Publications by authors named "S Lorraine Martin"

7,771 Publications

  • Page 1 of 1

Association of weight status and carbohydrate intake with gestational weight gain.

Clin Obes 2021 Apr 9:e12455. Epub 2021 Apr 9.

Department of Nutrition, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Test the hypothesis that women with obesity have greater gestation weight gain (GWG) with a moderately higher, vs lower, carbohydrate (CHO) diet, independent of energy intake, whereas GWG for women of normal weight would not differ by CHO group. This was a secondary analysis of data collected from glucose tolerant women with normal weight (NW) or obesity in pregnancy. Women completed a three-day food diary 16 to 20 weeks. A median split for percent kilocalories from CHO (median = 49.6%) categorized women into moderately highCHO vs lowCHO groups (n = 13-15/group). GWG was calculated between consent and the last prenatal care visit. A two-way ANOVA was used to examine whether there was an interaction between weight status and CHO group on GWG, independent of energy intake, time between consent and last prenatal visit, and age. Women in both highCHO groups consumed more sugars and starches compared to women in the lowCHO groups (P < .05). A significant interaction between weight status and CHO content of the diet was found (P < .05), such that, for women with obesity, those consuming a lowCHO diet had less GWG than those consuming a highCHO diet, whereas the pattern was opposite for women with NW. Results suggest that intake of a moderately lower CHO diet may help limit GWG among glucose tolerant women with obesity. Given that women in this study were eligible only if they had normal fasting glucose concentrations in early pregnancy, it is not clear if these results would generalize to all women with obesity during pregnancy.
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http://dx.doi.org/10.1111/cob.12455DOI Listing
April 2021

Nanoscale twinning in Fe-Mn-Al-Ni martensite: a backscatter Kikuchi diffraction study.

J Appl Crystallogr 2021 Feb 1;54(Pt 1):54-61. Epub 2021 Feb 1.

Institute of Materials Science, TU Bergakademie Freiberg, Gustav-Zeuner-Strasse 5, Freiberg, 09599, Germany.

Iron-based Fe-Mn-Al-Ni shape-memory alloys are of rather low materials cost and show remarkable pseudoelastic properties. To further understand the martensitic transformation giving rise to the pseudoelastic properties, different Fe-Mn-Al-Ni alloys have been heat treated at 1473 K and quenched in ice water. The martensite, which is formed from a body-centred cubic austenite, is commonly described as face-centered cubic (f.c.c.), even though there are also more complex, polytypical descriptions of martensite. The presently studied backscatter Kikuchi diffraction (BKD) patterns have been evaluated, showing a structure more complex than simple f.c.c. This structure can be described by nanoscale twins, diffracting simultaneously in the exciting volume. The twinned structure shows a tetragonal distortion, not uncommon for martensite in spite of the lack of interstitial elements. These features are evaluated by comparing the measured BKD patterns with dynamically simulated ones.
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http://dx.doi.org/10.1107/S1600576720013631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941309PMC
February 2021

Autologous Fat Grafting and the Occurrence of Radiation-Induced Capsular Contracture.

Ann Plast Surg 2021 Mar 24. Epub 2021 Mar 24.

From the Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Washington Medical Center, Seattle, WA Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Stanford, CA.

Introduction: Radiation therapy is a known risk factor for capsular contracture formation after implant-based breast reconstruction. Although autologous fat grafting (AFG) has been shown to reverse radiation-induced tissue fibrosis, its use as a prophylactic agent against capsular contraction has not been assessed in the clinical setting. In the setting of 2-stage implant-based reconstruction and postmastectomy radiation therapy, we explored the effect AFG has on the prevalence of capsular contracture.

Materials And Methods: A retrospective chart review of patients who underwent immediate tissue expander (TE) placement followed by postmastectomy radiation therapy and secondary implant-based reconstruction at our institution between January 2012 and December 2019 was performed. Patients were divided into 2 cohorts based on whether or not AFG was performed at the time of secondary reconstruction. The primary outcome of interest was the occurrence of capsular contracture after TE exchange.

Results: Overall 57 patients (57 breasts) were included, 33 of whom received AFG at the time of TE exchange. All but 1 patient underwent submuscular implant placement, and the mean follow-up was 1.96 years. There was no significant difference in the prevalence of medical comorbidities between the study groups.Capsular contracture occurred in 24 patients (42.1%). Seventeen of these patients had undergone AFG at the time of TE exchange (17/33 patients, 51.5%), and 7 of these patients had not (7/24 patients, 29.2%). Most of the capsular contracture cases were Baker grades III or IV (14 patients, 58.3%), and 50% of patients with capsular contracture of any grade ultimately required operative intervention. Multivariate logistic regression analysis demonstrated that AFG did not significantly influence the occurrence or severity of capsular contracture, or did not impact the need for operative intervention in this patient population.

