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Abstract The African buffalo (Syncerus caffer) is a wild bovid with a historical distribution across much of sub-Saharan Africa. Genomic analysis can provide insights into the evolutionary history of the species, and the key selective pressures shaping populations, including assessment of population level differentiation, population fragmentation, and population genetic structure. In this study we generated the highest quality de novo genome assembly (2.65 Gb, scaffold N50 69.17 Mb) of African buffalo to date, and sequenced a further 195 genomes from across the species distribution. Principal component and admixture analyses provided little support for the currently described four subspecies. Estimating Effective Migration Surfaces analysis suggested that geographical barriers have played a significant role in shaping gene flow and the population structure. Estimated effective population sizes indicated a substantial drop occurring in all populations 5-10,000 years ago, coinciding with the increase in human populations. Finally, signatures of selection were enriched for key genes associated with the immune response, suggesting infectious disease exert a substantial selective pressure upon the African buffalo. These findings have important implications for understanding bovid evolution, buffalo conservation and population management.

Background Second trimester miscarriage and preterm birth is a significant global problem. Surgical cervical cerclage is performed to prevent pregnancy loss and preterm birth. It utilises either a monofilament or braided suture. It is hypothesised that a braided material becomes colonised with pathogenic bacteria that causes vaginal dysbiosis, infection and cerclage failure. Objectives The primary objective of the study was to examine the effectiveness of using a monofilament suture material as opposed to a braided suture material on pregnancy loss in women requiring a vaginal cervical cerclage. Design Superiority open randomised controlled trial. Setting Seventy-five maternity sites across the UK. Participants Women experiencing a singleton pregnancy requiring a cervical cerclage. Interventions Monofilament suture or braided suture. Main outcome measures The primary outcome was pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life). Secondary outcomes included the core outcome set for preterm birth. Methods Women were randomised on a 1 : 1 basis to monofilament or braided cerclage utilising a bespoke randomisation service with minimisation dependent on the site, indication for cerclage, intention to use progesterone and planned surgical technique. The inclusion criteria were three or more previous mid-trimester losses or preterm births, insertion of a cerclage in a previous pregnancy, a history of a mid-trimester loss or preterm birth with a shortened cervical length in the current pregnancy or in women who clinicians deemed at risk of preterm birth. The exclusion criteria were an emergency or rescue cerclage, age of < 18 years, being unable to give informed consent or the cerclage having to be placed abdominally. The original sample size was calculated based on a relative risk reduction of 41% from a pregnancy loss rate of 19% in the braided group to 11% in the monofilament group with 90% power and alpha at p = 0.05. The independent data monitoring committee noted a lower-than-anticipated pooled event rate within the trial and recommended an increase in sample size to 2050. The outcome data were collected using clinical record forms from the maternal and neonatal medical records and reported to Birmingham Clinical Trials Unit. Results A total of 2049 women were randomised, after withdrawals and loss to follow-up, data on 1005 women in the monofilament group and 993 women in the braided group were included. The baseline demographics between the groups were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups (80/1003 vs. 75/993; adjusted risk ratio: 1.05, 95% confidence interval: 0.79 to 1.40; adjusted risk difference: 0.002, 95% confidence interval: −0.02 to 0.03). Limitations The trial did not collect long-term paediatric outcomes. There were no safety concerns. Conclusions There was no evidence of a difference in pregnancy loss between a monofilament suture and a braided suture. Future work Long-term follow-up of neonates born within the C-STICH (cerclage suture type for an insufficient cervix and its effects on health outcomes) trial. Trial registration This trial is registered as ISRCTN15373349. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award information. Plain language summary Cervical cerclage is an operation performed in pregnancy to prevent miscarriage and preterm birth. A cervical cerclage is sometimes recommended in women who have had babies born prematurely before or who have had previous cervical surgery. A cerclage operation involves a stitch being inserted around the neck of the womb (cervix) to keep it closed during pregnancy and to prevent it opening prematurely. When performing the operation, the doctor can use different types of threads made of different materials. The threads used to perform the operation are called sutures. One suture type is a single strand or monofilament thread, and the other is a multifilament braided thread with lots of thin strands woven together. Some evidence has suggested that using a monofilament suture thread prevented pregnancy loss by preventing infection. Therefore, we performed a randomised controlled trial of the use of monofilament suture thread versus braided suture thread, aiming to reduce pregnancy loss in women who were having a cerclage as part of their routine care. The women consented to take part in the study and were randomly allocated to their cerclage performed with either a monofilament or braided suture thread; there was no other change to their planned pregnancy care. What happened in their pregnancy was recorded from their medical records and analysed. A total of 2049 women agreed to take part in the study and consented to the analysis of their pregnancy and neonatal outcomes. Cerclage suture type for an insufficient cervix and its effects on health outcomes showed that there was no difference in pregnancy loss between the two suture threads. There was decreased maternal sepsis and decreased chorioamnionitis (which is an infection inside the womb during labour) in the women who received a monofilament suture, which needs further investigation. Although more women who had a cerclage using the monofilament thread needed a small operation and an anaesthetic, often between 36 and 37 weeks, to remove the monofilament suture prior to a vaginal birth, there were no differences in the outcomes for their babies. Scientific summary Background Preterm birth and second trimester miscarriage is a significant cause of worldwide neonatal morbidity and mortality. The aetiology is complex and multifactorial with a number of causes, including cervical insufficiency. One treatment to prevent preterm birth and second trimester miscarriage caused by cervical insufficiency is the placement of a vaginal cervical cerclage (CC). A CC is the placement of a purse string suture thread around the cervix aiming to prevent pregnancy loss and preterm birth. A CC can be performed with either a monofilament suture thread or a braided suture thread. The choice of thread used during surgical operations is dependent on the properties of the thread, with braided threads being multifilament in nature with lots of single strands woven together, which predisposes it to potentially becoming colonised with pathogenic bacteria. A prior feasibility study suggested a difference in pregnancy loss outcomes between monofilament and braided suture threads and the acceptability of either thread for clinicians and women. Therefore, a randomised controlled trial was designed to explore this discrepancy, aiming to reduce pregnancy loss for women at high risk of preterm birth. Objectives The primary objective of the study was to examine the effectiveness of using a monofilament suture material compared to a braided suture material on minimising the risk of pregnancy loss in women requiring a vaginal CC. The secondary objectives of the study included exploring the impact of suture material on maternal and neonatal outcomes. Design A pragmatic open, parallel, multicentre, randomised superiority trial of monofilament versus braided suture type during CC to prevent pregnancy loss. Setting The study was conducted in hospital settings across the UK (75 sites) between 2015 and 2022. Participants Women were eligible for the trial if they required a vaginal CC as part of their routine care within their current pregnancy and they fulfilled the following eligibility criteria: Inclusion Singleton pregnancy. Indication for CC for either: a history of three or more previous mid-term losses or premature births (≤ 28 weeks), OR insertion of cervical sutures in previous pregnancies, OR a history of mid-trimester loss or premature birth with a shortened (≤ 25 mm) cervix, OR women whom clinicians deemed to be at risk of preterm birth either because of their history or because of the results of an ultrasound scan. Exclusion Had taken part in C-STICH previously. Aged < 18 years old at the time of presentation. Requiring a rescue cerclage. Unwilling or unable to give informed consent. Those in whom a cerclage was to be placed by any route other than vaginally (e.g. via an abdominal route). Immediate need for insertion of a suture. Membranes that had ruptured or were surfacing. Interventions Women were randomised at a 1 : 1 ratio via a secure internet facility to have their CC performed using either a monofilament or braided suture thread. Minimisation was employed to balance for the following: indication for cerclage, planned bladder dissection, intention to commence patient on progesterone and recruiting site. Outcome measures The primary outcome measure was pregnancy loss (miscarriage and perinatal mortality). Key secondary outcome: Time from conception to pregnancy end (any reason). Maternal outcomes: Miscarriage and previable neonatal death (defined as delivery < 24 weeks). Stillbirth (defined as intrauterine death ≥ 24 weeks). Gestation at delivery (in live births ≥ 24 weeks). Gestational age of < 28/< 32/< 37 weeks at delivery (in live births ≥ 24 weeks). Time from conception to onset of spontaneous vaginal delivery (in live births ≥ 24 weeks). Sepsis (at any time in pregnancy and until 7 days