Publications by authors named "Ronak Patel"

238 Publications

A review of use errors reported in human factor validation studies of biological combination products.

J Med Eng Technol 2021 Jun 14:1-11. Epub 2021 Jun 14.

Clinical Development and Medical Affairs, Intas Pharmaceuticals Limited (Biopharma Division), Ahmedabad, India.

Drug-device combination products should be safe and effective for intended uses by intended users under intended use environment during human factor (HF) studies. All known use errors and use-related problems should be considered during design of device and use-related risk analysis. Availability of such information in a compiled manner is scarce. This review compiles information of use errors reported during HF validation studies of biological combination products (drug + device) approved by USFDA's Centre for Drug Evaluation and Research between 21 June 2011 and 31 December 2019. Information regarding product, indication, type of devices, use errors, root causes and mitigation strategies were collected from published documents. Total 280 use errors were reported during HF validation studies of 39 devices across 5 categories. Overall approach and methodology for use error data collection during HF validation studies was in line with the US FDA recommendations. Performance of participants for critical and essential tasks was evaluated during HF validation studies simulated use assessment, knowledge task assessment and interview. The root causes for use errors reported during HF validation studies were identified and use errors were mitigated by suitable corrective measures. Instructions for use clarification/improvement and labelling improvement were the most common mitigation strategies implemented across devices.
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http://dx.doi.org/10.1080/03091902.2021.1936239DOI Listing
June 2021

Delivering the Promise of Sendai Framework for Disaster Risk Reduction in Fragile and Conflict-Affected Contexts (FCAC): A Case Study of the NGO GOAL's Response to the Syria Conflict.

Prog Disaster Sci 2021 Apr 20;10. Epub 2021 Apr 20.

RAND Corporation,1200S Hayes St, Arlington, VA 22202, USA.

The Sendai Framework for Disaster Risk Reduction (SFDRR) has helped to reduce global disaster risk, but there has been a lack of progress in disaster risk reduction (DRR) for people living in fragile and conflict affected contexts (FCAC). Given the mounting evidence that DRR cannot be implemented through conventional approaches in FCAC, serious efforts must be made to understand how to meet SFDRR's goals. This paper offers a case study of international non-governmental organization GOAL's programming that responds to the protracted crisis in Syria, with critical discussion on SFDRR and how to adapt humanitarian relief and disaster resilience.
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http://dx.doi.org/10.1016/j.pdisas.2021.100172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171268PMC
April 2021

Case report of superficial femoral artery and popliteal artery aneurysm repair using brachial vein.

Vascular 2021 May 29:17085381211019588. Epub 2021 May 29.

Vascular Institute of New York, Brooklyn, NY, USA.

Background: Several veins have been well-recognized as acceptable conduits for infrainguinal bypass surgery when the ipsilateral greater saphenous vein is unavailable. However, there is a paucity of literature describing the brachial vein as an adequate alternative. In the absence of other viable autogenous conduits, we describe the use of a brachial vein as a successful alternative for lower extremity revascularization.

Methods: A 70-year-old man presented with a chief complaint of right calf pain. Duplex ultrasound imaging of his right lower extremity revealed right-sided 2.5 cm acutely thrombosed superficial femoral artery and popliteal artery aneurysms. The patient underwent a suction thrombectomy with tissue plasminogen activator using the Power Pulse feature and Solent catheter from the AngioJet® (Boston-Scientific, Marlborough, MA) system. To repair the thrombosed aneurysms, an open bypass was planned. Due to lack of viable alternative traditionally used venous conduits, a bypass was created using the patient's brachial vein.

Results: A bypass was created from the superficial femoral artery to the P2 segment of the popliteal artery using a non-reversed brachial vein with ligation of the side branches of the superficial femoral artery and popliteal artery aneurysm from within the sac lumen. Completion angiogram revealed runoff through the anterior tibial artery only. Follow-up imaging at three months demonstrated a patent brachial bypass.

Conclusion: Brachial veins can be safely used as viable venous conduits for lower extremity bypass surgery and should therefore be considered as an alternative when more commonly used veins are unsuitable or unavailable. However, more research is needed to determine the potential opportunities and challenges this alternative may present.
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http://dx.doi.org/10.1177/17085381211019588DOI Listing
May 2021

A General Method to Improve Fluorophores Using Deuterated Auxochromes.

JACS Au 2021 May 23;1(5):690-696. Epub 2021 Apr 23.

Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, Virginia 20147, United States.

Fluorescence microscopy relies on dyes that absorb and then emit photons. In addition to fluorescence, fluorophores can undergo photochemical processes that decrease quantum yield or result in spectral shifts and irreversible photobleaching. Chemical strategies that suppress these undesirable pathways-thereby increasing the brightness and photostability of fluorophores-are crucial for advancing the frontier of bioimaging. Here, we describe a general method to improve small-molecule fluorophores by incorporating deuterium into the alkylamino auxochromes of rhodamines and other dyes. This strategy increases fluorescence quantum yield, inhibits photochemically induced spectral shifts, and slows irreparable photobleaching, yielding next-generation labels with improved performance in cellular imaging experiments.
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http://dx.doi.org/10.1021/jacsau.1c00006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154212PMC
May 2021

Structural neuroimaging phenotypes of a novel multi-gene risk score in youth bipolar disorder.

J Affect Disord 2021 Jun 28;289:135-143. Epub 2021 Apr 28.

University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Background: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD.

Methods: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions.

Results: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; β=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC.

Limitations: Cross-sectional design, modest sample size.

Conclusions: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.
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http://dx.doi.org/10.1016/j.jad.2021.04.040DOI Listing
June 2021

Denosumab biosimilar in postmenopausal osteoporotic women: A randomized, assessor-blind, active-controlled clinical trial.

