Craniocervical instability in patients with Ehlers-Danlos syndromes: outcomes analysis following occipito-cervical fusion.

Craniocervical instability (CCI) is increasingly recognized in hereditary disorders of connective tissue and in some patients following suboccipital decompression for Chiari malformation (CMI) or low-lying cerebellar tonsils (LLCT). CCI is characterized by severe headache and neck pain, cervical medullary syndrome, lower cranial nerve deficits, myelopathy, and radiological metrics, for which occipital cervical fusion (OCF) has been advocated. We conducted a retrospective analysis of patients with CCI and Ehlers-Danlos syndrome (EDS) to determine whether the surgical outcomes supported the criteria by which patients were selected for OCF. Fifty-three consecutive subjects diagnosed with EDS, who presented with severe head and neck pain, lower cranial nerve deficits, cervical medullary syndrome, myelopathy, and radiologic findings of CCI, underwent open reduction, stabilization, and OCF. Thirty-two of these patients underwent suboccipital decompression for obstruction of cerebral spinal fluid flow. Questionnaire data and clinical findings were abstracted by a research nurse. Follow-up questionnaires were administered at 5-28 months (mean 15.1). The study group demonstrated significant improvement in headache and neck pain (p < 0.001), decreased use of pain medication (p < 0.0001), and improved Karnofsky Performance Status score (p < 0.001). Statistically significant improvement was also demonstrated for nausea, syncope (p < 0.001), speech difficulties, concentration, vertigo, dizziness, numbness, arm weakness, and fatigue (p = 0.001). The mental fatigue score and orthostatic grading score were improved (p < 0.01). There was no difference in pain improvement between patients with CMI/LLCT and those without. This outcomes analysis of patients with disabling CCI in the setting of EDS demonstrated significant benefits of OCF. The results support the reasonableness of the selection criteria for OCF. We advocate for a multi-center, prospective clinical trial of OCF in this population.

Safety and outcomes analysis: transcatheter implantation of autologous angiogenic cell precursors for the treatment of cardiomyopathy.

BACKGROUND: Stem cell transplantation is an emerging therapy for severe cardiomyopathy, proffering stem cell recruitment, anti-apoptosis, and proangiogenic capabilities. Angiogenic cell precursors (ACP-01) are autologous, lineage-specific, cells derived from a multipotent progenitor cell population, with strong potential to effectively engraft, form blood vessels, and support tissue survival and regeneration. METHODS: This IRB approved outcome analysis reports upon 74 consecutive patients who failed medical management for severe cardiomyopathy, and were selected to undergo transcatheter intramyocardial or intracoronary implantation of ACP-01. Serious adverse events (SAEs) were reported. Cell analysis was conducted for each treatment. The left ventricular ejection fraction (LVEF) was measured by multi-gated acquisition scan (MUGA) or echocardiogram at 4 months ± 1.9 months and 12 months ± 5.5 months. Patients reported quality of life statements at 6 months (± 5.6 months). RESULTS: Fifty-four of 74 patients met requirements for inclusion (48 males and five females; age 68.1 ± 11.3 years). The mean treatment cell number of 57 × 106 ACP-01 included 7.7 × 106 CD34 + and 21 × 106 CD31 + cells with 97.6% viability. SAEs included one death (previously unrecognized silent MI), ventricular tachycardia (n = 2) requiring cardioversion, and respiratory infection (n = 2). LVEF in the ischemic subgroup (n = 41) improved by 4.7% ± 9.7 from pre-procedure to the first follow-up (4 months ± 1.9 months) (p < 0.004) and by 7.2% ± 10.9 at final follow-up (n = 25) at average 12 months (p < 0.004). The non-ischemic dilated cardiomyopathy subgroup (n = 8) improved by 7.5% ± 6.0 at the first follow-up (p < 0.017) and by 12.2% ± 6.4 at final follow-up (p < 0.003, n = 6). Overall improvement in LVEF from pre-procedure to post-procedure was significant (Fisher's exact test p < 0.004). LVEF improvement was most marked in the patients with the most severe cardiomyopathy (LVEF < 20%) improving from a mean 14.6% ± 3.4% pre-procedurally to 28.4% ± 8% at final follow-up. Quality of life statements reflected improvement in 33/50 (66%), no change in 14/50 (28%), and worse in 3/50 (6%). CONCLUSION: Transcatheter implantation of ACP-01 for cardiomyopathy is safe and improves LVEF in the setting of ischemic and non-ischemic cardiomyopathy. The results warrant further investigation in a prospective, blinded, and controlled clinical study. TRIAL REGISTRATION: IRB from Genetic Alliance #APC01-001, approval date July 25, 2022. Cardiomyopathy is common and associated with high mortality. Stem cell transplantation is an emerging therapy. Angiogenic cell precursors (ACP-01) are lineage-specific endothelial progenitors, with strong potential for migration, engraftment, angiogenesis, and support of tissue survival and regeneration. A retrospective outcomes analysis of 53 patients with ischemic and non-ischemic dilated cardiomyopathy undergoing transcatheter implantation of ACP-01 demonstrated improvements in the left ventricular ejection fraction of 7.2% ± 10.9 (p < 0.004) and 12.2% ± 6.4, respectively, at 12 months (± 5) follow-up. Quality of life statements reflected improvement in 33/50 (66%) patients.

