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1.
Scand J Trauma Resusc Emerg Med ; 28(1): 9, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32028977

RESUMO

BACKGROUND: Resuscitative thoracotomy is a damage control procedure with an established role in the immediate treatment of patients in extremis or cardiac arrest secondary to cardiac tamponade however Its role in resuscitation of patients with abdominal exsanguination is uncertain. OBJECTIVE: The primary objective of this systematic review was to estimate mortality based on survival to discharge in patients with exsanguinating haemorrhage from abdominal trauma in cardiac arrest or a peri arrest clinical condition following a resuscitative thoracotomy. METHODS: A systematic literature search was performed to identify original research that reported outcomes in resuscitative thoracotomy either in the emergency department or pre-hospital environment in patients suffering or suspected of suffering from intra-abdominal injuries. The primary outcome was to assess survival to discharge. The secondary outcomes assessed were neurological function post procedure and the role of timing of intervention on survival. RESULTS: Seventeen retrospective case series were reviewed by a single author which described 584 patients with isolated abdominal trauma and an additional 1745 suffering from polytrauma including abdominal injuries. Isolated abdominal trauma survival to discharge ranged from 0 to 18% with polytrauma survival of 0-9.7% with the majority below 1%. Survival following a thoracotomy for abdominal trauma varied between studies and with no comparison non-intervention group no definitive conclusions could be drawn. Timing of thoracotomy was important with improved mortality in patients not in cardiac arrest or having the procedure performed just after a loss of signs of life. Normal neurological function at discharge ranged from 100 to 28.5% with the presence of a head injury having a negative impact on both survival and long-term morbidity. CONCLUSIONS: Pre-theatre thoracotomy may have a role in peri-arrest or arrested patient with abdominal trauma. The best outcomes are achieved with patients not in cardiac arrest or who have recently arrested and with no head injury present. The earlier the intervention can be performed, the better the outcome for patients, with survival figures of up to 18% following a resuscitative thoracotomy. More high-quality evidence is required to demonstrate a definitive mortality benefit for patients.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32049773

RESUMO

BACKGROUND: Sex differences in studies of antiretroviral(ART) drug exposure and treatment outcomes support the hypothesis that some ART combinations may not be well tolerated in women. We evaluated disparities in outcomes between men and women participating in ACTG A5288, an interventional strategy trial for individuals failing a protease inhibitor(PI)basedsecond line ART regimen in low and middle-income countries. METHODS: Participants were assigned to one of 4 cohorts (A-D) based on resistance profiles and ART history. Cohort A had no lopinavir/ritonavir(LPV/r) resistance and stayed on their second-line regimen, Cohorts B, C and D had increasing resistance and accessed novel ART regimens. In this secondary analysis, we evaluated sex differences in the primary endpoint, HIV-1 RNA ≤200 copies/mL at week 48; confirmed virologic failure≥1000 copies/mL (VF); and clinical outcomes and adverse events (intent-to-treat). RESULTS: Women made up258/545(47%) of the study population. More women than men were assigned to CohortA. Median follow-up was 72 weeks. Fewer women than men had HIV-1 RNA ≤200copies/mLat week 48: 39% vs 49% in cohort A and 83% vs 89% in CohortsB, C and D combined. More women experienced VF, Grade ≥3 signs and symptoms, but similar Grade ≥3 diagnoses or laboratory abnormalities. CONCLUSION: More women than men entered the study with a resistance profile suggesting that their second-line regimen could have been effective in maintaining virologic suppression. The more frequent occurrence of Grade≥3 signs and symptoms in women suggests that tolerability issues were under recognized in women on PI based therapy.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32015135

RESUMO

Aggregation of α-synuclein is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson's disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap-a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

5.
Sci Rep ; 10(1): 2121, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034258

RESUMO

We have previously designed a library of lentiviral vectors to generate somatic-transgenic rodents to monitor signalling pathways in diseased organs using whole-body bioluminescence imaging, in conscious, freely moving rodents. We have now expanded this technology to adeno-associated viral vectors. We first explored bio-distribution by assessing GFP expression after neonatal intravenous delivery of AAV8. We observed widespread gene expression in, central and peripheral nervous system, liver, kidney and skeletal muscle. Next, we selected a constitutive SFFV promoter and NFκB binding sequence for bioluminescence and biosensor evaluation. An intravenous injection of AAV8 containing firefly luciferase and eGFP under transcriptional control of either element resulted in strong and persistent widespread luciferase expression. A single dose of LPS-induced a 10-fold increase in luciferase expression in AAV8-NFκB mice and immunohistochemistry revealed GFP expression in cells of astrocytic and neuronal morphology. Importantly, whole-body bioluminescence persisted up to 240 days. We have validated a novel biosensor technology in an AAV system by using an NFκB response element and revealed its potential to monitor signalling pathway in a non-invasive manner in a model of LPS-induced inflammation. This technology complements existing germline-transgenic models and may be applicable to other rodent disease models.

