2023年 · 第136卷第14期

Cellular immune responses as well as generalized and periarticular bone loss are the key pathogenic features of rheumatoid arthritis (RA). Under the pathological conditions of RA, dysregulated inflammation and immune processes tightly interact with skeletal system, resulting in pathological bone damage via inhibition of bone formation or induction of bone resorption. Single-cell omics technologies are revolutionary tools in the field of modern biological research. They enable the display of the state and function of cells in various environments from a single-cell resolution, thus making it conducive to identify the dysregulated molecular mechanisms of bone destruction in RA as well as the discovery of potential therapeutic targets and biomarkers. Here, we summarize the latest findings of single-cell omics technologies in osteoimmunology research in RA. These results suggest that single-cell omics have made significant contributions to transcriptomics and dynamics of specific cells involved in bone remodeling, providing a new direction for our understanding of cellular heterogeneity in the study of osteoimmunology in RA.

Copper plays an important role in many metabolic activities in the human body. Copper level in the human body is in a state of dynamic equilibrium. Recent research on copper metabolism has revealed that copper dyshomeostasis can cause cell damage and induce or aggravate some diseases by affecting oxidative stress, proteasome, cuprotosis, and angiogenesis. The liver plays a central role in copper metabolism in the human body. Research conducted in recent years has unraveled the relationship between copper homeostasis and liver diseases. In this paper, we review the available evidence of the mechanism by which copper dyshomeostasis promotes cell damage and the development of liver diseases, and identify the future research priorities.

A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its performance in other populations is unknown. A functional PRS (fPRS) using functional SNPs (fSNPs) may improve the generalizability of the PRS across populations with distinct ethnicities.

We performed functional annotations on SNPs in strong linkage disequilibrium (LD) with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation. Subsequently, we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort. Finally, the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer.

During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases, we found no significant association between the PRS-112 and gastric cancer risk in the European population (hazard ratio [HR] = 1.00 [95% confidence interval (CI) 0.93–1.09], P = 0.846). We identified 125 fSNPs, including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs, and used them to construct the fPRS-125. Our result showed that the fPRS-125 was significantly associated with gastric cancer risk (HR = 1.11 [95% CI, 1.03–1.20], P = 0.009). Compared to participants with a low fPRS-125 (bottom quintile), those with a high fPRS-125 (top quintile) had a higher risk of incident gastric cancer (HR = 1.43 [95% CI, 1.12–1.84], P = 0.005). Moreover, we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer (HR = 4.99 [95% CI, 1.55-16.10], P = 0.007) compared to those with both a favorable lifestyle and a low genetic risk.

These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.

Textbook outcome (TO) can guide decision-making among patients and clinicians during preoperative patient selection and postoperative quality improvement. We explored the factors associated with achieving a TO for gallbladder carcinoma (GBC) after curative-intent resection and analyzed the effect of adjuvant chemotherapy (ACT) on TO and non-TO patients.

A total of 540 patients who underwent curative-intent resection for GBC at the Department of Hepatobiliary Surgery of the First Affiliated Hospital of Xi’an Jiaotong University from January 2011 to December 2020 were retrospectively analyzed. Multivariable logistic regression was used to investigate the factors associated with TO.

Among 540 patients with GBC who underwent curative-intent resection, 223 patients (41.3%) achieved a TO. The incidence of TO ranged from 19.0% to 51.0% across the study period, with a slightly increasing trend over the study period. The multivariate analysis showed that non-TO was an independent risk factor for prognosis among GBC patients after resection (P = 0.003). Age ≤60 years (P = 0.016), total bilirubin (TBIL) level ≤34.1 μmol/L (P <0.001), well-differentiated tumor (P = 0.008), no liver involvement (P <0.001), and T1-2 stage disease (P = 0.006) were independently associated with achieving a TO for GBC after resection. Before and after propensity score matching (PSM), the overall survival outcomes of non-TO GBC patients who received ACT and those who did not were statistically significant; ACT improved the prognosis of patients in the non-TO group (P <0.05).

