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1.
JMIR Public Health Surveill ; 7(3): e14837, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33687334

RESUMO

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.

2.
Heart Fail Rev ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33768376

RESUMO

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.

3.
Drug Res (Stuttg) ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33684953

RESUMO

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.

5.
Urology ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33548247

RESUMO

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/m2, 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.

6.
Fluids Barriers CNS ; 18(1): 3, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413468

RESUMO

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 Aß1-40 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.

7.
Am J Sports Med ; 49(1): 172-182, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33381993

RESUMO

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; P > .99). AVG DoLP values were not different between the ALC and ALL in the linear region (0.10 vs 0.10; P > .99). Similarly, STD AoP values were not different between the ALC and ALL (24.2 vs 21.7; P > .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.


Assuntos
Colágeno , Articulação do Joelho , Ligamentos , Lesões do Ligamento Cruzado Anterior , Fenômenos Biomecânicos , Cadáver , Humanos
8.
Artigo em Inglês | MEDLINE | ID: mdl-32800865

RESUMO

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.

9.
Bipolar Disord ; 2020 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-33368969

RESUMO

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.

10.
Annu Rev Med ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228437

RESUMO

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. Expected final online publication date for the Annual Review of Medicine, Volume 72 is January 27, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

11.
Surg Innov ; : 1553350620971181, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33153382

RESUMO

Background. 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. Methods. 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. Results. 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. Conclusions. 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.

12.
Clin Drug Investig ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33236287

RESUMO

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 (AUC0-∞) and maximum measured serum concentration (Cmax) of pegfilgrastim and area under the absolute neutrophil count (ANC) versus time curve from time zero to t (AUEC0-t) and maximum measured ANC (Emax) 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 [AUC0-∞ (90% CI 108.59-123.11) and Cmax (106.24-118.99)] and the primary PD endpoints [AUEC0-t (99.07-102.32) and Emax (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.

13.
Orthop J Sports Med ; 8(10): 2325967120959318, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33195712

RESUMO

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.

14.
Brain Stimul ; 13(6): 1834-1841, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33130252

RESUMO

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.

15.
ACS Pharmacol Transl Sci ; 3(5): 931-947, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33073192

RESUMO

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 CLN3 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 in vivo and in vitro 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.

16.
Mult Scler ; : 1352458520961534, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32976067

RESUMO

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 z-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 (ß = -0.68; 95% CI: -0.88, -0.48). Participants with elevated HADS-A scores performed worse on the SDMT than those without elevated scores (ß = -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 (ß = -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.

17.
Elife ; 92020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32931424

RESUMO

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.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32724761

RESUMO

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.

19.
Nat Methods ; 17(8): 815-821, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32719532

RESUMO

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.


Assuntos
Corantes Fluorescentes/química , Rodaminas/química , Linhagem Celular Tumoral , Humanos , Raios Infravermelhos , Microscopia de Fluorescência/métodos , Estrutura Molecular
20.
Cancer Chemother Pharmacol ; 86(2): 193-202, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32627073

RESUMO

PURPOSE: To demonstrate pharmacokinetic (PK) equivalence and to compare safety of INTP24 (bevacizumab biosimilar) with that of US-bevacizumab and EU-bevacizumab in healthy male subjects. METHODS: In this randomized, parallel-group, double-blind study, male subjects were randomized (1:1:1) to receive a single 1 mg/kg intravenous infusion of either INTP24, US-bevacizumab, or EU-bevacizumab. The primary endpoint was area under serum concentration (AUC) from time zero to infinity (AUC0-∞). Secondary endpoints were AUC from time zero to last quantifiable concentration (AUC0-t), maximum concentration (Cmax), other PK parameters, immunogenicity, and safety. RESULTS: A total of 117 subjects (39/group) were dosed; 113 subjects (37, 37, and 39 in INPT24, US-bevacizumab, and EU-bevacizumab groups, respectively) completed the study and were included in the PK analysis. Baseline demographics were similar across the three groups. The 90% confidence intervals (CI) of geometric mean ratios (GMR) of ln-transformed AUC0-∞ and Cmax of INTP24 relative to US-bevacizumab and EU-bevacizumab were within the acceptance range of 80%-125% (INTP24 vs. US-bevacizumab, 96.55-112.51% and 99.16-112.79%: INTP24 vs. EU-bevacizumab, 94.84-110.17% and 96.32-109.28%). The 90% CIs of GMRs for AUC0-t was also within 80-125% for INTP24 vs. US-bevacizumab and INTP24 vs. EU-bevacizumab. Safety and immunogenicity profiles were similar across the three groups. Twenty-one (17.95%) subjects experienced at least one AE and 9 (7.69%) were ADA positive. One treatment-related serious adverse event (varicella zoster infection) was reported in INTP24 group. CONCLUSION: This study demonstrated PK bioequivalence of INTP24 to US-bevacizumab and EU-bevacizumab in healthy male subjects and showed similar safety and immunogenicity profiles across the treatment groups.

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