Optimization of Gradient-Echo Echo-Planar Imaging for T2* Contrast in the Brain at 0.5 T.

Gradient-recalled echo (GRE) echo-planar imaging (EPI) is an efficient MRI pulse sequence that is commonly used for several enticing applications, including functional MRI (fMRI), susceptibility-weighted imaging (SWI), and proton resonance frequency (PRF) thermometry. These applications are typically not performed in the mid-field (<1 T) as longer T2* and lower polarization present significant challenges. However, recent developments of mid-field scanners equipped with high-performance gradient sets offer the possibility to re-evaluate the feasibility of these applications. The paper introduces a metric "T2* contrast efficiency" for this evaluation, which minimizes dead time in the EPI sequence while maximizing T2* contrast so that the temporal and pseudo signal-to-noise ratios (SNRs) can be attained, which could be used to quantify experimental parameters for future fMRI experiments in the mid-field. To guide the optimization, T2* measurements of the cortical gray matter are conducted, focusing on specific regions of interest (ROIs). Temporal and pseudo SNR are calculated with the measured time-series EPI data to observe the echo times at which the maximum T2* contrast efficiency is achieved. T2* for a specific cortical ROI is reported at 0.5 T. The results suggest the optimized echo time for the EPI protocols is shorter than the effective T2* of that region. The effective reduction of dead time prior to the echo train is feasible with an optimized EPI protocol, which will increase the overall scan efficiency for several EPI-based applications at 0.5 T.

Accessibility and Content of Fellowship Programs for Cardiovascular Disease.

Background The objective of this study was to assess the accessibility and content of the Accreditation Council for Graduate Medical Education (ACGME)-accredited general cardiology fellowship websites. Methods Using the online information provided by the Electronic Residency Application Services (ERAS), we compiled a list of ACGME-accredited cardiac fellowship programs. The program links on ERAS were evaluated followed by a standard Google search of the program name + "cardiology fellowship". Each program website was evaluated on the basis of program content, applying/recruiting and education. Results At the time of this study, we reviewed 231 general cardiology fellowship programs provided through ERAS. Of the 231 programs, 12 were excluded due to broken links, repeated links on ERAS, and websites with a general lack of content. We analyzed the data collected from the remaining 219 programs to assess the availability and general content of those websites. Data collected revealed a general lack of information regarding application processing and educational services but were sufficient in providing program descriptions and contact information. Conclusions ERAS can be used to locate general cardiology fellowships participating in the current match; however, the links provided by the program websites on ERAS are lacking in general content and accessibility. Although most websites did contain enough information about their program, there was a distinct lack of key information provided typically in the education services and application process.

Right Ventricular Thrombus Masquerading as a Tumor.

Cardiac tumors are an uncommon phenomenon. Although they can be cardiac in origin, most represent a distant neoplastic growth metastasizing to the heart. Cardiac tumors can be benign or malignant. They may be symptomatic or, more commonly, found incidentally. Clinical presentation is typically related to that of dispersed neoplasm. We report a case of a 36-year-old young man with an unusually large and smooth-surfaced right ventricular mass. The patient presented to the emergency department with exertional dyspnea for two weeks. Past medical history was significant for deep venous thrombosis with non-adherence to anti-coagulation. Computerized tomographic (CT) angiography showed bilateral pulmonary emboli and a hypodense opacity in the right ventricle. A transthoracic echocardiogram showed a right ventricular non-mobile mass. The patient underwent surgical removal of the mass, which pathology demonstrated to be a thrombus. Cardiac masses can be difficult to differentiate based on imaging alone. Physicians should maintain a high index of suspicion for intracardiac thrombi as early identification and prompt treatment are imperative in improving patient outcomes.

Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat ß-hemoglobinopathies.

A promising treatment for ß-hemoglobinopathies is the de-repression of γ-globin expression leading to increased fetal hemoglobin (HbF) by targeting BCL11A. Here, we aim to improve a lentivirus vector (LV) containing a single BCL11A shmiR (SS) to further increase γ-globin induction. We engineered a novel LV to express two shmiRs simultaneously targeting BCL11A and the γ-globin repressor ZNF410. Erythroid cells derived from human HSCs transduced with the double shmiR (DS) showed up to a 70% reduction of both BCL11A and ZNF410 proteins. There was a consistent and significant additional 10% increase in HbF compared to targeting BCL11A alone in erythroid cells. Erythrocytes differentiated from SCD HSCs transduced with the DS demonstrated significantly reduced in vitro sickling phenotype compared to the SS. Erythrocytes differentiated from transduced HSCs from ß-thalassemia major patients demonstrated improved globin chain balance by increased γ-globin with reduced microcytosis. Reconstitution of DS-transduced cells from Berkeley SCD mice was associated with a statistically larger reduction in peripheral blood hemolysis markers compared with the SS vector. Overall, these results indicate that the DS LV targeting BCL11A and ZNF410 can enhance HbF induction for treating ß-hemoglobinopathies and could be used as a model to simultaneously and efficiently target multiple gene products.

Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects.

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.

Tactical Masters Athletes: BMI Index Classifications.

Understanding the nexus between aging, physical activity, and obesity has been a source of ongoing investigation. A considerable amount of research has focused on Masters athletes in this regard, suggesting a beneficial relationship between Masters sport participation and a healthy body mass index (BMI). Some consider Active Duty military personnel as tactical athletes. As such, it is of interest to determine if aging Active Duty military personnel (or Masters Tactical Athletes) might have a similar BMI as other Masters athletes (MA). As such, this investigation examined previously recorded data of Active Duty Enlisted United States Marines (n = 402, male, 46-50 years old). The BMI of the Marines was stratified into categories of: underweight, normal, overweight, and obese. The Marines obesity prevalence was compared to US adult males (40-59 years) as well as male North American MA who competed at the 2009 Sydney World Masters Games. The Marines obesity prevalence was significantly lower than US adult males (p < 0.001) and those MA that competed in softball (p < 0.001); however, it was similar to MA that competed in football, track/field, swimming, and volleyball (p > 0.05). The average Marine BMI = 26.7 kg/m2 was similar to MA who competed in football, swimming, and volley ball (p > 0.05); however, it was higher than MA who competed in track/field (p < 0.05) and lower than MA who played softball (p < 0.05). It should be noted that the average BMI for the Marines and all MA sport categories were classified as being overweight. Within the parameters of this investigation, Tactical MA (i.e., aging US Marines) enjoy a similar beneficial BMI as other North American MA.

Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma.

RHOH/TFF, a member of the RAS GTPase super family, has important functions in lymphopoiesis and proximal T cell receptor signalling and has been implicated in a variety of leukaemias and lymphomas. RHOH was initially identified as a translocation partner with BCL-6 in non-Hodgkin lymphoma (NHL), and aberrant somatic hypermutation (SHM) in the 5' untranslated region of the RHOH gene has also been detected in Diffuse Large B-Cell Lymphoma (DLBCL). Recent data suggest a correlation between RhoH expression and disease progression in Acute Myeloid Leukaemia (AML). However, the effects of RHOH mutations and translocations on RhoH expression and malignant transformation remain unknown. We found that aged Rhoh-/- (KO) mice had shortened lifespans and developed B cell derived splenomegaly with an increased Bcl-6 expression profile in splenocytes. We utilized a murine model of Bcl-6 driven DLBCL to further explore the role of RhoH in malignant behaviour by crossing RhohKO mice with Iµ-HABcl-6 transgenic (Bcl-6Tg) mice. The loss of Rhoh in Bcl-6Tg mice led to a more rapid disease progression. Mechanistically, we demonstrated that deletion of Rhoh in these murine lymphoma cells was associated with decreased levels of the RhoH binding partner KAISO, a dual-specific Zinc finger transcription factor, de-repression of KAISO target Bcl-6, and downregulation of the BCL-6 target Blimp-1. Re-expression of RhoH in RhohKOBcl-6Tg lymphoma cell lines reversed these changes in expression profile and reduced proliferation of lymphoma cells in vitro. These findings suggest a previously unidentified regulatory role of RhoH in the proliferation of tumour cells via altered BCL-6 expression. (250).

Buprenorphine Prevalence in DUID Cases in Southwestern Virginia: Case Studies and Observations.

