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Targeting definite genomic locations using CRISPR-Cas systems requires a set of enzymes with unique protospacer adjacent motif (PAM) compatibilities. To expand this repertoire, we engineered nucleases, cytosine base editors, and adenine base editors from the archetypal Streptococcus thermophilus CRISPR1-Cas9 (St1Cas9) system. We found that St1Cas9 strain variants enable targeting to five distinct A-rich PAMs and provide a structural basis for their specificities. The small size of this ortholog enables expression of the holoenzyme from a single adeno-associated viral vector for in vivo editing applications. Delivery of St1Cas9 to the neonatal liver efficiently rewired metabolic pathways, leading to phenotypic rescue in a mouse model of hereditary tyrosinemia. These robust enzymes expand and complement current editing platforms available for tailoring mammalian genomes.
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Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes , Streptococcus thermophilus/enzimologia , Streptococcus thermophilus/genética , Animais , Proteína 9 Associada à CRISPR/química , Linhagem Celular , Células Cultivadas , Clivagem do DNA , Humanos , Mamíferos , Camundongos , Camundongos Knockout , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Sitting for prolonged periods of time impairs people's health. Prior research has mainly investigated sitting behavior on an aggregate level, for example, by analyzing total sitting time per day. By contrast, taking a dynamic approach, here we conceptualize sitting behavior as a continuous chain of sit-to-stand and stand-to-sit transitions. We use multilevel time-to-event analysis to analyze the timing of these transitions. We analyze â¼30,000 objectively measured posture transitions from 156 people during work time. Results indicate that the temporal dynamics of sit-to-stand transitions differ from stand-to-sit transitions, and that people are quicker to switch postures later in the workday, and quicker to stand up after having been more active in the recent hours. We found no evidence for associations with physical fitness. Altogether, these findings provide insights into the origins of people's stand-up and sit-down decisions, show that sitting behavior is fundamentally different from exercise behavior, and provide pointers for the development of interventions.
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Postura/fisiologia , Comportamento Sedentário , Postura Sentada , Adulto , Feminino , Humanos , Masculino , Saúde Ocupacional , Aptidão Física , Fatores de Tempo , Local de Trabalho , Adulto JovemRESUMO
Ischaemic preconditioning (IPC), brief periods of ischaemia immediately followed by reperfusion applied to a vascular bed, has emerged as a method to improve exercise performance. There is, however, a lack of research exploring repeated episodes of IPC on anaerobic performance. The aim of this study was to determine if a 2-week repeated IPC intervention could enhance anaerobic performance in male academy football players. Eight male academy football players completed two, 2-week intervention trials: six IPC episodes (4 × 5 min at 220 mmHg per episode), and six SHAM episodes (4 × 5 min at 20 mmHg per episode). Prior to and following each intervention trial, the participants completed assessments of anaerobic performance (Running Anaerobic Sprint Test [RAST]), and superficial femoral artery endothelial function (flow-mediated dilation [FMD]). IPC significantly enhanced peak and mean power output by 12% (p = 0.026) and 11% (p = 0.019) and significantly improved superficial femoral artery FMD (p = 0.049). The increase in endothelial function suggests that this may be a mechanism contributing to this enhancement of anaerobic performance. The present study supports the use of repeated IPC prior to matches and training sessions to enhance anaerobic performance.
