Pan-cancer analysis of CDKN2A alterations identifies a subset of gastric cancer with a cold tumor immune microenvironment.

BACKGROUND: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer. METHODS: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT). RESULTS: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response. CONCLUSIONS: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.

Trends in cardiovascular health among US adults by glycemic status based on Life's Essential 8.

OBJECTIVE: We aimed to assess the secular trends in cardiovascular health (CVH) among U.S. adults with different glycemic statuses based on the Life's Essential 8 (LE8). METHODS: This cross-sectional study used nationally representative data from 6 cycles of the National Health and Nutrition Examination Surveys between 2007 and 2018. Survey-weighted linear models were used to assess time trends in LE8 scores. Stratified analyses and sensitivity analyses were conducted to validate the stability of the results. RESULTS: A total of 23,616 participants were included in this study. From 2007 to 2018, there was no significant improvement in overall CVH and the proportion of ideal CVH among participants with diabetes and prediabetes. We observed an opposite trend between health behavior and health factors in the diabetes group, mainly in increasing physical activity scores and sleep scores (P for trend<0.001), and declining BMI scores [difference, -6.81 (95% CI, -12.82 to -0.80)] and blood glucose scores [difference, -6.41 (95% CI, -9.86 to -2.96)]. Dietary health remained at a consistently low level among participants with different glycemic status. The blood lipid scores in the prediabetes group improved but were still at a lower level than other groups. Education/income differences persist in the CVH of participants with diabetes or prediabetes, especially in health behavior factors. Sensitivity analyses of the absolute difference and change in proportion showed a consistent trend. CONCLUSIONS: Trends in CVH among participants with diabetes or prediabetes were suboptimal from 2007 to 2018, with persistent education/income disparities.

Neuron-derived exosomes mediate sevoflurane-induced neurotoxicity in neonatal mice via transferring lncRNA Gas5 and promoting M1 polarization of microglia.

Sevoflurane exposure during rapid brain development induces neuronal apoptosis and causes memory and cognitive deficits in neonatal mice. Exosomes that transfer genetic materials including long non-coding RNAs (lncRNAs) between cells play a critical role in intercellular communication. However, the lncRNAs found in exosomes derived from neurons treated with sevoflurane and their potential role in promoting neurotoxicity remain unknown. In this study, we investigated the role of cross-talk of newborn mouse neurons with microglial cells in sevoflurane-induced neurotoxicity. Mouse hippocampal neuronal HT22 cells were exposed to sevoflurane, and then co-cultured with BV2 microglial cells. We showed that sevoflurane treatment markedly increased the expression of the lncRNA growth arrest-specific 5 (Gas5) in neuron-derived extracellular vesicles, which inhibited neuronal proliferation and induced neuronal apoptosis by promoting M1 polarization of microglia and the release of inflammatory cytokines. We further revealed that the exosomal lncRNA Gas5 significantly upregulated Foxo3 as a competitive endogenous RNA of miR-212-3p in BV2 cells, and activated the NF-κB pathway to promote M1 microglial polarization and the secretion of inflammatory cytokines, thereby exacerbating neuronal damage. In neonatal mice, intracranial injection of the exosomes derived from sevoflurane-treated neurons into the bilateral hippocampi significantly increased the proportion of M1 microglia, inhibited neuronal proliferation and promoted apoptosis, ultimately leading to neurotoxicity. Similar results were observed in vitro in BV2 cells treated with the CM from HT22 cells after sevoflurane exposure. We conclude that sevoflurane induces the transfer of lncRNA Gas5-containing exosomes from neurons, which in turn regulates the M1 polarization of microglia and contributes to neurotoxicity. Thus, modulating the expression of lncRNA Gas5 or the secretion of exosomes could be a strategy for addressing sevoflurane-induced neurotoxicity.

Palmitoyltransferase ZDHHC3 is essential for the oncogenic activity of PML/RARα in acute promyelocytic leukemia.

The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.

The Success of Mifepristone and Misoprostol in the Management of Early Pregnancy Loss at a Community Hospital: A Prospective Study.

