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Situs viscerum inversus totalis (SIT) is a rare congenital anomaly. Deceased donors with this condition are often declined because of the technical issues in both the organ's procurement and its transplant. Only eight cases of deceased donor organs with SIT were reported to be used for liver transplantation (LT). We herein present a case of LT using a graft from an SIT donor: a modified retroversus piggyback technique was used. A 15 year-old female was referred to our institution as a potential donor. An SIT condition was discovered during standard donor evaluation together with the presence of a complex triple arterial pedicle. Procurement operative time was 125 min, from skin incision to cross-clamp. Liver extraction occurred 32 min after cold flush. The recipient was a 56 year-old male affected by recurrent hepatocellular carcinoma (HCC) on hepatitis C related liver cirrhosis. Position and orientation trials of the graft were made and it was decided to implant it with the retroversus technique. Direct duct-to-duct biliary reconstruction was achieved. The postoperative course was uneventful. To our knowledge, this is the first implant with retroversus technique combined to direct biliary reconstruction and the first repetition of that technique. Cases like this highlight how technical complexity can be overcome leading to successful management of difficult scenarios in a safe manner., Competing Interests: Declarations Conflict of interest The authors have no conflict of interest. Ethical approval and Research involving human participants and/or animals Not applicable. Informed consent Informed consent was obtained by the patient for the described procedure., (© 2024. The Author(s).)

Stress responses play a vital role in cellular survival against environmental challenges, often exploited by cancer cells to proliferate, counteract genomic instability, and resist therapeutic stress. Heat shock factor protein 1 (HSF1), a central transcription factor in stress response pathways, exhibits markedly elevated activity in cancer. Despite extensive research into the transcriptional role of HSF1, the mechanisms underlying its activation remain elusive. Upon exposure to conditions that induce protein damage, monomeric HSF1 undergoes rapid conformational changes and assembles into trimers, a key step for DNA binding and transactivation of target genes. This study investigates the role of HSF1 as a sensor of proteotoxic stress conditions. Our findings reveal that purified HSF1 maintains a stable monomeric conformation independent of molecular chaperones in vitro. Moreover, while it is known that heat stress triggers HSF1 trimerization, a notable increase in trimerization and DNA binding was observed in the presence of protein-based crowders. Conditions inducing protein misfolding and increased protein crowding in cells directly trigger HSF1 trimerization. In contrast, proteosynthesis inhibition, by reducing denatured proteins in the cell, prevents HSF1 activation. Surprisingly, HSF1 remains activated under proteotoxic stress conditions even when bound to Hsp70 and Hsp90. This finding suggests that the negative feedback regulation between HSF1 and chaperones is not directly driven by their interaction but is realized indirectly through chaperone-mediated restoration of cytoplasmic proteostasis. In summary, our study suggests that HSF1 serves as a molecular crowding sensor, trimerizing to initiate protective responses that enhance chaperone activities to restore homeostasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Simoncik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Interactions between bubbles and drops play an important role in many physical phenomena. Whether we consider the interaction between two bubbles (drops) or between many (foams or emulsions), these interactions are complex and still poorly understood. An interesting case arises when two equal- and constant-volume bubbles (drops) interact with each other while being held by two axisymmetrically positioned frames of circular opening - a configuration which is frequently used in characterisation devices. The minimisation of the surface energy of this "double bubble" (or "double drop") configuration, constrained by the fixed volume and the frame boundaries, creates a complex landscape of shape spaces where physically stable shapes are separated by different types of instabilities. Combining experiments, finite element simulations and theory, we provide here for the first time a complete analysis of these shape spaces, considering the adhesive energy between the bubbles and the drops (expressed by the contact angle) as an additional control parameter. We provide the full shape diagrams for different contact angles (0°, 60° and 90°), including a detailed discussion of four types of instabilities. Two of these instabilities break the axisymmetry, while the two others break the connectivity of the ensemble. As far as we are aware, two of these instabilities have never been reported before. We accompany the shape and stability analysis with detailed mechanical characterisation using force and pressure measurements. Experiments, simulations and theory showing excellent agreement. This work will not only be useful in guiding the exploitation of double bubble (double drop) experiments on frames, but it also opens the possibility to exploit these configurations for the characterisation of increasingly complex bubble or drop interactions. Since the contact angle of 90° corresponds to an "imaginary" film separating the two bubbles (drops), our analysis naturally includes the shape and stability of a capillary bridge between two circular frames.

Background : Supramaximal constant work rate tests (CWR) elicit intense hyperventilation, thus potentially up-shifting ventilation (⩒ E )-to-carbon dioxide (CO 2 ) responses when compared to graded exercise tests (GXT) in athletes. We predicted higher ventilatory efficiency on supramaximal CWR using a new method, challenging the classic orthodox interpretation of an increased ⩒ E -⩒CO 2 as ventilatory inefficiency. This misinterpretation could make difficult to differentiate between physiological hyperventilation from heart disease conditions in athletes. Methods : On different days, a GXT and a CWR at 110% of the maximal velocity achieved in the GXT were performed. Twenty-seven athletes completed the two tests and were compared for usual (linear regression) and log-transformed new variables for ventilatory efficiency through paired t -Student statistics. Results : The ⩒ E -⩒CO 2 slope (31.4 ± 4.9 vs . 26.2 ± 3.4, p  < .001), ⩒ E -⩒CO 2 intercept (7.2 ± 7.5 vs . 2.8 ± 4.2, p  < .007), ⩒ E /⩒CO 2 nadir (33.0 ± 3.6 vs . 25.4 ± 2.2, p  < .001), ⩒CO 2 -log⩒ E slope (10.8 ± 2.9 vs . 6.9 ± 2.2 L * logL -1 , p  < .001), and η⩒ E (36.0 ± 12 vs . 22.8 ± 8.1%, p  < .001) values were all significantly higher in the CWR compared to the GXT. We registered a bi-modal nadir response for ⩒ E/ ⩒CO 2 on CWR for 22 out of 27 subjects for the first time. A weak association was observed between ⩒ E /⩒CO 2 nadir (coefficient of determination ~ 27%) and time to exhaustion. Conclusions : The new method allows us to improve the quantification and interpretation of ventilatory efficiency in athletes, avoiding misinterpretation due to the up-shifting elicited by the usual ⩒ E -⩒CO 2 slope and ⩒ E /⩒CO 2 nadir indices, which may be confounded with ventilatory inefficiency. This study suggests that ventilatory changes underpin better ventilatory efficiency during CWR.

Weakly supervised object detection (WSup-OD) increases the usefulness and interpretability of image classification algorithms without requiring additional supervision. The successes of multiple instance learning in this task for natural images, however, do not translate well to medical images due to the very different characteristics of their objects (i.e. pathologies). In this work, we propose Weakly Supervised ROI Proposal Networks (WSRPN), a new method for generating bounding box proposals on the fly using a specialized region of interest-attention (ROI-attention) module. WSRPN integrates well with classic backbone-head classification algorithms and is end-to-end trainable with only image-label supervision. We experimentally demonstrate that our new method outperforms existing methods in the challenging task of disease localization in chest X-ray images. Code: https://anonymous.4open.science/r/WSRPN-DCA1.

Introduction: Chronic inflammatory dermatoses (CIDs) can significantly affect patients' lives. The Observatory of Chronic Inflammatory Skin Diseases (OMCCI) cohort was initiated to quantify the impact and disease evolution of four CID over 4 years' follow-up; at least 1,000 patients per CID are planned to be enrolled. The objective of this study was to present baseline characteristics of patients included in the OMCCI cohort between December 2020 and September 2022., Methods: This French, prospective, multicenter registry included adult patients treated in daily practice for moderate-to-severe psoriasis (PS), atopic dermatitis (AD), hidradenitis suppurativa (HS), or chronic urticaria (CU) starting or modifying a systemic treatment. At the inclusion visit and then every 6 months during 4 years, patient-reported outcomes and data on these diseases and their treatments are recorded., Results: A total of 2,058 patients from 24 centers were included: 1,137 PS, 413 AD, 301 HS, and 207 CU. Of these, 1,950 patients started or changed systemic treatment, and 108 reduced the dose of existing systemic treatment. Disease impact was qualified as debilitating by 80.1% (PS), 90.5% (AD), 90.5% (HS), and 89.4% (CU), affecting daily, family, and professional life. According to the SF-12 Survey, the impact of all four diseases was borderline pathological for physical health and severe for mental health. At inclusion, 20.4% of patients were receiving a conventional systemic or biologic treatment. After the first visit, this percentage raised to 83.3%. During the 6 months preceding study inclusion, 17.7% (PS), 27.9% (AD), 43.1% (HS), and 43.6% (CU) of patients missed work due to their illness, and 26.3% of patients with HS had been admitted to hospital (vs. 8.1%, 5.8%, and 13% of patients with PS, AD, or CU, respectively)., Conclusion: These CIDs (especially HS) had a major impact on all aspects of patients' quality of life. The low baseline use of systemic drugs and the high burden of these CIDs suggest that these agents are underused. Long-term and dynamic evaluation of the changes brought by the initiation or optimization of these treatments on the evolution of patients' lives will be studied prospectively during the 4-year follow-up of the OMCCI., (© 2024 S. Karger AG, Basel.)