Extracutaneous features and complications of the Ehlers-Danlos syndromes: A systematic review.

Introduction: The Ehlers-Danlos syndromes (EDS) comprise a group of inherited connective tissue disorders presenting with variable fragility to skin, soft tissue, and certain internal organs, which can cause significant complications, particularly arterial rupture, bowel perforation and joint difficulties. Currently, there are 14 proposed subtypes of EDS, with all except one subtype (hypermobile EDS) having an identified genetic etiology. An understanding of the extracutaneous features and complications within each subtype is key to maximizing clinical care and reducing the risk of further complications. Methods: A systematic review of EDS-related extracutaneous features and complications was undertaken. Results: We identified 839 EDS cases that met the inclusion criteria. We noted a high prevalence of joint hypermobility amongst kyphoscoliotic (39/39, 100%), spondylodysplastic (24/25, 96.0%), and hypermobile (153/160, 95.6%) EDS subtypes. The most common musculoskeletal complications were decreased bone density (39/43, 90.7%), joint pain (217/270, 80.4%), and hypotonia/weakness (79/140, 56.4%). Vascular EDS presented with cerebrovascular events (25/153, 16.3%), aneurysm (77/245, 31.4%), arterial dissection/rupture (89/250, 35.5%), and pneumothorax/hemothorax. Chronic pain was the most common miscellaneous complication, disproportionately affecting hypermobile EDS patients (139/157, 88.5%). Hypermobile EDS cases also presented with chronic fatigue (61/63, 96.8%) and gastrointestinal complications (57/63, 90.5%). Neuropsychiatric complications were noted in almost all subtypes. Discussion: Understanding the extracutaneous features and complications of each EDS subtype may help diagnose and treat EDS prior to the development of substantial comorbidities and/or additional complications. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022308151, identifier CRD42022308151.

Prescription Claims for Immunomodulator and Antiinflammatory Drugs Among Persons With Ehlers-Danlos Syndromes.

OBJECTIVE: Joint hypermobility in Ehlers-Danlos Syndromes (EDS) predisposes persons with EDS to frequent subluxations and dislocations, chronic arthralgia, and soft-tissue rheumatism. Epidemiologic trends of rheumatologic conditions among persons with EDS are lacking. Prescription claims databases can reflect underlying disease burdens by using medication claims as disease proxies. We examined the prevalence of prescription claims for commonly prescribed immunomodulator and antiinflammatory (IMD) drugs among persons with EDS compared with their matched control person, and hypothesized peripubertal increases among female persons with EDS. METHODS: We compared the percentages of IMD drug prescription claims among 3,484 persons with EDS (ages 5-62 years) against their age-, sex-, state of residence-, and earliest claim date-matched control persons using 10 years (2005-2014) of private prescription claims data and a minimum 2-year enrollment inclusion criterion. RESULTS: Our cohort comprised 70% adults and 74% female persons. At least 1 IMD medication was prescribed to 65.4% of persons with EDS compared with 47.4% of control persons. We observed 1.3 to 4.2 times higher odds (P < 0.0001) for 5 out of 6 IMD drug classes among persons with EDS compared with matched control persons, except for biologic agents (conditional odds ratio 1.3, 95% confidence interval 0.8-2.0). Peripubertal increases were observed for nonsteroidal antiinflammatory drugs, oral, and injectable steroids. CONCLUSIONS: To our knowledge, our study is the first to examine the full range of IMD drug prescription claim trends among persons with EDS. We believe our research findings can have notable diagnostic and management implications for EDS patients who present with multiple comorbidities and generally require a more granular assessment of their medical conditions.

A qualitative study of pain and related symptoms experienced by people with Ehlers-Danlos syndromes.

Introduction: Individuals with Ehlers-Danlos syndromes (EDS) often have complex and multi-faceted symptoms across the lifespan. Pain and the related symptoms of fatigue and sleep disorders are common. The objective of this qualitative study was to understand how participants manage their pain and related symptoms. Methods: The design was a qualitative thematic content analysis. Twenty-eight interviews were conducted to collect data from individuals who were participants in a prior quantitative longitudinal study. A semi-structured interview guide was designed to focus on and understand the trajectory of pain, sleep, fatigue, and general function. The interview continued with questions about coping mechanisms and obstacles to maintaining a sense of well-being. Results: Symptoms reported by participants were widespread and often interwoven. Pain was universal and often resulted in fatigue and disordered sleep which impacted physical function. Most participants reported that their symptoms worsened over time. Participants reported a wide range of effective interventions and most reported developing self-care strategies to adapt to their disabilities/limitations. Solutions included complementary interventions discovered when conventional medicine was unsuccessful. Very few relied on a "system" of health care and instead developed their own strategies to adapt to their disabilities/limitations. Discussion: EDS symptoms are often debilitating, and their progression is unknown. For most participants, symptoms worsened over the time. Even though participants in our study, by experience, were self-reliant, the importance of knowledgeable medical providers to help guide self-care should be emphasized.

Longitudinal analysis of symptoms in the Ehlers-Danlos syndromes.

Our study extends a cross-sectional dataset on the Ehlers-Danlos syndromes (EDS) assembled by the National Institute on Aging (NIA), under a protocol entitled Clinical and Molecular Manifestations of Heritable Disorders of Connective Tissue. We were successful in contacting 171 of the original 252 participants with EDS. Our study cohort included 91 participants who completed at least one of the following surveys: Brief Pain Inventory (BPI), Pittsburgh Sleep Quality Index (PSQI), Multidimensional Fatigue Inventory (MFI-20), and Short Form (SF-36) Health Survey, at both baseline and follow-up. Follow-up surveys occurred a median of 11.6 years after the baseline survey. We used mixed effects linear regression models to examine the change in scores for multiple indices reported by participants. There were small mean changes reflected in our estimates for the EDS population as a whole. There was wide heterogeneity between reported individual experiences, with some participants markedly improved and some dramatically worse. Men had a greater increase in mean pain severity over time than women. This is the first study to report a decade of longitudinal data in EDS.

The power of patient-led global collaboration.

In late 2017, the global nonprofit, The Ehlers-Danlos Society (TEDS), was awarded a "Pipeline to Proposal" Tier A award from the Patient-Centered Outcomes Research Institute (PCORI). The goal of this application was to form a team of patients, researchers, other community support groups and stakeholders who are focused on establishing the Ehlers-Danlos Comorbidity Coalition to address the common health issues associated with this group of high morbidity, high disease burden conditions. The ongoing Coalition that is now funded by individual donors and expanding in its mission and members, is an example of successful collaboration spanning over borders and priorities.

A case-control study of respiratory medication and co-occurring gastrointestinal prescription burden among persons with Ehlers-Danlos syndromes.

We previously reported increased pain and gastrointestinal (GI) medication prescription claims among persons with Ehlers-Danlos syndromes (EDS) and peripubertal increase in opioid and anti-emetic claims among women with EDS. Herein, we hypothesized a higher proportion of respiratory and co-occurring respiratory and GI medication prescription claims among persons with EDS compared to their matched controls with increases among peripubertal women with EDS. We compared the proportions of respiratory and co-occurring respiratory and GI medication prescription claims among persons with EDS (aged 5-62) against their age-, sex-, state of residence-, and earliest claim date-matched controls using 10 years of private prescription claims data. Prescription claims among persons with EDS versus matched controls were increased for eight medication classes (p < .0001): intranasal/inhaled corticosteroids (ICS) (30.8% vs. 19.0%), oral steroids (30.0% vs. 16.5%), H1-antihistamines (26.2% vs. 12.2%), short-acting beta agonists (22.7% vs. 11.6%), decongestants (21.6% vs. 15.9%), leukotriene modifiers (8.9% vs. 3.6%), ICS/long-acting beta agonists (5.7% vs. 2.9%), muscarinic antagonists (2.5% vs. 0.9%), and co-occurring prescriptions (29% vs. 10%). Our results suggest a critical time window for peripubertal intervention and research and a need to focus on the pathogenesis and clinical evaluation of EDS-specific respiratory and aerodigestive disorders.

Initial description and evaluation of EDS ECHO: An international effort to improve care for people with the Ehlers-Danlos syndromes and hypermobility spectrum disorders.

The Ehlers-Danlos Society Extension for Community Health Care Outcomes (EDS ECHO) is a portfolio of teleconferencing programs developed around the principles and practices of Project ECHO®, aimed at increasing awareness of Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) among clinicians, enhancing their confidence in the assessment and management of these complex conditions, and generating networks of clinicians across specialties. We assessed the outcomes of the first EDS ECHO program, launched in April 2019, with two hub locations: Indiana University Health, Indianapolis, Indiana, USA, and The Royal Society of Medicine, London, UK. Clinicians were surveyed before and 6 months after their participation. We describe the initial outcomes of the first four EDS ECHO programs, each comprising nine sessions. Participants reported increased levels of knowledge and confidence in providing care (93% and 95%, respectively) and an increase in referral network participation (65%). Additionally, 80% reported that their interest in EDS and HSD increased; 57% reporting a great increase. Also, 59% reported a decrease in feeling overwhelmed by EDS and HSD, and nearly half reported a decrease in their level of frustration because of participating in EDS ECHO. Clinicians participating in EDS ECHO programs know more, have more confidence in their ability to provide care, and feel energized by their participation.

Reproductive Factors and Risk of Thyroid Cancer in Women: An Analysis in the Nurses' Health Study II.

BACKGROUND: The incidence of thyroid cancer in women is increasing at an alarming rate, with greatest risk in the reproductive years. Establishing relationships of hormonally related reproductive factors with thyroid cancer has been difficult. We aimed to elucidate potential risk factors for thyroid cancer in a large cohort of women. METHODS: Among 116,228 women in the Nurses' Health Study II followed from 1989 to 2013, 620 cases of thyroid cancer were identified. We examined reproductive and hormone-related factors, including age at menarche, age at menopause, parity, oral contraceptive use, and postmenopausal hormone therapy use. Pregnancy, reproductive years, and months of breastfeeding were used as surrogate markers for exposure to endogenous reproductive hormones. We used multivariable Cox models to calculate relative risks and 95% confidence intervals for the associations between these factors and risk of thyroid cancer. RESULTS: Number of reproductive years of 41 years or more was associated with more than double the risk of thyroid cancer compared with 30 years or fewer (relative risk, 2.20; 95% confidence interval, 1.19-4.06). The other variables analyzed (parity number, months of breastfeeding, age at menarche, menopausal status, and postmenopausal hormone therapy) were not associated with the risk of thyroid cancer. Women who entered menopause at age 45 years or older had a higher risk of thyroid cancer compared with women who entered menopause at a younger age. This result did not reach statistical significance; however, there was a linear trend between later age at menopause and increased risk of thyroid cancer (ptrend = .009). CONCLUSIONS: This study used a unique large, longitudinal dataset to assess thyroid cancer risk factors and potential confounders over an extended time frame. Our key finding suggests increased risk of thyroid cancer may be associated with a variety of indicators of longer reproductive years. The Nurses' Health Study II has provided new insights into the hormonal risks associated with thyroid cancer.

Gastrointestinal medication burden among persons with the Ehlers-Danlos syndromes.

BACKGROUND: The Ehlers-Danlos syndromes (EDSs) are a group of heritable disorders of connective tissue associated with an increased prevalence of both structural and functional GI conditions. METHODS: We used 10 years (2005-2014) of administrative claims data comprised of 4294 people with clinician-diagnosed EDS, aged 5-62 years, and compared their frequency of GI drug prescription claims to their age-, sex-, state of residence-, and earliest claim date-matched controls. We categorized the GI medications into the following groups: acid suppressants, anti-emetics, irritable bowel syndrome drugs, and visceral hypersensitivity (VHS) medications. KEY RESULTS: Compared to controls, a significantly higher proportion of persons with EDS had prescription claims for at least one GI drug group, as well as for drugs in each of the four GI drug groups included in our study. By age-group, 25.7% children and 45.1% adults with EDS had prescription claims for at least one GI drug group compared with only 7.4% and 21.0% of controls, respectively (p < 0.0001). By gender, 44.0% of women and 25.3% of men with EDS had prescription claims for at least one class of GI drugs compared with 19.2% and 9.6% of controls, respectively (p < 0.0001). CONCLUSIONS AND KEY INFERENCES: Predominant medication burden occurs among women with EDS, beginning peri-pubertally for anti-emetics and VHS drugs. High GI medication burden underscores previous evidence that GI dysmotility is common among persons with EDS.

Post-Tonsillectomy Outcomes in Children With and Without Narcotics Prescriptions.

OBJECTIVE: To examine differences in outcomes after tonsillectomy in children who received outpatient narcotics prescriptions compared to those who did not. METHODS: The MarketScan database was analyzed for claims made for 14 days following tonsillectomy/adenotonsillectomy between 2008 and 2012 for privately insured children 1 to 17 years. Post-op bleeding, dehydration, emergency department (ED) visits, readmissions, and mean total costs for the 14 days after tonsillectomy were compared. RESULTS: Of the 294 795 patients included, 60.9% received a narcotic prescription. Acetaminophen/hydrocodone bitartrate was received by 53.2% of the group receiving narcotic drugs, 42.5% received acetaminophen/codeine phosphate, 3.0% received acetaminophen/oxycodone hydrochloride, and 0.5% received oxycodone hydrochloride alone. Children who had been prescribed narcotics had significantly higher percentages of bleeding complications (2.7% vs 2.5%, P < .001), and ED visits (6.8% vs 6.6%, P < .001) within 14 days, but a lower percentage of readmissions (1.0% vs 1.5%, P < .001). No significant difference was observed between groups for dehydration. There were some age-related differences. The mean total health-care costs for 14 days post-op were the same in each group, except for the 4- to 6-year-olds, where the narcotic group had higher costs (US $7060 vs US $5840, P = .006). CONCLUSION: In this large-scale study, we found small but statistically significant differences in outcomes related to use of narcotics. The only outcome that benefitted the narcotics group was a lower readmission rate.

A meta-analysis and systematic review of venous thromboembolism prophylaxis in patients undergoing vascular surgery procedures.

OBJECTIVE: Perioperative venous thromboembolism (VTE) is generally considered preventable. Whereas the non-vascular surgery literature is rich in providing data about the impact of VTE prophylaxis on VTE outcomes, vascular surgery data are relatively sparse on this topic. This study sought to evaluate the evidence for VTE prophylaxis specifically for the population of vascular surgery patients. METHODS: A systematic search was conducted in MEDLINE, Cochrane, and Embase databases in December 2018. Included were studies reporting primary and secondary outcomes for common vascular surgery procedures (open aortic operation, endovascular aneurysm repair [EVAR], peripheral artery bypass, amputation, venous reflux operation). A meta-analysis was performed comparing the patients who did not receive VTE prophylaxis and had VTE complications with patients who developed VTE despite receiving prophylaxis. RESULTS: From 3757 uniquely identified articles, 42 publications met the criteria for inclusion in this review (1 for the category of all vascular operations, 5 for open aortic reconstructions, 2 for EVAR, 1 for open aortic surgery or EVAR, 3 for abdominal or bypass surgery, 2 for peripheral bypass surgery, 2 for amputations, 1 for vascular trauma, and 25 for surgical treatment of superficial venous disease). Five studies met the criteria for inclusion in the meta-analysis. The results demonstrated slightly lower relative risk for development of VTE among patients receiving VTE prophylaxis (relative risk, 0.70; 95% confidence interval, 0.26-1.87). After open aortic reconstruction, the risk of VTE is 13% to 18% and is not reduced by VTE prophylaxis. For EVAR patients, the risk of VTE without prophylaxis is 6%. For patients undergoing peripheral bypass surgery and not receiving therapeutic or prophylactic anticoagulation, the risk of VTE is <2%. For patients undergoing amputations, VTE prophylaxis reduces the risk of VTE. For patients undergoing surgical treatment of superficial venous disease, there is an abundance of literature exploring the utility of VTE prophylaxis, but the evidence is conflicting; some studies demonstrated a benefit, whereas others showed no reduction of VTE with prophylaxis. CONCLUSIONS: Overall, there is a paucity of literature that addresses the effectiveness of VTE prophylaxis specifically in the population of vascular surgery patients. Our meta-analysis of the literature does not demonstrate a statistically significant benefit of VTE prophylaxis among the vascular surgery patients evaluated; however, it does suggest a low incidence of VTE among patients who receive VTE prophylaxis. Clinicians should identify the patients at high risk for development of postoperative VTE as the risk-benefit ratio may favor VTE prophylaxis in a selected group of patients. Clinicians should use their judgment and established VTE risk prediction models to assess VTE risk for patients. Vascular surgeons should consider reporting VTE incidence as a secondary outcome in publications.

Arterial Elasticity in Ehlers-Danlos Syndromes.

Ehlers-Danlos Syndromes (EDS) are a group of heritable disorders of connective tissue (HDCT) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Orthostatic intolerance (OI) is highly prevalent in EDS however mechanisms linking OI to EDS remain poorly understood. We hypothesize that impaired blood pressure (BP) and heart rate control is associated with lower arterial stiffness in people with EDS. Orthostatic vital signs and arterial stiffness were assessed in a cohort of 60 people with EDS (49 female, 36 ± 16 years). Arterial elasticity was assessed by central and peripheral pulse wave velocity (PWV). Central PWV was lower in people with EDS compared to reference values in healthy subjects. In participants with EDS, central PWV was correlated to supine systolic BP (r = 0.387, p = 0.002), supine diastolic BP (r = 0.400, p = 0.002), and seated systolic BP (r = 0.399, p = 0.002). There were no significant correlations between PWV and changes in BP or heart rate with standing (p > 0.05). Between EDS types, there were no differences in supine hemodynamics or PWV measures (p > 0.05). These data demonstrate that increased arterial elasticity is associated with lower BP in people with EDS which may contribute to orthostatic symptoms and potentially provides a quantitative clinical measure for future genotype-phenotype investigations.

Resistance to local anesthesia in people with the Ehlers-Danlos Syndromes presenting for dental surgery.

BACKGROUND: People with the Ehlers-Danlos Syndromes (EDS), a group of heritable disorders of connective tissue, often report experiencing dental procedure pain despite local anesthetic (LA) use. Clinicians have been uncertain how to interpret this apparent LA resistance, as comparison of EDS and non-EDS patient experience is limited to anecdotal evidence and small case series. The primary goal of this hypothesis-generating study was to investigate the recalled adequacy of pain prevention with LA administered during dental procedures in a large cohort of people with and without EDS. A secondary exploratory aim asked people with EDS to recall comparative LA experiences. METHODS: We administered an online survey through various social media platforms to people with EDS and their friends without EDS, asking about past dental procedures, LA exposures, and the adequacy of procedure pain prevention. Among EDS respondents who both received LA and recalled the specific LA used, we compared agent-specific pain prevention for lidocaine, procaine, bupivacaine, mepivacaine, and articaine. RESULTS: Among the 980 EDS respondents who had undergone a dental procedure LA, 88% (n = 860) recalled inadequate pain prevention. Among 249 non EDS respondents only 33% (n = 83) recalled inadequate pain prevention (P < 0.001 compared to EDS respondents). The agent with the highest EDS-respondent reported success rate was articaine (30%), followed by bupivacaine (25%), and mepivacaine (22%). CONCLUSIONS: EDS survey respondents reported nearly three times the rate of LA non-response compared to non-EDS respondents, suggesting that LAs were less effective in preventing their pain associated with routine office dental procedures.

