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1.
J Endod ; 2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38382736

ABSTRACT

INTRODUCTION: Diagnostic reference levels (DRLs) are intended to improve patient safety and ensure that patient ionizing radiation doses are as low as reasonably achievable. The purpose of this dosimetry study was to establish regional DRL levels for cone-beam computed tomography (CBCT) imaging for specialty endodontics. Another aim was to compare phantom-measured ionizing radiation dose index 1 (DI1) index doses to the manufacturer-provided dose area product (DAP) radiation output values for each of the CBCT machines studied, to ascertain their degree of correlation. DAP refers to the dose area product, a measure of radiation dose monitoring which represents the dose within the beam times the area within the beam at that position. METHODS: A thimble ionization chamber and polymethyl methacrylate phantom were used to obtain DI1 values using the SEDENTEXTCT method from 21 different CBCT units. DRLs were calculated based on the 75th percentile (third quartile) of the median output values. RESULTS: The proposed DRL from the CBCT units surveyed has a DAP value of 838 mGy cm2 and a DI1 value of 3.924 mGy. DAP versus DI1 values of 500.6 mGy cm2 versus 2.006 mGy, and 838 mGy cm2 versus 3.906 mGy represented the third quartile of the median values for the 4-cm × 4-cm and 5-cm × 5-cm field of views (FOVs), respectively. CONCLUSIONS: The DI1 and DAP values strongly correlated when 3 outlier CBCT machines (J Morita Veraview X800) using a novel 360° (full rotation) acquisition mode were excluded. The importance of selectable exposure parameters as directly related to ionizing radiation output is illustrated among the CBCT units surveyed. Although the actual FOV that is selected is ultimately dictated by the specific clinical requirements, a 4-cm × 4-cm FOV is recommended for specialist endodontics practice, whenever clinically practical, based on the decreased ionizing radiation output, as compared to that from a 5-cm × 5-cm FOV.

2.
J Am Dent Assoc ; 153(9): 822-823, 2022 09.
Article in English | MEDLINE | ID: mdl-35842314
3.
Trials ; 23(1): 357, 2022 Apr 27.
Article in English | MEDLINE | ID: mdl-35477835

ABSTRACT

Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist role due to a complex set of factors, most likely to have come to a head due to the COVID-19 pandemic. Academic clinical trial units and departments are struggling to recruit trial managers to vacant positions, and multiple influences are affecting the retention of this highly skilled workforce. Without tackling this issue, we face major challenges in the delivery on the Department of Health and Social Care's Future of UK Clinical Research Delivery implementation plan. This article, led by a leading network of and for UK Trial Managers, presents some of the issues and ways in which national stakeholders may be able to address this.


Subject(s)
Clinical Trials as Topic , Workforce , COVID-19 , Clinical Trials as Topic/organization & administration , Humans , Pandemics , Research Design
4.
J Am Dent Assoc ; 153(6): 501-502, 2022 06.
Article in English | MEDLINE | ID: mdl-35410700
5.
Data Brief ; 39: 107570, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34825034

ABSTRACT

The additive manufacturing (AM) of components through laser-blown-powder directed-energy-deposition (LBP-DED) is highly applicable to the repair of aerospace components. Fabrication of superalloys with this technique, as with other AM methods, often encounters complications that include the formation of undesired phases, irregular microstructure and texture leading to anisotropic elastic properties. Heat treatments and other post-processing techniques can be used to mitigate these issues. The collected data demonstrates the effects of different heat treatment protocols on the microstructure, elastic properties, and hardness of LBP-DED IN718. In this study eight different heat treatment were used to investigate the effects of treatment time and temperature. The microstructure was investigated through SEM, with XRD and EDX used for phase analysis. The texture was characterised using SEM coupled with EBSD and the elastic properties were determined from resonant ultrasound spectroscopy.

