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1.
Genet Med ; 26(4): 101056, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38153010

RESUMO

PURPOSE: Combinatorial pharmacogenetic (PGx) panels intended to aid psychiatric prescribing are available to clinicians. Here, we evaluated the documentation of PGx panel results and subsequent prescribing patterns within a tertiary health care system. METHODS: We performed a query of psychiatry service note text in our electronic health record using 71 predefined PGx terms. Patients who underwent combinatorial PGx testing were identified, and documentation of test results was analyzed. Prescription data following testing were examined for the frequency of prescriptions influenced by genes on the panel along with the medical specialties involved. RESULTS: A total of 341 patients received combinatorial PGx testing, and documentation of results was found to be absent or incomplete for 198 patients (58%). The predominant method of documentation was through portable document formats uploaded to the electronic health record's "Media" section. Among patients with at least 1 year of follow-up, a large majority (194/228, 85%) received orders for medications affected by the tested genes, including 132 of 228 (58%) patients receiving at least 1 non-psychiatric medication influenced by the test results. CONCLUSION: Results from combinatorial PGx testing were poorly documented. Medications affected by these results were often prescribed after testing, highlighting the need for discrete results and clinical decision support.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Medicina , Humanos , Farmacogenética/métodos , Prescrições de Medicamentos , Registros Eletrônicos de Saúde
2.
Pharmaceuticals (Basel) ; 14(9)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34577583

RESUMO

We present the case of a 27-year-old male with grade II knee osteoarthritis (OA) that was intraarticularly injected with a 2 mL umbilical cord-derived Wharton's jelly (UC-derived WJ) formulation. The patients' baseline radiographs were taken and baseline numeric pain rating scale (NPRS), knee injury and osteoarthritis outcome score (KOOS), 7-point Likert scale, and a 36-item short form survey (SF-36) were recorded. The NPRS was re-recorded immediately after the injection, and at 24 h, 48 h, 1 week, 6 weeks, and at 3 months follow-up post-injection. The KOOS and 7-point Likert scale was re-recorded at the patients' 1week, 6 week, and 3month follow-up, and SF-36 was re-recorded at 3 months. A final set of X-rays were also performed at 3 months follow-up post-injection. No adverse effects from the injection were reported over the duration of the study. No significant difference nor progression in OA on X-rays compared to baseline was observed. NPRS decreased by 50% and the 7-point Likert scale increased to Extremely Satisfied. KOOS increased overall by 10% and the SF-36 overall change was 25%. These results indicate the potential application of UC-derived WJ in the treatment of knee OA. Larger, long term, non-randomized and randomized control trials are warranted to adequately assess the safety and efficacy of UC-derived WJ and ultimate clinical use.

3.
Res Pract Thromb Haemost ; 5(6): e12576, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34430790

RESUMO

BACKGROUND: Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. OBJECTIVES: To investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. METHODS: This multicenter, open-label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 µg/kg intravenous dose of MarzAA to measure 24-hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 µg/kg SC dose to measure 48-hour PK/PD, then daily SC 30 µg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 µg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30-day follow-up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. RESULTS: In the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. CONCLUSIONS: The data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.

4.
Blood Coagul Fibrinolysis ; 32(8): 591-595, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34446680

RESUMO

The association between bleeding and joint hypermobility may not be as diagnostically obvious in patients with milder connective tissue disorders. We surveyed members of the Hemostasis and Thrombosis Research Society regarding their knowledge, evaluation, and management practices in patients with generalized hypermobility spectrum disorder/hypermobile Ehlers-Danlos syndrome (hEDS) and bleeding symptoms. The objectives of this study were to (1) evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS and (2) determine future education and research priorities regarding bleeding symptoms within this population. Evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS. Determine future education and research priorities regarding bleeding symptoms within this population. A web-based survey was sent to Hemostasis and Thrombosis Research Society physician members. Physician demographics, preferred evaluation for hEDS, management of bleeding episodes, and referral patterns were collected and descriptive statistics were performed. Only two-thirds of respondents reported evaluating for hypermobility, despite all respondents being aware of the association with bleeding. There were significant variations in referral patterns for genetic counseling, diagnostic evaluation, and management of nonhematologic symptoms. There were also significant variations in reported medical homes for this patient population. Research prioritization included understanding the evolution of bleeding symptoms with age in this population as well as the development of functional tests to identify the molecular mechanism of bleeding and the development of novel hemostatic agents for this population. Results from 33 respondents show differing physician practices regarding the evaluation and management of bleeding in hypermobile patients. Many physicians suggested further research priorities to include studying the natural history of the disease and development of functional diagnostic testing as well as targeted therapeutic options in this patient population.


