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1.
MGC Hendriks P Dogterom JT Ebels B Oosterhuis LR Geertsema T Hulot G Bianchetti and JHG Jonkman 《Fundamental & clinical pharmacology》1998,12(5):559-565
Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)1, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (cmin), the maximum plasma concentration (cmax), the time to reach that concentration (tmax), the time interval during which the plasma concentration exceeds 50% of cmax (t50), the area under the plasma concentration-time curve (AUC72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC72–96 (AUCNDM and AUCDAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated. 相似文献
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Johanna L. Schmidt MPH MGC CGC Amy Pizzino MS CGC Jessica Nicholl MS CGC Allison Foley MMSc CGC Yue Wang PhD FACMG Jill A. Rosenfeld MS CGC Lindsey Mighion MS CGC Lora Bean PhD Cristina da Silva MS Megan T. Cho MS CGC Rebecca Truty PhD John Garcia PhD Virginia Speare PhD Kirsten Blanco BS Zoe Powis MS CGC Grace M. Hobson PhD Susan Kirwin BS Bryan Krock PhD FACMG Hane Lee PhD Joshua L. Deignan PhD Maggie A. Westemeyer MS CGC Ryan L. Subaran PhD Isabelle Thiffault PhD FABMGG Ellen A. Tsai PhD Terry Fang PhD Guy Helman BS Adeline Vanderver MD 《American journal of medical genetics. Part A》2020,182(8):1906-1912
Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening. 相似文献
3.
Brittany C. McGill PhD MPsych Claire E. Wakefield PhD MPH Katherine M. Tucker MD Rebecca A. Daly MAP Mark W. Donoghoe PhD Janine Vetsch PhD Meera Warby MGC Noemi A. Fuentes-Bolanos MD PhD Kristine Barlow-Stewart PhD Judy Kirk MD Eliza Courtney MGC Tracey A. O’Brien MD MBA MHL Glenn M. Marshall MD Mark Pinese PhD Mark J. Cowley PhD Vanessa Tyrrell BAppSc MBA FHGSA ARCPA Rebecca J. Deyell MD MHSc David S. Ziegler MBBS MD Kate Hetherington MPsych PhD 《Cancer》2023,129(22):3620-3632
Background
Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These findings can have implications for diagnosis, treatment, and the child’s and family’s future cancer risk. Understanding parents’ perspectives of germline genome sequencing is critical to successful clinical implementation.Methods
A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child’s results, including clinically relevant germline findings (received by 13% of parents). Parents’ expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth.Results
At trial enrollment, most parents (63%) believed it was at least “somewhat likely” that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child’s genome sequencing results by their child’s clinician.Conclusions
Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results. 相似文献4.
5.
Victoria S. Blinder MD MSc Virginia W. Norris MGC Nancy W. Peacock MD Jennifer J. Griggs MD MPH David P. Harrington PhD Anne Moore MD Richard L. Theriault DO MBA FACP Ann H. Partridge MD MPH 《Cancer》2013,119(1):164-172
BACKGROUND:
Although the routine use of treatment plans and summaries (TPSs) has been recommended to improve the quality of cancer care, limited data exist about their impact on quality, including patient satisfaction and coordination of care.METHODS:
Patients received TPSs as part of the American Society of Clinical Oncology Breast Cancer Registry (BCR) pilot program of 20 community oncology practices. Participants were surveyed 2 to 4 weeks after receiving a TPS to evaluate their perceptions of the document. Patients who were receiving chemotherapy received the TPS as separate plan and summary documents (at the start and the end of treatment) and could complete 2 surveys. Others received a single integrated TPS. Eligible survey participants had stage 0 through III breast cancer and were enrolled in the BCR.RESULTS:
Of 292 consented patients, 174 (60%) completed at least 1 survey. Of 157 patients who recalled receiving a TPS, 148 (94%) believed that the documents improved patient‐physician communication, and 128 (82%) believed that they improved communication between physicians; 113 (72%) said the documents increased their peace of mind, whereas 2 (1%) had less peace of mind. Of 152 patients (97%) who still had their documents, 147 (97%) said they were useful, and 94 (62%) had given or planned to give the documents to another physician. All 63 patients who were surveyed after receiving a summary recommended that practices continue to provide TPSs to patients.CONCLUSIONS:
Participants in this study expressed high satisfaction with TPSs. Additional research is needed to study the broad‐scale implementation of the BCR and to evaluate the impact of routine use of TPSs on the quality of care delivered. Cancer 2013. © 2012 American Cancer Society. 相似文献6.
