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Background: Approximately 6.7 million American adults are living with heart failure (HF). Current therapies are geared toward preventing progression and managing symptoms, as there is no cure. Multiple studies have shown the benefit of including palliative care (PC) in patients with HF to improve symptoms and quality of life. Heart failure guidelines recommend the inclusion of PC in therapy, but referrals are often delayed. A previous pilot project demonstrated increased involvement of PC when targeted education was given to patients with HF. Objective: Educate patients with HF on PC and examine the impact on PC consults, readmission, mortality, intensive care unit (ICU) transfers and evaluate sustainability of the intervention. Methods: Patients (n = 124) admitted to an academic hospital with a diagnosis of HF were asked to view an educational module on PC. Patients who completed the module were placed in the intervention group (n = 39). Patients who declined were placed in the usual care group (n = 38). The number of PC consults, re-admissions, mortality, and transfers to the ICU were compared among participants and those who declined. Results were compared to previous pilot project. Results: Eleven patients in the intervention group (IG) requested a PC consult vs one in the usual care group (UCG) (P =.006). There was no statistically significant difference in readmissions, mortality, or ICU transfers between groups. Conclusions: This sustainable project again demonstrated education on PC increases utilization of PC but does not statistically impact mortality, re-admissions, or transfers to higher levels of care. [ABSTRACT FROM AUTHOR]

Patients with obesity and advanced heart failure requiring left ventricular assist device (LVAD) support are more likely to experience LVAD complications and may be disproportionately Black and/or female when compared to patients without obesity. Among these patients, obesity may represent a barrier to transplant eligibility and a marker of inequity in heart transplantation and health outcomes in advanced heart failure. To better understand this issue at our institution, we examined our active LVAD cohort and found that almost one-third of all patients had severe obesity with BMI ≥ 35 kg/m2. Patients with LVADs and severe obesity were significantly younger and more likely to self-identify as Black, and numerically more likely to be female. Weight management in this group represents a vital area for improved equity in health outcomes and barriers to heart transplantation. NA. [ABSTRACT FROM AUTHOR]

Non-invasive techniques are being increasingly used for the study of heritage objects. This article describes the results of pigment analysis on a fragmentary Egyptian sculpture using two non-invasive infrared methods: external reflectance Fourier-transform infrared (ER-FTIR) spectroscopy and visible-induced infrared luminescence (VIL) photography. ER-FTIR spectroscopy was used to identify certain of the pigments used on the sculpture, including Egyptian blue, in variously coloured areas. An optimized VIL photographic technique, using a high-resolution camera combined with focus-stacking, permitted detailed mapping of the location of Egyptian blue on the sculpture, including sub-millimeter grains of the pigment scattered across the object's surface, which were not visible to the naked eye. [ABSTRACT FROM AUTHOR]

Biallelic mutations in sorbitol dehydrogenase (SORD) have been recently identified as a common cause of recessive axonal Charcot‐Marie‐Tooth neuropathy (CMT2). We aimed to assess a novel long‐read sequencing approach to overcome current limitations in SORD neuropathy diagnostics due to the SORD2P pseudogene and the phasing of biallelic mutations in recessive disease. We conducted a screen of our Australian whole exome sequencing (WES) CMT cohort to identify individuals with homozygous or compound heterozygous SORD variants. Individuals detected with SORD mutations then underwent long‐read sequencing, clinical assessment, and serum sorbitol analysis. An individual was detected with compound heterozygous truncating mutations in SORD exon 7, NM_003104.5:c.625C>T (p.Arg209Ter) and NM_003104.5:c.757del (p.Ala253GlnfsTer27). Subsequent Oxford Nanopore Tech (ONT) long‐read sequencing was used to successfully differentiate SORD from the highly homologous non‐functional SORD2P pseudogene and confirmed that the mutations were biallelic through haplotype‐resolved analysis. The patient presented with axonal sensorimotor polyneuropathy (CMT2) and ulnar neuropathy without compression at the elbow. Burning neuropathic pain in the forearms and feet was also reported and was exacerbated by alcohol consumption and improved with alcohol cessation. UPLC‐tandem mass spectrometry confirmed that the patient had elevated serum sorbitol levels (12.0 mg/L) consistent with levels previously observed in patients with biallelic SORD mutations. This represents a novel clinical presentation and expands the phenotype associated with biallelic SORD mutations causing CMT2. Our study is the first report of long‐read sequencing for an individual with CMT and demonstrates the utility of this approach for clinical genomics. [ABSTRACT FROM AUTHOR]

