Publications by authors named "Howard Levy"

80 Publications

Application of a framework to guide genetic testing communication across clinical indications.

Genome Med 2021 Apr 29;13(1):71. Epub 2021 Apr 29.

Geisinger, 100 N Academy Blvd, Danville, PA, 17822, USA.

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.
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http://dx.doi.org/10.1186/s13073-021-00887-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086064PMC
April 2021

Stroke Treatment With PAR-1 Agents to Decrease Hemorrhagic Transformation.

Front Neurol 2021 15;12:593582. Epub 2021 Mar 15.

Department of Physiology and Neuroscience, Keck School of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United States.

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.
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http://dx.doi.org/10.3389/fneur.2021.593582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005555PMC
March 2021

Umbilical cord-derived Wharton's jelly for treatment of knee osteoarthritis: study protocol for a non-randomized, open-label, multi-center trial.

J Orthop Surg Res 2021 Feb 18;16(1):143. Epub 2021 Feb 18.

BioIntegrate, Lawrenceville, GA, USA.

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.
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http://dx.doi.org/10.1186/s13018-021-02300-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890617PMC
February 2021

A randomized intervention involving family to improve communication in breast cancer care.

NPJ Breast Cancer 2021 Feb 12;7(1):14. Epub 2021 Feb 12.

The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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).
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http://dx.doi.org/10.1038/s41523-021-00217-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881185PMC
February 2021

Safety, pharmacokinetics, and pharmacodynamics of a next-generation subcutaneously administered coagulation factor IX variant, dalcinonacog alfa, in previously treated hemophilia B patients.

J Thromb Haemost 2021 04 24;19(4):967-975. Epub 2021 Mar 24.

Catalyst Biosciences, South San Francisco, California, USA.

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 T 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.
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http://dx.doi.org/10.1111/jth.15259DOI Listing
April 2021

Preclinical evaluation of a next-generation, subcutaneously administered, coagulation factor IX variant, dalcinonacog alfa.

PLoS One 2020 28;15(10):e0240896. Epub 2020 Oct 28.

Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, California, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240896PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592742PMC
December 2020

Umbilical cord-derived Wharton's jelly for regenerative medicine applications.

J Orthop Surg Res 2020 Feb 13;15(1):49. Epub 2020 Feb 13.

Department of Musculoskeletal Disorders, School of Medicine and Surgery, University of Salerno, Fisciano, Italy.

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.
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http://dx.doi.org/10.1186/s13018-020-1553-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017504PMC
February 2020

Prevalence of hypermobile Ehlers-Danlos syndrome in postural orthostatic tachycardia syndrome.

Auton Neurosci 2020 03 10;224:102637. Epub 2020 Jan 10.

Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, USA; Autonomic Dysfunction Center and Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.

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.
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http://dx.doi.org/10.1016/j.autneu.2020.102637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282488PMC
March 2020

Genetics for the Generalist: Yes, This Is Important for Your Patient.

Authors:
Howard P Levy

Med Clin North Am 2019 11 24;103(6):xvii-xviii. Epub 2019 Aug 24.

Division of General Internal Medicine, Department of Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; 10753 Falls Road, Suite 325, Lutherville, MD 21093, USA. Electronic address:

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http://dx.doi.org/10.1016/j.mcna.2019.07.005DOI Listing
November 2019

Symptomatic Joint Hypermobility: The Hypermobile Type of Ehlers-Danlos Syndrome and the Hypermobility Spectrum Disorders.

Med Clin North Am 2019 Nov;103(6):1021-1033

Division of General Internal Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, 10753 Falls Road, Suite 325, Baltimore, MD 21093, USA.

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.
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http://dx.doi.org/10.1016/j.mcna.2019.08.002DOI Listing
November 2019

Sharing in care: engaging care partners in the care and communication of breast cancer patients.

Breast Cancer Res Treat 2019 Aug 4;177(1):127-136. Epub 2019 Jun 4.