Assuntos
Síndrome de Ehlers-Danlos , Instabilidade Articular , Médicos , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/diagnóstico , Hemorragia/diagnóstico , Hemorragia/etiologia , Hemorragia/terapia , Humanos , Instabilidade Articular/diagnóstico , Instabilidade Articular/terapia , Inquéritos e Questionários
5.
Contemp Clin Trials Commun ; 23: 100790, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34278040

RESUMO

INTRODUCTION: Erectile dysfunction (ED) affects a significant portion of the United States population and causes negative psychological burdens that affects men and their partner's quality of life and satisfaction. Extracorporeal shock therapy (ESWT) utilizing focused ESWT and radial ESWT in Low-intensity shock wave therapy has been used to treat ED with some success. Wharton's Jelly (WJ) is a biologic substance with large amounts of stem cells, growth factors, cytokines and extracellular components. The use of combined focused and radial ESWT (DualStim therapy) with injected WJ have potential uses in ED that may have advantages over current treatments. MATERIALS: A randomized, single-blinded, controlled clinical trial will be conducted to evaluate the efficacy and safety of DualStim therapy and intracavernosal injection of WJ in moderate to severe ED. A total of 60 patients with moderate to severe ED will be enrolled and treated with DualStim therapy with intracavernosal injection of WJ or saline for a period of 7 weeks. The International Index of Erectile Function - Erectile Function score will be used to gauge the treatment related changes in relation to the subject's baseline. The scores will be recorded at baseline and compared to follow-ups 1,3 and 6 months post-treatment. Any adverse events or severe adverse events will be recorded in the corresponding case report forms. Sexual Encounter Profile, as well as the Global Assessment Questionnaire and the Erection Hardness Score will be used to determine the sexual activity improvement from baseline leading to optimal penetration at follow-ups 1,3 and 6 months post-treatment. DISCUSSION: This clinical trial is one of the first studies to determine the immediate and short-term efficacy of DualStim therapy, with and without intracavernosal injection of formulated umbilical cord-derived WJ to improve and/or restore erectile function in patients with moderate to severe ED. This study will also provide insight into the safety and efficacy of WJ. We anticipate clinically significant improvement in patients suffering from moderate and severe ED treated with DualStim therapy with WJ compared to their baseline and DualStim with saline.

6.
J Orthop Surg Res ; 16(1): 352, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059080

RESUMO

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder in the United States of America (USA) with a fast-rising prevalence. Current treatment modalities are limited, and total knee replacement surgeries have shown disadvantages, especially for grade II/III OA. The interest in the use of biologics, including umbilical cord (UC)-derived Wharton's jelly (WJ), has grown in recent years. The results from a preliminary study demonstrated the presence of essential components of regenerative medicine, namely growth factors, cytokines, hyaluronic acid (HA), and extracellular vesicles, including exosomes, in WJ. The proposed study aims to evaluate the safety and efficacy of intra-articular injection of UC-derived WJ for the treatment of knee OA symptoms. METHODS: A randomized, controlled, single-blind, multi-center, prospective study will be conducted in which the safety and efficacy of intra-articular administration of UC-derived WJ are compared to HA (control) and saline (placebo control) in patients suffering from grade II/III knee OA. A total of 168 participants with grade II or III knee OA on the KL scale will be recruited across 53 sites in the USA with 56 participants in each arm and followed for 1 year post-injection. Patient satisfaction, Numeric Pain Rating Scale, Knee Injury and Osteoarthritis Outcome Score, 36-Item Short Form Survey (SF-36), and 7-point Likert Scale will be used to assess the participants. Physical exams, X-rays, and MRI with Magnetic Resonance Observation of Cartilage Repair Tissue score will be used to assess improvement in associated anatomy. DISCUSSION: The study results will provide valuable information into the safety and efficacy of intra-articular administration of Wharton's jelly for grade II/III knee osteoarthritis. The results of this study will also add to the treatment options available for grade II/III OA as well as help facilitate the development of a more focused treatment strategy for patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04711304 . Registered on January 15, 2021.