Achieving a TO is associated with a better long-term prognosis among GBC patients after curative-intent resection, and ACT can improve the prognosis of those with non-TO.

With the development of traditional Chinese medicine research, berberine has shown good efficacy and safety in the eradication of Helicobacter pylori (H. pylori). The present study aimed to evaluate the efficacy and safety of triple therapy containing berberine, amoxicillin, and vonoprazan for the initial treatment of H. pylori.

This study was a single-center, open-label, parallel, randomized controlled clinical trial. Patients with H. pylori infection were randomly (1: 1: 1) assigned to receive berberine triple therapy (berberine 500 mg, amoxicillin 1000 mg, vonoprazan 20 mg, A group), vonoprazan quadruple therapy (vonoprazan 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, colloidal bismuth tartrate 220 mg, B group), or rabeprazole quadruple therapy (rabeprazole 10 mg, amoxicillin 1000 mg, clarithromycin 500 mg, colloidal bismuth tartrate 220 mg, C group). The drugs were taken twice daily for 14 days. The main outcome was the H. pylori eradication rate. The secondary outcomes were symptom improvement rate, patient compliance, and incidence of adverse events. Furthermore, factors affecting the eradication rate of H. pylori were further analyzed.

A total of 300 H. pylori-infected patients were included in this study, and 263 patients completed the study. An intention-to-treat (ITT) analysis showed that the eradication rates of H. pylori in berberine triple therapy, vonoprazan quadruple therapy, and rabeprazole quadruple therapy were 70.0% (70/100), 77.0% (77/100), and 69.0% (69/100), respectively. The per-protocol (PP) analysis showed that the eradication rates of H. pylori in these three groups were 81.4% (70/86), 86.5% (77/89), and 78.4% (69/88), respectively. Both ITT analysis and PP analysis showed that the H. pylori eradication rate did not significantly differ among the three groups (P >0.05). In addition, the symptom improvement rate, overall adverse reaction rate, and patient compliance were similar among the three groups (P >0.05).

The efficacy of berberine triple therapy for H. pylori initial treatment was comparable to that of vonoprazan quadruple therapy and rabeprazole quadruple therapy, and it was well tolerated. It could be used as one choice of H. pylori initial treatment.

ClinicalTrials.gov, No. NCT05014334

Breast cancer is one of the most common cancer in women and a proportion of patients experiences brain metastases with poor prognosis. The study aimed to construct a novel predictive clinical model to evaluate the overall survival (OS) of patients with postoperative brain metastasis of breast cancer (BCBM) and validate its effectiveness.

From 2010 to 2020, a total of 310 female patients with BCBM were diagnosed in The Affiliated Cancer Hospital of Xinjiang Medical University, and they were randomly assigned to the training cohort and the validation cohort. Data of another 173 BCBM patients were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database as an external validation cohort. In the training cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression model was used to determine the fundamental clinical predictive indicators and the nomogram was constructed to predict OS. The model capability was assessed using receiver operating characteristic, C-index, and calibration curves. Kaplan-Meier survival analysis was performed to evaluate clinical effectiveness of the risk stratification system in the model. The accuracy and prediction capability of the model were verified using the validation and SEER cohorts.

LASSO Cox regression analysis revealed that lymph node metastasis, molecular subtype, tumor size, chemotherapy, radiotherapy, and lung metastasis were statistically significantly correlated with BCBM. The C-indexes of the survival nomogram in the training, validation, and SEER cohorts were 0.714, 0.710, and 0.670, respectively, which showed good prediction capability. The calibration curves demonstrated that the nomogram had great forecast precision, and a dynamic diagram was drawn to increase the maneuverability of the results. The Risk Stratification System showed that the OS of low-risk patients was considerably better than that of high-risk patients (P < 0.001).

The nomogram prediction model constructed in this study has a good predictive value, which can effectively evaluate the survival rate of patients with postoperative BCBM.

Currently, the effect of the 2022 nationwide coronavirus disease 2019 (COVID-19) wave on the perioperative prognosis of surgical patients in China is unclear. Thus, we aimed to explore its influence on postoperative morbidity and mortality in surgical patients.