This ISPOR Good Practices report provides a framework for assessing the suitability of electronic health records data for use in health technology assessments (HTAs). Although electronic health record (EHR) data can fill evidence gaps and improve decisions, several important limitations can affect its validity and relevance. The ISPOR framework includes 2 components: data delineation and data fitness for purpose. Data delineation provides a complete understanding of the data and an assessment of its trustworthiness by describing (1) data characteristics; (2) data provenance; and (3) data governance. Fitness for purpose comprises (1) data reliability items, ie, how accurate and complete the estimates are for answering the question at hand and (2) data relevance items, which assess how well the data are suited to answer the particular question from a decision-making perspective. The report includes a checklist specific to EHR data reporting: the ISPOR SUITABILITY Checklist. It also provides recommendations for HTA agencies and policy makers to improve the use of EHR-derived data over time. The report concludes with a discussion of limitations and future directions in the field, including the potential impact from the substantial and rapid advances in the diffusion and capabilities of large language models and generative artificial intelligence. The report's immediate audiences are HTA evidence developers and users. We anticipate that it will also be useful to other stakeholders, particularly regulators and manufacturers, in the future., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Trio exome sequencing can be used to investigate congenital abnormalities identified on pregnancy ultrasound, but its use in an Australian context has not been assessed., Aims: Assess clinical outcomes and changes in management after expedited genomic testing in the prenatal period to guide the development of a model for widespread implementation., Materials and Methods: Forty-three prospective referrals for whole exome sequencing, including 40 trios (parents and pregnancy), two singletons and one duo were assessed in a tertiary hospital setting with access to a state-wide pathology laboratory. Diagnostic yield, turn-around time (TAT), gestational age at reporting, pregnancy outcome, change in management and future pregnancy status were assessed for each family., Results: A clinically significant genomic diagnosis was made in 15/43 pregnancies (35%), with an average TAT of 12 days. Gestational age at time of report ranged from 16 + 5 to 31 + 6 weeks (median 21 + 3 weeks). Molecular diagnoses included neuromuscular and skeletal disorders, RASopathies and a range of other rare Mendelian disorders. The majority of families actively used the results in pregnancy decision making as well as in management of future pregnancies., Conclusions: Rapid second trimester prenatal genomic testing can be successfully delivered to investigate structural abnormalities in pregnancy, providing crucial guidance for current and future pregnancy management. The time-sensitive nature of this testing requires close laboratory and clinical collaboration to ensure appropriate referral and result communication. We found the establishment of a prenatal coordinator role and dedicated reporting team to be important facilitators. We propose this as a model for genomic testing in other prenatal services., (© 2024 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

A cell-penetrating peptide (CPP) is a short amino-acid sequence capable of efficiently translocating across the cellular membrane of mammalian cells. However, the potential of CPPs as a delivery vector is hampered by the strong reduction of its translocation efficiency when it bears an attached molecular cargo. To overcome this problem, we used previously developed diblock copolymers of elastin-like polypeptides (ELP BC s), which we end functionalized with TAT (transactivator of transcription), an archetypal CPP built from a positively charged amino acid sequence of the HIV-1 virus. These ELP BC s self-assemble into micelles at a specific temperature and present the TAT peptide on their corona. These micelles can recover the lost membrane affinity of TAT and can trigger interactions with the membrane despite the presence of a molecular cargo. Herein, we study the influence of membrane surface charge on the adsorption of TAT-functionalized ELP micelles onto giant unilamellar vesicles (GUVs). We show that the TAT-ELP BC micelles show an increased binding constant toward negatively charged membranes compared to neutral membranes, but no translocation is observed. The affinity of the TAT-ELP BC micelles for the GUVs displays a stepwise dependence on the lipid charge of the GUV, which, to our knowledge, has not been reported previously for interactions between peptides and lipid membranes. By unveiling the key steps controlling the interaction of an archetypal CPP with lipid membranes, through regulation of the charge of the lipid bilayer, our results pave the way for a better design of delivery vectors based on CPPs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. All rights reserved.)

Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC 50 's ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue.

Sodium bicarbonate (NaHCO3) is commonly utilized as a therapeutic to treat metabolic acidosis in people with chronic kidney disease (CKD). While increased dietary sodium chloride (NaCl) is known to promote volume retention and increase blood pressure, the effects of NaHCO3 loading on blood pressure and volume retention in CKD remain unclear. In the present study, we compared the effects of NaCl and NaHCO3 loading on volume retention, blood pressure, and kidney injury in both 2/3 and 5/6 nephrectomy remnant kidney rats, a well-established rodent model of CKD. We tested the hypothesis that NaCl loading promotes greater volume retention and increases in blood pressure than equimolar NaHCO3. Blood pressure was measured 24 h daily using radio telemetry. NaCl and NaHCO3 were administered in drinking water ad libitum or infused via indwelling catheters. Rats were housed in metabolic cages to determine volume retention. Our data indicate that both NaHCO3 and NaCl promote hypertension and volume retention in remnant kidney rats, with salt-sensitivity increasing with greater renal mass reduction. Importantly, while NaHCO3 intake was less pro-hypertensive than equimolar NaCl intake, NaHCO3 was not benign. NaHCO3 loading significantly elevated blood pressure and promoted volume retention in rats with CKD when compared with control rats receiving tap water. Our findings provide important insight into the effects of sodium loading with NaHCO3 in CKD and indicate that NaHCO3 loading in patients with CKD is unlikely to be benign., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Accelerated partial breast irradiation (APBI) is an alternative breast-conserving therapy approach where radiation is delivered in less time compared to whole breast irradiation (WBI), resulting in improved patient convenience, less toxicity, and cost savings. This prospective randomized study compares the external beam APBI with commonly used moderate hypofractionated WBI in terms of feasibility, safety, tolerance, and cosmetic effects., Methods: Early breast cancer patients after partial mastectomy were equally randomized into two arms- external APBI and moderate hypofractionated WBI. External beam technique using available technical innovations commonly used in targeted hypofractionated radiotherapy to minimize irradiated volumes was used (cone beam computed tomography navigation to clips in the tumor bed, deep inspiration breath hold technique, volumetric modulated arc therapy dose application, using flattening filter free beams and the six degrees of freedom robotic treatment couch). Cosmetics results and toxicity were evaluated using questionnaires, CTCAE criteria, and photo documentation., Results: The analysis of 84 patients with a median age of 64 years showed significantly fewer acute adverse events in the APBI arm regarding skin reactions, local and general symptoms during a median follow-up of 37 months (range 21-45 months). A significant difference in favor of the APBI arm in grade ≥ 2 late skin toxicity was observed (p = 0.026). Late toxicity in the breast area (deformation, edema, fibrosis, and pain), affecting the quality of life and cosmetic effect, occurred in 61% and 17% of patients in WBI and APBI arms, respectively. The cosmetic effect was more favorable in the APBI arm, especially 6 to 12 months after the radiotherapy., Conclusion: External APBI demonstrated better feasibility and less toxicity than the standard regimen in the adjuvant setting for treating early breast cancer patients. The presented study confirmed the level of evidence for establishing the external APBI in daily clinical practice., Trial Registration: NCT06007118., (© 2024. The Author(s).)

