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طب الكوارث : المبادئ الشاملة والممارسات
لقد نما اختصاص طب الكوارث على نحو كبير بعد الهجمات الإرهابية في الولايات المتحدة في 11 سبتمبر/ أيلول عام 2001، وما يدعم هذا النمو نشر عدد من الكتب المرجعية المتعلقة بالكوارث، وقد شارك في بعض الحالات فرق 9/12 ؛ وهم أشخاص أصبحوا مهتمين فجأة بالأمر، وغدو \"خبراء\" في الكوارث بعد أن أصبح الموضوع رائجا وازداد جريان التمويل الاتحادي المتعلق به بسهولة، وقد جعل ذلك تمويل الكثير من الأعمال ذات الصلة على نحو فعال ممكنا، وبقي التحدي المتعلق بوضع مؤلفين وطنيين ودوليين لكتاب محدد قائما، وقد فكرنا بتحرير مثل هذا الكتاب خلال السنوات العشر الماضية، لكن التوقيت لم يكن مناسبا، وقد ساورتنا الشكوك بإمكانية تحقيق ذلك \"بالطريقة الصحيحة\" دوما ؛ لأننا لم نكن ندري على وجه الدقة \"ما سننجزه\". من هنا جاءت فكرة هذا الكتاب الذي يعد فريد من نواح عديدة. حيث إننا اتخذنا أسلوبا متعدد الاختصاصات، وتعاونا مع أكاديميين وباحثين مرموقين من أنحاء العالم، وقد يوجد في بعض الحالات عدم اتفاق على طريقة وصف تحديات طب الكوارث أو مقاربتها، وبدلا من تقديم وجهة نظر واحدة نقدم مقاربة متوازنة مزودة بأفضل العلوم لدعم كل من وجهات النظر، وقد قدمنا من خلال هذا البناء وجهات نظر عالمية.
BOOK
Multi-functional genome-wide CRISPR system for high throughput genotype–phenotype mapping
Genome-scale engineering is an indispensable tool to understand genome functions due to our limited knowledge of cellular networks. Unfortunately, most existing methods for genome-wide genotype–phenotype mapping are limited to a single mode of genomic alteration, i.e. overexpression, repression, or deletion. Here we report a multi-functional genome-wide CRISPR (MAGIC) system to precisely control the expression level of defined genes to desired levels throughout the whole genome. By combining the tri-functional CRISPR system and array-synthesized oligo pools, MAGIC is used to create, to the best of our knowledge, one of the most comprehensive and diversified genomic libraries in yeast ever reported. The power of MAGIC is demonstrated by the identification of previously uncharacterized genetic determinants of complex phenotypes, particularly those having synergistic interactions when perturbed to different expression levels. MAGIC represents a powerful synthetic biology tool to investigate fundamental biological questions as well as engineer complex phenotypes for biotechnological applications.
Genome-scale engineering is generally limited to single methods of alteration such as overexpression, repression or deletion. Here the authors present a tri-functional CRISPR system that can engineer complex synergistic interactions in a genome-wide manner.
Journal Article
Structural and functional differences in the cingulate cortex relate to disease severity in anorexia nervosa
The dysfunction of specific brain areas might account for the distortion of body image in patients with anorexia nervosa. The present study was designed to reveal brain regions that are abnormal in structure and function in patients with this disorder. We hypothesized, based on brain areas of altered activity in patients with anorexia nervosa and regions involved in pain processing, an interrelation of structural aberrations in the frontoparietal–cingulate network and aberrant functional activation during thermal pain processing in patients with the disorder.
We determined pain thresholds outside the MRI scanner in patients with anorexia nervosa and matched healthy controls. Thereafter, thermal pain stimuli were applied during fMRI imaging. Structural analyses with high-resolution structural T1-weighted volumes were performed using voxel-based morphometry and a surface-based approach.
Twenty-six patients and 26 controls participated in our study, and owing to technical difficulties, 15 participants in each group were included in our fMRI analysis. Structural analyses revealed significantly decreased grey matter volume and cortical thickness in the frontoparietal–cingulate network in patients with anorexia nervosa. We detected an increased blood oxygen level–dependent signal in patients during the painful 45°C condition in the midcingulate and posterior cingulate cortex, which positively correlated with increased pain thresholds. Decreased grey matter and cortical thickness correlated negatively with pain thresholds, symptom severity and illness duration, but not with body mass index.
The lack of a specific quantification of body image distortion is a limitation of our study.