Assuntos
Ácido Hialurônico/administração & dosagem , Osteoartrite do Joelho/terapia , Solução Salina/administração & dosagem , Cordão Umbilical , Geleia de Wharton/transplante , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Segurança , Transplante Homólogo/métodos , Resultado do Tratamento , Adulto Jovem
7.
Haemophilia ; 27(4): 574-580, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33960073

RESUMO

AIM: Phase 2b study to assess efficacy, safety, thrombogenicity, immunogenicity and tolerability with 28 days of daily dosing of subcutaneous (SQ) dalcinonacog alfa as prophylaxis for haemophilia B (HB). METHODS: Adult males with a confirmed diagnosis of congenital HB (factor IX [FIX] activity <2%) received daily dalcinonacog alfa 100 IU/kg SQ until day 28. The primary efficacy endpoint was the number of participants who achieved a steady-state FIX activity level ≥12%. Tolerability, thrombogenicity and immunogenicity were study safety endpoints. RESULTS: Of 6 participants who received study drug, one discontinued the study on day 7 due to injection-site reactions (ISR). Of the 5 participants completing the study, FIX activity level exceeded 12% in 3 participants at day 7, increasing to 4 participants on days 14, 21 and 28 and all 5 at day 29. Pharmacokinetic findings (including mean alpha and beta half-life of 5.3 days and 3.9 days, respectively, and mean residence time of 6.2 days) supported prolonged effects. Thrombogenicity markers remained normal throughout prophylactic injections or showed some initial increases followed by decreases with continued dosing. Two participants had anti-drug antibodies to dalcinonacog alfa at study end, none had neutralizing antibody. Two participants had ISR, both resolved. Reports of redness, swelling, tenderness or pain among the first 3 participants prompted dose-splitting for the last 3 participants, leading to fewer ISR. CONCLUSION: Subcutaneous dalcinonacog alfa is effective in raising FIX levels into the mild haemophilia range, comparable to intravenous extended half-life FIX clotting factors.


Assuntos
Hemofilia A , Hemofilia B , Adulto , Testes de Coagulação Sanguínea , Fator IX/uso terapêutico , Meia-Vida , Hemofilia B/tratamento farmacológico , Humanos , Masculino
8.
Front Neurol ; 12: 593582, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790846

RESUMO

Ischemic stroke is the most widespread cause of disability and a leading cause of death in developed countries. To date, the most potent approved treatment for acute stroke is recanalization therapy with thrombolytic drugs such as tissue plasminogen activator (rt-PA or tPA) or endovascular mechanical thrombectomy. Although tPA and thrombectomy are widely available in the United States, it is currently estimated that only 10-20% of stroke patients get tPA treatment, in part due to restrictive selection criteria. Recently, however, tPA and thrombectomy selection criteria have loosened, potentially allowing more patients to qualify. The relatively low rate of treatment may also reflect the perceived risk of brain hemorrhage following treatment with tPA. In translational research and a single patient study, protease activated receptor 1 (PAR-1) targeted therapies given along with thrombolysis and thrombectomy appear to reduce hemorrhagic transformation after recanalization. Such adjuncts may likely enhance the availability of recanalization and encourage more physicians to use the recently expanded selection criteria for applying recanalization therapies. This narrative review discusses stroke therapies, the role of hemorrhagic transformation in producing poor outcomes, and presents the data suggesting that PAR-1 acting agents show promise for decreasing hemorrhagic transformation and improving outcomes.

9.
Genome Med ; 13(1): 71, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33926532

RESUMO

BACKGROUND: Genetic information is increasingly relevant across healthcare. Traditional genetic counseling (GC) may limit access to genetic information and may be more information and support than some individuals need. We report on the application and clinical implications of a framework to consistently integrate genetics expertise where it is most useful to patients. METHODS: The Clinical Genome Resource's (ClinGen) Consent and Disclosure Recommendations (CADRe) workgroup designed rubrics to guide pre- and post-genetic test communication. Using a standard set of testing indications, pre- and post-test rubrics were applied to 40 genetic conditions or testing modalities with diverse features, including variability in levels of penetrance, clinical actionability, and evidence supporting a gene-disease relationship. Final communication recommendations were reached by group consensus. RESULTS: Communication recommendations were determined for 478 unique condition-indication or testing-indication pairs. For half of the conditions and indications (238/478), targeted discussions (moderate communication depth) were the recommended starting communication level for pre- and post-test conversations. Traditional GC was recommended pre-test for adult-onset neurodegenerative conditions for individuals with no personal history and post-test for most conditions when genetic testing revealed a molecular diagnosis as these situations are likely higher in complexity and uncertainty. A brief communication approach was recommended for more straightforward conditions and indications (e.g., familial hypercholesterolemia; familial variant testing). CONCLUSIONS: The CADRe recommendations provide guidance for clinicians in determining the depth of pre- and post-test communication, strategically aligning the anticipated needs of patients with the starting communication approach. Shorter targeted discussions or brief communications are suggested for many tests and indications. Longer traditional GC consultations would be reserved for patients with more complex and uncertain situations where detailed information, education, and psychological support can be most beneficial. Future studies of the CADRe communication framework will be essential for determining if CADRe-informed care supports quality patient experience while improving access to genetic information across healthcare.


