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1.
J Pharm Sci ; 113(3): 505-512, 2024 03.
Article in English | MEDLINE | ID: mdl-38103689

ABSTRACT

Forced degradation, also known as stress testing, is used throughout pharmaceutical development for many purposes including assessing the comparability of biopharmaceutical products according to ICH Guideline Q5E. These formal comparability studies, the results of which are submitted to health authorities, investigate potential impacts of manufacturing process changes on the quality, safety, and efficacy of the drug. Despite the wide use of forced degradation in comparability assessments, detailed guidance on the design and interpretation of such studies is scarce. The BioPhorum Development Group is an industry-wide consortium enabling networking and sharing of common practices for the development of biopharmaceuticals. The BioPhorum Development Group Forced Degradation Workstream recently conducted several group discussions and a benchmarking survey to understand current industry approaches for the use of forced degradation studies to assess comparability of protein-based biopharmaceuticals. The results provide insight into the design of forced degradation studies, analytical characterization and testing strategies, data evaluation criteria, as well as some considerations and differences for non-platform modalities (e.g., non-traditional mAbs). This article presents survey responses from several global companies of various sizes and provides an industry perspective and experience regarding the practicalities of using forced degradation to assess comparability.


Subject(s)
Biological Products , Drug Development , Antibodies, Monoclonal , Drug Industry/methods
2.
Plants (Basel) ; 12(17)2023 Aug 27.
Article in English | MEDLINE | ID: mdl-37687318

ABSTRACT

Calcareous soil had sufficient phosphorus and potassium (PK) in different forms due to the high contents of PK-bearing minerals; however, the available PK state was reduced due to its PK-fixation capacity. Compost, coupled with high PK solubilization capacity microbes, is a sustainable solution for bioorganic fertilization of plants grown in calcareous soil. A 2-year field experiment was conducted to investigate the effect of compost (20 t ha-1) with Aspergillus niger through soil drenching (C-AN) along with partial substitution of PK fertilization on quinoa performance in normal and calcareous soils. Treatments included PK100% (72 kg P2O5 ha-1 + 60 kg K2O ha-1 as conventional rate), PK100%+C-AN, PK75%+C-AN, PK50%+C-AN, PK25%+C-AN, and only C-AN in normal and calcareous soils. Results showed that C-AN and reduced PK fertilization (up to 75 or 50%) increased photosynthetic pigments and promoted nutrient acquisition in quinoa grown in calcareous soil. Reduced PK fertilization to 75 or 50% plus C-AN in calcareous soil increased osmoprotectants, nonenzymatic antioxidants, and DPPH scavenging activity of quinoa's leaves compared to the PK0%+C-AN treatment. The integrative application of high PK levels and C-AN enhanced the quinoa's seed nutritional quality (i.e., lipids, carbohydrates, mineral contents, total phenolics, total flavonoids, half maximal inhibitory concentration, and antiradical power) in calcareous soil. At reduced PK fertilization (up to 75 or 50%), application of compost with Aspergillus niger through soil drenching increased plant dry weight by 38.7 or 53.2%, hectoliter weight by 3.0 or 2.4%, seed yield by 49.1 or 39.5%, and biological yield by 43.4 or 33.6%, respectively, compared to PK0%+C-AN in calcareous soil. The highest P-solubilizing microorganism's population was found at PK0%+C-AN in calcareous soil, while the highest Azotobacter sp. population was observed under high PK levels + C-AN in normal soil. Our study recommends that compost with Aspergillus niger as a bioorganic fertilization treatment can partially substitute PK fertilization and boost quinoa's tolerance to salt calcareous-affected soil.

3.
Pathogens ; 12(7)2023 Jun 30.
Article in English | MEDLINE | ID: mdl-37513742

ABSTRACT

In the Amazon, the treatment for Plasmodium vivax is chloroquine plus primaquine. However, this regimen is limited due to the risk of acute hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency. Primaquine is a prodrug that requires conversion by the CYP2D6 enzyme to be effective against malaria. A series of cases were performed at an infectious diseases reference hospital in the Western Brazilian Amazon. The STANDARD G6PD (SD Biosensor®) assay was used to infer G6PD status and real-time PCR to genotype G6PD, CYP2C19, CYP2D6 and CYP3A4. Eighteen patients were included, of which 55.6% had African A- variant (G202A/A376G), 11.1% African A+ variant (A376G), 5.6% Mediterranean variant (C563T) and 27.8% were wild type. CYP2C19, CYP2D6 and CYP3A4 genotyping showed no statistically significant differences in the frequency of star alleles between the groups G6PD deficient and G6PD normal. Elevated levels of liver and kidney markers in the G6PDd patients were observed in gNM, gRM and gUM of CYP2C19 and CYP2D6 (p < 0.05). Furthermore, in this study there was no influence of CYPs on hemolysis. These findings reinforce the importance of studies on the mapping of G6PD deficiency and genetic variations of CYP2C19, CYP2D6 and CYP3A4. This mapping will allow us to validate the prevalence of CYPs and determine their influence on hemolysis in patients with malaria, helping to decide on the treatment regimen.