OBJECTIVES: This prospective single-arm study was conducted to understand the expulsion rate of the gestational sac in the management of early pregnancy loss (EPL). METHODS: We recruited 441 participants; 188 met the eligibility criteria. Participants were 18 years of age and older who experienced a confirmed EPL (<12 weeks gestational age) defined by an intrauterine pregnancy with a non-viable embryonic or anembryonic gestational sac with no fetal heart activity. Participants were given 200 mg of mifepristone pre-treatment orally followed by 2 doses of misoprostol 800 µg vaginally after 24 and 48 hours. Participants were seen in follow-up on day 14 to confirm the absence of a gestational sac, classified as treatment success. For failed treatment (defined by retained gestational sac), we offered expectant management or a third dose of misoprostol and/or dilatation and curettage. We followed all participants for 30 days. We collected data on overtreatment for retained products of conception and hospital admissions for adverse events. RESULTS: Overall, 181 participants followed the protocol and 169 (93.3%) participants had a complete expulsion of the gestational sac by the second visit (day 14). Twelve (6.6%) failed the treatment and 1 had an adverse event of heavy vaginal bleeding requiring dilatation and curettage. Despite the expulsion of the gestational sac, 29 cases (17.1%) at subsequent follow-up were diagnosed as retained products of conception based on ultrasound assessment of thickened endometrium. CONCLUSIONS: Pretreatment with mifepristone followed by 2 doses of misoprostol with a 14-day follow-up resulted in a high expulsion rate and is a safe management option for EPL.

The Principles of Hip Joint Preservation.

The 3 primary factors involved with preservation of the hip joint are femoroacetabular impingement (FAI), hip dysplasia, and femoral torsion abnormalities. Each of these factors affects the health of the acetabular labrum and femoroacetabular cartilage. The appropriate surgical treatments for each of these factors include arthroscopic or open femoroplasty or acetabuloplasty for FAI, periacetabular osteotomy (PAO) for acetabular dysplasia, and de-rotational femoral osteotomy for femoral torsion abnormalities. When evaluating patients with prearthritic hip conditions, orthopaedic surgeons should be aware of the various factors involved in hip joint preservation and, if surgery is indicated, surgeons should be sure to address all factors that need surgical treatment rather than focusing on the most obvious issue or injury (e.g., a labral tear). The purpose of this infographic is to illustrate the importance of the factors involved in hip joint preservation and the appropriate treatments for pathology in any of these factors.

During Postless Hip Arthroscopy, Male Patients, High Body Mass Index, Low Beighton Scores, and Limited Range of Motion Require High Traction Force.

PURPOSE: To determine the effects of demographic and anatomic factors on traction force required during postless hip arthroscopy. METHODS: A prospectively collected database was retrospectively analyzed on patients undergoing hip arthroscopy by the senior author, including patient sex, age, body mass index (BMI), Beighton Hypermobility Score, hip range of motion in clinic and under anesthesia, hip dysplasia, acetabular version, and femoral version. All patients underwent postless hip arthroscopy under general anesthesia. At the initiation of hip arthroscopy, the traction force required to distract the hip joint was measured before and following interportal capsulotomy. Multiple regression analysis was performed to determine the effects of demographic and anatomic factors on measured distraction force. RESULTS: In total, 352 hips (114 male, 238 female) were included with a mean age of 32.6 years and a mean BMI of 24.1 kg/m2. Mean initial traction force was 109 lbs and decreased to 94.3 lbs following capsulotomy (P < .0001). The starting traction force was significantly greater in male patients (P < .001), patients with a lack of hypermobility (Beighton Hypermobility Score of 0-2) (P = .026), and in patients with lower abduction (P < .001), lower internal rotation (P = .002), and lower external rotation (P = .012) on multiple regression analysis. When performing a subanalysis divided by sex, male patients with elevated BMI required significantly greater starting traction force (P = .014). Lateral center edge angle, sourcil angle, and the presence of hip dysplasia did not demonstrate a significant correlation with traction force. CONCLUSIONS: Male patients, patients with reduced preoperative hip range of motion, patients with a lack of joint hypermobility, and male patients with an elevated BMI require greater initial traction force during postless hip arthroscopy. LEVEL OF EVIDENCE: Level IV, retrospective case series.