6.
J Patient Saf ; 18(4): 269-275, 2022 06 01.
Article in English | MEDLINE | ID: mdl-34508038

ABSTRACT

OBJECTIVES: The author conducted a study to determine the frequency and types of adverse events associated with endodontic ultrasonic devices as reported to the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. METHODS: Endodontic ultrasonic device-related adverse events reported to the MAUDE database from January 1, 2016, to October 31, 2020, were accessed and reviewed. RESULTS: A total of 1258 adverse event reports were submitted to the FDA MAUDE database, as classified under FDA product code ELC (ultrasonic scaler) during the study period. Among these reports, 403 were specific to the dedicated use of the 2 main types of ultrasonic devices used in endodontic treatment: ultrasonic tip devices and irrigation-related devices. Device malfunction-associated events, consisting primarily of device breakage, comprised 393 of the 1258 adverse event reports, whereas the remaining 10 reports were identified as being patient injury-related reports. CONCLUSIONS: The frequency, root causes, and economic costs of ultrasonic tip device breakage remain largely unstudied. Ultrasonic endodontic device-related adverse events and patient injuries occurring within clinical practice may be underreported at the present time. Consequently, the risks and ultimate impacts to patients from ultrasonic endodontic device breakage, malfunction and unknown cause-related adverse events, and patient injuries during their clinical usage remain largely unknown at the present time. Eight of the 10 patient injury-related reports made to the FDA MAUDE database during the period under study, containing descriptions of varying degrees of injury severity, were associated with an irrigation-related device.


Subject(s)
Endodontics , Ultrasonics , Databases, Factual , Equipment Failure , Humans , United States , United States Food and Drug Administration
7.
J Am Dent Assoc ; 152(11): 909-918, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34482947

ABSTRACT

BACKGROUND: Industry payments made to health care providers can create competing interests. The purpose of this study was to define the overall financial relationships between industry and academic endodontics faculty members, detail any variation in such payment data as related to individual faculty member characteristics and leadership position by institution type, and comment on the potential impacts from conflicts of interest (COIs) created by such relationships. METHODS: The author identified and characterized academic endodontists from information on their institutional websites. The author obtained reported industry payments from 2013 through 2019 from the Centers for Medicare & Medicaid Services Open Payments database. The author also noted the distributions of academic endodontists and industry payments by institution, academic rank, sex, and residency program director position. The author subjected the data to descriptive and nonparametric analyses. RESULTS: Of the 302 academic endodontists included, 240 (80%) accepted reported industry payments totaling $4,260,316.97. Overall, the median of total industry payments for all 302 faculty members was $217.89 (interquartile range [IQR], $34.06-$3,070.00). Among those accepting payments, the median amount was $382.80 (IQR, $110.40-$6,234.00). The top decile of paid academic endodontists received $3,669,291.47 in industry payments (86% of the total), with a median payment of $24,013 (IQR, $17,043-$91,190). Significant sex-associated industry payment differences were seen among the overall faculty and among those with the residency program director position. CONCLUSIONS: Most academic endodontists accept industry payments. Significant sex differences exist in overall faculty member academic rank distribution, leadership role, and accepted median industry payment amounts. COI issues have the potential to arise among academic endodontists when such industry payments are accepted. PRACTICAL IMPLICATIONS: Existing sex disparities in academic endodontics within the United States ideally should be acknowledged. COI issues can arise when academic faculty members accept industry payments. Public knowledge of these conflicts could negatively affect individual faculty members, their institutions, and related areas such as academic publishing. Appropriate faculty member COI disclosure, attestation, annual updates, and transparency are important mitigation measures.


Subject(s)
Endodontists , Sex Characteristics , Aged , Conflict of Interest , Disclosure , Female , Humans , Male , Medicare , United States
8.
J Autism Dev Disord ; 52(6): 2656-2669, 2022 Jun.
Article in English | MEDLINE | ID: mdl-34196890

ABSTRACT

COVID-19 has affected people across the world. The current study examined anxiety and worries during the first UK national lockdown in March 2020. Parents (n = 402) reported on their own anxiety and worries as well as that of their son/daughter with Special Education Needs and Disabilities (SEND) and typically developing (TD) child (n = 186) at three time points. Although both groups showed increased anxiety across the three time points, levels of anxiety in the SEND group, but not the TD siblings, were predicted by awareness about COVID-19. In addition, worries differed between the groups showing that COVID-19 impacts the wellbeing of those with SEND differently to that of their TD siblings.