Buprenorphine, a semisynthetic mixed agonist/antagonist opioid used primarily for the treatment of opioid use disorder, was reported in 194 driving under the influence of drugs (DUID) cases in Southwestern Virginia during the period from 2017 through 2019. Identifying and confirming buprenorphine in DUID cases is common in this region. Interpretation is complex due to the large range of concentrations of buprenorphine found in blood and frequent combinations with other therapeutic and abused drugs. Buprenorphine was identified by immunoassay and quantified by liquid chromatography-tandem mass spectrometry. A sensitive method was necessary as one-third of concentrations of buprenorphine and/or norbuprenorphine were <1.0 µg/L. Concentrations of buprenorphine ranged from <0.5 to 11 µg/L (mean 2.5 µg/L, median 1.8 µg/L) and concentrations of norbuprenorphine ranged from <0.5 to >20 µg/L (mean 3.3 µg/L, median 2.2 µg/L). Buprenorphine polysubstance use was common. Only 10% of the cases examined did not contain other drugs confirmed in routine DUID screening tests. The most common drug groups confirmed were benzodiazepines, amphetamines and cannabinoids. The DUID case histories presented represent examples of buprenorphine abuse, buprenorphine with no other drug groups, buprenorphine combined with other drug groups, cases consistent with impairment and cases with minimal impairment. Central nervous system depressant and narcotic analgesic symptoms were commonly observed; however, some cases contained stimulant symptoms. Buprenorphine-to-norbuprenorphine (B/NB) ratios had a mean and median ratio of 1.1 and 0.8, respectively. B/NB ratios >3.0 were found in 4.7% of the cases. The finding of a higher B/NB ratio may indicate a more recent buprenorphine administration and a greater potential for impairment. No relationship between the concentration of buprenorphine and/or norbuprenorphine in blood and the performance on drug recognition expert evaluation or standardized field sobriety tests could be determined.

A Case of Adrenal Crisis-Induced Stress Cardiomyopathy.

We report a case of a 36-year-old male who presented to the emergency department with complaints of weakness. On presentation the patient was hypotensive, hyperkalemic, and hyponatremic. The patient experienced a sudden cardiac arrest in the computed tomography (CT) scanner moments after arrival. Electrocardiogram (EKG) demonstrated PR prolongation and widened QRS. Echocardiogram demonstrated a left ventricular ejection fraction of 26%-30% with evidence of severe hypokinesis of the mid antero-septal and inferior-septal segments of the left ventricle. CT of the chest, abdomen, and pelvis demonstrated hypoplastic/atrophic adrenal glands. Total cortisol level was undetectable by lab measurement. The patient was diagnosed with stress cardiomyopathy secondary to adrenal crisis. He was managed with hydrocortisone and eventually made a full clinical recovery and improvement in left ventricular ejection fraction. This article references the rarity of this phenomenon and its relevance to early clinical detection.

A Fatal Extrapulmonary Manifestation of COVID-19.

Coronavirus disease 2019 (COVID-19) grew to pandemic proportions in 2020. Research has shown that the causative virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses the angiotensin-converting enzyme II (ACE-II) receptor to attack host cells. These ACE-II receptors are present essentially in all organs, acting as a route of entry for SARS-CoV-2 to cause a wide variety of manifestations. There is growing research showing the neurologic effects of COVID-19. There have been several cases of encephalopathy, stroke, and encephalitis associated with COVID-19, however, intraventricular hemorrhages (IVH) have rarely been reported. Here we present a case of an IVH in the setting of COVID-19. A 32-year-old male with no past medical history, and not taking any medications, presented to the emergency room after acute onset loss of consciousness. Inflammatory markers were elevated, and computerized tomographic (CT) of the head and chest showed an intraventricular hemorrhage and bilateral interstitial infiltrates, respectively. Although possibly coincidental, this may represent a rare extrapulmonary fatal manifestation of COVID-19. With the growing evidence of neurologic presentations in patients with COVID-19, clinicians should maintain a high index of suspicion for COVID-19 to cause fatal extrapulmonary manifestations.

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

Dissecting ELANE neutropenia pathogenicity by human HSC gene editing.

Severe congenital neutropenia (SCN) is a life-threatening disorder most often caused by dominant mutations of ELANE that interfere with neutrophil maturation. We conducted a pooled CRISPR screen in human hematopoietic stem and progenitor cells (HSPCs) that correlated ELANE mutations with neutrophil maturation potential. Highly efficient gene editing of early exons elicited nonsense-mediated decay (NMD), overcame neutrophil maturation arrest in HSPCs from ELANE-mutant SCN patients, and produced normal hematopoietic engraftment function. Conversely, terminal exon frameshift alleles that mimic SCN-associated mutations escaped NMD, recapitulated neutrophil maturation arrest, and established an animal model of ELANE-mutant SCN. Surprisingly, only -1 frame insertions or deletions (indels) impeded neutrophil maturation, whereas -2 frame late exon indels repressed translation and supported neutrophil maturation. Gene editing of primary HSPCs allowed faithful identification of variant pathogenicity to clarify molecular mechanisms of disease and encourage a universal therapeutic approach to ELANE-mutant neutropenia, returning normal neutrophil production and preserving HSPC function.