This study provides further evidence for confined structural and functional brain abnormalities in patients with anorexia nervosa in brain regions that are involved in perception and integration of bodily stimuli. The association of structural and functional deviations with thermal thresholds as well as with clinical characteristics might indicate a common neuronal origin.
Journal Article
The Low Dose Colchicine after Myocardial Infarction (LoDoCo-MI) study: A pilot randomized placebo controlled trial of colchicine following acute myocardial infarction
Following an acute myocardial infarction (MI), patients with persistently elevated biomarkers of inflammation, in particular C-reactive protein (CRP), are at significantly increased risk of further cardiovascular events. Colchicine is a unique anti-inflammatory medication that has shown promise in reducing such events in patients with stable coronary heart disease. The current study tested the ability of low dose colchicine to reduce CRP levels at 30 days after an acute MI, a key marker of future outcome, and its safety and tolerability in this setting.
We conducted a randomized, double-blind, trial of low-dose colchicine (0.5 mg daily) or matching placebo in 237 patients admitted with an acute MI. The primary end-point was the proportion of patients with a residual high sensitivity CRP level ≥2 mg/L after 30 days of treatment, a threshold associated with a worse prognosis.
At 30-day follow-up, 44% of patients treated with colchicine had a CRP level ≥2 mg/L compared to 50% of those randomized to placebo (P = .35) and the median CRP in patients randomized to colchicine was 1.6 mg/L (interquartile range [IQR] 0.7–3.5) compared to 2.0 mg/L (IQR 0.9–4.0) in patients randomized to placebo (P = .11). The median absolute reduction in CRP levels was −4.3 mg/L (IQR −1.1 to −14.1) among colchicine treated patients and −3.3 mg/L (IQR −0.9 to −14.4, P = .44) in placebo treated patients. The relative reduction was a fall of 78% compared to a fall of 64% (P = .09). Low dose colchicine was well tolerated and did not reduce compliance with other secondary preventative medications at 30-days.
Treatment with low dose colchicine was safe and well tolerated, but was not associated with a significantly increased likelihood of achieving a CRP level <2 mg/L or lower absolute levels of CRP 30 days after an acute MI.
Journal Article
Is breast arterial calcification associated with coronary artery disease?—A systematic review and meta-analysis
There is increasing evidence that breast arterial calcification (BAC), an incidental finding on 3-29% of mammograms, could be used to screen for coronary artery disease (CAD). We conducted a systematic review to assess the associations between BAC and CAD and its risk factors (hypertension, hypercholesterolemia, diabetes mellitus and smoking). MEDLINE and EMBASE databases and references of relevant papers were searched up to 18 February 2020 for English language studies that evaluated the associations of BAC and CAD and its risk factors. A single reviewer extracted all data and assessed study quality with verification by another independent reviewer, if required. Across 31 studies (n = 35,583; 3 longitudinal and 28 cross-sectional studies) that examined the association of BAC and CAD, the OR was 2.61 (95% CI 2.12-3.21; I.sup.2 = 71%). Sub-analysis of studies that graded BAC severity using the 4- (4 studies) or 12-point scale systems (3 studies) revealed an association with CAD and moderate-severe BAC (OR 4.83 (95%CI 1.50-15.54) and OR 2.95 (95%CI 1.49-5.84), respectively) but not mild BAC (OR 2.04 (95%CI 0.82-5.05) and OR 1.08 (95%CI 0.42-2.75), respectively). BAC was associated with hypertension (42 studies; n = 32,646; OR 1.80; 95% CI 1.47-2.21; I.sup.2 = 85%) and diabetes mellitus (51 studies; n = 53,464; OR 2.17; 95% CI 1.82-2.59; I.sup.2 = 75%) but not with hypercholesterolemia (OR 1.31; 95%CI 0.97-1.77; I.sup.2 = 67%). Smoking was inversely associated with BAC (35 studies; n = 40,002; OR 0.54; 95% CI 0.42-0.70; I.sup.2 = 83%). Studies mostly included symptomatic women. Marked heterogeneity existed and publication bias may be present. BAC is associated with CAD, diabetes mellitus and hypertension and inversely associated with smoking. Whether BAC could screen for CAD cannot be determined from current published data due to the lack of larger prospective studies. A consensus approach to quantifying BAC may also facilitate further translation into clinical care. PROSPERO: CRD42020141644.
