Papers by George Kachkovski
Home respiratory strategies in COPD patients with chronic hypercapnic respiratory failure: a systematic review and network meta-analysis
Respiratory care, Apr 3, 2024
BMJ Open Respiratory Research, Nov 30, 2023
Objectives We aimed to assess the available evidence for corticosteroids in fibrotic interstitial... more Objectives We aimed to assess the available evidence for corticosteroids in fibrotic interstitial lung disease (fILD) to inform the randomised embedded multifactorial adaptive platform ILD. Design Systematic review and meta-analysis. Data sources We searched Embase, Medline, Cochrane CENTRAL and Web of Science databases from inception to April 17 2023. Eligibility criteria We included studies that compared corticosteroids with standard care, placebo or no treatment in adult patients with fILD. Data extraction and synthesis We report on the change in forced vital capacity (FVC) and mortality. We used random-effects meta-analysis to estimate relative risk (RR) for dichotomous outcomes, and mean difference (MD) and standardised MDs for continuous outcomes, with 95% CIs. Results Of the 13 229 unique citations identified, we included 10 observational studies comprising 1639 patients. Corticosteroids had an uncertain effect on mortality compared with no treatment (RR 1.03 (95% CI 0.85 to 1.25); very low certainty evidence). The effect of corticosteroids on the rate of decline in FVC (% predicted) was uncertain when compared with no treatment (MD 4.29% (95% CI -8.26% to 16.83%); very low certainty evidence). However, corticosteroids might reduce the rate of decline in FVC in patients with non-idiopathic pulmonary fibrosis (IPF) fILD (MD 10.89% (95% CI 5.25% to 16.53%); low certainty evidence), while an uncertain effect was observed in patients with IPF (MD -3.80% (95% CI -8.94% to 1.34%); very low certainty evidence). Conclusions The current evidence on the efficacy and safety of corticosteroids in fILD is limited and of low certainty. Randomised trials are needed to address this significant research gap.
Non-Invasive Oxygenation Strategies in Adult Patients with Acute Hypoxemic Respiratory Failure: A Systematic Review and Network Meta-Analysis
Social Science Research Network, 2022
Noninvasive Oxygenation Strategies in Adult Patients With Acute Hypoxemic Respiratory Failure
Chest, Apr 1, 2023
Systematic Reviews, 2020
Background Acute hypoxemic respiratory failure is one of the leading causes of intensive care uni... more Background Acute hypoxemic respiratory failure is one of the leading causes of intensive care unit admission and is associated with high mortality. Noninvasive oxygenation strategies such as high-flow nasal cannula, standard oxygen therapy, and noninvasive ventilation (delivered by either face mask or helmet interface) are widely available interventions applied in these patients. It remains unclear which of these interventions are more effective in decreasing rates of invasive mechanical ventilation and mortality. The primary objective of this network meta-analysis is to summarize the evidence and compare the effect of noninvasive oxygenation strategies on mortality and need for invasive mechanical ventilation in patients with acute hypoxemic respiratory failure. Methods We will search key databases for randomized controlled trials assessing the effect of noninvasive oxygenation strategies in adult patients with acute hypoxemic respiratory failure. We will exclude studies in which t...
Attention can be shifted in the direction that another person is looking, but the role played by ... more Attention can be shifted in the direction that another person is looking, but the role played by an observer's mental attribution to the looker is controversial. And whether mental attribution to the looker is sufficient to trigger an attention shift is unknown. The current study introduces a novel paradigm to investigate this latter issue. An actor is presented on video turning his head to the left or right before a target appears, randomly, at the gazed-at or non-gazed at location. Time to detect the target is measured. The standard finding is that target detection is more efficient at the gazed-at than the nongazed-at location, indicating that attention is shifted to the gazed-at location. Critically, in the current study, an actor is wearing two identical masks --one covering his face and the other the back of his head. Thus, after the head turn, participants are presented with the profile of two faces, one looking left and one looking right. For a gaze cuing effect to emerge, participants must attribute a mental state to the actor --as looking through one mask and not the other. Over the course of four experiments we report that when mental attribution is necessary, a shift in social attention does not occur (i.e., mental attribution is not sufficient to produce a social attention effect); and when mental attribution is not necessary, a shift in social attention does occur. Thus, mental attribution is neither sufficient nor necessary for the occurrence of an involuntary shift in social attention. The present findings constrain future models of social attention that wish to link gaze cuing to mental attribution.