An ambispective cohort study was conducted at Xijing Hospital, China. We collected 10-day time-series data from December 29 until January 7 for the 2018–2022 period. The primary outcome was major postoperative complications (Clavien–Dindo class III–V). The association between COVID-19 exposure and postoperative prognosis was explored by comparing consecutive 5-year data at the population level and by comparing patients with and without COVID-19 exposure at the patient level.

The entire cohort consisted of 3350 patients (age: 48.5 ± 19.2 years), including 1759 females (52.5%). Overall, 961 (28.7%) underwent emergency surgery, and 553 (16.5%) had COVID-19 exposure (from the 2022 cohort). At the population level, major postoperative complications occurred in 5.9% (42/707), 5.7% (53/935), 5.1% (46/901), 9.4% (11/117), and 22.0% (152/690) patients in the 2018–2022 cohorts, respectively. After adjusting for potential confounding factors, the 2022 cohort (80% patients with COVID-19 history) had a significantly higher postoperative major complication risk than did the 2018 cohort (adjusted risk difference [aRD], 14.9% (95% confidence interval [CI], 11.5–18.4%); adjusted odds ratio [aOR], 8.19 (95% CI, 5.24–12.81)). At the patient level, the incidence of major postoperative complications was significantly greater in patients with (24.6%, 136/553) than that in patients without COVID-19 history (6.0% [168/2797]; aRD, 17.8% [95% CI, 13.6–22.1%]; aOR, 7.89 [95% CI, 5.76–10.83]). Secondary outcomes of postoperative pulmonary complications were consistent with primary findings. These findings were verified through sensitivity analyses using time-series data projections and propensity score matching.

Based on a single-center observation, patients with recent COVID-19 exposure were likely to have a high incidence of major postoperative complications.

NCT05677815 at https://clinicaltrials.gov/.

Angiogenesis is described as a complex process in which new microvessels sprout from endothelial cells of existing vasculature. This study aimed to determine whether long non-coding RNA (lncRNA) H19 induced the angiogenesis of gastric cancer (GC) and its possible mechanism.

Gene expression level was determined by quantitative real-time polymerase chain reaction and western blotting. Cell counting kit-8, transwell, 5-Ethynyl-2′-deoxyuridine (EdU), colony formation assay, and human umbilical vein endothelial cells (HUVECs) angiogenesis assay as well as Matrigel plug assay were conducted to study the proliferation, migration, and angiogenesis of GC in vitro and in vivo. The binding protein of H19 was found by RNA pull-down and RNA Immunoprecipitation (RIP). High-throughput sequencing was performed and next Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted to analyze the genes that are under H19 regulation. Methylated RIP (me-RIP) assay was used to investigate the sites and abundance among target mRNA. The transcription factor acted as upstream of H19 was determined through chromatin immunoprecipitation (ChIP) and luciferase assay.

In this study, we found that hypoxia-induced factor (HIF)-1α could bind to the promoter region of H19, leading to H19 overexpression. High expression of H19 was correlated with angiogenesis in GC, and H19 knocking down could inhibit cell proliferation, migration and angiogenesis. Mechanistically, the oncogenic role of H19 was achieved by binding with the N⁶-methyladenosine (m⁶A) reader YTH domain-containing family protein 1 (YTHDF1), which could recognize the m⁶A site on the 3′-untransated regions (3′-UTR) of scavenger receptor class B member 1 (SCARB1) mRNA, resulting in over-translation of SCARB1 and thus promoting the proliferation, migration, and angiogenesis of GC cells.

HIF-1α induced overexpression of H19 via binding with the promoter of H19, and H19 promoted GC cells proliferation, migration and angiogenesis through YTHDF1/SCARB1, which might be a beneficial target for antiangiogenic therapy for GC.