The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.
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http://dx.doi.org/10.1007/s10549-019-05306-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640103PMC
August 2019

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results.

Am J Hum Genet 2019 04;104(4):578-595

Social Issues Committee, American Society of Human Genetics, Rockville, MD 20852, USA; Division of General Internal Medicine, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.

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.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451731PMC
April 2019

Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke.

Ann Neurol 2019 01 7;85(1):125-136. Epub 2019 Jan 7.

The Scripps Research Institute, La Jolla, CA.

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.
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http://dx.doi.org/10.1002/ana.25383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342508PMC
January 2019

Oral carbon monoxide therapy in murine sickle cell disease: Beneficial effects on vaso-occlusion, inflammation and anemia.

PLoS One 2018 11;13(10):e0205194. Epub 2018 Oct 11.

University of Minnesota, Department of Medicine, Vascular Research Center, Division of Hematology, Oncology and Transplantation, Minneapolis, MN, United States of America.

Carbon monoxide (CO) at low, non-toxic concentrations has been previously demonstrated to exert anti-inflammatory protection in murine models of sickle cell disease (SCD). However CO delivery by inhalation, CO-hemoglobin infusion or CO-releasing molecules presents problems for daily CO administration. Oral administration of a CO-saturated liquid avoids many of these issues and potentially provides a platform for self-administration to SCD patients. To test if orally-delivered CO could modulate SCD vaso-occlusion and inflammation, a liquid CO formulation (HBI-002) was administered by gavage (10 ml/kg) once-daily to NY1DD and Townes-SS transgenic mouse models of SCD. Baseline CO-hemoglobin (CO-Hb) levels were 1.6% and 1.8% in NY1DD and Townes-SS sickle mice and 0.6% in Townes-AS control mice. CO-Hb levels reached 5.4%, 4.7% and 3.0% within 5 minutes in NY1DD, SS and AS mice respectively after gavage with HBI-002. After ten treatments, each once-daily, hemoglobin levels rose from 5.3g/dL in vehicle-treated Townes-SS mice to 6.3g/dL in HBI-002-treated. Similarly, red blood cell (RBC) counts rose from 2.36 x 106/μL in vehicle-treated SS mice to 2.89 x 106/μL in HBI-002-treated mice. In concordance with these findings, hematocrits rose from 26.3% in vehicle-treated mice to 30.0% in HBI-002-treated mice. Reticulocyte counts were not significantly different between vehicle and HBI-002-treated SS mice implying less hemolysis and not an increase in RBC production. White blood cell counts decreased from 29.1 x 103/μL in vehicle-treated versus 20.3 x 103/μL in HBI-002-treated SS mice. Townes-SS mice treated with HBI-002 had markedly increased Nrf2 and HO-1 expression and decreased NF-κB activation compared to vehicle-treated mice. These anti-inflammatory effects were examined for the ability of HBI-002 (administered orally once-daily for up to 5 days) to inhibit vaso-occlusion induced by hypoxia-reoxygenation. In NY1DD and Townes-SS sickle mice, HBI-002 decreased microvascular stasis in a duration-dependent manner. Collectively, these findings support HBI-002 as a useful anti-inflammatory agent to treat SCD and warrants further development as a therapeutic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181332PMC
March 2019

Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background.

Genet Med 2019 03 6;21(3):727-735. Epub 2018 Jul 6.

Geisinger, 100 North Academy Avenue, Danville, Pennsylvania, 17822, USA.

Purpose: In response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org ) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians.

Methods: We present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N = 18), nongenetics specialists (N = 27), and genetics clinicians (N = 32) on both rubrics.

Results: Formative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a "typical" patient.

Conclusion: We propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling.
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http://dx.doi.org/10.1038/s41436-018-0093-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320736PMC
March 2019

The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises.

Am J Hematol 2017 Jun 29;92(6):569-582. Epub 2017 Apr 29.

University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN, 55455, USA.

Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta-globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso-occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo-enzymes as well as key modulating genes that in sum, result in significant anti-inflammatory, anti-oxidant and anti-apoptotic effects as well as vasodilation and anti-adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti-polymerization HbS agent. In addition, considerable scientific data in the non-SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.
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http://dx.doi.org/10.1002/ajh.24750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723421PMC
June 2017

Value of prior imaging review before ordering renal sonography in the evaluation of abnormal renal function.

J Clin Ultrasound 2017 Nov 4;45(9):537-541. Epub 2017 Apr 4.

Christiana Care Health System, Department of Radiology, 4755 Ogletown-Stanton Road, Newark, DE, 19718.

Background: To determine the prognostic relevance of prior imaging studies in the evaluation of patients referred for renal ultrasound (US) examination to investigate abnormal renal function tests.

Methods: We conducted a retrospective study of 208 consecutive renal US examinations performed for abnormal renal function tests.

Results: 68% (142/208) of patients reviewed for the study had prior abdominal imaging with 15% (21/142) receiving that imaging within 1 month prior to the renal US study and 56% (80/142) within the prior year. Of all patients with prior imaging studies, only 6/142 (4%) demonstrated any significant interval change, with development of hydronephrosis, which was also clinically evident as a substantial rise in serum creatinine level.

Conclusions: Review of prior imaging studies, in addition to other pertinent clinical data, should result in a significant reduction in the number of unnecessary renal US examinations performed in patients with abnormal renal function. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:537-541, 2017.
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http://dx.doi.org/10.1002/jcu.22476DOI Listing
November 2017

The 2017 international classification of the Ehlers-Danlos syndromes.

Am J Med Genet C Semin Med Genet 2017 03;175(1):8-26

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.c.31552DOI Listing
March 2017

Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history.

Am J Med Genet C Semin Med Genet 2017 03 1;175(1):48-69. Epub 2017 Feb 1.

The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations-joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.c.31538DOI Listing
March 2017

A framework for the classification of joint hypermobility and related conditions.

Am J Med Genet C Semin Med Genet 2017 03 1;175(1):148-157. Epub 2017 Feb 1.

In the last decade, growing attention has been placed on joint hypermobility and related disorders. The new nosology for Ehlers-Danlos syndrome (EDS), the best-known and probably the most common of the disorders featuring joint hypermobility, identifies more than 20 different types of EDS, and highlights the need for a single set of criteria to substitute the previous ones for the overlapping EDS hypermobility type and joint hypermobility syndrome. Joint hypermobility is a feature commonly encountered in many other disorders, both genetic and acquired, and this finding is attracting the attention of an increasing number of medical and non-medical disciplines. In this paper, the terminology of joint hypermobility and related disorders is summarized. Different types of joint hypermobility, its secondary musculoskeletal manifestations and a simplified categorization of genetic syndromes featuring joint hypermobility are presented. The concept of a spectrum of pathogenetically related manifestations of joint hypermobility intersecting the categories of pleiotropic syndromes with joint hypermobility is introduced. A group of hypermobility spectrum disorders is proposed as diagnostic labels for patients with symptomatic joint hypermobility but not corresponding to any other syndromes with joint hypermobility. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.c.31539DOI Listing
March 2017

The Impact of Living with Klinefelter Syndrome: A Qualitative Exploration of Adolescents and Adults.

J Genet Couns 2017 Aug 10;26(4):728-737. Epub 2016 Nov 10.

Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Klinefelter syndrome (XXY) is a common yet significantly underdiagnosed condition with considerable medical, psychological and social implications. Many health care providers lack familiarity with XXY, resulting in medical management challenges and a limited understanding of the personal impact of the condition. Genetic counselors benefit from understanding the challenges adolescents and men with XXY face to effectively address their medical and psychosocial needs. The purpose of this study was to understand the impact of living with XXY as an adolescent or an adult. Individuals aged 14 to 75 years with self-reported XXY were recruited from online support networks to complete a web-based survey that included open-ended questions. Open-ended responses were coded and analyzed thematically (n = 169 to 210 for each open-ended question). Over half of respondents to the open-ended questions reported challenges in finding health care providers who are knowledgeable about XXY, with many describing an extensive diagnostic odyssey and relief when receiving a diagnosis. Individuals sought support coping with the challenges they face and acknowledgement of the positive aspects of XXY. Recommendations are made for how genetic counseling can enhance quality of life for individuals living with XXY.
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http://dx.doi.org/10.1007/s10897-016-0041-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425317PMC
August 2017

Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection.

Stroke 2016 12 1;47(12):2979-2985. Epub 2016 Nov 1.

From the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.L.); ZZ Biotech, LLC, Houston, TX (S.W., H.L., K.P.); Department of Biostatistics, University of Iowa, Iowa City (C.C., S.O.); Neurological Clinical Research Institute, Massachusetts General Hospital, Boston (M.C., S.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (M.F.); Department of Neurology, University of Virginia, Charlottesville (E.C.H.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (P.K.); Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (J.S.); Department of Neurology, State University of New York Downstate Medical Center, Brooklyn (S.L.); Department of Neurology, University of Kansas Hospital, Kansas City (M.R.); Department of Neurology, University of Pittsburgh Medical School, PA (L.W., A.J.); and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.M., S.W.).

Background And Purpose: The advent of intra-arterial neurothrombectomy (IAT) for acute ischemic stroke opens a potentially transformative opportunity to improve neuroprotection studies. Combining a putative neuroprotectant with recanalization could produce more powerful trials but could introduce heterogeneity and adverse event possibilities. We sought to demonstrate feasibility of IAT in neuroprotectant trials by defining IAT selection criteria for an ongoing neuroprotectant clinical trial.

Methods: The study drug, 3K3A-APC, is a pleiotropic cytoprotectant and may reduce thrombolysis-associated hemorrhage. The NeuroNEXT trial NN104 (RHAPSODY) is designed to establish a maximally tolerated dose of 3K3A-APC. Each trial site provided their IAT selection criteria. An expert panel reviewed site criteria and published evidence. Finally, the trial leadership designed IAT selection criteria.

Results: Derived selection criteria reflected consistency among the sites and comparability to published IAT trials. A protocol amendment allowing IAT (and relaxed age, National Institutes of Health Stroke Scale, and time limits) in the RHAPSODY trial was implemented on June 15, 2015. Recruitment before and after the amendment improved from 8 enrolled patients (601 screened, 1.3%) to 51 patients (821 screened, 6.2%; odds ratio [95% confidence limit] of 4.9 [2.3-10.4]; P<0.001). Gross recruitment was 0.11 patients per site month versus 0.43 patients per site per month, respectively, before and after the amendment.

Conclusions: It is feasible to include IAT in a neuroprotectant trial for acute ischemic stroke. Criteria are presented for including such patients in a manner that is consistent with published evidence for IAT while still preserving the ability to test the role of the putative neuroprotectant.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714.
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http://dx.doi.org/10.1161/STROKEAHA.116.013881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134840PMC
December 2016

Bioabsorbable Intracoronary Matrix for Prevention of Ventricular Remodeling After Myocardial Infarction.

J Am Coll Cardiol 2016 08;68(7):715-23

Duke Clinical Research Institute, Durham, North Carolina.

Background: Bioabsorbable cardiac matrix (BCM) is a novel device that attenuates adverse left ventricular (LV) remodeling after large myocardial infarctions in experimental models.

Objectives: This study aimed to analyze whether BCM, compared with saline control, would result in less LV dilation and fewer adverse clinical events between baseline and 6 months.