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BACKGROUND: Humans display an age-related decline in cerebral blood flow and increase in blood pressure (BP), but changes in the underlying control mechanisms across the lifespan are less well understood. We aimed to; (1) examine the impact of age, sex, cardiovascular disease (CVD) risk, and cardio-respiratory fitness on dynamic cerebral autoregulation and cardiac baroreflex sensitivity, and (2) explore the relationships between dynamic cerebral autoregulation (dCA) and cardiac baroreflex sensitivity (cBRS). METHODS: 206 participants aged 18-70 years were stratified into age categories. Cerebral blood flow velocity was measured using transcranial Doppler ultrasound. Repeated squat-stand manoeuvres were performed (0.10 Hz), and transfer function analysis was used to assess dCA and cBRS. Multivariable linear regression was used to examine the influence of age, sex, CVD risk, and cardio-respiratory fitness on dCA and cBRS. Linear models determined the relationship between dCA and cBRS. RESULTS: Age, sex, CVD risk, and cardio-respiratory fitness did not impact dCA normalised gain, phase, or coherence with minimal change in all models (P > 0.05). cBRS gain was attenuated with age when adjusted for sex and CVD risk (young-older; ß = - 2.86 P < 0.001) along with cBRS phase (young-older; ß = - 0.44, P < 0.001). There was no correlation between dCA normalised gain and phase with either parameter of cBRS. CONCLUSION: Ageing was associated with a decreased cBRS, but dCA appears to remain unchanged. Additionally, our data suggest that sex, CVD risk, and cardio-respiratory fitness have little effect.
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Barorreflexo , Doenças Cardiovasculares , Barorreflexo/fisiologia , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/etiologia , Circulação Cerebrovascular/fisiologia , Homeostase/fisiologia , Humanos , Ultrassonografia Doppler TranscranianaRESUMO
BACKGROUND AND OBJECTIVE: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). METHODS: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. RESULTS: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. CONCLUSION: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.
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Apneia Obstrutiva do Sono , Sono , Nível de Alerta , Cloridrato de Atomoxetina , Humanos , Ácidos Mandélicos , Apneia Obstrutiva do Sono/tratamento farmacológico , ZolpidemRESUMO
BACKGROUND: Dispensed prescription medicine labels (prescription labels) are important information sources supporting safe and appropriate medicines use. OBJECTIVE: To develop and user test patient-centred prescription label formats. METHODS: Five stages: developing 12 labels for four fictitious medicines of varying dosage forms; diagnostic user testing of labels (Round 1) with 40 consumers (each testing three labels); iterative label revision, and development of Round 2 labels (n = 7); user testing of labels (Round 2) with 20 consumers (each testing four labels); labelling recommendations. Evaluated labels stated the active ingredient and brand name, using various design features (eg upper case and bold). Dosing was expressed differently across labels: frequency of doses/day, approximate times of day (eg morning), explicit times (eg 7 to 9 AM), and/or explicit dosing interval. Participants' ability to find and understand medicines information and plan a dosing schedule were assessed. RESULTS: Participants demonstrated satisfactory ability to find and understand the dosage for all label formats. Excluding active ingredient and dosing schedule, 14/19 labels (8/12 in Round 1; 6/7 in Round 2) met industry standard on performance. Participants' ability to correctly identify the active ingredient varied, with clear medicine name sign-posting enabling all participants evaluating these labels to find and understand the active ingredient. When planning a dosing schedule, doses were correctly spaced if the label stated a dosing interval, or frequency of doses/day. Two-thirds planned appropriate dosing schedules using a dosing table. CONCLUSIONS: Effective prescription label formatting and sign-posting of active ingredient improved communication of information on labels, potentially supporting safe medicines use. PATIENT AND PUBLIC INVOLVEMENT: Consumers actively contributed to the development of dispensed prescription medicine labels. Feedback from consumers following the first round was incorporated in revisions of the labels for the next round. Patient and public involvement in this study was critical to the development of readable and understandable dispensed prescription medicine labels.
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Farmácias , Farmácia , Medicamentos sob Prescrição , Rotulagem de Medicamentos , Prescrições de Medicamentos , HumanosRESUMO
KEY POINTS: A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by â¼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia. ABSTRACT: A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10 mg zolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6 ± 12.3 vs. 40.3 ± 16.4 events/h (means ± SD), p = 0.938) or nadir oxyhaemoglobin saturation (79.6 ± 6.6 vs. 79.7 ± 7.4%, p = 0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9 ± 14% (83 ± 11 vs. 73 ± 17%, p = 0.010). Arousal threshold increased by 15 ± 5% with zolpidem throughout all sleep stages (p = 0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10 mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by â¼10%, which may be beneficial in people with OSA and insomnia.
