Public trust, policing, and the COVID-19 pandemic: Evidence from an electoral authoritarian regime.

We examine how trust shapes compliance with public health restrictions during the COVID- 19 pandemic in Uganda. We use an endorsement experiment embedded in a mobile phone survey to show that messages from government officials generate more support for public health restrictions than messages from religious authorities, traditional leaders, or international NGOs. We further show that compliance with these restrictions is strongly positively correlated with trust in government, but only weakly correlated with trust in local authorities or other citizens. We use measures of trust from both before and during the pandemic to rule out the possibility that trust is a function of the pandemic itself. The relationship between trust and compliance is especially strong for the Ministry of Health and-more surprisingly-the police. We conclude that trust is crucial for encouraging compliance but note that it may be difficult to sustain, particularly in settings where governments and police forces have reputations for repression.

Arthropod Predation of Vertebrates Structures Trophic Dynamics in Island Ecosystems.

AbstractOn isolated islands, large arthropods can play an important functional role in ecosystem dynamics. On the Norfolk Islands group, South Pacific, we monitored the diet and foraging activity of an endemic chilopod, the Phillip Island centipede (Cormocephalus coynei), and used a stable isotope mixing model to estimate dietary proportions. Phillip Island centipede diet is represented by vertebrate animals (48%) and invertebrates (52%), with 30.5% consisting of squamates, including the Lord Howe Island skink (Oligosoma lichenigera) and Günther's island gecko (Christinus guentheri); 7.9% consisting of black-winged petrel (Pterodroma nigripennis) nestlings; and 9.6% consisting of marine fishes scavenged from regurgitated seabird meals. Centipede predation was the principal source of petrel nestling mortality, with annual rates of predation varying between 11.1% and 19.6% of nestlings. This means that 2,109-3,724 black-winged petrel nestlings may be predated by centipedes annually. Petrels produce a single offspring per year; therefore, predation of nestlings by centipedes represents total breeding failure for a pair in a given year. Our work demonstrates that arthropods can play a leading role in influencing vertebrate reproductive output and modifying trophic structures and nutrient flow in island ecosystems.

Conceptual and Scientific Defects in the Supreme Court's "Method of Execution" Jurisprudence.

The Eighth Amendment to the US Constitution prohibits the infliction of cruel and unusual punishments. However, no method of executing prisoners has ever been deemed by the Supreme Court to constitute Cruel and Unusual Punishment. Constitutional challenges to the dominant mode of executing prisoners today - lethal injection - are hobbled by a lack of clinical data that would reveal the likelihood this method might inflict gratuitous pain. Here, we assess the contemporary Eighth Amendment jurisprudence, including its legal and scientific limitations, and suggest modifications.

The Landscape of Early Clinical Gene Therapies outside of Oncology.

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.e., strategies that modify an individual's protein make-up by introducing exogenous nucleic acid or nucleic acid modifiers, regardless of delivery. Unmodified cell therapies, oncology therapies (reviewed elsewhere), and vaccine programs (distinct therapeutic strategy) were not included. Using a December 31, 2018 cutoff date, we identified 336 gene therapies being developed for 138 different indications covering 165 genetic targets. In all, we found that the early clinical GT landscape comprises a very disparate group of drug candidates in terms of indications, organizations, and delivery methods. We also highlight interesting trends, revealing the evolution of the field toward in vivo therapies and adeno-associated virus vector-based delivery systems. It will be interesting to witness what proportion of this current list effectively translates into new medicines.

Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening.

Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.

Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens.

Functional genomics approaches can overcome limitations-such as the lack of identification of robust targets and poor clinical efficacy-that hamper cancer drug development. Here we performed genome-scale CRISPR-Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritize new targets in defined tissues and genotypes. We verified one of our most promising dependencies, the Werner syndrome ATP-dependent helicase, as a synthetic lethal target in tumours from multiple cancer types with microsatellite instability. Our analysis provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets and suggests specific new targets. The principles described in this study can inform the initial stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets.

Ossifying chronic subperiosteal haematoma of the iliac bone.

Ossifying subperiosteal haematoma is a rare finding which may mimic more aggressive pathologies. We present the case of a 17-year-old boy with a subperiosteal haematoma of the iliac bone and discuss the imaging features.

The Relationship Between Body Mass Index and Fatty Infiltration in the Shoulder Musculature.