Infections caused by Acinetobacter baumannii, a Gram-negative opportunistic pathogen, are difficult to eradicate due to the bacterium's propensity to quickly gain antibiotic resistances and form biofilms, a protective bacterial multicellular community. The A. baumannii DNA damage response (DDR) mediates the antibiotic resistance acquisition and regulates RecA in an atypical fashion; both RecA Low and RecA High cell types are formed in response to DNA damage. The findings of this study demonstrate that the levels of RecA can influence formation and dispersal of biofilms. RecA loss results in surface attachment and prominent biofilms, while elevated RecA leads to diminished attachment and dispersal. These findings suggest that the challenge to treat A. baumannii infections may be explained by the induction of the DDR, common during infection, as well as the delicate balance between maintaining biofilms in low RecA cells and promoting mutagenesis and dispersal in high RecA cells. This study underscores the importance of understanding the fundamental biology of bacteria to develop more effective treatments for infections., (© 2023 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

As the primary products of lipid oxidation, lipid hydroperoxides constitute an important class of lipids generated by aerobic metabolism. However, despite several years of effort, the structure of the hydroperoxidized bilayer has not yet been observed under electron microscopy. Here we use a 200 kV Cryo-TEM to image small unilamellar vesicles (SUVs) made (i) of pure POPC or SOPC, (ii) of their pure hydroperoxidized form, and (iii) of their equimolar mixtures. We show that the challenges posed by the determination of the thickness of the hydroperoxidized bilayers under these observation conditions can be addressed by an image analysis method that we developed and describe here., (Copyright © 2024. Published by Elsevier Inc.)

Background: Pregnant women with pre-existing mental illnesses have increased risks of adverse obstetric and neonatal outcomes compared with pregnant women without pre-existing mental illnesses. We aimed to estimate these differences in risks according to the highest level of pre-pregnancy specialist mental health care, defined as psychiatric hospital admission, crisis resolution team (CRT) contact, or specialist community care only, and the timing of the most recent care episode in the 7 years before pregnancy., Methods: Hospital and birth registration records of women with singleton births between April 1, 2014, and March 31, 2018 in England were linked to records of babies and records from specialist mental health services provided by the England National Health Service, a publicly funded health-care system. We compared the risks of adverse pregnancy outcomes, including fetal and neonatal death, preterm birth, and babies being born small for gestational age (SGA; birthweight <10th percentile), and composite indicators for neonatal adverse outcomes and maternal morbidity, between women with and without a history of contact with specialist mental health care. We calculated odds ratios adjusted for maternal characteristics (aORs), using logistic regression., Findings: Of 2 081 043 included women (mean age 30·0 years; range 18-55 years; 77·7% White, 11·4% South Asian, 4·7% Black, and 6·2% mixed or other ethnic background), 151 770 (7·3%) had at least one pre-pregnancy specialist mental health-care contact. 7247 (0·3%) had been admitted to a psychiatric hospital, 29 770 (1·4%) had CRT contact, and 114 753 (5·5%) had community care only. With a pre-pregnancy mental health-care contact, risk of stillbirth or neonatal death within 7 days of birth was not significantly increased (0·45-0·49%; aOR 1·11, 95% CI 0·99-1·24): risk of preterm birth (<37 weeks) increased (6·5-9·8%; aOR 1·53, 1·35-1·73), as did risk of SGA (6·2- 7·5%; aOR 1·34, 1·30-1·37) and neonatal adverse outcomes (6·4-8·4%; aOR 1·37, 1·21-1·55). With a pre-pregnancy mental health-care contact, risk of maternal morbidity increased slightly from 0·9% to 1·0% (aOR 1·18, 1·12-1·25). Overall, risks were highest for women who had a psychiatric hospital admission any time or a mental health-care contact in the year before pregnancy., Interpretation: Information about the level and timing of pre-pregnancy specialist mental health-care contacts helps to identify women at increased risk of adverse obstetric and neonatal outcomes. These women are most likely to benefit from dedicated community perinatal mental health teams working closely with maternity services to provide integrated care., Funding: National Institute for Health Research., Competing Interests: Declaration of interests LMH, HAO'M, JvdM, SB, DP, and HS declare funding from the National Institute of Health Research to deliver a study on the effectiveness of community perinatal mental health services (17/49/38). AK, TH, IG-U, and JvdM also declare funding from the Healthcare Quality Improvement Partnership to deliver the National Maternity and Perinatal Audit. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Ethnic and socioeconomic inequalities in obstetric outcomes are well established. However, the role of induction of labour (IOL) to reduce these inequalities is controversial, in part due to insufficient evidence. This national cohort study aimed to identify adverse perinatal outcomes associated with IOL with birth at 39 weeks of gestation ("IOL group") compared to expectant management ("expectant management group") according to maternal characteristics in women with low-risk pregnancies., Methods and Findings: All English National Health Service (NHS) hospital births between January 2018 and March 2021 were examined. Using the Hospital Episode Statistics (HES) dataset, maternal and neonatal data (demographic, diagnoses, procedures, labour, and birth details) were linked, with neonatal mortality data from the Office for National Statistics (ONS). Women with a low-risk pregnancy were identified by excluding pregnancies with preexisting comorbidities, previous cesarean section, breech presentation, placenta previa, gestational diabetes, or a baby with congenital abnormalities. Women with premature rupture of membranes, placental abruption, hypertensive disorders of pregnancy, amniotic fluid abnormalities, or antepartum stillbirth were excluded only from the IOL group. Adverse perinatal outcome was defined as stillbirth, neonatal death, or neonatal morbidity, the latter identified using the English composite neonatal outcome indicator (E-NAOI). Binomial regression models estimated risk differences (with 95% confidence intervals (CIs)) between the IOL group and the expectant management group, adjusting for ethnicity, socioeconomic background, maternal age, parity, year of birth, and birthweight centile. Interaction tests examined risk differences according to ethnicity, socioeconomic background, and parity. Of the 1 567 004 women with singleton pregnancies, 501 072 women with low-risk pregnancies and with sufficient data quality were included in the analysis. Approximately 3.3% of births in the IOL group (1 555/47 352) and 3.6% in the expectant management group (16 525/453 720) had an adverse perinatal outcome. After adjustment, a lower risk of adverse perinatal outcomes was found in the IOL group (risk difference -0.28%; 95% CI -0.43%, -0.12%; p = 0.001). This risk difference varied according to socioeconomic background from 0.38% (-0.08%, 0.83%) in the least deprived to -0.48% (-0.76%, -0.20%) in the most deprived national quintile (p-value for interaction = 0.01) and by parity with risk difference of -0.54% (-0.80%, -0.27%) in nulliparous women and -0.15% (-0.35%, 0.04%) in multiparous women (p-value for interaction = 0.02). There was no statistically significant evidence that risk differences varied according to ethnicity (p = 0.19). Key limitations included absence of additional confounding factors such as smoking, BMI, and the indication for induction in the HES datasets, which may mean some higher risk pregnancies were included., Conclusions: IOL with birth at 39 weeks was associated with a small reduction in the risk of adverse perinatal outcomes, with 360 inductions in low-risk pregnancies needed to avoid 1 adverse outcome. The risk reduction was mainly present in women from more socioeconomically deprived areas and in nulliparous women. There was no significant risk difference found by ethnicity. Increased uptake of IOL at 39 weeks, especially in women from more socioeconomically deprived areas, may help reduce inequalities in adverse perinatal outcomes., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: All authors have completed the ICMJE uniform disclosure form and declare: all individuals, apart from HK and JvdM, are or have been partially or wholly funded by the Healthcare Quality Improvement Partnership for their contribution to the submitted work. All authors also declare no financial relationships with any organisation that might have an interest in the submitted work in the previous three years. AK is the Vice President of the Royal College of Obstetricians and Gynaecologists. The authors report no other relationships or activities that could appear to have influenced the submitted work., (Copyright: © 2023 Muller et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates 24a and 28a with improved pan-serotype coverage (EC 50 's against the four DENV serotypes ranging from 0.0011 to 0.24 μM for 24a and from 0.00060 to 0.084 μM for 28a ), chiral stability, and oral bioavailability in preclinical species, as well as showing a dose-proportional increase in efficacy against DENV-2 infection in vivo in mice.