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Nível de Alerta , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Músculos Faríngeos , Sono , ZolpidemRESUMO
Targeted genome editing enables the creation of bona fide cellular models for biological research and may be applied to human cell-based therapies. Therefore, broadly applicable and versatile methods for increasing its efficacy in cell populations are highly desirable. We designed a simple and robust coselection strategy for enrichment of cells with either nuclease-driven nonhomologous end joining (NHEJ) or homology-directed repair (HDR) events by harnessing the multiplexing capabilities of CRISPR-Cas9 and Cpf1 systems. Selection for dominant alleles of the ubiquitous sodium/potassium pump (Na+/K+ ATPase) that rendered cells resistant to ouabain was used to enrich for custom genetic modifications at another unlinked locus of interest, thereby effectively increasing the recovery of engineered cells. The process is readily adaptable to transformed and primary cells, including hematopoietic stem and progenitor cells. The use of universal CRISPR reagents and a commercially available small-molecule inhibitor streamlines the incorporation of marker-free genetic changes in human cells.
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Sistemas CRISPR-Cas/genética , Células Cultivadas/fisiologia , Reparo do DNA/genética , Edição de Genes/métodos , Mutagênese Sítio-Dirigida , Marcadores Genéticos/genética , HumanosRESUMO
Pharyngeal and oesophageal manometry is used clinically and in research to quantify respiratory effort, upper-airway mechanics and the pathophysiological contributors to obstructive sleep apnea. However, the effects of this equipment on respiratory events and sleep in obstructive sleep apnea are unclear. As part of a clinical trial (ANZCTRN12613001106729), data from 28 participants who successfully completed a physiology night with an epiglottic catheter and nasal mask followed by a standard in-laboratory polysomnography were compared. The apnea-hypopnea index was not different during the physiology night versus standard polysomnography (22â ±â 14 versus 23â ±â 13â events per hr, pâ =â 0.71). Key sleep parameters were also not different compared between conditions, including sleep efficiency (79â ±â 13 versus 81â ±â 11%, pâ =â 0.31) and the arousal index (26â ±â 11 versus 27â ±â 11â arousals per hr, pâ =â 0.83). There were, however, sleep stage distribution changes between nights with less N3 and rapid eye movement sleep and more N1 on the physiology night, with no difference in N2 (53â ±â 15 versus 48â ±â 9, pâ =â 0.08). However, these changes did not increase next-day sleepiness. These findings indicate that while minor sleep stage distribution changes do occur towards lighter sleep, epiglottic manometry does not alter obstructive sleep apnea severity or sleep efficiency. Thus, epiglottic manometry can be used clinically and to collect detailed physiological information for research without major sleep disruption.
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Polissonografia/métodos , Apneia Obstrutiva do Sono/diagnóstico , Sono/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apneia Obstrutiva do Sono/fisiopatologiaRESUMO
Hypnotic use in obstructive sleep apnoea (OSA) is contraindicated due to safety concerns. Recent studies indicate that single-night hypnotic use worsens hypoxaemia in some and reduces OSA severity in others depending on differences in pathophysiology. However, longer clinical trial data are lacking. This study aimed to determine the effects of 1â month of zopiclone on OSA severity, sleepiness and alertness in patients with low-moderate respiratory arousal thresholds without major overnight hypoxaemia.69 participants completed a physiology screening night with an epiglottic catheter to quantify arousal threshold. 30 eligible patients (apnoea-hypopnoea index (AHI) 22±11â events·h-1) then completed standard in-laboratory polysomnography (baseline) and returned for two additional overnight sleep studies (nights 1 and 30) after receiving either nightly zopiclone (7.5â mg) or placebo during a 1-month, double-blind, randomised, parallel trial (ANZCTR identifier ANZCTRN12613001106729).The change in AHI from baseline to night 30 was not different between zopiclone versus placebo groups (-5.9±10.2 versus -2.4±5.5â events·h-1; p=0.24). Similarly, hypoxaemia, next-day sleepiness and driving simulator performance were not different.1 month of zopiclone does not worsen OSA severity, sleepiness or alertness in selected patients without major overnight hypoxaemia. As the first study to assess the effect of a hypnotic on OSA severity and sleepiness beyond single-night studies, these findings provide important safety data and insight into OSA pathophysiology.