Indian J Pharmacol 2021 Jan-Feb;53(1):6-12

Clinical Trial Operations and Medical Services, Lambda Therapeutic Research Ltd., Ahmedabad, Gujarat, India.

Objective: The study assessed the efficacy, safety, pharmacokinetic (PK), and immunogenicity profiles of denosumab-biosimilar and denosumab-reference in postmenopausal osteoporotic women from India.

Materials And Methods: In this randomized, assessor-blind, active-control, multicenter trial, 114 patients were randomly allocated to receive denosumab-biosimilar (n = 58) or denosumab-reference (n = 56) at a subcutaneous dose of 60 mg every 6 months, for a year. Vitamin D and oral calcium were given daily. Lumbar spine bone mineral density (BMD) change was the primary end point.

Results: Of 114 randomized patients, 111 (denosumab-biosimilar, n = 56; denosumab-reference, n = 55) completed the study. All 114 patients were part of safety and immunogenicity analyses, 110 (denosumab-biosimilar, n = 56; denosumab-reference, n = 54) were part of efficacy analysis, and 20 (denosumab-biosimilar, n = 10; denosumab-reference, n = 10) were part of PK analysis. The bone mineral density (BMD) (lumbar spine) percent change at 1 year with denosumab-biosimilar and denosumab-reference (7.22 vs. 7.62; difference:-0.40; 95% confidence interval: -5.92, 5.12) showed no statistically relevant difference. Likewise, alkaline phosphatase (bone-specific) and PK parameters also did not show statistically relevant differences. Adverse events were reported in 44.83% of patients on denosumab-biosimilar versus 33.93% of patients on denosumab-reference; most events were mild or moderate and not related to the study drugs. No patients showed anti-denosumab antibody positivity.

Conclusions: Denosumab-biosimilar and denosumab-reference showed biosimilarity in osteoporotic postmenopausal women. Availability of denosumab-biosimilar provides a treatment alternative for patients.
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http://dx.doi.org/10.4103/ijp.IJP_346_19DOI Listing
May 2021

Neuroenhancement of future surgeons - Opinions from students, surgeons and patients.

Brain Stimul 2021 May-Jun;14(3):616-618. Epub 2021 Mar 28.

Department of Surgery and Cancer, Imperial College London, UK.

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http://dx.doi.org/10.1016/j.brs.2021.03.012DOI Listing
March 2021

Clinical comparison of V122I genotypic variant of transthyretin amyloid cardiomyopathy with wild-type and other hereditary variants: a systematic review.

Heart Fail Rev 2021 Mar 25. Epub 2021 Mar 25.

Department of Cardiovascular Medicine, Medical Center, The University of Kansas, Kansas City, KS, USA.

V122I genotype variant (pV142I) is the most common hereditary transthyretin amyloidosis (hATTR) in the USA, with 3-3.5% of African-Americans being the carriers of this mutation. We aimed to compare baseline clinical features, cardiac parameters, and mortality in V122I-ATTR with the wild-type ATTR and other hATTR subtypes. We systematically searched PubMed/Medline and Google Scholar databases to identify relevant studies from inception to 10th September, 2020 reporting phenotypic, echocardiographic, and/or laboratory parameters in patients with hereditary and wild types of cardiac amyloidoses. A total of 2843 patients from 7 individual studies with 67-100% males and an overall follow-up duration of 51.6 ± 30.4 months were identified. The mean age of diagnosis among wild-type ATTR patients was 77 years, followed by 71.2 and 65 years in V122I and T60A group patients, respectively. V122I patients were mostly black, had a poor quality of life, and highest mortality risk compared with other subtypes. Merely, the presence of V122I mutation was identified as an independent predictor of mortality. V30M subtype correlated with the least severe cardiac disease and a median survival duration comparable with T60A subtype. V122I ATTR is an aggressive disease, prevalent in African-Americans, and is associated with a greater morbidity and mortality, which is partly attributed to its misdiagnosis and/or late diagnosis. Current advances in non-invasive studies to diagnose hATTR coupled with concurrent drug therapies have improved quality of life and provide a survival benefit to these patients.
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http://dx.doi.org/10.1007/s10741-021-10098-6DOI Listing
March 2021

Safety and efficacy of Razumab™ (world's first biosimilar ranibizumab) in wet age-related macular degeneration: a post-marketing, prospective ASSET study.

Int J Retina Vitreous 2021 Mar 24;7(1):24. Epub 2021 Mar 24.

Clinical Development & Medical Affairs, Intas Pharmaceuticals Ltd. (Biopharma), Ahmedabad, Gujarat, India.

Background: Razumab™ (world's first biosimilar ranibizumab) is approved for several macular disorders including wet age-related macular degeneration (AMD). We evaluated the safety and efficacy of biosimilar ranibizumab in wet AMD.

Methods: This prospective, multicentre, rAnibizumab bioSimilar Safety Efficacy postmarkeTing (ASSET) study enrolled patients aged ≥ 50 years with wet AMD having best-corrected visual acuity (BCVA) between 20/40 and 20/320. The patients received intravitreal biosimilar ranibizumab 0.5 mg every 4 weeks for 24 weeks. Safety endpoints included the incidence of adverse events (AEs), serious AEs (SAEs), and immunoreactivity after 6 months. The efficacy endpoints were the proportion of patients who lose fewer than 15 letters, increase in BCVA, change in central retinal thickness (CRT), and change in Visual Function Questionnaire-25 (VFQ-25) score, from baseline to 24 weeks.