Subject(s)
Autism Spectrum Disorder , COVID-19 , Anxiety/epidemiology , Child , Communicable Disease Control , Education, Special , Humans , SARS-CoV-2 , United Kingdom/epidemiology
9.
J Endod ; 47(2): 291-296, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33181168

ABSTRACT

INTRODUCTION: Several studies in radiology and medicine have evaluated the satisfaction of search (SOS) error effect in chest radiography, abdominal radiography, osteoradiology, and patients with multiple trauma. No research to date has been published evaluating the possible existence of the SOS error phenomenon made during dental periapical radiograph interpretations. The purpose of the present pilot study was to determine if an SOS error effect exists when dental clinicians interpret periapical radiographs. The null hypothesis was that the detection accuracy will be the same or will improve for the detection of native lesions in the presence of an added abnormality. The alternative hypothesis is that there will be a decrease in detection accuracy for native lesions in the presence of an added abnormality. METHODS: Six images were selected to be part of the present experiment. One of the 6 images served as the positive control, and another image served as the negative control. Four images, each including a single subtle carious lesion, were selected to represent the experimental images. The single subtle carious lesion present within the 4 experimental radiographs served as the native pathology, and an abnormality such as a periapical radiolucency, resorption, inadequate nonideal root canal obturation material, or recurrent carious lesion was artificially inserted into the image as the added pathology. Thus, the second set of images consisted of the same 4 images containing the native pathology including an added pathology that was inserted into the image using Adobe Photoshop CS6 (Adobe, Inc, San Jose, CA). Purposive sampling was obtained from 16 examiners including residents from endodontics and periodontics as well as alumni and faculty from the Saint Louis University Center for Advanced Dental Education, St Louis, MO. Each observer participated as a subject during 2 time-separated sessions. Each session was separated by a minimum period of 3 months' duration in order to prevent memory bias. Before starting each interpretation session, the participants were given verbal instructions. Subjects were instructed to provide a location (by tooth number), identify, and rate the presence of all suspected pathology using a Likert scale of 1-5 (1: definitely normal, 2: probably normal, 3: possibly abnormal, 4: probably abnormal, and 5: definitely abnormal). In the second session, the radiographs that were initially presented containing only the native lesion were presented again with the added abnormality, and vice versa. The observers' reports and confidence ratings were recorded and analyzed. Ratings of 3-5 were considered as being positive for the presence of pathology. RESULTS: A true SOS error occurs when the presence of the native lesion is reported correctly without an added abnormality but is not reported (missed) in the presence of an added abnormality. In our study, a true SOS error occurred in 13 of the 64 interpretation sets (20.31%). There was a total of 64 expected native lesions present within the 4 native images viewed by 16 observers. In the 4 added images, there was a total of 64 expected added findings. In the images containing only native lesions, the observers reported 30 of the 64 expected native lesions. In the images containing an artificially added abnormality, the observers reported 58 of the 64 expected added abnormalities and 25 of the 64 expected native lesions. Observers reported fewer native lesions in the presence of an added abnormality. CONCLUSIONS: The current investigation demonstrated the existence of the SOS effect during periapical radiographic interpretations. In 20.31% of interpretations, a true SOS error occurred. This study is clinically relevant because it can help clinicians in reducing false-negative errors made during radiographic interpretation, thus preventing misdiagnosis.


Subject(s)
Personal Satisfaction , Diagnostic Errors , Humans , Observer Variation , Pilot Projects , Radiography
10.
J Endod ; 47(1): 78-87, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32979435