The Windshield Wiper Sign Is an Instability-Related Osteochondral Defect of the Anterolateral Femoral Head.

PURPOSE: To investigate a radiographic sign believed to be indicative of hip instability and acetabular suction seal disruption in the native hip, coined the "windshield wiper" (WSW) sign. METHODS: A retrospective review was performed for patients who underwent periacetabular osteotomy (PAO) with the senior author between March 2021 and September 2023. A WSW sign was identified on plain films as a concave or flat osteochondral defect on the anterolateral femoral head extending medial to the head-neck junction with resultant loss of femoral head sphericity in the native hip. Every patient underwent a standardized series of radiographs, as well as computed tomography and magnetic resonance imaging. All patients underwent arthroscopy before PAO to address intra-articular pathology and other indicated procedures. The osteochondral defect and resultant suction seal disruption were verified during arthroscopy. These patients were then compared with a control group of arthroscopically treated hips without hip instability. RESULTS: Of 250 patients reviewed, a total of 19 hips in 17 patients (prevalence of 7.6%) demonstrated radiographic evidence of the WSW sign. All patients with a WSW sign presented with symptomatic clinical hip instability requiring a PAO. The mean patient age was 31.2 years, with a mean lateral center-edge angle (LCEA) of 14.3°. There were 13 hips (68.4%) with dysplasia, 4 (21.1%) with borderline dysplasia, and 2 (10.5%) with a normal LCEA. All patients with a WSW sign and LCEA ≥ 20° displayed significant femoral antetorsion abnormalities. All arthroscopic videos and images demonstrated a compromised suction seal. Of the 50 control group hips reviewed, the WSW sign was not identified. CONCLUSIONS: The WSW sign is an uncommon radiographic finding in patients with hip instability. When identified, it can be predictive of substantial instability, especially in cases which are otherwise considered borderline dysplasia or normal based on LCEA. LEVEL OF EVIDENCE: Level III, retrospective comparative case control study.

Patients Undergoing Postless Hip Arthroscopy Demonstrate Significantly Better Patient-Reported Outcomes and Clinically Significant Outcomes Compared to Conventional Post-Assisted Hip Arthroscopy at Short-Term Follow-Up.

PURPOSE: To prospectively compare the short-term clinical outcomes of patients undergoing hip arthroscopy with versus without the use of a perineal post. METHODS: A prospective, single-surgeon cohort study was performed on a subset of patients undergoing hip arthroscopy between 2020 and 2022. A post-free hip distraction system was used at 1 center at which the senior author operates, and a perineal post was used at another surgical location. An electronic survey of patient-reported outcome measures (PROMs) was completed by each patient at a minimum of 1 year postoperatively. PROMs included a visual analog scale for pain; University of California, Los Angeles (UCLA) Activity Scale; modified Harris Hip Score (mHHS); Hip Outcome Score-Sports-Specific Subscale (HOS-SSS); and a Single Assessment Numeric Evaluation. Postoperative scores and clinically significant outcomes, including the minimal clinically important difference, substantial clinical benefit, and patient acceptable symptom state, for each PROM were compared between groups. RESULTS: Sixty-nine patients were reached for follow-up (41 post, 28 postless) of 87 patients eligible for the study (79%). No significant differences were found between groups in terms of sex (post: 61% female, postless: 54% female, P = .54), age (post: 34 years, postless: 29 years, P = .11), body mass index (post: 26, postless: 24, P = .23), or follow-up duration (post: 24.4 months, postless: 21.3 months, P = .16). There was a significantly higher visual analog scale (3.1 vs 1.4, P = .01), a significantly lower UCLA Activity Scale score (7.0 vs 8.4, P = .02), and a significantly lower mHHS (73.7 vs 82.2, P = .03) in the post-assisted group. A significantly higher proportion of patients in the postless group achieved a patient acceptable symptom state for the UCLA (89.3% vs 68.3%, P = .04), mHHS (84.6% vs 61.0%, P = .04), and HOS-SSS (84.0% vs 61.0%, P = .048) and a substantial clinical benefit for HOS-SSS (72.0% vs 41.5%, P = .02). One patient (2.6%) in the post group underwent revision hip arthroscopy, and another was indicated for total hip arthroplasty by the time of follow-up. CONCLUSIONS: Postless hip arthroscopy may result in better clinical outcomes compared with post-assisted hip arthroscopy. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Bridging the notch: quantification of the end diastolic notch to better predict fetal growth restriction.

PURPOSE: We aimed to evaluate several quantitative methods to describe the diastolic notch (DN) and compare their performance in the prediction of fetal growth restriction. MATERIALS AND METHODS: Patients who underwent a placental scan at 16-26 weeks of gestation and delivered between Jan 2016 and Dec 2020 were included. The uterine artery pulsatility index was measured for all of the patients. In patients with a DN, it was quantified using the notch index and notch depth index. Odds ratios for small for gestational age neonates (defined as birth weight <10th and <5th percentile) were calculated. Predictive values of uterine artery pulsatility, notch, and notch depth index for fetal growth restriction were calculated. RESULTS: Overall, 514 patients were included, with 69 (13.4%) of them delivering a small for gestational age neonate (birth weight<10th percentile). Of these, 20 (20.9%) had a mean uterine artery pulsatility index >95th percentile, 13 (18.8%) had a unilateral notch, and 11 (15.9%) had a bilateral notch. 16 patients (23.2%) had both a high uterine artery pulsatility index (>95th percentile) and a diastolic notch. Comparison of the performance between uterine artery pulsatility, notch, and notch depth index using receiver operating characteristic curves to predict fetal growth restriction <10th percentile found area under the curve values of 0.659, 0.679, and 0.704, respectively, with overlapping confidence intervals. CONCLUSION: Quantifying the diastolic notch at 16-26 weeks of gestation did not provide any added benefit in terms of prediction of neonatal birth weight below the 10th or 5th percentile for gestational age, compared with uterine artery pulsatility index.

A prediction tool for mode of delivery in twin pregnancies-a secondary analysis of the Twin Birth Study.

BACKGROUND: One of the controversies regarding the management of twin gestations relates to the mode of delivery. Currently, counseling regarding the mode of delivery and the chance of successful vaginal twin delivery is based on the average risk for intrapartum cesarean delivery in the general population of twin pregnancies. Decision support tools that provide an individualized risk for intrapartum cesarean delivery based on the unique characteristics of each patient can improve counseling and decision-making regarding the choice of mode of delivery in twin pregnancies. OBJECTIVE: This study aimed to develop and validate a prediction model to determine the risk for intrapartum cesarean delivery in twin pregnancies. STUDY DESIGN: In this secondary analysis of the Twin Birth Study, a multicenter randomized controlled trial, we considered the subgroup of individuals who underwent a trial of vaginal delivery. Candidate predictors included maternal age, parity, previous cesarean delivery, conception method, chorionicity, diabetes and hypertension in pregnancy, gestational age at birth, the onset of labor, presentation of the second twin, sonographic fetal weight estimation, and fetal sex. The co-primary outcomes were overall intrapartum cesarean delivery and cesarean delivery of the second twin. Multivariable logistic regression models were used to estimate the probability of the study outcomes. Model performance was evaluated using measures of discrimination (the area under the receiver operating characteristic curve), calibration, and predictive accuracy. Internal validation was performed using the bootstrap resampling technique. RESULTS: A total of 1221 individuals met the study criteria. The rate of overall intrapartum cesarean delivery and cesarean delivery for the second twin was 25.4% and 5.7%, respectively. The most contributory predictor variables were nulliparity, term birth (≥37 weeks), a noncephalic presentation of the second twin, previous cesarean delivery, and labor induction. The models for overall intrapartum cesarean delivery and cesarean delivery of the second twin had good overall discriminatory accuracy (area under the receiver operating characteristic curve, 0.720; 95% confidence interval, 0.688-0.752 and 0.736; 95% confidence interval, 0.669-0.803, respectively) and calibration (as illustrated by the calibration plot and Brier scores of 0.168; 95% confidence interval, 0.156-0.180 and 0.051; 95% confidence interval, 0.040-0.061, respectively). The models achieved good specificity (66.7% and 81.6%, respectively), high negative predictive value (86.0% and 96.9%, respectively), and moderate sensitivity (68.1% and 57.1%, respectively). CONCLUSION: The prediction models developed in this study may assist care providers in counseling individuals regarding the optimal timing and mode of delivery in twin pregnancies by providing individualized estimates of the risk for intrapartum cesarean delivery.