Results: Of the 126 enrolled patients, majority (95.24%) of the patients received all 6 doses of biosimilar ranibizumab (total 3 mg). Nineteen AEs were reported (n = 16; 12.7%); majority (78.9%) were mild. There were no serious AEs reported, except one AE of death which was unrelated to the study drug. None of the patients discontinued the study due to an AE. The most common ocular AE was increase in intraocular pressure (4 events) and non-ocular AE was pyrexia (5 events). A total of 7.9% (10/126) patients prior to dosing and 7.1% (9/126) patients post-treatment were positive for anti-ranibizumab antibodies. No AEs suggestive of immunogenicity were noted. At 24-weeks, 97.60% patients in the intent-to-treat (ITT) population (N = 125) and 97.41% patients in the per-protocol (PP) population (N = 116) lost < 15 letters from baseline visual acuity. In the ITT and PP populations, 31.20% and 32.76% patients, respectively, showed improved visual acuity by ≥ 15 letters. Significant improvements in BCVA (mean difference: 8.8, 9.2, p < 0.001 for ITT, PP) and VFQ-25 (8.5, 9.2, p < 0.001 for ITT, PP) were seen; CRT reduced significantly (125 µm, 119.3 µm, p < 0.001 for ITT, PP).

Conclusion: Razumab™ (world's first biosimilar ranibizumab) was well-tolerated without new safety concerns and significantly improved visual acuity in wet AMD patients. Trial registration CTRI/2016/03/006739. Registered 18 March 2016-Prospectively registered, http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=13141&EncHid=&userName=2016/03/006739.
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http://dx.doi.org/10.1186/s40942-021-00293-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992797PMC
March 2021

Dataset of prefrontal transcranial direct-current stimulation to improve early surgical knot-tying skills.

Data Brief 2021 Apr 23;35:106905. Epub 2021 Feb 23.

Department of Surgery & Cancer, Imperial College London, St Mary's Hospital Campus, 10th Floor, QEQM Building, Praed Street, London W2 1NY, United Kingdom.

Transcranial direct-current stimulation (tDCS) has previously demonstrated promising effects in improving surgical performance with motor region stimulation [1], [2], [3], [4]. However, extensive prior research has revealed an important role of the prefrontal cortex in surgical skill development [5,6]. This article presents the data of a double-blind randomized sham-controlled trial investigating the effect of prefrontal tDCS on knot-tying performance [7]. Data was collected from an active ( = 20) and sham ( = 20) group across three blocks: pre-, online- (during) and post-tDCS. Group and block differences of knot-tying performance were analyzed using a Generalized linear mixed model and supported with a Friedman's test. Further sub-analyses were conducted to compare high vs. low skilled individuals and initial vs. last knots. Subjective workload was assessed after each block using a SURG-TLX questionnaire and side-effects of the tDCS block were recorded using an additional survey.
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http://dx.doi.org/10.1016/j.dib.2021.106905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941089PMC
April 2021

A Mobile App and Dashboard for Early Detection of Infectious Disease Outbreaks: Development Study.

JMIR Public Health Surveill 2021 03 9;7(3):e14837. Epub 2021 Mar 9.

School of Computer Science, The University of Sydney, Darlington, Australia.

Background: Outbreaks of infectious diseases pose great risks, including hospitalization and death, to public health. Therefore, improving the management of outbreaks is important for preventing widespread infection and mitigating associated risks. Mobile health technology provides new capabilities that can help better capture, monitor, and manage infectious diseases, including the ability to quickly identify potential outbreaks.

Objective: This study aims to develop a new infectious disease surveillance (IDS) system comprising a mobile app for accurate data capturing and dashboard for better health care planning and decision making.

Methods: We developed the IDS system using a 2-pronged approach: a literature review on available and similar disease surveillance systems to understand the fundamental requirements and face-to-face interviews to collect specific user requirements from the local public health unit team at the Nepean Hospital, Nepean Blue Mountains Local Health District, New South Wales, Australia.

Results: We identified 3 fundamental requirements when designing an electronic IDS system, which are the ability to capture and report outbreak data accurately, completely, and in a timely fashion. We then developed our IDS system based on the workflow, scope, and specific requirements of the public health unit team. We also produced detailed design and requirement guidelines. In our system, the outbreak data are captured and sent from anywhere using a mobile device or a desktop PC (web interface). The data are processed using a client-server architecture and, therefore, can be analyzed in real time. Our dashboard is designed to provide a daily, weekly, monthly, and historical summary of outbreak information, which can be potentially used to develop a future intervention plan. Specific information about certain outbreaks can also be visualized interactively to understand the unique characteristics of emerging infectious diseases.

Conclusions: We demonstrated the design and development of our IDS system. We suggest that the use of a mobile app and dashboard will simplify the overall data collection, reporting, and analysis processes, thereby improving the public health responses and providing accurate registration of outbreak information. Accurate data reporting and collection are a major step forward in creating a better intervention plan for future outbreaks of infectious diseases.
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http://dx.doi.org/10.2196/14837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988388PMC
March 2021

Thymoquinone with Metformin Decreases Fasting, Post Prandial Glucose, and HbA1c in Type 2 Diabetic Patients.

Drug Res (Stuttg) 2021 Mar 8. Epub 2021 Mar 8.

Jina Pharmaceuticals Inc., Libertyville, IL, USA.

Objective: Antihyperglycemic activity of Thymoquinone (TQ) was evaluated in diabetic mouse model and patients.

Methods: TQ (50 mg/kg) was orally administered daily for 21 days in combination with metformin in diabetic mice and a reduction on blood glucose level was monitored. In human, a 90-day randomized study was carried out in 60 Type 2 Diabetes mellitus patients to evaluate safety and efficacy of TQ administration with metformin in a 3-arm study. Patients in arm 1 (T1) received 1 tablet of metformin SR 1000 mg and 1 tablet of TQ 50 mg once daily. The second arm (T2) patients received 1 tablet of metformin SR 1000 mg and 2 tablets of TQ 50 mg once daily. Patients in arm 3 (R) received 1 tablet of metformin SR 1000 mg only.