ABSTRACT

INTRODUCTION: Cone-beam computed tomography (CBCT) machines produce relatively low levels of harmful ionizing radiation, as compared with the computed tomography devices used in medical practices. The Carestream CS9600 CBCT imaging device has been recently introduced into the marketplace, and the manufacturer reports the use of an increased x-ray tube voltage (120 kVp) for the device, along with a reduced patient dose that is achieved using added filtration. Independent dosimetry studies are performed to ensure appropriate radiation exposure dose levels are within recommended safety guidelines.The purpose of this study is to independently evaluate and measure the radiation exposure dose performance parameters of the CS9600 CBCT, including its multiple field of view, exposure settings, and filtration options. METHODS: A thimble ionization chamber and PMMA phantom were used to characterize dose index using the established SEDENTEXTCT evaluation method. RESULTS: The phantom-obtained radiation dose index measures ranged from 0.128782-13.848 milligrays (mGy) for the various scanning options evaluated. The field of view, type of filter used, and phantom size all had a direct impact on the relationship between the experimentally obtained dose index measures and the dose area product values reported by the manufacturer. CONCLUSIONS: A strong linear correlation was observed between the experimentally obtained dose index measures and the manufacturer-reported dose area product values. The 0.7 mm Cu filter that has been added to the CS9600 reduced the exposure dose index measures even with the x-ray tube kilovoltage peak (kVp) being increased to 120 kVp, as compared with the 0.15 mm Cu filter at 90 kVp.


Subject(s)
Cone-Beam Computed Tomography , Tomography, X-Ray Computed , Humans , Phantoms, Imaging , Radiation Dosage
11.
BMC Public Health ; 19(1): 1633, 2019 Dec 04.
Article in English | MEDLINE | ID: mdl-31801512

ABSTRACT

BACKGROUND: The border area between French Guiana and Brazil is an active HIV-transmission zone. The aim of the present study was to describe HIV knowledge, risk and the level of stigma among inhabitants of this border area. METHODS: A cross-sectional study was conducted among 621 inhabitants over 18 years of age in the border cities of Saint-Georges-de-l'Oyapock in French Guiana and Oiapoque in Brazil. It was conducted between October 2017 and February 2018. An anonymous standardized questionnaire was filled out by culturally-trained mediators, then analyzed using STATA 12. RESULTS: Almost half (45.9%) of the individuals had a low education level. Participants whose native language was Portuguese or French demonstrated better HIV knowledge than other populations, notably native Amerindian and creole-speaking people. HIV risk behavior was more frequent in men and in younger age groups. People with good HIV knowledge reported having performed more HIV tests in the last year than participants with poor knowledge. The stigma level was high and reported in 74.8% of respondents. CONCLUSIONS: These results illustrate the need for initiatives to improve HIV prevention among autochthonous populations on both sides of this border area. Cross-border collaboration on health policies could produce common key messages adapted to the education level and multi-linguistic populations who live in this area.


Subject(s)
HIV Infections/epidemiology , Health Knowledge, Attitudes, Practice , Social Stigma , Acquired Immunodeficiency Syndrome/epidemiology , Adolescent , Adult , Age Factors , Brazil/epidemiology , Cross-Sectional Studies , Ethnicity/psychology , Ethnicity/statistics & numerical data , Female , French Guiana/epidemiology , HIV Infections/prevention & control , HIV Infections/psychology , Humans , Knowledge , Male , Middle Aged , Risk Factors , Sex Factors , Socioeconomic Factors , Young Adult
12.
Ann Oncol ; 29(8): 1869-1876, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29912274

ABSTRACT

Background: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. Results: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. Conclusions: These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.


Subject(s)
Brain Neoplasms/drug therapy , Carcinoma, Neuroendocrine/drug therapy , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Thyroid Neoplasms/drug therapy , Adult , Brain Neoplasms/secondary , Carbazoles/pharmacology , Carbazoles/therapeutic use , Carcinoma, Neuroendocrine/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Female , Humans , Liver Neoplasms/secondary , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Oncogene Proteins, Fusion/antagonists & inhibitors , Oncogene Proteins, Fusion/genetics , Piperidines/pharmacology , Piperidines/therapeutic use , Proof of Concept Study , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-ret/genetics , Pyrazoles/pharmacology , Pyridines/pharmacology , Thyroid Neoplasms/pathology , Treatment Outcome , Xenograft Model Antitumor Assays
13.
J Endod ; 43(12): 1984-1989, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29032821