Issues concerning the study of conformationally ordered oligomers in solution for the development of a binding site for guest molecules are discussed. Use of induced circular dichroism spectroscopy reveals the reaction of an achiral oligomer with a chiral molecule indicating that binding occurs within the hydrophobic tubular cavity of the oligomer helix.

Background: Optic neuritis (ON) occurs in immune-mediated disorders including multiple sclerosis (MS), aquaporin-4 antibody-positive (AQP4) neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination (MOGAD). Accurate determination of aetiology is critical for appropriate treatment and prognostication. Objective: To evaluate demyelination and axonal loss in MOG-ON to facilitate differentiation from MS-ON and AQP4-ON. Methods: 15 MOGAD patients with previous ON (25 eyes) underwent multifocal visual evoked potential (mfVEP) recordings and optical coherence tomography scans. Comparison was made to previously reported MS patients (n = 67, 69 eyes) and AQP4-NMOSD patients (n = 15, 23 eyes) with prior ON and healthy controls (n = 37, 74 eyes). Results: MOG-ON patients had less retinal nerve fibre layer (RNFL) loss than AQP4-ON patients (p < 0.05) and less mfVEP latency prolongation than MS-ON patients (p < 0.01). Number of ON episodes in MOGAD was associated with reduced RNFL thickness (global, p = 0.07; temporal, p < 0.001) and mfVEP amplitude (p < 0.001). There was no abnormality in non-ON eyes. Conclusions: Our study demonstrated a distinct pattern of damage in MOG-ON compared to AQP4-ON and MS-ON. ON in MOGAD produces less axonal loss than AQP4-NMOSD. Damage accumulates with relapses, supporting the role of maintenance immunosuppression to induce remission. Compared to MS, MOGAD causes less demyelination. [ABSTRACT FROM AUTHOR]

Background and purpose: Nitrous oxide misuse is a recognized issue worldwide. Prolonged misuse inactivates vitamin B12, causing a myeloneuropathy. Methods: Twenty patients presenting between 2016 and 2020 to tertiary hospitals in Sydney with myeloneuropathy due to nitrous oxide misuse were reviewed. Results: The average age was 24 years, and mean canister consumption was 148 per day for 9 months. At presentation, paresthesias and gait unsteadiness were common, and seven patients were bedbound. Mean serum B12 was normal (258 pmol/L, normal range [NR] = 140–750) as was active B12 (87 pmol/L, normal > 35). In contrast, mean serum homocysteine was high (51 μmol/L, NR = 5–15). Spinal magnetic resonance imaging (MRI) showed characteristic dorsal column T2 hyperintensities in all 20 patients. Nerve conduction studies showed a predominantly axonal sensorimotor neuropathy (n = 5). Patients were treated with intramuscular vitamin B12, with variable functional recovery. Three of the seven patients who were bedbound at presentation were able to walk again with an aid at discharge. Of eight patients with follow‐up data, most had persistent paresthesias and/or sensory ataxia. Mobility scores at admission and discharge were not significantly correlated with the serum total and active B12 levels or cumulative nitrous oxide use. There were no significant trends between serum active B12 level and cumulative nitrous oxide use (Spearman rho = −0.331, p = 0.195). Conclusions: Nitrous oxide misuse can cause a severe but potentially reversible subacute myeloneuropathy. Serum and active B12 can be normal, while elevated homocysteine and dorsal column high T2 signal on MRI strongly suggest the diagnosis. Neurological deficits can improve with abstinence and B12 supplementation, even in the most severely affected patients. [ABSTRACT FROM AUTHOR]