Methods: In an international, randomized, double-blind, controlled trial, 303 subjects with large areas of infarction despite successful primary percutaneous coronary intervention (PCI) of ST-segment elevation myocardial infarction (STEMI) were randomized 2:1 to BCM or saline injected into the infarct-related artery 2 to 5 days after primary PCI. The primary outcome was mean change from baseline in LV end-diastolic volume index (LVEDVI) at 6 months. Secondary outcomes included change in Kansas City Cardiomyopathy Questionnaire score, 6-minute walk time, and New York Heart Association functional class at 6 months. The primary safety endpoint was a composite of cardiovascular death, recurrent MI, target-vessel revascularization, stent thrombosis, significant arrhythmia requiring therapy, or myocardial rupture through 6 months.

Results: In total, 201 subjects were assigned to BCM and 102 to saline control. There was no significant difference in change in LVEDVI from baseline to 6 months between the groups (mean change ± SD: BCM 14.1 ± 28.9 ml/m(2) vs. saline 11.7 ± 26.9 ml/m(2); p = 0.49). There was also no significant difference in the secondary endpoints. The rates of the primary safety outcome were similar between the 2 groups (BCM 11.6% vs. saline 9.1%; p = 0.37).

Conclusions: Intracoronary deployment of BCM 2 to 5 days after successful reperfusion in subjects with large myocardial infarction did not reduce adverse LV remodeling or cardiac clinical events at 6 months. (IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction [PRESERVATION I]; NCT01226563).
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http://dx.doi.org/10.1016/j.jacc.2016.05.053DOI Listing
August 2016

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.

Am J Hum Genet 2015 Jul;97(1):6-21

American Society of Human Genetics, Bethesda, MD 20814, USA.

In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.
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http://dx.doi.org/10.1016/j.ajhg.2015.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570999PMC
July 2015

Pancreatic Duct Dilatation in Elderly Patient With Abdominal Pain. Partial Supradiaphragmatic Herniation of the Pancreas.

Gastroenterology 2015 Aug 26;149(2):292-3. Epub 2015 Jun 26.

Gastroenterology Associates PA, Newark, Delaware.

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http://dx.doi.org/10.1053/j.gastro.2015.03.051DOI Listing
August 2015

Prevalence of hereditary angioedema in untested first-degree blood relatives of known subjects with hereditary angioedema.

Allergy Asthma Proc 2015 May-Jun;36(3):206-12. Epub 2015 Mar 23.

University of California-San Diego School of Medicine, La Jolla, CA, USA.

Hereditary angioedema (HAE) is a rare autosomal-dominant disease characterized by recurring attacks of nonpruritic, nonpitting edema caused by an inherited deficiency or dysfunction of C1 esterase inhibitor (C1 INH). Symptoms can present years before an accurate diagnosis is made. The objective of this study, the Angioedema Clinical Epidemiology Testing Initiative for the Study of Hereditary Angioedema, was to determine the prevalence and clinical manifestations of HAE in untested first-degree blood relatives of known patients with HAE. Patients with a confirmed diagnosis of HAE recruited first-degree relatives who had not been evaluated for HAE. Enrolled subjects underwent complement testing (C4, C1 INH antigen, and functional C1 INH). If the lab tests were abnormal, the enrolled subjects returned to the site for a follow-up visit and questionnaire. Overall, 31 patients with HAE and 46 first-degree relatives enrolled in the study. Of 46 enrolled relatives, 30 (65%) had lab test results that ruled out a diagnosis of HAE, two (4%) were categorized as "HAE not ruled out," and 14 (30%) were newly diagnosed with HAE. Of 14 newly diagnosed subjects, nine (64%) reported having experienced symptoms that may have been related to HAE, such as swelling in the throat, face, or extremities or abdominal pain. When reported, median age of symptom onset in these 14 subjects was nine years whereas newly diagnosed asymptomatic subjects had a median chronological age of six years. These 14 subjects reported a historic mean standard deviation rate of 2.51 (5.59) swelling episodes per month with a mean standard deviation duration of 1.6 (0.74) days. This study's findings reinforce the importance of testing family members of patients with HAE to detect this hereditary condition.
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http://dx.doi.org/10.2500/aap.2015.36.3833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405600PMC
February 2016

Comparison of chromogenic and ELISA functional C1 inhibitor tests in diagnosing hereditary angioedema.

