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Background: Many women of childbearing age with inflammatory bowel disease (IBD) require advanced therapies. While biologics are largely low risk during pregnancy, the novel small molecules tofacitinib, filgotinib, upadacitinib and ozanimod (TFUO) have shown concerning teratogenic effects, and decreased fertility in animal studies. Therefore, their use in women of childbearing age needs careful consideration. Design: RAND/University of California Los Angeles (UCLA) Appropriateness Method (RAM). Objective: To evaluate the appropriateness of TFUO in women of childbearing age. Methods: We convened a panel of six gastroenterologists, two IBD nurses, one IBD pharmacist and three expert patients. Following a literature review, 13 statements were drafted and voted upon in 2 rounds. Results: All 13 statements were deemed appropriate. The panel concluded that women with IBD of childbearing age who wish to commence therapy with TFUO, need to use effective contraception and be counselled regarding the risk in unplanned pregnancies. For women using contraception while on Janus kinase inhibitor (JAKi) therapy, we suggest the preferred use of progesterone-only or non-hormonal long-acting contraception. TFUO are contraindicated during pregnancy and breast feeding. We recommend that women receiving TFUO cease therapy in time to establish clinical remission for at least 3 months prior to conception. Therapies other than TFUO should be considered as first-line therapy in women with IBD of childbearing age, except in select individual circumstances. TFUO may be appropriate for women of childbearing age after failure of, intolerance or contraindications to one biological agent. Conclusion: TFUO should be avoided during pregnancy and breastfeeding, and alternative therapies should be considered as first-line treatments. Summary: We provide clinical practice recommendations regarding the use of TFUO for IBD in women of childbearing age.

Background Refractory ulcerative proctitis presents a huge clinical challenge not only for the patients living with this chronic, progressive condition but also for the professionals who care for them. Currently, there is limited research and evidence-based guidance, resulting in many patients living with the symptomatic burden of disease and reduced quality of life. The aim of this study was to establish a consensus on the thoughts and opinions related to refractory proctitis disease burden and best practice for management.Methods A three-round Delphi consensus survey was conducted among patients living with refractory proctitis and the healthcare experts with knowledge on this disease from the UK. A brainstorming stage involving a focus group where the participants came up with an initial list of statements was completed. Following this, there were three rounds of Delphi surveys in which the participants were asked to rank the importance of the statements and provide any additional comments or clarifications. Calculation of mean scores, analysis of comments and revisions were performed to produce a final list of statements.Results In total, 14 statements were suggested by the focus group at the initial brainstorming stage. Following completion of three Delphi survey rounds, all 14 statements reached consensus following appropriate revision.Conclusions We established consensus on the thoughts and opinions related to refractory proctitis from both the experts who manage this disease and the patients living with it. This represents the first step towards developing clinical research data and ultimately the evidence needed for best practice management guidance of this condition.

Background: Medication adherence in inflammatory bowel disease (IBD) is crucial, particularly during pregnancy. Unplanned pregnancies are common; therefore, efforts to maximise adherence should not be restricted to pregnant women. Objectives: We aimed to assess medication adherence in women with IBD of childbearing age, regardless of their reproduction plans. Design: We performed a multi-centre pilot questionnaire study of women with IBD age 18–45 years. Methods: Survey questions included patient demographics, disease history, and validated assessments of IBD and pregnancy knowledge, medication adherence and quality of life. The primary outcome was rates and predictors of medication adherence. Results: In all, 72 women [58.3% Crohn’s disease (CD) and 37.5% ulcerative colitis] completed the survey. The median patient age was 30 years [interquartile range (IQR): 24.8–36.0) and 37.5% had children. Medication adherence was high (84%; median Medication Adherence Report Scale: 19.0/20; IQR: 17.0–20.0). Knowledge scores were adequate for both the Crohn’s and Colitis Knowledge (CCKnow; median: 15.5/30; IQR: 12.3–18.0) and Crohn’s and Colitis Pregnancy Knowledge (CCPKnow; median: 8.0/17; IQR: 4.0–11.0). Disease knowledge was predictive of high medication adherence (CCPKnow: p = 0.02; CCKnow: p ⩽ 0.01). Higher adherence was significantly associated with a diagnosis of CD ( p = 0.01), exposure to biological agents ( p = 0.03) and immunomodulators ( p = 0.04), childbearing after diagnosis with IBD ( p = 0.03), and correctly understanding the importance of delivery modality ( p = 0.02) and IBD activity in pregnancy ( p = 0.01). Conclusions: Following dedicated education at the IBD clinic, medication adherence, disease-specific and pregnancy-specific knowledge in women with IBD of childbearing age tends to be high. Unplanned pregnancies are frequent; therefore, we should aim to maximise medication adherence in all women of childbearing age to optimise maternofoetal outcomes if unexpected pregnancies occur.