Conclusions: Implant-based reconstruction of the irradiated breast is associated with high postoperative capsular contracture rates. Although AFG has shown promise in reversing radiation-induced dermal fibrosis, no protective effect on the development of capsular contracture after stage 2 reconstruction was observed in this study population. Further investigation in the form of randomized, prospective studies is needed to better assess the utility of AFG in preventing capsular contracture in irradiated patients.
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http://dx.doi.org/10.1097/SAP.0000000000002817DOI Listing
March 2021

Revision Rates in Prepectoral Versus Subpectoral Delayed-Immediate Autologous Breast Reconstruction.

Ann Plast Surg 2021 Mar 24. Epub 2021 Mar 24.

From the College of Medicine, SUNY Upstate Medical University, Syracuse, NY College of Medicine, University of Nebraska Medical Center, Omaha, NE Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University Medical Center, Stanford, CA.

Introduction: Breast reconstruction in the prepectoral plane has recently fallen into favor. Minimizing the number of revisionary procedures after reconstruction is an important factor in improving patient care, but long-term studies on the effects of prepectoral reconstruction are limited. In this study, we compare the revision rates after delayed-immediate, autologous reconstruction between prepectoral and subpectoral reconstructions.

Methods: Postoperative charts for all patients undergoing subpectoral or prepectoral delayed-immediate autologous breast reconstruction were retrospectively reviewed at our single tertiary-care institution between 2009 and 2018. Patient demographics, comorbidities, and oncologic history were recorded. Charts after second stage reconstruction were reviewed for up to eighteen months to determine if revisions were necessary. Data collected included the total number of surgeries performed, the average number of procedures performed during each surgery, and the type of revision that was performed. Statistical tests included the chi squared test, unpaired t-test, and logistic regressions.

Results: Data from 89 patients with 125 breast reconstructions were collected. There was a 41.6% of these that were prepectoral reconstructions (P), and 58.4% were subpectoral reconstructions (S). For both groups, nipple sparing, followed by skin sparing mastectomies were most common. Mastectomy rates were not statistically different. Fewer breasts in the prepectoral cohort required any revisions (P, 21.2% vs S, 47.9%; P = 0.002). The subpectoral cohort had higher rates of soft tissue rearrangement (P, 7.7% vs S, 21.9%, P = 0.032), fat grafting (P, 9.6% vs S, 27.4%; P = 0.014), and nipple reconstruction (P: 5.8% vs 20.5%, P = 0.020). Mean follow-up time was not significantly different between patient groups (P, 290.5 days vs S, 375.0 days, P = 0.142). Subpectoral expander placement was found to be the only variable independently predictive of requiring 1 or more revision (P = 0.034).

Conclusions: Breast reconstruction performed in the prepectoral plane is associated with lower overall rates of revisionary surgery. Rates of soft tissue rearrangement, fat grafting, and nipple reconstruction after autologous reconstruction trended higher in subpectoral reconstructions.
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http://dx.doi.org/10.1097/SAP.0000000000002760DOI Listing
March 2021

Analysis of major fatty acids from matched plasma and serum samples reveals highly comparable absolute and relative levels.

Prostaglandins Leukot Essent Fatty Acids 2021 Mar 31;168:102268. Epub 2021 Mar 31.

Department of Kinesiology, University of Guelph-Humber, Toronto, ON, M9W 5L7, Canada; Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, N1G2W1, Canada. Electronic address:

Measuring fatty acid (FA) levels in blood as a risk factor for chronic disease has been studied extensively. Previous research has used either plasma or serum samples to examine these associations. However, whether results from plasma and serum samples can be compared remains unclear, as differences in methodology related to the separation of plasma and serum from whole blood may impact FA levels. This study analyzed the individual FA content of matched plasma and serum samples in both absolute (μg/mL) and relative percent (%) composition. Analyses were performed using archived fasted morning samples from the Florey Adelaide Male Ageing Study (FAMAS). Matched plasma and serum samples were available from 98 male subjects aged 40-85. Total FA were analyzed by gas-liquid chromatography equipped with a flame ionization detector (GLC-FID). Analyses comprised of over 60 FA including major FA such as Palmitic Acid (PA), Palmitoleic acid (POA), Stearic Acid (SA), Oleic Acid (OA), Linoleic Acid (LNA), alpha-linolenic acid (ALA), Eicosapentaenoic acid (EPA), Arachidonic Acid (ARA), and Docosahexaenoic acid (DHA). Differences between groups was determined by t-test. Correlation and Bland-Altman analyses were also performed to examine the relationship between plasma and serum samples. There were no significant differences between major plasma and serum fatty acids expressed in μg/mL and relative % composition. Correlation analysis determined a strong and significantly positive association (r ≥ 0.65, p < 0.05) between major plasma and serum FA in absolute and relative terms. Bland-Altman analysis further supported the strong agreement between plasma and serum values in both absolute and relative terms. These findings demonstrate that studies reporting plasma or serum fatty acid analyzed by GLC-FID can be compared with one another.
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http://dx.doi.org/10.1016/j.plefa.2021.102268DOI Listing
March 2021

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [Lu]Lu-PSMA-617.

