Maternal malnutrition during pregnancy impacts fetal growth, with developmental consequences that extend to later life outcomes. In underdeveloped countries, this malnutrition typically takes the ...form of poor dietary protein content and quality, even if adequate calories are consumed. Here, we report the establishment of a nonhuman primate model of gestational protein restriction (PR) in order to understand how placental function and pregnancy outcomes are affected by protein deficiency. Rhesus macaques were assigned to either a control diet containing 26% protein or switched to a 13% PR diet prior to conception and maintained on this PR diet throughout pregnancy. Standard fetal biometry, Doppler ultrasound of uteroplacental blood flow, ultrasound-guided amniocentesis, and contrast-enhanced ultrasound (CE-US) to assess placental perfusion were performed mid-gestation (gestational day 85 G85 where term is G168) and in the early third trimester (G135). Our data demonstrate that a 50% reduction in dietary protein throughout gestation results in reduced placental perfusion, fetal growth restriction, and a 50% rate of pregnancy loss. In addition, we demonstrate reduced total protein content and evidence of fetal hypoxia in the amniotic fluid. This report highlights the use of CE-US for in vivo assessment of placental vascular function. The ability to detect placental dysfunction, and thus a compromised pregnancy, early in gestation, may facilitate the development of interventional strategies to optimize clinical care and improve long-term offspring outcomes, which are future areas of study in this new model.
To assess cross-sectional associations of neurofibrillary tangles, measured by tau-PET, with cognitive performance in cognitively unimpaired (CU) adults.
Tau- and amyloid-PET were performed in 579 CU ...participants aged 50-98 from the population-based Mayo Clinic Study of Aging. Associations between tau-PET signal in 43 brain regions and cognitive test scores were assessed using penalized linear regression. In additional models, participants were classified by normal/abnormal global amyloid-PET (A+/A-) and normal/abnormal regional tau-PET (T+/T-). Regional tau-PET cutpoints were defined as standardized uptake value ratio (SUVR) greater than the 95th percentile of tau-PET SUVR in that region among 117 CU participants aged 30-49.
Higher tau-PET signal was associated with poorer memory performance in all medial temporal lobe (MTL) regions and also in the middle temporal pole and frontal olfactory regions. The largest association with tau-PET and memory
scores was seen in the entorhinal cortex; this association was independent of tau-PET signal in other brain regions. Tau-PET in the entorhinal cortex was also associated with poorer global and language performance. In the entorhinal cortex, T+ was associated with lower memory performance among both A- and A+.
Tau deposition in MTL regions, as reflected by tau-PET signal, was associated with poorer performance on memory tests in CU participants. The association with entorhinal cortex tau-PET was independent of tau-PET signal in other brain regions. Longitudinal studies are needed to understand the fate of CU participants with elevated medial temporal tau-PET signal.
Levels of insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, and their ratio in the blood may be useful for monitoring those at risk of cognitive and functional decline. However, the ...association between IGF measures and functional and cognitive outcomes has been mixed, and the associations may vary by sex. The present study investigated the cross-sectional, sex-specific associations between serum measures total IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio, gait speed, and cognition in 1320 cognitively unimpaired participants aged 50–95 years enrolled in the Mayo Clinic Study of Aging. We used multivariable linear regression models to determine the association between IGF measures and gait speed or cognitive test performance by sex. IGF measures were not associated with cognitive or functional performance among men. Among women, higher levels of log total IGF-1 and IGFBP-3 were associated with better performance in attention, visuospatial, and global cognitive domains, independent of the gait speed. These findings suggest that among women, IGF measures are associated with cognition, and these associations are independent of function.
The warm conveyor belt (WCB), the major cloud‐forming airstream of midlatitude cyclones, is the primary mechanism for rapidly transporting air pollution from one continent to another. However, ...relatively little has been written on WCB transport across the North Pacific Ocean. To address this important intercontinental transport route, this study describes the life cycle of a WCB associated with the export of a highly polluted air mass from Asia to North America. This event was sampled using in situ measurements from an aircraft platform flying above the North American West Coast during the 2002 Intercontinental Transport and Chemical Transformation (ITCT 2K2) experiment on 5 May. Satellite imagery, trajectory ensembles, in situ measurements, and animations are used to illustrate the formation of the WCB near eastern Asia, its entrainment of polluted air masses, its transport path across the Pacific, and its decay above the eastern North Pacific Ocean and western North America. A major finding is that a WCB can entrain air from a variety of source regions and not just the atmospheric boundary layer. We estimate that 8% of the WCB's mass originated in the stratosphere and 44% passed through the lower troposphere, of which two thirds passed through the lower troposphere above the populated regions of eastern Asia. The remaining 48% traveled entirely within the middle and upper troposphere over the previous 5.5 days. Interestingly, an estimated 18% of the WCB's mass was entrained from an upwind and decaying WCB via a newly discovered but apparently common transport mechanism. Only 9% of the WCB's mass subsequently passed through the lower troposphere of the United States, with the remainder passing over North America in the middle and upper troposphere.