4.
Glycobiology ; 33(9): 715-731, 2023 10 29.
Article in English | MEDLINE | ID: mdl-37289485

ABSTRACT

Hypercoagulability, a major complication of metastatic cancers, has usually been treated with heparins from natural sources, or with their synthetic derivatives, which are under intense investigation in clinical oncology. However, the use of heparin has been challenging for patients with risk of severe bleeding. While the systemic administration of heparins, in preclinical models, has shown primarily attenuating effects on metastasis, their direct effect on established solid tumors has generated contradictory outcomes. We investigated the direct antitumoral properties of two sulfated fucans isolated from marine echinoderms, FucSulf1 and FucSulf2, which exhibit anticoagulant activity with mild hemorrhagic potential. Unlike heparin, sulfated fucans significantly inhibited tumor cell proliferation (by ~30-50%), and inhibited tumor migration and invasion in vitro. We found that FucSulf1 and FucSulf2 interacted with fibronectin as efficiently as heparin, leading to loss of prostate cancer and melanoma cell spreading. The sulfated fucans increased the endocytosis of ß1 integrin and neuropilin-1 chains, two cell receptors implicated in fibronectin-dependent adhesion. The treatment of cancer cells with both sulfated fucans, but not with heparin, also triggered intracellular focal adhesion kinase (FAK) degradation, with a consequent overall decrease in activated focal adhesion kinase levels. Finally, only sulfated fucans inhibited the growth of B16-F10 melanoma cells implanted in the dermis of syngeneic C57/BL6 mice. FucSulf1 and FucSulf2 arise from this study as candidates for the design of possible alternatives to long-term treatments of cancer patients with heparins, with the advantage of also controlling local growth and invasion of malignant cells.


Subject(s)
Integrin beta1 , Melanoma , Male , Animals , Humans , Mice , Focal Adhesion Protein-Tyrosine Kinases , Integrin beta1/metabolism , Fibronectins/metabolism , Neuropilin-1 , Heparin/pharmacology , Endocytosis
5.
Acad Radiol ; 30(5): 798-806, 2023 05.
Article in English | MEDLINE | ID: mdl-35803888

ABSTRACT

RATIONALE AND OBJECTIVES: Determine whether there are patterns of lesion recall among breast imaging subspecialists interpreting screening mammography, and if so, whether recall patterns correlate to morphologies of screen-detected cancers. MATERIALS AND METHODS: This Institutional Review Board-approved, retrospective review included all screening examinations January 3, 2012-October 1, 2018 interpreted by fifteen breast imaging subspecialists at a large academic medical center and two outpatient imaging centers. Natural language processing identified radiologist recalls by lesion type (mass, calcifications, asymmetry, architectural distortion); proportions of callbacks by lesion types were calculated per radiologist. Hierarchical cluster analysis grouped radiologists based on recall patterns. Groups were compared to overall practice and each other by proportions of lesion types recalled, and overall and lesion-specific positive predictive value-1 (PPV1). RESULTS: Among 161,859 screening mammograms with 13,086 (8.1%) recalls, Hierarchical cluster analysis grouped 15 radiologists into five groups. There was substantial variation in proportions of lesions recalled: calcifications 13%-18% (Chi-square 45.69, p < 0.00001); mass 16%-44% (Chi-square 498.42, p < 0.00001); asymmetry 13%-47% (Chi-square 660.93, p < 0.00001) architectural distortion 6%-20% (Chi-square 283.81, p < 0.00001). Radiologist groups differed significantly in overall PPV1 (range 5.6%-8.8%; Chi-square 17.065, p = 0.0019). PPV1 by lesion type varied among groups: calcifications 9.2%-15.4% (Chi-square 2.56, p = 0.6339); mass 5.6%-8.5% (Chi-square 1.31, p = 0.8597); asymmetry 3.4%-5.9% (Chi-square 2.225, p = 0.6945); architectural distortion 5.6%-10.8% (Chi-square 5.810, p = 0.2138). Proportions of recalled lesions did not consistently correlate to proportions of screen-detected cancer. CONCLUSION: Breast imaging subspecialists have patterns for screening mammography recalls, suggesting differential weighting of imaging findings for perceived malignant potential. Radiologist recall patterns are not always predictive of screen-detected cancers nor lesion-specific PPV1s.


