Oxygen-enhanced MRI detects incidence, onset and heterogeneity of radiation-induced hypoxia modification in HPV-associated oropharyngeal cancer.

PURPOSE: Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced (OE)-MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in HPV-associated oropharyngeal head and neck squamous cell cancer (HNSCC). EXPERIMENTAL DESIGN: 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy then at weeks 2 and 4 (W2, W4) into therapy. Two pre-treatment scans assessed biomarker within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modelling. Responding lesions were identified by comparing HVMRI change to RC limits of agreement (LOA). RESULTS: OE-MRI identified hypoxia in all lesions. HVMRI wCV was 24.6% and RC LOA were -45.7% to 84.1%. Cohort median pre-treatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both p < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients. CONCLUSIONS: Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in HPV-associated oropharyngeal carcinoma.

A systematic review of 4D magnetic resonance imaging techniques for abdominal radiotherapy treatment planning.

Background and purpose: Four-dimensional magnetic resonance imaging (4DMRI) has gained interest as an alternative to the current standard for motion management four-dimensional tomography (4DCT) in abdominal radiotherapy treatment planning (RTP). This review aims to assess the 4DMRI literature in abdomen, focusing on technical considerations and the validity of using 4DMRI for patients within radiotherapy protocols. Materials and methods: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed across the Medline, Embase, Scopus, and Web of Science databases, covering all years up to December 31, 2023. The studies were grouped into two categories: 4DMRI reconstructed from 3DMRI acquisition; and 4DMRI reconstructed from multi-slice 2DMRI acquisition. Results: A total of 39 studies met the inclusion criteria and were analysed to provide key findings. Key findings were 4DMRI had the potential to improve abdominal RTP for patients by providing accurate tumour definition and motion assessment compared to 4DCT. 4DMRI reconstructed from 3DMRI acquisition showed promise as a feasible approach for motion management in abdominal RTP regarding spatial resolution. Currently,the slice thickness achieved on 4DMRI reconstructed from multi-slice 2DMRI acquisitions was unsuitable for clinical purposes. Lastly, the current barriers for clinical implementation of 4DMRI were the limited availability of validated commercial solutions and the lack of larger cohort comparative studies to 4DCT for target delineation and plan optimisation. Conclusion: 4DMRI showed potential improvements in abdominal RTP, but standards and guidelines for the use of 4DMRI in radiotherapy were required to demonstrate clinical benefits.

The relationship between parameters measured using intravoxel incoherent motion and dynamic contrast-enhanced MRI in patients with breast cancer undergoing neoadjuvant chemotherapy: a longitudinal cohort study.

Purpose: The primary aim of this study was to explore whether intravoxel incoherent motion (IVIM) can offer a contrast-agent-free alternative to dynamic contrast-enhanced (DCE)-MRI for measuring breast tumor perfusion. The secondary aim was to investigate the relationship between tissue diffusion measures from DWI and DCE-MRI measures of the tissue interstitial and extracellular volume fractions. Materials and methods: A total of 108 paired DWI and DCE-MRI scans were acquired at 1.5 T from 40 patients with primary breast cancer (median age: 44.5 years) before and during neoadjuvant chemotherapy (NACT). DWI parameters included apparent diffusion coefficient (ADC), tissue diffusion (Dt), pseudo-diffusion coefficient (Dp), perfused fraction (f), and the product f×Dp (microvascular blood flow). DCE-MRI parameters included blood flow (Fb), blood volume fraction (vb), interstitial volume fraction (ve) and extracellular volume fraction (vd). All were extracted from three tumor regions of interest (whole-tumor, ADC cold-spot, and DCE-MRI hot-spot) at three MRI visits: pre-treatment, after one, and three cycles of NACT. Spearman's rank correlation was used for assessing between-subject correlations (r), while repeated measures correlation was employed to assess within-subject correlations (rrm) across visits between DWI and DCE-MRI parameters in each region. Results: No statistically significant between-subject or within-subject correlation was found between the perfusion parameters estimated by IVIM and DCE-MRI (f versus vb and f×Dp versus Fb; P=0.07-0.81). Significant moderate positive between-subject and within-subject correlations were observed between ADC and ve (r=0.461, rrm=0.597) and between Dt and ve (r=0.405, rrm=0.514) as well as moderate positive within-subject correlations between ADC and vd and between Dt and vd (rrm=0.619 and 0.564, respectively) in the whole-tumor region. Conclusion: No correlations were observed between the perfusion parameters estimated by IVIM and DCE-MRI. This may be attributed to imprecise estimates of fxDp and vb, or an underlying difference in what IVIM and DCE-MRI measure. Care should be taken when interpreting the IVIM parameters (f and f×Dp) as surrogates for those measured using DCE-MRI. However, the moderate positive correlations found between ADC and Dt and the DCE-MRI parameters ve and vd confirms the expectation that as the interstitial and extracellular volume fractions increase, water diffusion increases.