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Compostos Azabicíclicos/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Piperazinas/administração & dosagem , Apneia Obstrutiva do Sono/tratamento farmacológico , Apneia Obstrutiva do Sono/fisiopatologia , Adulto , Nível de Alerta/efeitos dos fármacos , Compostos Azabicíclicos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Polissonografia , Índice de Gravidade de Doença , Sono/efeitos dos fármacos , Resultado do TratamentoRESUMO
Sedentary behavior has a strong association with cardiovascular disease (CVD) risk, which may be independent of physical activity. To date, the mechanism(s) that mediate this relationship are poorly understood. We hypothesize that sedentary behavior modifies key hemodynamic, inflammatory, and metabolic processes resulting in impaired arterial health. Subsequently, these vascular impairments directly and indirectly contribute to the development of CVD.
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Doenças Cardiovasculares/fisiopatologia , Comportamento Sedentário , Glicemia/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Exercício Físico/fisiologia , Hemodinâmica/fisiologia , Humanos , Inflamação/fisiopatologia , Estresse Oxidativo/fisiologia , Fatores de RiscoRESUMO
In this chapter, we intend to review gene therapy concepts applied to the potential treatment of tyrosinemia for parents and pediatricians. Therefore, our main objective is to give general informations in a comprehensible manner. Considering the nature of tyrosinemia and the current state of technology, a particular focus will be put on strategies using viral delivery of DNA to the liver. In light of the recent development of the CRISPR technology and the revival of promises for previously unavailable therapeutical tools, the present chapter aims at presenting up to date facts and potential pitfalls towards an application for metabolic diseases, in particular tyrosinemia.
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Tirosinemias/genética , Tirosinemias/terapia , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Humanos , Fígado/metabolismoRESUMO
Periods of prolonged sitting impairs endothelial function in lower limb conduit arteries, which is attenuated with physical activity breaks. The effect of activity breaks on upper limb arteries has not been examined. This study assessed changes in brachial artery endothelial function following either a prolonged sitting period or breaking up this sedentary time by performing sets of callisthenics exercises. Ten healthy participants (6 men) completed 2 conditions in a counterbalanced order: (a) 1-h 26-min sitting, or (b) breaking up this period every 20 min by performing a set of 5 callisthenics exercises. Brachial artery endothelial function was assessed via ultrasound using the flow-mediated dilation (FMD) technique prior to and following each condition, while brachial shear rate (SR) was acquired after each set of callisthenics. There was no significant change in FMD over time (P = 0.09) or between conditions (P = 0.12). Compared to sitting, brachial SR increased following each set of callisthenics, with a significant difference after the third break (Sit: 33.94 ± 12.79 s-1; Callisthenics: 57.16 ± 30.48 s-1, P = 0.02). Alterations in SR in the upper limbs suggest callisthenics may be an effective intervention to break up sedentary time and attenuate the potentially deleterious effects of prolonged sitting on cardiovascular health.
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Artéria Braquial/fisiologia , Endotélio Vascular/fisiologia , Exercício Físico/fisiologia , Comportamento Sedentário , Pressão Sanguínea/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Fluxo Sanguíneo Regional , Fatores de Tempo , Extremidade Superior/fisiologiaRESUMO
Advancing age may be the most potent independent predictor of future cardiovascular events, a relationship that is not fully explained by time-related changes in traditional cardiovascular risk factors. Since some arteries exhibit differential susceptibility to atherosclerosis, generalisations regarding the impact of ageing in humans may be overly simplistic, whereas in vivo assessment of arterial function and health provide direct insight. Coronary and peripheral (conduit, resistance and skin) arteries demonstrate a gradual, age-related impairment in vascular function that is likely to be related to a reduction in endothelium-derived nitric oxide bioavailability and/or increased production of vasoconstrictors (e.g. endothelin-1). Increased exposure and impaired ability for defence mechanisms to resist oxidative stress and inflammation, but also cellular senescence processes, may contribute to age-related changes in vascular function and health. Arteries also undergo structural changes as they age. Gradual thickening of the arterial wall, changes in wall content (i.e. less elastin, advanced glycation end-products) and increase in conduit artery diameter are observed with older age and occur similarly in central and peripheral arteries. These changes in structure have important interactive effects on artery function, with increases in small and large arterial stiffness representing a characteristic change with older age. Importantly, direct measures of arterial function and structure predict future cardiovascular events, independent of age or other cardiovascular risk factors. Taken together, and given the differential susceptibility of arteries to atherosclerosis in humans, direct measurement of arterial function and health may help to distinguish between biological and chronological age-related change in arterial health in humans.