According to the latestReport of Cancer Epidemiology in China,^[1]published by the National Cancer Center (NCC), lung cancer is the malignancy with the highest incidence in China (57.26/100,000). We have developed theEvaluation of Pulmonary Nodules: Clinical Practice Consensus Guidelines for Asia,^[2]and theChinese Expert Consensus on the Diagnosis and Treatment of Pulmonary Nodules.^[3]To enhance the early diagnosis of lung cancer and improve the prognosis, we also developed theChinese Expert Consensus on the Screening and Management of Lung Cancer.^[4]However, challenges remain in clinical practice, therefore, the Chinese Alliance Against Lung Cancer (CAALC) invited clinical, information technology (IT), and health economics experts to discuss these issues, and drafted this document,Criteria for Lung Cancer Screening and Standardized Management in China.^[5]

As the efficacy of programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors combined with chemotherapy in curing breast cancer is still controversial, this meta-analysis compares the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy and chemotherapy alone in the treatment of breast cancer, which provides guidance for the clinical treatment.

Relevant studies published as of April 2022 in the various databases including EMBASE, PubMed, and Cochrane Library were selected. Randomized controlled trials (RCTs) in which control patients underwent chemotherapy alone and experimental group patients underwent combination chemotherapy and PD-1/PD-L1 inhibitor treatment were included in this investigation. Investigations without complete information, researches from which information could not be extracted, duplicate articles, animal studies, review articles, and systematic reviews were excluded. STATA 15.1 was employed for all statistical analyses.

In total, eight eligible studies were identified, revealing that combination chemotherapy and PD-1/PD-L1 inhibitor treatment was linked to significant increases in progression-free survival (PFS) relative to chemotherapy alone (hazard ratio [HR] = 0.83, 95% confidence interval [CI]: 0.70–0.99, P = 0.032) but not overall survival (HR = 0.92, 95% CI: 0.80–1.06, P = 0.273). Pooled adverse event rates were also increased within the group of combination treatment relative to the chemotherapy group (risk ratio [RR] = 1.08, 95% CI: 1.03–1.14, P = 0.002). Specifically, nausea rates were lesser within the group of combination treatment relative to the group of chemotherapy (RR = 0.48, 95% CI: 0.25–0.92, P = 0.026). Subgroup analyses indicated that the PFS of patients who underwent combination atezolizumab or pembrolizumab and chemotherapy treatment were substantially longer than those of patients who underwent chemotherapy alone (HR = 0.79, 95% CI: 0.69-0.89, P ≤0.001; HR = 0.79, 95% CI: 0.67–0.92, P = 0.002).

The pooled results suggest that combination chemotherapy and PD-1/PD-L1 inhibitor treatment approaches help prolong PFS in breast cancer patients, but have no statistically significant effect on overall survival (OS). Additionally, combination therapy can significantly improve complete response rate (CRR) compared with chemotherapy alone. However, combination therapy was associated with greater rates of adverse events.

To the Editor:Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by abnormal and excessive accumulation of pulmonary surfactant in the alveolar cavity. Cases of PAP are usually categorized into three etiological forms: congenital, secondary, and idiopathic PAP. Whole-lung lavage (WLL) has been widely used to treat PAP.^[1]According to the literature, case reports of PAP associated with lung cancer are rare. Furthermore, to our knowledge, few cases of PAP with lung cancer receiving definitive thoracic radiation therapy (TRT) has been reported. Herein, we reported a case of PAP associated with limited stage-small cell lung cancer (LS-SCLC), which was treated using a combination of chemotherapy and sequential TRT. Unexpectedly, the patient’s clinical and radiographical abnormalities of PAP were completely relieved after TRT.

