US regulatory considerations for low field magnetic resonance imaging systems.

Although there has been a resurgence of interest in low field magnetic resonance imaging (MRI) systems in recent years, low field MRI is not a new concept. FDA has a long history of evaluating the safety and effectiveness of MRI systems encompassing a wide range of field strengths. Many systems seeking marketing authorization today include new technological features (such as artificial intelligence), but this does not fundamentally change the regulatory paradigm for MR systems. In this review, we discuss some of the US regulatory considerations for low field magnetic resonance imaging (MRI) systems, including applicability of existing laws and regulations and how the U.S. Food and Drug Administration (FDA) evaluates low field MRI systems for market authorization. We also discuss regulatory considerations in the review of low field MRI systems incorporating novel AI technology. We foresee that MRI systems of all field strengths intended for general diagnostic use will continue to be evaluated for marketing clearance by the metric of substantial equivalence set forth in the premarket notification pathway.

Secular trends in the utility of SGLT-2 inhibitors in heart failure patients with type 2 diabetes mellitus across Metro South Health hospitals in South-East Queensland.

BACKGROUND: The 2018 Australian Heart Failure (HF) guidelines strongly recommended commencing sodium-glucose co-transporter-2 inhibitors (SGLT-2is) in HF patients with type 2 diabetes mellitus (T2DM). The uptake of SGLT-2is for HF patients with T2DM in our health service is unknown. AIMS: To determine the adoption of the 2018 HF guidelines by assessing the temporal trends of SGLT-2is' usage in HF patients with T2DM at Metro South Health (MSH) hospitals, in South-East Queensland. METHODS: Retrospective analysis of all HF patients (ejection fraction (EF) < 50%) with T2DM who were managed within MSH hospitals between June 2018 and June 2021. RESULTS: A total of 666 patients met the inclusion criteria with 918 HF encounters. Mean age was 72 years and 71% were male (473/666). Mean EF was 30% (SD ± 11%), and mean estimated glomerular filtration rate was 48 mL/min/1.73 m2 (SD ± 25). Fifty-four per cent (362/666) had contraindications to SGLT-2is. Among those without contraindications, there was a five-fold increase in the utility of SGLT-2is, 7% (2/29) before versus 38% (103/275) after implementation of the HF guidelines (P < 0.001). Patients on SGLT-2is were younger (64 years vs 69 years, P = 0.002) and had a lower number of HF hospitalisations (1.1 vs 2.1, P = 0.01). CONCLUSIONS: During the study period, 54% of our HF patients with T2DM were not on SGLT-2is due to prescribing guidelines/limitations in the Australian context. We observed a five-fold significant increase in the uptake of SGLT-2is before and after implementation of HF guidelines among patients without contraindications to SGLT-2is. There were significantly fewer HF hospitalisations among patients on SGLT-2is compared to those without.

Analysis of patient-specific NF1 variants leads to functional insights for Ras signaling that can impact personalized medicine.

We have created a panel of 29 NF1 variant complementary DNAs (cDNAs) representing missense variants, many with clinically relevant phenotypes, in-frame deletions, splice variants, and nonsense variants. We have determined the functional consequences of the variants, assessing their ability to produce mature neurofibromin and restore Ras signaling activity in NF1 null (-/-) cells. cDNAs demonstrate variant-specific differences in neurofibromin protein levels, suggesting that some variants lead to neurofibromatosis type 1 (NF1) gene or protein instability or enhanced degradation. When expressed at high levels, some variant proteins are still able to repress Ras activity, indicating that the NF1 phenotype may be due to low protein abundance. In contrast, other variant proteins are incapable of repressing Ras activity, indicating that some do not functionally engage Ras and stimulate GTPase activity. We observed that effects on protein abundance and Ras activity can be mutually exclusive. These assays allow us to categorize variants by functional effects, may help to classify variants of unknown significance, and may have future implications for more directed therapeutics.

Glottalized lateral in Rikvani Andi: an acoustic study.