Subject(s)
Breast Neoplasms , Calcinosis , Humans , Female , Mammography/methods , Breast Neoplasms/diagnostic imaging , Early Detection of Cancer/methods , Breast/diagnostic imaging , Mass Screening/methods , Retrospective Studies , Radiologists
6.
Diabetologia ; 66(4): 709-723, 2023 04.
Article in English | MEDLINE | ID: mdl-36459178

ABSTRACT

AIMS/HYPOTHESIS: The rapid remission of type 2 diabetes by a diet very low in energy correlates with a marked improvement in glucose-stimulated insulin secretion (GSIS), emphasising the role of beta cell dysfunction in the early stages of the disease. In search of novel mechanisms of beta cell dysfunction after long-term exposure to mild to severe glucotoxic conditions, we extensively characterised the alterations in insulin secretion and upstream coupling events in human islets cultured for 1-3 weeks at ~5, 8, 10 or 20 mmol/l glucose and subsequently stimulated by an acute stepwise increase in glucose concentration. METHODS: Human islets from 49 non-diabetic donors (ND-islets) and six type 2 diabetic donors (T2D-islets) were obtained from five isolation centres. After shipment, the islets were precultured for 3-7 days in RPMI medium containing ~5 mmol/l glucose and 10% (vol/vol) heat-inactivated FBS with selective islet picking at each medium renewal. Islets were then cultured for 1-3 weeks in RPMI containing ~5, 8, 10 or 20 mmol/l glucose before measurement of insulin secretion during culture, islet insulin and DNA content, beta cell apoptosis and cytosolic and mitochondrial glutathione redox state, and assessment of dynamic insulin secretion and upstream coupling events during acute stepwise stimulation with glucose [NAD(P)H autofluorescence, ATP/(ATP+ADP) ratio, electrical activity, cytosolic Ca2+ concentration ([Ca2+]c)]. RESULTS: Culture of ND-islets for 1-3 weeks at 8, 10 or 20 vs 5 mmol/l glucose did not significantly increase beta cell apoptosis or oxidative stress but decreased insulin content in a concentration-dependent manner and increased beta cell sensitivity to subsequent acute stimulation with glucose. Islet glucose responsiveness was higher after culture at 8 or 10 vs 5 mmol/l glucose and markedly reduced after culture at 20 vs 5 mmol/l glucose. In addition, the [Ca2+]c and insulin secretion responses to acute stepwise stimulation with glucose were no longer sigmoid but bell-shaped, with maximal stimulation at 5 or 10 mmol/l glucose and rapid sustained inhibition above that concentration. Such paradoxical inhibition was, however, no longer observed when islets were acutely depolarised by 30 mmol/l extracellular K+. The glucotoxic alterations of beta cell function were fully reversible after culture at 5 mmol/l glucose and were mimicked by pharmacological activation of glucokinase during culture at 5 mmol/l glucose. Similar results to those seen in ND-islets were obtained in T2D-islets, except that their rate of insulin secretion during culture at 8 and 20 mmol/l glucose was lower, their cytosolic glutathione oxidation increased after culture at 8 and 20 mmol/l glucose, and the alterations in GSIS and upstream coupling events were greater after culture at 8 mmol/l glucose. CONCLUSIONS/INTERPRETATION: Prolonged culture of human islets under moderate to severe glucotoxic conditions markedly increased their glucose sensitivity and revealed a bell-shaped acute glucose response curve for changes in [Ca2+]c and insulin secretion, with maximal stimulation at 5 or 10 mmol/l glucose and rapid inhibition above that concentration. This novel glucotoxic alteration may contribute to beta cell dysfunction in type 2 diabetes independently from a detectable increase in beta cell apoptosis.


Subject(s)
Diabetes Mellitus, Type 2 , Islets of Langerhans , Humans , Glucose/metabolism , Insulin Secretion , Calcium/metabolism , Diabetes Mellitus, Type 2/metabolism , Islets of Langerhans/metabolism , Insulin/metabolism , Glutathione/metabolism , Adenosine Triphosphate/metabolism , Cells, Cultured
7.
Stud Health Technol Inform ; 294: 813-814, 2022 May 25.
Article in English | MEDLINE | ID: mdl-35612213

ABSTRACT

The availability of mHealth for people with dementia is increasing. Various mHealth design guidelines for this population have been proposed. In this study, we developed a binary checklist with evaluation statements to assess the implementation of twenty design suggestions in seven currently available mHealth apps for people with dementia. Between 17%-65% of the evaluation statements in the checklist were implemented in these apps. Not all statements were considered applicable for each assessed mHealth app, which resulted in dividing the criteria in two groups as either key evaluation statements or optional evaluation statements. In future work we want to augment this checklist to contribute to the future design of mHealth for people with dementia.