National and international guidelines on the management of twin pregnancies: a comparative review.

Twin gestations are associated with increased risk of pregnancy complications. However, high-quality evidence regarding the management of twin pregnancies is limited, often resulting in inconsistencies in the recommendations of various national and international professional societies. In addition, some recommendations related to the management of twin gestations are often missing from the clinical guidelines dedicated to twin pregnancies and are instead included in the practice guidelines on specific pregnancy complications (eg, preterm birth) of the same professional society. This can make it challenging for care providers to easily identify and compare recommendations for the management of twin pregnancies. This study aimed to identify, summarize, and compare the recommendations of selected professional societies from high-income countries on the management of twin pregnancies, highlighting areas of both consensus and controversy. We reviewed clinical practice guidelines of selected major professional societies that were either specific to twin pregnancies or were focused on pregnancy complications or aspects of antenatal care that may be relevant for twin pregnancies. We decided a priori to include clinical guidelines from 7 high-income countries (United States, Canada, United Kingdom, France, Germany, and Australia and New Zealand grouped together) and from 2 international societies (International Society of Ultrasound in Obstetrics and Gynecology and the International Federation of Gynecology and Obstetrics). We identified recommendations regarding the following care areas: first-trimester care, antenatal surveillance, preterm birth and other pregnancy complications (preeclampsia, fetal growth restriction, and gestational diabetes mellitus), and timing and mode of delivery. We identified 28 guidelines published by 11 professional societies from the 7 countries and 2 international societies. Thirteen of these guidelines focus on twin pregnancies, whereas the other 16 focus on specific pregnancy complications predominantly in singletons but also include some recommendations for twin pregnancies. Most of the guidelines are recent, with 15 of the 29 guidelines published over the past 3 years. We identified considerable disagreement among guidelines, primarily in 4 key areas: screening and prevention of preterm birth, using aspirin to prevent preeclampsia, defining fetal growth restriction, and the timing of delivery. In addition, there is limited guidance on several important areas, including the implications of the "vanishing twin" phenomenon, technical aspects and risks of invasive procedures, nutrition and weight gain, physical and sexual activity, the optimal growth chart to be used in twin pregnancies, the diagnosis and management of gestational diabetes mellitus, and intrapartum care.This consolidation of key recommendations across several clinical practice guidelines can assist healthcare providers in accessing and comparing recommendations on the management of twin pregnancies and identifies high-priority areas for future research based on either continued disagreement among societies or limited current evidence to guide care.

Kelch-like proteins in the gastrointestinal tumors.

Gastrointestinal tumors have become a worldwide health problem with high morbidity and poor clinical outcomes. Chemotherapy and surgery, the main treatment methods, are still far from meeting the treatment needs of patients, and targeted therapy is in urgent need of development. Recently, emerging evidence suggests that kelch-like (KLHL) proteins play essential roles in maintaining proteostasis and are involved in the progression of various cancers, functioning as adaptors in the E3 ligase complex and promoting the specific degradation of substrates. Therefore, KLHL proteins should be taken into consideration for targeted therapy strategy discovery. This review summarizes the current knowledge of KLHL proteins in gastrointestinal tumors and discusses the potential of KLHL proteins as potential drug targets and prognostic biomarkers.

Arctigenin impairs UBC12 enzyme activity and cullin neddylation to attenuate cancer cells.