Communication Research, Mar 31, 2019
The 180-degree rule is thought to help smooth the change between film shots. When two individuals... more The 180-degree rule is thought to help smooth the change between film shots. When two individuals are speaking to each other, there is an imaginary axis of action running between them. If the camera crosses this axis, it breaks the 180-degree rule. A violation of the 180-degree rule is thought to have negative effects on viewers' enjoyment of films. The present study investigated this idea. Experiment 1 established that naive participants can detect violations in videos. Experiment 2 tested the putative negative effects of 180-degree rule violations. The results indicated that violations can confuse and disorient viewers. Critically, as revealed by Experiment 3, violations did not alter the viewers' liking of a video: Viewers were as likely to prefer a video with a 180-degree violation as one without. Collectively, these data shed light on fundamental beliefs regarding the 180-degree rule, which may help inform filming decisions around film enjoyment.
Communication Research, 2019
The 180-degree rule is thought to help smooth the change between film shots. When two individuals... more The 180-degree rule is thought to help smooth the change between film shots. When two individuals are speaking to each other, there is an imaginary axis of action running between them. If the camera crosses this axis, it breaks the 180-degree rule. A violation of the 180-degree rule is thought to have negative effects on viewers’ enjoyment of films. The present study investigated this idea. Experiment 1 established that naive participants can detect violations in videos. Experiment 2 tested the putative negative effects of 180-degree rule violations. The results indicated that violations can confuse and disorient viewers. Critically, as revealed by Experiment 3, violations did not alter the viewers’ liking of a video: Viewers were as likely to prefer a video with a 180-degree violation as one without. Collectively, these data shed light on fundamental beliefs regarding the 180-degree rule, which may help inform filming decisions around film enjoyment.
Attention can be shifted in the direction that another person is looking, but the role played by ... more Attention can be shifted in the direction that another person is looking, but the role played by an observer's mental attribution to the looker is controversial. And whether mental attribution to the looker is sufficient to trigger an attention shift is unknown. The current study introduces a novel paradigm to investigate this latter issue. An actor is presented on video turning his head to the left or right before a target appears, randomly, at the gazed-at or non-gazed at location. Time to detect the target is measured. The standard finding is that target detection is more efficient at the gazed-at than the nongazed-at location, indicating that attention is shifted to the gazed-at location. Critically, in the current study, an actor is wearing two identical masks -- one covering his face and the other the back of his head. Thus, after the head turn, participants are presented with the profile of two faces, one looking left and one looking right. For a gaze cuing effect to emer...
Journal of the Endocrine Society, May 1, 2021
Journal of Endocrinology, May 1, 2020
Sucrose consumption is associated with type 2 diabetes, cardiovascular disease, and cognitive def... more Sucrose consumption is associated with type 2 diabetes, cardiovascular disease, and cognitive deficits. Sucrose intake during pregnancy might have particularly prominent effects on metabolic, endocrine, and neural physiology. It remains unclear how consumption of sucrose affects parous females, especially in brain circuits that mediate food consumption and reward processing. Here, we examine whether a human-relevant level of sucrose before, during, and after pregnancy (17-18 weeks total) influences metabolic and neuroendocrine physiology in female rats. Females were fed either a control diet or a macronutrient-matched, isocaloric sucrose diet (25% of kcal from sucrose). Metabolically, sucrose impairs glucose tolerance, increases liver lipids, and increases a marker of adipose inflammation, but has no effect on body weight or overall visceral adiposity. Sucrose also decreases corticosterone levels in serum but not in the brain. Sucrose increases progesterone levels in serum and in the brain and increases the brain:serum ratio of progesterone in the mesocorticolimbic system and hypothalamus. These data suggest a dysregulation of systemic and local steroid signalling. Moreover, sucrose decreases tyrosine hydroxylase (TH), a catecholamine-synthetic enzyme, in the medial prefrontal cortex. Finally, sucrose consumption alters the expression pattern of FOSB, a marker of phasic dopamine signalling, in the nucleus accumbens. Overall, chronic consumption of sucrose at a human-relevant level alters metabolism, steroid levels, and brain dopamine signalling in a female rat model.