postnatal). Preterm prelabour rupture of membranes (PPROM). Mode of initiation of labour (spontaneous or induced). Mode of delivery (vaginal, operative vaginal or caesarean). Cerclage placement complications (cervical laceration/bleeding from cervix/ruptured membranes/bladder injury). Cerclage removal complications (cervical tears/need for anaesthetic/difficult to remove). Other maternal complications: vaginal bleeding/steroid use/chorioamnionitis/maternal pyrexia of 38°C (intrapartum/postnatal)/admission to high dependency unit (HDU) or intensive therapy unit (ITU) (pre/post delivery). Neonatal outcomes: Early neonatal death (defined as a death within 7 days after delivery) (in live births ≥ 24 weeks). Late neonatal death (defined as a death beyond 7 days and before 28 days after delivery) (in live births ≥ 24 weeks). Birth-weight centile adjusted for gestational age and sex (in live births ≥ 24 weeks). Small for gestational age and sex (< 10th centile, in live births ≥ 24 weeks). Resuscitation at birth (in live births ≥ 24 weeks). Additional care required [special care baby unit (SCBU)/neonatal intensive care unit (NICU)/HDU/transitional care] and length of stay in additional care (in live births ≥ 24 weeks). Antibiotics within 72 hours (in live births ≥ 24 weeks). Sepsis (clinically diagnosed/proven) (in live births ≥ 24 weeks). Early neurodevelopmental morbidity (severe abnormality on cranial ultrasound scan) (in live births ≥ 24 weeks). Respiratory support and days on respiratory support (in live births ≥ 24 weeks). Supplementary oxygen requirements at 36 weeks post menstrual age (in live births ≥ 24 weeks). Necrotising enterocolitis (Bell’s stage 2 or 3) (in live births ≥ 24 weeks). Retinopathy of prematurity requiring laser treatment (in live births ≥ 24 weeks). Disabilities (live births ≥ 24 weeks). Congenital anomalies (in live births ≥ 24 weeks). The core outcome set for preterm birth was fully collected within the trial. Sample size The original sample size was based on a meta-analysis of non-randomised studies, where the pooled pregnancy loss rate in the monofilament group was 7% compared to 19% in the braided group. To allow for the observational nature of these data, we powered the study to detect a more plausible relative reduction of 41% (19% with braided sutures to 11.2% with monofilament sutures) with 90% power (alpha = 0.05). We planned to recruit 900 women. As a result of some uncertainty around the sample size parameters, the data monitoring committee reviewed the pooled event rate throughout the study. The sample size was subsequently increased to 2050 women to allow for a lower-than-anticipated event rate in order to maintain sufficient power to detect the same relative risk reduction. The primary analysis was by intention to treat. Results The trial opened for recruitment in August 2015 and completed recruitment in January 2021. A total of 2049 women were randomised into the trial and data for analysis was available for 1003 women in the monofilament group and 993 women in the braided group. The baseline demographic characteristics of women in the monofilament and braided group were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups [80/1003 vs. 75/993; adjusted risk ratio (RR) 1.05, 95% confidence interval (CI) 0.79 to 1.40; adjusted risk difference 0.002, 95% CI −0.02 to 0.03]. There was no difference in conception to pregnancy end (median time to pregnancy end: 37.9 weeks vs. 38.0 weeks; adjusted hazard ratio 1.04, 95% CI 0.95 to 1.14). Regarding maternal outcomes there was a decrease in maternal sepsis in the monofilament group (4%) compared to the braided group (7%) (RR 0.58, 95% CI 0.40 to 0.82) and a decreased risk of chorioamnionitis in the monofilament group (3%) compared to the braided group (6%) (RR 0.45, 95% CI 0.29 to 0.71). There was no difference in any neonatal outcomes. CC removal complications showed an increase in the monofilament group (56% vs. 42%, RR 1.25, 95% CI 1.15 to 1.36), with increased difficulty of removal and an increased need for anaesthetic for removal being the most common complications. Conclusions There was no evidence of a difference between a monofilament suture thread and a braided suture for pregnancy outcomes. We can be relatively confident that using a monofilament suture is unlikely to have a substantial impact on pregnancy loss compared to a braided suture. The uncertainty around our comparative estimate for this outcome is at most 2% in favour of the monofilament in absolute terms. While this margin may not completely rule out missing a clinically important difference, we consider this scenario to be unlikely. Therefore, clinicians should consider the relative merits and disadvantages of the physical suture properties when selecting the material to perform a vaginal CC. The trial was robustly conducted with minimal limitations. An important strength of the study is the recognition early in the trial that the event rate was lower than anticipated and, therefore, the sample size was increased allowing the effectiveness of a monofilament versus braided suture thread to be fully evaluated. Trial registration This trial is registered as ISRCTN15373349. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award project information.