ABSTRACT

INTRODUCTION: The rapid antibiotic sensitivity test (RAST) is a novel in-office culture and sensitivity system for endodontic infections. The purpose of this research was to validate the RAST system as a viable, in-office alternative to antibiotic sensitivity testing using turbidity to determine antibiotic sensitivities of endodontic infections. METHODS: Aspirates were taken from the root canals of 9 necrotic human teeth at the initiation of root canal therapy. These samples were cultured in the RAST medium, and antibiotic sensitivity to 6 antibiotics was tested. Further analysis was performed using 16S ribosomal RNA (rRNA) gene sequencing. RESULTS: Thirty-one bacterial phyla were identified as well as 2 phyla of the kingdom Archaea. Augmentin (Dr. Reddy's Laboratories Ltd, Hyderabad, India) and ampicillin performed identically at 24 hours, inhibiting turbidity in 100% of the samples. At 48 hours in anaerobic conditions, Augmentin outperformed ampicillin by 13%. Ciprofloxacin was the least efficacious antibiotic. At 48 hours, only 22% of anaerobic ciprofloxacin cultures affectively inhibited bacterial growth. CONCLUSIONS: The RAST medium is a viable in-office alternative to antibiotic susceptibility testing in an off-site laboratory. It is able to support the growth of a wide variety of microorganisms in both aerobic and anaerobic environments, and, in combination with 16S rRNA gene sequencing, it led to the identification of a new archaebacterial phylum, Crenarchaeota, as part of the endodontic infection microbiome.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Dental Pulp Necrosis/microbiology , RNA, Bacterial/analysis , RNA, Bacterial/drug effects , RNA, Ribosomal, 16S/analysis , RNA, Ribosomal, 16S/drug effects , Base Sequence/drug effects , Humans , Microbial Sensitivity Tests , Treatment Outcome
14.
Vet Rec ; 180(3): 68, 2017 Jan 21.
Article in English | MEDLINE | ID: mdl-28100768

ABSTRACT

This report describes how Mycobacterium bovis infection was controlled and eventually eradicated in a farmed red deer herd in the north of England, following sustained tuberculin skin testing supplemented with serological (antibody) tests over a period of approximately two years. By taking advantage of the anamnestic antibody response produced by the skin test to detect skin test-negative, antibody-positive infected individuals, a total of 35 additional animals were identified, including 2 with gross visible lesions typical of bovine tuberculosis (BTB). Without detection and removal, these animals would have posed a continued risk of BTB persistence within the herd and potentially contributed to the spread of infection from deer into wildlife and surrounding cattle farms in an area of low BTB incidence. This case supports the use of ancillary diagnostic serological tests to speed up the resolution of incidents of BTB caused by M bovis in captive deer herds.


Subject(s)
Deer/microbiology , Disease Eradication/methods , Mycobacterium bovis/isolation & purification , Tuberculosis/prevention & control , Tuberculosis/veterinary , Animal Culling , Animals , Antibodies, Bacterial/blood , England/epidemiology , Serologic Tests/veterinary , Tuberculin Test/veterinary , Tuberculosis/epidemiology
15.
J Immigr Minor Health ; 18(6): 1498-1521, 2016 12.
Article in English | MEDLINE | ID: mdl-26467788

ABSTRACT

Compared to White women, Latinas are 4 times more likely to contract HIV. In an effort to determine the overall state of the science meant to address this disparity, we reviewed the current HIV prevention intervention literature for U.S. Latinas. We searched 5 online electronic databases from their inception through July, 2014, for HIV prevention interventions including a majority sample of Latinas. Of 1041 articles identified, 20 studies met inclusion criteria. We documented study designs, participant characteristics, outcomes, theories used, and other intervention characteristics. Overall, HIV knowledge and attitudes were the predominant outcome; a small minority of studies included self-reported condom use or STD incidence. Strategies used to address cultural factors specific to Latinas and HIV included; lay health advisors, using ethnographic narratives, or using the Theory of Gender and Power, however few of the interventions adopted these strategies. This study identified several gaps in the intervention literature that need to be addressed. In addition to including more direct measures of decreased HIV risk (ex. condom use), more systematic use of strategies meant to address gender and cultural factors that may place Latinas at increased risk (e.g., gender inequity, traditional gender role norms such as machismo and marianismo, and relationship power dynamics).


Subject(s)
HIV Infections/ethnology , HIV Infections/prevention & control , Health Education/organization & administration , Health Knowledge, Attitudes, Practice , Hispanic or Latino/psychology , Acquired Immunodeficiency Syndrome/ethnology , Acquired Immunodeficiency Syndrome/prevention & control , Condoms/statistics & numerical data , Emigrants and Immigrants/psychology , Female , Gender Identity , Humans , Interpersonal Relations , Social Capital , United States
16.
Forensic Sci Rev ; 18(1): 9-41, 2006 Jan.
Article in English | MEDLINE | ID: mdl-26247108

ABSTRACT

The need for and prevalence of workplace drug-testing programs mandate the development of an effective and efficient two-step test strategy. Successful implementation of the two-step test strategy relies on the establishment of a reasonable correlation between the preliminary and the confirmatory test data and the selection of an appropriate cutoff for each test step. Correlations of test data derived form these two test steps were most commonly studied qualitatively by comparing the positive/negative test result concluded by these two test steps; however, when instrument-based immunoassays (IA) are used in the preliminary test step, the resulting "semiquantitative" and "apparent" concentration of the targeted analyte can be quantitatively correlated to the analyte concentration as determined by gas chromatography-mass spectrometry (GC-MS). Specimens selected for quantitative correlation studies should be clinical specimens with the distributions of metabolites similar to that present in test specimens; if the resulting correlation data are to be used for selecting appropriate/corresponding cutoffs for these two test steps, the concentrations of the targeted analyte in these specimens should also be within a narrow range centering on the proposed GC-MS cutoff concentration. Among the very significant number of reports correlating IA and GC-MS test data, cannabis and urine are the most common drug category and test specimen studied. The degree of correlation between IA and the GC-MS test data varies with the IA reagent manufacturers, and even with manufacture dates/lots of those supplied by the same manufacturer. The most important factors underlying the observed degree of correlation are undoubtedly the cross-reacting characteristics of the antibody and the metabolite distribution pattern of the drug of concern. Over time, specificities of IA reagents have been optimized so that the two-step test strategy can be most effectively and efficiently applied using the cutoffs mandated by workplace drug-testing programs. The nature of correlation and the selection of appropriate/corresponding cutoffs between IA and GC-MS test data derived from alternate biological matrices are yet to be fully understood and established.

17.
J Clin Endocrinol Metab ; 100(6): 2158-64, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25871839

ABSTRACT

BACKGROUND: LHX4 encodes a member of the LIM-homeodomain family of transcription factors that is required for normal development of the pituitary gland. To date, only incompletely penetrant heterozygous mutations in LHX4 have been described in patients with variable combined pituitary hormone deficiencies. OBJECTIVE/HYPOTHESIS: To report a unique family with a novel recessive variant in LHX4 associated with a lethal form of congenital hypopituitarism that was identified through screening a total of 97 patients. METHOD: We screened 97 unrelated patients with combined pituitary hormone deficiency, including 65% with an ectopic posterior pituitary, for variants in the LHX4 gene using Sanger sequencing. Control databases (1000 Genomes, dbSNP, Exome Variant Server, ExAC Browser) were consulted upon identification of variants. RESULTS: We identified the first novel homozygous missense variant (c.377C>T, p.T126M) in two deceased male patients of Pakistani origin with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia. Both were born small for gestational age with a small phallus, undescended testes, and mid-facial hypoplasia. The parents' first-born child was a female with mid-facial hypoplasia (DNA was unavailable). Despite rapid commencement of hydrocortisone and T4 in the brothers, all three children died within the first week of life. The LHX4(p.T126M) variant is located within the LIM2 domain, in a highly conserved location. The absence of homozygosity for the variant in over 65 000 controls suggests that it is likely to be responsible for the phenotype. CONCLUSION: We report, for the first time to our knowledge, a novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life.