Hypertension, also known as high blood pressure, is a serious medical condition that may cause severe health problems, such as heart attack and stroke. According to the World Health Organization (WHO),^[1]an estimated 1.28 billion adults worldwide aged 30–79 years had hypertension in 2021, two-third of whom were living in low- and middle-income countries. Many national and international clinical practice guidelines (CPGs) on the diagnosis, evaluation, and treatment of hypertension have been published to promote its control. Among these, comprehensive hypertension guidelines provide broader direction to more target users, especially primary healthcare practitioners, than "narrow" types of guidelines. The credibility of hypertension guidelines is of great concern to stakeholders. Many researchers have used the Appraisal of Guidelines for REsearch & Evaluation (AGREE) instrument and the Reporting Items for practice Guidelines in HealThcare (RIGHT) checklist to evaluate the quality of hypertension guidelines. However, due to the development of guideline methodology and the continuous publication of new evidence on hypertension, the earlier results may no longer reflect the present status of hypertension guidelines. The purpose of this study was to assess the methodological and reporting quality of comprehensive hypertension guidelines published in the past 6 years, find the main problems, and, based on the present situation, specifically address the situation in China to evaluate the need for new guidelines for hypertension.

To the Editor:Despite optimal secondary prevention treatments, a large proportion of patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI) are still at a high risk of recurrent cardiovascular events. Inflammation is a well-known component of residual cardiovascular risk and contributes to progression of atherosclerosis, leading to destabilization and rupture of atheroma plaques.^[1]As a downstream protein in the activated inflammatory pathway that mediates the progression of atherosclerosis, high-sensitivity C-reactive protein (hsCRP) is widely used as a biomarker of inflammatory status and predictor of adverse outcomes in the settings of primary and secondary prevention of cardiovascular disease. Obesity is regarded as a growing global burden and also a remarkable risk factor for cardiovascular disease. Several studies have previously proposed and tested the hypothesis that body mass index (BMI) could modify the association between hsCRP and cardiovascular risk.^[2,3]However, the relationship is not clear in CAD patients. Therefore, we aimed to examine the interrelationship of BMI, hsCRP, and long-term outcomes after PCI based on a large, prospective cohort.

To the Editor: Bile reflux (BR), also known as duodenogastric reflux, refers to the reflux of duodenal contents such as bile, pancreatic juice, and duodenal juice into the stomach. BR that occurs without gastric surgery is called primary bile reflux (PBR).^[1]A retrospective study showed that the prevalence of PBR in patients with chronic gastritis was as high as 20.5%.^[2]BR can contribute to the development of upper gastrointestinal diseases,^[3,4,5]but the corresponding risk factors are currently unknown. We aimed to identify the related risk factors for PBR.

To the Editor: Multiple myeloma (MM) is a plasma cell disorder characterized by heterogeneous features.^[1]Accurate risk stratification could predict diverse prognoses of patients with myeloma and attain risk-adapted therapy to extend their lifespan. Recently, the European Myeloma Network (EMN) conducted a large retrospective analysis involving more than 7000 patients with myeloma and developed a new risk model defined as the Second Revision of International Staging System (R2-ISS), with excellent risk distribution among patients enrolled in clinical trials.^[2]The R2-ISS stratifications were based on weighted risk scores of different prognostic factors: ISS II 1.0 point, ISS III 1.5 points, del(17p) 1.0 point, elevated lactate dehydrogenase (LDH) 1.0 point, t(4;14) 1.0 point, and 1q21+ 0.5 points. In terms of cumulative total scores, patients were further distributed into four risk groups: R2-ISS I (0 points), II (0.5–1.0 points), III (1.5-2.5 points), and IV (3.0–5.0 points). However, the evidence about the applicability and predictive performance of the R2-ISS in the real world was limited. Thus, this study aimed to determine whether R2-ISS was valid for patients with MM undergoing real-world treatment patterns in China.

To the Editor:Total knee arthroplasty (TKA) has became an established treatment for end-stage joint disease. In China, there was a 5.9-fold increase in the number of TKA cases between 2011 and 2019. All kinds of infections are catastrophic complications of TKA. Recent reports have highlighted the underestimated prevalence of surgical site infections (SSIs) and projected an increase in complex SSIs following hip and knee arthroplasties by 14% between 2020 and 2030.^[1]However, there are few reports describing SSIs in Chinese population. This preliminary retrospective study aimed to gain some insights into the occurrence, risk factors, and microbiological patterns of SSIs in China.