Results: The diabetic mice treated with combination of TQ and metformin showed significant decrease in blood sugar compared to those treated with only metformin. In patients who completed the study, the glycated hemoglobin (HbA1c) values in T1, T2 and R decreased after 3 months from 7.2, 7.2 and 7.3 to 6.7, 6.8, and 7.1, respectively. A greater reduction in Fasting Blood Glucose and Post Prandial Blood Glucose was also observed in T1 and T2 arms compared to R.

Conclusion: At dose levels of 50 and 100 mg of TQ combined with a daily dose of 1000 mg Metformin demonstrated a reduction in the levels of HbA1c and blood glucose compared to the standard treatment of diabetic patients with metformin alone.
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http://dx.doi.org/10.1055/a-1388-5415DOI Listing
March 2021

Revision Surgery for Inflatable Penile Prosthesis (IPP): A Single-Center Experience and Pictorial Representation.

Urology 2021 Jun 3;152:42-51. Epub 2021 Feb 3.

Mayo Clinic Florida, Jacksonville, FL. Electronic address:

Objective: To elucidate factors influencing Inflatable Penile Prosthesis (IPP) revision and describe outcomes associated with revision surgery.

Methods: A single surgeon, retrospective review of all patients who underwent IPP revision between 2008-2016, was performed. Patient age, BMI, operative duration, blood loss, hospital duration, time from most recent penile implant to revision surgery, etiology of revision, and whether the patient had a prior failed revision surgery were all collected and analyzed.

Results: A total of 57 patients, who had undergone IPP revision between the years 2008-2016, with at least 3 years of follow-up, were included in the investigation. Mean patient age and BMI were 68 and 29.2 kg/m, respectively. The mean time between the most recent implant operation to revision was 8.4 years. Four patients (7%) reported IPP revision failure within a 3-year follow-up period.

Conclusion: IPP revision demonstrates a relatively high success rate, in the short term, and should be offered to patients as a safe and effective option.
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http://dx.doi.org/10.1016/j.urology.2020.11.072DOI Listing
June 2021

Performance of Regression-Based Norms for Cognitive Functioning of Persons With Multiple Sclerosis in an Independent Sample.

Front Neurol 2020 14;11:621010. Epub 2021 Jan 14.

Department of Psychology & Neuroscience, Dalhousie University, Halifax, NS, Canada.

Cognitive impairment is common in multiple sclerosis (MS). Interpretation of neuropsychological tests requires the use of normative data. Traditionally, normative data have been reported for discrete categories such as age. More recently continuous norms have been developed using multivariable regression equations that account for multiple demographic factors. Regression-based norms have been developed for use in the Canadian population for tests included in the MACFIMS and BICAMS test batteries. Establishing the generalizability of these norms is essential for application in clinical and research settings. We aimed to (i) test the performance of previously published Canadian regression-based norms in an independently collected sample of Canadian healthy controls; (ii) compare the ability of Canadian and non-Canadian regression-based norms to discriminate between healthy controls and persons with MS; and (iii) develop regression-based norms for several cognitive tests drawn from batteries commonly used in MS that incorporated race/ethnicity in addition to age, education, and sex. We included 93 adults with MS and 96 healthy adults in this study, with a replication sample of 104 (MS) and 39 (healthy adults). Participants reported their sociodemographic characteristics, and each was administered the oral Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test (CVLT-II), and the Brief Visuospatial Memory Test-Revised (BVMT-R). From the healthy control data, we developed regression-based norms incorporating race, age, education and sex. We then applied existing discrete norms and regression-based norms for the cognitive tests to the healthy controls, and generated z-scores which were compared using Spearman rank and concordance coefficients. We also used receiver operating characteristic (ROC) curves to compare the ability of each set of norms to discriminate between participants with and without MS. Within the MS samples we compared the ability of each set of norms to discriminate between differing levels of disability and employment status using relative efficiency. When we applied the published regression norms to our healthy sample, impairment classification rates often differed substantially from expectations (7%), even when the norms were derived from a Canadian (Ontario) population. Most, but not all of the Spearman correlations between z-scores based on different existing published norms for the same cognitive test exceeded 0.90. However, concordance coefficients were often lower. All of the norms for the SDMT reliably discriminated between the MS and healthy control groups. In contrast, none of the norms for the CVLT-II or BVMT-R discriminated between the MS and healthy control groups. Within the MS population, the norms varied in their ability to discriminate between disability levels or employment status; locally developed norms for the SDMT and CVLT-II had the highest relative efficiency. Our findings emphasize the value of local norms when interpreting the results of cognitive tests and demonstrate the need to consider and assess the performance of regression-based norms developed in other populations when applying them to local populations, even when they are from the same country. Our findings also strongly suggest that the development of regression-based norms should involve larger, more diverse samples to ensure broad generalizability.
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http://dx.doi.org/10.3389/fneur.2020.621010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840703PMC
January 2021

Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro.

Fluids Barriers CNS 2021 Jan 7;18(1). Epub 2021 Jan 7.

Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Jerry H. Hodge School of Pharmacy, 1300 South Coulter Street, Amarillo, TX, 79106, USA.

Background: Alzheimer's disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1, and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of a mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs).

Methods: iPSC lines from patients suffering from a familial form of Alzheimer's disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporter activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1, and lysosomal acidification by acridine orange.

Results: iPSC-derived BMECs from the FAD patient presenting a mutation in the PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to the control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Aβ1-40 peptides compared to control-BMECs.