Subject(s)
Dementia , Mobile Applications , Telemedicine , Checklist , Dementia/diagnosis , Dementia/therapy , Humans
8.
Curr Probl Diagn Radiol ; 51(3): 323-327, 2022.
Article in English | MEDLINE | ID: mdl-34266693

ABSTRACT

OBJECTIVES: To evaluate the impact of an electronic workflow update on screening mammography turnaround time and time to diagnostic imaging for mammography performed on our urban mobile mammography van and at an urban community health center. METHOD: Prior to 10/15/2019, screening exams for the mammography van and urban community health center were made available for interpretation to a single designated radiologist via a manually generated paper list. On 10/15/2019, screening exams were routed electronically onto PACS for any breast radiologist across our Network to interpret. Screening mammogram turnaround time (defined as time form image acquisition to report finalization), time to diagnostic imaging, and time to tissue sampling were collected for pre- and post-implementation periods (6/1-9/30/2019 and 11/1/2019-2/29/2020, respectively) and compared via student t-test and statistical process control analyses. RESULTS: The number of screening exams in the pre- and post-implementation periods were 851 and 728 exams, respectively. Patients were predominately Black and/or African American (400/1579, 25%), non-English speaking (858/1579, 54%) and insured by Medicaid (751/1579, 48%). After implementation of the electronic workflow, turnaround time decreased from 101.0 to 36.4 hours (63.9%, P <0.001) and statistical process control analyses showed sustained decrease in mean turnaround time. However, mean time to diagnostic imaging and tissue sampling were unchanged after implementation (39 vs 45, days; P = 0.330 and 43 vs 59; P = 0.187, respectively). CONCLUSION: Electronic workflow management can reduce screening mammography turnaround time for underserved populations, but additional efforts are warranted to improve time to imaging follow-up for abnormal screening mammograms.


Subject(s)
Breast Neoplasms , Mammography , Breast Neoplasms/diagnostic imaging , Early Detection of Cancer , Electronics , Female , Humans , Mammography/methods , Mass Screening/methods , Vulnerable Populations
9.
PLoS Negl Trop Dis ; 15(5): e0009415, 2021 05.
Article in English | MEDLINE | ID: mdl-34003840

ABSTRACT

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency greatly hinders Plasmodium vivax malaria radical cure and further elimination due to 8-aminoquinolines-associated hemolysis. Although the deleterious health effects of primaquine in G6PD deficient individuals have been known for over 50 years, G6PD testing is not routinely performed before primaquine treatment in most P. vivax endemic areas. METHOD/PRINCIPAL FINDINGS: The qualitative CareStart G6PD screening test was implemented in 12 malaria treatment units (MTUs) in the municipality of Rio Preto da Eva, Western Brazilian Amazon, a malaria endemic area, between February 2019 and early January 2020. Training materials were developed and validated; evaluations were conducted on the effectiveness of training health care professionals (HCPs) to perform the test, the interpretation and reliability of routine testing performed by HCPs, and perceptions of HCPs and patients. Most HCPs were unaware of G6PD deficiency and primaquine-related adverse effects. Most of 110 HCPs trained (86/110, 78%) were able to correctly perform the G6PD test after a single 4-hour training session. The test performed by HCPs during implementation showed 100.0% (4/4) sensitivity and 68.1% (62/91) specificity in identifying G6PD deficient patients as compared to a point-of-care quantitative test (Standard G6PD). CONCLUSIONS/SIGNIFICANCE: G6PD screening using the qualitative CareStart G6PD test performed by HCPs in MTUs of an endemic area showed high sensitivity and concerning low specificity. The amount of false G6PD deficiency detected led to substantial loss of opportunities for radical cure.


Subject(s)
Antimalarials/therapeutic use , Glucosephosphate Dehydrogenase Deficiency/diagnosis , Malaria, Vivax/drug therapy , Primaquine/therapeutic use , Antimalarials/adverse effects , Brazil , Glucosephosphate Dehydrogenase Deficiency/complications , Health Personnel/education , Hemolysis/drug effects , Humans , Plasmodium vivax , Point-of-Care Testing , Primaquine/adverse effects , Sensitivity and Specificity
10.
AJR Am J Roentgenol ; 217(3): 587-594, 2021 09.
Article in English | MEDLINE | ID: mdl-32966113