Assuntos
Comunicação , Testes Genéticos , Revelação , Humanos , Consentimento Livre e Esclarecido
10.
J Thromb Haemost ; 19(4): 967-975, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540485

RESUMO

BACKGROUND: Dalcinonacog alfa (DalcA), a next-generation, recombinant human factor IX (FIX) variant, was developed using a rational design approach for increased procoagulant activity and longer duration of action to be administered subcutaneously (SC) for prophylaxis of hemophilia B bleeding episodes. OBJECTIVES: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DalcA. METHODS: This multicenter, phase 1/2a study (NCT03186677) was conducted in 11 males aged 12 to 65 years with severe hemophilia B. In cohort 1, subjects received intravenous (IV) 75 IU/kg BeneFIX and DalcA. Cohorts 2 and 3 had DalcA IV 75 IU/kg and SC 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SC 150 IU/kg DalcA for 6 days and cohort 6 received IV 75 IU/kg and daily SC 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD, and anti-drug antibody measurement. Subjects were monitored for safety endpoints for 30 days postdosing. RESULTS: DalcA demonstrated a 24-fold greater potency over BeneFIX and longer mean residence time (33.8 h). SC bioavailability 8.2% to 20.3%, beta half-life 53.9 to 106.9 h and Tmax 24 to 48 h. A median 15.7% FIX activity level (interquartile range, 14.9%-16.6%) was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wild-type FIX, occurred in two cousins. CONCLUSIONS: The data demonstrated that DalcA achieved protective FIX activity levels between 11% and 18%, corresponding to a reduced chance of spontaneous bleeds. Based on the results, a phase 2b trial to assess the safety and efficacy of 28 daily SC doses of DalcA was performed.


Assuntos
Hemofilia A , Hemofilia B , Adolescente , Adulto , Idoso , Testes de Coagulação Sanguínea , Criança , Fator IX , Meia-Vida , Hemofilia B/diagnóstico , Hemofilia B/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Adulto Jovem
11.
J Orthop Surg Res ; 16(1): 143, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602286

RESUMO

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder in the USA, and knee OA has the highest prevalence. Inflammation and decrease in vascularization are key factors in the degeneration of articular cartilage and the associated pain and decrease in function. To combat this process, the use of biologics including umbilical cord-derived Wharton's Jelly (UC-derived WJ) has grown. UC-derived WJ contains large quantities of regenerative factors, including growth factors (GFs), cytokines (CKs), hyaluronic acid (HA), and extracellular vesicles (EVs). The proposed study evaluates the safety and efficacy of intraarticular injection of UC-derived WJ for treatment of knee OA symptoms. METHODS AND ANALYSIS: This is a non-randomized, open-label, multi-center, prospective study in which the safety and efficacy of intraarticular UC-derived WJ in patients suffering from grade II/III OA will be assessed. Twelve patients with grade II/III OA who meet the inclusion and exclusion criteria will be recruited for this study which will be conducted at up to two sites within the USA. The participants will be followed for 1 s. Participants will be assessed using the Numeric Pain Rating Scale (NPRS), Knee Injury and Osteoarthritis Outcome Score (KOOS), 36-item short form survey (SF-36), Single Assessment Numeric Evaluation (SANE), physical exams, plain radiography, and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score for improvements in pain, satisfaction, function, and cartilage regeneration. DISCUSSION: This prospective study will contribute to the limited amount of data on UC-derived WJ, particularly with regard to its safety and efficacy. The outcomes from this study will also lay the groundwork for a large placebo-controlled trial of intraarticular UC-derived WJ for symptomatic knee OA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04719793 . Registered on 22 January 2021.