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Envelhecimento/patologia , Artérias/crescimento & desenvolvimento , Aterosclerose/etiologia , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Animais , Artérias/metabolismo , Artérias/fisiologia , Hemodinâmica , HumanosRESUMO
OBJECTIVE: To explore physical activity (PA) and sedentary behaviors (SB) in individuals with lower limb (LL) Osteoarthritis (OA) and the influence of age, sex, and body mass index (BMI) on these behaviors. DESIGN: Systematic review search: PubMed, Cochrane Library, ScienceDirect, and CINAHL databases were searched from inception until July 2023. Study criteria: Studies that reported quantifiable device-based or self-reported data for PA and SB variables in adults clinically diagnosed with LL OA were included. DATA SYNTHESIS: A synthesis of PA and SB levels for those diagnosed with LL OA and the influence age, sex, and BMI have on these behaviors. RESULTS: From the 1930 studies identified through the electronic search process, 48 met the inclusion criteria. PA guidelines were met by 33% of the sample population that measured moderate and moderate to vigorous PA. No studies reported 75 minutes per week or more of vigorous PA. Additionally, 58% of the population reporting SB were sedentary for 8 hours per day or more. Also, increasing age, BMI, and the female sex were identified as negative influences on PA levels. There were numerous methodological inconsistencies in how data were collected and reported, such as various activity monitor cut points for PA and SB bout duration. CONCLUSION: Adults with LL OA may be at an increased risk of noncommunicable diseases due to low PA and high SB levels. It is important to consider age, sex, and BMI when investigating behavior patterns in those with LL OA.
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Exercício Físico , Comportamento Sedentário , Adulto , Humanos , Feminino , Índice de Massa Corporal , AutorrelatoRESUMO
Acute intermittent hypoxia (AIH) can induce sustained facilitation of motor output in people with spinal cord injury (SCI). Most studies of corticospinal tract excitability in humans have used 9% fraction inspired oxygen ([Formula: see text]) AIH (AIH-9%), with inconsistent outcomes. We investigated the effect of single sessions of 9% [Formula: see text] and 12% [Formula: see text] AIH (AIH-12%) on corticospinal excitability of a hand and leg muscle in able-bodied adults. Ten naïve participants completed three sessions on separate days comprising 15 epochs of 1 min of AIH-9%, AIH-12%, or sham (SHAM-21%) followed by 1 min of room air (21% [Formula: see text]) in a randomized crossover design. Motor-evoked potentials (MEPs; n = 30, â¼1 mV) elicited at rest by transcranial magnetic stimulation and maximal M-waves (Mmax) evoked by peripheral nerve stimulation were measured from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles at baseline and at â¼0, 20, 40, and 60 min post intervention. AIH-9% induced the greatest reduction in peripheral oxygen saturation (to 85% vs. 93% and 100% in AIH-12% and SHAM-21%, respectively; P < 0.001) and the greatest increase in ventilation [by 22% vs. 12% and -3% in AIH-9%, AIH-12%, and SHAM-21%, respectively (P < 0.001)]. There was no difference in MEP amplitudes (%Mmax) after any of the three conditions (AIH-9%, AIH-12%, SHAM-21%) for both the FDI (P = 0.399) and TA (P = 0.582). Despite greater cardiorespiratory changes during AIH-9%, there was no evidence of corticospinal facilitation (tested with MEPs) in this study. Further studies could explore variability in response to AIH between individuals and other methods to measure motor facilitation in people with and without spinal cord injuries.NEW & NOTEWORTHY This is the first study that tests whether acute intermittent hypoxia (AIH) induces motor output facilitation in humans after two different doses of AIH (9% and 12% [Formula: see text]) and the reproducibility of participant responses after a repeat AIH intervention at 9% AIH. There was no motor output facilitation in response to either dose of AIH. The results question the effectiveness of a single 30-min session of AIH in inducing motor output facilitation, tested in this way.