ABSTRACT

BACKGROUND. Patients with a history of breast cancer are at higher risk of subsequent breast cancers and need close clinical and imaging follow-up. Limited data are available on screening of these patients with digital breast tomosynthesis (DBT) versus full-field digital mammography (FFDM). OBJECTIVE. The purpose of this study was to evaluate the screening mammography performance of DBT compared with FFDM among patients with a history of breast cancer undergoing imaging at a large academic oncology center. METHODS. This retrospective study included consecutively registered patients with a personal history of breast cancer treated with mastectomy or lumpectomy who underwent screening FFDM from October 2014 through September 2016 (5706 examinations of 4091 patients) or screening DBT from February 2017 through December 2018 (4440 examinations of 3647 patients). An institutional mammographic database was queried to obtain imaging type, breast density, history of mastectomy or lumpectomy, and BI-RADS category. An institutional breast cancer registry identified cancer diagnoses. Screening performance metrics were compared between FFDM and DBT groups. RESULTS. Recall rate was significantly lower with DBT than with FFDM (7.9% vs 10.1%; p < .001). DBT and FFDM did not differ in PPV1 (7.7% vs 6.1%; p = .36) or cancer detection rate (CDR) (6.1/1000 vs 6.0/1000; p = .97). Sensitivity was 96.4% for DBT and 71.4% for FFDM (p = .008). Specificity was 92.3% for DBT and 90.0% for FFDM (p < .001). With stratification by breast density, patients with nondense breast tissue had a lower recall rate with DBT than with FFDM (5.9% vs 8.8%; p < .001) and a nonsignificant increase in PPV1 (12.0% vs 6.4%; p = .05). The metrics were not otherwise different between DBT and FFDM among patients with nondense and those with dense breast tissue. Recall rates were lower with DBT than with FFDM among both patients who underwent mastectomy (7.8% vs 9.1%; p = .09) and those who underwent lumpectomy (7.9% vs 11.0%; p = .002). PPV1 and CDR were not different between DBT and FFDM among patients who underwent mastectomy and those who underwent lumpectomy. CONCLUSION. For patients with a personal history of breast cancer who have nondense breasts, the use of DBT as opposed to FFDM reduces recall rate and improves sensitivity and specificity. CDR and PPV1 remain unchanged. CLINICAL IMPACT. For women with a personal history of breast cancer and nondense breasts, DBT offers the potential to maintain the benefits of early cancer detection while reducing the potential harms of false-positive findings.


Subject(s)
Breast Neoplasms/diagnostic imaging , Mammography/methods , Neoplasm Recurrence, Local/diagnostic imaging , Adult , Aged , Aged, 80 and over , Breast/diagnostic imaging , Female , Humans , Middle Aged , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity
11.
PLoS One ; 15(8): e0237087, 2020.
Article in English | MEDLINE | ID: mdl-32813723

ABSTRACT

Water buffalo (Bubalus bubalis) is an important source of meat and milk in countries with relatively warm weather. Compared to the cattle genome, a little has been done to reveal its genome structure and genomic traits. This is due to the complications stemming from the large genome size, the complexity of the genome, and the high repetitive content. In this paper, we introduce a high-quality draft assembly of the Egyptian water buffalo genome. The Egyptian breed is used as a dual purpose animal (milk/meat). It is distinguished by its adaptability to the local environment, quality of feed changes, as well as its high resistance to diseases. The genome assembly of the Egyptian water buffalo has been achieved using a reference-based assembly workflow. Our workflow significantly reduced the computational complexity of the assembly process, and improved the assembly quality by integrating different public resources. We also compared our assembly to the currently available draft assemblies of water buffalo breeds. A total of 21,128 genes were identified in the produced assembly. A list of milk virgin-related genes; milk pregnancy-related genes; milk lactation-related genes; milk involution-related genes; and milk mastitis-related genes were identified in the assembly. Our results will significantly contribute to a better understanding of the genetics of the Egyptian water buffalo which will eventually support the ongoing breeding efforts and facilitate the future discovery of genes responsible for complex processes of dairy, meat production and disease resistance among other significant traits.


Subject(s)
Buffaloes/genetics , Genome , Animals , Molecular Sequence Annotation , Whole Genome Sequencing
12.
J Am Coll Radiol ; 17(12): 1684-1691, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32634382

ABSTRACT

OBJECTIVE: Determine predictors of self-reported burnout among academic radiologists. METHODS: In 2017, radiologists at an urban medical center completed the Stanford Wellness Survey, rating burnout via Likert scale (0: no burnout; 1: occasional stress, no burnout; 2: one or more burnout symptoms; 3: persistent burnout symptoms; 4: completely burned out). Univariate analyses assessed age, gender, family situation, clinical versus research focus, and academic rank for association with burnout (Likert scale ≥ 2). Responses in 11 domains querying definitions of burnout (professional fulfillment, emotional exhaustion, interpersonal disengagement), individual factors (sleep-related impairment, self-compassion, negative work impact on personal relationships), institutional factors (perceived appreciation, control over schedule, organizational or personal values alignment, electronic health record experience, supervisor's leadership quality) were evaluated for association with burnout, using χ2 and logistic regression to calculate odds ratios (ORs). RESULTS: In 159 of 204 (77.9%) completed radiologist surveys, 35.2% (56 of 159) reported burnout. Age < 40 years (P = .0068) and clinical focus (P = .0111) were significantly associated with burnout. In univariate analysis, all domains except electronic health record were statistically significant: emotional exhaustion (OR = 1.93, P < .0001); professional fulfillment (OR = 0.78, P < .0001); self-compassion (OR = 1.36, P < .0001); perceived appreciation (OR = 0.78, P < .0001); sleep-related impairment (OR = 1.20, P < .0001); supervisor's leadership quality (OR = 0.91, P < .0001); interpersonal disengagement (OR = 1.31, P < .0001); organizational or personal values alignment (OR = 0.87, P = .0004); negative work impact on personal relationships (OR = 1.10, P = .0070); control over schedule (OR = 0.80, P = .0054); electronic health record experience (OR=1.03, P = .5392). DISCUSSION: Nearly all questions significantly predicted self-reported burnout, observed in over one-third of academic radiologists. Younger age and clinical focus were associated with burnout. Initiatives targeting individual factors (eg, sleep impairment, self-compassion) and institutional factors (eg, physician appreciation, leadership-faculty interactions) may reduce burnout.


