Untangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers.

The MRE11-RAD50-NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol ß) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.

Routine ultrasound for fetal assessment before 24 weeks' gestation.

BACKGROUND: Ultrasound examination of pregnancy before 24 weeks gestation may lead to more accurate dating and earlier diagnosis of pathology, but may also give false reassurance. It can be used to monitor development or diagnose conditions of an unborn baby. This review compares the effect of routine or universal, ultrasound examination, performed before 24 completed weeks' gestation, with selective or no ultrasound examination.  OBJECTIVES: To assess the effect of routine pregnancy ultrasound before 24 weeks as part of a screening programme, compared to selective ultrasound or no ultrasound, on the early diagnosis of abnormal pregnancy location, termination for fetal congenital abnormality, multiple pregnancy, maternal outcomes and later fetal compromise. To assess the effect of first trimester (before 14 weeks) and second trimester (14 to 24 weeks) ultrasound, separately. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization's International Clinical Trials Registry Platform (ICTRP) on 11 August 2020. We also examined the reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs and RCTs published in abstract form. We included all trials with pregnant women who had routine or revealed ultrasound versus selective ultrasound, no ultrasound, or concealed ultrasound, before 24 weeks' gestation. All eligible studies were screened for scientific integrity and trustworthiness. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and risk of bias, extracted data and checked extracted data for accuracy. Two review authors independently used the GRADE approach to assess the certainty of evidence for each outcome MAIN RESULTS: Our review included data from 13 RCTs including 85,265 women. The review included four comparisons. Four trials were assessed to be at low risk of bias for both sequence generation and allocation concealment and two as high risk. The nature of the intervention made it impossible to blind women and staff providing care to treatment allocation.  Sample attrition was low in the majority of trials and outcome data were available for most women. Many trials were conducted before it was customary for trials to be registered and protocols published. First trimester routine versus selective ultrasound: four studies, 1791 women, from Australia, Canada, the United Kingdom (UK) and the United States (US). First trimester scans probably reduce short-term maternal anxiety about pregnancy (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.65 to 0.99; moderate-certainty evidence). We do not have information on whether the reduction was sustained.  The evidence is very uncertain about the effect of first trimester scans on perinatal loss (RR 0.97, 95% CI 0.55 to 1.73; 648 participants; one study; low-certainty evidence) or induction of labour for post-maturity (RR 0.83, 95% CI 0.50 to 1.37; 1474 participants; three studies; low-certainty evidence). The effect of routine first trimester ultrasound on birth before 34 weeks or termination of pregnancy for fetal abnormality was not reported. Second trimester routine versus selective ultrasound: seven studies, 36,053 women, from Finland, Norway, South Africa, Sweden and the US. Second trimester scans probably make little difference to perinatal loss (RR 0.98, 95% CI 0.81 to 1.20; 17,918 participants, three studies; moderate-certainty evidence) or intrauterine fetal death (RR 0.97, 95% CI 0.66 to 1.42; 29,584 participants, three studies; low-certainty evidence). Second trimester scans may reduce induction of labour for post-maturity (RR 0.48, 95% CI 0.31 to 0.73; 24,174 participants, six studies; low-certainty evidence), presumably by more accurate dating. Routine second trimester ultrasound may improve detection of multiple pregnancy (RR 0.05, 95% CI 0.02 to 0.16; 274 participants, five studies; low-certainty evidence). Routine second trimester ultrasound may increase detection of major fetal abnormality before 24 weeks (RR 3.45, 95% CI 1.67 to 7.12; 387 participants, two studies; low-certainty evidence) and probably increases the number of women terminating pregnancy for major anomaly (RR 2.36, 95% CI 1.13 to 4.93; 26,893 participants, four studies; moderate-certainty evidence). Long-term follow-up of children exposed to scans before birth did not indicate harm to children's physical or intellectual development (RR 0.77, 95% CI 0.44 to 1.34; 603 participants, one study; low-certainty evidence). The effect of routine second trimester ultrasound on birth before 34 weeks or maternal anxiety was not reported. Standard care plus two ultrasounds and referral for complications versus standard care: one cluster-RCT, 47,431 women, from Democratic Republic of Congo, Guatemala, Kenya, Pakistan and Zambia. This trial included a co-intervention, training of healthcare workers and referral for complications and was, therefore, assessed separately. Standard pregnancy care plus two scans, and training and referral for complications, versus standard care probably makes little difference to whether women with complications give birth in a risk appropriate setting with facilities for caesarean section (RR 1.03, 95% CI 0.89 to 1.19; 11,680 participants; moderate-certainty evidence).  The intervention also probably makes little to no difference to low birthweight (< 2500 g) (RR 1.01, 95% CI 0.90 to 1.13; 47,312 participants; moderate-certainty evidence). The evidence is very uncertain about whether the community intervention (including ultrasound) makes any difference to maternal mortality (RR 0.92, 95% CI 0.55 to 1.55; 46,768 participants; low-certainty evidence). Revealed ultrasound results (communicated to both patient and doctor) versus concealed ultrasound results (blinded to both patient and doctor at any time before 24 weeks): one study, 1095 women, from the UK. The evidence was very uncertain for all results relating to revealed versus concealed ultrasound scan (very low-certainty evidence). AUTHORS' CONCLUSIONS: Early scans probably reduce short term maternal anxiety.  Later scans may reduce labour induction for post-maturity. They may improve detection of major fetal abnormalities and increase the number of women who choose termination of pregnancy for this reason. They may also reduce the number of undetected twin pregnancies. All these findings accord with observational data.  Neither type of scan appears to alter other important maternal or fetal outcomes, but our review may underestimate the effect in modern practice because trials were mostly  from relatively early in the development of the technology, and many control participants also had scans. The trials were also underpowered to show an effect on other important maternal or fetal outcomes.