Background: Pulmonary vein isolation (PVI) with autonomic modulation may be more successful than PVI alone for atrial fibrillation (AF) ablation and may be signaled by changes in sinus rhythm heart rate (HR) post ablation. We sought to determine if a change in sinus rhythm HR predicted AF recurrence post PVI. Methods: Patients who underwent AF ablation from 2000 to 2011 were included if sinus rhythm was noted on ECG within 90 days pre and 7 days post ablation. Basic ECG interval and HR changes were analyzed and outcomes determined. Results: A total of 1152 patients were identified (74.3% male, mean age 57 ± 11 years). Mean AF duration was 5.2 ± 5.3 years. Paroxysmal AF was noted in 712 (61.8%) of the patients. Mean EF was 61% ± 6%. Sinus rhythm HR was 61 ± 11 pre‐ablation and 76 ± 13 bpm post‐ablation (27% ± 24% increase, p <.001). The ability of relative HR change post‐ablation to predict AF recurrence was borderline (hazard ratio 0.65 [0.41–1.01], p =.067). With patients separated into quartiles based on the relative HR change, the upper quartile with the largest relative increase in HR had a significantly lower rate of AF recurrence compared to the lowest quartile following multi variable modeling (p =.038). There were significant changes in PR (171 ± 28 to 167 ± 30 ms) and QTc (424 ± 25 to 434 ± 29 ms) intervals (both p <.001) but these were not predictive of outcome. Conclusion: Relative changes in HR post AF ablation correlates with AF recurrence. Further prospective studies are needed to confirm this relationship. [ABSTRACT FROM AUTHOR]

Background: Guillain–Barré syndrome (GBS) causes acute neuromuscular weakness. Severe cases are life‐threatening and many are left disabled. Intravenous immunoglobulin (IVIg) and plasma exchange (PE), along with supportive care, are the mainstays of treatment. Treatment choice is influenced by multiple factors. The clinico‐epidemiological features of GBS in Australia have not been reviewed in 30 years and few studies have assessed contemporary treatment choices. Aims: To investigate the clinico‐epidemiological features, choice of treatment, clinical course and outcomes of GBS patients in an Australian tertiary metropolitan hospital. Methods: A retrospective observational study was performed of GBS presentations to a tertiary hospital in Sydney, Australia, over 5 years. Clinico‐epidemiological features, treatment choices, clinical course and outcomes were assessed. Results: We reviewed 46 GBS patients (54% male), average age 55 years. Antecedent infection was identified in 61%. Twenty‐eight per cent had preceding immunogenic events or conditions. Acute inflammatory demyelinating polyradiculoneuropathy was the most common subtype (78%). Cerebrospinal fluid albumino‐cytologic dissociation was present in 43%. Electrodiagnostic testing most frequently demonstrated demyelination (64%). Ninety‐eight per cent received immunotherapy, mostly IVIg (93%). Twenty‐two per cent received further treatment due to treatment‐related fluctuations or lack of improvement. Thirteen per cent required ICU admission and 46% needed rehabilitation. There were no deaths or need for mechanical ventilation. Seventy‐one per cent of the follow‐up cohort had residual disability at 6 months, but this was generally mild. Conclusions: The clinico‐epidemiological features are consistent with previous cohorts. Our experience in a large Australian tertiary centre demonstrates a clear preference for IVIg over PE. [ABSTRACT FROM AUTHOR]

