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Objectives To investigate whether delirium motor subtypes differ in terms of phenomenology and contributory aetiology. Design Cross-sectional study. Setting International study incorporating data from Ireland and India across palliative care, old age liaison psychiatry and general adult liaison psychiatry settings. Participants 1757 patients diagnosed with delirium using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM IV). Primary and secondary outcome measures Hyperactive, mixed and hypoactive delirium subtypes were identified using the abbreviated version of the Delirium Motor Subtype Scale. Phenomenology was assessed using the Delirium Rating Scale Revised. Contributory aetiologies were assessed using the Delirium Aetiology Checklist (DEC), with a score >2 indicating that the aetiology was likely or definitely contributory. Results Hypoactive delirium was associated with dementia, cerebrovascular and systemic infection aetiologies (p<0.001) and had a lower overall burden of delirium symptoms than the other motor subtypes. Hyperactive delirium was associated with younger age, drug withdrawal and the DEC category other systemic aetiologies (p<0.001). Mixed delirium showed the greatest symptom burden and was more often associated with drug intoxication and metabolic disturbance (p<0.001). All three delirium motor subtypes had similar levels of impairment in attention and visuospatial functioning but differed significantly when compared with no subtype (p<0.001). Conclusions This study indicates a pattern of aetiology and symptomatology of delirium motor subtypes across a large international sample that had previously been lacking. It serves to improve our understanding of this complex condition and has implications in terms of early detection and management of delirium.

Introduction Peripherally inserted central catheters (PICCs) are vital for the delivery of medical therapies, but up to 30% of PICCs are associated with complications such as deep vein thrombosis or infection. The integration of antimicrobial and hydrophobic catheter materials, and pressure-activated valves, into polyurethane PICCs are innovations designed to prevent infective and/or thrombotic complications. Methods and analysis A multicentre, parallel group, superiority randomised controlled trial with two experimental arms ((1) hydrophobic PICC (with pressure-activated valve); (2) chlorhexidine gluconate-impregnated PICC (with external clamp)) and one control group ((3) conventional polyurethane PICC (with external clamp)). Recruitment of 1098 adult and paediatric patients will take place over 2 years at three tertiary-referral hospitals in Queensland, Australia. Patients are eligible for inclusion if their PICC is to be inserted for medical treatment, with a vascular size sufficient to support a 4-Fr PICC or larger, and with informed consent. The primary outcome is PICC failure, a composite of thrombotic (venous thrombosis, breakage and occlusion) and infective complications (PICC-associated bloodstream infection and local infection). Secondary outcomes include: all-cause PICC complication; thrombotic complications; infective complications; adverse events (local or systemic reaction); PICC dwell time; patient/parent satisfaction; and healthcare costs. Differences between both intervention groups and the control group will be compared using Cox proportional hazards regression. Effect estimates will be presented as HRs with corresponding 95% CI. Ethics and dissemination Ethical approval from Queensland Health (HREC/QCHQ/48682) and Griffith University (Ref. No. 2019/094). Results will be published. Trial registration number ACTRN12619000022167.

Objective To study short-term (<90 days) morbidity and mortality following radical cystectomy (RC) for bladder cancer and identify modifiable risk factors associated with these. Design Systematic review. Methods The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed and EMBASE were searched for relevant papers on 11 June 2019 and rerun on 27 May 2020. Studies reporting complications, reoperations, length of stay and mortality within 90 days were included. Studies were reviewed according to criteria from the Oxford Centre for Evidence-Based Medicine and the quality of evidence was assessed using the Newcastle–Ottawa Scale. Results The search retrieved 1957 articles. Sixty-six articles were included. The quality of evidence was poor to good. Most studies were retrospective, and no randomised clinical trials were identified. Of included studies a median of 6 Martin criteria for reporting complications after surgery were fulfilled. The Clavien-Dindo classification for grading complications was most frequently used. The weighted overall complication rate after RC was 34.9% (range 28.8–68.8) for in-house complications, 39.0% (range 27.3–80.0) for 30-day complications and 58.5% (range 36.1–80.5) for 90-day complications. The most common types of complications reported were gastrointestinal (29.0%) and infectious (26.4%). The weighted mortality rate was 2.4% (range 0.9–4.7) for in-house mortality, 2.1% (0.0–3.7) for 30-day mortality and 4.7% (range 0.0–7.0) for 90-day mortality. Age and comorbidity were identified as the best predictors for complications following RC. Conclusion Short-term morbidity and mortality are high following RC. Reporting of complications is heterogeneous and the quality of evidence is generally low. There is a continuous need for randomised studies to address any intervention that can reduce morbidity and mortality following RC. PROSPERO registration number 104937.