Aortic thrombosis and renal infarction in a young female with patent foramen ovale and COVID-19 antibody.

Thrombotic complications in patients with prior COVID-19 infection raises concern for a persistent hypercoagulable state among these patients. Thus, there is a dire need for further research aimed at anticoagulation guidelines for the same.

Coating Reactions on Vanadium and V-Si-B Alloys during Powder Pack-Cementation.

Alloys in the V-Si-B system are a new and promising class of light-weight refractory metal materials for high temperature applications. Presently, the main attention is focused on three-phase alloy compositions that consist of a vanadium solid solution phase and the two intermetallic phases V3Si and V5SiB2. Similar to other refractory metal alloys, a major drawback is the poor oxidation resistance. In this study, initial pack-cementation experiments were performed on commercially available pure vanadium and a three-phase alloy V-9Si-5B to achieve an oxidation protection for this new type of high temperature material. This advance in oxidation resistance now enables the attractive mechanical properties of V-Si-B alloys to be used for high temperature structural applications.

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy.

In this work we provide preclinical data to support initiation of a first-in-human trial for sickle cell disease (SCD) using an approach that relies on reversal of the developmental fetal-to-adult hemoglobin switch. Erythroid-specific knockdown of BCL11A via a lentiviral-encoded microRNA-adapted short hairpin RNA (shRNAmiR) leads to reactivation of the gamma-globin gene while simultaneously reducing expression of the pathogenic adult sickle ß-globin. We generated a refined lentiviral vector (LVV) BCH-BB694 that was developed to overcome poor vector titers observed in the manufacturing scale-up of the original research-grade LVV. Healthy or sickle cell donor CD34+ cells transduced with Good Manufacturing Practices (GMP)-grade BCH-BB694 LVV achieved high vector copy numbers (VCNs) >5 and gene marking of >80%, resulting in a 3- to 5-fold induction of fetal hemoglobin (HbF) compared with mock-transduced cells without affecting growth, differentiation, and engraftment of gene-modified cells in vitro or in vivo. In vitro immortalization assays, which are designed to measure vector-mediated genotoxicity, showed no increased immortalization compared with mock-transduced cells. Together these data demonstrate that BCH-BB694 LVV is non-toxic and efficacious in preclinical studies, and can be generated at a clinically relevant scale in a GMP setting at high titer to support clinical testing for the treatment of SCD.

Design and construction of a gradient coil for high resolution marmoset imaging.

A gradient coil with integrated second and third order shims has been designed and constructed for use inside an actively shielded 310 mm horizontal bore 9.4 T small animal MRI. An extension of the boundary element method, to minimise the power deposited in conducting surfaces, was used to design the gradients, and a boundary element method with a constraint on mutual inductance was used to design the shims. The gradient coil allows for improved imaging performance and was optimized for an imaging region appropriate for marmoset imaging studies. Efficiencies of 1.5 mT m-1 A-1 were achieved in a 15 cm wide bore while maintaining gradient uniformity ≤5% over the 8 cm region of interest. Two new cooling methods were implemented which allowed the gradient coil to operate at 100 A RMS, 25 % of max current with a temperature rise below 30 C.

Cardiovascular and Psychophysical Response to Repetitive Lifting Tasks in Women.

BACKGROUND: Understanding the cardiovascular and psychophysical demands of repetitive lifting tasks is important in job design strategies. This study determined the cardiovascular (oxygen consumption (VO2) and heart rate (HR) and psychophysical response to repetitive lifting tasks in women. METHODS: Ten female (age 27 ± 5 yrs) participants transferred 11.4, 15.9, and 20.5 kg weights back and forth from a rung 40.6 cm high to a rung 156.2 cm high. Rungs were 195.6 cm apart horizontally. Three, 10 minute bouts (1 = 11.4 kg; 2 = 15.9 kg; 3 = 20.5 kg) were performed at 6 lifts per minute. Cardiovascular and psychophysical (rating of perceived exertion, RPE) parameters were monitored throughout the bouts. VO2max and HRmax were determined via a maximal treadmill test. RESULTS: VO2, HR, and RPE were significantly different between each work bout (p < 0.01), with each outcome variable increasing as load increased. VO2max and HRmax equaled 46.5 ± 7.5 mL·kg-1·min-1 and 191 ± 11 bpm, respectively. Work at 11.4 kg was performed at 38% VO2max and 63% HRmax; at 15.9 kg at 41% VO2max and 72% HRmax; and at 20.5 kg at 49% VO2max and 81% HRmax. RPE at 11.4, 15.9, and 20.5 kgs were: 8.4 ± 1.6, 11.4 ± 1.9, and 15.0 ± 2.2. CONCLUSION: During these repetitive lifting tasks, metabolic cost and perceived exertion increased with weight lifted; average work intensity ranged from 63 to 81% of HRmax and 38 to 49% of VO2max. Results have important implications in relation to job pacing and design, and worksite health promotion strategies aimed at reducing work place injury.

