Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale.

BACKGROUND: Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury. METHODS: Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively. RESULTS: In VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls. CONCLUSIONS: UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.

Detection and diagnosis of posterior circulation calcification: An interobserver agreement study.

Background: Posterior cerebral ischemic stroke and its underlying causes can be easily misdiagnosed in routine practice. Therefore, more than a third of positive cases can be easily missed during routine CT image reporting unless expert neuroimaging radiologists carefully report it. Objective: To assess the inter-rater agreement level between senior residents and general radiologists and a specialized expert neuroradiologist when detecting and diagnosing posterior cerebral circulation calcification. Methods: This was a cross-sectional observational study. A total of fifteen senior radiology residents (SRRs) and fifteen general radiologists (GRs) at four different hospitals in Riyadh, Saudi Arabia, were included in the study. A total of four CT-scanned brain cases with the presence of posterior circulation calcification (PCC) with different degrees of severity and one brain case with negative PCC were selected. These cases were predefined by expert neuroradiologists at our center. The cases were uploaded into the picture archiving and communication systems (PACS) at four different centers as outsider cases. These cases were then randomly assigned to the participating SRRs and GRs for reporting. All radiologists were blinded to the findings of the cases. Inter-observer agreement was assessed using the weighted kappa coefficient of agreement (k) between the two groups. Results: The cerebral calcification misdiagnosis rate for the SRRs and GRs was > 93% for most of the positive cases. There was 1) poor inter-observer agreement between the SRRs and GRs for the detection of severe posterior cerebral calcification(PCC) in a negative stroke case (agreement for misdiagnosis, k = 0.93; correct diagnosis, k = 0.00), 2) poor inter-observer agreement for mild PCC in a negative stroke case (agreement for misdiagnosis, k = 0.93; correct diagnosis, k = 0.00), 3) moderate PCC in a positive posterior stroke case (agreement for misdiagnosis, k = 0.92; correct diagnosis, k = 0.00), and 4) poor interobserver agreement for severe PCC in a positive posterior cerebral stroke case (agreement for misdiagnosis, k = 0.846; correct diagnosis, k = 0.00). There was excellent agreement between the SRRs and GRs when reporting negative cases of PCC and stroke. Conclusion: Our study concluded that most of the SRRs and GRs missed the diagnosis of posterior cerebral calcification in the presented cases.

Assessment of Patient Knowledge Level Towards MRI Safety Before the Scanning in Saudi Arabia.

Purpose: Magnetic resonance imaging (MRI) is an important diagnostic method in modern clinical medicine. Patients' knowledge about MRI is of utmost importance for optimizing the workflow, safety, and patient comfort and saving valuable time for the MRI department. This study investigates patient knowledge levels regarding MRI safety before an MRI examination. Patients and Methods: A cross-sectional survey was completed by 200 patients who required MRI. Recruitment occurred over eight weeks in governmental and private hospitals in Saudi Arabia; both hospitals and participants were selected randomly. The questionnaire was given to the patients prior to their MRI scans. Descriptive statistics and chi-square tests were performed to identify relationships between knowledge of MRI safety and selected demographic groupings (age, gender, education level, income level). It also evaluates their source of information and assesses the patient's previous experience regarding MRI scans. . Results: The study sample consisted of 200 patients from 230 surveys distributed in Saudi Arabia, and the response rate was ~ 87%. Depending on the P-values of the chi-square statistical test to find the relationship between socio-demographic factors and patient' knowledge level, the results showed a significant association (p-value=0.006) between age and gender and the level of knowledge relating to MRI safety issues. A similar significance (p-value=0.042) is observed between the knowledge level of patients and their educational level and annual income. In addition, a highly significant association (p-value<0.001) is found between education level or previous experience and whether people seek information about MRI safety. Conclusion: The study findings suggest that a complex combination of factors affects patient knowledge regarding MRI safety before an MRI examination. Hence, the hospital and radiological department must provide the patient with accurate information about MRI. .

Investigating Pathways of Ventilation Induced Brain Injury on Cerebral White Matter Inflammation and Injury After 24 h in Preterm Lambs.