Conclusions: Our study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMEC metabolism. In particular, mutation in the PSEN1 gene was associated with a more detrimental phenotype than mutation in PSEN2, as noted by a reduced barrier function, reduced drug efflux pump activity, and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer's disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.
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http://dx.doi.org/10.1186/s12987-020-00235-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789219PMC
January 2021

Microstructural and Mechanical Properties of the Anterolateral Ligament of the Knee.

Am J Sports Med 2021 01;49(1):172-182

Washington University in St Louis, St Louis, Missouri, USA.

Background: The variable anatomy and controversy of the anterolateral ligament (ALL) reflect the complex relationship among the anterolateral knee structures.

Purpose/hypothesis: The purpose was to quantify the microstructural and mechanical properties of the ALL as compared with the anterolateral capsule (ALC) and lateral collateral ligament (LCL). The primary hypotheses were that (1) there is no difference in these properties between the ALL and ALC and (2) the LCL has significantly different properties from the ALL and ALC.

Study Design: Descriptive laboratory study.

Methods: The LCL, ALL, and ALC were harvested from 25 cadaveric knees. Mechanical testing and microstructural analyses were performed using quantitative polarized light imaging. The average degree of linear polarization (AVG DoLP; mean strength of collagen alignment) and standard deviation of the angle of polarization (STD AoP; degree of variation in collagen angle orientation) were calculated.

Results: Linear region moduli were not different between the ALC and ALL (3.75 vs 3.66 MPa, respectively; > .99). AVG DoLP values were not different between the ALC and ALL in the linear region (0.10 vs 0.10; > .99). Similarly, STD AoP values were not different between the ALC and ALL (24.2 vs 21.7; > .99). The LCL had larger modulus, larger AVG DoLP, and smaller STD AoP values than the ALL and ALC. Of 25 knee specimens, 3 were observed to have a distinct ALL, which exhibited larger modulus, larger AVG DoLP, and smaller STD AoP values as compared with nondistinct ALL samples.

Conclusion: There were no differences in the mechanical and microstructural properties between the ALL and ALC. The ALC and ALL exhibited comparably weak and disperse collagen alignment. However, when a distinct ALL was present, the properties were suggestive of a ligamentous structure.

Clinical Relevance: The properties of the ALL are similar to those of a ligament only when a distinct ALL is present, but otherwise, for the majority of specimens, ALL properties are closer to those of the capsule. Variability in the ligamentous structure of the ALL suggests that it may be more important in some patients than others and reconstruction may be considered in selective patients. Further study is needed to better understand its selective role and optimal indications for reconstruction.
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http://dx.doi.org/10.1177/0363546520974381DOI Listing
January 2021

Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder.

Bipolar Disord 2020 Dec 25. Epub 2020 Dec 25.

Jina Pharmaceuticals Inc, Libertyville, IL, USA.

Objectives: Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients.

Methods: A multicenter, double-blind, active-controlled study was conducted using a daily dose of 8 mg endoxifen compared to 1000 mg divalproex, the current standard treatment, in patients with BPD I acute manic episodes with/without mixed features. The primary endpoint of our study was the mean change in total Young Mania Rating Scale (YMRS) score at day 21.

Results: Endoxifen (n = 116) significantly (p < 0.0001) reduced total YMRS score (from 33.1 to 17.8. A significant (p < 0.001) improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) score was observed for endoxifen (4.8 to 2.5). Early time to remission of the disease was observed with endoxifen compared to divalproex. None of the patients required rescue medication and there was no drug-associated withdrawals. Changes in Clinical Global Impressions-Bipolar Disorder and Clinical Global Impression-Severity of Illness scores showed that treatment with endoxifen was well-tolerated.

Conclusions: Endoxifen at a low daily dose of 8 mg was as efficacious and safe in patients with BPD I acute manic episodes with/without mixed features.
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http://dx.doi.org/10.1111/bdi.13041DOI Listing
December 2020

Single-Dose Pharmacokinetics, Pharmacodynamics and Immunogenicity, and Multiple-Dose Immunogenicity of INTP5 (Pegfilgrastim Biosimilar) Versus Reference Pegfilgrastim in Healthy Subjects.

Clin Drug Investig 2021 Jan 24;41(1):29-42. Epub 2020 Nov 24.

Intas Pharmaceuticals Ltd. (Biopharma), Plot No: 423/P/A, Sarkhej-Bavla Highway, Moraiya, Sanand, Ahmedabad, Gujarat, 382213, India.

BACKGROUND AND OBJECTIVE: INTP5 has been developed as a pegfilgrastim biosimilar. Single-dose, crossover study compared the pharmacokinetics and pharmacodynamics (PK/PD) of INTP5 (pegfilgrastim biosimilar) with reference pegfilgrastim (Neulasta, pegfilgrastim-ref) and a multiple-dose, parallel-group study compared the immunogenicity of INTP5 with pegfilgrastim-ref in healthy subjects as part of a complete clinical development plan.

Methods: In the PK/PD study, subjects received a single subcutaneous 6 mg dose of INTP5 and pegfilgrastim-ref (N = 142) separated by a 6-week washout period. The primary endpoints were area under the serum concentration-time curve measured from time zero to infinity (AUC) and maximum measured serum concentration (C) of pegfilgrastim and area under the absolute neutrophil count (ANC) versus time curve from time zero to t (AUEC) and maximum measured ANC (E) of baseline non-adjusted ANCs. In the immunogenicity study, subjects received two 6 mg doses of INTP5 (N = 100) or pegfilgrastim-ref (N = 100) separated by 21 days. The primary endpoints were incidence of anti-drug antibodies (ADAs) in the two treatment groups.

Results: The primary PK endpoints [AUC (90% CI 108.59-123.11) and C (106.24-118.99)] and the primary PD endpoints [AUEC (99.07-102.32) and E (100.24-104.25)] met the acceptance criteria of 80-125%. The incidence of ADAs was 10.6% in the INTP5 arm and 9.0% in the pegfilgrastim-ref arm. The 90% CI for risk difference of the ADA incidence between INTP5 and pegfilgrastim-ref was 1.64% (- 5.40 to 8.68) and was within the 10% margin. No neutralizing antibodies were reported. Immunogenicity did not impact PK/PD parameters and subjects with aberrant PK/PD/safety did not show immunogenicity concerns. Incidence of adverse events (AEs) was similar with INTP5 and pegfilgrastim-ref in both studies. The most common AEs were musculoskeletal pain and headache.

Conclusion: INTP5 showed PK/PD equivalence with pegfilgrastim-ref following a single dose, no clinically meaningful difference in the immune response following multiple doses, and a comparable safety profile.
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http://dx.doi.org/10.1007/s40261-020-00987-3DOI Listing
January 2021

Eosinophilic Esophagitis: Etiology and Therapy.

Annu Rev Med 2021 01 23;72:183-197. Epub 2020 Nov 23.

Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; email:

Eosinophilic esophagitis (EoE) is a relatively recently identified but now frequently encountered antigen/immune-mediated disease which places significant burden on patients and the healthcare system. With its growing prevalence and recognition by healthcare providers in multiple disciplines, substantial progress has been made regarding the diagnostic criteria, clinical evaluation, tools for disease assessment, and immune pathways related to pathogenesis. Current treatment goals focus on the amelioration of inflammation and prevention of remodeling consequences using proton pump inhibitors, swallowed topical steroids, elimination diets, and esophageal dilation. Ongoing research holds promise for more efficacious and targeted therapies as well as a personalized approach to the care of patients with EoE.
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http://dx.doi.org/10.1146/annurev-med-052819-023848DOI Listing
January 2021

Patellar Tendon Imbrication Is a Safe and Efficacious Technique to Shorten the Patellar Tendon in Patients With Patella Alta.

Orthop J Sports Med 2020 Oct 27;8(10):2325967120959318. Epub 2020 Oct 27.

Sports Health, The Cleveland Clinic Foundation, Garfield Heights, Ohio, USA.

Background: Patella alta has been noted to be a risk factor for recurrent patellar instability.

Purpose: We conducted a radiographic study to determine whether a patellar tendon imbrication technique normalizes patellar height as well as whether the shortened length is maintained at a minimum 2-year follow-up.

Study Design: Case series; Level of evidence, 4.

Methods: A total of 54 consecutive patients were identified after a retrospective chart review was performed on patients who underwent patellar tendon imbrication between 2008 and 2013. Preoperative, 3 weeks postoperative, and minimum 2 years postoperative lateral radiographs were analyzed using Insall-Salvati (IS), Blackburne-Peel (BP), and Caton-Deschamps (CD) indices to determine the amount of shortening that was achieved after the procedure and to what degree that shortening was maintained at a minimum 2-year follow-up.

Results: A total of 27 patients (32 knees) completed a minimum 2-year follow-up. The mean patellar tendon length preoperatively was 6.1 cm (range, 5-8 cm). At 3 weeks and 2 years, the mean tendon lengths were 5.1 and 5.2 cm, respectively. Thus, the mean ± SD change in patellar tendon length from preoperative to 3 weeks postoperative was 0.97 ± 0.67 cm. IS, BP, and CD ratios had minimal change (loss of correction) from 3-week to 2-year follow-up; the delta values were 0.04, -0.03, and 0.09, respectively. There were no complications directly related to the technique.

Conclusion: Patellar tendon imbrication is a safe and effective procedure to correct patella alta in the setting of lateral patellar instability. On average, the technique allowed 1 cm of patellar tendon shortening and maintained the correction at a minimum 2-year follow-up. In the skeletally immature patient, this technique allows correction of patella alta by avoidance of a tibial tuberosity osteotomy.
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http://dx.doi.org/10.1177/2325967120959318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605011PMC
October 2020

An Ancillary Central Catheter Emergency Support Service Team Staffed by Surgical Personnel Improves Workflow During the Coronavirus Disease 2019 Crisis.

Surg Innov 2021 Apr 6;28(2):231-235. Epub 2020 Nov 6.

Department of Surgery, 219212NYU Langone Hospital Brooklyn, USA.

. The SARS-CoV-2 novel coronavirus disease 2019 (COVID-19) pandemic has posed significant challenges to urban health centers across the United States. Many hospitals are reallocating resources to best handle the influx of critical patients. . At our New York City hospital, we developed the ancillary central catheter emergency support service (ACCESS), a team for dedicated central access staffed by surgical residents to assist in the care of critical COVID-19 patients. We conducted a retrospective review of all patients for whom the team was activated. Furthermore, we distributed a survey to the critical care department to assess their perceived time saved per patient. . The ACCESS team placed 104 invasive catheters over 10 days with a low complication rate of .96%. All critical care providers surveyed found the service useful and felt it saved at least 30 minutes of procedural time per patient, as patient to critical care provider ratios were increased from 12 patients to one provider to 44 patients to one provider. . The ACCESS team has helped to effectively redistribute surgical staff, provide a learning experience for residents, and improve efficiency for the critical care team during this pandemic.
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http://dx.doi.org/10.1177/1553350620971181DOI Listing
April 2021

Prefrontal transcranial direct-current stimulation improves early technical skills in surgery.

Brain Stimul 2020 Nov - Dec;13(6):1834-1841. Epub 2020 Oct 31.

Department of Surgery & Cancer, Imperial College London, St Mary's Hospital Campus, 10th Floor, QEQM Building, Praed Street, London, W2 1NY, UK.