Cardiovascular diseases are the leading cause of death worldwide. The diagnoses of cardiovascular diseases are usually carried out by cardiologists utilizing Electrocardiograms (ECGs). To assist these physicians in making an accurate diagnosis, there is a growing need for reliable and automatic ECG classifiers.In this study, a new method is proposed to classify 12-lead ECG recordings. The proposed model is composed of four components: the CNN(Convolutional Neural Network) module, the transformer module, the global hybrid pooling layer, and a classification layer. To improve the classification performance, the model takes the discrete wavelet transform of ECG signals as the model inputs and utilizes a hybrid pooling layer to condense the most important features over each period.The proposed model is evaluated using the test set of the China Physiological Signal Challenge 2018 dataset with 12-lead ECGs. It performs with an average accuracy of 0.86 and an average F1-scores of 0.83. The scores are particularly good for the block conditions (LBBB, RBBB, I-AVB). The main advantage of the proposed model is that, it obtains good results with a significantly smaller number of parameters compared to other individual and ensemble models.Clinical relevance- This work establishes a new ECG classifier model with high performance and low model size. It can make automatic ECG analysis more accessible, efficient, and accurate, especially in remote or underserved areas.

Entry of micro- or nanosized objects into cells or vesicles made of lipid membranes occurs in many processes such as entry of viruses into host cells, microplastics pollution, drug delivery, or biomedical imaging. Here we investigate the microparticle crossing of lipid membranes in giant unilamellar vesicles in the absence of strong binding interactions (e.g., streptavidin-biotin binding). In these conditions, we observe that organic and inorganic particles can always penetrate inside the vesicles provided an external piconewton force is applied and for relatively low membrane tensions. In the limit of vanishing adhesion, we identify the role of the membrane area reservoir and show that a force minimum exists when the particle size is comparable to the bendocapillary length.

Nucleic acids aptamers often fail to efficiently target some proteins because of the hydrophilic character of the natural nucleotides. Here we present hydrophobic 7-phenylbutyl-7-deaadenine-modified DNA aptamers against the Heat Shock Protein 70 that were selected via PEX and magnetic bead-based SELEX. After 9 rounds of selection, the pool was sequenced and a number of candidates were identified. Following initial screening, two modified aptamers were chemically synthesised in-house and their binding affinity analysed by two methods, bio-layer interferometry and fluorescent-plate-based binding assay. The binding affinities of the modified aptamers were compared with that of their natural counterparts. The resulting modified aptamers bound with higher affinity (low nanomolar range) to the Hsp70 than their natural sequence (>5 µM) and hence have potential for applications and further development towards Hsp70 diagnostics or even therapeutics., (© 2023. The Author(s).)

Immune checkpoint inhibitors (ICI) are the main therapy currently used in advanced malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Despite the wide variety of uses, the possibility of predicting ICI efficacy in these tumor types is scarce. The aim of our study was to find new predictive biomarkers for ICI treatment. We analyzed, by immunohistochemistry, various cell subsets, including CD3+, CD8+, CD68+, CD20+, and FoxP3+ cells, and molecules such as LAG-3, IDO1, and TGFβ. Comprehensive genomic profiles were analyzed. We evaluated 46 patients with advanced MM (31) and NSCLC (15) treated with ICI monotherapy. When analyzing the malignant melanoma group, shorter median progression-free survival (PFS) was found in tumors positive for nuclear FoxP3 in tumor-infiltrating lymphocytes (TILs) ( p = 0.048, HR 3.04) and for CD68 expression ( p = 0.034, HR 3.2). Longer PFS was achieved in patients with tumors with PD-L1 TPS ≥ 1 ( p = 0.005, HR 0.26). In the NSCLC group, only FoxP3 positivity was associated with shorter PFS and OS. We found that FoxP3 negativity was linked with a better response to ICI in both histological groups.

The standard model of pore formation was introduced more than fifty years ago, and it has been since, despite some refinements, the cornerstone for interpreting experiments related to pores in membranes. A central prediction of the model concerning pore opening under an electric field is that the activation barrier for pore formation is lowered proportionally to the square of the electric potential. However, this has only been scarcely and inconclusively confronted to experiments. In this paper, we study the electropermeability of model lipid membranes composed of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) containing different fractions of POPC-OOH, the hydroperoxidized form of POPC, in the range 0 to 100 mol %. By measuring ion currents across a 50-μm-diameter black lipid membrane (BLM) with picoampere and millisecond resolution, we detect hydroperoxidation-induced changes to the intrinsic bilayer electropermeability and to the probability of opening angstrom-size or larger pores. Our results over the full range of lipid compositions show that the energy barrier to pore formation is lowered linearly by the absolute value of the electric field, in contradiction with the predictions of the standard model.

Case of a patient developing multiple rashes of squamous cell carcinoma 6 weeks after the introduction of dupilumab due to atopic eczema., Competing Interests: None to declare., (© 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Osteoarthritis (OA) is a highly prevalent degenerative joint condition that disproportionately affects females. The pathophysiology of the disease is not well understood, which makes diagnosis and treatment difficult. Given the physical connection of synovial fluid (SF) with articular tissues, the SF's composition can reflect relevant biological modifications, and has therefore been a focus of research. Previously, we demonstrated that extracellular vesicles isolated from the synovial fluid of OA patients carry different cargo (protein and miRNA) in a sex-specific manner. Given the increased prevalence and severity of OA in females, this study aims to identify differential protein content within the synovial fluid of female OA and non-osteoarthritic (non-OA) patients. We found that several proteins were differentially expressed in osteoarthritic females compared with age-matched controls. Presenilin, Coagulation Factor X, Lysine-Specific Demethylase 2B, Tenascin C, Leucine-Rich Repeat-Containing Protein 17 fragments, and T-Complex Protein 1 were negatively regulated in the OA group, with PGD Synthase, Tubulointerstitial Nephritis Antigen, and Nuclear Receptor Binding SET Domain Protein 1 positively regulated in the OA group. Database for Annotation, Visualization, and Integrated Discovery (DAVID) and QuickGO analyses established these proteins as significantly involved in many biological, cellular, and molecular processes. In conclusion, the protein content of female synovial fluid is altered in OA patients, which is likely to provide insights into gender-specific pathophysiology.

Lipid peroxidation is a process which is key in cell signaling and disease, it is exploited in cancer therapy in the form of photodynamic therapy. The appearance of hydrophilic moieties within the bilayer's hydrocarbon core will dramatically alter the structure and mechanical behavior of membranes. Here, we combine viscosity sensitive fluorophores, advanced microscopy, and X-ray diffraction and molecular simulations to directly and quantitatively measure the bilayer's structural and viscoelastic properties, and correlate these with atomistic molecular modelling. Our results indicate an increase in microviscosity and a decrease in the bending rigidity upon peroxidation of the membranes, contrary to the trend observed with non-oxidized lipids. Fluorescence lifetime imaging microscopy and MD simulations give evidence for the presence of membrane regions of different local order in the oxidized membranes. We hypothesize that oxidation promotes stronger lipid-lipid interactions, which lead to an increase in the lateral heterogeneity within the bilayer and the creation of lipid clusters of higher order., (© 2023. The Author(s).)

Introduction Recent publications have described drug reaction with eosinophilia and systemic symptoms (DRESS) with topiramate. Topiramate has been associated with other severe cutaneous adverse reactions, including Stevens-Johnson syndrome, but a relationship to DRESS has not been established. To determine if there is a causal association between topiramate and DRESS, we conducted a comprehensive review of the data in the Janssen Research & Development Global Safety Database (GSD), signaling databases, and the literature. Methods The primary data were post-marketing reports of DRESS in the Janssen topiramate GSD (cumulative through 1 July 2022), representing >14,000,000 patient-years (PY) exposure. Cases were reviewed, assigned a Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) score, and assessed for overall contribution of topiramate to DRESS based on temporality, concomitant medications, dechallenge/rechallenge, and baseline patient factors. Statistical disproportionality was evaluated in European Medicines Agency's EudraVigilance (EV) safety database and the United States Food and Drug Administration Adverse Event Reporting System (FAERS). For EV, the overall disproportionality threshold was the lower limit of the 95% confidence interval (CI) for the reporting odds ratio (ROR025) >1 and N ≥5. The overall threshold for FAERS was the Empirical Bayesian Geometric Mean (EBGM) ≥2, lower bound of the 90% CI (EB05) of >1, and N ≥3. To account for the role of concomitant drugs, Empirical Bayes regression-adjusted arithmetic mean (ERAM) scores were calculated, with a threshold ≥2, a lower bound of the 90% CI (ER05) of >1, and N ≥3. An integrated search of major biomedical literature was performed for reports of topiramate and DRESS. Results There were 17 reports of DRESS in the GSD (reporting rate 0.12/100,000 PY). RegiSCAR scores ranged from -3 to 7 (average -0.4). No cases met full diagnostic criteria and were highly confounded by the presence of other suspect drugs. Disproportionality scores exceeded thresholds for statistical significance in FAERS (N=72, EBGM=2.06, EB05=1.69), but not in EV (N=33, ROR025=0.79). When accounting for co-administered drugs, ERAM was statistically significant for carbamazepine (4.53), lamotrigine (ERAM=6.54), phenytoin (ERAM=2.91), and zonisamide (ERAM=2.25) exceeding disproportionality thresholds, but the score of topiramate was no longer significant (0.25). Conclusion A comprehensive review of all available evidence does not support a causal association between topiramate and DRESS., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Thoms et al.)