J Allergy Clin Immunol Pract 2015 Mar-Apr;3(2):200-5. Epub 2014 Oct 11.

Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California-San Diego, La Jolla, Calif.

Introduction: Measuring functional C1 inhibitor (C1 INH) with chromogenic or ELISA methods can confirm a diagnosis of hereditary angioedema (HAE) due to C1 INH deficiency. Previous studies found differences in the agreement of these assays.

Objective: To evaluate the agreement between chromogenic or ELISA methods in the context of an observational study.

Methods: Patients with previously confirmed HAE underwent functional C1 INH testing. These patients contacted first-degree relatives (parents, siblings, or offspring) not previously evaluated for HAE, who underwent a panel of complement testing, including for functional C1 INH.

Results: Overall, 31 patients with HAE and 46 untested relatives enrolled. Of 46 relatives, 14 (30.4%) were newly diagnosed with HAE based on their laboratory results. Among the 31 patients previously confirmed with HAE, all had low functional C1 INH according to the chromogenic method, whereas 22 (71.0%) had low, 7 (22.6%) had equivocal, and 2 (6.5%) had normal functional C1 INH according to the ELISA method. In the 14 newly diagnosed relatives, all had low functional C1 INH according to the chromogenic method, whereas 11 (78.5%) had low and 3 (21.4%) had equivocal results according to the ELISA method.

Conclusion: Despite the apparent discordance in the ELISA and chromogenic assays in a small number of patients, both were useful in measuring functional C1 INH. To establish the diagnosis of HAE due to C1 INH deficiency, functional C1 INH results should be interpreted in combination with family and clinical history, and with other complement tests.
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http://dx.doi.org/10.1016/j.jaip.2014.08.002DOI Listing
December 2015

Factors associated with adaptation to Klinefelter syndrome: the experience of adolescents and adults.

Patient Educ Couns 2015 Jan 27;98(1):90-5. Epub 2014 Aug 27.

Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Objective: The purpose of this study was to understand the impact of living with Klinefelter syndrome (XXY) as an adolescent or an adult and to examine the factors that contribute to adaptation.

Methods: Individuals (n = 310) aged 14-75 years with self-reported XXY were recruited from online support networks to complete a self-administered survey. Perceived consequences, perceived severity, perceived stigma, and coping were measured and evaluated as correlates of adaptation.

Results: The use of problem-focused coping strategies was positively correlated with adaptation (p < 0.01) and age was negatively correlated with adaptation (p < 0.05).

Conclusion: The majority of participants reported significant negative consequences of XXY, including infertility, psychological co-morbidities and differences in appearance. How participants coped with their negative appraisals was the greatest predictor of adaptation.

Practice Implications: Interventions designed to help individuals reframe negative appraisals, to increase perceived manageability of the challenges of living with XXY, and to facilitate effective coping may improve adaptation among individuals with XXY.
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http://dx.doi.org/10.1016/j.pec.2014.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5160995PMC
January 2015

Ruptured extratesticular epidermal inclusion cyst mimicking polyorchidism with torsion on sonography.

Emerg Radiol 2014 Dec 7;21(6):643-5. Epub 2014 May 7.

Department of Radiology, Christiana Care Health System, Christiana Hospital, P.O. Box 6001, Newark, DE, 19718, USA,

The sonographic appearance of epidermal inclusion cysts varies in accordance with the contents of the cyst, ranging from an anechoic lesion to a hyperechoic solid appearing mass. Supernumerary testes are an uncommon congenital abnormality, in which more than two testes are present. We present a rare case of a ruptured scrotal extratesticular epidermal inclusion cyst, which had the sonographic appearance of a supernumerary testicle with torsion.
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http://dx.doi.org/10.1007/s10140-014-1229-xDOI Listing
December 2014