Background COVID-19 was first detected in Wuhan, China, in 2019 and spread worldwide within a few weeks. The COVID-19 epidemic started to gain traction in France in March 2020. Subnational hospital admissions and deaths were then recorded daily and served as the main policy indicators. Concurrently, mobile phone positioning data have been curated to determine the frequency of users being colocalized within a given distance. Contrarily to individual tracking data, these can be a proxy for human contact networks between subnational administrative units.Methods Motivated by numerous studies correlating human mobility data and disease incidence, we developed predictive time series models of hospital incidence between July 2020 and April 2021. We added human contact network analytics, such as clustering coefficients, contact network strength, null links or curvature, as regressors.Findings We found that predictions can be improved substantially (by more than 50%) at both the national level and the subnational level for up to 2 weeks. Our subnational analysis also revealed the importance of spatial structure, as incidence in colocalized administrative units improved predictions. This original application of network analytics from colocalization data to epidemic spread opens new perspectives for epidemic forecasting and public health.

Variants of severe acute respiratory syndrome coronavirus 2 raise concerns regarding the control of coronavirus disease epidemics. We analyzed 40,000 specific reverse transcription PCR tests performed on positive samples during January 26–February 16, 2021, in France. We found high transmission advantage of variants and more advanced spread than anticipated.

Introduction: Fecundity may be reduced in women with active inflammatory bowel disease (IBD) or prior IBD-related surgery, and these women may require assisted reproductive technology (ART). There are no guidelines for women with IBD to outline referral criteria for ART. Methods: We performed a prospective, multicentre, international questionnaire of gastroenterologists, gastroenterology trainees, and IBD nurses. The primary outcome was to establish clinical practices and fertility therapy referral patterns among gastroenterology team members. We hypothesised that the lack of knowledge and awareness may delay or prevent initiation of fertility consultation referrals. Discussion: Of 182 participants, most had never initiated a referral for fertility therapy (69.8%), and of respondents who do initiate referrals, 50% wait until the patient has been unsuccessfully attempting conception for 12 months. Participants were significantly more likely to initiate a fertility therapy referral if they believed ART was effective ( p = 0.038), not impeded by IBD-related surgery ( p = 0.053), and if they had access to a dedicated IBD-pregnancy clinic ( p = 0.027). Superior pregnancy knowledge was predictive of a greater likelihood of fertility therapy referrals ( p = 0.037). All participants thought they had inadequate knowledge about ART in IBD, and 96.2% expressed desire to improve their knowledge. Conclusion: Gastroenterology team members infrequently initiate referrals for fertility therapy consultation in women with IBD, increasing their risk of remaining childless. Implementation of dedicated IBD pregnancy clinics and targeted education programmes to increase awareness of ART in women with IBD might increase referral rates and reduce infertility.

Human papillomaviruses (HPVs), the most oncogenic virus known to humans, are often associated with Herpes Simplex Virus-2 (HSV-2) infections. The involvement of the latter in cervical cancer is controversial but its long-term infections might modulate the mucosal microenvironment in a way that favors carcinogenesis. We know little about coinfections between HSV-2 and HPVs, and studying the immunological and microbiological dynamics in the early stages of these infections may help identify or rule out potential interactions. We report two cases of concomitant productive, although asymptomatic, HSV-2 and HPV infections in young women (aged 20 and 25). The women were followed up for approximately a year, with clinical visits every two months and weekly self-samples. We performed quantitative analyses of their HSV-2 and HPV viral loads, immunological responses (IgG and IgM antibodies and local cytokines expression profiles), vaginal microbiota composition, as well as demographic and behavior data. We detect interactions between virus loads, immune response, and the vaginal microbiota, which improve our understanding of HSV-2 and HPVs’ coinfections and calls for further investigation with larger cohorts.

Human Papillomaviruses (HPV) are one of the most prevalent sexually transmitted infections (STI) and the most oncogenic viruses known to humans. The vast majority of HPV infections clear in less than 3 years, but the underlying mechanisms, especially the involvement of the immune response, are still poorly known. Building on earlier work stressing the importance of randomness in the type of cell divisions in the clearance of HPV infection, we develop a stochastic mathematical model of HPV dynamics that combines the previous aspect with an explicit description of the intracellular level. We show that the random partitioning of virus episomes upon stem cell division and the occurrence of symmetric divisions dramatically affect viral persistence. These results call for more detailed within-host studies to better understand the relative importance of stochasticity and immunity in HPV infection clearance.

Interactions within a population shape the spread of infectious diseases but contact patterns between individuals are difficult to access. We hypothesised that key properties of these patterns can be inferred from multiple infection data in longitudinal follow-ups. We developed a simulator for epidemics with multiple infections on networks and analysed the resulting individual infection time series by introducing similarity metrics between hosts based on their multiple infection histories. We find that, depending on infection multiplicity and network sampling, multiple infection summary statistics can recover network properties such as degree distribution. Furthermore, we show that by mining simulation outputs for multiple infection patterns, one can detect immunological interference between pathogens (i.e. the fact that past infections in a host condition future probability of infection). The combination of individual-based simulations and analysis of multiple infection histories opens promising perspectives to infer and validate transmission networks and immunological interference for infectious diseases from longitudinal cohort data.

SARS-CoV-2 virus has spread over the world rapidly creating one of the largest pandemics ever. The absence of immunity, presymptomatic transmission, and the relatively high level of virulence of the COVID-19 infection led to a massive flow of patients in intensive care units (ICU). This unprecedented situation calls for rapid and accurate mathematical models to best inform public health policies.We develop an original parsimonious discrete-time model that accounts for the effect of the age of infection on the natural history of the disease. Analysing the ongoing COVID-19 in France as a test case, through the publicly available time series of nationwide hospital mortality and ICU activity, we estimate the value of the key epidemiological parameters and the impact of lock-down implementation delay.This work shows that including memory-effects in the modelling of COVID-19 spreading greatly improves the accuracy of the fit to the epidemiological data. We estimate that the epidemic wave in France started on Jan 20 [Jan 12, Jan 28] (95% likelihood interval) with a reproduction number initially equal to 2.99 [2.59, 3.39], which was reduced by the national lock-down started on Mar 17 to 24 [21, 27] of its value. We also estimate that the implementation of the latter a week earlier or later would have lead to a difference of about respectively −13k and +50k hospital deaths by the end of lock-down.The present parsimonious discrete-time framework constitutes a useful tool for now- and forecasting simultaneously community incidence and ICU capacity strain.

Poor adherence to daily antiretrovirals can significantly affect treatment efficacy, but oral long-acting antiretrovirals are currently lacking. Here, the authors develop a once-weekly oral dosage form for anti-HIV drugs, assess its pharmacokinetics in pigs, and model its impact on viral resistance and disease epidemics.

Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory condition with intestinal and extraintestinal manifestations. Medications are the cornerstone of treatment of IBD. However, patients often adhere to medication poorly. Adherence to medications is defined as the process by which patients take their medications as prescribed. Treatment non-adherence is a common problem among chronic diseases, averaging 50% in developed countries and is even poorer in developing countries. In this review, we will examine the adherence data in IBD which vary greatly depending on the study population, route of administration, and methods of adherence measurement used. We will also discuss the adverse clinical outcomes related to non-adherence to medical treatment including increased disease activity, flares, loss of response to anti-tumor necrosis factor therapy, and so forth. There are many methods to measure medication adherence namely direct and indirect methods, each with their advantages and drawbacks. Finally, we will explore different intervention strategies to improve adherence to medications.

The oral polio vaccine (OPV) contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. Widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of 10,000 or more and has driven wild poliovirus (WPV) to the brink of eradication. However, in instances that have so far been rare, OPV can paralyze vaccine recipients and generate vaccine-derived polio outbreaks. To complete polio eradication, OPV use should eventually cease, but doing so will leave a growing population fully susceptible to infection. If poliovirus is reintroduced after OPV cessation, under what conditions will OPV vaccination be required to interrupt transmission? Can conditions exist in which OPV and WPV reintroduction present similar risks of transmission? To answer these questions, we built a multi-scale mathematical model of infection and transmission calibrated to data from clinical trials and field epidemiology studies. At the within-host level, the model describes the effects of vaccination and waning immunity on shedding and oral susceptibility to infection. At the between-host level, the model emulates the interaction of shedding and oral susceptibility with sanitation and person-to-person contact patterns to determine the transmission rate in communities. Our results show that inactivated polio vaccine (IPV) is sufficient to prevent outbreaks in low transmission rate settings and that OPV can be reintroduced and withdrawn as needed in moderate transmission rate settings. However, in high transmission rate settings, the conditions that support vaccine-derived outbreaks have only been rare because population immunity has been high. Absent population immunity, the Sabin strains from OPV will be nearly as capable of causing outbreaks as WPV. If post-cessation outbreak responses are followed by new vaccine-derived outbreaks, strategies to restore population immunity will be required to ensure the stability of polio eradication.

Over the course of cortical neurogenesis, the transition of progenitors from proliferation to differentiation requires a precise regulation of involved gene networks under varying environmental conditions. In order to identify such regulatory mechanisms, we analyzed microRNA (miRNA) target networks in progenitors during early and late stages of neurogenesis. We found that cyclin D1 is a network hub whose expression is miRNA-dosage sensitive. Experimental validation revealed a feedback regulation between cyclin D1 and its regulating miRNAs miR-20a, miR-20b, and miR-23a. Cyclin D1 induces expression of miR-20a and miR-20b, whereas it represses miR-23a. Inhibition of any of these miRNAs increases the developmental stage-specific mean and dynamic expression range (variance) of cyclin D1 protein in progenitors, leading to reduced neuronal differentiation. Thus, miRNAs establish robustness and stage-specific adaptability to a critical dosage-sensitive gene network during cortical neurogenesis. Understanding such network regulatory mechanisms for key developmental events can provide insights into individual susceptibilities for genetically complex neuropsychiatric disorders.