Glottalized sonorants are a rare sound type that has been under scrutiny for a number of reasons of general relevance to the phonetic theory. It has been claimed that the timing of glottalization of glottalized sonorants may shift in accordance with the position in the syllable onset (pre-glottalization) or coda (post-glottalization), to provide a cue for its place of articulation; other studies argued against this claim. The paper investigates acoustic properties of the glottalized lateral in Rikvani Andi, a one-village dialect of Andi (East Caucasian). Based on the data from elicitations and free narratives, we consider the acoustic correlates that have been argued in the literature to differentiate glottalized sonorants from their modal counterparts, including aperiodicity, intensity, duration and spectral tilt. In Rikvani Andi, all of the correlates prove to be statistically significant in recordings of isolated words, but the differences tend to decrease in free narratives. The timing of glottalization does not support the existing generalizations - while the glottalized lateral only occurs in Rikvani Andi in the syllable onset, it tends to be mid- to post-glottalized. We discuss two possible explanations of why the Rikvani Andi glottalized sonorant fails to comply with typological expectations.

A randomized cohort study of the efficacy of PO magnesium in the treatment of acute concussions in adolescents.

INTRODUCTION/STUDY OBJECTIVE: Concussions are becoming a growing concern in society today with one out of every five adolescents being affected. This accounts for 1.6 to 3.8 million emergency department visits annually. The current standard of care involves an initial period of mental rest with symptomatic care and symptom-based return to daily activities/sports. High dose IV magnesium has been proven to be neuroprotective in severe TBI. We hypothesized that oral magnesium replacement following a concussion will decrease the overall symptomatic period allowing a quicker return to functional baseline. METHODS: We used a randomized cohort study involving patients aged 12-18 who presented within 48 h after a concussion. Our study design had a treatment arm including acetaminophen, ondansetron, and magnesium PO and a placebo arm of acetaminophen and ondansetron. We then utilized the Post- Concussion Severity Score (PCSS) to evaluate the extent of the patient's symptoms. This score was collected immediately prior to obtaining medications, 1 h, 48 h, and 120 h after starting the study. The study relied on outpatient follow up through phone conversations, and a Sports Medicine clinic locally. RESULTS: Our data shows that there was a statistically significant decrease in the PCSS at 48 h (p = 0.016) in the magnesium group relative to the placebo treatment arm. This study does imply that magnesium supplementation has potential benefit in treatment of concussions acutely. CONCLUSION: Oral magnesium replacement decreases symptoms acutely following a concussion and should be provided with symptomatic management following a concussion in the emergency setting.

Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism.

Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li-Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival. Systems-level analyses identified that expression of SFRP2 increases during LFS OS development and can induce angiogenesis. Ectopic SFRP2 overexpression in normal osteoblast precursors is sufficient to suppress normal osteoblast differentiation and to promote OS phenotypes through induction of oncogenic molecules such as FOXM1 and CYR61 in a ß-catenin-independent manner. Conversely, inhibition of SFRP2, FOXM1, or CYR61 represses the tumorigenic potential. In summary, these findings demonstrate the oncogenic role of SFRP2 in the development of p53 mutation-associated OS and that inhibition of SFRP2 is a potential therapeutic strategy.

Development of best practice recommendations to enhance access to and use of formal community care services for people with dementia in Europe: a Delphi process conducted by the Actifcare project.

OBJECTIVES: Home-dwelling people with dementia and their informal carers experience barriers impeding access to community care services. This study is a part of the Actifcare project where eight countries participated. The aim was to achieve consensus on best practice recommendations for enhancing access to and use of formal community care services. METHOD: A Delphi consensus process was conducted. A total of 48 professional experts, 14 people with dementia and 20 informal carers rated the importance of 72 statements on a 7-point Likert scale. Consensus was based on the median and level of dispersion. RESULTS: Sixty-two statements reached consensus, resulting in three categories of recommendations. An appointed contact person was central in Recommendations to enhance access. Coordination and flexibility in setting and type of services were among the Recommendations to enhance use. Training of health care personnel and person-centred care were central Recommendations that can facilitate access or use indirectly. CONCLUSION: The Actifcare Best Practice Recommendations suggest practical measures that can be taken by decision makers to enhance access and use of community care services, and thereby enhance quality of care and quality of life for home dwelling people with dementia and their informal carers.