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Potencial Evocado Motor , Hipóxia , Extremidade Inferior , Músculo Esquelético , Estimulação Magnética Transcraniana , Humanos , Masculino , Potencial Evocado Motor/fisiologia , Hipóxia/fisiopatologia , Adulto , Feminino , Músculo Esquelético/fisiopatologia , Estimulação Magnética Transcraniana/métodos , Extremidade Inferior/fisiopatologia , Adulto Jovem , Tratos Piramidais/fisiopatologia , Estudos Cross-Over , Extremidade Superior/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
OBJECTIVES: To assess the evidence for anti-racist interventions which aim to reduce ethnic disparities in healthcare, with a focus on implementation in the UK healthcare system. DESIGN: Umbrella review. DATA SOURCES: Embase, Medline, Social Policy and Practice, Social Care Online and Web of Science were searched for publications from the year 2000 up to November 2023. ELIGIBILITY CRITERIA: Only systematic and scoping reviews of anti-racist interventions reported in English were included. Reviews were excluded if no interventions were reported, no comparator interventions were reported or the study was primarily descriptive. DATA EXTRACTION AND SYNTHESIS: A narrative synthesis approach was used to integrate and categorise the evidence on anti-racist interventions for healthcare. Quality appraisal (including risk of bias) was assessed using the AMSTAR-2 tool. RESULTS: A total of 29 reviews are included in the final review. 26 are from the healthcare sector and three are from education and criminal justice. The most promising interventions targeting individuals include group-based health education and providing culturally tailored interventions. On a community level, participation in all aspects of care pathway development that empowers ethnic minority communities may provide an effective approach to reducing ethnic health disparities. Interventions to improve quality of care for conditions with disproportionately worse outcomes in ethnic minority communities show promise. At a policy level, structural interventions including minimum wage policies and integrating non-medical interventions such as housing support in clinical care has some evidence for improving outcomes in ethnic minority communities. CONCLUSIONS: Many of the included studies were low or critically low quality due to methodological or reporting limitations. For programme delivery, different types of pathway integration, and providing a more person-centred approach with fewer steps for patients to navigate can contribute to reducing disparities. For organisations, there is an overemphasis on individual behaviour change and recommendations should include a shift in focus and resources to policies and practices that seek to dismantle institutional and systemic racism through a multilevel approach.
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Direito Penal , Etnicidade , Humanos , Atenção à Saúde , Grupos Minoritários , Reino UnidoRESUMO
BACKGROUND: The physical demands of golf caddying, including walking while carrying a golf bag, may potentially affect body composition, and markers of metabolic, cardiovascular, and musculoskeletal health. Therefore, this study examined the impact of 24 weeks of caddying on physical health in middle-older aged males. METHODS: Eleven full-time experienced male caddies (age: 59 [8] y; caddying experience: 14 [12] y) were recruited from a local golf course. The following were assessed at preseason and after 24 weeks of caddying (March-September 2022): body composition, heart rate, blood pressure, blood lipids, and performance tests (static and dynamic balance, strength, and submaximal fitness). Physical activity (PA) levels were assessed at preseason and at the mid-point of the caddying season. Across the caddying season, participants completed a monthly average of 24.0 (3.8) rounds. RESULTS: Following the caddying season, improvements in static balance (Δ = 13.5 s), dynamic balance (Δ = -1.8 s), and lower back absolute strength (Δ = 112.8 N), and muscle quality (Δ = 2.0 N·kg-1) were observed (all P < .05). Additionally, blood lipids, including total cholesterol (Δ = -0.6 mmol·L-1), high-density lipoprotein cholesterol (Δ = 0.1 mmol·L-1), low-density lipoprotein cholesterol (Δ = -0.6 mmol·L-1) (all P < .05), and body composition, including body mass (Δ = -2.7 kg), fat mass (Δ = -1.9 kg), fat percentage (Δ = -1.4%), fat-to-muscle ratio (Δ = -0.03), and body mass index (Δ = -0.9 kg·m-2) (all P < .05) improved. Caddying did not offer beneficial changes to cardiovascular variables or cardiorespiratory fitness (P > .05), while coronary heart disease risk score decreased (Δ = -3.3%) (P < .05). In relation to PA, light- (Δ = 145 min) and moderate-intensity (Δ = 71 min) PA, moderate to vigorous PA (Δ = 73 min), and total PA (Δ = 218 min) between preseason and the mid-point of the caddying season increased, while sedentary time (Δ = -172 min) decreased (all P < .05). CONCLUSION: Golf caddying can provide several physical health benefits such as improvements in various markers of cardiometabolic health, lower back absolute strength, and static and dynamic balance. The physical health improvements that caddying offers is likely contributed to by increased PA volume and intensity through walking on the golf course. Therefore, caddying may represent a feasible model for increasing PA volume and intensity and achieve physical health-related benefits.