Journal Article
Metabolic engineering of Rhodotorula toruloides IFO0880 improves C16 and C18 fatty alcohol production from synthetic media
Background
The oleaginous, carotenogenic yeast
Rhodotorula toruloides
has been increasingly explored as a platform organism for the production of terpenoids and fatty acid derivatives. Fatty alcohols, a fatty acid derivative widely used in the production of detergents and surfactants, can be produced microbially with the expression of a heterologous fatty acyl-CoA reductase. Due to its high lipid production,
R. toruloides
has high potential for fatty alcohol production, and in this study several metabolic engineering approaches were investigated to improve the titer of this product.
Results
Fatty acyl-CoA reductase from
Marinobacter aqueolei
was co-expressed with SpCas9 in
R. toruloides
IFO0880 and a panel of gene overexpressions and Cas9-mediated gene deletions were explored to increase the fatty alcohol production. Two overexpression targets (
ACL1
and
ACC1
, improving cytosolic acetyl-CoA and malonyl-CoA production, respectively) and two deletion targets (the acyltransferases
DGA1
and
LRO1
) resulted in significant (1.8 to 4.4-fold) increases to the fatty alcohol titer in culture tubes. Combinatorial exploration of these modifications in bioreactor fermentation culminated in a 3.7 g/L fatty alcohol titer in the
LRO1
Δ mutant. As
LRO1
deletion was not found to be beneficial for fatty alcohol production in other yeasts, a lipidomic comparison of the
DGA1
and
LRO1
knockout mutants was performed, finding that
DGA1
is the primary acyltransferase responsible for triacylglyceride production in
R. toruloides
, while
LRO1
disruption simultaneously improved fatty alcohol production, increased diacylglyceride and triacylglyceride production, and increased glucose consumption.
Conclusions
The fatty alcohol titer of fatty acyl-CoA reductase-expressing
R. toruloides
was significantly improved through the deletion of
LRO1
, or the deletion of
DGA1
combined with overexpression of
ACC1
and
ACL1
. Disruption of
LRO1
surprisingly increased both lipid and fatty alcohol production, creating a possible avenue for future study of the lipid metabolism of this yeast.
Journal Article
The Risk of Cancer from CT Scans and Other Sources of Low-Dose Radiation: A Critical Appraisal of Methodologic Quality
Concern exists that radiation exposure from computerized tomography (CT) will cause thousands of malignancies. Other experts share the same perspective regarding the risk from additional sources of low-dose ionizing radiation, such as the releases from Three Mile Island (1979; Pennsylvania USA) and Fukushima (2011; Okuma, Fukushima Prefecture, Japan) nuclear power plant disasters. If this premise is false, the fear of cancer leading patients and physicians to avoid CT scans and disaster responders to initiate forced evacuations is unfounded.
This investigation provides a quantitative evaluation of the methodologic quality of studies to determine the evidentiary strength supporting or refuting a causal relationship between low-dose radiation and cancer. It will assess the number of higher quality studies that support or question the role of low-dose radiation in oncogenesis.
This investigation is a systematic, methodologic review of articles published from 1975-2017 examining cancer risk from external low-dose x-ray and gamma radiation, defined as less than 200 millisievert (mSv). Following the PRISMA guidelines, the authors performed a search of the PubMed, Cochrane, Scopus, and Web of Science databases. Methodologies of selected articles were scored using the Newcastle Ottawa Scale (NOS) and a tool identifying 11 lower quality indicators. Manuscript methodologies were ranked as higher quality if they scored no lower than seven out of nine on the NOS and contained no more than two lower quality indicators. Investigators then characterized articles as supporting or not supporting a causal relationship between low-dose radiation and cancer.
Investigators identified 4,382 articles for initial review. A total of 62 articles met all inclusion/exclusion criteria and were evaluated in this study. Quantitative evaluation of the manuscripts' methodologic strengths found 25 studies met higher quality criteria while 37 studies met lower quality criteria. Of the 25 studies with higher quality methods, 21 out of 25 did not support cancer induction by low-dose radiation (P = .0003).
A clear preponderance of articles with higher quality methods found no increased risk of cancer from low-dose radiation. The evidence suggests that exposure to multiple CT scans and other sources of low-dose radiation with a cumulative dose up to 100 mSv (approximately 10 scans), and possibly as high as 200 mSv (approximately 20 scans), does not increase cancer risk.