Association of malnutrition with geriatric assessment impairments and health-related quality of life among older adults with gastrointestinal malignancies.

BACKGROUND: A majority of older adults with cancer develop malnutrition; however, the implications of malnutrition among this vulnerable population are poorly understood. The goal of this study was to quantify the prevalence of nutrition related-symptoms and malnutrition among older adults with gastrointestinal (GI) malignancies and the association of malnutrition with geriatric assessment (GA) impairment, health-related quality of life (HRQoL), and health care utilization. METHODS: We performed a cross-sectional study of older adults (≥60 years) who were referred to the GI Oncology clinic at the University of Alabama at Birmingham. Participants underwent the Cancer & Aging Resilience Evaluation survey that includes the abbreviated Patient-Generated Subjective Global Assessment of nutrition. Nutrition scores were dichotomized into normal (0-5) and malnourished (≥6), and multivariate analyses adjusted for demographics, cancer type, and cancer stage were used to examine associations with GA impairment, HRQoL, and health care utilization. RESULTS: A total of 336 participants were included (men, 56.8%; women, 43.2%), with a mean age of 70 years (standard deviation, ±7.2 years) and colorectal cancer (33.6%) and pancreatic cancer (24.4%) being the most common diagnoses. Overall, 52.1% of participants were identified as malnourished. Malnutrition was associated with a higher prevalence of several GA impairments, including 1 or more falls (adjusted odds ratio [aOR], 2.1), instrumental activities of daily living impairment (aOR, 4.1), and frailty (aOR, 8.2). Malnutrition was also associated with impaired HRQoL domains; both physical (aOR, 8.7) and mental (aOR, 5.0), and prior hospitalizations (aOR, 2.2). CONCLUSION: We found a high prevalence of malnutrition among older adults with GI malignancies that was associated with increased GA impairments, reduced HRQoL, and increased health care utilization.

Ensembl Genomes 2018: an integrated omics infrastructure for non-vertebrate species.

Ensembl Genomes (http://www.ensemblgenomes.org) is an integrating resource for genome-scale data from non-vertebrate species, complementing the resources for vertebrate genomics developed in the Ensembl project (http://www.ensembl.org). Together, the two resources provide a consistent set of programmatic and interactive interfaces to a rich range of data including genome sequence, gene models, transcript sequence, genetic variation, and comparative analysis. This paper provides an update to the previous publications about the resource, with a focus on recent developments and expansions. These include the incorporation of almost 20 000 additional genome sequences and over 35 000 tracks of RNA-Seq data, which have been aligned to genomic sequence and made available for visualization. Other advances since 2015 include the release of the database in Resource Description Framework (RDF) format, a large increase in community-derived curation, a new high-performance protein sequence search, additional cross-references, improved annotation of non-protein-coding genes, and the launch of pre-release and archival sites. Collectively, these changes are part of a continuing response to the increasing quantity of publicly-available genome-scale data, and the consequent need to archive, integrate, annotate and disseminate these using automated, scalable methods.

[THE SIGNIFICANCE OF TORSIONAL NYSTAGMUS ON THE ROLL REST].