OBJECTIVE: Fatty infiltration in the rotator cuff muscles has been well studied in the setting of rotator cuff tendon tears to help predict outcomes of surgical repair. Fatty infiltration in the rotator cuff has also been independently correlated to the variables of age and sex. The purpose of our study was to determine if there is a relationship between body mass index and fatty infiltration in patients with no imaging evidence of rotator cuff tendinosis or tear. METHODS: Radiology reports of all magnetic resonance imaging examinations of the shoulder were searched over a 2-year period. Studies with imaging findings of rotator cuff tendinosis, partial tear, or full thickness tear were excluded from the study, resulting in a total of 143 patients with normal rotator cuffs who were included in the study. These studies were reviewed by consensus by 2 fellowship-trained musculoskeletal radiologists who used the Goutallier 5-stage scoring system to grade the supraspinatus, infraspinatus, subscapularis, teres minor, teres major, and deltoid muscles. RESULTS: Sex was shown not to be significantly associated with fatty infiltration with the exception of the deltoid muscle, which showed a statistically significant increase in fatty infiltration associated with female sex (P = 0.038). Age was shown to be a statistically significant predictor of fatty infiltration for all 6 muscles (P < 0.05). Body mass index was shown to be a statistically significant predictor of fatty infiltration for all of the evaluated shoulder musculature (P < 0.05) with the exception of the teres minor. CONCLUSIONS: Our results suggest that increased body mass index is associated with increased fatty infiltration in the supraspinatus, infraspinatus, subscapularis, teres major, and deltoid muscles. This relationship could help guide the decisions of orthopedic surgeons when considering rotator cuff repair.

Applications of CRISPR genome editing technology in drug target identification and validation.

INTRODUCTION: The analysis of pharmaceutical industry data indicates that the major reason for drug candidates failing in late stage clinical development is lack of efficacy, with a high proportion of these due to erroneous hypotheses about target to disease linkage. More than ever, there is a requirement to better understand potential new drug targets and their role in disease biology in order to reduce attrition in drug development. Genome editing technology enables precise modification of individual protein coding genes, as well as noncoding regulatory sequences, enabling the elucidation of functional effects in human disease relevant cellular systems. Areas covered: This article outlines applications of CRISPR genome editing technology in target identification and target validation studies. Expert opinion: Applications of CRISPR technology in target validation studies are in evidence and gaining momentum. Whilst technical challenges remain, we are on the cusp of CRISPR being applied in complex cell systems such as iPS derived differentiated cells and stem cell derived organoids. In the meantime, our experience to date suggests that precise genome editing of putative targets in primary cell systems is possible, offering more human disease relevant systems than conventional cell lines.

In Vivo Tracking of Human Hematopoiesis Reveals Patterns of Clonal Dynamics during Early and Steady-State Reconstitution Phases.

Hematopoietic stem/progenitor cells (HSPCs) are capable of supporting the lifelong production of blood cells exerting a wide spectrum of functions. Lentiviral vector HSPC gene therapy generates a human hematopoietic system stably marked at the clonal level by vector integration sites (ISs). Using IS analysis, we longitudinally tracked >89,000 clones from 15 distinct bone marrow and peripheral blood lineages purified up to 4 years after transplant in four Wiskott-Aldrich syndrome patients treated with HSPC gene therapy. We measured at the clonal level repopulating waves, populations' sizes and dynamics, activity of distinct HSPC subtypes, contribution of various progenitor classes during the early and late post-transplant phases, and hierarchical relationships among lineages. We discovered that in-vitro-manipulated HSPCs retain the ability to return to latency after transplant and can be physiologically reactivated, sustaining a stable hematopoietic output. This study constitutes in vivo comprehensive tracking in humans of hematopoietic clonal dynamics during the early and late post-transplant phases.

Comparison of radiation dose estimates and scan performance in pediatric high-resolution thoracic CT for volumetric 320-detector row, helical 64-detector row, and noncontiguous axial scan acquisitions.

