Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.

A roadmap to precision treatments for familial pulmonary fibrosis.

Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring of the lung parenchyma often resulting in respiratory failure and death. Inherited factors directly cause, or contribute significantly to the risk of developing ILD, so called familial pulmonary fibrosis (FPF), and monogenic forms may have a poor prognosis and respond poorly to current treatments. Specific, variant-targeted or precision treatments are lacking. Clinical trials of repurposed drugs, anti-fibrotic medications and specific treatments are emerging but for many patients no interventions exist. We convened an expert working group to develop an overarching framework to address the existing research gaps in basic, translational, and clinical research and identified areas for future development of preclinical models, candidate medications and innovative clinical trials. In this Position Paper, we summarise working group discussions, recommendations, and unresolved questions concerning precision treatments for FPF.

Uptake rates and attitudes to influenza and COVID-19 vaccination in pregnancy - a prospective cohort study.

Influenza and COVID-19 are highly prevalent RNA viruses. Pregnancy increases the frequency of severe maternal morbidity and mortality associated with these viruses. Vaccination plays an important role in protecting pregnant women and their infants from adverse outcomes. In this prospective study, we aimed to determine the vaccination uptake rate for influenza and COVID-19 in a pregnant population and to explore reasons why women remained unvaccinated. A prospective cohort study was conducted over a two-week period in December 2022 in the National Maternity Hospital, Dublin. There were 588 women surveyed over the 2-week period. Overall, 377 (57%) were vaccinated that year for seasonal influenza, a significant rise from 39% in a similar study in 2016. The majority (n = 488, 83%) of women reported receiving at least one COVID-19 vaccine. However only 132 (22%) received a COVID-19 vaccine in pregnancy, despite 76% (n = 466) stating they would be happy to receive it. Factors such as age, obesity, co-morbidities, ethnic group, and type of antenatal care received were shown to influence vaccination rates. We recommend that the importance of vaccination be stressed regularly to eligible patients at their antenatal clinic visits and where possible combining influenza/COVID-19 vaccination on the same day to improve uptake.

Developing future clinical leaders in patient safety: the Irish experience.

INTRODUCTION: It is 20 years since the Institute of Medicine advocated a national approach to improve care and patient safety. Patient safety infrastructure has greatly improved in certain countries. In Ireland, patient safety infrastructure is in ongoing development. To contribute to this, the Royal College of Physicians of Ireland/International Society for Quality in Healthcare Scholar in Residence Programme was launched in 2016. This programme aims to improve patient safety and develop a movement of future clinician leaders to drive improvements in patient safety and the quality of care. METHODS: Doctors in postgraduate training complete a year-long immersive mentorship. This involves monthly group meetings with key patient safety opinion makers, one-on-one mentorship, leadership courses, conference attendance and presentations. Each scholar undertakes a quality improvement (QI) project. RESULTS: A QI project was associated with a decrease in caesarean section rates from 13.7% to 7.6% (p=0.0002) among women in spontaneous labour at term with a cephalic presentation. Other projects are ongoing. CONCLUSION: Medical error, patient safety and QI must be addressed comprehensively at both undergraduate and postgraduate level. We believe the Irish mentorship programme will help to change the paradigm and improve patient safety.

Pregnancy outcomes following recurrent miscarriage.

BACKGROUND: Recurrent miscarriage affects 1-2% of the population, and the literature has focussed on causes, treatment, and live birth rate. AIM: This study aimed to assess the reproductive outcomes for patients who attended a specialist recurrent miscarriage clinic for investigation and treatment. METHODS: Prospective analysis of all patients who attended a recurrent miscarriage clinic from January 2014 to January 2021. RESULTS: Of the 488 patients who attended a specialist clinic, 318 had a further pregnancy with 299 included in this study. The median age was 37 years, with 55.6% having a previous live birth. The subsequent live birth rate was 75.3%, 22.0% had a further pregnancy loss, 1.7% had an ongoing pregnancy, and 1% attended another institution after the second trimester. The rate of preeclampsia was 2.2%, pregnancy-induced hypertension was 2.2%, fetal growth restriction was 5.3%, preterm birth ≤ 34 weeks was 1.8%, and preterm birth > 34 weeks < 37 weeks was 6.6%. CONCLUSION: Patients who attend a dedicated recurrent miscarriage clinic for investigation and treatment have a high live birth rate in a subsequent pregnancy. A subsequent pregnancy following recurrent pregnancy loss does not appear to be associated with an increased risk of adverse pregnancy outcomes.

Second-trimester miscarriage: a review of postnatal investigations and subsequent pregnancy outcomes.

BACKGROUND: Second-trimester loss is pregnancy loss after the 12th and before the 24th completed weeks of pregnancy. This study aims to review cases of second-trimester miscarriage who attended a large maternity hospital and to examine pregnancy outcomes in this group of women. METHODS: This study is a review of cases of second-trimester miscarriage using descriptive, exploratory design, involving a retrospective chart review. RESULTS: In this study, 106 cases of second-trimester miscarriage were reviewed. The cause of the miscarriage was found in 42.5% (n = 45) of cases. The majority of women, 84.5% (n = 82) had a normal pelvic ultrasound scan and 18.3% (n = 17) of cases were diagnosed with antiphospholipid syndrome. In women who became pregnant again, 60.9% (n = 39) had a live birth. CONCLUSIONS: Establishing the cause of second-trimester miscarriage can be challenging, despite completing all recommended investigations. Outcomes in subsequent pregnancies are reassuring. This review highlights the need to undertake all recommended investigations to elicit the cause of second-trimester miscarriage and underpins the need for further research in this area.

Utilization of an Outpatient Integrated Infusion Suite to Decrease Length of Stay, Increase Revenue, and Improve Patient Experience for Elective Chemotherapy Admissions.

PURPOSE: Reduction of chemotherapy start times (CST) and length of stay (LOS) for elective chemotherapy admissions is a priority. The aim of this project was to improve efficiency of patient care while simultaneously increasing revenue by reducing LOS and transitioning high-cost chemotherapy to the outpatient setting. METHODS: A multidisciplinary quality improvement team proposed building a new outpatient infusion suite in close proximity to the inpatient unit. This suite was then integrated into the flow of elective inpatient chemotherapy admissions and discharges for etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R). Quality measures such as CST, LOS, and revenue were used to evaluate the new infusion suite. RESULTS: In the pilot phase of the study, the average CST improved by approximately 1 hour 45 minutes (P = .0218). The mean LOS was reduced from 4.3 to 4.1 midnights (P = .0214). In terms of hours, LOS was reduced from 105.8 to 95.5 hours (P < .0001). A mean quarterly revenue of $309,410 US dollars was noted during the pilot that had not been previously billed. These improvements were sustained throughout the control phase. CONCLUSION: Delays in CST and prolonged LOS lead to patient dissatisfaction and increased cost to the health care system. Focus groups and patient feedback are important when designing and implementing new workflows. The creation of an outpatient integrated infusion suite allows medical centers to meet patients' expectations of reducing number of visits while also reducing LOS and capturing new revenue. Adherence to scheduling guidelines further reduces the CST for elective chemotherapy administration.

Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling.

Viruses must effectively remodel host cellular pathways to replicate and evade immune defenses, and they must do so with limited genomic coding capacity. Targeting post-translational modification (PTM) pathways provides a mechanism by which viruses can broadly and rapidly transform a hostile host environment into a hospitable one. We use mass spectrometry-based proteomics to quantify changes in protein abundance and two PTM types-phosphorylation and ubiquitination-in response to HIV-1 infection with viruses harboring targeted deletions of a subset of HIV-1 genes. PTM analysis reveals a requirement for Aurora kinase activity in HIV-1 infection and identified putative substrates of a phosphatase that is degraded during infection. Finally, we demonstrate that the HIV-1 Vpr protein inhibits histone H1 ubiquitination, leading to defects in DNA repair.