OBJECTIVES: To characterize a subgroup of patients that were diagnosed with benign paroxysmal positional vertigo of the posterior semicircular canal pBPPV, with findings of geotropic-torsional nystagmus on the roll rest (RT) that intensified on the Dix-Hallpike exam (DH). METHODS: The study population consisted of patients with the diagnosis of pBPPV. First, the roll test (RT) and then the DH test were performed. Characteristics were compared between group 1 - patients with a negative RT and positive DH (in keeping with pBPPV), and group 2- patients with a torsional-geotropic nystagmus on the RT, that intensified on DH. Patients from both groups were treated with the Epley maneuver. If the nystagmus continued, further Epley maneuvers were performed until it subsided. Patients continued follow-up visits until they were asymptomatic and the exam was normal. RESULTS: Ninety-one consecutive patients were diagnosed with pBPPV. Sixty nine patients belonged to group 1 and 22 to group 2. The average age was just under 60 and the percentage of males was 22 in group 1 and 45 in group 2, which was significantly different. Additional significant differences included: 1. Symptom duration, in days, until diagnosis (43.2 in group 1 and 22.3 in group 2). 2. The fraction of patients requiring only one Epley maneuver in the first treatment session was 77.4% in group 1 and 23.4% in group 2. CONCLUSIONS: The appearance of a torsional-geotropic nystagmus during RT is most probably due to pBPPV, with a more severe clinical presentation, requiring more Epley maneuvers than in patients with a negative RT. These patients had increased symptoms and were diagnosed earlier. However, the response to treatment was similar in both groups. It is most important to differentiate these patients in group 2 from patients with BPPV arising from the horizontal semicircular canal, which has different clinical features and is treated differently.

Granulocyte colony-stimulating factor mobilizes dormant hematopoietic stem cells without proliferation in mice.

Granulocyte colony-stimulating factor (G-CSF) is used clinically to treat leukopenia and to enforce hematopoietic stem cell (HSC) mobilization to the peripheral blood (PB). However, G-CSF is also produced in response to infection, and excessive exposure reduces HSC repopulation capacity. Previous work has shown that dormant HSCs contain all the long-term repopulation potential in the bone marrow (BM), and that as HSCs accumulate a divisional history, they progressively lose regenerative potential. As G-CSF treatment also induces HSC proliferation, we sought to examine whether G-CSF-mediated repopulation defects are a result of increased proliferative history. To do so, we used an established H2BGFP label retaining system to track HSC divisions in response to G-CSF. Our results show that dormant HSCs are preferentially mobilized to the PB on G-CSF treatment. We find that this mobilization does not result in H2BGFP label dilution of dormant HSCs, suggesting that G-CSF does not stimulate dormant HSC proliferation. Instead, we find that proliferation within the HSC compartment is restricted to CD41-expressing cells that function with short-term, and primarily myeloid, regenerative potential. Finally, we show CD41 expression is up-regulated within the BM HSC compartment in response to G-CSF treatment. This emergent CD41Hi HSC fraction demonstrates no observable engraftment potential, but directly matures into megakaryocytes when placed in culture. Together, our results demonstrate that dormant HSCs mobilize in response to G-CSF treatment without dividing, and that G-CSF-mediated proliferation is restricted to cells with limited regenerative potential found within the HSC compartment.

Bright radio emission from an ultraluminous stellar-mass microquasar in M 31.

A subset of ultraluminous X-ray sources (those with luminosities of less than 10(40) erg s(-1); ref. 1) are thought to be powered by the accretion of gas onto black holes with masses of ∼5-20M cicled dot, probably by means of an accretion disk. The X-ray and radio emission are coupled in such Galactic sources; the radio emission originates in a relativistic jet thought to be launched from the innermost regions near the black hole, with the most powerful emission occurring when the rate of infalling matter approaches a theoretical maximum (the Eddington limit). Only four such maximal sources are known in the Milky Way, and the absorption of soft X-rays in the interstellar medium hinders the determination of the causal sequence of events that leads to the ejection of the jet. Here we report radio and X-ray observations of a bright new X-ray source in the nearby galaxy M 31, whose peak luminosity exceeded 10(39) erg s(-1). The radio luminosity is extremely high and shows variability on a timescale of tens of minutes, arguing that the source is highly compact and powered by accretion close to the Eddington limit onto a black hole of stellar mass. Continued radio and X-ray monitoring of such sources should reveal the causal relationship between the accretion flow and the powerful jet emission.

Pterostilbene down-regulates hTERT at physiological concentrations in breast cancer cells: Potentially through the inhibition of cMyc.