Clinical trials traditionally aim to show a new treatment is superior to placebo or standard treatment, that is, superiority trials. There is an increasing number of trials demonstrating a new treatment is non-inferior to standard treatment. The hypotheses, design and interpretation of non-inferiority trials are different to superiority trials. Non-inferiority trials are designed with the notion that the new treatment offers advantages over standard treatment in certain important aspects. The non-inferior margin is a predetermined margin of difference between the new and standard treatment that is considered acceptable or tolerable for the new treatment to be considered 'similar' or 'not worse'. Both relative difference and absolute difference methods can be used to define the non-inferior margin. Sequential testing for non-inferiority and superiority is often performed. Non-inferiority trials may be necessary in situations where it is no longer ethical to test any new treatment against placebo. There are inherent assumptions in non-inferiority trials which may not be correct and which are not being tested. Successive non-inferiority trials may introduce less and less effective treatments even though these treatments may have been shown to be non-inferior. Furthermore, poor quality trials favour non-inferior results. Intention-to-treat analysis, the preferred way to analyse randomised trials, may favour non-inferiority. Both intention-to-treat and per-protocol analyses should be recommended in non-inferiority trials. Clinicians should be aware of the pitfalls of non-inferiority trials and not accept non-inferiority on face value. The focus should not be on the p values but on the effect size and confidence limits. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of [18F]fluoromisonidazole ([18F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.Procedures: Mice with BT474, HER2+ tumors, were imaged with [18F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.Results: [18F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P < 0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P < 0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r 2  = 0.85).Conclusions: [18F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by dysfunction at multiple levels of the neuraxis. It remains a clinical diagnosis without a definitive diagnostic investigation. Electrodiagnostic testing provides supportive information and, along with imaging and biochemical markers, can help exclude mimicking conditions. Neuromuscular ultrasound has a valuable role in the diagnosis and monitoring of ALS and provides complementary information to clinical assessment and electrodiagnostic testing as well as insights into the underlying pathophysiology of this disease. This review highlights the evidence for ultrasound in the evaluation of bulbar, limb and respiratory musculature and peripheral nerves in ALS. Further research in this evolving area is required. [ABSTRACT FROM AUTHOR]

Despite the central importance of transcriptional regulation in biology, it has proven difficult to determine the regulatory mechanisms of individual genes, let alone entire gene networks. It is particularly difficult to decipher the biophysical mechanisms of transcriptional regulation in living cells and determine the energetic properties of binding sites for transcription factors and RNA polymerase. In this work, we present a strategy for dissecting transcriptional regulatory sequences using in vivo methods (massively parallel reporter assays) to formulate quantitative models that map a transcription factor binding site’s DNA sequence to transcription factor-DNA binding energy. We use these models to predict the binding energies of transcription factor binding sites to within 1 kBT of their measured values. We further explore how such a sequence-energy mapping relates to the mechanisms of trancriptional regulation in various promoter contexts. Specifically, we show that our models can be used to design specific induction responses, analyze the effects of amino acid mutations on DNA sequence preference, and determine how regulatory context affects a transcription factor’s sequence specificity. [ABSTRACT FROM AUTHOR]

Background: Quantitative diffusion-weighted MRI (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI) have the potential to impact patient care by providing noninvasive biological information in breast cancer.Purpose/hypothesis: To quantify the repeatability, reproducibility, and accuracy of apparent diffusion coefficient (ADC) and T1 -mapping of the breast in community radiology practices.Study Type: Prospective.Subjects/phantom: Ice-water DW-MRI and T1 gel phantoms were used to assess accuracy. Normal subjects (n = 3) and phantoms across three sites (one academic, two community) were used to assess reproducibility. Test-retest analysis at one site in normal subjects (n = 12) was used to assess repeatability.Field Strength/sequence: 3T Siemens Skyra MRI quantitative DW-MRI and T1 -mapping.Assessment: Quantitative DW-MRI and T1 -mapping parametric maps of phantoms and fibroglandular and adipose tissue of the breast.Statistical Tests: Average values of breast tissue were quantified and Bland-Altman analysis was performed to assess the repeatability of the MRI techniques, while the Friedman test assessed reproducibility.Results: ADC measurements were reproducible across sites, with an average difference of 1.6% in an ice-water phantom and 7.0% in breast fibroglandular tissue. T1 measurements in gel phantoms had an average difference of 2.8% across three sites, whereas breast fibroglandular and adipose tissue had 8.4% and 7.5% average differences, respectively. In the repeatability study, we found no bias between first and second scanning sessions (P = 0.1). The difference between repeated measurements was independent of the mean for each MRI metric (P = 0.156, P = 0.862, P = 0.197 for ADC, T1 of fibroglandular tissue, and T1 of adipose tissue, respectively).Data Conclusion: Community radiology practices can perform repeatable, reproducible, and accurate quantitative T1 -mapping and DW-MRI. This has the potential to dramatically expand the number of sites that can participate in multisite clinical trials and increase clinical translation of quantitative MRI techniques for cancer response assessment.Level Of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. [ABSTRACT FROM AUTHOR]