Objectives Childhood vaccination coverage in Nagaland has lagged almost all states in India for more than two decades. This study aims to find drivers and barriers of childhood vaccination in Nagaland from the perspective of demand, supply and local health governance. Design A cross-sectional study was designed using a survey conducted by the Directorate of Health and Family in 2015. Setting Households, community-based health centres and health committees were surveyed. Participants 285 children aged under 2 years with vaccination cards and data on households, health centres and health committees were included. Outcomes Variables indicating whether a child received each of bacillus calmette–guérin (BCG), diphtheria-tetanus-pertussis (DTP3), oral polio (OPV3) and measles vaccination and all of them were outcome variables. Associated factors were identified using multilevel logistic regressions. Results Antenatal care at least three times was significantly associated with BCG, DTP3, OPV3 and full vaccination with adjusted ORs ranging from 2.4 (95% CI 1.1 to 5.1) to 3.3 (1.1 to 9.9). The availability of bus to health centre was slightly significant for BCG and OPV3 with the adjusted ORs of 2.0 (0.9 to 4.5) and 2.1 (0.9 to 4.8), respectively. Health committees’ budget provision to health centres was significant for OPV3 and full vaccination with the respective adjusted ORs of 15.7 (1.0 to 234.1) and 15.9 (1.2 to 214.7), the wide 95% CIs of which were driven by a small sample size. Health committees’ review of expenditure of health centres was significant for measles and full vaccination with the adjusted ORs of 4.0 (1.4 to 11.4) and 5.2 (1.4 to 19.4), respectively. Conclusion This study suggests that enhancing the utilisation of antenatal care and providing reliable transportation between villages and health centres are required to improve childhood vaccination coverage. Also, the significant association of budget administration of health committees suggests that supporting local health committees for effective financial management is important.

Introduction A novel coronavirus, designated SARS-CoV-2, caused an international outbreak of a respiratory illness, termed COVID-19 in December 2019. There is a lack of specific therapeutic agents based on evidence for this novel coronavirus infection; however, several medications have been evaluated as a potential therapy. Therapy is required to treat symptomatic patients and decrease the virus carriage duration to limit the communitytransmission. Methods and analysis We hypothesise that patients with mild COVID-19 treated with favipiravir will have a shorter duration of time to virus clearance than the control group. The primary outcome is to evaluate the effect of favipiravir on the timing of the PCR test conversion from positive to negative within 15 days after starting the medicine. Adults (>18 years, men or nonpregnant women, diagnosed with mild COVID-19 within 5 days of disease onset) are being recruited by physicians participating from the Ministry of National Guard Health Affairs and the Ministry of Health ethics committee approved primary healthcare centres. This double-blind, randomised trial comprises three significant parts: screening, treatment and a follow-up period. The treating physician and patients are blinded. Eligible participants are randomised in a 1:1 ratio to either the therapy group (favipiravir) or a control group (placebo) with 1800 mg by mouth two times per day for the first day, followed by 800 mg two times per day for 4–7 days. Serial nasopharyngeal/oropharyngeal swab samples are obtained on day 1 (5 days before therapy). On day5±1 day, 10±1 day, 15±2 days, extra nasopharyngeal/oropharyngeal PCR COVID-19 samples are requested. The primary analysis population for evaluating both the efficacy and safety outcomes will be a modified intention to treat population. Anticipating a 10% dropout rate, we expect to recruit 288 subjects per arm. The results assume that the hazard ratio is constant throughout the study and that the Cox proportional hazard regression is used to analyse the data. Ethics and dissemination The study was approved by the King Abdullah International Medical Research Centre Institutional Review Board (28 April 2020) and the Ministry of Health Institutional Review Board (1 July 2020). Protocol details and any amendments will be reported to https://clinicaltrials.gov/ct2/show/NCT04464408. The results will be published in peer-reviewed journals. Trial registration number National Clinical Trial Registry (NCT04464408).

