Abstract Introduction The association between extreme birth spacing and adverse outcomes is controversial, and available evidence is fragmented into different classifications of birth spacing. Material and methods We conducted a systematic review of observational studies to evaluate the association between birth spacing (i.e., interpregnancy interval and interoutcome interval) and adverse outcomes (i.e., pregnancy complications, adverse birth outcomes). Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated using a random‐effects model, and the dose–response relationships were evaluated using generalized least squares trend estimation. Results A total of 129 studies involving 46 874 843 pregnancies were included. In the general population, compared with an interpregnancy interval of 18–23 months, extreme intervals (<6 months and ≥ 60 months) were associated with an increased risk of adverse outcomes, including preterm birth, small for gestational age, low birthweight, fetal death, birth defects, early neonatal death, and premature rupture of fetal membranes (pooled OR range: 1.08–1.56; p < 0.05). The dose–response analyses further confirmed these J‐shaped relationships ( p non‐linear < 0.001–0.009). Long interpregnancy interval was only associated with an increased risk of preeclampsia and gestational diabetes ( p non‐linear < 0.005 and p non‐linear < 0.001, respectively). Similar associations were observed between interoutcome interval and risk of low birthweight and preterm birth ( p non‐linear < 0.001). Moreover, interoutcome interval of ≥60 months was associated with an increased risk of cesarean delivery (pooled OR 1.72, 95% CI 1.04–2.83). For pregnancies following preterm births, an interpregnancy interval of 9 months was not associated with an increased risk of preterm birth, according to dose–response analyses ( p non‐linear = 0.008). Based on limited evidence, we did not observe significant associations between interpregnancy interval or interoutcome interval after pregnancy losses and risk of small for gestational age, fetal death, miscarriage, or preeclampsia (pooled OR range: 0.76–1.21; p > 0.05). Conclusions Extreme birth spacing has extensive adverse effects on maternal and infant health. In the general population, interpregnancy interval of 18–23 months may be associated with potential benefits for both mothers and infants. For women with previous preterm birth, the optimal birth spacing may be 9 months.
The essentially infinite expansion potential and pluripotency of human embryonic stem cells (hESCs) makes them attractive for cell-based therapeutics. In contrast to mouse embryonic stem cells (mESCs), hESCs normally undergo high rates of spontaneous apoptosis and differentiation, making them difficult to maintain in culture. Here we demonstrate that p53 protein accumulates in apoptotic hESCs induced by agents that damage DNA. However, despite the accumulation of p53, it nevertheless fails to activate the transcription of its target genes. This inability of p53 to activate its target genes has not been observed in other cell types, including mESCs. We further demonstrate that p53 induces apoptosis of hESCs through a mitochondrial pathway. Reducing p53 expression in hESCs in turn reduces both DNA damage-induced apoptosis as well as spontaneous apoptosis. Reducing p53 expression also reduces spontaneous differentiation and slows the differentiation rate of hESCs. Our studies reveal the important roles of p53 as a critical mediator of human embryonic stem cells survival and differentiation.
Cardiovascular diseases (CVDs) are currently the leading cause of global health loss, accounting for one-third of deaths worldwide[1] and estimated to cause 7.8 million premature deaths in 2025.[2] Hypertension is the top preventable risk factor of CVDs globally and in China.[2,3] Conservative estimates indicated that the national economic loss due to CVDs in China can reach $8.8 trillion over 2012 to 2030.[4] Hypertension treatment in Chinese adults aged 35 to 84 years was analyzed to reap savings later for around 800,000 CVDs events prevention annually and improved the quality of life and economic productivity.[5] In 2010, an estimated 1.39 billion people worldwide affected hypertension but only one in seven patients under blood pressure (BP) control.[6] In comparison with hypertension management programs successfully performed[7,8] in high-income countries and substantially increasing hypertension control rate, disparities remain between hypertension burden and control rate in low- and middle-income countries.[6] The recent China Hypertension Survey (2012–2015) recruited a nationally representative sample of 451, 755 residents aged ≥18 years from all 31 provinces in the mainland of China, observing that 23.2% (estimated 244.5 million) and 41.3% (estimated 435.3 million) of the Chinese adult population had hypertension and prehypertension, respectively. However, the rates of awareness, treatment, and control were only 46.9%, 40.7%, 15.3%, and even decrease according to the 2017 ACC/AHA guideline.[9,10] Multiple factors may contribute to the poor hypertension control rate in China. First, disparities on medical resources among diverse-level medical centers and immature health care delivery system for hypertension management limit systemic treatment and control for hypertension. Even among different provincial or prefectural level medical centers, hypertension discipline construction process and evaluation criteria are biased. In addition, awareness and capacities for hypertension screening, treatment, and control at primary care centers are limited, whereas incentives and trainings for primary care providers are particularly lacking, leading to hurdles on implementation for hypertension patient management. Also, issues on antihypertension medications are significant, including unaffordable, inconsistent medication supply, and unreasonable treatment algorithms at primary care centers with a few antihypertensive combination therapy and limited use of single-pill combination (SPC) treatment. Lastly, hypertension patient adherence and public concern on health promotion are unsatisfying. Nationwide efforts are therefore urgent to promote hypertension management, particularly, on building discipline capacity and strengthening the integrated healthcare system for hypertension. The main objectives include: (1) advancing and generalizing the guideline based screening, diagnosis, and treatment of hypertension, for both primary and secondary hypertension; (2) promoting regularly standardized trainings, continuing education, and intellectual resource cultivation on hypertension discipline; (3) constructing National Medical Alliance for Hypertension (NMAH); (4) developing comprehensive mode of hypertension patient management;(5) reinforcing patient education, improving public awareness and patient adherence of hypertension management; and (6) advancing scientific researches in hypertension field. Specialized hypertension discipline promotion requires multidiscipline collaboration, such as cardiology, nephrology, endocrinology, neurology, vascular surgery, urology, psychology, and genetics. Backup system construction is also required of hypertension screening, diagnosis, and treatment, including: (1) laboratory examinations for primary and secondary hypertension, such as levels of renin, aldosterone, and catecholamines; (2) vascular function evaluation, such as endothelial function test (flow-mediated dilation), pulse wave velocity, and ankle- brachial index; (3) imaging examinations, such as adrenal computed tomography, metaiodobenzylguanidine scintigraphy, renal arteriography, and adrenal venous sampling; (4) sleep respiration monitoring or polysomnography, utilized for obstructive sleep apnea syndrome evaluation; (5) renal biopsy and pathological examination, assisting etiology diagnosis of renal hypertension; (6) minimally invasive surgical and interventional techniques for hypertension therapy, such as renal sympathetic denervation and laparoscopic adrenal adenoma resection; (7) genetic diagnosis, identifying monogenic hypertension and guiding individualized medication treatment based on phamacogenomics; (8) mental state evaluation, such as questionnaires of self-rating anxiety scale and self-rating depression scale; and (9) novel techniques for hypertension diagnosis and treatment, such as digital transformation and artificial intelligence. In terms of specialized hypertension center construction and discipline capacity advancement, the "Chinese Hypertension Center Certification" project was initiated on October 4, 2018, authorized by the Specialized Committee for Hypertension of Chinese Medical Doctor Association, the National Center for Cardiovascular Diseases, the Chinese Society of Cardiology, and the Specialized Committee for Hypertension of Health Exchange and Cooperation Across the Taiwan Straits. Five sections with 83 detailed standardized criteria were established for the "Chinese Hypertension Center" assessment. Core criteria contain: (1) organization construction (25%), including infrastructure construction of hypertension clinic or ward, expert committee establishment, and medical equipment; (2) standardized diagnosis and treatment for primary hypertension (25%); (3) screening, diagnosis, and treatment for secondary hypertension (20%), such as causes of renal diseases, primary aldosteronism, pheochromocytoma and paraganglioma, Cushing's syndrome, renovascular stenosis, aortic coarctation, and obstructive sleep apnea syndrome; (4) guidance for hypertension management capacity-building at primary care centers (20%). For instance, hierarchical medical system construction (local Medical Alliance for Hypertension with dual referral systems) and trainings for primary care providers are mainly concerned; and (5) capacity for hypertension research (10%). By October 2020, 40 province-level centers [Supplementary Table 1, https://links.lww.com/CM9/A959] have been certificated as "Chinese Hypertension Center" after the process of registration, initiation, online application (http://gxy.nccd.org.cn), initial audit online, site audit, and voting. The annual material update is obligatory of the certificated center for surveillance and evaluation. In addition, the NMAH, a national collaboration network for standardized hypertension diagnosis and treatment, capacity-building of healthcare systems for hypertension, and efficient hypertension management, was initiated on November 25, 2017, guided by the National Health Commission of the People's Republic of China, and authorized by the National Center for Cardiovascular Diseases. The NMAH collaborates multilevel centers or hospitals from all geographically province-level and prefecture-level administrative regions in the mainland of China except for Tibet, incorporating