Steroid profiling of glucocorticoids in microdissected mouse brain across development
Developmental Neurobiology, Jan 25, 2021
Corticosterone is produced by the adrenal glands and also produced locally by other organs, such ... more Corticosterone is produced by the adrenal glands and also produced locally by other organs, such as the brain. Local levels of corticosterone in specific brain regions during development are not known. Here, we microdissected brain tissue and developed a novel liquid chromatography tandem mass spectrometry method (LC‐MS/MS) to measure a panel of seven steroids (including 11‐deoxycorticosterone (DOC), corticosterone, and 11‐dehydrocorticosterone (DHC) in the blood, hippocampus (HPC), cerebral cortex (CC), and hypothalamus (HYP) of mice at postnatal day (PND) 5, 21, and 90. In a second cohort of mice, we measured the expression of three genes that code for steroidogenic enzymes that regulate corticosterone levels (Cyp11b1, Hsd11b1, and Hsd11b2) in the HPC, CC, and HYP. There were region‐specific patterns of steroid levels across development, including higher corticosterone levels in the HPC and HYP than in the blood at PND5. In contrast, corticosterone levels were higher in the blood than in all brain regions at PND21 and PND90. Brain corticosterone levels were not positively correlated with blood corticosterone levels, and correlations across brain regions increased with age. Local corticosterone levels were best predicted by local DOC levels at PND5, but by local DHC levels at PND21 and PND90. Transcripts for the three enzymes were detectable in all samples (with highest expression of Hsd11b1) and showed region‐specific changes with age. These data demonstrate that individual brain regions fine‐tune local levels of corticosterone during early development and that coupling of glucocorticoid levels across regions increases with age.
bioRxiv (Cold Spring Harbor Laboratory), Aug 12, 2021
Androgens regulate behavioural flexibility, which is essential to adapt to a changing environment... more Androgens regulate behavioural flexibility, which is essential to adapt to a changing environment and depends on the medial prefrontal cortex (mPFC). Testosterone (T) administration decreases behavioural flexibility. It is well known that T is produced in the gonads, but T is also produced in the mesocorticolimbic system, which modulates behavioural flexibility. It is unclear how T produced in the brain versus the gonads influences behavioural flexibility. Here, we assess the effects of the androgen synthesis inhibitor abiraterone acetate (ABI) and long-term gonadectomy (GDX) on behavioural flexibility in two paradigms. In Experiment 1, ABI independent of GDX reduced the number of trials to criterion and perseverative errors in a strategy set-shifting task. Similarly, in Experiment 2, ABI but not GDX reduced perseverative errors in a reversal learning task. In subjects from Experiment 1, we also examined tyrosine hydroxylase immunoreactivity (TH-ir), and ABI but not GDX increased TH-ir in the mPFC. Our findings suggest that neurally-produced androgens modulate behavioural flexibility via modification of dopamine signalling in the mesocorticolimbic system. These results suggest novel roles for neurosteroids and possible side effects of ABI treatment for prostate cancer.
Maternal sucrose consumption alters behaviour and steroids in adult rat offspring
Journal of Endocrinology, Dec 1, 2021
Maternal diets can have dramatic effects on the physiology, metabolism, and behaviour of offsprin... more Maternal diets can have dramatic effects on the physiology, metabolism, and behaviour of offspring that persist into adulthood. However, the effects of maternal sucrose consumption on offspring remain unclear. Here, female rats were fed either a sucrose diet with a human-relevant level of sucrose (25% of kcal) or a macronutrient-matched, isocaloric control diet before, during, and after pregnancy. After weaning, all offspring were fed a standard low-sucrose rodent chow. We measured indicators of metabolism (weight, adipose, glucose tolerance, and liver lipids) during development and adulthood (16–24 weeks). We also measured food preference and motivation for sugar rewards in adulthood. Finally, in brain regions regulating these behaviours, we measured steroids and transcripts for steroidogenic enzymes, steroid receptors, and dopamine receptors. In male offspring, maternal sucrose intake decreased body mass and visceral adipose tissue, increased preference for high-sucrose and high-fat diets, increased motivation for sugar rewards, and decreased mRNA levels of Cyp17a1 (an androgenic enzyme) in the nucleus accumbens. In female offspring, maternal sucrose intake increased basal corticosterone levels. These data demonstrate the enduring, diverse, and sex-specific effects of maternal sucrose consumption on offspring phenotype.
Journal of the Endocrine Society
Consumption of sucrose (table sugar) is high in much of the world. The effects of maternal sucros... more Consumption of sucrose (table sugar) is high in much of the world. The effects of maternal sucrose intake on the placenta and fetal brain remain unknown. In rats, maternal consumption of sucrose at a human-relevant level alters the mother's physiology and steroids, as well as the adult offspring's brain and behavior. Effects in mothers are impaired glucose tolerance, increased liver lipids, increased adipose inflammation, and decreased corticosterone levels in the blood but not in the brain. In contrast, in adult female offspring, maternal sucrose intake increases corticosterone levels in the blood and the brain. In adult male offspring, maternal sucrose intake increases preference for high-sucrose and high-fat diets as well as motivation for sugar rewards in a progressive ratio task. In this study, we investigate the underlying mechanisms of the observed behavioral and endocrine effects in the adult offspring. We examine anti-inflammatory steroids, steroidogenic enzymes and...