Initiation of respiratory support in the delivery room increases the risk and severity of brain injury in preterm neonates through two major pathways: an inflammatory pathway and a haemodynamic pathway. The relative contribution of each pathway on preterm brain injury is not known. We aimed to assess the role of the inflammatory and haemodynamic pathway on ventilation-induced brain injury (VIBI) in the preterm lamb. Fetal lambs (125 ± 1 day gestation) were exteriorised, instrumented and ventilated with a high tidal-volume (VT) injurious strategy for 15 min either with placental circulation intact to induce the inflammatory pathway only (INJINF; n = 7) or umbilical cord occluded to induce both the inflammatory and haemodynamic pathways (INJINF+HAE; n = 7). Sham controls were exteriorised but not ventilated (SHAM; n = 5) while unoperated controls (UNOP; n = 7) did not undergo fetal instrumentation. Fetuses were returned in utero following intervention and the ewe allowed to recover. Arterial blood gases and plasma were sampled periodically. Twenty-four hours following intervention, lambs were delivered and maintained on non-injurious ventilation for ∼40 min then brains were collected post-mortem for immunohistochemistry and RT-qPCR to assess inflammation, vascular pathology and cell death within white matter regions. Compared to INJINF lambs, INJINF+HAE lambs achieved a consistently higher VT during injurious ventilation and carotid blood flow was significantly lower than baseline by the end of ventilation. Throughout the 24 h recovery period, systemic arterial IL-6 levels of INJINF+HAE lambs were significantly higher than SHAM while there was no difference between INJINF and SHAM animals. At 24 h, mRNA expression levels of pro-inflammatory cytokines, tight junction proteins, markers of cell death, and histological injury indices of gliosis, blood vessel protein extravasation, oligodendrocyte injury and cell death were not different between groups. Injurious ventilation, irrespective of strategy, did not increase brain inflammation or injury 24 h later when compared to control animals. However, the haemodynamic pathway did influence carotid blood flow adaptations during injurious ventilation and increased systemic arterial IL-6 that may underlie long-term pathology. Future studies are required to further characterise the pathways and their long-term effects on VIBI.

Assessment Awareness of Public About Breast Cancer and its Screening Measurements in Asir Region, KSA.

Breast cancer (BC) has a major impact on women's health worldwide. The Kingdom of Saudi Arabia is no exception, where it is considered the most common malignancy, embodying the second leading cause of cancer deaths after lung cancer. In today's world, people are more health conscious and more aware of different medical specialties. Despite the tremendous advancements in education, there seems to be a limited knowledge among the public regarding this issue. Various studies have been conducted in many regions to determine the perception/awareness about breast cancer. The present study is of the first of its type in our region, assessing the awareness of the public about breast cancer and its screening measurements. As per our knowledge, there is no study that estimated the awareness of breast cancer and its screening measurements among the public in the Asir region. Therefore, this study aims to estimate the awareness of breast cancer and its screening measurements among public and assess the knowledge about Breast Self-Examination (BSE) and their opinion about its effectiveness in early diagnosis of breast cancer to detect the relationship between awareness and socioeconomic status. This study is a cross-sectional prospective study, with a sample of 1046 participants aged between 12 and 80 years (male and female) from the Asir region evaluated by questionnaire after attaining consent. The selection of participants was based on the simple random sampling method. The majority of participants were of age 20 to less than 30 years (56.9%). About half of them were males (52.7%). The majority was single (61.2%). Most of them (74.0%) have a high education level (University and more). About one-third of the participants (32.7%) worked in the medical field, and most of them worked in the non-medical field (46.6%). Regarding general knowledge, the score was 60.2%, which represented a relatively good knowledge. The overall knowledge regarding breast cancer as recorded by our population reported that only 18.8% had good knowledge. Participants of this resettlement colony have poor knowledge about breast cancer, be it about risk factors, signs, and symptoms, or early detection procedures, where the overall knowledge score was only 18.8%.

Correction to: Assessment Awareness of Public About Breast Cancer and its Screening Measurements in Asir Region, KSA.

[This corrects the article DOI: 10.1007/s13193-019-00899-5.].

Diffusion tensor imaging detects ventilation-induced brain injury in preterm lambs.