typical Chinese governmental and administrative models with specialized hypertension management and discipline promotion strategies [Figure 1]. By November 30, 2020, NMAH includes 38 province-level centers, 237 prefecture-level subcenters, 7314 registered medical centers (including county, township, or community-level centers), and 35,643 doctors [Supplementary Table 2, https://links.lww.com/CM9/A959]. Stepwise guidance for healthcare system strengthening is incorporated. The expert committee of NMAH, consisting of national and provincial hypertension leaders corresponding to the organizing structure of NMAH, has also developed an annual National Hypertension Congress covering about 150 experts and around 1.34 million audiences per time in 2021, and regular doctors' trainings of 58 training sessions with over 290 expert lectures covering 24 provinces and 287,789 audience per time between February 2021 and September 2021. The standardized training materials include versions for hypertension professionals and primary healthcare providers (ie, National guideline for hypertension management in China [2019][11]), and standardized patient education materials (ie, National guideline for hypertension patient education in China [2021][12]). Relative materials, training slides, and videos are also updated online into the integrated supportive system of NMAH.[13] The information platform was designed with digital service Apps for real-time interactions between doctors and patients, online workstations with innovated "Green Channel" for promoting convenient referral and remote consultation via the stepped-up structure of NMAH, a big data center (cloud computing) supporting medical researches for hypertension, and open ports reserved for third-party access, such as BP data automatically uploaded from electronic sphygmomanometers (office, automatic arm-in, and home BP monitors) and artificial intelligence based techniques. Currently, the platform is utilized as an innovative App management model evaluated in the Strategy of BP intervention in the elderly hypertensive patients (STEP) trial[14] for patient adherence promotion.Figure 1: Organizing framework for NMAH. NMAH collaborates multilevel centers or hospitals from all geographically province-level and prefecture-level administrative regions in the mainland of China except for Tibet. By November 30, 2020, NMAH includes 38 province-level centers, 237 prefecture-level subcenters, 7314 registered medical centers, including county, township, or community-level centers, and 35,643 doctors. The distribution of centers, hospitals, and doctors of NMAH is also presented. NMAH: National Medical Alliance for Hypertension.On the basis of organizing framework, digital platform, and training materials of NMAH, the "Hypertension Prevention and Control Initiative in China" project (ClinicalTrials identifier: NCT04289701) was initiated on October 8, 2019, authorized by the National Health Commission of the People's Republic of China, and initiated by the National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences. The main objectives of the project are: (1) to explore a feasible and reproducible archetype for hypertension management; (2) to improve the registration, management, treatment, and control rates of hypertension in China; and (3) to improve the management mode of primary chronic disease by taking hypertension as the entry point. NMAH will consecutively spread 40 county-level medical alliances from 31 provinces for pilot project implementation. The local Task Force will then be established on the basis of medical resources, collaborated multilevel structure, and shared information platform from NMAH. The collaboration between the local Task Force and the local CDC, supervised by the local Health Commission, is encouraged. The main workflow for the project includes [Supplementary Figure 1, https://links.lww.com/CM9/B289]: (1) Regularly online and onsite trainings for healthcare providers. Extending from the experiences of the Canadian Hypertension Education Program,[8] all our training manuals are based on the hypertension guidelines and translated to simple implementable messages focusing on diagnosis, risk stratification, interventions (majorly lifestyle and pharmacologic), and management for hypertension, anchoring diverse targeted groups and reviewed by the Expert Committee of NMAH. (2) Patient-centered hypertension management. All adult hypertensive residents in pilot sites diagnosed according to the Chinese Hypertension Guideline[15] are eligible to participate in the project. A responsible doctor will be chosen by each patient and conduct "one-to-one" management at primary healthcare centers, after guideline-based risk stratification and transferring high-risk patients to the specialist center via the "Green Panel" of NMAH. (3) Simplified hypertension treatment protocol recommendation. The expert committee of NMAH recommends the standardized hypertension treatment protocols based on the Chinese hypertension guidelines and key elements of simplified protocols utilized in other successful hypertension prevention and control program.