Patient perspectives on their outcomes from strabismus surgery undertaken for psychosocial reasons.

BACKGROUND: Strabismus surgery undertaken for psychosocial reasons aims to align the eyes in a straighter position, reduce the psychosocial symptoms experienced and improve health related quality of life (HRQoL). Greater evidence of the postoperative outcomes in adults undergoing strabismus surgery for psychosocial reasons is required to inform funding and commissioning decisions about strabismus surgery. METHODS: Semi-structured interviews were conducted with adults who had previously undergone strabismus surgery for psychosocial reasons to explore their perceptions of their postoperative outcomes. Maximum variation sampling was used to recruit males and females, younger and older participants. Interviews were transcribed and analysed using thematic analysis following the principles of grounded theory. RESULTS: Thirteen adults were recruited and interviewed, mean 12.2 months postoperatively (range 4.5-20 months). Participants reported a range of improvements in vision, task performance, physical symptoms and confidence and emotions. Some worsening of physical symptoms was reported. CONCLUSION: Despite undergoing strabismus surgery for psychosocial reasons, a range of improvements in vision, task performance and physical symptoms were reported by adult patients postoperatively, in addition to the expected improvements in confidence and emotions.

A comprehensive analysis of minimally differentially methylated regions common to pediatric and adult solid tumors.

Cancer is the second most common cause of death in children aged 1-14 years in the United States, with 11,000 new cases and 1200 deaths annually. Pediatric cancers typically have lower mutational burden compared to adult-onset cancers, however, the epigenomes in pediatric cancer are highly altered, with widespread DNA methylation changes. The rarity of pediatric cancers poses a significant challenge to developing cancer-type specific biomarkers for diagnosis, prognosis, or treatment monitoring. In the current study, we explored the potential of a DNA methylation profile common across various pediatric cancers. To do this, we conducted whole genome bisulfite sequencing (WGBS) on 31 recurrent pediatric tumor tissues, 13 normal tissues, and 20 plasma cell-free (cf)DNA samples, representing 11 different pediatric cancer types. We defined minimal focal regions that were differentially methylated across samples in the multiple cancer types which we termed minimally differentially methylated regions (mDMRs). These methylation changes were also observed in 506 pediatric and 5691 adult cancer samples accessed from publicly available databases, and in 44 pediatric cancer samples we analyzed using a targeted hybridization probe capture assay. Finally, we found that these methylation changes were detectable in cfDNA and could serve as potential cfDNA methylation biomarkers for early detection or minimal residual disease.

Influence of childhood trauma and traumatic stress on a woman's risk of having a child with a fetal alcohol spectrum disorder.

BACKGROUND: Maternal risk factors for having a child diagnosed on the fetal alcohol spectrum disorders (FASD) continuum are complex and include not only the quantity, frequency, and timing of alcohol use but also a woman's physical stature, socio-economic status, and pregnancy-related factors. Exposure to trauma may predispose women to a range of physiological and mental disorders. A woman's mental and physical health may in turn influence her probability of having a child with FASD. This study investigated the role of maternal childhood trauma and lifetime traumatic stress on prenatal alcohol consumption and on the risk of having a child with FASD. METHODS: A nested, case-control study was conducted for maternal risk assessment. Study participants were mothers of first-grade learners from five rural communities in the Western Cape Province of South Africa who were assessed for FASD. Face-to-face surveys were conducted, which included mental health and trauma assessment questionnaires. RESULTS: In logistic regression analyses, higher maternal childhood trauma scores were associated with an increased likelihood of having a child diagnosed with FASD, although the increase in risk was modest (OR = 1.014, p = 0.015). In addition, structural equation modeling investigated relationships between maternal drinking, childhood trauma, traumatic stress, and a child's FASD diagnosis. Traumatic stress and drinking during pregnancy, but not lifetime alcohol use, were associated with maternal childhood trauma. Lifetime alcohol use influenced drinking during pregnancy, which in turn was significantly associated with having a child diagnosed on the continuum of FASD. CONCLUSION: No direct influence of maternal childhood trauma on FASD diagnosis could be demonstrated. However, maternal trauma may indirectly contribute to the risk of having a child diagnosed with FASD.