Neddylation is a type of posttranslational protein modification that has been observed to be overactivated in various cancers. UBC12 is one of two key E2 enzymes in the neddylation pathway. Reports indicate that UBC12 deficiency may suppress lung cancer cells, such that UBC12 could play an important role in tumor progression. However, systematic studies regarding the expression profile of UBC12 in cancers and its relationship to cancer prognosis are lacking. In this study, we comprehensively analyzed UBC12 expression in diverse cancer types and found that UBC12 is markedly overexpressed in most cancers (17/21), a symptom that negatively correlates with the survival rates of cancer patients, including gastric cancer. These results demonstrate the suitability of UBC12 as a potential target for cancer treatment. Currently, no effective inhibitor targeting UBC12 has been discovered. We screened a natural product library and found, for the first time, that arctigenin has been shown to significantly inhibit UBC12 enzyme activity and cullin neddylation. The inhibition of UBC12 enzyme activity was newly found to contribute to the effects of arctigenin on suppressing the malignant phenotypes of cancer cells. Furthermore, we performed proteomics analysis and found that arctigenin intervened with cullin downstream signaling pathways and substrates, such as the tumor suppressor PDCD4. In summary, these results demonstrate the importance of UBC12 as a potential therapeutic target for cancer treatment, and, for the first time, the suitability of arctigenin as a potential compound targeting UBC12 enzyme activity. Thus, these findings provide a new strategy for inhibiting neddylation-overactivated cancers.

Guideline No. 440: Management of Monochorionic Twin Pregnancies.

OBJECTIVE: This guideline reviews the evidence-based management of normal and complicated monochorionic twin pregnancies. TARGET POPULATION: Women with monochorionic twin or higher order multiple pregnancies. BENEFITS, HARMS, AND COSTS: Implementation of these recommendations should improve the management of both complicated and uncomplicated monochorionic (and higher order multiple) twin pregnancies. They will help users monitor monochorionic twin pregnancies appropriately and identify and manage monochorionic twin complications optimally in a timely manner, thereby reducing perinatal morbidity and mortality. These recommendations entail more frequent ultrasound monitoring of monochorionic twins compared to dichorionic twins. EVIDENCE: Published literature was retrieved through searches of PubMed and the Cochrane Library using appropriate MeSH headings (Twins, Monozygotic; Ultrasonography, Prenatal; Placenta; Fetofetal Transfusion; Fetal Death; Fetal Growth Retardation). Results were restricted to systematic reviews, randomized controlled clinical trials, and observational studies. There were no date limits, but results were limited to English or French language materials. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the principal authors. The Board of the SOGC approved the final draft for publication. The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Maternal-fetal medicine specialists, obstetricians, radiologists, sonographers, family physicians, nurses, midwives, residents, and other health care providers who care for women with monochorionic twin or higher order multiple pregnancies. TWEETABLE ABSTRACT: Canadian (SOGC) guidelines for the diagnosis, ultrasound surveillance and management of monochorionic twin pregnancy complications, including TTTS, TAPS, sFGR (sIUGR), acardiac (TRAP), monoamniotic twins and intrauterine death of one MC twin. SUMMARY STATEMENTS: RECOMMENDATIONS.

Directive clinique no 440 : Prise en charge de la grossesse gémellaire monochoriale.

OBJECTIF: Cette directive clinique passe en revue les données probantes sur la prise en charge de la grossesse gémellaire monochoriale normale et compliquée. POPULATION CIBLE: Les femmes menant une grossesse gémellaire ou multiple de haut rang. BéNéFICES, RISQUES ET COûTS: L'application des recommandations de cette directive devrait améliorer la prise en charge des grossesses gémellaires (ou multiples de haut rang) monochoriales compliquées et non compliquées. Ces recommandations aideront les fournisseurs de soins à surveiller adéquatement les grossesses gémellaires monochoriales ainsi qu'à détecter et prendre en charge rapidement les complications associées de façon optimale afin de réduire les risques de morbidité et mortalité périnatales. Ces recommandations impliquent une surveillance échographique plus fréquente en cas de grossesse monochoriale qu'en cas de grossesse bichoriale. DONNéES PROBANTES: La littérature publiée a été colligée par des recherches dans les bases de données PubMed et Cochrane Library au moyen de termes MeSH pertinents (Twins, Monozygotic; Ultrasonography, Prenatal; Placenta; Fetofetal Transfusion; Fetal Death; Fetal Growth Retardation). Les résultats ont été restreints aux revues systématiques, aux essais cliniques randomisés et aux études observationnelles. Aucune date limite n'a été appliquée, mais les résultats ont été limités aux contenus en anglais ou en français. MéTHODES DE VALIDATION: Les auteurs principaux ont rédigé le contenu et les recommandations et ils se sont entendus sur ces derniers. Le conseil d'administration de la SOGC a approuvé la version définitive aux fins de publication. Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant le cadre méthodologique GRADE (Grading of Recommendations Assessment, Development and Evaluation). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et conditionnelles [faibles]). PROFESSIONNELS CONCERNéS: Spécialistes en médecine fœto-maternelle, obstétriciens, radiologues, échographistes, médecins de famille, infirmières, sages-femmes, résidents et autres fournisseurs de soins de santé qui s'occupent de femmes menant une grossesse gémellaire ou multiple de haut rang. RéSUMé POUR TWITTER: Directive canadienne (SOGC) pour le diagnostic, la surveillance échographique et la prise en charge des complications de la grossesse gémellaire monochoriale (p. ex., STT, TAPS, retard de croissance sélectif, cojumeau acardiaque, monoamnionicité et mort d'un jumeau). DÉCLARATIONS SOMMAIRES: RECOMMANDATIONS.