[7,16] Three independent algorithms, including calcium channel blocker, angiotensin receptor blocker or SPC as first-line therapy, and dose- and category specific antihypertension drugs at each step, can be referred. Affordable, high-quality, and long-term drugs are recommended such as drugs procured from the Chinese national pharmaceutical policy for patients with the minimal price of amlodipine ∼$0.01 per tablet (5 mg), irbesartan ∼$0.05 per tablet (150 mg), and SPC ∼$0.15 per tablet (irbesartan 150 mg and hydrochlorothiazide 12.5 mg). (4) Periodical patient follow-up via BP monitor-sharing system equipped with automatically BP data update to ensure real-time monitoring and data authenticity. (5) Outcome and performance evaluation. Key outcome indicators include the number of patients registered, under management, on treatment, with BP control, or with the onset of cardiovascular events.[14] (6) Incentives and subsidies. Predecided compensation will be offered to local healthcare organizations for extra healthcare services. In addition to reimbursement, the ranking list of performance for primary care centers will be presented with representative healthcare providers for attending continuing education programs at higher level medical centers via NMAH and for invited lecture at the annual National Hypertension Congress. The project will also provide targeted subsides to patients through several approaches such as free home BP monitors. The overall project has a three-step-wedged design consecutively spreading until 2025. By April 23, 2020, the first four pilot sites (Beijing, Heilongjiang Province, Yunnan Province, and Jiangxi Province) have 3251 patients under management with a control rate of ∼53% by September 2021. Steps 2 and 3 will integrate with the "Hypertension, Hyperlipidemia, Hyperglycemia Prevention, and Control program" of "Healthy China 2030 plan," recruiting overall 40 pilot counties covering 31 provinces in the mainland of China. In essence, we promote multiple projects, including "Chinese Hypertension Center Certification," "Construction of National Medical Alliance for Hypertension in China," and "Hypertension Prevention and Control Initiative in China." Referable models for hypertension management and discipline promotion may herein be developed. Acknowledgments We appreciate all members and collaborators of the National Medical Alliance for Hypertension, as well as all participants for the "Chinese Hypertension Center Certification" and "Hypertension Prevention and Control Initiative in China" projects. Funding This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-007), National Natural Science Foundation of China (No. 81825002), Beijing Outstanding Young Scientist Program (No. BJJWZYJH01201910023029), and Beijing Municipal Science & Technology Commission (No. Z191100006619106, Z201100005620006). Conflicts of interest None.
Despite progress in the design of advanced surgical techniques, stenosis recurs in a large percentage of vascular anastomosis.In this study, a novel heparin-poloxamer (HP) hydrogel was designed and its effects for improving the quality and safety of vascular anastomosis were studied.HP copolymer was synthesized and its structure was confirmed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy ( 1 H-NMR).Hydrogels containing HP were prepared and their important characteristics related to the application in vascular anastomosis including gelation temperature, rheological behaviour and micromorphology were measured.Vascular anastomosis were performed on the right common carotid arteries of rabbits, and the in vivo efficiency and safety of HP hydrogel to achieve vascular anastomosis was verified and compared with Poloxamer 407 hydrogel and the conventional hand-sewn method using Doppler ultrasound, CT angiograms, scanning electron microscopy (SEM) and histological technique.Our results showed that HP copolymer displayed special gel-sol-gel phase transition behavior with increasing temperature from 5 to 60 °C.HP hydrogel prepared from 18 wt% HP solution had a porous sponge-like structure, with gelation temperature at approximately 38 °C and maximum elastic modulus at 10,000 Pa.In animal studies, imaging and histological examination of rabbit common jugular artery confirmed that HP hydrogel group had similar equivalent patency, flow and burst strength as Poloxamer 407 group.Moreover, HP hydrogel was superior to poloxamer 407 hydrogel and hand-sewn method for restoring the functions and epithelial structure of the broken vessel junctions after operation.By combining the advantages of heparin and poloxamer 407, HP hydrogel holds high promise for improving vascular anastomosis quality and safety.
Objective To explore the necessity of large-scale screening of mitochondria DNA (mtDNA) A1555G mutation for prevention of aminoglycoside antibiotic induced deafness in newborns.Methods One thousand blood filter samples were collected from neonates born in July 2008 in Shenzhen.DNA was extracted with Chelex-100 Resin and amplified by PCR. The mtDNA A1555G mutation was determined by denaturing high-performance liquid chromatography (DHPLC) for PCR products. The positive frequency was calculated. Results The mitochondrial DNA A1555G mutation was detected in 2 cases of 1000 neonates. The frequency of mutation was 0. 2%. Conclusion There is a high frequency of mtDNAA1555G mutation in neonates, the large-scale screening of mtDNAA1555G mutation in newborns might detect the individuals sensitive to aminoglycoside antibiotic, which is helpful to guide a rational medication for newborns and the maternal relatives at high-risk. Furthermore, it might be useful to prevent aminoglycoside antibiotic induced deafness.