6.
Stat Med ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003492

RESUMO

Individual randomized trials (IRTs) and cluster randomized trials (CRTs) with binary outcomes arise in a variety of settings and are often analyzed by logistic regression (fitted using generalized estimating equations for CRTs). The effect of stratification on the required sample size is less well understood for trials with binary outcomes than for continuous outcomes. We propose easy-to-use methods for sample size estimation for stratified IRTs and CRTs and demonstrate the use of these methods for a tuberculosis prevention CRT currently being planned. For both IRTs and CRTs, we also identify the ratio of the sample size for a stratified trial vs a comparably powered unstratified trial, allowing investigators to evaluate how stratification will affect the required sample size when planning a trial. For CRTs, these can be used when the investigator has estimates of the within-stratum intracluster correlation coefficients (ICCs) or by assuming a common within-stratum ICC. Using these methods, we describe scenarios where stratification may have a practically important impact on the required sample size. We find that in the two-stratum case, for both IRTs and for CRTs with very small cluster sizes, there are unlikely to be plausible scenarios in which an important sample size reduction is achieved when the overall probability of a subject experiencing the event of interest is low. When the probability of events is not small, or when cluster sizes are large, however, there are scenarios where practically important reductions in sample size result from stratification.

7.
Hum Mol Genet ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31919491

RESUMO

Gaucher disease is caused by mutations in the GBA gene, which encodes for the lysosomal enzyme ß-glucocerebrosidase (GCase), resulting in the accumulation of storage material in visceral organs and in some cases the brain of affected patients. While there is a commercially available treatment for the systemic manifestations, neuropathology still remains untreatable. We previously demonstrated that gene therapy represents a feasible therapeutic tool for the treatment of the neuronopathic forms of Gaucher disease (nGD). In order to further enhance the therapeutic affects to the central nervous system, we systemically delivered an adeno-associated virus (AAV) serotype 9 carrying the human GBA gene under control of a neuron-specific promoter to a nGD mouse model. Gene therapy increased the life span of treated animals, rescued the lethal neurodegeneration, normalised the locomotor behavioural defects and ameliorated the visceral pathology. Together these results provided further indication of gene therapy as a possible effective treatment option for the neuropathic forms of Gaucher disease.

8.
Clin Rheumatol ; 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31955323

RESUMO

Optimal wound care is an essential component in the management of systemic sclerosis (SSc) digital ulcers (DUs). DU debridement has been suggested to reduce ulcer-related pain and improve tissue healing. However, only a minority of rheumatologists perform DU debridement, and there is no standard of care/protocol. Our objectives were to (i) evaluate the current evidence for the use of debridement in DU management and (ii) assess whether there are any specific protocols. A systematic literature review was performed searching the PubMed database (between 01/01/1950-01/03/2019) in accordance with PRISMA guidelines. Two independent reviewers screened and extracted the abstracts/full manuscripts. Articles in English, which focussed on SSc-DU debridement/curettage, were included. Exclusion criteria included studies of juvenile/paediatric patients and basic/non-clinical research. Our search identified 1497 studies of which 4 studies were included in our final analysis. Three studies used scalpel debridement, and one study used this in combination with autolytic debridement. No studies specifically reported the effect on DU healing from debridement. Autolytic debridement with hyaluronate-based products was associated with significant ulcer pain and inflammation. Local anaesthetic significantly reduces pain both during and after debridement. Combined local and oral analgesia is often required for more severe or infected DUs. DU (scalpel and autolytic) debridement is being used by some clinicians in rheumatology; however, there are no standardised protocols. To improve wound care for SSc-DUs, future research should focus on developing a standardised protocol for SSc-DU debridement, with a view to facilitate randomised controlled trials to demonstrate safety and treatment efficacy.Key Points• Optimal wound care is an essential component in the management of systemic sclerosis-digital ulcers.• 'Sharp' debridement uses a scalpel, whereas 'autolytic' debridement uses dressings to optimize endogenous tissue lysis.• There is significant variation in the use of digital ulcer debridement in systemic sclerosis.• A standardized protocol and randomized controlled trials are needed to demonstrate debridement the safety and efficacy of digital ulcer debridement in systemic sclerosis.