RATIONALE AND OBJECTIVES: Efforts to decrease radiation exposure during pediatric high-resolution thoracic computed tomography (HRCT), while maintaining diagnostic image quality, are imperative. The objective of this investigation was to compare organ doses and scan performance for pediatric HRCT using volume, helical, and noncontiguous axial acquisitions. MATERIALS AND METHODS: Thoracic organ doses were measured using 20 metal oxide semiconductor field-effect transistor dosimeters. Mean and median organ doses and scan durations were determined and compared for three acquisition modes in a 5-year-old anthropomorphic phantom using similar clinical pediatric scan parameters. Image noise was measured and compared in identical regions within the thorax. RESULTS: There was a significantly lower dose in lung (1.8 vs 2.7 mGy, P < .02) and thymus (2.3 vs 2.7 mGy, P < .02) between volume and noncontiguous axial modes and in lung (1.8 vs 2.3 mGy, P < .02), breast (1.8 vs 2.6 mGy, P < .02), and thymus (2.3 vs 2.4 mGy, P < .02) between volume and helical modes. There was a significantly lower median image noise for volume compared to helical and axial modes in lung (55.6 vs 79.3 and 70.7) and soft tissue (76.0 vs 111.3 and 89.9). Scan times for volume, helical, and noncontiguous axial acquisitions were 0.35, 3.9, and 24.5 seconds, respectively. CONCLUSION: Volumetric HRCT provides an opportunity for thoracic organ dose and image noise reduction, at significantly faster scanning speeds, which may benefit pediatric patients undergoing surveillance studies for diffuse lung disease.

Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.

Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.

Radiation dose estimation for prospective and retrospective ECG-gated cardiac CT angiography in infants and small children using a 320-MDCT volume scanner.

OBJECTIVE: The purpose of this study is to determine patient dose estimates for clinical pediatric cardiac-gated CT angiography (CTA) protocols on a 320-MDCT volume scanner. MATERIALS AND METHODS: Organ doses were measured using 20 metal oxide semiconductor field effect transistor (MOSFET) dosimeters. Radiation dose was estimated for volumetrically acquired clinical pediatric prospectively and retrospectively ECG-gated cardiac CTA protocols in 5-year-old and 1-year-old anthropomorphic phantoms on a 320-MDCT scanner. Simulated heart rates of 60 beats/min (5-year-old phantom) and 120 beats/min (1- and 5-year-old phantoms) were used. Effective doses (EDs) were calculated using average measured organ doses and International Commission on Radiological Protection 103 tissue-weighting factors. Dose-length product (DLP) was recorded for each examination and was used to develop dose conversion factors for pediatric cardiac examinations acquired with volume scan mode. DLP was also used to estimate ED according to recently published dose conversion factors for pediatric helical chest examinations. Repeated measures and paired Student t test analyses were performed. RESULTS: For the 5-year-old phantom, at 60 beats/min, EDs ranged from 1.2 mSv for a prospectively gated examination to 4.5 mSv for a retrospectively gated examination. For the 5-year-old phantom, at 120 beats/min, EDs ranged from 3.0 mSv for a prospectively gated examination to 4.9 mSv for a retrospectively gated examination. For the 1-year-old phantom, at 120 beats/min, EDs ranged from 2.7 mSv for a prospectively gated examination to 4.5 mSv for a retrospectively gated examination. CONCLUSION: EDs for 320-MDCT volumetrically acquired ECG-gated pediatric cardiac CTA are lower than those published for conventional 16- and 64-MDCT scanners.

The application of next-generation sequencing technologies to drug discovery and development.

Next-generation sequencing (NGS) technologies represent a paradigm shift in sequencing capability. The technology has already been extensively applied to biological research, resulting in significant and remarkable insights into the molecular biology of cells. In this review, we focus on current and potential applications of the technology as applied to the drug discovery and development process. Early applications have focused on the oncology and infectious disease therapeutic areas, with emerging use in biopharmaceutical development and vaccine production in evidence. Although this technology has great potential, significant challenges remain, particularly around the storage, transfer and analysis of the substantial data sets generated.

ADAMTSL3 as a candidate gene for schizophrenia: gene sequencing and ultra-high density association analysis by imputation.

We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re-sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations.

CCR2 and coronary artery disease: a woscops substudy.

BACKGROUND: Several lines of evidence support a role for CCL2 (monocyte chemotactic protein-1) and its receptor CCR2 in the development of atherosclerosis. The aim of the present study was to determine the association of the CCR2 Val64Ile polymorphism with the development of coronary artery disease in the WOSCOPS study sample set. FINDINGS: A total of 443 cases and 1003 controls from the West of Scotland Coronary Prevention Study (WOSCOPS) were genotyped for the Val64Ile polymorphism in the CCR2 gene. Genotype frequencies were compared between cases and controls. The CCR2 Val64Ile polymorphism was found not to be associated with coronary events in this study population (odds ratio 1.15, 95% CI 0.82-1.61, p = 0.41). CONCLUSIONS: This case-control study does not support an association of the CCR2 Val64Ile polymorphism with coronary artery disease in the WOSCOPS sample set and does not confirm a possible protective role for CCR2 Val64Ile in the development of coronary artery disease.