The placenta is a vital organ necessary for healthy fetal development. Placental insufficiency creates an in utero environment where the fetus is at risk of insufficient oxygen or nutrient exchange. ...This is primarily caused by impairment of either maternal or fetal circulation or vascular thrombosis such as placental infarction. As a result of placental dysfunction, affected fetuses may be growth restricted, neurologically impaired, and at risk of increased morbidity and mortality. In a cohort of 4 pregnant Rhesus macaques, we describe antenatal detection of naturally occurring intrauterine growth restriction (IUGR) and aberrant fetal neurodevelopment in 1 animal. Abnormal growth parameters were detected by Doppler ultrasound, and vascular insufficiency in the intervillous space was characterized by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Furthermore, placental oxygen reserve was shown to be reduced compared to control animals by measurements of placental water T
*. To characterize the effects of IUGR on fetal brain development, T
and diffusion anisotropy images of the fetal brain were acquired in utero. Reduced brain volume and cerebral cortical surface area were apparent macroscopically. Microstructural abnormalities within the developing white matter and cerebral cortex were also observed through analysis of water diffusion anisotropy. After delivery by cesarean section, pathological examination confirmed placental insufficiency with hypoxia. These findings exemplify how DCE-MRI and T
*-based measurements of blood oxygenation within the placenta can provide noninvasive imaging methods for assessing in vivo placental health to potentially identify pregnancies affected by placental insufficiency and abnormal fetal neurodevelopment prior to the onset of fetal and neonatal distress.
Patients surviving ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) are at a high risk of death due to a recurrence of arrhythmia. The implantable cardioverter defibrillator ...(ICD) terminates VT or VF, but it is not known whether this device prolongs life in these patients compared with medical therapy with amiodarone.
A total of 659 patients with resuscitated VF or VT or with unmonitored syncope were randomly assigned to treatment with the ICD or with amiodarone. The primary outcome measure was all-cause mortality, and the secondary outcome was arrhythmic death. A total of 328 patients were randomized to receive an ICD. A thoracotomy was done in 33, no ICD was implanted in 18, and the rest had a nonthoracotomy ICD. All 331 patients randomized to amiodarone received it initially. At 5 years, 85.4% of patients assigned to amiodarone were still receiving it at a mean dose of 255 mg/day, 28.1% of ICD patients were also receiving amiodarone, and 21.4% of amiodarone patients had received an ICD. A nonsignificant reduction in the risk of death was observed with the ICD, from 10.2% per year to 8.3% per year (19.7% relative risk reduction; 95% confidence interval, -7.7% to 40%; P=0.142). A nonsignificant reduction in the risk of arrhythmic death was observed, from 4.5% per year to 3.0% per year (32.8% relative risk reduction; 95% confidence interval, -7.2% to 57.8%; P=0.094).
A 20% relative risk reduction occurred in all-cause mortality and a 33% reduction occurred in arrhythmic mortality with ICD therapy compared with amiodarone; this reduction did not reach statistical significance.
Fluoroquinolones have been, and continue to be, routinely used for treatment of many bacterial infections. In recent years, most parts of the world have reported an increasing trend of ...fluoroquinolone resistant (FQR) Gram-negative bacteria.
A cross-sectional study was conducted between March 2017 and July 2018 among children admitted due to fever to referral hospitals in Dar es Salaam, Tanzania. Rectal swabs were used to screen for carriage of extended-spectrum β-lactamase-producing Enterobacterales (ESBL-PE). ESBL-PE isolates were tested for quinolone resistance by disk diffusion method. Randomly selected fluroquinolone resistant isolates were characterized by using whole genome sequencing.
A total of 142 ESBL-PE archived isolates were tested for fluoroquinolone resistance. Overall phenotypic resistance to ciprofloxacin, levofloxacin and moxifloxacin was found in 68% (97/142). The highest resistance rate was seen among Citrobacter spp. (100%, 5/5), followed by Klebsiella. pneumoniae (76.1%; 35/46), Escherichia coli (65.6%; 42/64) and Enterobacter spp. (31.9%; 15/47). Whole genome sequencing (WGS) was performed on 42 fluoroquinolone resistant-ESBL producing isolates and revealed that 38/42; or 90.5%, of the isolates carried one or more plasmid mediated quinolone resistance (PMQR) genes. The most frequent PMQR genes were aac(6')-lb-cr (74%; 31/42), followed by qnrB1 (40%; 17/42), oqx, qnrB6 and qnS1. Chromosomal mutations in gyrA, parC and parE were detected among 19/42 isolates, and all were in E. coli. Most of the E. coli isolates (17/20) had high MIC values of > 32 µg/ml for fluoroquinolones. In these strains, multiple chromosomal mutations were detected, and all except three strains had additional PMQR genes. Sequence types, ST131 and ST617 predominated among E. coli isolates, while ST607 was more common out of 12 sequence types detected among the K. pneumoniae. Fluoroquinolone resistance genes were mostly associated with the IncF plasmids.
The ESBL-PE isolates showed high rates of phenotypic resistance towards fluoroquinolones likely mediated by both chromosomal mutations and PMQR genes. Chromosomal mutations with or without the presence of PMQR were associated with high MIC values in these bacteria strains. We also found a diversity of PMQR genes, sequence types, virulence genes, and plasmid located antimicrobial resistance (AMR) genes towards other antimicrobial agents.
Background
The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the ...development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost‐effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis.
Methods
We searched nine international biomedical databases for published, in‐progress, and unpublished evidence. Studies were independently screened by two reviewers against predefined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication, and combined symptom and medication scores. Secondary outcomes of interest included cost‐effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random‐effects meta‐analyses.
Results
We identified 5960 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD −0.53, 95% CI −0.63, −0.42), medication (SMD −0.37, 95% CI −0.49, −0.26), and combined symptom and medication (SMD −0.49, 95% CI −0.69, −0.30) scores while on treatment that were robust to prespecified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post‐discontinuation of AIT, suggesting a benefit in relation to symptom scores.
Conclusions
AIT is effective in improving symptom, medication, and combined symptom and medication scores in patients with allergic rhinoconjunctivitis while on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy.
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