Strabismus Surgery for Psychosocial Reasons-A Literature Review.

Introduction: Strabismus surgery may be undertaken for visual benefit, to improve or eliminate diplopia symptoms, or to restore or improve binocular single vision (BSV). In patients without visual symptoms or expected visual benefit, strabismus surgery may still be undertaken if the presence of strabismus causes the patient psychosocial symptoms. To evaluate strabismus surgery undertaken for psychosocial reasons, evidence of postoperative outcomes in this specific cohort is needed. Methods: A systematic search of the literature was conducted (1946-2023) to identify evidence where postoperative outcomes were reported for adult patients (age 18 years and above) who had undergone strabismus surgery for psychosocial reasons. Results: Sixty-nine papers were included in the literature review. Most sources of evidence included patients within heterogeneous cohorts of strabismus surgery outcomes, with a range of symptoms and differing surgical aims. Discussion: In adults who underwent strabismus surgery for psychosocial reasons, improved postoperative ocular alignment and/or improved health related quality of life (HRQoL) were common. Strabismus surgery outcomes appeared to be measured satisfactorily at three months postoperatively. Additional surgical outcomes, including an expanded field of vision, unexpected BSV, improved binocular summation, improved task performance and improved eye movements have been reported, but not fully investigated. There was a lack of consensus on how postoperative success should be defined and measured. A core outcome set for strabismus has been suggested and there is potential to add to the available evidence by investigating which outcome measures are most relevant to those with strabismus and psychosocial symptoms. There is a growing need for robust evidence in this specific subgroup of patients due to a lack of evidence specifically reporting postoperative outcomes in adults with strabismus and psychosocial symptoms.

Biochemical, structural, and computational analyses of two new clinically identified missense mutations of ALDH7A1.

Aldehyde dehydrogenase 7A1 (ALDH7A1) catalyzes a step of lysine catabolism. Certain missense mutations in the ALDH7A1 gene cause pyridoxine dependent epilepsy (PDE), a rare autosomal neurometabolic disorder with recessive inheritance that affects almost 1:65,000 live births and is classically characterized by recurrent seizures from the neonatal period. We report a biochemical, structural, and computational study of two novel ALDH7A1 missense mutations that were identified in a child with rare recurrent seizures from the third month of life. The mutations affect two residues in the oligomer interfaces of ALDH7A1, Arg134 and Arg441 (Arg162 and Arg469 in the HGVS nomenclature). The corresponding enzyme variants R134S and R441C (p.Arg162Ser and p.Arg469Cys in the HGVS nomenclature) were expressed in Escherichia coli and purified. R134S and R441C have 10,000- and 50-fold lower catalytic efficiency than wild-type ALDH7A1, respectively. Sedimentation velocity analytical ultracentrifugation shows that R134S is defective in tetramerization, remaining locked in a dimeric state even in the presence of the tetramer-inducing coenzyme NAD+. Because the tetramer is the active form of ALDH7A1, the defect in oligomerization explains the very low catalytic activity of R134S. In contrast, R441C exhibits wild-type oligomerization behavior, and the 2.0 Å resolution crystal structure of R441C complexed with NAD+ revealed no obvious structural perturbations when compared to the wild-type enzyme structure. Molecular dynamics simulations suggest that the mutation of Arg441 to Cys may increase intersubunit ion pairs and alter the dynamics of the active site gate. Our biochemical, structural, and computational data on two novel clinical variants of ALDH7A1 add to the complexity of the molecular determinants underlying pyridoxine dependent epilepsy.

Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/SUO Guideline (2017; Amended 2020, 2024).

PURPOSE: Although representing approximately 25% of patients diagnosed with bladder cancer, muscle-invasive bladder cancer (MIBC) carries a significant risk of death that has not significantly changed in decades. Increasingly, clinicians and patients recognize the importance of multidisciplinary collaborative efforts that take into account survival and quality of life concerns. This guideline provides a risk-stratified, clinical framework for the management of muscle-invasive urothelial bladder cancer. METHODOLOGY/METHODS: In 2024, the MIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from May 2020 to November 2023. This review identified 3739 abstracts, of which 46 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made regarding neoadjuvant/adjuvant chemotherapy, radical cystectomy, pelvic lymphadenectomy, multi-modal bladder preserving therapy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with MIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Are Horizontal Fusional Vergences Comparable When Measured Using a Prism Bar and Synoptophore?

Aim: To determine whether horizontal fusional vergences are comparable when measured using a prism bar and synoptophore. Methods: Thirty two participants (18-23 years) had their blur, break, and recovery points measured for convergence and divergence amplitudes using a prism bar (6 m) and synoptophore. All participants had VA of 0.1 LogMAR or better in either eye, were heterophoric or orthophoric and had binocular single vision. The prism bar target was a 0.2 LogMAR letter. The synoptophore target was the foveal 'rabbit' fusion slides. The prism bar was placed over the dominant eye and the testing speed was two seconds per two prism dioptres (Δ), increasing to five seconds per 5Δ when the increments began to increase in 5Δ. Synoptophore testing speed was two seconds per degree. Results: The synoptophore measured significantly higher convergence break points than the prism bar (Z = 3.37, p = 0.001). No significant differences were found between both tests for divergence break points (Z = 0.99, p = 0.32). However, both tests displayed wide limits of agreement (LoA) when measuring convergence (-24Δ to + 49.59Δ) and divergence break points (-7.70Δ to + 10.19Δ). Differences when measuring convergence and divergence blur and recovery points were not statistically significant. Conclusion: There was a statistically and clinically significant difference when measuring convergence break points using the prism bar and synoptophore but no significant difference when measuring divergence break points. However, both tests displayed wide LoA when measuring convergence and divergence break points, indicating they should not be used interchangeably in clinic to measure horizontal fusional vergences.

Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline: 2024 Amendment.

PURPOSE: The purpose of this American Urological Association (AUA)/Society of Urologic Oncology (SUO) guideline amendment is to provide a useful reference on the effective evidence-based treatment strategies for non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: In 2023, the NMIBC guideline was updated through the AUA amendment process in which newly published literature is reviewed and integrated into previously published guidelines in an effort to maintain currency. The amendment allowed for the incorporation of additional literature released since the previous 2020 amendment. The updated search gathered literature from July 2019 to May 2023. This review identified 1918 abstracts, of which 75 met inclusion criteria.When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) in support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: Updates were made to statements on variant histologies, urine markers after diagnosis of bladder cancer, intravesical therapy, BCG maintenance, enhanced cystoscopy, and future directions. Further revisions were made to the methodology and reference sections as appropriate. CONCLUSIONS: This guideline seeks to improve clinicians' ability to evaluate and treat patients with NMIBC based on currently available evidence. Future studies will be essential to further support or refine these statements to improve patient care.

Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study.

OBJECTIVES: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction. DESIGN: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy. SETTING: Six PICUs in Australia and New Zealand. PATIENTS: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021. INTERVENTIONS: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33). MEASUREMENTS AND MAIN RESULTS: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29-120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0-26.0) days in the intervention and 21.0 (0.0-25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5-11.3) days in the intervention group versus 6.9 (3.0-11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6-101.2) hours in the intervention group versus 47.3 (22.4-106.8) hours in the standard care group (median difference -12 hr; 95% CI, -56.8 to 32.7 hr). CONCLUSIONS: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT.

Early life thymectomy induces arterial dysfunction in mice.