Introduction The NHS Health Check aims to identify individuals at increased risk of cardiovascular diseases (CVDs) among the adult population in England. The Health Check includes calculation of CVD risk and discussion of pharmacological and lifestyle approaches to manage risk, including referral to lifestyle support services. The programme is commissioned by Local Authorities (LAs) and is delivered by a range of different providers in different settings. There is significant variation in activity, with uptake ranging from 25% to 85% in different areas, and clear evidence of variation in implementation and delivery practice. Methods and analysis We aim to understand how the NHS Health Check programme works in different settings, for different groups, so that we can recommend improvements to maximise intended outcomes. To do so, we will undertake a realist review and a survey of LA public health teams. Our review will follow Pawson’s five iterative stages: (1) locate existing theories, (2) search for evidence, (3) article selection, (4) extract and organise data and (5) synthesise evidence and draw conclusions. Our review will include documents describing local implementation alongside published research studies. We will recruit a stakeholder group (including Public Health England, commissioners and providers of Health Checks, plus members of the public and patients) to advise us throughout. Our survey will be sent to all 152 LAs in England to gather detailed information on programme delivery (including COVID-19-related changes) and available referral services. This will enable us to map delivery across England and relate these data to programme outcomes. Ethics and dissemination Ethical approval is not required for this review. For the survey, we have received approval from the University of Kent Research Ethics Committee. Our findings will be used to develop recommendations on tailoring, implementation and design strategies to improve delivery of the NHS Health Check in different settings, for different groups. PROSPERO registration number CRD42020163822.

Molecular simulations have played an instrumental role in uncovering the structural dynamics and physical properties of virus capsids. In this work, we move beyond equilibrium physicochemical characterization of a virus system to study a stage of the infection process that is required for viral proliferation. Despite many biochemical and functional studies, the molecular mechanism of host cell entry by non-enveloped viruses remains largely unresolved. Flock House virus (FHV) is a model system for non-enveloped viruses and is the subject of the current study. FHV infects through the acid-dependent endocytic pathway, where low pH triggers externalization of membrane-disrupting () peptides from the capsid interior. Using all-atom equilibrium and enhanced sampling simulations, the mechanism and energetics of peptide liberation and the effect of pH on this process are investigated. Our computations agree with experimental findings and reveal nanoscopic details regarding the pH control mechanism, which are not readily accessible in experiments.

Particle sorting is a fundamental method in various fields of medical and biological research. However, existing sorting applications are not capable for high-throughput sorting of large-size (>100 micrometers) particles. Here, we present a novel on-chip sorting method using traveling vortices generated by on-demand microjet flows, which locally exceed laminar flow condition, allowing for high-throughput sorting (5 kilohertz) with a record-wide sorting area of 520 micrometers. Using an activation system based on fluorescence detection, the method successfully sorted 160-micrometer microbeads and purified fossil pollen (maximum dimension around 170 micrometers) from lake sediments. Radiocarbon dates of sorting-derived fossil pollen concentrates proved accurate, demonstrating the method’s ability to enhance building chronologies for paleoenvironmental records from sedimentary archives. The method is capable to cover urgent needs for high-throughput large-particle sorting in genomics, metabolomics, and regenerative medicine and opens up new opportunities for the use of pollen and other microfossils in geochronology, paleoecology, and paleoclimatology.

The compelling need to provide adoptive cell therapy (ACT) to an increasing number of oncology patients within a meaningful therapeutic window makes the development of an efficient, fast, versatile, and safe genetic tool for creating recombinant T cells indispensable. In this study, we used nonintegrating minimally sized DNA vectors with an enhanced capability of generating genetically modified cells, and we demonstrate that they can be efficiently used to engineer human T lymphocytes. This vector platform contains no viral components and is capable of replicating extrachromosomally in the nucleus of dividing cells, providing persistent transgene expression in human T cells without affecting their behavior and molecular integrity. We use this technology to provide a manufacturing protocol to quickly generate chimeric antigen receptor (CAR)–T cells at clinical scale in a closed system and demonstrate their enhanced anti-tumor activity in vitro and in vivo in comparison to previously described integrating vectors.

The need for high-precision microprinting processes that are controllable, scalable, and compatible with different materials persists throughout a range of biomedical fields. Electrospinning techniques offer scalability and compatibility with a wide arsenal of polymers, but typically lack precise three-dimensional (3D) control. We found that charge reversal during 3D jet writing can enable the high-throughput production of precisely engineered 3D structures. The trajectory of the jet is governed by a balance of destabilizing charge-charge repulsion and restorative viscoelastic forces. The reversal of the voltage polarity lowers the net surface potential carried by the jet and thus dampens the occurrence of bending instabilities typically observed during conventional electrospinning. In the absence of bending instabilities, precise deposition of polymer fibers becomes attainable. The same principles can be applied to 3D jet writing using an array of needles resulting in complex composite materials that undergo reversible shape transitions due to their unprecedented structural control.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate–ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

Early germinal centers (GCs) contain unswitched IgM+ and switched IgG+ B cells but ultimately support mature IgG antibody responses. Sundling et al. show that IgG+ B cells are enriched and IgM+ B cells depleted from GCs by a process of positive selection based on the antigen receptor constant region.

