Standardising neonatal and paediatric antibiotic clinical trial design and conduct: the PENTA-ID network view.

Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators

Prevalence of adenomyosis in endometrial cancer patients: a systematic review and meta-analysis

Introduction: Several studies have assessed the histological co-existence of endometrial carcinoma (EC) and adenomyosis. However, the significance of this association is still unclear. Objective: To assess the prevalence of adenomyosis in women with EC for a better understanding of the association between the two diseases. Materials and methods: A systematic review and meta-analysis was performed by searching electronics databases from their inception to March 2020, for all studies that allowed extraction of data about prevalence of adenomyosis in EC patients. Adenomyosis prevalence was calculated for each included study and as pooled estimate, with 95% confidence interval (CI). Results: Eight retrospective cohort studies assessing 5573 EC patients were included in our analysis. Of total, 1322 were patients with adenomyosis, and 4251 were patients without adenomyosis. Pooled prevalence of adenomyosis in EC patients was 22.6% (95% CI 12.7–37.1%). Conclusion: Adenomyosis prevalence in EC patients was not different from that reported for other gynecological conditions. The supposed association between the two diseases appears unsupported

Successful private–public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines

The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMAPaediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres. Conclusion: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private–public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of offpatent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes

Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.

BACKGROUND: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged 44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating

Surveillance of HIV Drug Resistance in Children Receiving Antiretroviral Therapy: A Pilot Study of the World Health Organization's Generic Protocol in Maputo, Mozambique

Between 2007 and 2008, the Mozambique Ministry of Health conducted an assessment of human immunodeficiency virus drug resistance (HIVDR) using World Health Organization (WHO) methods in a cohort of children initiating antiretroviral therapy (ART) at the main pediatric ART referral center in Mozambique. It was shown that prior to ART initiation 5.4% of children had HIVDR that was associated with nevirapine perinatal exposure (P < .001). Twelve months after ART initiation, 77% had viral load suppression (<1000 copies/mL), exceeding the WHO target of ≥70%; 10.3% had HIVDR at 12 months. Baseline HIVDR (P = .04), maternal prevention of mother-to-child transmission (P = .02), and estimated days of missed medication (P = .03) predicted HIVDR at 12 months. As efforts to eliminate pediatric AIDS are intensified, implementation of ritonavir-boosted protease inhibitor regimens in children with prevention of mother-to-child transmission exposure may reduce risk of virological failure in our settin

Application of deep learning model in the sonographic diagnosis of uterine adenomyosis

Background: This study aims to evaluate the diagnostic performance of Deep Learning (DL) machine for the detection of adenomyosis on uterine ultrasonographic images and compare it to intermediate ultrasound skilled trainees. Methods: Prospective observational study were conducted between 1 and 30 April 2022. Transvaginal ultrasound (TVUS) diagnosis of adenomyosis was investigated by an experienced sonographer on 100 fertile-age patients. Videoclips of the uterine corpus were recorded and sequential ultrasound images were extracted. Intermediate ultrasound-skilled trainees and DL machine were asked to make a diagnosis reviewing uterine images. We evaluated and compared the accuracy, sensitivity, positive predictive value, F1-score, specificity and negative predictive value of the DL model and the trainees for adenomyosis diagnosis. Results: Accuracy of DL and intermediate ultrasound-skilled trainees for the diagnosis of adenomyosis were 0.51 (95% CI, 0.48–0.54) and 0.70 (95% CI, 0.60–0.79), respectively. Sensitivity, specificity and F1-score of DL were 0.43 (95% CI, 0.38–0.48), 0.82 (95% CI, 0.79–0.85) and 0.46 (0.42–0.50), respectively, whereas intermediate ultrasound-skilled trainees had sensitivity of 0.72 (95% CI, 0.52–0.86), specificity of 0.69 (95% CI, 0.58–0.79) and F1-score of 0.55 (95% CI, 0.43–0.66). Conclusions: In this preliminary study DL model showed a lower accuracy but a higher specificity in diagnosing adenomyosis on ultrasonographic images compared to intermediate-skilled trainees

Mathematical practice, crowdsourcing, and social machines

The highest level of mathematics has traditionally been seen as a solitary endeavour, to produce a proof for review and acceptance by research peers. Mathematics is now at a remarkable inflexion point, with new technology radically extending the power and limits of individuals. Crowdsourcing pulls together diverse experts to solve problems; symbolic computation tackles huge routine calculations; and computers check proofs too long and complicated for humans to comprehend. Mathematical practice is an emerging interdisciplinary field which draws on philosophy and social science to understand how mathematics is produced. Online mathematical activity provides a novel and rich source of data for empirical investigation of mathematical practice - for example the community question answering system {\it mathoverflow} contains around 40,000 mathematical conversations, and {\it polymath} collaborations provide transcripts of the process of discovering proofs. Our preliminary investigations have demonstrated the importance of "soft" aspects such as analogy and creativity, alongside deduction and proof, in the production of mathematics, and have given us new ways to think about the roles of people and machines in creating new mathematical knowledge. We discuss further investigation of these resources and what it might reveal. Crowdsourced mathematical activity is an example of a "social machine", a new paradigm, identified by Berners-Lee, for viewing a combination of people and computers as a single problem-solving entity, and the subject of major international research endeavours. We outline a future research agenda for mathematics social machines, a combination of people, computers, and mathematical archives to create and apply mathematics, with the potential to change the way people do mathematics, and to transform the reach, pace, and impact of mathematics research.Comment: To appear, Springer LNCS, Proceedings of Conferences on Intelligent Computer Mathematics, CICM 2013, July 2013 Bath, U

A differential U-module algebra for U=U_q sl(2) at an even root of unity

We show that the full matrix algebra Mat_p(C) is a U-module algebra for U = U_q sl(2), a 2p^3-dimensional quantum sl(2) group at the 2p-th root of unity. Mat_p(C) decomposes into a direct sum of projective U-modules P^+_n with all odd n, 1<=n<=p. In terms of generators and relations, this U-module algebra is described as the algebra of q-differential operators "in one variable" with the relations D z = q - q^{-1} + q^{-2} z D and z^p = D^p = 0. These relations define a "parafermionic" statistics that generalizes the fermionic commutation relations. By the Kazhdan--Lusztig duality, it is to be realized in a manifestly quantum-group-symmetric description of (p,1) logarithmic conformal field models. We extend the Kazhdan--Lusztig duality between U and the (p,1) logarithmic models by constructing a quantum de Rham complex of the new U-module algebra.Comment: 29 pages, amsart++, xypics. V3: The differential U-module algebra was claimed quantum commutative erroneously. This is now corrected, the other results unaffecte