Objective. To present the first 3D CGO-based absolute EIT reconstructions from experimental tank data. Approach. CGO-based methods for absolute EIT imaging are compared to traditional TV regularized non-linear least squares reconstruction methods. Additional robustness testing is performed by considering incorrect modeling of domain shape. Main Results. The CGO-based methods are fast, and show strong robustness to incorrect domain modeling comparable to classic difference EIT imaging and fewer boundary artefacts than the TV regularized non-linear least squares reference reconstructions. Significance. This work is the first to demonstrate fully 3D CGO-based absolute EIT reconstruction on experimental data and also compares to TV-regularized absolute reconstruction. The speed (1-5 s) and quality of the reconstructions is encouraging for future work in absolute EIT., (© 2022 Institute of Physics and Engineering in Medicine.)

Defining dynamic protein-protein interactions in the ubiquitin conjugation reaction is a challenging research area. Generating peptide aptamers that target components such as ubiquitin itself, E1, E2, or E3 could provide tools to dissect novel features of the enzymatic cascade. Next-generation deep sequencing platforms were used to identify peptide sequences isolated from phage-peptide libraries screened against Ubiquitin and its ortholog NEDD8. In over three rounds of selection under differing wash criteria, over 13,000 peptides were acquired targeting ubiquitin, while over 10,000 peptides were selected against NEDD8. The overlap in peptides against these two proteins was less than 5% suggesting a high degree in specificity of Ubiquitin or NEDD8 toward linear peptide motifs. Two of these ubiquitin-binding peptides were identified that inhibit both E3 ubiquitin ligases MDM2 and CHIP. NMR analysis highlighted distinct modes of binding of the two different peptide aptamers. These data highlight the utility of using next-generation sequencing of combinatorial phage-peptide libraries to isolate peptide aptamers toward a protein target that can be used as a chemical tool in a complex multi-enzyme reaction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lisowska, Lickiss, Gil-Mir, Huart, Trybala, Way, Hernychova, Krejci, Muller, Krejcir, Zhukow, Jurczak, Rodziewicz-Motowidło, Ball, Vojtesek, Hupp and Kalathiya.)

We introduce DeepNash, an autonomous agent that plays the imperfect information game Stratego at a human expert level. Stratego is one of the few iconic board games that artificial intelligence (AI) has not yet mastered. It is a game characterized by a twin challenge: It requires long-term strategic thinking as in chess, but it also requires dealing with imperfect information as in poker. The technique underpinning DeepNash uses a game-theoretic, model-free deep reinforcement learning method, without search, that learns to master Stratego through self-play from scratch. DeepNash beat existing state-of-the-art AI methods in Stratego and achieved a year-to-date (2022) and all-time top-three ranking on the Gravon games platform, competing with human expert players.

Learning to combine control at the level of joint torques with longer-term goal-directed behavior is a long-standing challenge for physically embodied artificial agents. Intelligent behavior in the physical world unfolds across multiple spatial and temporal scales: Although movements are ultimately executed at the level of instantaneous muscle tensions or joint torques, they must be selected to serve goals that are defined on much longer time scales and that often involve complex interactions with the environment and other agents. Recent research has demonstrated the potential of learning-based approaches applied to the respective problems of complex movement, long-term planning, and multiagent coordination. However, their integration traditionally required the design and optimization of independent subsystems and remains challenging. In this work, we tackled the integration of motor control and long-horizon decision-making in the context of simulated humanoid football, which requires agile motor control and multiagent coordination. We optimized teams of agents to play simulated football via reinforcement learning, constraining the solution space to that of plausible movements learned using human motion capture data. They were trained to maximize several environment rewards and to imitate pretrained football-specific skills if doing so led to improved performance. The result is a team of coordinated humanoid football players that exhibit complex behavior at different scales, quantified by a range of analysis and statistics, including those used in real-world sport analytics. Our work constitutes a complete demonstration of learned integrated decision-making at multiple scales in a multiagent setting.

Objective: Physicians use electrocardiograms (ECG) to diagnose cardiac abnormalities. Sometimes they need to take a deeper look at abnormal heartbeats to diagnose the patients more precisely. The objective of this research is to design a more accurate heartbeat classification algorithm to assist physicians in identifying specific types of the heartbeat., Methods and Procedures: In this paper, we propose a novel feature called a segment label, to improve the performance of a heartbeat classifier. This feature, provided by a Convolutional Neural Network, encodes the information surrounding the particular heartbeat. The random forest classifier is trained based on this new feature and other traditional features to classify the heartbeats., Results: We validate our method on the MIT-BIH Arrhythmia dataset following the inter-patient evaluation paradigm. The proposed method is competitive with other similar works. It achieves an accuracy of 0.96, and F1-scores for normal beats, ventricular ectopic beats, and Supra-Ventricular Ectopic Beats (SVEB) of 0.98, 0.93, and 0.74, respectively. The precision and sensitivity for SVEB are 0.76 and 0.78, which outperforms the state-of-the-art methods., Conclusion: This study demonstrates that the segment label can contribute to precisely classifying heartbeats, especially those that require rhythm information as context information (e.g. SVEB). Clinical impact: Using a medical devices embedding our algorithm could ease the physicians' processes of diagnosing cardiovascular diseases, especially for SVEB, in clinical implementation.

Introduction: Monitoring early diagnosis is a priority of cancer policy in England. Information on stage has not always been available for a large proportion of patients, however, which may bias temporal comparisons. We previously estimated that early-stage diagnosis of colorectal cancer rose from 32% to 44% during 2008-2013, using multiple imputation. Here we examine the underlying assumptions of multiple imputation for missing stage using the same dataset., Methods: Individually-linked cancer registration, Hospital Episode Statistics (HES), and audit data were examined. Six imputation models including different interaction terms, post-diagnosis treatment, and survival information were assessed, and comparisons drawn with the a priori optimal model. Models were further tested by setting stage values to missing for some patients under one plausible mechanism, then comparing actual and imputed stage distributions for these patients. Finally, a pattern-mixture sensitivity analysis was conducted., Results: Data from 196,511 colorectal patients were analysed, with 39.2% missing stage. Inclusion of survival time increased the accuracy of imputation: the odds ratio for change in early-stage diagnosis during 2008-2013 was 1.7 (95% CI: 1.6, 1.7) with survival to 1 year included, compared to 1.9 (95% CI 1.9-2.0) with no survival information. Imputation estimates of stage were accurate in one plausible simulation. Pattern-mixture analyses indicated our previous analysis conclusions would only change materially if stage were misclassified for 20% of the patients who had it categorised as late., Interpretation: Multiple imputation models can substantially reduce bias from missing stage, but data on patient's one-year survival should be included for highest accuracy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The S100ß protein (PS100ß) is a biomarker, which has demonstrated its importance in diagnoses ruling out intracranial hemorrhages in people with light head traumas This study aims to evaluate if the PS100ß presents an interest in the diagnostic strategy for subarachnoid hemorrhages (SAH)., Methods: Prospective non-randomized multicentric study in three hospitals from October 2018 to January 2020. Every patient who came into the emergency department for an intense non-traumatic headache lasting less than 3 h received an PS100ß assay and a non-injected head computed tomography (CT) scan. The primary endpoint was the number of patients with a diagnosis of SAH on the head CT scan with a PS100ß level of under 0.10 μg/L., Results: 60 patients were included and five patients had a SAH. Four patients had an SAH with a PS100ß level lower than 0.10 μg/L and one patient had an SAH with a PS100ß level higher than 0.10 μg/L. The negative predictive value for the PS100ß with a discriminating threshold less than or equal to 0,10 μg/L in the diagnosis ruling out SAH was 93% [IC 95%: 0,86-1]., Conclusion: S100ß protein assay with a discriminating threshold of 0,10 μg/L does not demonstrate any interest in the diagnostic strategy for non-traumatic SAH., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Minimal surface problems arise naturally in many soft matter systems whose free energies are dominated by surface or interface energies. Of particular interest are the shapes, stability, and mechanical stresses of minimal surfaces spanning specific geometric boundaries. The "catenoid" is the best-known example where an analytical solution is known which describes the form and stability of a minimal surface held between two parallel, concentric circular frames. Here we extend this problem to nonaxisymmetric, parallel frame shapes of different orientations by developing a perturbation approach around the known catenoid solution. We show that the predictions of the perturbation theory are in good agreement with experiments on soap films and finite element simulations (Surface Evolver). Combining theory, experiment, and simulation, we analyze in depth how the shapes, stability, and mechanical properties of the minimal surfaces depend on the type and orientation of elliptic and three-leaf clover shaped frames. In the limit of perfectly aligned nonaxisymmetric frames, our predictions show excellent agreement with a recent theory established by Alimov et al. [Phys. Fluids 33, 052104 (2021)1070-663110.1063/5.0047461]. Moreover, we put in evidence the intriguing capacity of minimal surfaces between nonaxisymmetric frames to transmit a mechanical torque despite being completely liquid. These forces could be interesting to exploit for mechanical self-assembly of soft matter systems or as highly sensitive force captors.