STING translocation from the endoplasmic reticulum to the Golgi apparatus is required for its activation. Fang et al. demonstrate that Golgi apparatus-synthesized sulfated glycosaminoglycans (sGAGs) interact with STING to initiate its oligomerization at the Golgi apparatus, thus identifying sGAGs as necessary coligands for STING activation and downstream IFN signaling.

S. L. Hills et al.

J. L. Cannon et al.

D. Álamo-Junquera et al.

Abstract Background Application methods of |Attractive Toxic Sugar Baits (ATSB) need to be improved for wide-scale use, and effects on non-target organisms (NTOs) must be assessed. The goals of this study were to determine, at the village level, the effect of different configurations of bait stations to (1) achieve < 25% Anopheles mosquito vector daily feeding rate for both males and females and (2) minimize the effect on non-target organisms. Methods Dye was added to Attractive Sugar Bait Stations (without toxin) to mark mosquitoes feeding on the baits, and CDC UV light traps were used to monitor for marked mosquitoes. An array of different traps were used to catch dye marked NTOs, indicating feeding on the ASB. Stations were hung on homes (1, 2, or 3 per home to optimize density) at different heights (1.0 m or 1.8 m above the ground). Eight villages were chosen as for the experiments. Results The use of one ASB station per house did not mark enough mosquitoes. Use of two and three stations per house gave feeding rates above the 25% goal. There was no statistical difference in the percentage of marked mosquitoes between two and three stations, however, the catches using two and three bait stations were both significantly higher than using one. There was no difference in An. gambiae s.l. feeding when stations were hung at 1.0 and 1.8 m. At 1.8 m stations sustained less accidental damage. ASB stations 1.8 m above ground were fed on by three of seven monitored insect orders. The monitored orders were: Hymenoptera, Lepidoptera, Coleoptera, Diptera, Hemiptera, Neuroptera and Orthoptera. Using one or two stations significantly reduced percentage of bait-fed NTOs compared to three stations which had the highest feeding rates. Percentages were as follows: 6.84 ± 2.03% Brachycera followed by wasps (Hymenoptera: Vespidae) 5.32 ± 2.27%, and Rhopalocera 2.22 ± 1.79%. Hanging the optimal number of stations per house for catching mosquitoes (two) at 1.8 m above ground, limited the groups of non-targets to Brachycera, Chironomidae, Noctuoidea, Rhopalocera, parasitic wasps and wasps (Hymenoptera). Feeding at 1.8 m only occurred when stations were damaged. Conclusions The goal of marking quarter of the total Anopheles population per day was obtained using 2 bait stations at 1.8 m height above the ground. This configuration also had minimal effects on non-target insects.

Abstract Background Cryptosporidiosis is a disease caused by infection with an intestinal coccidian parasite Cryptosporidium. Cryptosporidium species are the second leading cause of diarrheal disease and death in children in developing countries. Until now, no data have been available or published on its prevalence among children with diarrhea in Sudan. Therefore, this paper was designed to determine the prevalence rate of Cryptosporidium among children with diarrhea under 5 years who were admitted to Kosti Teaching Hospital. Methods A hospital-based cross-sectional study including children under 5 years old admitted to the pediatric section of the hospital between September 2020 and December 2020. A total of one-hundred and fifty stool samples were collected. All stool samples were examined using the modified Ziehl Neelsen (mZN) staining technique and then examined microscopically for Cryptosporidium infection. Results A total of 150 children were examined out of which 70 presented with diarrhea. A greater prevalence of 19/70 (27.1%) of Cryptosporidium was observed in children with diarrhea than children without diarrhea 7/80 (8.8%). There was a significant relationship between the prevalence of Cryptosporidium and the presence of diarrhea in children under 5 years in the Kosti Teaching Hospital(P < 0.05). It was found that a higher prevalence was registered among children using piped-water sources for drinking. Conclusions The overall prevalence of parasite detected was 17.3% among children admitted to Kosti Teaching Hospital. The prevalence rate of the infection among Children with diarrhoea was 27.1%. Studying the prevalence rate of cryptosporidiosis among diarrheic children may predict their health status, leading to a better diagnosis, treatment, and, therefore, patients’ status improvement.

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