Key words:
screen; drug-induced deafness; mitochondria DNA mutation
Background A recent genome-wide scan has identified two genetic variants in the HLA-DP region strongly associated with hepatitis B infection in Japanese. This study evaluates the effects of these risk variants in Chinese, where the HBV infection is the most popular in the world. Methods and Findings We have assessed the relationship between these two single nucleotide polymorphisms (rs3077 and rs9277535) and chronic hepatitis B infection in two independent case-control studies. The first population in Chinese Han included 736 patients and 782 spontaneously recovered controls. The second set was established in Chinese Zhuang minority of 177 patients and 208 controls. Both A alleles of rs3077 and rs9277535 significantly deceased the risk to CHB in Chinese Han (OR = 0.540, 95%CI: 0.464–0.628, P = 4.068×10−16 and OR = 0.696, 95%CI: 0.601–0.806, P = 1.062×10−6, respectively). Conceivably, rs9277535 was found to be associated with decreased risk of the disease in Chinese Zhuang, with an OR of 0.606 (95%CI, 0.441–0.833, P = 0.002). Conclusion Chronic hepatitis B susceptibility loci in HLA-DP region (rs3077 and rs9277535) identified by genome-wide scan in Japanese population were validated in Chinese population. These findings might provide clues to develop screening and surveillance strategies.
The characterization of induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) routinely includes analyses of chromosomal integrity. The belief is that pluripotent stem cells best suited to the generation of differentiated derivatives should display a euploid karyotype; although, this does not appear to have been formally tested. While aneuploidy is commonly associated with cell transformation, several types of somatic cells, including hepatocytes, are frequently aneuploid and variation in chromosomal content does not contribute to a transformed phenotype. This insight has led to the proposal that dynamic changes in the chromosomal environment may be important to establish genetic diversity within the hepatocyte population and such diversity may facilitate an adaptive response by the liver to various insults. Such a positive contribution of aneuploidy to liver function raises the possibility that, in contrast to existing dogma, aneuploid iPSCs may be capable of generating hepatocyte-like cells that display hepatic activities. We examined whether a human iPSC line that had multiple chromosomal aberrations was competent to differentiate into hepatocytes and found that loss of normal chromosomal content had little impact on the production of hepatocyte-like cells from iPSCs. iPSCs that harbor an abnormal chromosomal content retain the capacity to generate hepatocyte–like cells with high efficiency.
We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.
// Elizabeth B. Perry 1,2 , Alvin Makohon-Moore 3 , Caihong Zheng 4 , Charles K. Kaufman 5 , Jun Cai 4 , Christine A. Iacobuzio-Donahue 3 and Richard M. White 1 1 Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center, New York, New York, USA 2 Biostatistics, Yale University, New Haven, Connecticut, USA 3 The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA 4 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China 5 Washington University School of Medicine, St. Louis, Missouri, USA Correspondence to: Elizabeth B. Perry, email: // Richard M. White, email: // Keywords : restriction-site associated DNA sequencing, RADseq, cancer, next-generation sequencing, tumor evolution Received : April 09, 2017 Accepted : May 12, 2017 Published : June 03, 2017 Abstract Summary: Cancer is an evolutionary disease, and there is increasing interest in applying tools from evolutionary biology to understand cancer progression. Restriction-site associated DNA sequencing (RADseq) was developed for the field of evolutionary genetics to study adaptation and identify evolutionary relationships among populations. Here we apply RADseq to study tumor evolution, which allows for unbiased sampling of any desired frequency of the genome, overcoming the selection bias and cost limitations inherent to exome or whole-genome sequencing. We apply RADseq to both human pancreatic cancer and zebrafish melanoma samples. Using either a low-frequency (SbfI, 0.4% of the genome) or high-frequency (NsiI, 6-9% of the genome) cutter, we successfully identify single nucleotide substitutions and copy number alterations in tumors, which can be augmented by performing RADseq on sublineages within the tumor. We are able to infer phylogenetic relationships between primary tumors and metastases. These same methods can be used to identify somatic mosaicism in seemingly normal, non-cancerous tissues. Evolutionary studies of cancer that focus on rates of tumor evolution and evolutionary relationships among tumor lineages will benefit from the flexibility and efficiency of restriction-site associated DNA sequencing.
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