Subject(s)
Burnout, Professional , Radiology , Academic Medical Centers , Adult , Burnout, Professional/epidemiology , Faculty , Humans , Job Satisfaction , Self Report , Surveys and Questionnaires
13.
Article in English | MEDLINE | ID: mdl-32366712

ABSTRACT

Cytochrome P450 (CYP) enzymes are involved in the biotransformation of chloroquine (CQ), but the role of the different profiles of metabolism of this drug in relation to Plasmodium vivax recurrences has not been properly investigated. To investigate the influence of the CYP genotypes associated with CQ metabolism on the rates of P. vivax early recurrences, a case-control study was carried out. The cases included patients presenting with an early recurrence (CQ-recurrent individuals), defined as a recurrence during the first 28 days after initial infection and plasma concentrations of CQ plus desethylchloroquine (DCQ; the major CQ metabolite) higher than 100 ng/ml. A control group with no parasite recurrence over the follow-up (the CQ-responsive group) was also included. CQ and DCQ plasma levels were measured on day 28. CQ-metabolizing CYP (CYP2C8, CYP3A4, and CYP3A5) genotypes were determined by real-time PCR. An ex vivo study was conducted to verify the efficacy of CQ and DCQ against P. vivax isolates. The frequency of alleles associated with normal and slow metabolism was similar between the cases and the controls for the CYP2C8 (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 0.51 to 4.14, P = 0.570), CYP3A4 (OR = 2.38, 95% CI = 0.92 to 6.19, P = 0.105), and CYP3A5 (OR = 4.17, 95% CI = 0.79 to 22.04, P = 1.038) genes. DCQ levels were higher than CQ levels, regardless of the genotype. Regarding the DCQ/CQ ratio, there was no difference between groups or between those patients who had a normal genotype and those patients who had a mutant genotype. DCQ and CQ showed similar efficacy ex vivo CYP genotypes had no influence on early recurrence rates. The similar efficacy of CQ and DCQ ex vivo could explain the absence of therapeutic failure, despite the presence of alleles associated with slow metabolism.


Subject(s)
Cytochrome P-450 CYP2C8 , Cytochrome P-450 CYP3A , Malaria, Vivax , Case-Control Studies , Cytochrome P-450 CYP2C8/genetics , Cytochrome P-450 CYP3A/genetics , Genotype , Humans , Malaria, Vivax/genetics , Plasmodium vivax , Recurrence
14.
J Am Coll Radiol ; 17(8): 999-1003, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32068009

ABSTRACT

OBJECTIVE: Compare diagnostic performance of screening full-field digital mammography (FFDM), a hybrid FFDM and digital breast tomosynthesis (DBT) environment, and DBT only. MATERIALS AND METHODS: This institutional review board-approved, retrospective study consisted of all patients undergoing screening mammography at an urban academic medical center and outpatient imaging facility between January 1, 2011, and December 31, 2017. We used the electronic health record data warehouse to extract report data and patient demographics. A validated natural language processing algorithm extracted BI-RADS score from each report. An institutional cancer registry identified cancer diagnoses. Primary outcomes of recall rate, cancer detection rate (CDR), and positive predictive value 1 (PPV1) were calculated for three periods: FFDM-only environment, hybrid environment, and DBT-only environment. A χ2 test was used to compare recall rate, CDR, and PPV1. RESULTS: A total of 179,028 screening mammograms comprised the study cohort: 41,818 (23.3%) during the FFDM-only period, 83,125 (46.4%) during the hybrid period, and 54,084 (30.2%) during the DBT-only period. Recall rates were 10.4% (4,279 of 41,280) for the FFDM-only period, 10.6% (8,761 of 82,917) for the hybrid period, and 10.8% (5,850 of 54,020) for the DBT-only period (P = .96). CDR (cancers per 1,000 examinations) was 2.6 per 1,000, 4.9 per 1,000, and 6.0 per 1,000 for FFDM only, hybrid, and DBT only, respectively (P < .01). PPV1s (number of cancers per number of recalls) were 2.5% for the FFDM-only period, 4.6% for the hybrid period, and 5.6% for the DBT-only period (P < .01). CONCLUSION: Recall rates were not significantly different within the three periods in the breast imaging practice. However, PPV1 and CDR were significantly higher with DBT only.