Aging of the arteries is characterized by increased large artery stiffness and impaired endothelium-dependent dilation. We have previously shown that in old (22-24 month) mice T cells accumulate within aorta and mesentery. We have also shown that pharmacologic and genetic deletion of these T cells ameliorates age-related arterial dysfunction. These data indicate that T cells contribute to arterial aging; however, it is unknown if aged T cells alone can induce arterial dysfunction in otherwise young mice. To produce an aged-like T cell phenotype, mice were thymectomized at three-weeks of age or were left with their thymus intact. At 9 months of age, thymectomized mice exhibited greater proportions of both CD4 + and CD8 + memory T cells compared to controls in the blood. Similar changes were observed in the T cells accumulating in the aorta and mesentery. We also observed greater numbers of proinflammatory cytokine producing T cells in the aorta and mesentery. The phenotypic T cell changes in the blood, aorta and mesentery of thymectomized mice were similar to those observed when we compared young (4-6 month) to old thymus intact mice. Along with these alterations, compared to controls, thymectomized mice exhibited augmented large artery stiffness and greater aortic collagen deposition as well as impaired mesenteric artery endothelium dependent dilation due to blunted nitric oxide bioavailability. These results indicate that early life thymectomy results in arterial dysfunction and suggest that an aged-like T cell phenotype alone is sufficient to induce arterial dysfunction in otherwise young mice.

A community-endorsed open-source lexicon for contrast agent-based perfusion MRI: A consensus guidelines report from the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

This manuscript describes the ISMRM OSIPI (Open Science Initiative for Perfusion Imaging) lexicon for dynamic contrast-enhanced and dynamic susceptibility-contrast MRI. The lexicon was developed by Taskforce 4.2 of OSIPI to provide standardized definitions of commonly used quantities, models, and analysis processes with the aim of reducing reporting variability. The taskforce was established in February 2020 and consists of medical physicists, engineers, clinicians, data and computer scientists, and DICOM (Digital Imaging and Communications in Medicine) standard experts. Members of the taskforce collaborated via a slack channel and quarterly virtual meetings. Members participated by defining lexicon items and reporting formats that were reviewed by at least two other members of the taskforce. Version 1.0.0 of the lexicon was subject to open review from the wider perfusion imaging community between January and March 2022, and endorsed by the Perfusion Study Group of the ISMRM in the summer of 2022. The initial scope of the lexicon was set by the taskforce and defined such that it contained a basic set of quantities, processes, and models to enable users to report an end-to-end analysis pipeline including kinetic model fitting. We also provide guidance on how to easily incorporate lexicon items and definitions into free-text descriptions (e.g., in manuscripts and other documentation) and introduce an XML-based pipeline encoding format to encode analyses using lexicon definitions in standardized and extensible machine-readable code. The lexicon is designed to be open-source and extendable, enabling ongoing expansion of its content. We hope that widespread adoption of lexicon terminology and reporting formats described herein will increase reproducibility within the field.

The impact of water exchange on estimates of myocardial extracellular volume calculated using contrast enhanced T1 measurements: A preliminary analysis in patients with severe aortic stenosis.

PURPOSE: Guidelines recommend measuring myocardial extracellular volume (ECV) using T1 -mapping before and 10-30 min after contrast agent administration. Data are then analyzed using a linear model (LM), which assumes fast water exchange (WX) between the ECV and cardiomyocytes. We investigated whether limited WX influences ECV measurements in patients with severe aortic stenosis (AS). METHODS: Twenty-five patients with severe AS and 5 healthy controls were recruited. T1 measurements were made on a 3 T Siemens system using a multiparametric saturation-recovery single-shot acquisition (a) before contrast; (b) 4 min post 0.05 mmol/kg gadobutrol; and (c) 4 min, (d) 10 min, and (e) 30 min after an additional gadobutrol dose (0.1 mmol/kg). Three LM-based ECV estimates, made using paired T1 measurements (a and b), (a and d), and (a and e), were compared to ECV estimates made using all 5 T1 measurements and a two-site exchange model (2SXM) accounting for WX. RESULTS: Median (range) ECV estimated using the 2SXM model was 25% (21%-39%) for patients and 26% (22%-29%) for controls. ECV estimated in patients using the LM at 10 min following a cumulative contrast dose of 0.15 mmol/kg was 21% (17%-32%) and increased significantly to 22% (19%-35%) at 30 min (p = 0.0001). ECV estimated using the LM was highest following low dose gadobutrol, 25% (19%-38%). CONCLUSION: Current guidelines on contrast agent dose for ECV measurements may lead to underestimated ECV in patients with severe AS because of limited WX. Use of a lower contrast agent dose may mitigate this effect.