Low- and middle-income countries are underresourced in subspecialist care. This study describes a unique maternal-fetal medicine clinical fellowship training program at Moi University School of Medicine and Moi Teaching and Referral Hospital in Eldoret, Western Kenya. The first of its kind in Eastern Africa, it has met with success in the retention of highly qualified practitioners providing complex pregnancy care to a population that has been heretofore underserved.

The ecology of forest ecosystems depends on the composition of trees. Capturing fine-grained information on individual trees at broad scales provides a unique perspective on forest ecosystems, forest restoration, and responses to disturbance. Individual tree data at wide extents promises to increase the scale of forest analysis, biogeographic research, and ecosystem monitoring without losing details on individual species composition and abundance. Computer vision using deep neural networks can convert raw sensor data into predictions of individual canopy tree species through labeled data collected by field researchers. Using over 40,000 individual tree stems as training data, we create landscape-level species predictions for over 100 million individual trees across 24 sites in the National Ecological Observatory Network (NEON). Using hierarchical multi-temporal models fine-tuned for each geographic area, we produce open-source data available as 1 km2 shapefiles with individual tree species prediction, as well as crown location, crown area, and height of 81 canopy tree species. Site-specific models had an average performance of 79% accuracy covering an average of 6 species per site, ranging from 3 to 15 species per site. All predictions are openly archived and have been uploaded to Google Earth Engine to benefit the ecology community and overlay with other remote sensing assets. We outline the potential utility and limitations of these data in ecology and computer vision research, as well as strategies for improving predictions using targeted data sampling.

Abstract Background Migraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors. Methods We used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol. Results We found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions’ interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity. Conclusions Altogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol’s prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing.