In multiagent worlds, several decision-making individuals interact while adhering to the dynamics constraints imposed by the environment. These interactions, combined with the potential stochasticity of the agents' dynamic behaviors, make such systems complex and interesting to study from a decision-making perspective. Significant research has been conducted on learning models for forward-direction estimation of agent behaviors, for example, pedestrian predictions used for collision-avoidance in self-driving cars. In many settings, only sporadic observations of agents may be available in a given trajectory sequence. In football, subsets of players may come in and out of view of broadcast video footage, while unobserved players continue to interact off-screen. In this paper, we study the problem of multiagent time-series imputation in the context of human football play, where available past and future observations of subsets of agents are used to estimate missing observations for other agents. Our approach, called the Graph Imputer, uses past and future information in combination with graph networks and variational autoencoders to enable learning of a distribution of imputed trajectories. We demonstrate our approach on multiagent settings involving players that are partially-observable, using the Graph Imputer to predict the behaviors of off-screen players. To quantitatively evaluate the approach, we conduct experiments on football matches with ground truth trajectory data, using a camera module to simulate the off-screen player state estimation setting. We subsequently use our approach for downstream football analytics under partial observability using the well-established framework of pitch control, which traditionally relies on fully observed data. We illustrate that our method outperforms several state-of-the-art approaches, including those hand-crafted for football, across all considered metrics., (© 2022. The Author(s).)

Objectives: Compare the functional outcomes of comparative studies of ankle arthrodesis (AA) and total ankle replacements (TAR)., Design: Systematic review using PRISMA guidelines., Data Sources: Medline, Cochrane and EMBASE databases in July 2020., Eligibility Criteria: Studies that directly compared TAR and AA which reported patient reported outcomes measures (PROMs) of pain, function and quality of life., Data Extraction and Synthesis: Two authors independently reviewed all papers. PROMs were allocated into pain, function or quality of life domains. Two summary statistics were created to allow for analysis of the PROMs. These statistics were the mean difference in post-operative score and the mean difference in the change of score., Results: 1323 papers were assessed of which 20 papers were included. 898 ankle arthrodesis and 1638 ankle replacements were evaluated. The mean follow up was 3.3 years (range 0.5-13.0 years). AA patients had a mean age of 55.7 (range 20-82) and TAR 62.5 (range 21-89). There was major heterogeneity in outcomes used. We were unable to find a significant difference between the reported change in PROMs following TAR and AA. 29.3% of PROMs and their subscores showed TAR had better outcomes, 68.7% showed no significant difference and only 2.0% showed AA to have better outcomes., Conclusions: The majority of published studies found equality in patient reported outcomes following TAR and AA although the quality of the studies was of low-level evidence. There is an urgent need for randomised controlled studies to definitively answer this important clinical question., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To assess the association between hospital-level rates of induction of labour and emergency caesarean section, as measures of "practice style", and rates of adverse perinatal outcomes., Design: National study using electronic maternity records., Setting: English National Health Service., Participants: Hospitals providing maternity care to women between April 2015 and March 2017., Main Outcome Measures: Stillbirth, admission to a neonatal unit, and babies receiving mechanical ventilation., Results: Among singleton term births, the risk of stillbirth was 0.15%; of admission to a neonatal unit 5.4%; and of mechanical ventilation 0.54%. There was considerable between-hospital variation in the induction of labour rate (minimum 17.5%, maximum 40.7%) and the emergency caesarean section rate (minimum 5.6%, maximum 17.1%). Women who gave birth in hospitals with a higher induction of labour rate had better perinatal outcomes. For each 5%-point increase in induction, there was a decrease in the risk of term stillbirth by 9% (OR 0.91; 95% CI 0.85 to 0.97) and mechanical ventilation by 14% (OR 0.86; 95% CI 0.79 to 0.94). There was no significant association between hospital-level induction of labour rates and neonatal unit admission at term (p>0.05). There was no significant association between hospital-level emergency caesarean section rates and adverse perinatal outcomes (p always >0.05)., Conclusions: There is considerable between-hospital variation in the use of induction of labour and emergency caesarean section. Hospitals with a higher induction rate had a lower risk of adverse birth outcomes. A similar association was not found for caesarean section., (This article is protected by copyright. All rights reserved.)

Background: people approaching the end-of-life frequently face inappropriate care. With Alzheimer Disease or Related Syndromes (ADRS), end-of-life is characterised by progressive decline, but this period remains difficult to identify. This leads to a lack of anticipation and sometimes with unfavourable healthcare utilisation trajectories (HUTs)., Objective: to quantify unfavourable HUTs during the last year of life and identify their potential determinants in both community and nursing-home settings., Design: nationwide cohort study using administrative database., Setting: French community and nursing-home residents., Subjects: incident ADRS people identified in 2012, who died up to 31 December 2017., Methods: we used multidimensional clustering to identify 15 clusters of HUTs, using 11 longitudinal healthcare dimensions during the last year of life. Clusters were qualitatively assessed by pluri-disciplinary experts as favourable or unfavourable HUTs. Individual and contextual potential determinants of unfavourable HUTs were studied by setting using logistic random-effect regression models., Results: 62,243 individuals died before 31 December 2017; 46.8% faced unfavourable end-of-life HUTs: 55.2% in the community and 31.8% in nursing-homes. Individual potential determinants were identified: younger age, male gender, ADRS identification through hospitalisation, shorter survival, life-limiting comorbidities, psychiatric disorders, acute hospitalisations and polypharmacy. In the community, deprivation and autonomy were identified as potential determinants. Contextual potential determinants raised mostly in the community, such as low nurse or physiotherapist accessibilities., Conclusions: Nearly half of people with ADRS faced unfavourable HUTs during their last year of life. Individual potential determinants should help anticipate advance care planning and palliative care needs assessment. Contextual potential determinants suggest geographical disparities and health inequalities., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To compare the incidence of systemic conditions between women who had surgical treatment for stress incontinence with mesh and without mesh., Design: National cohort study., Setting: English National Health Service., Population: Women with no previous record of systemic disease who had first-time urinary incontinence surgery between 1 January 2006 and 31 December 2013, followed up to the earliest of 10 years or 31 March 2019., Methods: Competing-risks regression was used to estimate hazard ratios (HR), adjusted for patient characteristics, with HR > 1 indicating increased incidence following mesh surgery., Main Outcome Measures: First postoperative admission with a record of autoimmune disease, fibromyalgia or myalgic encephalomyelitis up to 10 years following the first incontinence procedure., Results: The cohort included 88 947 women who had mesh surgery and 3389 women who had non-mesh surgery. Both treatment groups were similar with respect to age, socio-economic deprivation, comorbidity and ethnicity. The 10-year cumulative incidence of autoimmune disease, fibromyalgia or myalgic encephalomyelitis was 8.1% (95% CI 7.9-8.3%) in the mesh group and 9.0% (95% CI 8.0-10.1%) in the non-mesh group (adjusted HR 0.89, 95% CI 0.79-1.01; P = 0.07). A sensitivity analysis including only autoimmune diseases as an outcome returned a similar result., Conclusions: These findings do not support claims that synthetic mesh slings cause systemic disease., Tweetable Abstract: No evidence of increased risk of systemic conditions after stress incontinence treatment with a mesh sling., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

