparous women with singleton pregnancies (>20 weeks) who gave birth in a hospital in Ontario between 2012 and 2014. Logistic regression models were used to estimate adjusted ORs (Canadian Task Force Classification II-2)., Results: Among 113 942 nulliparous women, 6.1% delivered at <37 weeks, at a mean gestational age of 33.9 weeks. Of those women, 34.1% did not meet the criteria for the presence of any clinical phenotype; 42.3% had one maternal, fetal, or placental condition; 22.3% had two clinical conditions; and 1.3% had three clinical conditions. The most common preterm birth phenotypes were worsening of maternal diseases (24.0%), intrauterine growth restriction (23.5%), and fetal distress (23.0%). Compared with preterm births without any significant clinical phenotype, those with maternal, fetal, or placental phenotypes were associated with increased odds of Caesarean section (adjusted ORs 2.70 [95% confidence interval [CI] 2.30-3.17], 1.66 [95% CI 1.36-2.03], and 6.49 [95% CI 4.29-9.80], respectively)., Conclusion: Approximately two thirds of nulliparous preterm births were grouped into distinct clinical phenotypes. This study demonstrated that outcomes varied across phenotypes, thus providing evidence of benefit for the phenotypic classification model., (Copyright © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: The Global Alliance to Prevent Prematurity and Stillbirth developed a phenotypic classification for preterm birth using clinical presentation (rather than risk factors) to improve surveillance. The objective of this study was to determine distributions of preterm birth phenotypes and associations with Caesarean section, low Apgar score, and neonatal death in multiparous women, stratifying by first versus recurrent preterm births., Methods: This population-based cohort study used the Better Outcomes Registry and Network (BORN) of multiparous women giving birth in hospital with a singleton after 20 weeks in Ontario from 2012 to 2014 (Canadian Task Force Classification II-2)., Results: In multiparous women with preterm birth, 29.6% had a history of recurrence, of whom 66.2% had at least one clinical condition associated with the phenotypic model, compared with 63.5% of first preterm births. In recurrent preterm births, criteria for maternal, fetal, and placental conditions were met in 44.5%, 37.9%, and 8.2%, respectively, compared with 36.8%, 39.0%, and 10.4%, respectively, of first preterm births. Associations of preterm birth with Caesarean section, low Apgar score, and neonatal death varied across clinical conditions but were similar between first and recurrent preterm births; for example, for recurrent preterm birth, Caesarean section for maternal, fetal, and placental conditions had odds ratios of 1.66 (95% confidence interval [CI] 1.32-2.07), 1.09 (95% CI 0.80-1.49), and 3.92 (95% CI 1.98-7.78), compared with first preterm birth odds ratios of 1.21 (95% CI 1.03-1.41), 0.92 (95% CI 0.77-1.10), and 6.24 (95% CI 4.07-9.56)., Conclusion: This study provides novel evidence of the utility of the preterm birth phenotypic classification model by using stratification for previous preterm birth, a robust predictor-with variation in phenotypes in initial and recurrent preterm births., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The reported positive association between opiatic drug use during pregnancy and adverse pregnancy outcomes might be confounded by other factors related to high-risk behaviors, including the use of other harmful substances. In rural areas of Iran, opium use during pregnancy is relatively common among women who otherwise do not have a hazardous lifestyle, which reduces the risk of residual confounding and increasing the possibility to identify its effects. We aimed to examine the association of antenatal exposure to opium with risks of small for gestational age, short birth length, and small head circumference at birth., Method: In this cohort study in the rural area of the Golestan province, Iran, we randomly selected 920 women who were exposed to opium during pregnancy and 920 unexposed women during 2008-2010. Log-binomial regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI) for the associations between prenatal exposure to opium and risks of small for gestational age, short birth length, and small head circumference at birth., Results: Compared with non-use of opium and tobacco during pregnancy, using opium only and dual use of opium and tobacco were associated with increased risks of small for gestational age at births (RR = 1.71; 95% CI 1.34-2.18 and RR = 1.62; 95% CI 1.13-2.30, respectively). Compared with non-use of opium and tobacco, exposure to only opium or dual use of opium and tobacco were also associated with more than doubled increased risks of short birth length, and small head circumference in term infants., Conclusion: Maternal opium use during pregnancy is associated with increased risks of giving birth to a small for gestational age infant, as well as a term infant with short birth length or small head circumference.