Abstract Taenia solium taeniasis/cysticercosis (TSTC) is a foodborne, zoonotic neglected tropical disease affecting predominately low- and middle-income countries. Humans are definitive hosts for T. solium, whereas pigs act as intermediate hosts. Taeniasis, i.e. intestinal infection with adult T. solium in the human host, occurs through ingestion of undercooked pork infected with the larval stage (porcine cysticercosis, PCC). Human cysticercosis occurs after humans ingest T. solium eggs, acting as accidental intermediate hosts. Migration of cysticerci to the human brain results in neurocysticercosis (NCC), manifesting in a variety of clinical symptoms, most notably epilepsy. NCC is the leading cause of acquired epilepsy cases in endemic areas. PCC results in reduced pork value because of condemnation or the risk of condemnation of the meat. Available serological diagnostic tests for porcine and human cysticercosis are characterized by low sensitivity and are not cost-effective. An effective vaccine for T. solium cysticercosis in pigs has been developed, although it is not yet commercially available in all endemic countries, and still no vaccine is available for use in humans. This primer highlights the recent development in the field of diagnostic tests and vaccine production and explores possible strategies for future control and eradication of T. solium. In the absence of highly specific diagnostic tests and human vaccines, treatment of infected pigs and tapeworm carriers and prevention of disease transmission remain the principal means to interrupt the zoonotic cycle of T. solium in endemic countries. Graphical abstract

Measuring autonomic parameters like heart rate in behaving mice is not only a standard procedure in cardiovascular research but is applied in many other interdisciplinary research fields. With an electrocardiogram (ECG), the heart rate can be measured by deriving the electrical potential between subcutaneously implanted wires across the chest. This is an inexpensive and easy-to-implement technique and particularly suited for repeated recordings of up to eight weeks. This protocol describes a step-by-step guide for manufacturing the needed equipment, performing the surgical procedure of electrode implantation, and processing of acquired data, yielding accurate and reliable detection of heartbeats and calculation of heart rate (HR). We provide MATLAB graphical user interface (GUI)–based tools to extract and start processing the acquired data without a lot of coding knowledge. Finally, based on an example of a data set acquired in the context of defensive reactions, we discuss the potential and pitfalls in analyzing HR data.Key features• Next to surgical steps, the protocol provides a detailed description of manufacturing custom-made ECG connectors and a shielded, light-weight patch cable.• Suitable for recordings in which signal quality is challenged by ambient noise or noise from other recording devices.• Described for 2-channel differential recording but easily expandable to record from more channels.• Includes a summary of potential analysis methods and a discussion on the interpretation of HR dynamics in the case study of fear states.

When wild honey bee colonies (Apis mellifera) nest in hollow tree cavities, they coat the rough cavity walls with a continuous layer of propolis, a substance comprised primarily of plant resins. Studies have shown that the resulting "propolis envelope" leads to both individual- and colony-level health benefits. Unfortunately, the smooth wooden boxes most commonly used in beekeeping do little to stimulate propolis collection. As a result, most managed bees live in hives that are propolis-poor. In this study, we assessed different surface texture treatments (rough wood boxes, boxes outfitted with propolis traps, and standard, smooth wood boxes) in terms of their ability to stimulate propolis collection, and we examined the effect of propolis on colony health, pathogen loads, immune gene expression, bacterial gene expression, survivorship, and honey production in both stationary and migratory beekeeping contexts. We found that rough wood boxes are the most effective box type for stimulating propolis deposition. Although the use of rough wood boxes did not improve colony survivorship overall, Melissococcus plutonius detections via gene expression were significantly lower in rough wood boxes, and viral loads for multiple viruses tended to decrease as propolis deposition increased. By the end of year one, honey bee populations in migratory rough box colonies were also significantly larger than those in migratory control colonies. The use of rough wood boxes did correspond with decreased honey production in year one migratory colonies but had no effect during year two. Finally, in both stationary and migratory operations, propolis deposition was correlated with a seasonal decrease and/or stabilization in the expression of multiple immune and bacterial genes, suggesting that propolis-rich environments contribute to hive homeostasis. These findings provide support for the practical implementation of rough box hives as a means to enhance propolis collection and colony health in multiple beekeeping contexts.

Abstract Background Cervical cancer is caused by oncogenic human papillomaviruses (HR-HPV) and is common among Kenyan women. Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of HR-HPV detection in cervical specimens. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. Methods Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. Results Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08–8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13–17.58, P = 0.032). Conclusions Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies, including mechanistic studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.

