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Each of us has millions of sequence variations in our genomes. Signatures of purifying or negative selection should help identify which of those variations is functionally important. Khurana et al. ( 1235587 ) used sequence polymorphisms from 1092 humans across 14 populations to identify patterns of selection, especially in noncoding regulatory regions. Noncoding regions under very strong negative selection included binding sites of some chromatin and general transcription factors (TFs) and core motifs of some important TF families. Positive selection in TF binding sites tended to occur in network hub promoters. Many recurrent somatic cancer variants occurred in noncoding regulatory regions and thus might indicate mutations that drive cancer. Regions under strong selection in the human genome identify noncoding regulatory elements with possible roles in disease. Interpreting variants, especially noncoding ones, in the increasing number of personal genomes is challenging. We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations (“ultrasensitive”) and variants that are disruptive because of mechanistic effects on transcription-factor binding (that is, “motif-breakers”). We also found variants in regions with higher network centrality tend to be deleterious. Insertions and deletions followed a similar pattern to single-nucleotide variants, with some notable exceptions (e.g., certain deletions and enhancers). On the basis of these patterns, we developed a computational tool (FunSeq), whose application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.

Background Induction of labour (IOL) is one of the commonest obstetric interventions, with significant impact on both the individual woman and health service delivery. Outpatient IOL is an attractive option to reduce these impacts. To date there is little data comparing outpatient and inpatient IOL methods, and potential safety concerns (hyperstimulation) if prostaglandins, the standard inpatient IOL medications, are used in the outpatient setting. The purpose of this study was to assess feasibility, clinical effectiveness and patient acceptability of outpatient Foley catheter (OPC) vs. inpatient vaginal PGE2 (IP) for induction of labour (IOL) at term. Methods Women with an unfavourable cervix requiring IOL at term (N = 101) were randomised to outpatient care using Foley catheter (OPC, n = 50) or inpatient care using vaginal PGE2 (IP, n = 51). OPC group had Foley catheter inserted and were discharged overnight following a reassuring cardiotocograph. IP group received 2 mg/1 mg vaginal PGE2 if nulliparous or 1 mg/1 mg if multiparous. Main outcome measures were inpatient stay (prior to birth, in Birthing Unit, total), mode of birth, induction to delivery interval, adverse reactions and patient satisfaction. Results OPC group had shorter hospital stay prior to birth (21.3 vs. 32.4 hrs, p < .001), IP were more likely to achieve vaginal birth within 12 hours of presenting to Birthing Unit (53% vs. 28%, p = .01). Vaginal birth rates (66% OPC Vs. 71% IP), total induction to delivery time (33.5 hrs vs. 31.3 hrs) and total inpatient times (96 hrs OPC Vs. 105 hrs IP) were similar. OPC group felt less pain (significant discomfort 26% Vs 58%, p = .003), and had more sleep (5.8 Vs 3.4 hours, p < .001), during cervical preparation, but were more likely to require oxytocin IOL (88 Vs 59%, p = .001). Conclusions OPC was feasible and acceptable for IOL of women with an unfavourable cervix at term compared to IP, however did not show a statistically significant reduction in total inpatient stay and was associated with increased oxytocin IOL. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN:12609000420246.

The management of oncogene‐driven non–small cell lung cancer (NSCLC) during pregnancy presents unique challenges due to limited safety data on targeted therapies. Anaplastic lymphoma kinase (ALK)‐rearranged NSCLC is a rare but increasingly recognized entity in young women, including during pregnancy. Here, we report the case of a 37‐year‐old woman diagnosed with metastatic ALK‐rearranged NSCLC during her first pregnancy, who was commenced on alectinib. Following this, she had a successful second pregnancy whilst being treated with alectinib (withheld during weeks 6–10 of gestation to avoid the critical period of organogenesis). Both pregnancies resulted in healthy infants with no complications or evidence of developmental delays. This case highlights the importance of a multidisciplinary approach involving oncology, maternal‐fetal medicine, clinical genetics, obstetrics medicine, and obstetrics to balance maternal cancer control and fetal health. While preclinical studies of alectinib suggest teratogenic risks, this and other reported cases demonstrate its potential for safe use during pregnancy with careful planning. Pathological examination of the placenta in our case revealed no malignant cells, and maternal disease remained controlled. As targeted therapies extend survival in advanced NSCLC, more patients may contemplate pregnancy, emphasizing the need for robust evidence to guide treatment decisions. This case contributes to the growing body of evidence supporting the feasibility of managing pregnancy in patients with ALK‐rearranged NSCLC using targeted therapies like alectinib, while underscoring the importance of long‐term follow‐up for the exposed offspring.