Human telomerase reverse transcriptase (hTERT) encodes the catalytic subunit of telomerase, which has been shown to be upregulated in many cancers. Pterostilbene is a naturally occurring stilbenoid and phytoalexin found primarily in blueberries that exhibits antioxidant activity and inhibits the growth of various cancer cell types. Therefore, the aim of this study was to determine whether treatment with pterostilbene, at physiologically achievable concentrations, can inhibit the proliferation of breast cancer cells and down-regulate the expression of hTERT. We found that pterostilbene inhibits the cellular proliferation of MCF-7 and MDA-MB-231 breast cancer cells in both a time- and dose-dependent manner, without significant toxicity to the MCF10A control cells. Pterostilbene was also shown to increase apoptosis in both breast cancer cell lines. Dose-dependent cell cycle arrest in G1 and G2/M phase was observed after treatment with pterostilbene in MCF-7 and MDA-231 cells, respectively. hTERT expression was down-regulated after treatment in both a time- and dose-dependent manner. Pterostilbene also reduced telomerase levels in both cell lines in a dose-dependent manner. Moreover, cMyc, a proposed target of the pterostilbene-mediated inhibition of hTERT, was down-regulated both transcriptionally and posttranscriptionally after treatment. Collectively, these findings highlight a promising use of pterostilbene as a natural, preventive, and therapeutic agent against the development and progression of breast cancer.

The association between otogenic lateral sinus thrombosis and thrombophilia - A long-term follow-up.

PURPOSE: Otogenic lateral sinus thrombosis (OLST) is an intracranial, potentially life-threatening complication of acute and chronic otitis media. Since congenital thrombophilic disorders are risk factors for cerebral venous thrombosis, OLST may be related to thrombophilia. The aim of our study was twofold: to evaluate whether patients who suffered from OLST in childhood also have thrombophilia, and whether these patients experienced thromboembolic episodes in future years. STUDY DESIGN: Retrospective case series. METHODS: The medical charts of all children hospitalized for OLST at Soroka University Medical Center of Israel, a tertiary referral hospital, from January 1983 to September 2014 were reviewed. The patients were invited for a follow-up visit and comprehensive medical history was taken along with a physical examination and laboratory work-up for thrombophilia. MAIN FINDINGS: Seven patients were included in the study. Of these, 3 (43%) had results suggesting thrombophilic disorders manifested by elevated levels of factor IX and decreased levels of protein S activity (n = 1), decreased levels of proteins C and S activity (n = 1), and elevated levels of antibodies to cardiolipin (n = 1). No patients experienced clear thrombophilic events; however, 2 patients (29%) with later proven thrombophilia suffered neurologic sequelae, possibly suggesting thrombophilic events. CONCLUSIONS: Pediatric OLST secondary to acute otitis media and mastoiditis may reflect an underlying thrombophilia. Laboratory work-up for thrombophilia should be performed, and anticoagulant treatment may be warranted in managing these patients.

Expectations of health care quality among rural Maya villagers in Sololá Department, Guatemala: a qualitative analysis.

BACKGROUND: Indigenous populations in Latin America have worse health outcomes than their nonindigenous counterparts. Differences in access to and use of biomedical resources may explain some of the observed disparities. Efforts to address these differences could be aided in part by better understanding the socio-medical contexts in which they occur. METHODS: We performed a qualitative analysis of field notes collected during a 2008 program evaluation of a health post in a rural Maya village in Sololá Department, Guatemala. Forty-one interviews were conducted among a community-based convenience sample of adult men and women. Interviews focused on experiences, perceptions, and behaviors related to the local biomedical and ethnomedical health care resources. RESULTS: Penetrance of the local health post was high, with most (90%) of respondents having accessed it within the prior five years. The prevailing attitude toward the health post was positive. We identified facilitators and barriers to health post use that corresponded with three thematic areas: clinic operations, visits and consultations, and medical resources. Proximity to the home, free consultations and medications, and social support services were among the most commonly cited facilitators. Barriers included limited clinic hours, medication stock-outs, provision of care that did not meet patient expectations, and unavailability of diagnostic tests. CONCLUSIONS: In a rural Maya community in Guatemala, operational and quality-based factors, independent of sociocultural considerations, informed the perception of and decision to access biomedical resources. Interventions that address these factors may increase health care utilization and alleviate some of the health disparities that accompany indigeneity in Guatemala and similar contexts.