J Med Chem 2021 Apr 7. Epub 2021 Apr 7.

Department of Nuclear Medicine, Saarland University-Medical Center, Kirrbergerstrasse, D-66421 Homburg, Germany.

In recent years, radiolabeled tracers targeting prostate-specific membrane antigen (PSMA) have had a tremendous impact on prostate cancer management. Here, we report on the formation of radioactive impurities formed during the clinical production of Lu-labeled PSMA-617. We provide compelling evidence that these impurities are the result of a spontaneous, thermally mediated condensation reaction of the Glu-CO-Lys moiety resulting in the formation of three different five-membered ring systems. Density functional theory (DFT) calculations show that the condensation and cyclization of the Glu-CO-Lys moiety is thermodynamically spontaneous. In cell experiments, no affinity of these cyclized compounds toward PSMA was observed. HPLC analyses of urine samples from patient studies showed rapid renal excretion of these radioactive cyclized species. Radiolabeling conditions were identified that significantly reduced the formation of cyclized side products yielding Lu-labeled PSMA-617 in high radiochemical yield and purity in concordance with current good manufacturing practice (cGMP) requirements.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00045DOI Listing
April 2021

Comparing impulsivity in borderline personality, schizophrenia and obsessional-compulsive disorders: Who is ahead?

J Clin Psychol 2021 Apr 6. Epub 2021 Apr 6.

Psychosocial Laboratory, Aix-Marseille and Nîmes Universities, Nîmes, France.

Objective: Impulsivity impacts life domains and in a psychiatric context is often associated with disorders severity and stigmatization. Borderline personality disorder's (BPD), Schizophrenic disorder's (SZD), and obsessional compulsive disorder's (OCD) impulsivity issues relate to worse prognosis. This study aims to compare these disorders assessing their proneness to impulsivity and urgency.

Methods: We recruited 90 patients among them OCD (n = 25), SZD (n = 23), and BPD (n = 50), and 24 healthy control participants (HC). We assessed the diagnosis according and measured the impulsivity level.

Results: Our results showed that BPD was significantly more impulsive than HC, SZD, and OCD. HC, SZD, and OCD being equivalent on their global Urgency-Premeditation-Perseverance-Sensation seeking scores. For urgency, BPD was also superior to others, OCD was superior to HC, but SZD and HC were equivalent. The urgency was correlated to SZD's scale for SZD, no link appeared between borderline personality questionnaire and Yale-Brown Obsessive-Compulsive Scale's score.

Conclusion: These results question the existent literature relating impulsivity and SZD.
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http://dx.doi.org/10.1002/jclp.23129DOI Listing
April 2021

Rapid and Efficient Generation of Myelinating Human Oligodendrocytes in Organoids.

Front Cell Neurosci 2021 17;15:631548. Epub 2021 Mar 17.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.

Human stem cell derived brain organoids are increasingly gaining attention as an ideal model system for investigating neurological diseases, particularly those that involve myelination defects. However, current protocols for generating brain organoids with sufficiently mature oligodendrocytes that deposit myelin on endogenously produced neurons are lengthy and complicated. Taking advantage of a human pluripotent stem cell line that reports on SOX10 expression, we developed a protocol that involves a 42 day exposure of neuroectoderm-derived organoids to a cocktail of growth factors and small molecules that collectively foster oligodendrocyte specification and survival. Importantly, the resulting day 42 brain organoids contain both myelinating oligodendrocytes, cortical neuronal cells and astrocytes. These oligodendrocyte brain organoids therefore constitute a valuable and tractable platform for functional neurogenomics and drug screening for white matter diseases.
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http://dx.doi.org/10.3389/fncel.2021.631548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010307PMC
March 2021

Telerehabilitation in Acquired Brain Injury.

Phys Med Rehabil Clin N Am 2021 05 6;32(2):223-238. Epub 2021 Mar 6.

HonorHealth Rehabilitation Hospital, 8850 E Pima Center Pkwy, Scottsdale, AZ 85258, USA.

With the rapid shift to telemedicine brought on by the COVID-19 pandemic, physiatrists must get accustomed to the new technology and learn how to optimize their evaluations. For those practitioners managing patients with acquired brain injuries, which include stroke and traumatic brain injury, this can seem a daunting task given potential physical and cognitive barriers. However, as the authors discuss techniques to optimize visits, the aim is to illustrate how telehealth appointments can not only be comparable to in-person examinations but also may help increase outreach, compliance, and even satisfaction among this unique population.
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http://dx.doi.org/10.1016/j.pmr.2021.01.001DOI Listing
May 2021

Modulation of Ion Transport to Restore Airway Hydration in Cystic Fibrosis.

Genes (Basel) 2021 Mar 22;12(3). Epub 2021 Mar 22.

School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.

Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR) Cl channel. Loss of Cl secretion across the apical membrane of airway lining epithelial cells results in dehydration of the airway surface liquid (ASL) layer which impairs mucociliary clearance (MCC), and as a consequence promotes bacterial infection and inflammation of the airways. Interventions that restore airway hydration are known to improve MCC. Here we review the ion channels present at the luminal surface of airway epithelial cells that may be targeted to improve airway hydration and MCC in CF airways.
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http://dx.doi.org/10.3390/genes12030453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004921PMC
March 2021

Intratumoural Cytochrome P450 Expression in Breast Cancer: Impact on Standard of Care Treatment and New Efforts to Develop Tumour-Selective Therapies.

Biomedicines 2021 Mar 12;9(3). Epub 2021 Mar 12.

Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK.

Despite significant advances in treatment strategies over the past decade, selective treatment of breast cancer with limited side-effects still remains a great challenge. The cytochrome P450 (CYP) family of enzymes contribute to cancer cell proliferation, cell signaling and drug metabolism with implications for treatment outcomes. A clearer understanding of CYP expression is important in the pathogenesis of breast cancer as several isoforms play critical roles in metabolising steroid hormones and xenobiotics that contribute to the genesis of breast cancer. The purpose of this review is to provide an update on how the presence of CYPs impacts on standard of care (SoC) drugs used to treat breast cancer as well as discuss opportunities to exploit CYP expression for therapeutic intervention. Finally, we provide our thoughts on future work in CYP research with the aim of supporting ongoing efforts to develop drugs with improved therapeutic index for patient benefit.
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http://dx.doi.org/10.3390/biomedicines9030290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998590PMC
March 2021

Coffee and Lower Risk of Type 2 Diabetes: Arguments for a Causal Relationship.

Nutrients 2021 Mar 31;13(4). Epub 2021 Mar 31.

West-German Centre of Diabetes and Health, Duesseldorf Catholic Hospital Group, Hohensandweg 37, 40591 Duesseldorf, Germany.

Prospective epidemiological studies concur in an association between habitual coffee consumption and a lower risk of type 2 diabetes. Several aspects of these studies support a cause-effect relationship. There is a dependency on daily coffee dose. Study outcomes are similar in different regions of the world, show no differences between sexes, between obese versus lean, young versus old, smokers versus nonsmokers, regardless of the number of confounders adjusted for. Randomized controlled intervention trials did not find a consistent impact of drinking coffee on acute metabolic control, except for effects of caffeine. Therefore, lowering of diabetes risk by coffee consumption does not involve an acute effect on the post-meal course of blood glucose, insulin or insulin resistance. Several studies in animals and humans find that the ingestion of coffee phytochemicals induces an adaptive cellular response characterized by upregulation and de novo synthesis of enzymes involved in cell defense and repair. A key regulator is the nuclear factor erythroid 2-related factor 2 (Nrf2) in association with the aryl hydrocarbon receptor, AMP-activated kinase and sirtuins. One major site of coffee actions appears to be the liver, causing improved fat oxidation and lower risk of steatosis. Another major effect of coffee intake is preservation of functional beta cell mass via enhanced mitochondrial function, lower endoplasmic reticulum stress and prevention or clearance of aggregates of misfolded proinsulin or amylin. Long-term preservation of proper liver and beta cell function may account for the association of habitual coffee drinking with a lower risk of type 2 diabetes, rather than acute improvement of metabolic control.
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http://dx.doi.org/10.3390/nu13041144DOI Listing
March 2021

ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization.

Int J Mol Sci 2021 Mar 7;22(5). Epub 2021 Mar 7.

Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49, Bus 1023, 3000 Leuven, Belgium.

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson's disease and Kufor-Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.
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http://dx.doi.org/10.3390/ijms22052689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962109PMC
March 2021

Cerebral Expression of Metabotropic Glutamate Receptor Subtype 5 in Idiopathic Autism Spectrum Disorder and Fragile X Syndrome: A Pilot Study.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR expression provide conflicting findings about the nature of dysregulation of cerebral mGluR pathways in subtypes of ASD. The demonstration of reduced mGluR expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR expression in ASD. We aimed to (A) compare and contrast mGluR expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently administered 3-[F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB), a novel, specific mGluR PET ligand to quantitatively measure the density and the distribution of mGluRs in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR expression in clinical trials of individuals with IASD and FXS and related conditions.
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http://dx.doi.org/10.3390/ijms22062863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999711PMC
March 2021

Assessment of Comprehensibility of Industry Conflicts of Interest and Disclosures by Multiple Sclerosis Researchers at Medical Conferences.

JAMA Netw Open 2021 Apr 1;4(4):e212167. Epub 2021 Apr 1.

Anne Rowling Clinic, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.2167DOI Listing
April 2021

Psychological risk profile for overuse injuries in sport: An exploratory study.

J Sports Sci 2021 Mar 31:1-10. Epub 2021 Mar 31.

Center of Research on Welfare Health and Sport, Halmstad University, Halmstad, Sweden.