While a large share of Disability Insurance recipients in OECD countries are expected to recover, outflow rates from temporary disability schemes are typically negligible. We estimate the disincentive effects of disability benefits on the response to a (mental) health improvement using administrative data on all Dutch disability benefit applicants. We compare those below the DI eligibility threshold with those above and find that disincentives significantly reduce work resumption after health improves. Approximately half of the response to recovery is offset by benefits. Estimates from a structural labor supply model suggest that disincentives are substantially larger when the worker's earnings capacity is fully restored., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The COVID-19 pandemic has disrupted maternity services worldwide and imposed restrictions on societal behaviours. This national study aimed to compare obstetric intervention and pregnancy outcome rates in England during the pandemic and corresponding pre-pandemic calendar periods, and to assess whether differences in these rates varied according to ethnic and socioeconomic background., Methods and Findings: We conducted a national study of singleton births in English National Health Service hospitals. We compared births during the COVID-19 pandemic period (23 March 2020 to 22 February 2021) with births during the corresponding calendar period 1 year earlier. The Hospital Episode Statistics database provided administrative hospital data about maternal characteristics, obstetric inventions (induction of labour, elective or emergency cesarean section, and instrumental birth), and outcomes (stillbirth, preterm birth, small for gestational age [SGA; birthweight < 10th centile], prolonged maternal length of stay (≥3 days), and maternal 42-day readmission). Multi-level logistic regression models were used to compare intervention and outcome rates between the corresponding pre-pandemic and pandemic calendar periods and to test for interactions between pandemic period and ethnic and socioeconomic background. All models were adjusted for maternal characteristics including age, obstetric history, comorbidities, and COVID-19 status at birth. The study included 948,020 singleton births (maternal characteristics: median age 30 years, 41.6% primiparous, 8.3% with gestational diabetes, 2.4% with preeclampsia, and 1.6% with pre-existing diabetes or hypertension); 451,727 births occurred during the defined pandemic period. Maternal characteristics were similar in the pre-pandemic and pandemic periods. Compared to the pre-pandemic period, stillbirth rates remained similar (0.36% pandemic versus 0.37% pre-pandemic, p = 0.16). Preterm birth and SGA birth rates were slightly lower during the pandemic (6.0% versus 6.1% for preterm births, adjusted odds ratio [aOR] 0.96, 95% CI 0.94-0.97; 5.6% versus 5.8% for SGA births, aOR 0.95, 95% CI 0.93-0.96; both p < 0.001). Slightly higher rates of obstetric intervention were observed during the pandemic (40.4% versus 39.1% for induction of labour, aOR 1.04, 95% CI 1.03-1.05; 13.9% versus 12.9% for elective cesarean section, aOR 1.13, 95% CI 1.11-1.14; 18.4% versus 17.0% for emergency cesarean section, aOR 1.07, 95% CI 1.06-1.08; all p < 0.001). Lower rates of prolonged maternal length of stay (16.7% versus 20.2%, aOR 0.77, 95% CI 0.76-0.78, p < 0.001) and maternal readmission (3.0% versus 3.3%, aOR 0.88, 95% CI 0.86-0.90, p < 0.001) were observed during the pandemic period. There was some evidence that differences in the rates of preterm birth, emergency cesarean section, and unassisted vaginal birth varied according to the mother's ethnic background but not according to her socioeconomic background. A key limitation is that multiple comparisons were made, increasing the chance of false-positive results., Conclusions: In this study, we found very small decreases in preterm birth and SGA birth rates and very small increases in induction of labour and elective and emergency cesarean section during the COVID-19 pandemic, with some evidence of a slightly different pattern of results in women from ethnic minority backgrounds. These changes in obstetric intervention rates and pregnancy outcomes may be linked to women's behaviour, environmental exposure, changes in maternity practice, or reduced staffing levels., Competing Interests: All authors have received support from Healthcare Quality Improvement Partnership. JJ and LW are or have been members of the RCOG COVID-19 guidance cell which produces clinical guidance and policy documents to support the management of pregnant women during the pandemic in the UK. AK is PI of COVID-19 in pregnancy studies and a member of the COVAX Working Group on COVID-19 in pregnancy.

Background: There is a debate about the safety and effectiveness of surgical treatments for stress urinary incontinence. Controversy about the use of synthetic mesh sling insertion has led to an increased uptake of retropubic colposuspension and autologous sling procedures. Comparative evidence on the long-term outcomes from these procedures is needed., Objective: To compare the risk of reoperation at 10 years after operation between women treated for stress urinary incontinence with retropubic colposuspension, mesh sling insertion, and autologous sling procedures., Study Design: The records of admissions to National Health Service hosptials were used to identify women who had first-time stress incontinence surgery between 2006 and 2013 in England. The first incidence of the following outcomes was assessed: further stress incontinence surgery, surgery for a complication (either mesh removal, prolapse repair, or incisional hernia repair), and any reoperation (either further stress incontinence surgery, mesh removal, prolapse repair, or incisional hernia repair). The cumulative incidence of each of these outcomes up to 10 years after surgery was calculated, considering death as a competing event. Multivariable modeling was then used to estimate the reoperation hazard ratios for the different initial surgery types with adjustments for patient characteristics and concurrent prolapse surgery or hysterectomy., Results: The analysis included 2262 women treated with retropubic colposuspension, 92,524 treated with mesh sling insertion, and 1234 treated with autologous sling. The cumulative incidence of any first reoperation at 10 years was 21.3% (95% confidence interval, 19.5-23.0) after retropubic colposuspension, 10.9% (10.7-11.1) after mesh sling insertion, and 12.0% (10.2-13.9) after autologous sling procedures. The women who had a retropubic colposuspension were significantly more likely to have a reoperation than women who had an autologous sling (adjusted hazard ratio for any reoperation: 1.79 [1.47-2.17]; for further stress incontinence surgery: 1.64 [1.19-2.26]; for surgery for complications: 1.89 [1.49-2.40]), whereas the women who had mesh slings had a similar hazard (for any reoperation: 0.90 [0.76-1.07]; for further stress incontinence surgery: 0.75 [0.57-0.99]; for surgery for complications: 1.11 [0.89-1.36]). A sensitivity analysis excluding the women who had concurrent prolapse surgery or hysterectomy produced similar results., Conclusion: Retropubic colposuspension is associated with higher risk of reoperation at 10 years after surgery than mesh sling insertion or autologous sling procedures, with 1 in 5 women requiring reoperation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The in vivo rituximab effects in B cell malignancies are only partially understood. Here we analyzed in a large chronic lymphocytic leukemia (CLL) cohort (n = 80) the inter-patient variability in CLL cell count reduction within the first 24 h of rituximab administration in vivo, and a phenomenon of blood repopulation by malignant cells after anti-CD20 antibody therapy. Larger CLL cell elimination after rituximab infusion was associated with lower pre-therapy CLL cell counts, higher CD20 levels, and the non-exhausted capacity of complement-dependent cytotoxicity (CDC). The absolute amount of cell-surface CD20 molecules (CD20 density x CLL lymphocytosis) was a predictor for complement exhaustion during therapy. We also describe that a highly variable decrease in CLL cell counts at 5 h (88 %-2%) following rituximab infusion is accompanied in most patients by peripheral blood repopulation with CLL cells at 24 h, and in ∼20 % of patients, this resulted in CLL counts higher than before therapy. We provide evidence that CLL cells recrudescence is linked with i) CDC exhaustion, which leads to the formation of an insufficient amount of membrane attack complexes, likely resulting in temporary retention of surviving rituximab-opsonized cells by the mononuclear-phagocyte system (followed by their release back to blood), and ii) CLL cells regression from immune niches (CXCR4 dim CD5 bright intraclonal subpopulation). Patients with major peripheral blood CLL cell repopulation exhibited a longer time-to-progression after chemoimmunotherapy compared to patients with lower or no repopulation, suggesting chemotherapy vulnerability of CLL cells that repopulate the blood., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness., Objective: To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE., Design: Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003)., Setting: England., Participants: Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019., Intervention: Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks., Measurements: The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events., Results: At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P  < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P  = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 10 9 /L) at 52 weeks in a subset of patients ( n  = 25) with available data., Limitations: Small sample size; biomarker primary end point., Conclusion: Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy., Primary Funding Source: Versus Arthritis.