Association of Persistent Rubella Virus With Idiopathic Skin Granulomas in Clinically Immunocompetent Adults.

Importance: Vaccine-derived and wild-type rubella virus (RuV) has been identified within granulomas in patients with inborn errors of immunity, but has not been described in granulomas of healthy adults. Objective: To determine the association between RuV and atypical granulomatous inflammation in immune-competent adults. Design, Setting, and Participants: This case series, conducted in US academic dermatology clinics from January 2019 to January 2021, investigated the presence of RuV in skin specimens using RuV immunofluorescent staining of paraffin-embedded tissue sections, real-time reverse-transcription polymerase chain reaction, whole-genome sequencing with phylogenetic analyses, and cell culture by the US Centers for Disease Control and Prevention. Rubella immunoglobulin G, immunoglobulin M enzyme-linked immunoassay, and viral neutralization assays were performed for the sera of immunocompetent individuals with treatment refractory cutaneous granulomas and histopathology demonstrating atypical palisaded and necrotizing granulomas. Clinical immune evaluation was performed. Main Outcomes and Measures: Identification, genotyping, and culture of vaccine-derived and wild-type RuV within granulomatous dermatitis of otherwise clinically immune competent adults. Results: Of the 4 total immunocompetent participants, 3 (75%) were women, and the mean (range) age was 61.5 (49.0-73.0) years. The RuV capsid protein was detected by immunohistochemistry in cutaneous granulomas. The presence of RuV RNA was confirmed by real-time reverse-transcription polymerase chain reaction in fresh-frozen skin biopsies and whole-genome sequencing. Phylogenetic analysis of the RuV sequences showed vaccine-derived RuV in 3 cases and wild-type RuV in 1. Live RuV was recovered from the affected skin in 2 participants. Immunology workup results demonstrated no primary immune deficiencies. Conclusions and Relevance: The case series study results suggest that RuV (vaccine derived and wild type) can persist for years in cutaneous granulomas in clinically immunocompetent adults and is associated with atypical (palisaded and necrotizing type) chronic cutaneous granulomas. These findings represent a potential paradigm shift in the evaluation, workup, and management of atypical granulomatous dermatitis and raises questions regarding the potential transmissibility of persistent live RuV.

Early detection of cancer.

Survival improves when cancer is detected early. However, ~50% of cancers are at an advanced stage when diagnosed. Early detection of cancer or precancerous change allows early intervention to try to slow or prevent cancer development and lethality. To achieve early detection of all cancers, numerous challenges must be overcome. It is vital to better understand who is at greatest risk of developing cancer. We also need to elucidate the biology and trajectory of precancer and early cancer to identify consequential disease that requires intervention. Insights must be translated into sensitive and specific early detection technologies and be appropriately evaluated to support practical clinical implementation. Interdisciplinary collaboration is key; advances in technology and biological understanding highlight that it is time to accelerate early detection research and transform cancer survival.

Multicancer early detection test: Preclinical, translational, and clinical evidence-generation plan and provocative questions.

Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case-control and cohort studies. These demonstrations of feasibility herald the potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation.

Delivering on the promise of early detection with liquid biopsies.

Liquid biopsy approaches are relatively well developed for cancer therapy monitoring and disease relapse, but they also have incredible potential in the cancer early detection and screening field. There are, however, several challenges to overcome before this potential can be met. Research in this area needs to be cohesive and, as a driver of research, Cancer Research UK is in an ideal position to enable this.

Mid-luteal uterine artery Doppler indices in the prediction of pregnancy outcome in nulliparous women undergoing assisted reproduction.