Journal Article
Characteristics and Outcomes of Young Patients With ST-Elevation Myocardial Infarction Without Standard Modifiable Risk Factors
Patients with ST-elevation myocardial infarction (STEMI) with no standard modifiable risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, and smoking) have worse short-term mortality than those with SMuRFs. Whether this association extends to younger patients is unclear. A retrospective cohort study was performed of patients aged 18 to 45 years with STEMI at 3 Australian hospitals between 2010 and 2020. Nonatherosclerotic causes of STEMI were excluded. The primary outcome was 30-day all-cause mortality. Secondary outcomes included 1 and 2-year mortality. Cox proportional hazards analysis was used. Of 597 patients, the median age was 42 (interquartile range 38 to 44) years, 85.1% were men and 8.4% were SMuRF-less. Patients who are SMuRF-less were >2 times more likely to have cardiac arrest (28.0% vs 12.6%, p = 0.003); require vasopressors (16.0% vs 6.8%, p = 0.018), mechanical support (10.0% vs 2.3%, p = 0.046), or intensive care admission (20.0% vs 5.7%, p <0.001); and have higher rate of left anterior descending artery infarcts than those with SMuRFs (62.0% vs 47.2%, p = 0.045). No significant differences in thrombolysis or percutaneous intervention were observed. Guideline-directed medical therapy at discharge was high (>90%), and not different in the SMuRF-less. 30-day mortality was almost fivefold higher in the SMuRF-less (hazard ratio 4.70, 95% confidence interval 1.66 to 13.35, p = 0.004), remaining significant at 1 and 2 years. In conclusion, young patients who are SMuRF-less have a higher 30-day mortality after STEMI than their counterparts with SMuRFs. This may be partially mediated by higher rates of cardiac arrest and left anterior descending artery territory events. These findings further highlight the need for improved prevention and management of SMuRF-less STEMI.
Journal Article
Cruciferous vegetables lower blood pressure in adults with mildly elevated blood pressure in a randomized, controlled, crossover trial: the VEgetableS for vaScular hEaLth (VESSEL) study
Background
Higher cruciferous vegetable intake is associated with lower cardiovascular disease risk in observational studies. The pathways involved remain uncertain. We aimed to determine whether cruciferous vegetable intake (active) lowers 24-h brachial systolic blood pressure (SBP; primary outcome) compared to root and squash vegetables (control) in Australian adults with mildly elevated BP (SBP 120–160 mmHg inclusive).
Methods
In this randomized, controlled, crossover trial, participants completed two 2-week dietary interventions separated by a 2-week washout. Cruciferous vegetables were compared to root and squash vegetables (~ 300 g/day) consumed with lunch and dinner meals. Participants were blinded to which interventions were the active and control. Adherence was assessed using food diaries and biomarkers (S-methyl cysteine sulfoxide (SMCSO, active) and carotenoids (control)). Twenty-four-hour brachial ambulatory SBP and secondary outcomes were assessed pre- and post each intervention. Differences were tested using linear mixed effects regression.
Results
Eighteen participants were recruited (median (IQR) age: 68 (66–70); female:
n
= 16/18; mean ± SD clinic SBP: 135.9 ± 10.0 mmHg). For both interventions, 72% participants had 100% adherence (IQR: 96.4–100%). SMCSO and carotenoids were significantly different between interventions (mean difference active vs. control SMCSO: 22.93 mg/mL, 95%CI 15.62, 30.23,
P
< 0.0001; carotenoids: − 0.974 mg/mL, 95%CI − 1.525, − 0.423,
P
= 0.001). Twenty-four-hour brachial SBP was significantly reduced following the active vs. control (mean difference − 2.5 mmHg, 95%CI − 4.2, − 0.9,
P
= 0.002; active pre: 126.8 ± 12.6 mmHg, post: 124.4 ± 11.8 mmHg; control pre: 125.5 ± 12.1 mmHg, post: 124.8 ± 13.1 mmHg,
n
= 17), driven by daytime SBP (mean difference − 3.6 mmHg, 95%CI − 5.4, − 1.7,
P
< 0.001). Serum triglycerides were significantly lower following the active vs. control (mean difference − 0.2 mmol/L, 95%CI − 0.4, − 0.0,
P
= 0.047).
Conclusions
Increased intake of cruciferous vegetables resulted in reduced SBP compared to root and squash vegetables. Future research is needed to determine whether targeted recommendations for increasing cruciferous vegetable intake benefits population health.
Trial registration
Clinical trial registry ACTRN12619001294145.
https://www.anzctr.org.au
Journal Article