Androgen synthesis inhibition increases behavioural flexibility and mPFC tyrosine hydroxylase in gonadectomized male rats
Journal of Neuroendocrinology, 2022
Journal of the Endocrine Society, 2021
Consumption of sucrose (table sugar) is high in much of the world. The effects of a maternal diet... more Consumption of sucrose (table sugar) is high in much of the world. The effects of a maternal diet high in sucrose on the placenta and fetal brain remain unknown. In rats, maternal consumption of sucrose at a human-relevant level has effects on the mother’s physiology and steroids, as well as long-lasting and sex-specific effects on the adult offspring’s brain and behavior. In the mothers, there are metabolic effects of sucrose intake, such as impaired glucose tolerance, increased liver lipids, and increased adipose inflammation. In rat dams, sucrose intake also decreases corticosterone levels in the blood but not in the brain. In the adult male offspring, preference for a high-sucrose diet and a high-fat diet increases due to maternal sucrose intake. In addition, maternal sucrose intake increases motivation for sugar rewards in a progressive ratio schedule of reinforcement in adult male offspring. In adult female offspring, corticosterone levels increase in the blood and brain as a ...
bioRxiv, 2021
Androgens regulate behavioural flexibility, which is essential to adapt to a changing environment... more Androgens regulate behavioural flexibility, which is essential to adapt to a changing environment and depends on the medial prefrontal cortex (mPFC). Testosterone (T) administration decreases behavioural flexibility. It is well known that T is produced in the gonads, but T is also produced in the mesocorticolimbic system, which modulates behavioural flexibility. It is unclear how T produced in the brain versus the gonads influences behavioural flexibility. Here, we assess the effects of the androgen synthesis inhibitor abiraterone acetate (ABI) and long-term gonadectomy (GDX) on behavioural flexibility in two paradigms. In Experiment 1, ABI independent of GDX reduced the number of trials to criterion and perseverative errors in a strategy set-shifting task. Similarly, in Experiment 2, ABI but not GDX reduced perseverative errors in a reversal learning task. In subjects from Experiment 1, we also examined tyrosine hydroxylase immunoreactivity (TH-ir), and ABI but not GDX increased TH...
Steroid profiling of glucocorticoids in microdissected mouse brain across development
Developmental Neurobiology, 2021
Corticosterone is produced by the adrenal glands and also produced locally by other organs, such ... more Corticosterone is produced by the adrenal glands and also produced locally by other organs, such as the brain. Local levels of corticosterone in specific brain regions during development are not known. Here, we microdissected brain tissue and developed a novel liquid chromatography tandem mass spectrometry method (LC‐MS/MS) to measure a panel of seven steroids (including 11‐deoxycorticosterone (DOC), corticosterone, and 11‐dehydrocorticosterone (DHC) in the blood, hippocampus (HPC), cerebral cortex (CC), and hypothalamus (HYP) of mice at postnatal day (PND) 5, 21, and 90. In a second cohort of mice, we measured the expression of three genes that code for steroidogenic enzymes that regulate corticosterone levels (Cyp11b1, Hsd11b1, and Hsd11b2) in the HPC, CC, and HYP. There were region‐specific patterns of steroid levels across development, including higher corticosterone levels in the HPC and HYP than in the blood at PND5. In contrast, corticosterone levels were higher in the blood ...
Journal of Endocrinology, 2020
Sucrose consumption is associated with type 2 diabetes, cardiovascular disease, and cognitive def... more Sucrose consumption is associated with type 2 diabetes, cardiovascular disease, and cognitive deficits. Sucrose intake during pregnancy might have particularly prominent effects on metabolic, endocrine, and neural physiology. It remains unclear how consumption of sucrose affects parous females, especially in brain circuits that mediate food consumption and reward processing. Here, we examine whether a human-relevant level of sucrose before, during, and after pregnancy (17–18 weeks total) influences metabolic and neuroendocrine physiology in female rats. Females were fed either a control diet or a macronutrient-matched, isocaloric sucrose diet (25% of kcal from sucrose). Metabolically, sucrose impairs glucose tolerance, increases liver lipids, and increases a marker of adipose inflammation, but has no effect on body weight or overall visceral adiposity. Sucrose also decreases corticosterone levels in serum but not in the brain. Sucrose increases progesterone levels in serum and in th...
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Papers by George Kachkovski