Overuse injuries account for a substantial part of sport injury incidence among athletes of various sports and levels. Despite the gradual onset of symptoms, athletes often persevere in training and competing. The present exploratory study aimed to identify a psychological risk profile for overuse injury. One hundred and forty-nine athletes competing in various sports responded to a range of questionnaires measuring the following psychological variables: negative life stress, perfectionistic concerns, perfectionistic strivings, athletic identity, and the coach-athlete relationship. Participants subsequently answered the OSTRC Overuse Injury Questionnaire on a weekly basis during a 10-week period. Using a latent profile analysis, athletes were classified into three latent profiles regarding their psychological characteristics. Athletes in the second profile, characterized by a combination of high athletic identity, perfectionistic concerns and negative life stress and poor coach-athlete relationship, were found to be significantly more often affected by overuse injuries (74% of the time) than individuals in the two other profiles (52% and 48% of the time, respectively). In conclusion, psychological factors may contribute to the risk of overuse injuries through complex interactions (i.e. accounting for interdependencies within a specific configuration of variables) rather than through their independent influences.
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http://dx.doi.org/10.1080/02640414.2021.1907904DOI Listing
March 2021

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.

J Med Chem 2021 Mar 30. Epub 2021 Mar 30.

CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States.

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., ) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00114DOI Listing
March 2021

Value of Machine Learning-based Coronary CT Fractional Flow Reserve Applied to Triple-Rule-Out CT Angiography in Acute Chest Pain.

Radiol Cardiothorac Imaging 2020 Jun 25;2(3):e190137. Epub 2020 Jun 25.

Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Ashley River Tower, 25 Courtenay Dr, Charleston, SC 29425-2260 (S.S.M., D.M., M.v.A., C.N.D.C., R.R.B., C.T., A.V.S., A.M.F., B.E.J., L.P.G., U.J.S.); Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Frankfurt, Germany (S.S.M., T.J.V.); Stanford University School of Medicine, Department of Radiology, Stanford, Calif (D.M.); Division of Cardiothoracic Imaging, Nuclear Medicine and Molecular Imaging, Department of Radiology and Imaging Sciences, Emory University, Atlanta, Ga (C.N.D.C.); Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, SC (R.R.B.); Department of Cardiology and Intensive Care Medicine, Heart Center Munich-Bogenhausen, Munich, Germany (C.T.); Department of Cardiology, Munich University Clinic, Ludwig-Maximilians-University, Munich, Germany (C.T.); Siemens Medical Solutions USA, Malvern, Pa (P.S.); and Department of Emergency Medicine, Medical University of South Carolina, Charleston, SC (A.J.M.).

Purpose: To evaluate the additional value of noninvasive artificial intelligence (AI)-based CT-derived fractional flow reserve (CT FFR), derived from triple-rule-out coronary CT angiography for acute chest pain (ACP) in the emergency department (ED) setting.

Materials And Methods: AI-based CT FFR from triple-rule-out CT angiography data sets was retrospectively obtained in 159 of 271 eligible patients (102 men; mean age, 57.0 years ± 9.7 [standard deviation]) presenting to the ED with ACP. The agreement between CT FFR (≤ 0.80) and stenosis at triple-rule-out CT angiography (≥ 50%), as well as downstream cardiac diagnostic testing, was investigated. Furthermore, the predictive value of CT FFR for coronary revascularization and major adverse cardiac events (MACE) was assessed over a 1-year follow-up period.

Results: CT FFR and triple-rule-out CT angiography demonstrated agreement in severity of coronary artery disease (CAD) in 52% (82 of 159) of all cases. CT FFR of 0.80 and less served as a better predictor for coronary revascularization and MACE than stenosis of 50% and greater at triple-rule-out CT angiography (odds ratio, 3.4; 95% confidence interval: 1.4, 8.2 vs odds ratio, 2.2; 95% confidence interval: 0.9, 5.3) ( < .01). In the subgroup of patients with additional noninvasive cardiac testing (94 of 159), there was higher agreement as to the presence or absence of significant disease with CT FFR (55%) than with coronary triple-rule-out CT angiography (47%) ( = .23).

Conclusion: CT FFR derived from triple-rule-out CT angiography was a better predictor for coronary revascularization and MACE and showed better agreement with additional diagnostic testing than triple-rule-out CT angiography. Therefore, CT FFR may improve the specificity in identifying patients with ACP with significant CAD in the ED setting and reduce unnecessary downstream testing.© RSNA, 2020See also the commentary by Ihdayhid and Ben Zekry in this issue.
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http://dx.doi.org/10.1148/ryct.2020190137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978005PMC
June 2020

Scenario Planning: Embracing the Potential for Extreme Events in the Colorado River Basin.

Clim Change 2021 21;165(1):27. Epub 2021 Mar 21.

Tucson Water; School of Geography, Development and Environment, University of Arizona, Tucson, AZ USA.