Applications of stem cell biology to oculoplastic surgery.

PURPOSE OF REVIEW: The review examines the utility of stem cell biology in ophthalmology and oculoplastic surgery. RECENT FINDINGS: The applicability of stem cell biology varies across a range of different subfields within ophthalmology and oculoplastic surgery. Resident stem cells have been identified in the lacrimal gland, corneal limbus, orbital fat, and muscles of the eye, and can potentially be applied for in-vitro cell and organ cultures with the intent of disease modeling and transplants. The discovery of adipocyte-derived stem cells offered a potentially powerful tool for a variety of oculoplastic applications, such as wound healing, skin rejuvenation, and burn therapeutics. Several groups are currently identifying new uses for stem cells in oculoplastic surgery. SUMMARY: The need for stem cell treatment spans a wide array of subfields within ophthalmology, ranging from reconstruction of the eyelid to the generation of artificial lacrimal glands and oncological therapeutics. The advent of induced pluripotent stem cells opened the realm of regenerative medicine, making the modeling of patient-specific diseases a possibility. The identification and characterization of endogenous stem cell populations in the eye makes it possible to obtain specific tissues through induced pluripotent stem cells differentiation, permitting their use in transplants for oculoplastic surgery.

Ensembl Genomes 2013: scaling up access to genome-wide data.

Ensembl Genomes (http://www.ensemblgenomes.org) is an integrating resource for genome-scale data from non-vertebrate species. The project exploits and extends technologies for genome annotation, analysis and dissemination, developed in the context of the vertebrate-focused Ensembl project, and provides a complementary set of resources for non-vertebrate species through a consistent set of programmatic and interactive interfaces. These provide access to data including reference sequence, gene models, transcriptional data, polymorphisms and comparative analysis. This article provides an update to the previous publications about the resource, with a focus on recent developments. These include the addition of important new genomes (and related data sets) including crop plants, vectors of human disease and eukaryotic pathogens. In addition, the resource has scaled up its representation of bacterial genomes, and now includes the genomes of over 9000 bacteria. Specific extensions to the web and programmatic interfaces have been developed to support users in navigating these large data sets. Looking forward, analytic tools to allow targeted selection of data for visualization and download are likely to become increasingly important in future as the number of available genomes increases within all domains of life, and some of the challenges faced in representing bacterial data are likely to become commonplace for eukaryotes in future.

Randomized study comparing inflammatory response after tonsillectomy versus tonsillotomy.

To determine if there was a difference in the inflammatory reaction after tonsil surgery with "traditional" techniques (tonsillectomy and adenoidectomy or TA) compared to partial intracapsular tonsillectomy and adenoidectomy (PITA). DESIGN: Randomized, double-blind study. SETTING: tertiary care academic hospital. Children under the age of 16 years with a diagnosis of obstructive sleep disordered breathing were randomly allocated into three study groups: TA with electrocautery (n = 34), PITA with CO2 laser (n = 30) and PITA with debrider (n = 28). All of the children underwent adenoidectomy with a current at the same surgical procedure. MAIN OUTCOME MEASURE: c-reactive protein level (CRP) was the primary endpoint. In addition, the following were assessed: white blood cells (WBC), neutrophils (NEU), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Pre- and post-procedure measurements were compared between the groups. Parents filled out a questionnaire daily during the first postoperative week assessing pain, swallowing and snoring. CRP levels ascended higher in the PITA groups after surgery (p = 0.023), WBC and NEU showed the same pattern, IL-6 levels were higher in PITA group and there was no difference in TNF-alpha levels between the two types of procedures. Postoperative pain and postoperative hemorrhage were significantly lower in the PITA groups as compared to the TA group (p = 0.01 and 0.048). PITA in comparison to TA is associated with lower morbidity; however, the inflammatory response does not differ significantly in the first 24 h after surgery. Additional long-term studies assessing efficacy of PITA are warranted. LEVEL OF EVIDENCE: Level 1, prospective randomized controlled trial.