Episiotomy and Initiation of Human Milk Feeds: A Retrospective Observational Study.

Objective: To investigate the association, in the United Kingdom, between having an episiotomy during childbirth and giving human milk by any modality as an infant's first feed. We also identified maternal demographic factors and perinatal experiences associated with increased chance of the infant's first feed being human milk. Study Design: Retrospective observational cohort study at two large maternity units within district general hospitals in the United Kingdom. Population: Mothers giving birth vaginally to singleton babies at ≥34 weeks and ≥1,800 g. Methods and Main Outcome Measures: Deidentified data from hospital records were analyzed. The odds ratio (OR) of a mother giving human milk for an infant's first feed after episiotomy versus no episiotomy was calculated using a chi-squared test. Logistic regression was used to investigate and then control for confounders known to affect breastfeeding. Results: A total of 13,906 women met the inclusion criteria (2,113 had had an episiotomy and 11,793 had not). Human milk was given as a first feed to 70% of infants in the study population. Women whose infants received their first feed as human milk were on average older, had lower body mass index, lived in an area of less socioeconomic deprivation, and had fewer previous births than those women who gave formula milk as the first feed to their infant. The occurrence of an episiotomy during delivery was not associated with a change in the odds of the infant receiving human milk for the first feed (OR: 1.12 [confidence interval, CI: 0.96-1.38]). Where a woman had skin-to-skin care with her infant straight after birth, the infant was more likely to receive human milk as a first feed (OR: 4.23 [CI: 3.59-4.98]). Conclusion: There is no link between episiotomy during delivery and the odds of a woman giving human milk as the first feed to her infant.

Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis.

BACKGROUND: As pregnancy is a physiological prothrombotic state, pregnant women may be at increased risk of developing coagulopathic and/or thromboembolic complications associated with COVID-19. METHODS: Two biomedical databases were searched between September 2019 and June 2020 for case reports and series of pregnant women with a diagnosis of COVID-19 based either on a positive swab or high clinical suspicion where no swab had been performed. Additional registry cases known to the authors were included. Steps were taken to minimise duplicate patients. Information on coagulopathy based on abnormal coagulation test results or clinical evidence of disseminated intravascular coagulation (DIC), and on arterial or venous thrombosis, were extracted using a standard form. If available, detailed laboratory results and information on maternal outcomes were analysed. RESULTS: One thousand sixty-three women met the inclusion criteria, of which three (0.28, 95% CI 0.0 to 0.6) had arterial and/or venous thrombosis, seven (0.66, 95% CI 0.17 to 1.1) had DIC, and a further three (0.28, 95% CI 0.0 to 0.6) had coagulopathy without meeting the definition of DIC. Five hundred and thirty-seven women (56%) had been reported as having given birth and 426 (40%) as having an ongoing pregnancy. There were 17 (1.6, 95% CI 0.85 to 2.3) maternal deaths in which DIC was reported as a factor in two. CONCLUSIONS: Our data suggests that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Detection of the former may be useful in the identification of women at risk of deterioration.

Chemical modulation of autophagy as an adjunct to chemotherapy in childhood and adolescent brain tumors.

Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a "Janus"-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor. On the other face, at later stages of tumor progression, autophagy can function as a pro-survival pathway in response to metabolic stresses such as nutrient depravation, hypoxia and indeed to chemotherapy itself, and can support cell growth by supplying much needed energy. In the context of chemotherapy, autophagy may, in some cases, mediate resistance to treatment. We present an overview of the relevance of autophagy in central nervous system tumors including how its chemical modulation can serve as a useful adjunct to chemotherapy, and use this knowledge to consider how targeting of autophagy may be relevant in pediatric brain tumors.