Subject(s)
Genes, Lethal , Hypopituitarism/congenital , Hypopituitarism/genetics , LIM-Homeodomain Proteins/genetics , Mutation, Missense , Perinatal Death , Transcription Factors/genetics , Base Sequence , Female , Genes, Recessive , HEK293 Cells , Humans , Infant, Newborn , LIM-Homeodomain Proteins/chemistry , Male , Models, Molecular , Pedigree , Siblings , Transcription Factors/chemistry
18.
Toxicology ; 330: 9-18, 2015 Apr 01.
Article in English | MEDLINE | ID: mdl-25637670

ABSTRACT

Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45 mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45 mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral(®) 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is considered when safety of the overall product is assessed rather than relying on just the particle size. This study has addressed some concerns surrounding particulate drug delivery, demonstrating safe delivery of CsA whilst achieving augmented serum concentrations.


Subject(s)
Cyclosporine/blood , Cyclosporine/toxicity , Drug Carriers/toxicity , Hematopoietic Stem Cells/drug effects , Nanoparticles/toxicity , Polyesters/toxicity , Animals , Body Weight/drug effects , Body Weight/physiology , Dose-Response Relationship, Drug , Hematopoietic Stem Cells/metabolism , Male , Microspheres , Particle Size , Random Allocation , Rats , Rats, Sprague-Dawley
19.
J Contam Hydrol ; 164: 100-13, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24973505

ABSTRACT

Management and closure of contaminated sites is increasingly being proposed on the basis of mass flux of dissolved contaminants in groundwater. Better understanding of the links between source mass removal and contaminant mass fluxes in groundwater would allow greater acceptance of this metric in dealing with contaminated sites. Our objectives here were to show how measurements of the distribution of contaminant mass flux and the overall mass discharge emanating from the source under undisturbed groundwater conditions could be related to the processes and extent of source mass depletion. In addition, these estimates of mass discharge were sought in the application of agreed remediation targets set in terms of pumped groundwater quality from offsite wells. Results are reported from field studies conducted over a 5-year period at a brominated DNAPL (tetrabromoethane, TBA; and tribromoethene, TriBE) site located in suburban Perth, Western Australia. Groundwater fluxes (qw; L(3)/L(2)/T) and mass fluxes (Jc; M/L(2)/T) of dissolved brominated compounds were simultaneously estimated by deploying Passive Flux Meters (PFMs) in wells in a heterogeneous layered aquifer. PFMs were deployed in control plane (CP) wells immediately down-gradient of the source zone, before (2006) and after (2011) 69-85% of the source mass was removed, mainly by groundwater pumping from the source zone. The high-resolution (26-cm depth interval) measures of qw and Jc along the source CP allowed investigation of the DNAPL source-zone architecture and impacts of source mass removal. Comparable estimates of total mass discharge (MD; M/T) across the source zone CP reduced from 104gday(-1) to 24-31gday(-1) (70-77% reductions). Importantly, this mass discharge reduction was consistent with the estimated proportion of source mass remaining at the site (15-31%). That is, a linear relationship between mass discharge and source mass is suggested. The spatial detail of groundwater and mass flux distributions also provided further evidence of the source zone architecture and DNAPL mass depletion processes. This was especially apparent in different mass-depletion rates from distinct parts of the CP. High mass fluxes and groundwater fluxes located near the base of the aquifer dominated in terms of the dissolved mass flux in the profile, although not in terms of concentrations. Reductions observed in Jc and MD were used to better target future remedial efforts. Integration of the observations from the PFM deployments and the source mass depletion provided a basis for establishing flux-based management criteria for the site.


Subject(s)
Environmental Monitoring/methods , Environmental Restoration and Remediation/methods , Groundwater , Hydrocarbons, Brominated/chemistry , Water Pollutants, Chemical/chemistry , Water Pollutants, Chemical/analysis , Western Australia
20.
Environ Monit Assess ; 4(1): 99-103, 1984 Mar.
Article in English | MEDLINE | ID: mdl-24259150

ABSTRACT

Acid deposition-induced drinking water degradation is discussed with respect to the geographical extent of and the potential for dealing with possibly adverse human health impacts. Qualitative evidence from the northeastern United States and Sweden strongly suggests the existence of a linkage between these two environmental concerns. It is argued that water treatment and reduction of acid rain as solutions to the problem of water toxicity need closer evaluation. More research into the causal link is warranted since the addition of human health impacts to acid rain's environmental insults could have a significant bearing on discussions relating to acid rain controls.

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