Scenario planning (SP) has been increasingly utilized by water managers and planners in the 21st century as climate and other uncertainties have challenged traditional planning approaches. This paper discusses the potential for scenario planning processes in the Colorado River Basin in the southwestern United States to build collective understanding of compound and cascading risks, and to identify possible solutions at multiple scales. Under the Colorado River Conversations Project, we convened a series of conferences and scenario planning workshops over the past 3 years to explore the potential to enhance the use of social and physical sciences in river management, and to broaden the community of people and entities engaged in discussions about managing the Colorado River. Working with a group of thirty water managers and other interested parties representing all 7 basin states, several Tribes, NGO's and Mexico, we used a participatory, mixed-methods approach to scenario planning that identified multiple drivers of change and developed eight science-based storylines from the intersection of these drivers. The development of the storylines and the subsequent conversations with participants about impacts and solutions resulted in a framework for understanding low probability-high consequence climate and other risks across the Colorado River Basin. We highlight three lessons that speak to the value and role of SP for fostering collaboration and creativity. These lessons include: (1) the importance of process in SP in fostering deliberate community building across sectors and geographies; (2) identifying challenges with engaging with uncertainty, complexity, and risk; and (3) determining what these findings mean for future SP in the Colorado River Basin and beyond.
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http://dx.doi.org/10.1007/s10584-021-03013-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981391PMC
March 2021

Missing the human connection: A rapid appraisal of healthcare workers' perceptions and experiences of providing palliative care during the COVID-19 pandemic.

Palliat Med 2021 Mar 29:2692163211004228. Epub 2021 Mar 29.

Department of Targeted Intervention and Rapid Research Evaluation and Appraisal Lab (RREAL), University College London, London, UK.

Background: During infectious epidemics, healthcare workers are required to deliver traditional care while facing new pressures. Time and resource restrictions, a focus on saving lives and new safety measures can lead to traditional aspects of care delivery being neglected.

Aim: Identify barriers to delivering end-of-life care, describe attempts to deliver care during the COVID-19 pandemic, and understand the impact this had on staff.

Design: A rapid appraisal was conducted incorporating a rapid review of policies from the United Kingdom, semi-structured telephone interviews with healthcare workers, and a review of mass print media news stories and social media posts describing healthcare worker's experiences of delivering care during the pandemic. Data were coded and analysed using framework analysis.

Setting/participants: From a larger ongoing study, 22 interviews which mentioned death or caring for patients at end-of-life, eight government and National Health Service policies affecting end-of-life care delivery, eight international news media stories and 3440 publicly available social media posts were identified. The social media analysis centred around 274 original tweets with the highest reach, engagement and relevance. Incorporating multiple workstreams provided a broad perspective of end-of-life care during the COVID-19 pandemic in the United Kingdom.

Results: Three themes were developed: (1) restrictions to traditional care, (2) striving for new forms of care and (3) establishing identity and resilience.

Conclusions: The COVID-19 pandemic prohibited the delivery of traditional care as practical barriers restricted human connections. Staff prioritised communication and comfort orientated tasks to re-establish compassion at end-of-life and displayed resilience by adjusting their goals.
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http://dx.doi.org/10.1177/02692163211004228DOI Listing
March 2021

CT-gestützte intrapedikuläre Biopsie und Radiofrequenzablation (RFA) eines Osteoidosteoms HWK 2.

Rofo 2021 Mar 26. Epub 2021 Mar 26.

Department of Diagnostic and Interventional Radiology, Hospital of the Goethe University Frankfurt, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1055/a-1408-9921DOI Listing
March 2021

Perforating dermatosis in rheumatoid arthritis.

Rheumatology (Oxford) 2021 Mar 26. Epub 2021 Mar 26.

Department of Rheumatology, 63 000 Clermont-Ferrand, 58 rue Montalembert, FRANCE.

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http://dx.doi.org/10.1093/rheumatology/keab311DOI Listing
March 2021

Cytotoxic and radiosensitising effects of a novel thioredoxin reductase inhibitor in breast cancer.

Invest New Drugs 2021 Mar 25. Epub 2021 Mar 25.

Nottingham Breast Cancer Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

Radiotherapy is an effective treatment modality for breast cancer but, unfortunately, not all patients respond fully with a significant number experiencing local recurrences. Overexpression of thioredoxin and thioredoxin reductase has been reported to cause multidrug and radiation resistance - their inhibition may therefore improve therapeutic efficacy. Novel indolequinone compounds have been shown, in pancreatic cancer models, to inhibit thioredoxin reductase activity and exhibit potent anticancer activity. The present study evaluates, using in vitro breast cancer models, the efficacy of a novel indolequinone compound (IQ9) as a single agent and in combination with ionising radiation using a variety of endpoint assays including cell proliferation, clonogenic survival, enzyme activity, and western blotting. Three triple-negative breast cancer (MDA-MB-231, MDA-MB-468, and MDA-MB-436) and two luminal (MCF-7 and T47D) breast cancer cell lines were used. Results show that treatment with IQ9 significantly inhibited thioredoxin reductase activity, and inhibited cell growth and colony formation of breast cancer cells with IC values in the low micromolar ranges. Enhanced radiosensitivity of triple-negative breast cancer cells was observed, with sensitiser enhancement ratios of 1.20-1.43, but with no evident radiosensitisation of luminal breast cancer cell lines. IQ9 upregulated protein expression of thioredoxin reductase in luminal but not in triple-negative breast cancer cells which may explain the observed differential radiosensitisation. This study provides important evidence of the roles of the thioredoxin system as an exploitable radiobiological target in breast cancer cells and highlights the potential therapeutic value of indolequinones as radiosensitisers.***This study was not part of a clinical trial. Clinical trial registration number: N/A.
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http://dx.doi.org/10.1007/s10637-021-01106-5DOI Listing
March 2021

Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL.