Background: Studies applying transcranial direct-current stimulation (tDCS) to motor regions to enhance surgical skills have observed modest benefits in performance. Early surgical skills acquisition is known to be dependent on the prefrontal cortex (PFC) which could be a suitable target for performance enhancement in fields with high cognitive demand.

Objective: To assess whether prefrontal tDCS could improve early phases of surgical skill development.

Methods: In a randomized sham-controlled double-blind parallel design, 40 surgical novices performed an open knot-tying task repeated in three blocks; pre-, online- and post-tDCS. During online stimulation, participants were randomized to either active tDCS (2 mA for 15 min) to the prefrontal cortex (anode over F3, cathode over F4) or sham tDCS. Performance score (PS) was computed using a validated algorithm and introspective workload domains were assessed using a SURG-TLX questionnaire.

Results: There was no difference in demographics or PS between groups prior to receiving tDCS. PS significantly improved from pre-to online- (p < 0.001) and from pre-to post-tDCS (p < 0.001) in the active group only. Following active tDCS, PS was closer to the defined proficiency benchmark and significantly greater compared to sham (p = 0.002). Only the active group reported significantly improved temporal demand scores from pre-to online- (p = 0.004) to post-tDCS (p = 0.002).

Conclusions: This study demonstrates significantly improved early phase surgical-skill acquisition following prefrontal tDCS. Further work is required to determine the underlying neurophysiological mechanisms and whether the benefits observed are retained long-term.
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http://dx.doi.org/10.1016/j.brs.2020.10.013DOI Listing
March 2021

An iPSC-Derived Neuron Model of CLN3 Disease Facilitates Small Molecule Phenotypic Screening.

ACS Pharmacol Transl Sci 2020 Oct 1;3(5):931-947. Epub 2020 Sep 1.

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.

The neuronal ceroid lipofuscinoses (NCLs) are a family of rare lysosomal storage disorders. The most common form of NCL occurs in children harboring a mutation in the gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with current and models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier and establishes the suitability of an iPSC-derived neuron model of the disease to facilitate compound screening. Upon differentiation, hallmarks of CLN3 disease are apparent, including lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and attenuated Bcl-2 expression. The model led to the identification of small molecules that cleared subunit c accumulation by mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction.
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http://dx.doi.org/10.1021/acsptsci.0c00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551715PMC
October 2020

Anxiety and depression affect performance on the symbol digit modalities test over time in MS and other immune disorders.

Mult Scler 2020 Sep 25:1352458520961534. Epub 2020 Sep 25.

Departments of Psychiatry, Psychology & Neuroscience, and Medicine, Dalhousie University, Halifax, NS, Canada.

Background: Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited.

Objective: We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases (IMID).

Methods: We followed participants (MS: 255, IBD: 247, RA: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores ⩾ 11) of anxiety (HADS-A) and depression (HADS-D) with SDMT -scores using multivariable linear models-estimating between-person and within-person effects.

Results: Participants with MS performed worse on the SDMT than participants in the DEP/ANX cohort (β = -0.68; 95% CI: -0.88, -0.48). Participants with elevated HADS-A scores performed worse on the SDMT than those without elevated scores (β = -0.43; 95% CI: -0.65, -0.21), particularly those with RA. Time-varying within-person elevations in depressive symptoms were associated with worse SDMT performance (β = -0.12; 95% CI: -0.21, -0.021).

Conclusions: Across persons, elevated symptoms of anxiety adversely affected information processing. Elevated symptoms of depression within-persons over time were associated with declines in information processing speed.
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http://dx.doi.org/10.1177/1352458520961534DOI Listing
September 2020

Erasable labeling of neuronal activity using a reversible calcium marker.

Elife 2020 09 15;9. Epub 2020 Sep 15.

Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, United States.

Understanding how the brain encodes and processes information requires the recording of neural activity that underlies different behaviors. Recent efforts in fluorescent protein engineering have succeeded in developing powerful tools for visualizing neural activity, in general by coupling neural activity to different properties of a fluorescent protein scaffold. Here, we take advantage of a previously unexploited class of reversibly switchable fluorescent proteins to engineer a new type of calcium sensor. We introduce rsCaMPARI, a genetically encoded calcium marker engineered from a reversibly switchable fluorescent protein that enables spatiotemporally precise marking, erasing, and remarking of active neuron populations under brief, user-defined time windows of light exposure. rsCaMPARI photoswitching kinetics are modulated by calcium concentration when illuminating with blue light, and the fluorescence can be reset with violet light. We demonstrate the utility of rsCaMPARI for marking and remarking active neuron populations in freely swimming zebrafish.
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http://dx.doi.org/10.7554/eLife.57249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492087PMC
September 2020

Neurostructural phenotypes of CACNA1C rs1006737 in adolescents with bipolar disorder and healthy controls.

Prog Neuropsychopharmacol Biol Psychiatry 2021 01 13;104:110071. Epub 2020 Aug 13.

Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Pharmacology, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada. Electronic address:

Objective: Investigate the effects of CACNA1C rs1006737 on cortical and subcortical neurostructural phenotypes in Caucasian bipolar disorder (BD) and healthy control (HC) adolescents.

Methods: Seventy-one adolescents (14-20 years; 38BD, 33HC) underwent 3-Tesla Magnetic Resonance Imaging (MRI). Region of interest (ROI) and vertex-wise analyses examined cortical volume, surface area (SA), and thickness, as well as subcortical volume. ROIs included the ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), putamen, and amygdala. General linear models included main effects of diagnosis and rs1006737, and an interaction term, controlling for age, sex, and total intracranial volume.