Maternal risk factors for fetal alcohol spectrum disorders: Distal variables.

BACKGROUND: A variety of maternal risk factors for fetal alcohol spectrum disorders (FASD) have been described in the literature. Here, we conducted a multivariate analysis of a large array of potential distal influences on FASD risk. METHODS: Interviews were conducted with 2515 mothers of first-grade students whose children were evaluated to assess risk for FASD. Topics included: physical/medical status, childbearing history, demographics, mental health, domestic violence, and trauma. Regression modeling utilized usual level of alcohol consumption by trimester and six selected distal variables (maternal head circumference, body mass index, age at pregnancy, gravidity, marital status, and formal years of education) to differentiate children with FASD from control children. RESULTS: Despite individual variation in distal maternal risk factors among and within the mothers of children with each of the common diagnoses of FASD, patterns emerged that differentiated risk among mothers of children with FASD from mothers whose children were developing typically. Case-control comparisons indicate that mothers of children with FASD were significantly smaller physically, had higher gravidity and parity, and experienced more miscarriages and stillbirths, were less likely to be married, reported later pregnancy recognition, more depression, and lower formal educational achievement. They were also less engaged with a formal religion, were less happy, suffered more childhood trauma and interpersonal violence, were more likely to drink alone or with her partner, and drank to deal with anxiety, tension, and to be part of a group. Regression analysis showed that the predictor variables explain 57.5% of the variance in fetal alcohol syndrome (FAS) diagnoses, 30.1% of partial FAS (PFAS) diagnoses, and 46.4% of alcohol-related neurodevelopmental disorder (ARND) diagnoses in children with FASD compared to controls. While the proximal variables explained most of the diagnostic variance, six distal variables explained 16.7% (1 /6 ) of the variance in FAS diagnoses, 13.9% (1 /7 ) of PFAS, and 12.1% (1 /8 ) of ARND. CONCLUSIONS: Differences in distal FASD risks were identified. Complex models to quantify risk for FASD hold promise for guiding prevention/intervention.

Physiological confounders of renal blood flow measurement.

OBJECTIVES: Renal blood flow (RBF) is controlled by a number of physiological factors that can contribute to the variability of its measurement. The purpose of this review is to assess the changes in RBF in response to a wide range of physiological confounders and derive practical recommendations on patient preparation and interpretation of RBF measurements with MRI. METHODS: A comprehensive search was conducted to include articles reporting on physiological variations of renal perfusion, blood and/or plasma flow in healthy humans. RESULTS: A total of 24 potential confounders were identified from the literature search and categorized into non-modifiable and modifiable factors. The non-modifiable factors include variables related to the demographics of a population (e.g. age, sex, and race) which cannot be manipulated but should be considered when interpreting RBF values between subjects. The modifiable factors include different activities (e.g. food/fluid intake, exercise training and medication use) that can be standardized in the study design. For each of the modifiable factors, evidence-based recommendations are provided to control for them in an RBF-measurement. CONCLUSION: Future studies aiming to measure RBF are encouraged to follow a rigorous study design, that takes into account these recommendations for controlling the factors that can influence RBF results.

MRI-guided Pelvic Radiation Therapy: A Primer for Radiologists.