The Course and Neonatal Outcome of Choroid Plexus Extension to the Anterior Horn at the Routine Anatomy Scan.

OBJECTIVES: Our objective was to examine the pregnancy course and immediate neonatal outcome of fetuses with an isolated extension of choroid plexus (CP) to the anterior horn during the second trimester. METHODS: We prospectively collected the cases referred to us between July 2012 and January 2021 with isolated finding of CP extension to the anterior horn. Relevant clinical and demographic information was recorded, and a full anatomy scan including a comprehensive neurosonogram was performed. In cases of confirmed isolated extension of CP to the anterior horns, women were offered further investigation including fetal MRI, and ultrasound follow up. RESULTS: We collected 29 eligible cases for analysis. The mean gestational age (GA ± SD) for diagnosis and referral was 19.24 ± 2.3 weeks. No other intracranial anomalies were detected in any of the cases, and the finding resolved at 25 ± 2.6 weeks. The average extension length and width to the anterior horn were 0.7 ± 0.3 cm, and 0.5 ± 0.1 cm, respectively. Eleven fetuses (38%) had choroid plexus cyst (CPC) in addition to the extension. Ten patients (35%) completed a fetal brain MRI, with no identified abnormalities. Gross neurological exam and Apgar score at birth were normal. CONCLUSION: Extension of CP to anterior horn with or without CPC at mid-trimester seems to have spontaneous resolution with likely a good prognosis and no further implications.

The smaller firstborn: exploring the association of parity and fetal growth.

PURPOSE: To investigate the association of parity with a range of neonatal anthropometric measurements in a cohort of uncomplicated term singleton pregnancies. METHODS: Retrospective cohort study of patients with a singleton term birth at a single tertiary center (2014-2020) was carried out. The primary exposure was parity. The following neonatal anthropometric measures were considered: birthweight, head circumference, length, ponderal index, and neonatal body mass index (BMI). RESULTS: A total of 8134 patients met the study criteria, 1949 (24.0%) of whom were nulliparous. Compared with multiparous patients, infants of nulliparous patients had a lower mean percentile for birthweight (43.1 ± 26.4 vs. 48.3 ± 26.8 percentile, p < 0.001), head circumference (44.3 ± 26.4 vs. 48.1 ± 25.5 percentile, p < 0.001), length (52.6 ± 25.1 vs. 55.5 ± 24.6 percentile, p < 0.001), ponderal index (34.4 ± 24.0 vs. 37.6 ± 24.2 percentile, p < 0.001), and BMI (39.1 ± 27.1 vs. 43.9 ± 27.3 percentile, p < 0.001). In addition, infants of nulliparous patients had higher odds of having a small (< 10th percentile for gestational age) birthweight (aOR 1.32 [95% CI 1.12-1.56]), head circumference (aOR 1.54 [95% CI 1.29-1.84]), length (aOR 1.50 [95% CI 1.16-1.94]), ponderal index (aOR 1.30 [95% CI 1.12-1.51]), and body mass index (aOR 1.42 [95% CI 1.22-1.65]). Most neonatal anthropometric measures increased with parity until a parity of 2, where it seemed to reach a plateau. CONCLUSION: Parity has an independent impact on a wide range of neonatal anthropometric measures, suggesting that parity is associated with both fetal skeletal growth and body composition. In addition, the association of parity with fetal growth does not follow a continuous relationship but instead reaches a plateau after the second pregnancy.