Abstract Background Understanding the variation between well and poorly adapted cattle breeds to local environments and pathogens is essential for breeding cattle with improved climate and disease-resistant phenotypes. Although considerable progress has been made towards identifying genetic differences between breeds, variation at the epigenetic and chromatin levels remains poorly characterized. Here, we generate, sequence and analyse over 150 libraries at base-pair resolution to explore the dynamics of DNA methylation and chromatin accessibility of the bovine immune system across three distinct cattle lineages. Results We find extensive epigenetic divergence between the taurine and indicine cattle breeds across immune cell types, which is linked to the levels of local DNA sequence divergence between the two cattle sub-species. The unique cell type profiles enable the deconvolution of complex cellular mixtures using digital cytometry approaches. Finally, we show distinct sub-categories of CpG islands based on their chromatin and methylation profiles that discriminate between classes of distal and gene proximal islands linked to discrete transcriptional states. Conclusions Our study provides a comprehensive resource of DNA methylation, chromatin accessibility and RNA expression profiles of three diverse cattle populations. The findings have important implications, from understanding how genetic editing across breeds, and consequently regulatory backgrounds, may have distinct impacts to designing effective cattle epigenome-wide association studies in non-European breeds.

ABSTRACTIntroduction It remains unclear whether long-term non-invasive ventilation (LT-NIV) for patients with chronic obstructive pulmonary disease (COPD) improves survival and reduces admissions as results from randomized trials are inconsistent. We aim to determine whether LT-NIV initiated after an admission with acute hypercapnic respiratory failure (AHRF) can affect survival and admission rate in COPD patients.Methods A randomized controlled open-label trial, allocating patients with COPD to LT-NIV or standard of care immediately after an admission with AHRF treated with acute NIV. LT-NIV was aimed to normalize PaCO2 using high-pressure NIV.Results The study was discontinued before full sample size due to slow recruitment. 28 patients were randomized to LT-NIV and 27 patients to standard of care. 42% of patients had a history of ≥ 2 admissions with AHRF. Median IPAP was 24 cmH2O (IQR 20–28). The primary outcome, time to readmission with AHRF or death within 12 months, did not reach significance, hazard ratio 0.53 (95% CI 0.25–1.12) p = 0.097. In a competing risk analysis, adjusted for history of AHRF, the odds ratio for AHRF within 12 months was 0.30 (95% CI 0.11–0.87) p = 0.024. The LT-NIV group had less exacerbations (median 1 (0–1) vs 2 (1–4) p = 0.021) and readmissions with AHRF (median 0 (0–1) vs 1 (0–1) p = 0.016).Conclusion The risk of the primary outcome, time to readmission with AHRF or death within 12 months was numerically smaller in the LT-NIV group, however, did not reach significance. Nevertheless, several secondary outcome analyses like risk of AHRF, number of episodes of AHRF and exacerbations were all significantly reduced in favour of high-pressure LT-NIV, especially in patients with frequent AHRF.

The signal-to-noise ratio in bioimages is often low, which is problematic for segmentation. Here the authors report a deep learning method, deepflash2, to facilitate the segmentation of ambiguous bioimages through multi-expert annotations and integrated quality assurance.

Nissley and co-workers predict protein misfolding into kinetically trapped, entangled conformations that can bypass the proteostasis network to remain soluble but less-functional for long timescales is widespread within the E. coli proteome.