Radiation therapy (RT) is a core pillar of oncologic treatment, and half of all patients with cancer receive this therapy as a curative or palliative treatment. The recent integration of MRI into the RT workflow has led to the advent of MRI-guided RT (MRIgRT). Using MRI rather than CT has clear advantages for guiding RT to pelvic tumors, including superior soft-tissue contrast, improved organ motion visualization, and the potential to image tumor phenotypic characteristics to identify the most aggressive or treatment-resistant areas, which can be targeted with a more focal higher radiation dose. Radiologists should be familiar with the potential uses of MRI in planning pelvic RT; the various RT techniques used, such as brachytherapy and external beam RT; and the impact of MRIgRT on treatment paradigms. Current clinical experience with and the evidence base for MRIgRT in the settings of prostate, cervical, and bladder cancer are discussed, and examples of treated cases are illustrated. In addition, the benefits of MRIgRT, such as real-time online adaptation of RT (during treatment) and interfraction and/or intrafraction adaptation to organ motion, as well as how MRIgRT can decrease toxic effects and improve oncologic outcomes, are highlighted. MRIgRT is particularly beneficial for treating mobile pelvic structures, and real-time adaptive RT for tumors can be achieved by using advanced MRI-guided linear accelerator systems to spare organs at risk. Future opportunities for development of biologically driven adapted RT with use of functional MRI sequences and radiogenomic approaches also are outlined. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

OvaPrint-A Cell-free DNA Methylation Liquid Biopsy for the Risk Assessment of High-grade Serous Ovarian Cancer.

PURPOSE: High-grade serous ovarian carcinoma (HGSOC) is the most lethal epithelial ovarian cancer (EOC) and is often diagnosed at late stage. In women with a known pelvic mass, surgery followed by pathologic assessment is the most reliable way to diagnose EOC and there are still no effective screening tools in asymptomatic women. In the current study, we developed a cell-free DNA (cfDNA) methylation liquid biopsy for the risk assessment of early-stage HGSOC. EXPERIMENTAL DESIGN: We performed reduced representation bisulfite sequencing to identify differentially methylated regions (DMR) between HGSOC and normal ovarian and fallopian tube tissue. Next, we performed hybridization probe capture for 1,677 DMRs and constructed a classifier (OvaPrint) on an independent set of cfDNA samples to discriminate HGSOC from benign masses. We also analyzed a series of non-HGSOC EOC, including low-grade and borderline samples to assess the generalizability of OvaPrint. A total of 372 samples (tissue n = 59, plasma n = 313) were analyzed in this study. RESULTS: OvaPrint achieved a positive predictive value of 95% and a negative predictive value of 88% for discriminating HGSOC from benign masses, surpassing other commercial tests. OvaPrint was less sensitive for non-HGSOC EOC, albeit it may have potential utility for identifying low-grade and borderline tumors with higher malignant potential. CONCLUSIONS: OvaPrint is a highly sensitive and specific test that can be used for the risk assessment of HGSOC in symptomatic women. Prospective studies are warranted to validate OvaPrint for HGSOC and further develop it for non-HGSOC EOC histotypes in both symptomatic and asymptomatic women with adnexal masses.

Maternal dietary intake among alcohol-exposed pregnancies is linked to early infant physical outcomes in South Africa.

Maternal dietary intake is likely a contributing factor to fetal alcohol spectrum disorders (FASD). Two, 24-hour dietary recalls were completed by pregnant women (n = 196) in South African communities with high rates of FASD. More than 50% of all women in this study were below the Estimated Average Requirement (EAR) for pregnancy for vitamins A, C, D, E, riboflavin, vitamin B6, folate, calcium, magnesium, iron, and zinc. More than 90% of mothers were below the Recommended Dietary Allowance (RDA) or Adequate Intake (AI) for pregnancy on vitamin A, K, D, E, choline, calcium, magnesium, zinc, and potassium. More than 80% were below RDA/AI for pantothenic acid, vitamin B6, and folate. Women who consumed alcohol reported significantly lower intake of calcium and three saturated fatty acids and significantly higher intake of two monounsaturated fatty acids. On average, infants were < 40th centile on length, weight, and head circumference at 6 weeks old, regardless of alcohol exposure. Twenty nutrients correlated with at least one measure of 1st trimester drinking (drinks per drinking day, number of drinking days per week, and/or total drinks per week). Nutrients included four saturated fatty acids, eight amino acids, calcium, B-complex vitamins, choline, and betaine. Calcium correlated with all three drinking measures. Further analyses revealed seven nutrients were associated with infant length, weight, and/or head circumference among unexposed infants, and 12 nutrients were associated among infants with prenatal alcohol exposure. Inadequate maternal dietary intake, with alcohol exposure, may increase risk for poor infant growth and likelihood of FASD in this population.