Assuntos
Osteoartrite do Joelho/cirurgia , Medicina Regenerativa/métodos , Cordão Umbilical , Geleia de Wharton/transplante , Regeneração Óssea , Cartilagem Articular/fisiopatologia , Vesículas Extracelulares , Seguimentos , Humanos , Ácido Hialurônico , Injeções Intra-Articulares , Peptídeos e Proteínas de Sinalização Intercelular , Osteoartrite do Joelho/fisiopatologia , Estudos Prospectivos , Geleia de Wharton/química
12.
NPJ Breast Cancer ; 7(1): 14, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579966

RESUMO

We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access (n = 63) or usual care (n = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p < 0.001) and logged into the patient's account (61.2% vs 0% of those registered; p < 0.001), but few sent messages to clinicians (6.1% vs 0%; p = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p = 0.24) and satisfaction numerically higher (15.8-16.2 vs 18.0-17.4; p = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).

13.
PLoS One ; 15(10): e0240896, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33112889

RESUMO

INTRODUCTION: The rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy. AIM: This study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs. METHODS: Two hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted. RESULTS: There was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days. CONCLUSION: The increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.


Assuntos
Fator IX/administração & dosagem , Fator IX/farmacocinética , Hemofilia B/tratamento farmacológico , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fator IX/química , Feminino , Hemofilia B/sangue , Injeções Subcutâneas , Masculino , Modelos Moleculares , Tempo de Tromboplastina Parcial , Tempo de Coagulação do Sangue Total
14.
J Orthop Surg Res ; 15(1): 49, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054483

RESUMO

BACKGROUND: The last decade has seen an explosion in the interest in using biologics for regenerative medicine applications, including umbilical cord-derived Wharton's Jelly. There is insufficient literature assessing the amount of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes in these products. The present study reports the development of a novel Wharton's jelly formulation and evaluates the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles including exosomes. METHODS: Human umbilical cords were obtained from consenting caesarian section donors. The Wharton's jelly was then isolated from the procured umbilical cord and formulated into an injectable form. Randomly selected samples from different batches were analyzed for sterility testing and to quantify the presence of growth factors, cytokines, hyaluronic acid, and extracellular vesicles. RESULTS: All samples passed the sterility test. Growth factors including IGFBP 1, 2, 3, 4, and 6, TGF-α, and PDGF-AA were detected. Several immunomodulatory cytokines, such as RANTES, IL-6R, and IL-16, were also detected. Pro-inflammatory cytokines MCSFR, MIP-1a; anti-inflammatory cytokines TNF-RI, TNF-RII, and IL-1RA; and homeostatic cytokines TIMP-1 and TIMP-2 were observed. Cytokines associated with wound healing, ICAM-1, G-CSF, GDF-15, and regenerative properties, GH, were also expressed. High concentrations of hyaluronic acid were observed. Particles in the extracellular vesicle size range were also detected and were enclosed by the membrane, indicative of true extracellular vesicles. CONCLUSION: There are numerous growth factors, cytokines, hyaluronic acid, and extracellular vesicles present in the Wharton's jelly formulation analyzed. The amount of these factors in Wharton's jelly is higher compared with other biologics and may play a role in reducing inflammation and pain and augment healing of musculoskeletal injuries.


Assuntos
Medicina Regenerativa/tendências , Cordão Umbilical/química , Cordão Umbilical/metabolismo , Geleia de Wharton/química , Geleia de Wharton/metabolismo , Citocinas/análise , Citocinas/metabolismo , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Feminino , Humanos , Ácido Hialurônico/análise , Ácido Hialurônico/metabolismo , Mediadores da Inflamação/análise , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/análise , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Gravidez
15.
Auton Neurosci ; 224: 102637, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31954224

RESUMO

Despite well-established clinical associations between Hypermobile Ehlers-Danlos syndrome (hEDS) and postural orthostatic tachycardia syndrome (POTS), the precise prevalence is unknown. We therefore evaluated for hEDS in 91 POTS participants using the 2017 hEDS diagnostic checklist, which has three major criteria: 1) generalized joint hypermobility (Beighton score), 2) systemic features, family history, and 3) absence of exclusion criteria. Overall, 28 out of 91 POTS participants (31%) met clinical criteria for hEDS. An additional 24% of participants had generalized joint hypermobility without meeting hEDS criteria. Identifying the prevalence of hEDS in POTS is important for understanding possible mechanisms connecting these two syndromes.