Background: Socioeconomic deprivation and minority ethnic background are risk factors for adverse pregnancy outcomes. We aimed to quantify the magnitude of these socioeconomic and ethnic inequalities at the population level in England., Methods: In this cohort study, we used data compiled by the National Maternity and Perinatal Audit, based on birth records from maternity information systems used by 132 National Health Service hospitals in England, linked to administrative hospital data. We included women who gave birth to a singleton baby with a recorded gestation between 24 and 42 completed weeks. Terminations of pregnancy were excluded. We analysed data on stillbirth, preterm birth (<37 weeks of gestation), and fetal growth restriction (FGR; liveborn with birthweight <3rd centile by the UK definition) in England, and compared these outcomes by socioeconomic deprivation quintile and ethnic group. We calculated attributable fractions for the entire population and specific groups compared with least deprived groups or White women, both unadjusted and with adjustment for smoking, body-mass index (BMI), and other maternal risk factors., Findings: We identified 1 233 184 women with a singleton birth between April 1, 2015, and March 31, 2017, of whom 1 155 981 women were eligible and included in the analysis. 4505 (0·4%) of 1 155 981 births were stillbirths. Of 1 151 476 livebirths, 69 175 (6·0%) were preterm births and 22 679 (2·0%) were births with FGR. Risk of stillbirth was 0·3% in the least socioeconomically deprived group and 0·5% in the most deprived group (p<0·0001), risk of a preterm birth was 4·9% in the least deprived group and 7·2% in the most deprived group (p<0·0001), and risk of FGR was 1·2% in the least deprived group and 2·2% in the most deprived group (p<0·0001). Population attributable fractions indicated that 23·6% (95% CI 16·7-29·8) of stillbirths, 18·5% (16·9-20·2) of preterm births, and 31·1% (28·3-33·8) of births with FGR could be attributed to socioeconomic inequality, and these fractions were substantially reduced when adjusted for ethnic group, smoking, and BMI (11·6% for stillbirths, 11·9% for preterm births, and 16·4% for births with FGR). Risk of stillbirth ranged from 0·3% in White women to 0·7% in Black women (p<0·0001); risk of preterm birth was 6·0% in White women, 6·5% in South Asian women, and 6·6% in Black women (p<0·0001); and risk of FGR ranged from 1·4% in White women to 3·5% in South Asian women (p<0·0001). 11·7% of stillbirths (95% CI 9·8-13·5), 1·2% of preterm births (0·8-1·6), and 16·9% of FGR (16·1-17·8) could be attributed to ethnic inequality. Adjustment for socioeconomic deprivation, smoking, and BMI only had a small effect on these ethnic group attributable fractions (13·0% for stillbirths, 2·6% for preterm births, and 19·2% for births with FGR). Group-specific attributable fractions were especially high in the most socioeconomically deprived South Asian women and Black women for stillbirth (53·5% in South Asian women and 63·7% in Black women) and FGR (71·7% in South Asian women and 55·0% in Black women)., Interpretation: Our results indicate that socioeconomic and ethnic inequalities were responsible for a substantial proportion of stillbirths, preterm births, and births with FGR in England. The largest inequalities were seen in Black and South Asian women in the most socioeconomically deprived quintile. Prevention should target the entire population as well as specific minority ethnic groups at high risk of adverse pregnancy outcomes, to address risk factors and wider determinants of health., Funding: Healthcare Quality Improvement Partnership., Competing Interests: Declaration of interests All authors declare funding from the Healthcare Quality Improvement Partnership to deliver the National Maternity and Perinatal Audit Programme. We declare no other competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Some studies have suggested that women with SARS-CoV-2 infection during pregnancy are at increased risk of adverse pregnancy and neonatal outcomes, but these associations are still not clear., Objective: This study aimed to determine the association between SARS-CoV-2 infection at the time of birth and maternal and perinatal outcomes., Study Design: This is a population-based cohort study in England. The inclusion criteria were women with a recorded singleton birth between May 29, 2020, and January 31, 2021, in a national database of hospital admissions. Maternal and perinatal outcomes were compared between pregnant women with a laboratory-confirmed SARS-CoV-2 infection recorded in the birth episode and those without. Study outcomes were fetal death at or beyond 24 weeks' gestation (stillbirth), preterm birth (<37 weeks' gestation), small for gestational age infant (small for gestational age; birthweight at the .05) in the rate of other maternal outcomes. The risk of neonatal adverse outcome (adjusted odds ratio, 1.45; 95% confidence interval, 1.27-1.66; P<.001), need for specialist neonatal care (adjusted odds ratio, 1.24; 95% confidence interval, 1.02-1.51; P=.03), and prolonged neonatal admission after birth (adjusted odds ratio, 1.61; 95% confidence interval, 1.49-1.75; P<.001) were all significantly higher for infants with mothers with laboratory-confirmed SARS-CoV-2 infection. When the analysis was restricted to pregnancies delivered at term (≥37 weeks), there were no significant differences in neonatal adverse outcome (P=.78), need for specialist neonatal care after birth (P=.22), or neonatal readmission within 4 weeks of birth (P=.05). Neonates born at term to mothers with laboratory-confirmed SARS-CoV-2 infection were more likely to have prolonged admission after birth (21.1% compared with 14.6%; adjusted odds ratio, 1.61; 95% confidence interval, 1.49-1.75; P<.001)., Conclusion: SARS-CoV-2 infection at the time of birth is associated with higher rates of fetal death, preterm birth, preeclampsia, and emergency cesarean delivery. There were no additional adverse neonatal outcomes, other than those related to preterm delivery. Pregnant women should be counseled regarding risks of SARS-CoV-2 infection and should be considered a priority for vaccination., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background:  During resection of intrinsic brain tumors in eloquent areas, particularly under awake mapping, subcortical stimulation is mandatory to avoid irreversible deficits by damaging white fiber tracts. The current practice is to alternate between subcortical stimulation with an appropriate probe and resection of tumoral tissue with an ultrasound aspiration device. Switching between different devices induces supplementary movement and possible tissue trauma, loss of time, and inaccuracies in the localization of the involved area., Objective:  To use one device for both stimulation as well as a resecting tool., Methods:  The tip of different ultrasound aspiration devices is currently used for monopolar current transmission (e.g., for vessel coagulation in liver surgery). We use the same circuitry for monopolar subcortical stimulation when connected with the usual stimulator devices., Results:  We have applied this method since 2004 in over 500 patients during tumor resection with cortical and subcortical stimulation, mostly with awake language and motor monitoring., Conclusion:  A method is presented using existing stimulation and wiring devices by which simultaneous subcortical stimulation and ultrasonic aspiration are applied with the same tool. The accuracy, safety, and speed of intrinsic intracranial lesion resection can be improved when subcortical stimulation is applied., Competing Interests: None declared., (Thieme. All rights reserved.)

The first numerical implementation of a t exp method in 3D using simulated electrode data is presented. Results are compared to Calderón's method as well as more common TV and smoothness regularization-based methods. The t exp method for EIT is based on tailor-made non-linear Fourier transforms involving the measured current and voltage data. Low-pass filtering in the non-linear Fourier domain is used to stabilize the reconstruction process. In 2D, t exp methods have shown great promise for providing robust real-time absolute and time-difference conductivity reconstructions but have yet to be used on practical electrode data in 3D, until now. Results are presented for simulated data for conductivity and permittivity with disjoint non-radially symmetric targets on spherical domains and noisy voltage data. The 3D t exp and Calderón methods are demonstrated to provide comparable quality to their 2D counterparts, and hold promise for real-time reconstructions due to their fast, non-optimized, computational cost.