Results: Vertex-wise analysis found significant BD-by-rs1006737 interactions for prefrontal and occipital regions such that BD A-carriers were found to have greater SA relative to BD non-carriers, while HC A-carriers had reduced SA relative to HC non-carriers. ROI analysis found an interaction in the ACC such that BD A-carriers were found to have greater SA relative to BD non-carriers, while no significant difference was found in HCs. Main effects of rs1006737 were also found on ACC SA from ROI analysis, and occipital SA from vertex-wise analysis, such that A-carriers had larger SA relative to non-carriers in both of these regions.

Conclusions: The current study identified neurostructural intermediate phenotypes relevant to the impact of CACNA1C rs1006737 on adolescent BD. Further investigation is warranted into the neurofunctional and neurocognitive relevance of rs1006737 associations with BD-specific elevations in regional SA.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110071DOI Listing
January 2021

Practitioner Approaches to Measuring Community Resilience: The Analysis of the Resilience of Communities to Disasters Toolkit.

Int J Disaster Risk Reduct 2020 Nov 23;50. Epub 2020 Jun 23.

Harvard University, USA.

To be useful for operational programs, measures of resilience must not just be valid, but be easy to use and useful. Unfortunately, while resilience measurement techniques have progressed tremendously over the past decade, most progress has been on improving validity rather than utility and ease of use. In this article we present a new tool for measuring community resilience that incorporates issues of utility and ease of use, the Analysis of Resilience of Communities to Disasters (ARC-D) toolkit. The toolkit was developed over the course of ten years by the international humanitarian and development organization GOAL to enable aid organizations to measure community resilience in a way that supports resilience building interventions. It offers an approach to measurement that is cognizant of the resilience policy landscape, including the Sendai Framework, approaches to data collection and measurement uses relevant to aid agencies. We first present the core tenants of community resilience measurement before describing the toolkit, which consists of 30 measures, a guidebook, and an online platform. To illustrate its use, we a case study of a resilience building program in Tegucigalpa, Honduras. By developing one of the first resilience toolkits focused beyond validity and providing a description of how such an assessment works, this article has implications for resilience researchers and practitioners.
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http://dx.doi.org/10.1016/j.ijdrr.2020.101714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386397PMC
November 2020

A general method to optimize and functionalize red-shifted rhodamine dyes.

Nat Methods 2020 08 27;17(8):815-821. Epub 2020 Jul 27.

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.

Expanding the palette of fluorescent dyes is vital to push the frontier of biological imaging. Although rhodamine dyes remain the premier type of small-molecule fluorophore owing to their bioavailability and brightness, variants excited with far-red or near-infrared light suffer from poor performance due to their propensity to adopt a lipophilic, nonfluorescent form. We report a framework for rationalizing rhodamine behavior in biological environments and a general chemical modification for rhodamines that optimizes long-wavelength variants and enables facile functionalization with different chemical groups. This strategy yields red-shifted 'Janelia Fluor' (JF) dyes useful for biological imaging experiments in cells and in vivo.
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http://dx.doi.org/10.1038/s41592-020-0909-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396317PMC
August 2020

Prophylactic treatment with transdermal deferoxamine mitigates radiation-induced skin fibrosis.

Sci Rep 2020 07 23;10(1):12346. Epub 2020 Jul 23.

Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA, 94305-5148, USA.

Radiation therapy can result in pathological fibrosis of healthy soft tissue. The iron chelator deferoxamine (DFO) has been shown to improve skin vascularization when injected into radiated tissue prior to fat grafting. Here, we evaluated whether topical DFO administration using a transdermal drug delivery system prior to and immediately following irradiation (IR) can mitigate the chronic effects of radiation damage to the skin. CD-1 nude immunodeficient mice were split into four experimental groups: (1) IR alone (IR only), (2) DFO treatment for two weeks after recovery from IR (DFO post-IR), (3) DFO prophylaxis with treatment through and post-IR (DFO ppx), or (4) no irradiation or DFO (No IR). Immediately following IR, reactive oxygen species and apoptotic markers were significantly decreased and laser doppler analysis revealed significantly improved skin perfusion in mice receiving prophylactic DFO. Six weeks following IR, mice in the DFO post-IR and DFO ppx groups had improved skin perfusion and increased vascularization. DFO-treated groups also had evidence of reduced dermal thickness and collagen fiber network organization akin to non-irradiated skin. Thus, transdermal delivery of DFO improves tissue perfusion and mitigates chronic radiation-induced skin fibrosis, highlighting a potential role for DFO in the treatment of oncological patients.
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http://dx.doi.org/10.1038/s41598-020-69293-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378074PMC
July 2020

Ubiquilin-2 differentially regulates polyglutamine disease proteins.

Hum Mol Genet 2020 08;29(15):2596-2610

Department of Neurology, University of Michigan, Ann Arbor, MI 48109-2200, USA.

Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins. Here we employ cellular models, primary neurons and mouse models to investigate the potential differential regulation by UBQLN2 of two polyglutamine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3). In cells, overexpressed UBQLN2 selectively lowered levels of full-length pathogenic HTT but not of HTT exon 1 fragment or full-length ATXN3. Consistent with these results, UBQLN2 specifically reduced accumulation of aggregated mutant HTT but not mutant ATXN3 in mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), respectively. Normally a cytoplasmic protein, UBQLN2 translocated to the nuclei of neurons in HD mice but not in SCA3 mice. Remarkably, instead of reducing the accumulation of nuclear mutant ATXN3, UBQLN2 induced an accumulation of cytoplasmic ATXN3 aggregates in neurons of SCA3 mice. Together these results reveal a selective action of UBQLN2 toward polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient to promote UBQLN2-mediated clearance of this class of disease proteins. Additional factors, including nuclear translocation of UBQLN2, may facilitate its action to clear intranuclear, aggregated disease proteins like HTT.
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http://dx.doi.org/10.1093/hmg/ddaa152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471500PMC
August 2020