Background: Use of narcotic or "recreational" drugs has been associated with adverse pregnancy outcomes such as preterm delivery. However, the associations might be confounded by other factors related to high-risk behaviours. This is the first study to investigate the association between traditional opium use during pregnancy and risk of preterm delivery., Method and Findings: We performed a population-based cohort study in the rural areas of the Golestan province, Iran between 2008 and 2010. We randomly selected 920 women who used (usually smoked) opium during pregnancy and 920 women who did not. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations between the opium use during pregnancy and preterm delivery and adjustment was made for potential confounding factors. This study shows compared with non-use of opium and tobacco, use of only opium during pregnancy was associated with an increased risk of preterm delivery (OR = 1.56; 95% CI 1.05-2.32), and the risk was more than two-fold increased among dual users of opium and tobacco (OR = 2.31; 95% CI 1.37-3.90). We observed that opium use only was associated with a doubled risk for preterm caesarean delivery (OR = 2.05; 95% CI 1.10-3.82) but not for preterm vaginal delivery (OR = 1.25; 95% CI 0.75-2.07). Dual use of opium and tobacco was associated with a substantially increased risk of vaginal preterm delivery (OR = 2.58; 95% CI 1.41-4.71)., Conclusions: Opium use during pregnancy among non-tobacco smokers is associated with an increased risk of preterm caesarean delivery, indicating an increased risk of a compromised foetus before or during labour. Women who use both opium and smoked during pregnancy have an increased risk of preterm vaginal delivery, indicating an increased risk of spontaneous preterm delivery.

Background: Results of previous studies on the association between maternal haemoglobin concentration during pregnancy and stillbirth risk are inconclusive. It is not clear if haemoglobin concentration before pregnancy has a role. Using prospectively collected information from pre-pregnancy and antenatal visits, we investigated associations of maternal haemoglobin concentrations before and during pregnancy and haemoglobin dilution with stillbirth risk., Methods: In a population-based case-control study from rural Golestan, a province in northern Iran, we identified 495 stillbirths (cases) and randomly selected 2,888 control live births among antenatal health-care visits between 2007 and 2009. Using logistic regression, we estimated associations of maternal haemoglobin concentrations, haemoglobin dilution at different stages of pregnancy, with stillbirth risk., Results: Compared with normal maternal haemoglobin concentration (110-120 g/l) at the end of the second trimester, high maternal haemoglobin concentration (≥140 g/l) was associated with a more than two-fold increased stillbirth risk (OR = 2.31, 95 % CI [1.30-4.10]), while low maternal haemoglobin concentration (<110 g/l) was associated with a 37 % reduction in stillbirth risk. Haemoglobin concentration before pregnancy was not associated with stillbirth risk. Decreased haemoglobin concentration, as measured during pregnancy (OR = 0.61, 95 % CI [0.46, 0.80]), or only during the second trimester (OR = 0.75, 95 % CI [0.62, 0.90]), were associated with reduced stillbirth risk. The associations were essentially similar for preterm and term stillbirths., Conclusions: Haemoglobin concentration before pregnancy is not associated with stillbirth risk. High haemoglobin level and absence of haemoglobin dilution during pregnancy could be considered as indicators of a high-risk pregnancy.

Introduction: Consanguineous marriage is associated with increased risks for congenital anomalies, low birthweight, and other adverse perinatal outcomes. In this population-based, case-control study we investigated the association between consanguineous marriage (first-cousin marriage) and stillbirth risk, using prospectively collected information from prepregnancy visits., Material and Methods: From 2007 to 2009, we identified 283 stillbirths (cases) and 2088 randomly selected live control births through prepregnancy visits in rural Golestan, Iran. The associations between consanguinity and prepregnancy maternal characteristics and stillbirth risk were examined using multivariate logistic regression., Results: The rate of consanguineous marriage was 19.4% among cases and 13.6% among controls. Consanguinity was associated with increased stillbirth risk [odds ratio (OR) 1.53; 95% CI 1.10-2.14]. The association was significantly increased for preterm stillbirth (< 37 gestational weeks) (OR 2.43; 95% CI 1.46-4.04) but not for term stillbirth (≥ 37 weeks) (OR 1.14; 95% CI 0.75-1.74). Low and high maternal age, underweight, obesity, nulliparity, a history of infertility or miscarriage, previous obstetric complications (preeclampsia, preterm delivery, and stillbirth in previous pregnancies) were also associated with increased stillbirth risks., Conclusions: Consanguineous marriage is associated with increased risk of stillbirth, particularly preterm stillbirth. Findings for other maternal risk factors for stillbirth in rural Iran are consistent with previously reported findings from high-income countries., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