Introduction Greater understanding is required of how smokers with smokingrelated diseases respond to smoking cessation medications. This post hoc analysis of EAGLES data compared continuous abstinence rates (CARs) in smokers with/ without smoking-related diseases and assessed participant demographic and baseline characteristics that may serve as predictors of continuous abstinence (CA). Methods EAGLES was a 24-week (12-week treatment, 12-week follow-up), doubleblind, active- (nicotine replacement therapy; patch) and placebo-controlled study in motivated-to-quit smokers with/without psychiatric disorders. This analysis assessed CARs at weeks 9-12 (CAR9-12) and 9-24 (CAR9-24) in participants with smoking-related diseases [asthma, chronic obstructive pulmonary disease (COPD), diabetes, and/or cardiovascular disease (n=1372)] versus controls without these comorbidities (n=6039). Participants received varenicline 1 mg twice daily, bupropion 150 mg twice daily, nicotine patches 21 mg/day with taper, or placebo for 12 weeks. Stepwise logistic modeling was also performed to analyze odds ratio (OR) for predictors of CA at weeks 9-12 (CA9-12) and 9-24 (CA9-24). Results Smokers with smoking-related diseases were older, had a longer smoking history, more quit attempts, and were more likely to have a psychiatric disorder and reside in the US versus smokers without comorbidities. Fagerström Test for Cigarette Dependence scores and treatment adherence were comparable between cohorts. Smokers with smoking-related diseases had lower CARs versus controls (CAR9-12: 20.8% vs 24.0%; CAR9-24: 13.0% vs 16.9%). Use of smoking cessation medication was the strongest predictor of CA after control for demographics, smoking characteristics, and psychiatric disorder. By treatment, OR and CI were: varenicline CA9-12 (OR=3.82; 95% CI: 3.21-4.54) and CA9-24 (OR=2.92; 95% CI: 2.40-3.54); bupropion CA9-12 (OR=2.17; 95% CI: 1.81-2.60) and CA9-24 (OR=1.99; 95% CI: 1.63-2.44); nicotine patches CA9-12 (OR=2.23; 95% CI: 1.87-2.67) and CA9-24 (OR=1.86; 95% CI: 1.52-2.28). Conclusions Smokers with smoking-related diseases had lower quit rates than controls. Of the active treatments compared, varenicline was most effective in smokers with asthma, COPD, diabetes, or cardiovascular disease.

Background: Glioblastoma (GBM) is the most common brain tumor with an overall survival (OS) of less than 30% at two years. Valproic acid (VPA) demonstrated survival benefits documented in retrospective and prospective trials, when used in combination with chemo-radiotherapy (CRT). Purpose: The primary goal of this study was to examine if the differential alteration in proteomic expression pre vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA as compared to standard-of-care CRT. The second goal was to explore the associations between the proteomic alterations in response to VPA/RT/TMZ correlated to patient outcomes. The third goal was to use the proteomic profile to determine the mechanism of action of VPA in this setting. Materials and Methods: Serum obtained pre- and post-CRT was analyzed using an aptamer-based SOMAScan® proteomic assay. Twenty-nine patients received CRT plus VPA, and 53 patients received CRT alone. Clinical data were obtained via a database and chart review. Tests for differences in protein expression changes between radiation therapy (RT) with or without VPA were conducted for individual proteins using two-sided t-tests, considering p-values of p-value < 0.005) to show the survival probability vs. the protein expression percentiles. Results: A total of 124 proteins were identified pre- vs. post-CRT that were differentially expressed between the cohorts who received CRT plus VPA and those who received CRT alone. Clinical factors did not confound the results, and distinct proteomic clustering in the VPA-treated population was identified. Time-dependent ROC curves for OS and PFS for landmark times of 20 months and 6 months, respectively, revealed AUC of 0.531, 0.756, 0.774 for OS and 0.535, 0.723, 0.806 for PFS for protein expression, clinical factors, and the combination of protein expression and clinical factors, respectively, indicating that the proteome can provide additional survival risk discrimination to that already provided by the standard clinical factors with a greater impact on PFS. Several proteins of interest were identified. Alterations in GALNT14 (increased) and CCL17 (decreased) (p = 0.003 and 0.003, respectively, FDR 0.198 for both) were associated with an improvement in both OS and PFS. The pre-CRT protein expression revealed 480 proteins predictive for OS and 212 for PFS (p < 0.05), of which 112 overlapped between OS and PFS. However, FDR-adjusted p values were high, with OS (the smallest p value of 0.586) and PFS (the smallest p value of 0.998). The protein PLCD3 had the lowest p-value (p = 0.002 and 0.0004 for OS and PFS, respectively), and its elevation prior to CRT predicted superior OS and PFS with VPA administration. Cancer hallmark genesets associated with proteomic alteration observed with the administration of VPA aligned with known signal transduction pathways of this agent in malignancy and non-malignancy settings, and GBM signaling, and included epithelial–mesenchymal transition, hedgehog signaling, Il6/JAK/STAT3, coagulation, NOTCH, apical junction, xenobiotic metabolism, and complement signaling. Conclusions: Differential alteration in proteomic expression pre- vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA. Using pre- vs. post-data, prognostic proteins emerged in the analysis. Using pre-CRT data, potentially predictive proteins were identified. The protein signals and hallmark gene sets associated with the alteration in the proteome identified between patients who received VPA and those who did not, align with known biological mechanisms of action of VPA and may allow for the identification of novel biomarkers associated with outcomes that can help advance the study of VPA in future prospective trials.