Traditionally, the assessment of endometrial receptivity at transvaginal ultrasound scan has been based on the thickness and the morphological appearance of the endometrium. The objective of this study was to prospectively evaluate endometrial thickness (ET), endometrial morphology and uterine artery Doppler parameters prior to assisted reproduction treatment (ART) in the prediction of pregnancy outcome. This was a prospective cohort study. ET, morphology and uterine artery Doppler (UtAD) pulsatility index (PI) and resistance index (RI) were measured in the mid-luteal stage of the menstrual cycle ultrasonographically, timed with urinary luteinizing hormone testing. A total of 50 women were included in the analysis. The clinical pregnancy rate (CPR) per embryo transfer was 42.0% (n = 21/50). Twenty nine women (58.0%) had an unsuccessful outcome. There were no differences in mean ± SD endometrial thickness (ET) (10.0 ± 1.8 mm vs. 10.5 ± 2.4; p = 0.43), or endometrial morphology (100% (n = 21) vs 100% (n = 29); p = 1.00) between the pregnant and not pregnant groups. Similarly, there were no differences in mean ± SD UtAD PI (2.17 ± 0.83 vs. 2.07 ± 0.81; p = 0.67 or mean ± SD UtAD RI (0.84 ± 0.10 vs. 0.81 ± 0.10; p = 0.30). Ultrasonographic endometrial assessment did not differentiate between those who would have a subsequent clinical pregnancy.

Case report and literature review of management of preterm prelabour rupture of membranes before fetal viability.

Preterm prelabour rupture of membranes (PPROM) complicates up to 3% of pregnancy and is responsible for one third of preterm deliveries. PPROM at extremely preterm gestations (<24 weeks) affects 0.4% of pregnancies and is associated with low neonatal survival rates, high rate of neonatal complications in survivors, and carries major risk of maternal morbidity and mortality. We present a rare case of pregnancy complicated by PPROM at 14 weeks which resulted in a term delivery and a good neonatal outcome.

The impact of accurately timed mid-luteal endometrial injury in nulligravid women undergoing their first or second embryo transfer.

INTRODUCTION: Endometrial injury or 'scratch' preceding an assisted reproductive therapy (ART) cycle has recently been shown not to improve livebirth rates among women undergoing ART. The objective of this study was to compare pregnancy outcomes in nulliparous women who underwent an accurately timed mid-luteal scratch biopsy prior to ART with those who did not. METHODS: This was a prospective cohort study. Women were recruited between October 2016 and February 2018 inclusive. Women who met the inclusion criteria and who did not undergo an endometrial scratch in the study period were used as a comparison group. Patients underwent a cycle of ART in the menstrual cycle following endometrial scratch. RESULTS: Ninety-eight women were eligible for participation in the study. There were no differences in rates of implantation (35.7% (n = 20/56) vs. 35.4% (n = 17/48); p = 1.00), clinical pregnancy (40.0% (n = 20/50) vs. 39.5% (n = 17/43); p = 1.00) or live birth (34.0% (n = 17/50) vs. 25.6% (n = 11/43); p = 0.50) per embryo transfer between those who underwent a scratch and those who did not. CONCLUSION: Endometrial scratch is a simple, inexpensive and low-risk procedure. However, in this relatively small cohort study, no differences in rates of implantation, clinical pregnancy or live birth in women with primary infertility were determined between those who underwent a scratch and those who did not.

Shotgun sequencing of the vaginal microbiome reveals both a species and functional potential signature of preterm birth.