Comparison of Forward and Reverse Wingate Anaerobic Tests: A Brief Technical Note.

BACKGROUND: The Wingate anaerobic test (WAT) is traditionally performed in the forward pedaling direction on a cycle ergometer. However, reverse (backward) pedaling during a WAT test may be a novel way to convey meaningful information related to performance and rehabilitation. This study compared peak power measurements between 30-second forward pedaling WAT (FWAT) with a 30-second reverse pedaling WAT (RWAT). METHODS: 10 male and 10 female participants (age 27.6 ± 7.31 yrs, mass 74.9 ± 21.3 kg and height 172.6 ± 10.9 cm) volunteered to participate. Participants performed one FWAT and one RWAT at 7.5% of body mass on a specially modified Monark cycle ergometer. Tests were separated 2 days of rest. Peak power output (PPO), mean power output (MPO), relative PPO (RPPO), relative MPO (RMPO), fatigue index (%FI), and rating of perceived exertion (RPE) were measured. RESULTS: The FWAT power measurements were all significantly greater (p < 0.05) than RWAT power measurements except MPO (p > 0.05); and that RPE was significantly greater (p < 0.05) in FWAT than RWAT. Specifically, FWAT vs. RWAT (M ± SD) are as follows: PPO watts (w) = 731.7 ± 237.1 vs. 529.6 ± 192.2; RPPO w/kg = 10.2 ± 2.3 vs. 7.2 ± 1.6; MPO w = 510.2 ± 162.1 vs. 415.1 ± 146.2; RMPO w/kg = 7.3 ± 1.5 vs. 5.8 ± 1.3; %FI = 49.2 ± 8.7 vs. 37.4 ± 13.7; and RPE = 19.4 ± 1.1 vs. 15.8 ± 1.5. Gender did not impact the relative differences in these relationships. CONCLUSION: Practitioners and clinicians may use this information to begin to understand the power and perceived exertion relationships of forward versus reverse pedaling during a WAT; exercise prescription for rehabilitation and performance may benefit.

Low-cost optical scanner and 3-dimensional printing technology to create lead shielding for radiation therapy of facial skin cancer: First clinical case series.

PURPOSE: Three-dimensional printing has been implemented at our institution to create customized treatment accessories, including lead shields used during radiation therapy for facial skin cancer. To effectively use 3-dimensional printing, the topography of the patient must first be acquired. We evaluated a low-cost, structured-light, 3-dimensional, optical scanner to assess the clinical viability of this technology. METHODS AND MATERIALS: For ease of use, the scanner was mounted to a simple gantry that guided its motion and maintained an optimum distance between the scanner and the object. To characterize the spatial accuracy of the scanner, we used a geometric phantom and an anthropomorphic head phantom. The geometric phantom was machined from plastic and included hemispherical and tetrahedral protrusions that were roughly the dimensions of an average forehead and nose, respectively. Polygon meshes acquired by the optical scanner were compared with meshes generated from high-resolution computed tomography images. Most optical scans contained minor artifacts. Using an algorithm that calculated the distances between the 2 meshes, we found that most of the optical scanner measurements agreed with those from the computed tomography scanner within approximately 1 mm for the geometric phantom and approximately 2 mm for the head phantom. We used this optical scanner along with 3-dimensional printer technology to create custom lead shields for 10 patients receiving orthovoltage treatments of nonmelanoma skin cancers of the face. Patient, tumor, and treatment data were documented. RESULTS: Lead shields created using this approach were accurate, fitting the contours of each patient's face. This process added to patient convenience and addressed potential claustrophobia and medical inability to lie supine. CONCLUSIONS: The scanner was found to be clinically acceptable, and we suggest that the use of an optical scanner and 3-dimensional printer technology become the new standard of care to generate lead shielding for orthovoltage radiation therapy of nonmelanoma facial skin cancer.