PURPOSE: Injurious mechanical ventilation causes white matter (WM) injury in preterm infants through inflammatory and haemodynamic pathways. The relative contribution of each of these pathways is not known. We hypothesised that in vivo magnetic resonance imaging (MRI) can detect WM brain injury resulting from mechanical ventilation 24 h after preterm delivery. Further we hypothesised that the combination of inflammatory and haemodynamic pathways, induced by umbilical cord occlusion (UCO) increases brain injury at 24 h. METHODS: Fetuses at 124±2 days gestation were exposed, instrumented and either ventilated for 15 min using a high tidal-volume (VT) injurious strategy with the umbilical cord intact (INJ; inflammatory pathway only), or occluded (INJ+UCO; inflammatory and haemodynamic pathway). The ventilation groups were compared to lambs that underwent surgery but were not ventilated (Sham), and lambs that did not undergo surgery (unoperated control; Cont). Fetuses were placed back in utero after the 15 min intervention and ewes recovered. Twenty-four hours later, lambs were delivered, placed on a protective ventilation strategy, and underwent MRI of the brain using structural, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) techniques. RESULTS: Absolute MRS concentrations of creatine and choline were significantly decreased in INJ+UCO compared to Cont lambs (P = 0.03, P = 0.009, respectively); no significant differences were detected between the INJ or Sham groups and the Cont group. Axial diffusivities in the internal capsule and frontal WM were lower in INJ and INJ+UCO compared to Cont lambs (P = 0.05, P = 0.04, respectively). Lambs in the INJ and INJ+UCO groups had lower mean diffusivities in the frontal WM compared to Cont group (P = 0.04). DTI colour mapping revealed lower diffusivity in specific WM regions in the Sham, INJ, and INJ+UCO groups compared to the Cont group, but the differences did not reach significance. INJ+UCO lambs more likely to exhibit lower WM diffusivity than INJ lambs. CONCLUSIONS: Twenty-four hours after injurious ventilation, DTI and MRS showed increased brain injury in the injuriously ventilated lambs compared to controls. DTI colour mapping threshold approach provides evidence that the haemodynamic and inflammatory pathways have additive effects on the progression of brain injury compared to the inflammatory pathway alone.

Diffusion Tensor Imaging Colour Mapping Threshold for Identification of Ventilation-Induced Brain Injury after Intrauterine Inflammation in Preterm Lambs.

PURPOSE: The aim of this study is to examine whether advanced magnetic resonance imaging (MRI) techniques can detect early brain injury caused by intrauterine inflammation and inappropriate initial respiratory support in preterm lambs. HYPOTHESIS: Neuropathology caused by intrauterine inflammation is exacerbated by mechanical ventilation at birth and is detectable with advanced MRI techniques. METHODS: Pregnant ewes received intra-amniotic lipopolysaccharide (LPS) 7 days prior to delivery at ~125 days of gestation (85% of gestation), whereupon lambs were delivered and randomised to receive an injurious (LPS + INJ, n = 6) or protective (LPS + PROT, n = 6) ventilation strategy. MRI of the brain was conducted 90 min after preterm delivery, using structural, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) techniques. A colour map threshold technique was utilised to compare distributions of low diffusivity voxels in the brains of LPS-exposed lambs with those not exposed to LPS (PROT, n = 7 PROT and INJ, n = 10). RESULTS: No overt cerebral injury was identified on structural MRI images of any lamb. However, on DTI, axial diffusivity, radial diffusivity, and mean diffusivity values were lower and significantly more heterogeneous in specific brain regions of lambs in the LPS + INJ group compared to the LPS + PROT group. Colour mapping revealed lower diffusivity in the thalamus, periventricular white matter, internal capsule, and frontal white matter in the LPS + INJ group compared to LPS + PROT group. The MRS peak area ratios of lactate, relative to those for the metabolites creatine, choline, and N-acetylaspartate, were not different between LPS-exposed groups. Lambs exposed to LPS had lower diffusivity within the white matter regions assessed than non-LPS-treated control lambs. CONCLUSION: DTI colour map threshold techniques detected early brain injury in preterm lambs exposed to intrauterine inflammation and detected differences between injurious and protective ventilation strategies. DTI mapping approaches are potentially useful for early detection of subtle brain injury in premature infants.