Accuracy in predicting soft tissue changes of orthodontic class III cases using Dolphin® software.

OBJECTIVES: The prediction of posttreatment outcomes is conducive to the final determination of ideal therapeutic options. However, the prediction accuracy in orthodontic class III cases is unclear. Therefore, this study conducted exploration on prediction accuracy in orthodontic class III patients using the Dolphin® software. MATERIALS AND METHODS: In this retrospective study, lateral cephalometric radiographs of pre- and posttreatment were collected from 28 angle class III adults who received completed non-orthognathic orthodontic therapy (8 males, 20 females; mean age = 20.89 ± 4.26 years). The values of 7 posttreatment parameters were recorded and inserted into the Dolphin® Imaging software to generate a predicted outcome, and then the prediction radiograph and actual posttreatment radiograph were superimposed and compared in terms of soft tissue parameters and landmarks. RESULTS: The prediction showed significant differences with the actual outcomes in nasal prominence (the difference between the prediction and the actual value was - 0.78 ± 1.82 mm), the distance from the lower lip to the H line (0.55 ± 1.11 mm), and the distance from the lower lip to the E line (0.77 ± 1.62 mm) (p < 0.05). Point subnasale (Sn) (an accuracy of 92.86% in the horizontal direction and 100% in the vertical direction in 2 mm) and point soft tissue A (ST A) (an accuracy of 92.86% in the horizontal direction and 85.71% in the vertical direction in 2 mm) were proven to be the most accurate landmarks, while the predictions in the chin region were relatively inaccurate. Furthermore, the predictions in the vertical direction were of higher accuracy compared to the horizontal direction except for the points around the chin. CONCLUSIONS: The Dolphin® software demonstrated acceptable prediction accuracy in midfacial changes in class III patients. However, there were still limitations for changes in the chin and lower lip prominence. CLINICAL RELEVANCE: Clarifying the accuracy of Dolphin® software in predicting soft tissue changes of orthodontic class III cases will facilitate physician-patient communication and clinical treatment.

Angiotensin II type-2 receptor activation in alveolar macrophages mediates protection against cigarette smoke-induced chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. Cumulative evidence has implicated renin-angiotensin system (RAS) in the pathogenesis of COPD. Alveolar macrophages (AMs) are the first line immune defense in the respiratory system and play a critical role in the lung homeostasis. This study aimed to investigate the role of AMs in contributing to the protective effects of angiotensin II type-2 receptor (AT2R) activation in cigarette smoke (CS)-induced COPD. The AM polarization, phagocytosis and metabolism, and the underlying biochemical mechanisms of compound 21 (C21), a selective and potent non-peptide small molecule AT2R agonist, were evaluated in a two-week CS-induced COPD mouse model. C21 restored AM phagocytosis ability, reversing CS-induced AM phagocytosis impairment. CS exposure polarized AMs towards M1 phenotype, whereas, C21 skewed the CS-exposed AMs towards M2 phenotype. C21 reprogrammed CS-exposed AM metabolism from a high glycolysis-driven process to support inflammation energy demand to a high mitochondrial respiration process to limit inflammation. Besides, C21 upregulated AT2R and Mas receptor levels in CS-exposed AMs, favoring the anti-inflammatory Ang II/AT2R axis and Ang 1-7/Mas axis in the RAS. C21 restored the normal levels of sirtuin 1 (SIRT1) and MAPK phosphatase 1 (MKP1) in CS-exposed AMs, leading to the reduction of phospho-p38, phospho-ERK and p65 subunit of NF-κB levels in CS-exposed AMs. We report here for the first time that AT2R agonist C21 acts by boosting the protective functions of AMs against CS-induced COPD, and our results support the development of AT2R agonist for the treatment of COPD.