Purpose: Quantitative evaluation of dynamic contrast enhanced MRI (DCE‐MRI) allows for estimating perfusion, vessel permeability, and tissue volume fractions by fitting signal intensity curves to pharmacokinetic models. These compart mental models assume rapid equilibration of contrast agent within each voxel. However, there is increasing evidence that this assumption is violated for small molecular weight gadolinium chelates. To evaluate the error introduced by this invalid assumption, we simulated DCE‐MRI experiments with volume fractions computed from entire histological tumor cross‐sections obtained from murine studies. Methods: A 2D finite element model of a diffusion‐compensated Tofts‐Kety model was developed to simulate dynamic T1 signal intensity data. Digitized histology slices were segmented into vascular (vp), cellular and extravascular extracellular (ve) volume fractions. Within this domain, Ktrans (the volume transfer constant) was assigned values from 0 to 0.5 min−1. A representative signal enhancement curve was then calculated for each imaging voxel and the resulting simulated DCE‐MRI data analyzed by the extended Tofts‐Kety model. Results: Results indicated parameterization errors of −19.1% ± 10.6% in Ktrans, −4.92% ± 3.86% in ve, and 79.5% ± 16.8% in vp for use of Gd‐DTPA over 4 tumor domains. Conclusion: These results indicate a need for revising the standard model of DCE‐MRI to incorporate a correction for slow diffusion of contrast agent. Magn Reson Med 80:330–340, 2018. © 2017 International Society for Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]

This work evaluates quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRI) parameters as early biomarkers of response in a preclinical model of triple negative breast cancer (TNBC). The standard Tofts' model of DCE-MRI returns estimates of the volume transfer constant ( Ktrans) and the extravascular extracellular volume fraction ( ve). DW-MRI returns estimates of the apparent diffusion coefficient (ADC). Mice ( n = 38) were injected subcutaneously with MDA-MB-231. Tumors were grown to approximately 275 mm3 and sorted into the following groups: saline controls, low-dose Abraxane (15 mg/kg) and high-dose Abraxane (25 mg/kg). Animals were imaged at days zero, one and three. On day three, tumors were extracted for immunohistochemistry. The positive percentage change in ADC on day one was significantly higher in both treatment groups relative to the control group ( p < 0.05). In addition, the positive percentage change in Ktrans was significantly higher than controls ( p < 0.05) on day one for the high-dose group and on days one and three for the low-dose group. The percentage change in tumor volume was significantly different between the high-dose and control groups on day three ( p = 0.006). Histology confirmed differences at day three through reduced numbers of proliferating cells (Ki67 staining) in the high-dose group ( p = 0.03) and low-dose group ( p = 0.052) compared with the control group. Co-immunofluorescent staining of vascular maturity [using von Willebrand Factor (vWF) and α-smooth muscle actin (α-SMA)] indicated significantly higher vascular maturation in the low-dose group compared with the controls on day three ( p = 0.03), and trending towards significance in the high-dose group compared with controls on day three ( p = 0.052). These results from quantitative imaging with histological validation indicate that ADC and Ktrans have the potential to serve as early biomarkers of treatment response in murine studies of TNBC. [ABSTRACT FROM AUTHOR]