Assuntos
Aptidão Cardiorrespiratória , Golfe , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Exercício Físico/fisiologia , Golfe/fisiologia , Caminhada/fisiologia , Aptidão Cardiorrespiratória/fisiologia , Composição Corporal/fisiologia , HDL-Colesterol , Aptidão Física/fisiologiaRESUMO
Hereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Québec, Canada. Mutating functionally related 'modifier' genes (i.e., genes that, when mutated, affect the phenotypic impacts of mutations in other genes) is an emerging strategy for treating human genetic diseases. In vivo somatic genome editing in animal models of these diseases is a powerful means to identify modifier genes and fuel treatment development. In this study, we demonstrate that mutating additional enzymes in the tyrosine catabolic pathway through liver-specific genome editing can relieve or worsen the phenotypic severity of a murine model of tyrosinemia type 1. Neonatal gene delivery using recombinant adeno-associated viral vectors expressing Staphylococcus aureus Cas9 under the control of a liver-specific promoter led to efficient gene disruption and metabolic rewiring of the pathway, with systemic effects that were distinct from the phenotypes observed in whole-body knockout models. Our work illustrates the value of using in vivo genome editing in model organisms to study the direct effects of combining pathological mutations with modifier gene mutations in isogenic settings.
RESUMO
Altered neural processing and increased respiratory sensations have been reported in chronic obstructive pulmonary disease (COPD) as larger respiratory-related evoked potentials (RREPs), but the effect of healthy-aging has not been considered adequately. We tested RREPs evoked by brief airway occlusions in 10 participants with moderate-to-severe COPD, 11 age-matched controls (AMC) and 14 young controls (YC), with similar airway occlusion pressure stimuli across groups. Mean age was 76 years for COPD and AMC groups, and 30 years for the YC group. Occlusion intensity and unpleasantness was rated using the modified Borg scale, and anxiety rated using the Hospital Anxiety and Depression Scale. There was no difference in RREP peak amplitudes across groups, except for the N1 peak, which was significantly greater in the YC group than the COPD and AMC groups (p = 0.011). The latencies of P1, P2 and P3 occurred later in COPD versus YC (p < 0.05). P3 latency occurred later in AMC than YC (p = 0.024). COPD and AMC groups had similar Borg ratings for occlusion intensity (3.0 (0.5, 3.5) [Median (IQR)] and 3.0 (3.0, 3.0), respectively; p = 0.476) and occlusion unpleasantness (1.3 (0.1, 3.4) and 1.0 (0.75, 2.0), respectively; p = 0.702). The COPD group had a higher anxiety score than AMC group (p = 0.013). A higher N1 amplitude suggests the YC group had higher cognitive processing of respiratory inputs than the COPD and AMC groups. Both COPD and AMC groups showed delayed neural responses to the airway occlusion, which may indicate impaired processing of respiratory sensory inputs in COPD and healthy aging.