9.
Clin Infect Dis ; 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927562

RESUMO

BACKGROUND: Early antiretroviral treatment (ART) is recommended for HIV-infected infants. However, few antiretroviral options are available for neonates. METHODS: The Early Infant Treatment Study in Botswana tested HIV-exposed infants using DNA PCR within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6mg/kg BID, zidovudine (ZDV), and lamivudine (3TC) at age <7 days. Nevirapine trough concentrations were tested at 1 and 2 weeks. NVP was switched to lopinavir-ritonavir (LPV-r) at week 2, 3, 4, or 5 according to delivery gestational age (≥38, 37, 36, 35 weeks). RESULTS: Forty HIV-infected infants started ART at median age 2 days (range 1-5). Nevirapine trough concentrations were highly variable and below therapeutic target (3000ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only one unscheduled treatment modification was required. Within 4 weeks of transition to LPV-r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV-r palatability. At 12 weeks, HIV-1 RNA was <40 copies/mL for 22 (55%) of 40 (93% <400 copies/mL); by 24 weeks, 27 (71%) of 38 were <40 copies/mL (84% <400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA, or other factors. CONCLUSIONS: NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV-r, but by 12 and 24 weeks most children achieved and maintained viral suppression.

10.
J Clin Rheumatol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31977650
12.
Clin Infect Dis ; 70(3): 436-445, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30919881

RESUMO

BACKGROUND: Household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB) are at high risk of infection and subsequent disease. There is limited evidence on the willingness of MDR-TB HHCs to take MDR-TB preventive therapy (MDR TPT) to decrease their risk of TB disease. METHODS: In this cross-sectional study of HHCs of MDR-TB and rifampicin-resistant tuberculosis (RR-TB) index cases from 16 clinical research sites in 8 countries, enrollees were interviewed to assess willingness to take a hypothetical, newly developed MDR TPT if offered. To identify factors associated with willingness to take MDR TPT, a marginal logistic model was fitted using generalized estimating equations to account for household-level clustering. RESULTS: From 278 MDR-TB/RR-TB index case households, 743 HHCs were enrolled; the median age of HHCs was 33 (interquartile range, 22-49) years, and 62% were women. HHC willingness to take hypothetical MDR TPT was high (79%) and remained high even with the potential for mild side effects (70%). Increased willingness was significantly associated with current employment or schooling (adjusted odds ratio [aOR], 1.83 [95% confidence interval {CI}, 1.07-3.13]), appropriate TB-related knowledge (aOR, 2.22 [95% CI, 1.23-3.99]), confidence in taking MDR TPT (aOR, 7.16 [95% CI, 3.33-15.42]), and being comfortable telling others about taking MDR TPT (aOR, 2.29 [95% CI, 1.29-4.06]). CONCLUSIONS: The high percentage of HHCs of MDR-TB/RR-TB index cases willing to take hypothetical MDR TPT provides important evidence for the potential uptake of effective MDR TPT when implemented. Identified HHC-level variables associated with willingness may inform education and counseling efforts to increase HHC confidence in and uptake of MDR TPT.

13.
Clin Infect Dis ; 70(3): 425-435, 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30942853

RESUMO

BACKGROUND: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. METHODS: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. RESULTS: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. CONCLUSIONS: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.

14.
Biophys J ; 118(1): 162-171, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31839258

RESUMO

Previous studies have shown that nucleic acids can nucleate protein aggregation in disease-related proteins, but in other cases, they can act as molecular chaperones that prevent protein aggregation, even under extreme conditions. In this study, we describe the link between these two behaviors through a combination of electron microscopy and aggregation kinetics. We find that two different proteins become soluble under harsh conditions through oligomerization with DNA. These DNA/protein oligomers form "networks," which increase the speed of oligomerization. The cases of DNA both increasing and preventing protein aggregation are observed to stem from this enhanced oligomerization. This observation raises interesting questions about the role of nucleic acids in aggregate formation in disease states.

15.
Ambio ; 49(2): 640-649, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31201615

RESUMO

Understanding fisher beliefs and attitudes towards specific management strategies can help inform and improve fisheries management, and thus stock sustainability. Previous studies highlight a lack of fisher awareness regarding environmental issues influencing the systems they utilise and the negative impacts of specific strategies, such as stock enhancement. Our study used a two-phase approach to first elicit and then measure the strength of common fishers' beliefs and associated attitudes regarding stock enhancement. Specifically, this research focused on recreational fishers of an estuarine crab fishery (Portunus armatus) in south-western Australia. The results demonstrate that recreational fishers believe stock enhancement could have strong positive outcomes, but also recognise that this management strategy could lead to some negative outcomes, though the latter are perceived as less likely to happen. This contrasts with previous research on fisheries stocking and demonstrates the value of using the two-phase approach to clarify fishers' perceptions of particular management approaches. To reduce fisher dissatisfaction with management actions, careful communication on the benefits and costs of stock enhancement is recommended. Our study highlights the significance of integrating social sciences into fisheries research, and the need to better understand fishing community beliefs to ensure effective management of the fishery.