Subject(s)
Breast Neoplasms , Mammography , Breast Neoplasms/diagnostic imaging , Early Detection of Cancer , Female , Humans , Mass Screening , Radiographic Image Enhancement , Retrospective Studies
15.
J Am Coll Radiol ; 17(4): 504-510, 2020 Apr.
Article in English | MEDLINE | ID: mdl-31901429

ABSTRACT

OBJECTIVE: Determine radiologist ability to accurately select the probability of recommendation of additional imaging (RAI) for themselves and colleagues when arrayed in a feedback report. METHODS: In this institutional review board-approved study, we analyzed 318,366 diagnostic imaging reports from examinations performed in the radiology department of a large quaternary teaching hospital during calendar year 2016. A validated machine learning algorithm identified reports containing RAI. A multivariable logistic regression model was then used to determine the probability of RAI. In 2018, an e-mailed survey asked radiologists to identify their own RAI probability and that of their colleagues from a report arrayed lowest to highest. Radiologists were grouped into quartiles based on their RAI probability. χ2 Analysis compared self-assessment and assessment of colleagues between quartiles. RESULTS: Forty-eight of 57 radiologists completed the survey (84.2%). Fourteen (29.2%) accurately self-identified their RAI probability (chose the correct quartile); 34 (70.8%) did not. There was no statistically significant difference between quartiles of radiologists and their ability to self-identify their RAI probability (ie, radiologists in the bottom or top quartile of RAI probabilities did not correctly predict their RAI probability). However, radiologists were better able to identify the RAI probability of their colleagues who were in the top and bottom quartiles. DISCUSSION: Radiologists were unable to estimate their own RAI probability but were better at predicting the RAI probability of colleagues. Given that radiologists, and physicians in general, may be poor evaluators of their own performance, objective assessment tools are likely needed to help reduce unwarranted variation.


Subject(s)
Practice Patterns, Physicians' , Self-Assessment , Diagnostic Imaging , Humans , Logistic Models , Radiologists
16.
J Am Coll Radiol ; 17(6): 765-772, 2020 Jun.
Article in English | MEDLINE | ID: mdl-31954707

ABSTRACT

PURPOSE: The aim of this study was to assess the prevalence of unscheduled radiologic examination orders in an electronic health record, and the proportion of unscheduled orders that are clinically necessary, by modality. METHODS: This retrospective study was conducted from January to October 2016 at an academic institution. All unscheduled radiologic examination orders were retrieved for seven modalities (CT, MR, ultrasound, obstetric ultrasound, bone densitometry, mammography, and fluoroscopy). After excluding duplicates, 100 randomly selected orders from each modality were assigned to two physician reviewers who classified their clinical necessity, with 10% overlap. Interannotator agreement was assessed using κ statistics, the percentage of clinically necessary unscheduled orders was compared, and χ2 analysis was used to assess differences by modality. RESULTS: A total 494,503 radiologic examination orders were placed during the study period. After exclusions, 33,546 unscheduled orders were identified, 7% of all radiologic examination orders. Among 700 reviewed unscheduled orders, agreement was substantial (κ = 0.63). Eighty-seven percent of bone densitometric examinations and sixty-five percent of mammographic studies were considered clinically necessary, primarily for follow-up management. The majority of orders in each modality were clinically necessary, except for CT, obstetric ultrasound, and fluoroscopy (P < .0001). CONCLUSIONS: Large numbers of radiologic examination orders remain unscheduled in the electronic health record. A substantial portion are clinically necessary, representing potential delays in executing documented provider care plans. Clinically unnecessary unscheduled orders may inadvertently be scheduled and performed. Identifying and performing clinically necessary unscheduled radiologic examination orders may help reduce diagnostic errors related to diagnosis and treatment delays and enhance patient safety, while eliminating clinically unnecessary unscheduled orders will help avoid unneeded testing.