J Clin Oncol 2021 Mar 25:JCO2002262. Epub 2021 Mar 25.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD.

Purpose: CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined.

Methods: We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables.

Results: Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease-negative by flow cytometry. Utilization of fludarabine/cyclophosphamide-based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non-fludarabine/cyclophosphamide-based lymphodepletion (2/8, 25%; = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease-negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8).

Conclusion: We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696).
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http://dx.doi.org/10.1200/JCO.20.02262DOI Listing
March 2021

Development of the Alopecia Areata Patient Priority Outcomes Instrument: A Qualitative Study.

Dermatol Ther (Heidelb) 2021 Apr 9;11(2):599-613. Epub 2021 Mar 9.

Patient-Centered Outcomes Assessment, Pfizer, Inc., New York, NY, USA.

Introduction: Although alopecia areata (AA) profoundly impacts patients' physical appearance, emotional state, and daily activities, no treatment approved for AA currently exists. Patient-reported outcome (PRO) instruments currently used to capture patients' AA experiences do not meet the requirements to support claims of treatment benefit as described in the US Food and Drug Administration's 2009 PRO guidance. Our objective was to explore the consequences and priority treatment outcomes among individuals with AA and develop a PRO measure consistent with regulatory requirements that assesses these priorities and represents clinical benefit from the AA patient perspective.

Methods: Targeted literature and instrument reviews informed an initial concept set. Concept elicitation interviews with 20 adults with AA confirmed the relevance and importance of the initial concepts, identified additional relevant concepts, and informed an AA consequence model. Thematic analysis yielded a draft item pool, which was evaluated through two iterative rounds of cognitive debriefing interviews with 16 patients with AA (9 adults; 7 adolescents).

Results: Hair loss was the primary consequence of importance to patients with AA. Patients emphasized the need to differentiate hair loss by location: scalp, eyebrows, eyelashes, and body. Consequences of AA include difficulty conducting daily activities, particularly outdoor activities and exercise, and emotional impacts such as sadness, frustration, and negative self-image. Following cognitive debriefing interviews, 11 items were included to form the Alopecia Areata Patient Priority Outcome (AAPPO), assessing AA-related symptoms and impacts over the past week.

Conclusions: The AAPPO is a novel, content-valid PRO that captures the consequences of AA of the highest priority to patients.
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http://dx.doi.org/10.1007/s13555-021-00508-wDOI Listing
April 2021

Quantification of COVID-19 Opacities on Chest CT - Evaluation of a Fully Automatic AI-approach to Noninvasively Differentiate Critical Versus Noncritical Patients.

Acad Radiol 2021 Mar 6. Epub 2021 Mar 6.

Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Frankfurt am Main, Germany.

Objectives: To evaluate the potential of a fully automatic artificial intelligence (AI)-driven computed tomography (CT) software prototype to quantify severity of COVID-19 infection on chest CT in relationship with clinical and laboratory data.

Methods: We retrospectively analyzed 50 patients with laboratory confirmed COVID-19 infection who had received chest CT between March and July 2020. Pulmonary opacifications were automatically evaluated by an AI-driven software and correlated with clinical and laboratory parameters using Spearman-Rho and linear regression analysis. We divided the patients into sub cohorts with or without necessity of intensive care unit (ICU) treatment. Sub cohort differences were evaluated employing Wilcoxon-Mann-Whitney-Test.

Results: We included 50 CT examinations (mean age, 57.24 years), of whom 24 (48%) had an ICU stay. Extent of COVID-19 like opacities on chest CT showed correlations (all p < 0.001 if not otherwise stated) with occurrence of ICU stay (R = 0.74), length of ICU stay (R = 0.81), lethal outcome (R = 0.56) and length of hospital stay (R = 0.33, p < 0.05). The opacities extent was correlated with laboratory parameters: neutrophil count (NEU) (R = 0.60), lactate dehydrogenase (LDH) (R = 0.60), troponin (TNTHS) (R = 0.55) and c-reactive protein (CRP) (R = 0.51). Differences (p < 0.001) between ICU group and non-ICU group concerned longer length of hospital stay (24.04 vs. 10.92 days), higher opacity score (12.50 vs. 4.96) and severity of laboratory data changes such as c-reactive protein (11.64 vs. 5.07 mg/dl, p < 0.01).