In order to search for additional regulatory elements in the human CYP17 (steroid 17 alpha-hydroxylase) gene and to compare it with potential regulatory elements in bovine CYP17 genes, 3.5 kb of 5' flanking region of CYP17 was cloned and analyzed. The newly acquired sequence was shown to be a highly defective copy of the human endogenous retrovirus HERV-K family. This retroviral sequence was itself interrupted by a novel element, a low copy number repeat occurring about 20 times in the human genome, including a known copy in the human catechol-O-methyltransferase gene. A reanalysis of the entire 5' flanking region of human CYP17 indicates that only the 300 bp immediately distal to the promoter is of unique sequence; other regulatory sequences, including any that are similar to the upstream region of the bovine genes, are unlikely to occur within 5.5 kb of the promoter.

DNA methylation of CYP17 (steroid 17 alpha-hydroxylase) was studied in bovine adrenocortical cells, which lose the capacity to express this tissue-specific gene in culture by phenotypic switching. Restriction enzyme digestions, and sequencing of a lambda clone of a second CYP17 gene (CYP17A2), showed that there are at least three CYP17 genes in the bovine genome. Southern blotting of DNA digested with Msp I or Hpa II together with Eco RI was used to investigate the methylation status of Hpa II sites at -1.0 kb (H1), -1.8 kb (H2), and -2.3 kb (H4) in CYP17A1 and CYP17A2 and at -0.7 kb (H0) in CYP17A3. In cells and tissues other than white blood cells, H0 was nonmethylated whereas H1 was always methylated; H2 and H4 showed variation in methylation status among different cells and tissues. In particular, whereas H4 was methylated in the bovine adrenal cortex in vivo, there was a rapid and complete demethylation at H4 when adrenocortical cells were placed in culture. Sites downstream from H4 did not change methylation over the first six passages in culture; additionally, the coding region of CYP17 remained fully methylated under all conditions. In contrast to adrenocortical cells, DNA from fibroblasts was nonmethylated at H2, whereas all downstream sites were fully methylated. Digestion with another methylation-sensitive enzyme, Bsa HI, which has a site between H2 and H4, showed that this region is methylated in intact adrenal cortex but nonmethylated both in cultured adrenocortical cells and in fibroblasts. The specific changes in methylation at this site and at H4 in adrenocortical cells indicate a reproducible, environmentally determined change in methylation in adrenocortical cells when they are placed in culture.

In adrenocortical cells in culture, increased intracellular cyclic AMP resulting from exposure to agents such as ACTH and cholera toxin causes a change in cell morphology termed 'retraction' or 'rounding'. The breakdown of actin-containing stress fibers in rounding suggested a role for microfilaments in steroidogenesis. Previously, we showed that cultured bovine adrenal cells under standard conditions (medium with 10% fetal bovine serum) do not round in response to intracellular cyclic AMP. Here, we show that these cells do round in defined, serum-free medium. Rounding was maximal within 1 h of addition of 1 nM cholera toxin and after 10 h most cells remained rounded. Cycloheximide at 100 micrograms/ml did not inhibit the response to cholera toxin. The rounding response was abolished when 10% fetal bovine serum, horse serum, or ether-extracted fetal bovine serum was included in the medium. The inhibitory effect of serum was not mimicked by growth factors with the exception that insulin and insulin-like growth factor-I (IGF-I), while not preventing rounding, accelerated the return of cells to a flattened morphology. A monoclonal antibody against urokinase plasminogen activator completely prevented rounding whereas a monoclonal antibody against tissue plasminogen activator had only a slight effect. Fluorescence visualization of F-actin with N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-phallacidin showed that rounding in cultured bovine adrenocortical cells resembles that defined earlier for human and rat adrenocortical cells and includes depolymerization of actin microfilaments. These cytoskeletal changes in adrenal cells are unlikely to play a role in steroidogenesis; however, they may be involved in tissue remodeling occurring as part of the indirect mitogenic effects of ACTH.