Subject(s)
Electronic Health Records , Radiology , Diagnostic Errors , Humans , Radiography , Retrospective Studies
17.
Prostaglandins Other Lipid Mediat ; 148: 106407, 2020 06.
Article in English | MEDLINE | ID: mdl-31899373

ABSTRACT

Over the last decade, cases of metabolic syndrome and type II diabetes have increased exponentially. Exercise and ω-3 polyunsaturated fatty acid (PUFA)-enriched diets are usually prescribed but no therapy is effectively able to restore the impaired glucose metabolism, hypertension, and atherogenic dyslipidemia encountered by diabetic patients. PUFAs are metabolized by different enzymes into bioactive metabolites with anti- or pro-inflammatory activity. One important class of PUFA metabolizing enzymes are the cytochrome P450 (CYP) enzymes that can generate a series of bioactive products, many of which have been attributed protective/anti-inflammatory and insulin-sensitizing effects in animal models. PUFA epoxides are, however, further metabolized by the soluble epoxide hydrolase (sEH) to fatty acid diols. The biological actions of the latter are less well understood but while low concentrations may be biologically important, higher concentrations of diols derived from linoleic acid and docosahexaenoic acid have been linked with inflammation. One potential application for sEH inhibitors is in the treatment of diabetic retinopathy where sEH expression and activity is elevated as are levels of a diol of docosahexaenoic acid that can induce the destabilization of the retina vasculature.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Diabetes Mellitus, Type 2/pathology , Epoxide Hydrolases/metabolism , Epoxy Compounds/metabolism , Fatty Acids, Unsaturated/metabolism , Metabolic Syndrome/pathology , Animals , Diabetes Mellitus, Type 2/metabolism , Diet , Humans , Metabolic Syndrome/metabolism
18.
Pathogens ; 10(1)2020 Dec 30.
Article in English | MEDLINE | ID: mdl-33396824

ABSTRACT

BACKGROUND: Early recurrence of Plasmodium vivax is a challenge for malaria control in the field, particularly because this species is associated with lower parasitemia, which hinders diagnosis and monitoring through blood smear testing. Early recurrences, defined as the persistence of parasites in the peripheral blood despite adequate drug dosages, may arise from resistance to chloroquine. The objective of the study was to estimate early recurrence of P. vivax in the Brazilian Amazon by using a highly-sensitive detection method, in this case, PCR. METHODS: An ultra-sensitive qPCR that targeted mitochondrial DNA was used to compare a standard qPCR that targeted 18S rDNA to detect early recurrence of P. vivax in very low densities in samples from patients treated with chloroquine. RESULTS: Out of a total of 312 cases, 29 samples (9.3%) were characterized as recurrences, from which 3.2% (10/312) were only detected through ultra-sensitive qPCR testing. CONCLUSIONS: Studies that report the detection of P. vivax early recurrences using light microscopy may severely underestimate their true incidence.

20.
Radiology ; 291(3): 700-707, 2019 06.
Article in English | MEDLINE | ID: mdl-31063082

ABSTRACT

Background Variation between radiologists when making recommendations for additional imaging and associated factors are, to the knowledge of the authors, unknown. Clear identification of factors that account for variation in follow-up recommendations might prevent unnecessary tests for incidental or ambiguous image findings. Purpose To determine incidence and identify factors associated with follow-up recommendations in radiology reports from multiple modalities, patient care settings, and imaging divisions. Materials and Methods This retrospective study analyzed 318 366 reports obtained from diagnostic imaging examinations performed at a large urban quaternary care hospital from January 1 to December 31, 2016, excluding breast and US reports. A subset of 1000 reports were randomly selected and manually annotated to train and validate a machine learning algorithm to predict whether a report included a follow-up imaging recommendation (training-and-validation set consisted of 850 reports and test set of 150 reports). The trained algorithm was used to classify 318 366 reports. Multivariable logistic regression was used to determine the likelihood of follow-up recommendation. Additional analysis by imaging subspecialty division was performed, and intradivision and interradiologist variability was quantified. Results The machine learning algorithm classified 38 745 of 318 366 (12.2%) reports as containing follow-up recommendations. Average patient age was 59 years ± 17 (standard deviation); 45.2% (143 767 of 318 366) of reports were from male patients. Among 65 radiologists, 57% (37 of 65) were men. At multivariable analysis, older patients had higher rates of follow-up recommendations (odds ratio [OR], 1.01 [95% confidence interval {CI}: 1.01, 1.01] for each additional year), male patients had lower rates of follow-up recommendations (OR, 0.9; 95% CI: 0.9, 1.0), and follow-up recommendations were most common among CT studies (OR, 4.2 [95% CI: 4.0, 4.4] compared with radiography). Radiologist sex (P = .54), presence of a trainee (P = .45), and years in practice (P = .49) were not significant predictors overall. A division-level analysis showed 2.8-fold to 6.7-fold interradiologist variation. Conclusion Substantial interradiologist variation exists in the probability of recommending a follow-up examination in a radiology report, after adjusting for patient, examination, and radiologist factors. © RSNA, 2019 See also the editorial by Russell in this issue.


Subject(s)
Practice Patterns, Physicians'/statistics & numerical data , Radiography/statistics & numerical data , Radiologists/statistics & numerical data , Referral and Consultation/statistics & numerical data , Adult , Aged , Algorithms , Female , Humans , Machine Learning , Male , Medical Informatics , Middle Aged , Retrospective Studies
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