To the Editor: Wilms tumor, or nephroblastoma, is the most frequently diagnosed pediatric kidney cancer, accounting for >90% of all renal tumors in children 1–7 years old, and the disease may be related to genetic factors.^[1]As an emerging research spot, the epitranscriptome has been implicated in different RNA modifications in human diseases, including cancers.^[2]Methyltransferase-like 1 (METTL1), a critical RNA N7-methylguanosine (m7G) methyltransferase, can catalyze the formation of a m7G modification (mostly at nucleotide position 46 in the variable region of transfer RNAs [tRNAs]) by complexing with WD repeat domain 4 (WDR4). Depending on the different positions, the tRNA m7G modifications have various functions. In particular, the tRNA modifications located in the anticodon region play a crucial role in translation and growth, while those outside the anticodon region are responsible for the regulation of tRNA folding, stability, and protein synthesis. The m7G modification is evolutionarily conserved and has more complicated and important physiological functions in mammals.^[3]Increasing evidence strongly supports that the dysregulation or mutation ofMETTL1m7G methyltransferase is closely associated with tumorigenesis and poor prognosis.^[2]Mechanistically, an underlying molecular mechanism has been identified for howMETTL1-mediated m7G modification leads to malignant transformation and tumorigenesis. Orellanaet al^[2]discovered that an m7G modification of tRNAs is upregulated in certain cancers, and this process is catalyzed by theMETTL1/WDR4complex. The m7G-modified tRNAs can decode the corresponding oncogenic and cell cycle-regulating messenger RNAs (mRNAs) that are enriched in m7G-tRNAs-dependent codons without ribosomal collisions, thereby facilitating the translation of these mRNAs and potential malignant transformations of cells.

To the Editor: Advanced carbohydrate counting (CC) is a recommended dietary strategy and necessary nutritional knowledge for individuals with type 1 diabetes mellitus (T1DM).^[1]Evidence supports the positive effects of advanced CC on glucose control, quality of life, and food flexibility.^[2]However, the education and awareness of advanced CC are far from ideal for T1DM patients and even healthcare professionals.^[3]Accordingly, a measure for T1DM patients that quantifies their understanding of such nutrition knowledge would be essential for tailored care.

To the Editor: Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age. PCOS is characterized by infrequent or absent ovulation, high androgen levels, and hyperinsulinaemia. Androgenic excess is the main pathophysiological mechanism of the disease. Metformin can lower insulin and androgen levels, increase estradiol levels, and induce ovulation.^[1]Pioglitazone can increase the sensitivity of peripheral tissues to insulin, improve insulin resistance, reduce androgen levels, restore the menstrual cycle, and promote ovulation.^[2]Despite extensive research, the molecular mechanisms that mediate the beneficial effects of metformin or pioglitazone in the treatment of PCOS are still unclear. There are also differences in individual patient responses to drugs. Reportedly, genetic factors may contribute to this variability.^[3]The effects of coding single nucleotide polymorphisms (SNPs) in organic cation transporter 1 (OCT1) on the uptake and thus efficacy of metformin have been extensively investigated previously.^[4,5]Moreover, lipin-1 is required at an early step in adipocyte differentiation for the induction of the adipogenic gene transcription program, including the key regulator peroxisome proliferator-activated receptor γ (PPARγ).^[6]To date,LPIN1polymorphisms have been reported to be associated with type 2 diabetes and metabolic syndrome.^[7]Therefore, in this study, we aimed to determine the influence of genetic polymorphisms inOCT1andLPIN1on the response to pioglitazone-metformin tablets in 30 patients with PCOS.

To the Editor:Approximately 15 million preterm babies, i.e., those delivered at <37 weeks of gestational age (GA), are born globally every year, and of them, 0.4% are extremely premature infants (EPIs), i. e., those delivered at <28 weeks of GA.^[1]Iterations of neonatal care have significantly extended the viability of preterm babies. However, improved viability is accompanied by an increased risk of unreversed injuries, such as bronchopulmonary dysplasia and intraventricular hemorrhage. Therefore, a more physiological simulatingin uterostatus is needed to protect EPIs’ immature organs during the transitional period and ensure that they develop in the same manner that they would have in the womb.