Conclusions: Automatically AI-driven quantification of opacities on chest CT correlates with laboratory and clinical data in patients with confirmed COVID-19 infection and may serve as non-invasive predictive marker for clinical course of COVID-19.
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http://dx.doi.org/10.1016/j.acra.2021.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936551PMC
March 2021

A Phase I Randomized, Controlled Trial of Valganciclovir in Idiopathic Pulmonary Fibrosis.

Ann Am Thorac Soc 2021 Mar 19. Epub 2021 Mar 19.

Vanderbilt University Medical Center, 12328, Medicine, Nashville, Tennessee, United States.

Rationale: Human herpesviruses Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) are frequently detectable in the lungs of idiopathic pulmonary fibrosis (IPF) patients and could contribute to disease pathogenesis.

Objectives: With the goal of inhibiting herpesvirus replication, we tested the safety and tolerability of adding valganciclovir to standard IPF therapy (pirfenidone).

Methods: We performed a single-center, phase I, double-blind, randomized placebo-controlled trial comparing valganciclovir 900 mg daily to placebo in IPF patients with serologic evidence of prior EBV and/or CMV infection who were tolerating full-dose pirfenidone (2403 mg/day). Subjects were randomized to valganciclovir or placebo 2:1 for 12 weeks of active treatment with off-treatment follow-up for up to 12 months. The primary safety endpoint was the number of subjects discontinuing study drug before completing 12 weeks of treatment.

Measurements And Main Results: Thirty-one subjects with IPF were randomized to valganciclovir (n=20) or placebo (n=11). All subjects completed assigned therapy except one subject in the valganciclovir group who discontinued the study drug after developing a rash. Total adverse events were similar between study groups. In prespecified analyses of secondary physiologic endpoints, we observed a trend towards improved forced vital capacity (FVC) from randomization to week 12 in valganciclovir-treated subjects (-10 ml [interquartile range -65, 70 ml]) versus placebo-treated subjects (40 ml [IQR -130, 60 ml]), which persisted through 12 months of follow-up.

Conclusion: Valganciclovir is safe and well-tolerated as add-on therapy to pirfenidone in IPF patients. Clinical trial registered with ClinicalTrials.gov (NCT02871401).
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http://dx.doi.org/10.1513/AnnalsATS.202102-108OCDOI Listing
March 2021

Penicillin Allergy Testing: An Outpatient Nurse-Driven Program for Patients With Cancer.

Clin J Oncol Nurs 2021 Apr;25(2):143-150

Memorial Sloan Kettering Cancer Center.

Background: Penicillin allergy testing (PAT) can decrease the use of unnecessary antibiotics by clarifying who is truly allergic.

Objectives: This article describes the development and implementation of an oncology outpatient nurse-driven PAT program.

Methods: A nurse-driven program, initiated with allergy screening at the first encounter, was designed to identify patients with oncologic diagnoses eligible for PAT. Once verified eligible, patients undergo a three-step testing process (scratch test, intradermal injection, and IV challenge dose) administered by the infusion nurse.

Findings: From November 2018 to December 2019, 82 outpatients with reported penicillin allergies were screened; 90% were eligible for PAT, and 97% of patients tested were negative for penicillin allergy. A significant reduction in aztreonam use among patients admitted for hematopoietic stem cell transplantation was also noted as compared to before PAT was offered.

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http://dx.doi.org/10.1188/21.CJON.143-150DOI Listing
April 2021

Pedigree-based assessment of recent population connectivity in a threatened rattlesnake.

Mol Ecol Resour 2021 Mar 19. Epub 2021 Mar 19.

Department of Evolution, Ecology, and Organismal Biology and Ohio Biodiversity Conservation Partnership, The Ohio State University, Columbus, OH, USA.

Managing endangered species in fragmented landscapes requires estimating dispersal rates between populations over contemporary timescales. Here, we developed a new method for quantifying recent dispersal using genetic pedigree data for close and distant kin. Specifically, we describe an approach that infers missing shared ancestors between pairs of kin in habitat patches across a fragmented landscape. We then applied a stepping-stone model to assign unsampled individuals in the pedigree to probable locations based on minimizing the number of movements required to produce the observed locations in sampled kin pairs. Finally, we used all pairs of reconstructed parent-offspring sets to estimate dispersal rates between habitat patches under a Bayesian model. Our approach measures connectivity over the timescale represented by the small number of generations contained within the pedigree and so is appropriate for estimating the impacts of recent habitat changes due to human activity. We used our method to estimate recent movement between newly discovered populations of threatened Eastern Massasauga rattlesnakes (Sistrurus catenatus) using data from 2996 RAD-based genetic loci. Our pedigree analyses found no evidence for contemporary connectivity between five genetic groups, but, as validation of our approach, showed high dispersal rates between sample sites within a single genetic cluster. We conclude that these five genetic clusters of Eastern Massasauga rattlesnakes have small numbers of resident snakes and are demographically isolated conservation units. More broadly, our methodology can be widely applied to determine contemporary connectivity rates, independent of bias from shared genetic similarity due to ancestry that impacts other approaches.
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http://dx.doi.org/10.1111/1755-0998.13383DOI Listing
March 2021