Assuntos
Conservação dos Recursos Naturais , Pesqueiros , Peixes
16.
Artigo em Inglês | MEDLINE | ID: mdl-31812353

RESUMO

Musculoskeletal (MSK) involvement of the hands is a significant source of morbidity, impacting on quality of life in patients with systemic sclerosis (SSc). MSK complications are common in SSc and can affect the whole of the MSK system. MSK hand involvement can occur early in the course of the disease. A wide range of articular involvement is recognised including from arthralgia to inflammatory joint and tendon disease. Mechanistic insights have been made into enthesitis, hand contractures and tendon friction rubs and could inform the development inform novel treatment approaches to MSK involvement in SSc. Bony involvement can include osteomyelitis from digital ulceration. Other important manifestations include (but are not limited to) calcinosis, acro-osteolysis and carpal tunnel syndrome. MSK imaging is an important tool that allows insight into both disease pathogenesis and to inform the clinical management of MSK complications. The purpose of this review is to provide an overview of the MSK hand complications in patients with SSc, highlighting the breadth and burden of pathology relevant to clinical practice.

17.
Hum Mol Genet ; 28(23): 3867-3879, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31807779

RESUMO

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

18.
Sci Rep ; 9(1): 19153, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844107

RESUMO

Electrical correlates of the physiological state of a cell, such as membrane conductance and capacitance, as well as cytoplasm conductivity, contain vital information about cellular function, ion transport across the membrane, and propagation of electrical signals. They are, however, difficult to measure; gold-standard techniques are typically unable to measure more than a few cells per day, making widespread adoption difficult and limiting statistical reproducibility. We have developed a dielectrophoretic platform using a disposable 3D electrode geometry that accurately (r2 > 0.99) measures mean electrical properties of populations of ~20,000 cells, by taking parallel ensemble measurements of cells at 20 frequencies up to 45 MHz, in (typically) ten seconds. This allows acquisition of ultra-high-resolution (100-point) DEP spectra in under two minutes. Data acquired from a wide range of cells - from platelets to large cardiac cells - benchmark well with patch-clamp-data. These advantages are collectively demonstrated in a longitudinal (same-animal) study of rapidly-changing phenomena such as ultradian (2-3 hour) rhythmicity in whole blood samples of the common vole (Microtus arvalis), taken from 10 µl tail-nick blood samples and avoiding sacrifice of the animal that is typically required in these studies.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31841265

RESUMO

OBJECTIVES: Digital ulcers (DUs) are a major cause of disease-related morbidity and difficult to treat vascular complication of systemic sclerosis (SSc). Demonstrating treatment efficacy has traditionally focussed upon clinician assessment of DUs alone. No existing patient reported outcome (PRO) instrument captures the multi-faceted impact of SSc-DU. We report the findings of a multi-centre qualitative research study exploring the patient experience of SSc-DU. METHODS: Patient focus groups (FGs) were conducted across 3 scleroderma units, following a topic guide devised by SSc patients, experts and experienced qualitative researchers. A purposive sampling framework ensured the experiences of a diverse group of patients were captured. FGs were audio recorded, transcribed, anonymised, and analysed using inductive thematic analysis. We continued FGs until thematic saturation was achieved. RESULTS: Twenty-nine SSc patients with a history of DU disease participated in 4 FGs across the UK (Bath, Manchester and London). Five major inter-related themes (and sub-themes) were identified which encompass the patient experience of SSc-DUs: 'Disabling pain and hypersensitivity', 'Deep and broad-ranging emotional impact', 'Impairment of physical and social activity', 'Factors aggravating occurrence, duration and impact' and 'Mitigating, managing and adapting'. CONCLUSION: The patient experience of SSc-DU is multi-faceted and comprises a complex interplay of experiences associated with significant pain and morbidity. Patient experiences of SSc-DU are not captured using existing SSc-DU outcomes. Our findings shall inform the development of a novel PRO instrument to assess the severity and impact of SSc-DUs for use in future SSc-DU clinical trials.

20.
J Immunol ; 203(12): 3209-3215, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31676672

RESUMO

Innate lymphoid cells (ILCs) are critical for host defense and tissue repair but can also contribute to chronic inflammatory diseases. The transcription factor RORα is required for ILC2 development but is also highly expressed by other ILC subsets where its function remains poorly defined. We previously reported that Rorasg/sg bone marrow chimeric mice (C57BL/6J) were protected from Salmonella-induced intestinal fibrosis due to defective ILC3 responses. In this study, single-cell RNA analysis of ILCs isolated from inflamed tissues indicates that RORα perturbation led to a reduction in ILC3 lineages. Furthermore, residual Rorasg/sg ILC3s have decreased expression of key signature genes, including Rorc and activating cytokine receptors. Collectively, our data suggest that RORα plays a key role in preserving functional ILC3s by modulating their ability to integrate environmental cues to efficiently produce cytokines.

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