Assuntos
Síndrome de Ehlers-Danlos/epidemiologia , Síndrome da Taquicardia Postural Ortostática/epidemiologia , Adolescente , Adulto , Síndrome de Ehlers-Danlos/complicações , Feminino , Humanos , Instabilidade Articular/complicações , Masculino , Pessoa de Meia-Idade , Síndrome da Taquicardia Postural Ortostática/complicações , Prevalência , Adulto Jovem
16.
Med Clin North Am ; 103(6): 1021-1033, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582002

RESUMO

Joint hypermobility may be syndromic or nonsyndromic, asymptomatic or symptomatic. However, asymptomatic joint hypermobility can cause repetitive use injury, alter biomechanics, or become symptomatic later in life. Symptomatic joint hypermobility can result from soft tissue injury or muscular strain caused by muscular imbalance. Treatment is straightforward once joint hypermobility is recognized. Generalized joint hypermobility can be assessed using a standardized in-office examination. Generalized joint hypermobility may also be a feature of a heritable connective tissue disorder with other systemic findings. Therefore, assessing joint hypermobility in the context of musculoskeletal complaints may lead to recognizing systemic manifestations and allow treatment accordingly.


Assuntos
Síndrome de Ehlers-Danlos , Instabilidade Articular , Síndrome de Ehlers-Danlos/classificação , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Instabilidade Articular/etiologia , Instabilidade Articular/fisiopatologia , Instabilidade Articular/terapia , Administração dos Cuidados ao Paciente/métodos
18.
Breast Cancer Res Treat ; 177(1): 127-136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165374

RESUMO

PURPOSE: Family is often overlooked in cancer care. We developed a patient-family agenda setting intervention to engage family in cancer care communication. METHODS: We conducted a pilot randomized controlled trial (NCT03283553) of patients on active treatment for breast cancer and their family "care partner." Intervention dyads (n = 69) completed a self-administered checklist to clarify care partner roles, establish a shared visit agenda, and facilitate MyChart patient portal access. Control dyads (n = 63) received usual care. We assessed intervention acceptability and initial effects from post-visit surveys and MyChart utilization at 6 weeks. RESULTS: At baseline, most patients (89.4%) but few care partners (1.5%) were registered for MyChart. Most patients (79.4%) wanted their care partner to have access to their records and 39.4% of care partners reported accessing MyChart. In completing the checklist, patients and care partners endorsed active communication roles for the care partner and identified a similar visit agenda: most (> 90%) reported the checklist was easy, useful, and recommended it to others. At 6 weeks, intervention (vs control) care partners were more likely to be registered for MyChart (75.4% vs 1.6%; p < 0.001), to have logged in (43.5% vs 0%; p < 0.001) and viewed clinical notes (30.4% vs 0%; p < 0.001), but were no more likely to exchange direct messages with clinicians (1.5% vs 0%; p = 0.175). No differences in patients' MyChart use were observed, but intervention patients more often viewed clinical notes (50.7% vs 9.5%; p < 0.001). CONCLUSIONS: A patient-family agenda setting intervention was acceptable and affected online practices of cancer patients and care partners.


Assuntos
Neoplasias da Mama/epidemiologia , Cuidadores , Assistência ao Paciente , Adulto , Idoso , Comunicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Relações Médico-Paciente , Fatores de Tempo
19.
Am J Hum Genet ; 104(4): 578-595, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30951675

RESUMO

The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant's clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis. There has been discussion concerning the extent of this obligation in the context of both research and clinical care. Although clinical recommendations have begun to emerge, guidance is lacking on the responsibilities of researchers to inform participants of reinterpreted results. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in November 2018. The workgroup included representatives from the National Society of Genetic Counselors, the Canadian College of Medical Genetics, and the Canadian Association of Genetic Counsellors. The final statement includes twelve position statements that were endorsed or supported by the following organizations: Genetic Alliance, European Society of Human Genetics, Canadian Association of Genetic Counsellors, American Association of Anthropological Genetics, Executive Committee of the American Association of Physical Anthropologists, Canadian College of Medical Genetics, Human Genetics Society of Australasia, and National Society of Genetic Counselors.


Assuntos
Dever de Recontatar , Responsabilidade pela Informação/legislação & jurisprudência , Testes Genéticos/normas , Genética Médica/normas , Genômica/normas , Austrália , Canadá , Ética em Pesquisa , Europa (Continente) , Genética Médica/educação , Genética Médica/ética , Humanos , Responsabilidade Legal , Sujeitos da Pesquisa , Sociedades Médicas , Estados Unidos
20.
Ann Neurol ; 85(1): 125-136, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30450637

RESUMO

OBJECTIVE: Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. METHODS: The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 µg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. RESULTS: Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 µg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). INTERPRETATION: RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 µg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/cirurgia , Proteína C/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Terapia Combinada/métodos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Método Simples-Cego , Acidente Vascular Cerebral/diagnóstico por imagem
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