Predictors of appropriate implantable defibrillator therapies in patients with arrhythmogenic right ventricular dysplasia 总被引:2,自引:0,他引:2
Jonathan P. Piccini MD Darshan Dalal MD MPH Ariel Roguin MD PhD Chandra Bomma MD Alan Cheng MD Kalpana Prakasa MD Jun Dong MD Crystal Tichnell MGC Cynthia James PhD ScM Stuart Russell MD Jane Crosson MD Ronald D. Berger MD PhD Joseph E. Marine MD Gordon Tomaselli MD Hugh Calkins MD 《Heart rhythm》2005,2(11):237-1194
BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden cardiac death. The risk factors for sudden death and indications for implantable cardioverter-defibrillator (ICD) placement in patients with ARVD are not well defined. OBJECTIVES: The purpose of this study was to determine which clinical and electrophysiologic variables best predict appropriate ICD therapies in patients with ARVD. Particular attention focused on whether the ICD was implanted for primary or second prevention. METHODS: We enrolled 67 patients (mean age 36 +/- 14 years) with definite or probable ARVD who had undergone ICD placement. Appropriate ICD therapies were recorded, and Kaplan-Meier analysis was used to compare the event-free survival time between patients based upon the indication for ICD placement (primary vs secondary prevention), results of electrophysiologic testing, and whether the patient had probable or definite ARVD. RESULTS: Over a mean follow-up of 4.4 +/- 2.9 years, 40 (73%) of 55 patients who met task force criteria for ARVD and 4 (33%) of 12 patients with probable ARVD had appropriate ICD therapies for ventricular tachycardia/ventricular fibrillation (VT/VF; P = .027). Mean time to ICD therapy was 1.1 +/- 1.4 years. Eleven of 28 patients who received an ICD for primary prevention (39%) and 33 of 35 patients who received an ICD for secondary prevention (85%) experienced appropriate ICD therapies (P = .001). Electrophysiologic testing did not predict appropriate ICD interventions in patients who received an ICD for primary prevention. Fourteen patients (21%) received ICD therapy for life-threatening (VT/VF >240 bpm) arrhythmias. There was no difference in the incidence of life-threatening arrhythmias in the primary and secondary prevention groups (P = .29). CONCLUSION: Patients who meet task force criteria for ARVD are at high risk for sudden cardiac death and should undergo ICD placement for primary and secondary prevention, regardless of electrophysiologic testing results. Further research is needed to confirm that a low-risk subset of patients who may not require ICD placement can be identified. 相似文献
7.
KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction 下载免费PDF全文
Jessica Duis MD MS Shannon Dean MD PhD Carolyn Applegate MGC CGC Amy Harper MD Rui Xiao PhD Weimin He PhD James D. Dollar MD Lisa R. Sun MD Marta Biderman Waberski MD Thomas O. Crawford MD Ada Hamosh MD MPH Carl E. Stafstrom MD PhD 《Annals of neurology》2016,80(4):633-637
Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop‐loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy‐terminus of the protein has a dominant‐negative effect, causing mitochondrial dysfunction in the setting of an abnormal kinesin “motor.” These results highlight the role of expanded testing and whole‐exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation. Ann Neurol 2016;80:633–637 相似文献
8.
The importance of prenatal 3‐dimensional sonography in a case of a segmental overgrowth syndrome with unclear chromosomal microarray results 下载免费PDF全文
Mehmet Resit Asoglu MD Amanda Higgs MGC CGC Sertac Esin MD Julie Kaplan MD Sifa Turan MD 《Journal of clinical ultrasound : JCU》2018,46(5):351-354
PIK3CA‐related overgrowth spectrum, caused by mosaic mutations in the PIK3CA gene, is associated with regional or generalized asymmetric overgrowth of the body or a body part in addition to other clinical findings. Three‐dimensional ultrasonography (3‐D US) has the capability to display structural abnormalities in soft tissues or other organs, thereby facilitating identification of segmental overgrowth lesions. We present a case suspected of having a segmental overgrowth disorder based on 3‐D US, whose chromosomal microarray result was abnormal, but apparently was not the cause of the majority of the fetus's clinical features. 相似文献
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Right ventricular strain by MR quantitatively identifies regional dysfunction in patients with arrhythmogenic right ventricular cardiomyopathy 下载免费PDF全文