Comparative functional analysis of the atypical Notch ligands DLK1 and DLK2 in vertebrate development

DLK1 and DLK2 are vertebrate specific non-canonical Notch ligands. Dlk1 is imprinted throughout murine development [76] but selectively loses its imprint in the postnatal neurogenic niche by an unknown mechanism [78]. Possessing both secreted and membrane-tethered isoforms[212, 211], DLK1 plays critical roles in a wide range of developmental processes and is implicated in several diseases, including obesity and cancer[35, 241]. Apart from a few exceptions[78], in the majority of processes, the precise roles and relative contributions of membrane-bound and secreted DLK1 are unknown . DLK2 is a related gene with homology to DLK1 [108, 49]; however virtually nothing is known about it. Preliminary data from the Ferguson-Smith lab suggests that it is involved in neurogenesis in the Zebrafish. This project investigates the role that DLK2 plays in wild-type mice and compares the gene to DLK1.My work was funded by a Wellcome Trust studentship and a Lander studentship from my college

An investigation into reinforced and functionally graded lattice structures

Lattice structures are regarded as excellent candidates for use in lightweight energy absorbing applications, such as crash protection. In this paper we investigate the crushing behaviour, mechanical properties and energy absorption of lattices made by an additive manufacturing (AM) process. Two types of lattice were examined; body-centred-cubic (BCC) and a reinforced variant called BCCz. The lattices were subject to compressive loads in two orthogonal directions, allowing an assessment of their mechanical anisotropy to be made. We also examined functionally graded versions of these lattices, which featured a density gradient along one direction. The graded structures exhibited distinct crushing behaviour, with a sequential collapse of cellular layers preceding full densification. For the BCCz lattice, the graded structures were able to absorb around 114% more energy per unit volume than their non-graded counterparts before full densification, 1371 +or- 9 kJ/m3 vs. 640 +or- 10 kJ/m3. This highlights the strong potential for functionally graded lattices to be used in energy absorbing applications. Finally, we determined several of the Gibson-Ashby coefficients relating the mechanical properties of lattice structures to their density; these are crucial in establishing the constitutive models required for effective lattice design. These results improve the current understanding of AM lattices, and will enable the design of sophisticated, functional, lightweight components in the future

Fate specification and tissue-specific cell cycle control of the <i>Caenorhabditis elegans</i> intestine

Coordination between cell fate specification and cell cycle control in multicellular organisms is essential to regulate cell numbers in tissues and organs during development, and its failure may lead to oncogenesis. In mammalian cells, as part of a general cell cycle checkpoint mechanism, the F-box protein β-transducin repeat-containing protein (β-TrCP) and the Skp1/Cul1/F-box complex control the periodic cell cycle fluctuations in abundance of the CDC25A and B phosphatases. Here, we find that the Caenorhabditis elegans β-TrCP orthologue LIN-23 regulates a progressive decline of CDC-25.1 abundance over several embryonic cell cycles and specifies cell number of one tissue, the embryonic intestine. The negative regulation of CDC-25.1 abundance by LIN-23 may be developmentally controlled because CDC-25.1 accumulates over time within the developing germline, where LIN-23 is also present. Concurrent with the destabilization of CDC-25.1, LIN-23 displays a spatially dynamic behavior in the embryo, periodically entering a nuclear compartment where CDC-25.1 is abundant

An investigation into reinforced and functionally graded lattice structures

Lattice structures are regarded as excellent candidates for use in lightweight energy absorbing applications, such as crash protection. In this paper we investigate the crushing behaviour, mechanical properties and energy absorption of lattices made by an additive manufacturing (AM) process. Two types of lattice were examined; body-centred-cubic (BCC) and a reinforced variant called BCCz. The lattices were subject to compressive loads in two orthogonal directions, allowing an assessment of their mechanical anisotropy to be made. We also examined functionally graded versions of these lattices, which featured a density gradient along one direction. The graded structures exhibited distinct crushing behaviour, with a sequential collapse of cellular layers preceding full densification. For the BCCz lattice, the graded structures were able to absorb around 114% more energy per unit volume than their non-graded counterparts before full densification, 1371 +or- 9 kJ/m3 vs. 640 +or- 10 kJ/m3. This highlights the strong potential for functionally graded lattices to be used in energy absorbing applications. Finally, we determined several of the Gibson-Ashby coefficients relating the mechanical properties of lattice structures to their density; these are crucial in establishing the constitutive models required for effective lattice design. These results improve the current understanding of AM lattices, and will enable the design of sophisticated, functional, lightweight components in the future

Financial incentives to improve adherence to anti-psychotic maintenance medication in non-adherent patients - a cluster randomised controlled trial (FIAT)

Background Various interventions have been tested to achieve adherence to anti-psychotic maintenance medication in non-adherent patients with psychotic disorders, and there is no consistent evidence for the effectiveness of any established intervention. The effectiveness of financial incentives in improving adherence to a range of treatments has been demonstrated; no randomised controlled trial however has tested the use of financial incentives to achieve medication adherence for patients with psychotic disorders living in the community. Methods/Design In a cluster randomised controlled trial, 34 mental health teams caring for difficult to engage patients in the community will be randomly allocated to either the intervention group, where patients will be offered a financial incentive for each anti-psychotic depot medication they receive over a 12 month period, or the control group, where all patients will receive treatment as usual. We will recruit 136 patients with psychotic disorders who use these services and who have problems adhering to antipsychotic depot medication, although all conventional methods to achieve adherence have been tried. The primary outcome will be adherence levels, and secondary outcomes are global clinical improvement, number of voluntary and involuntary hospital admissions, number of attempted and completed suicides, incidents of physical violence, number of police arrests, number of days spent in work/training/education, subjective quality of life and satisfaction with medication. We will also establish the cost effectiveness of offering financial incentives. Discussion The study aims to provide new evidence on the effectiveness and cost effectiveness of offering financial incentives to patients with psychotic disorders to adhere to antipsychotic maintenance medication. If financial incentives improve adherence and lead to better health and social outcomes, they may be recommended as one option to improve the treatment of non-adherent patients with psychotic disorders. Trial Registration Current controlled trials ISRCTN77769281

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication