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Quantitative muscle fat fraction (FF) responsiveness is lower in younger Charcot-Marie-Tooth disease type 1A (CMT1A) patients with lower baseline calf-level FF. We investigated the practicality, validity, and responsiveness of foot-level FF in this cohort involving 22 CMT1A patients and 14 controls. The mean baseline foot-level FF was 25.9 ± 20.3% in CMT1A patients, and the 365-day FF (n = 15) increased by 2.0 ± 2.4% (p < 0.001 vs controls). Intrinsic foot-level FF demonstrated large responsiveness (12-month standardized response mean (SRM) of 0.86) and correlated with the CMT examination score (ρ = 0.58, P = 0.01). Intrinsic foot-level FF has the potential to be used as a biomarker in future clinical trials involving younger CMT1A patients. ANN NEUROL 2024;96:170-174.
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Doença de Charcot-Marie-Tooth , Progressão da Doença , Pé , Imageamento por Ressonância Magnética , Músculo Esquelético , Humanos , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Masculino , Feminino , Adolescente , Imageamento por Ressonância Magnética/métodos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Adulto JovemRESUMO
The flavoenzyme nicotine oxidoreductase (NicA2) is a promising injectable treatment to aid in the cessation of smoking, a behavior responsible for one in ten deaths worldwide. NicA2 acts by degrading nicotine in the bloodstream before it reaches the brain. Clinical use of NicA2 is limited by its poor catalytic activity in the absence of its natural electron acceptor CycN. Without CycN, NicA2 is instead oxidized slowly by dioxygen (O2), necessitating unfeasibly large doses in a therapeutic setting. Here, we report a genetic selection strategy that directly links CycN-independent activity of NicA2 to growth of Pseudomonas putida S16. This selection enabled us to evolve NicA2 variants with substantial improvement in their rate of oxidation by O2. The encoded mutations cluster around a putative O2 tunnel, increasing flexibility and accessibility to O2 in this region. These mutations further confer desirable clinical properties. A variant form of NicA2 is tenfold more effective than the wild type at degrading nicotine in the bloodstream of rats.
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Nicotina , Pseudomonas putida , Ratos , Animais , Oxigênio , Oxirredutases/metabolismo , OxirreduçãoRESUMO
Preterm birth has been associated with altered microstructural properties of the white matter and lower cognitive ability in childhood and adulthood. Due to methodological limitations of the diffusion tensor model, it is not clear whether alterations in myelination or variation in fibre orientation are driving these differences. Novel models applied to multi-shell diffusion imaging have been used to disentangle these effects, but to date this has not been used to study the preterm brain in adulthood. This study investigated whether novel advanced diffusion MRI metrics such as microscopic anisotropy and orientation dispersion are altered in adults born preterm, and whether this was associated with cognitive performance. Seventy-two preterm born participants (<37 weeks gestational age) were recruited from a 1982-1984 cohort (33 males, mean age 33.5 ± 1.0 years). Seventy-two term born (>37 weeks gestational age) controls (34 males, mean age 30.9 ± 4.0 years) were recruited from the general population. Tensor FA was calculated with FSL, while microscopic FA and orientation dispersion entropy (ODE) were estimated using the Spherical Mean Technique (SMT). Estimated Full Scale IQ (FSIQ), Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI) were obtained from the WASI-II (abbreviated) IQ test. Voxel-wise comparisons using FSL's tract-based spatial statistics were performed to test between-group differences in diffusion MRI metrics as well as within-group associations of diffusion MRI metrics and IQ outcomes. The preterm group had significantly lower FSIQ, VCI and PRI scores. Preterm subjects demonstrated widespread decreases in ODE reflecting increased fibre dispersion, but no differences in microscopic FA. Tensor FA was increased in a small area in the anterior corona radiata. Lower FA values in the preterm population were associated with lower FSIQ and PRI scores. An increase in fibre dispersion in white matter and lower IQ scores after preterm birth exist in adulthood. Advanced diffusion MRI metrics such as the orientation dispersion entropy can be used to monitor white matter alterations across the lifespan in preterm born individuals. Although not significantly different between preterm and term groups, tensor FA values in the preterm group were associated with cognitive outcome.
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Nascimento Prematuro , Substância Branca , Masculino , Adulto , Feminino , Humanos , Recém-Nascido , Substância Branca/diagnóstico por imagem , Nascimento Prematuro/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Encéfalo/diagnóstico por imagem , Imagem de Difusão por Ressonância MagnéticaRESUMO
1H-magnetic resonance spectroscopy (MRS) has the potential to improve the noninvasive diagnostic accuracy for paediatric brain tumours. However, studies analysing large, comprehensive, multicentre datasets are lacking, hindering translation to widespread clinical practice. Single-voxel MRS (point-resolved single-voxel spectroscopy sequence, 1.5 T: echo time [TE] 23-37 ms/135-144 ms, repetition time [TR] 1500 ms; 3 T: TE 37-41 ms/135-144 ms, TR 2000 ms) was performed from 2003 to 2012 during routine magnetic resonance imaging for a suspected brain tumour on 340 children from five hospitals with 464 spectra being available for analysis and 281 meeting quality control. Mean spectra were generated for 13 tumour types. Mann-Whitney U-tests and Kruskal-Wallis tests were used to compare mean metabolite concentrations. Receiver operator characteristic curves were used to determine the potential for individual metabolites to discriminate between specific tumour types. Principal component analysis followed by linear discriminant analysis was used to construct a classifier to discriminate the three main central nervous system tumour types in paediatrics. Mean concentrations of metabolites were shown to differ significantly between tumour types. Large variability existed across each tumour type, but individual metabolites were able to aid discrimination between some tumour types of importance. Complete metabolite profiles were found to be strongly characteristic of tumour type and, when combined with the machine learning methods, demonstrated a diagnostic accuracy of 93% for distinguishing between the three main tumour groups (medulloblastoma, pilocytic astrocytoma and ependymoma). The accuracy of this approach was similar even when data of marginal quality were included, greatly reducing the proportion of MRS excluded for poor quality. Children's brain tumours are strongly characterised by MRS metabolite profiles readily acquired during routine clinical practice, and this information can be used to support noninvasive diagnosis. This study provides both key evidence and an important resource for the future use of MRS in the diagnosis of children's brain tumours.
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Biomarcadores Tumorais , Neoplasias Encefálicas , Humanos , Criança , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Imageamento por Ressonância MagnéticaRESUMO
Hypoxia-ischaemia (HI) can result in structural brain abnormalities, which in turn can lead to behavioural deficits in various cognitive and motor domains, in both adult and paediatric populations. Cardiorespiratory arrest (CA) is a major cause of hypoxia-ischaemia in adults, but it is relatively rare in infants and children. While the effects of adult CA on brain and cognition have been widely studied, to date, there are no studies examining the neurodevelopmental outcome of children who suffered CA early in life. Here, we studied the long-term outcome of 28 children who suffered early CA (i.e., before age 16). They were compared to a group of control participants (n = 28) matched for age, sex and socio-economic status. The patient group had impairments in the domains of memory, language and academic attainment (measured using standardised tests). Individual scores within the impaired range were most commonly found within the memory domain (79%), followed by academic attainment (50%), and language (36%). The patient group also had reduced whole brain grey matter volume, and reduced volume and fractional anisotropy of the white matter. In addition, lower performance on memory tests was correlated with bilaterally reduced volume of the hippocampi, thalami, and striatum, while lower attainment scores were correlated with bilateral reduction of fractional anisotropy in the superior cerebellar peduncle, the main output tract of the cerebellum. We conclude that patients who suffered early CA are at risk of developing specific cognitive deficits associated with structural brain abnormalities. RESEARCH HIGHLIGHTS: Our data shed light on the long-term outcome and associated neural mechanisms after paediatric hypoxia-ischaemia as a result of cardiorespiratory arrest. Patients had impaired scores on memory, language and academic attainment. Memory impairments were associated with smaller hippocampi, thalami, and striatum. Lower academic attainment correlated with reduced fractional anisotropy of the superior cerebellar peduncle.
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Cognição , Parada Cardíaca , Humanos , Masculino , Feminino , Criança , Cognição/fisiologia , Pré-Escolar , Adolescente , Encéfalo/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Memória/fisiologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Lactente , Imageamento por Ressonância MagnéticaRESUMO
AIM: This study aimed to (1) quantify attention and executive functioning in children with developmental coordination disorder (DCD), (2) assess whether some children with DCD are more likely to show attention difficulties, and (3) characterize brain correlates of motor and attention deficits. METHOD: Fifty-three children (36 with DCD and 17 without) aged 8 to 10 years underwent T1-weighted and diffusion-weighted magnetic resonance imaging, and standardized attention and motor assessments. Parents completed questionnaires of executive functioning and symptoms of inattention and hyperactivity. We assessed regional cortical thickness and surface area, and cerebellar, callosal, and primary motor tract structure. RESULTS: Analyses of covariance and one-sample t-tests identified impaired attention, non-motor processing speed, and executive functioning in children with DCD, yet partial Spearman's rank correlation coefficients revealed these were unrelated to one another or the type or severity of the motor deficit. Robust regression analyses revealed that cortical morphology in the posterior cingulate was associated with both gross motor skills and inattentive symptoms in children with DCD, while gross motor skills were also associated with left corticospinal tract (CST) morphology. INTERPRETATION: Children with DCD may benefit from routine attention and hyperactivity assessments. Alterations in the posterior cingulate and CST may be linked to impaired forward modelling during movements in children with DCD. Overall, alterations in these regions may explain the high rate of non-motor impairments in children with DCD. WHAT THIS PAPER ADDS: Children with developmental coordination disorder have difficulties in attention, processing speed, and executive functioning. Non-motor impairments were not interrelated or correlated with the type or severity of motor deficit. Posterior cingulate morphology was associated with gross motor skills and inattention. Gross motor skills were also associated with left corticospinal tract morphology.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtornos das Habilidades Motoras , Criança , Humanos , Transtornos das Habilidades Motoras/psicologia , Encéfalo/diagnóstico por imagem , Função Executiva , Cognição , Neuroimagem , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Destreza MotoraRESUMO
BACKGROUND: Health service policy in many jurisdictions is driving greater investment into digital primary care services. While some patients and practices may benefit, there are concerns that not all are able or wish to access primary care services online. "Digital facilitation" is the "range of processes, procedures, and personnel seeking to support patients in their uptake and use of online services" and may address such concerns. OBJECTIVE: As part of a multimethod research program, we undertook surveys of practice staff and patients to gain insight into the support being offered by practices and explore patients' experiences of this support. METHODS: General practices from 4 regions of England were sent a questionnaire exploring the modes of digital facilitation offered, the personnel involved in its delivery, and views on the motivations and drivers for providing support. Moreover, 12,822 patients registered with 62 general practices (predominantly those providing practice survey responses) were sent a questionnaire exploring their experiences of any support offered by their practice to use online services. RESULTS: Almost one-third of practices (156/500, 31.2%) responded to the practice survey, with most reporting using passive modes of digital facilitation (eg, display, leaflets, and SMS text messages) and few using active modes (eg, offering tablets or computers or using practice champions). However, 90.9% (130/143) reported providing ad hoc support. Practices agreed that it was the responsibility of both the practice (105/144, 72.9%) and the wider National Health Service (118/143, 82.5%) to support patients in using online services and that providing such support benefited the practice (126/144, 87.5%) and their patients (132/144, 91.7%). Nearly a quarter of the patients (3051/12,822, 23.8%) responded to the patient survey, with few (522/3051, 17.11% or less) reporting awareness of any modes of digital facilitation apart from text messages and emails (1205/3051, 39.5%) and only 13.36% (392/2935) reporting receiving support to use online services. Adjusted logistic regression analyses showed that older patients had a lower likelihood of 4 outcomes: being aware of, or of using, digital facilitation efforts, or being told about or being helped to use online services (all P<.05), particularly with regard to being helped to use online services (adjusted odds ratio for patients aged 85 years versus those aged 55-64 years: 0.08, 95% CI 0.02-0.36). However, ethnic minority participants or those for whom their first language was not English had positive associations with these outcomes. CONCLUSIONS: General practices recognize that patients would benefit from support to access online services. However, the support provided is often passive or ad hoc, and patients were seldom aware of digital facilitation efforts that their practice provided. There is potential to increase engagement with online primary care services by providing more support for all patients, particularly to provide targeted support for older patients.
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Atenção Primária à Saúde , Humanos , Atenção Primária à Saúde/estatística & dados numéricos , Inglaterra , Pessoa de Meia-Idade , Adulto , Feminino , Masculino , Inquéritos e Questionários , Internet , Idoso , Adolescente , Adulto JovemRESUMO
Neuropsychiatric symptoms (NPS) severely affect patients and their caregivers, and are associated with worse long-term outcomes. This study tested the hypothesis that altered protein levels in blood plasma could serve as biomarkers of NPS; and that altered protein levels are associated with persisting NPS and cognitive decline over time. We performed a cross-sectional and longitudinal study in older subjects with cognitive impairment and cognitively unimpaired in a memory clinic setting. NPS were recorded through the Neuropsychiatric Inventory Questionnaire (NPI-Q) while cognitive and functional impairment was assessed using the clinical dementia rating sum of boxes (CDR-SoB) score at baseline and follow-up visits. Shotgun proteomic analysis based on liquid chromatography-mass spectrometry was conducted in blood plasma samples, identifying 420 proteins. The presence of Alzheimer's Disease (AD) pathology was determined by cerebrospinal fluid biomarkers. Eighty-five subjects with a mean age of 70 (±7.4) years, 62% female and 54% with mild cognitive impairment or mild dementia were included. We found 15 plasma proteins with altered baseline levels in participants with NPS (NPI-Q score > 0). Adding those 15 proteins to a reference model based on clinical data (age, CDR-SoB) significantly improved the prediction of NPS (from receiver operating characteristic area under the curve [AUC] 0.75 to AUC 0.91, p = 0.004) with a specificity of 89% and a sensitivity of 74%. The identified proteins additionally predicted both persisting NPS and cognitive decline at follow-up visits. The observed associations were independent of the presence of AD pathology. Using proteomics, we identified a panel of specific blood proteins associated with current and future NPS, and related cognitive decline in older people. These findings show the potential of untargeted proteomics to identify blood-based biomarkers of pathological alterations relevant for NPS and related clinical disease progression.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Feminino , Idoso , Masculino , Estudos Longitudinais , Estudos Transversais , Proteômica , Testes Neuropsicológicos , Disfunção Cognitiva/patologia , Doença de Alzheimer/patologia , Proteínas Sanguíneas , Biomarcadores/líquido cefalorraquidianoRESUMO
IMPORTANCE: While most plant-pathogenic Streptomyces species cause scab disease on a variety of plant hosts, Streptomyces ipomoeae is the sole causative agent of soil rot disease of sweet potato and closely related plant species. Here, genome sequencing of virulent and avirulent S. ipomoeae strains coupled with comparative genomic analyses has identified genome content and organization features unique to this streptomycete plant pathogen. The results here will enable future research into the mechanisms used by S. ipomoeae to cause disease and to persist in its niche environment.
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Solanum tuberosum , Streptomyces , Genômica , Streptomyces/genética , Sequência de Bases , Doenças das PlantasRESUMO
Climate change and atmospheric deposition of nitrogen (N) and sulfur (S) are important drivers of forest demography. Here we apply previously derived growth and survival responses for 94 tree species, representing >90% of the contiguous US forest basal area, to project how changes in mean annual temperature, precipitation, and N and S deposition from 20 different future scenarios may affect forest composition to 2100. We find that under the low climate change scenario (RCP 4.5), reductions in aboveground tree biomass from higher temperatures are roughly offset by increases in aboveground tree biomass from reductions in N and S deposition. However, under the higher climate change scenario (RCP 8.5) the decreases from climate change overwhelm increases from reductions in N and S deposition. These broad trends underlie wide variation among species. We found averaged across temperature scenarios the relative abundance of 60 species were projected to decrease more than 5% and 20 species were projected to increase more than 5%; and reductions of N and S deposition led to a decrease for 13 species and an increase for 40 species. This suggests large shifts in the composition of US forests in the future. Negative climate effects were mostly from elevated temperature and were not offset by scenarios with wetter conditions. We found that by 2100 an estimated 1 billion trees under the RCP 4.5 scenario and 20 billion trees under the RCP 8.5 scenario may be pushed outside the temperature record upon which these relationships were derived. These results may not fully capture future changes in forest composition as several other factors were not included. Overall efforts to reduce atmospheric deposition of N and S will likely be insufficient to overcome climate change impacts on forest demography across much of the United States unless we adhere to the low climate change scenario.
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Mudança Climática , Florestas , Árvores , Biomassa , TemperaturaRESUMO
Nicotine oxidoreductase (NicA2), a member of the flavin-containing amine oxidase family, is of medical relevance as it shows potential as a therapeutic to aid cessation of smoking due to its ability to oxidize nicotine into a non-psychoactive metabolite. However, the use of NicA2 in this capacity is stymied by its dismal O2-dependent activity. Unlike other enzymes in the amine oxidase family, NicA2 reacts very slowly with O2, severely limiting its nicotine-degrading activity. Instead of using O2 as an oxidant, we discovered that NicA2 donates electrons to a cytochrome c, which means that NicA2 is actually a dehydrogenase. This is surprising, as enzymes of the flavin-containing amine oxidase family were invariably thought to use O2 as an electron acceptor. Our findings establish new perspectives for engineering this potentially useful therapeutic and prompt a reconsideration of the term 'oxidase' in referring to members of the flavin-containing amine 'oxidase' family.
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Proteínas de Bactérias/química , Citocromos c/química , Flavina-Adenina Dinucleotídeo/química , Nicotina/química , Oxirredutases/química , Pseudomonas putida/química , Alcaloides/química , Alcaloides/metabolismo , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Biotransformação , Bovinos , Clonagem Molecular , Citocromos c/genética , Citocromos c/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Flavina-Adenina Dinucleotídeo/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Cinética , Modelos Moleculares , Nicotina/metabolismo , Oxirredução , Oxirredutases/genética , Oxirredutases/metabolismo , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Pseudomonas putida/enzimologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homologia Estrutural de Proteína , Especificidade por SubstratoRESUMO
Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.
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Pseudoneglect, that is the tendency to pay more attention to the left side of space, is typically assessed with paper-and-pencil tasks, particularly line bisection. In the present study, we used an everyday task with more complex stimuli. Subjects' task was to look for pre-specified objects in images of real-world scenes. In half of the scenes, the search object was located on the left side of the image (L-target); in the other half of the scenes, the target was on the right side (R-target). To control for left-right differences in the composition of the scenes, half of the scenes were mirrored horizontally. Eye-movement recordings were used to track the course of pseudoneglect on a millisecond timescale. Subjects' initial eye movements were biased to the left of the scene, but less so for R-targets than for L-targets, indicating that pseudoneglect was modulated by task demands and scene guidance. We further analyzed how horizontal gaze positions changed over time. When the data for L- and R-targets were pooled, the leftward bias lasted, on average, until the first second of the search process came to an end. Even for right-side targets, the gaze data showed an early left-bias, which was compensated by adjustments in the direction and amplitude of later saccades. Importantly, we found that pseudoneglect affected search efficiency by leading to less efficient scan paths and consequently longer search times for R-targets compared with L-targets. It may therefore be prudent to take spatial asymmetries into account when studying visual search in scenes.
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Movimentos Oculares , Movimentos Sacádicos , HumanosRESUMO
Gene flow can affect evolutionary inference when species are undersampled. Here, we evaluate the effects of gene flow and geographic sampling on demographic inference of 2 hummingbirds that hybridize, Allen's hummingbird (Selasphorus sasin) and rufous hummingbird (Selasphorus rufus). Using whole-genome data and extensive geographic sampling, we find widespread connectivity, with introgression far beyond the Allen's × rufous hybrid zone, although the Z chromosome resists introgression beyond the hybrid zone. We test alternative hypotheses of speciation history of Allen's, rufous, and Calliope (S. calliope) hummingbird and find that rufous hummingbird is the sister taxon to Allen's hummingbird, and Calliope hummingbird is the outgroup. A model treating the 2 subspecies of Allen's hummingbird as a single panmictic population fit observed genetic data better than models treating the subspecies as distinct populations, in contrast to morphological and behavioral differences and analyses of spatial population structure. With additional sampling, our study builds upon recent studies that came to conflicting conclusions regarding the evolutionary histories of these 2 species. Our results stress the importance of thorough geographic sampling when assessing demographic history in the presence of gene flow.
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Evolução Biológica , Aves , Animais , Aves/genéticaRESUMO
BACKGROUND: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based and technology-supported cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation, especially during the SARS-CoV-2 pandemic. This is an update of a review previously published in 2009, 2015, and 2017. OBJECTIVES: To compare the effect of home-based (which may include digital/telehealth interventions) and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 16 September 2022. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials that compared centre-based cardiac rehabilitation (e.g. hospital, sports/community centre) with home-based programmes (± digital/telehealth platforms) in adults with myocardial infarction, angina, heart failure, or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references for inclusion based on predefined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Certainty of evidence was assessed using GRADE. MAIN RESULTS: We included three new trials in this update, bringing a total of 24 trials that have randomised a total of 3046 participants undergoing cardiac rehabilitation. A further nine studies were identified and are awaiting classification. Manual searching of trial registers until 16 September 2022 revealed a further 14 clinical trial registrations - these are ongoing. Participants had a history of acute myocardial infarction, revascularisation, or heart failure. Although there was little evidence of high risk of bias, a number of studies provided insufficient detail to enable assessment of potential risk of bias; in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported. No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in our primary outcomes up to 12 months of follow-up: total mortality (risk ratio [RR] = 1.19, 95% confidence interval [CI] 0.65 to 2.16; participants = 1647; studies = 12/comparisons = 14; low-certainty evidence) or exercise capacity (standardised mean difference (SMD) = -0.10, 95% CI -0.24 to 0.04; participants = 2343; studies = 24/comparisons = 28; low-certainty evidence). The majority of evidence (N=71 / 77 comparisons of either total or domain scores) showed no significant difference in health-related quality of life up to 24 months follow-up between home- and centre-based cardiac rehabilitation. Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate-certainty evidence). There was a similar level of trial completion (RR 1.03, 95% CI 0.99 to 1.08; participants = 2638; studies = 22/comparisons = 26; low-certainty evidence) between home-based and centre-based participants. The cost per patient of centre- and home-based programmes was similar. AUTHORS' CONCLUSIONS: This update supports previous conclusions that home- (± digital/telehealth platforms) and centre-based forms of cardiac rehabilitation formally supported by healthcare staff seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction, or revascularisation, or with heart failure. This finding supports the continued expansion of healthcare professional supervised home-based cardiac rehabilitation programmes (± digital/telehealth platforms), especially important in the context of the ongoing global SARS-CoV-2 pandemic that has much limited patients in face-to-face access of hospital and community health services. Where settings are able to provide both supervised centre- and home-based programmes, consideration of the preference of the individual patient would seem appropriate. Although not included in the scope of this review, there is an increasing evidence base supporting the use of hybrid models that combine elements of both centre-based and home-based cardiac rehabilitation delivery. Further data are needed to determine: (1) whether the short-term effects of home/digital-telehealth and centre-based cardiac rehabilitation models of delivery can be confirmed in the longer term; (2) the relative clinical effectiveness and safety of home-based programmes for other heart patients, e.g. post-valve surgery and atrial fibrillation.
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Reabilitação Cardíaca , Insuficiência Cardíaca , Infarto do Miocárdio , Adulto , Humanos , Qualidade de Vida , Hospitais , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
On 29 April 2021, Professor Hugh Angus Macleod, Angus as he was known to his family and friends, passed away at his home in Tucson, Arizona. Angus was a leading authority in the field of thin film optics, and he leaves behind a legacy of extraordinary contributions to the thin film community. This article outlines Angus's career in optics-a career that spanned over 60 years. Not only was Angus an eminent and distinguished scientist, he was also a great teacher, mentor, colleague and friend to the entire thin film optics world.
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A major challenge for clinical management of melanoma is the prevention and treatment of metastatic disease. Drug discovery efforts over the last 10â years have resulted in several drugs that improve the prognosis of metastatic melanoma; however, most patients develop early resistance to these treatments. We designed and synthesized, through a concise synthetic strategy, a series of hybrid olefin-pyridinone compounds that consist of structural motifs from tamoxifen and ilicicolin H. These compounds were tested against a human melanoma cell line and patient-derived melanoma cells that had metastasized to the brain. Three compounds 7 b, 7 c, and 7 g demonstrated promising activity (IC50=0.4-4.3â µM). Cell cycle analysis demonstrated that 7 b and 7 c induce cell cycle arrest predominantly in the G1 phase. Both 7 b and 7c significantly inhibited migration of A375 melanoma cells; greater effects were demonstrated by 7 b. Molecular modelling analysis provides insight into a plausible mechanism of action.
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Antineoplásicos , Melanoma , Humanos , Melanoma/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Apoptose , Tamoxifeno , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
INTRODUCTION: Rural General Practice (GP) surgeries often struggle to employ and retain multidisciplinary team members. Existing research into rural recruitment and retention issues is limited, and usually focussed on doctors. Rural practices often rely on income from dispensing medications; little is known about how maintaining dispensing services contributes to the recruitment and retention of staff. This study aimed to understand the barriers and facilitators to working and remaining in rural dispensing practices, and to explore how the primary care team value dispensing services. METHODS: We undertook semi-structured interviews with multidisciplinary team members of rural dispensing practices across England. Interviews were audio-recorded, transcribed and anonymised. Framework analysis was conducted using Nvivo 12. RESULTS: Seventeen staff members (including GPs, practice nurses, practice managers, dispensers and administrative staff) from 12 rural dispensing practices across England were interviewed. Personal and professional reasons for taking up a role in a rural dispensing practice included perceived career autonomy and development opportunities, and preference for working and living in a rural setting. Key factors impacting retention of staff included revenue generated by dispensing, opportunities for staff development, job satisfaction and the positive work environment. Perceived challenges to retention were the balancing of the required skillset of dispensing with the wages available for the role, lack of skilled job applicants, travel difficulties and negative perceptions of rural primary care practice. DISCUSSION: These findings will inform national policy and practice with the aim of providing further understanding of the drivers and challenges of working in rural dispensing primary care in England.
Assuntos
Seleção de Pessoal , Serviços de Saúde Rural , Humanos , Inglaterra , Satisfação no EmpregoRESUMO
The enzyme nicotine oxidoreductase (NicA2) is a member of the flavoprotein amine oxidase family that uses a cytochrome c protein (CycN) as its oxidant instead of dioxygen, which is the oxidant used by most other members of this enzyme family. We recently identified a potential binding site for CycN on the surface of NicA2 through rigid body docking [J. Biol. Chem. 2022, 298 (8), 102251]. However, this potential binding interface has not been experimentally validated. In this paper, we used unnatural amino acid incorporation to probe the binding interface between NicA2 and CycN. Our results are consistent with a structural model of the NicA2-CycN complex predicted by protein-protein docking and AlphaFold, suggesting that this is the binding site for CycN on NicA2's surface. Based on additional mutagenesis of potentially redox active residues in NicA2, we propose that electron transfer from NicA2's flavin to CycN's heme occurs without the assistance of a protein-derived wire.
Assuntos
Nicotina , Oxirredutases , Aminas , Aminoácidos/metabolismo , Citocromos c/genética , Citocromos c/metabolismo , Transporte de Elétrons , Elétrons , Flavinas/metabolismo , Flavoproteínas/metabolismo , Heme/metabolismo , Nicotina/química , Oxidantes , Oxirredução , Oxirredutases/metabolismo , OxigênioRESUMO
BACKGROUND: Neuroinflammation may contribute to psychiatric symptoms in older people, in particular in the context of Alzheimer's disease (AD). We sought to identify systemic and central nervous system (CNS) inflammatory alterations associated with neuropsychiatric symptoms (NPS); and to investigate their relationships with AD pathology and clinical disease progression. METHODS: We quantified a panel of 38 neuroinflammation and vascular injury markers in paired serum and cerebrospinal fluid (CSF) samples in a cohort of cognitively normal and impaired older subjects. We performed neuropsychiatric and cognitive evaluations and measured CSF biomarkers of AD pathology. Multivariate analysis determined serum and CSF neuroinflammatory alterations associated with NPS, considering cognitive status, AD pathology, and cognitive decline at follow-up visits. RESULTS: NPS were associated with distinct inflammatory profiles in serum, involving eotaxin-3, interleukin (IL)-6 and C-reactive protein (CRP); and in CSF, including soluble intracellular cell adhesion molecule-1 (sICAM-1), IL-8, 10-kDa interferon-γ-induced protein, and CRP. AD pathology interacted with CSF sICAM-1 in association with NPS. Presenting NPS was associated with subsequent cognitive decline which was mediated by CSF sICAM-1. CONCLUSIONS: Distinct systemic and CNS inflammatory processes are involved in the pathophysiology of NPS in older people. Neuroinflammation may explain the link between NPS and more rapid clinical disease progression.