An association between the vaginal microbiota and preterm birth (PTB) has been reported in several research studies. Population shifts from high proportions of lactobacilli to mixed species communities, as seen with bacterial vaginosis, have been linked to a twofold increased risk of PTB. Despite the increasing number of studies using next-generation sequencing technologies, primarily involving 16S rRNA-based approaches, to investigate the vaginal microbiota during pregnancy, no distinct microbial signature has been associated with PTB. Shotgun metagenomic sequencing offers a powerful tool to reveal community structures and their gene functions at a far greater resolution than amplicon sequencing. In this study, we employ shotgun metagenomic sequencing to compare the vaginal microbiota of women at high risk of preterm birth (n = 35) vs. a low-risk control group (n = 14). Although microbial diversity and richness did not differ between groups, there were significant differences in terms of individual species. In particular, Lactobacillus crispatus was associated with samples from a full-term pregnancy, whereas one community state-type was associated with samples from preterm pregnancies. Furthermore, by predicting gene functions, the functional potential of the preterm microbiota was different from that of full-term equivalent. Taken together, we observed a discrete structural and functional difference in the microbial composition of the vagina in women who deliver preterm. Importance: with an estimated 15 million cases annually, spontaneous preterm birth (PTB) is the leading cause of death in infants under the age of five years. The ability to accurately identify pregnancies at risk of spontaneous PTB is therefore of utmost importance. However, no single cause is attributable. Microbial infection is a known risk factor, yet the role of vaginal microbes is poorly understood. Using high-resolution DNA-sequencing techniques, we investigate the microbial communities present in the vaginal tracts of women deemed high risk for PTB. We confirm that Lactobacillus crispatus is strongly linked to full-term pregnancies, whereas other microbial communities associate with PTB. Importantly, we show that the specific functions of the microbes present in PTB samples differs from FTB samples, highlighting the power of our sequencing approach. This information enables us to begin understanding the specific microbial traits that may be influencing PTB, beyond the presence or absence of microbial taxa.

A Quantitative Genetic Interaction Map of HIV Infection.

We have developed a platform for quantitative genetic interaction mapping using viral infectivity as a functional readout and constructed a viral host-dependency epistasis map (vE-MAP) of 356 human genes linked to HIV function, comprising >63,000 pairwise genetic perturbations. The vE-MAP provides an expansive view of the genetic dependencies underlying HIV infection and can be used to identify drug targets and study viral mutations. We found that the RNA deadenylase complex, CNOT, is a central player in the vE-MAP and show that knockout of CNOT1, 10, and 11 suppressed HIV infection in primary T cells by upregulating innate immunity pathways. This phenotype was rescued by deletion of IRF7, a transcription factor regulating interferon-stimulated genes, revealing a previously unrecognized host signaling pathway involved in HIV infection. The vE-MAP represents a generic platform that can be used to study the global effects of how different pathogens hijack and rewire the host during infection.

Influence of body mass index on the relationship between endometrial thickness and pregnancy outcome in single blastocyst frozen embryo transfer cycles.

To date there is limited published data assessing whether body mass index (BMI) influences endometrial thickness (ET) and whether this impacts on pregnancy outcomes in single blastocyst FET cycles. The objective of this study, therefore, was to examine the relationship between BMI and ET on the outcome of single blastocyst FET cycles over a five-year period from 2012 until 2016. Patient age, BMI, endometrial pattern and ET prior to FET were recorded. Pregnancy outcomes included: implantation rate, clinical pregnancy rate and live birth rate. A total of 464 cycles met the inclusion criteria and the female age was 36.0 ± 3.0 years (mean ± SD). The mean ± SD BMI was 23.3 ± 3.1 kg/m2 and median ± SD ET was 8.1 ± 1.5 mm. BMI and ET were modestly correlated (Pearson r = 0.244) and there was an association between higher BMI category and higher median ET (7.2, 8.0, 8.3, 8.9 mm; p < 0.001). However, there was no association between ET and pregnancy outcome, either unadjusted, or adjusted for BMI, age, endometrial pattern or embryo quality. The data suggests that although ET increases with increasing BMI, there are no differences in cycle outcome. Importantly, this implies that an ET <8 mm may not jeopardize pregnancy outcome in women with lower BMI. The development of a norm referenced test for BMI and ET may prove to be a helpful adjunct in the clinical IVF setting.