The current Australian national maternity reform agenda focuses on improving access to maternity care for women and their families while preserving safety and quality. The caseload midwifery model of care offers the level of access to continuity of care proposed in the reforms however the introduction of these models in Australia continues to meet with strong resistance. In many places access to caseload midwifery care is offered as a token, usually restricted to well women, within limited metropolitan and regional facilities and where available, places for women are very small as a proportion of the total service provided. This case study outlines a major clinical redesign of midwifery care at a metropolitan tertiary referral maternity hospital in Sydney. Caseload midwifery care was introduced under randomised trial conditions to provide midwifery care to 1500 women of all risk resulting in half of the publicly insured women receiving midwifery group practice care. The paper describes the organisational quality and safety tools that were utilised to facilitate the process while discussing the factors that facilitated the process and the barriers that were encountered within the workforce, operational and political context.

Objective: Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e. 0.5 g/kg. Methods: This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH. Results: A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 × 10 9 /l (range 8-269) in the 0.5 g/kg group versus 110 × 10 9 /l (range 11-279) in the 1 g/kg group (p = 0.644). Conclusion: The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.

An accessory diaphragm, also known as diaphragmatic duplication, is a congenital anomaly in which there is a fibromuscular membrane on top of the normally formed diaphragm dividing the hemithorax into two compartments trapping part of the pulmonary parenchyma. It is a very rare anomaly with less than 40 cases reported in the literature, of which only five were diagnosed in the newborn period, with no reports on any clinical clues for the antenatal diagnosis of this condition. We describe a case of congenital accessory diaphragm presenting in the antenatal period as hydrops fetalis. We also describe the radiological features of this rare anomaly on the antenatal fetal ultrasound.

An accessory diaphragm, also known as diaphragmatic duplication, is a congenital anomaly in which there is a fibromuscular membrane on top of the normally formed diaphragm dividing the hemithorax into two compartments trapping part of the pulmonary parenchyma. It is a very rare anomaly with less than 40 cases reported in the literature, of which only five were diagnosed in the newborn period, with no reports on any clinical clues for the antenatal diagnosis of this condition. We describe a case of congenital accessory diaphragm presenting in the antenatal period as hydrops fetalis. We also describe the radiological features of this rare anomaly on the antenatal fetal ultrasound.

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Human foot rigidity is thought to provide a more effective lever with which to push against the ground. Tension of the plantar aponeurosis (PA) with increased metatarsophalangeal (MTP) joint dorsiflexion (i.e., the windlass mechanism) has been credited with providing some of this rigidity. However, there is growing debate on whether MTP joint dorsiflexion indeed increases arch rigidity. Further, the arch can be made more rigid independent of additional MTP joint dorsiflexion (e.g., when walking with added mass). The purpose of the present study was therefore to compare the influence of increased MTP joint dorsiflexion with the influence of added mass on the quasi-stiffness of the midtarsal joint in walking. Participants walked with a rounded wedge under their toes to increase MTP joint dorsiflexion in the toe-wedge condition, and wore a weighted vest with 15% of their body mass in the added mass condition. Plantar aponeurosis behavior, foot joint energetics, and midtarsal joint quasi-stiffness were compared between conditions to analyze the mechanisms and effects of arch rigidity differences. Midtarsal joint quasi-stiffness was increased in the toe-wedge and added mass conditions compared with the control condition (both p < 0.001). In the toe-wedge condition, the time-series profiles of MTP joint dorsiflexion and PA strain and force were increased throughout mid-stance (p < 0.001). When walking with added mass, the time-series profile of force in the PA did not increase compared with the control condition although quasi-stiffness did, supporting previous evidence that the rigidity of the foot can be actively modulated. Finally, more mechanical power was absorbed (p = 0.006) and negative work was performed (p < 0.001) by structures distal to the rearfoot in the toe-wedge condition, a condition which displayed increased midtarsal joint quasi-stiffness. This indicates that a more rigid foot may not necessarily transfer power to the ground more efficiently.

We used 20 de novo genome assemblies to probe the speciation history and architecture of gene flow in rapidly radiating Heliconius butterflies. Our tests to distinguish incomplete lineage sorting from introgression indicate that gene flow has obscured several ancient phylogenetic relationships in this group over large swathes of the genome. Introgressed loci are underrepresented in low-recombination and gene-rich regions, consistent with the purging of foreign alleles more tightly linked to incompatibility loci. Here, we identify a hitherto unknown inversion that traps a color pattern switch locus. We infer that this inversion was transferred between lineages by introgression and is convergent with a similar rearrangement in another part of the genus. These multiple de novo genome sequences enable improved understanding of the importance of introgression and selective processes in adaptive radiation.