Objective: Succinate dehydrogenase subunit (SDHx) pathogenic variants predispose to phaeochromocytoma and paraganglioma (PPGL). Lifelong surveillance is recommended for all patients to enable prompt detection and treatment. There is currently limited evidence for optimal surveillance strategies in hereditary PPGL. We aim to detail the clinical presentation of PPGL in our cohort of non-index SDHB and SDHD pathogenic variant carriers. Methods: Retrospective analysis of medical and genetic records from a single tertiary referral centre identified SDHB or SDHD pathogenic variants in 74 non-index cases (56 SDHB and 18 SDHD). Surveillance screening for asymptomatic relatives consisted of annual plasma metanephrine measurement and whole-body MRI with contrast at 3–5 yearly intervals. Results: Twenty-three out of 74 non-index patients (10 SDHB and 13 SDHD) were diagnosed with PPGL, 17 patients through surveillance screening (24 tumours in total) and 6 diagnosed prior to commencement of cascade screening with symptomatic presentation. MRI with contrast identified PPGL in 22/24 screen- detected tumours and 5/24 tumours had elevated plasma metanephrine levels. Penetranc e in non-index family members was 15.2 and 47.2% for SDHB carriers and 71.6 and 78.7% for SDHD carriers at age of 50 and 70 years, respectively. Conclusion: Surveillance screening with combined biochemical testing and imaging enables early detection of PPGL in asymptomatic relatives with SDHx pathogenic variants. The presence of disease at first screen was significant in our cohort and hence further multi-centre long-term data are needed to inform counselling of family members undergoing lifelong surveillance.

Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states.

The risk of heavy bleeding after a miscarriage is higher in women undergoing medical management compared with surgical. According to the literature, oxytocin receptor mRNA expression in the myometrium is not well formed during early gestation. Adrenaline may be considered in miscarriage which remains refractory to uterotonics and where bleeding from the placental bed may contribute to haemorrhage, before proceeding to surgical intervention. It is used in various settings to control bleeding in gynaecological procedures. A 34-year-old woman in her third pregnancy presented at 15 + 1 weeks of gestation with an open cervical os and bulging membrane. Within three hours of admission, she passed the fetus but failed to deliver the placenta and continued to bleed. She was taken to theatre for surgical management of miscarriage. The bleeding persisted following suction evacuation and despite the standard dose of oxytocin, and misoprostol uterotonics were given. Because the source of bleeding could be the placental bed, potentially low lying at this stage, a 4.4 ml prefix combination of 12.5 μg/ml adrenaline (1:80,000) and lidocaine (20 mg/ml) was administered as an intracervical block equally at four quadrants at the level of the cervical isthmus. This arrested the bleeding immediately and controlled the bleeding until discharge. This technique has not been described previously, which we believe causes vasoconstriction of the placental bed.