Effect of intra-op morphine on children with OSA undergoing tonsillectomy.

OBJECTIVES: 1. To compare outcomes after tonsillectomy for pediatric patients with obstructive sleep apnea (OSA) given morphine intra-operatively and post operatively compared to those who were not - specifically Recovery Room (RR) time, length of stay (LOS), Emergency Department (ER) visits. STUDY DESIGN: Retrospective case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: All children between 1 and 17 years old who had undergone tonsillectomy in a single institution from 2013 to 2016. Comparison between children who had received morphine intra-operatively was made for outcomes. RESULTS: 556 patients were included, 73 patients had morphine intraoperatively and 483 did not; these latter children were older (8.8 vs 6.5 years, P < 0.001), and had fewer episodes of obstructive apnea and hypopnea (AHI 4.47 vs 10.15, p = 0.003) than children who did not receive intra-op morphine. There were no differences in co-morbidities including asthma, whether they had a sleep study, time in the operating room, emergence time, RR time, airway complications, IMC/PICU admission for respiratory distress, ER visits, readmissions, bleeding or post-discharge nurse phone calls. There was a longer LOS (25.9 vs 21.4 h, P = 0.011) for the group receiving intra-op morphine. CONCLUSION: Children with OSA who receive intra-op morphine have a longer LOS suggesting that its use should be examined more closely in this population.

Use of Cluster Analysis to Delineate Symptom Profiles in an Ehlers-Danlos Syndrome Patient Population.

CONTEXT: The Ehlers-Danlos Syndromes (EDSs) are a set of rare heritable disorders of connective tissue, characterized by defects in the structure and synthesis of extracellular matrix elements that lead to a myriad of problems including joint hypermobility and skin abnormalities. Because EDS affects multiple organ systems, defining clear boundaries and recognizing overlapping clinical features shared by disease phenotypes is challenging. OBJECTIVES: The objective of this study was to seek evidence of phenotypic subgroups of patients with distinctive symptom profiles and describe these resulting subgroups. METHODS: Data were extracted from a repository assembled 2001-2013 by the National Institute on Aging Intramural Research Program. Agglomerative hierarchical clustering was used to form distinct subgroups of patients with respect to the domains of pain, physical and mental fatigue, daytime sleepiness, and nighttime sleep. Domains were selected based on literature review, clinician expertise, and guidance from patient advisors. RESULTS: One hundred seventy-five patients met all inclusion criteria. Three subgroups were identified. The Pain Dominant subgroup (39 patients) had the highest mean pain values, but lowest mean values of other symptoms. The High Symptom Burden subgroup (71 patients) had high mean values in all domains. The Mental Fatigue subgroup (65 patients) had a high mean value for mental fatigue and daytime sleepiness, but a lower mean value for pain. CONCLUSION: The subgroups aligned with clinical observation of the heterogeneous nature of EDS, with overlapping symptoms between subtypes and a wide divergence in degree of symptoms within subtypes. This exploratory study helps characterize the various phenotypes and comorbidities of patients with EDS.

Postoperative Bleeding Associated with Ibuprofen Use after Tonsillectomy: A Meta-analysis.

OBJECTIVE: To better quantify the risk of ibuprofen-associated posttonsillectomy hemorrhage (PTH). DATA SOURCES: PUBMED/MEDLINE, Web of Science, and Cochrane Clinical Trials Database. REVIEW METHOD: Literature searches were performed for English-language publications containing the terms tonsillectomy, ibuprofen, and tonsillectomy from database inception to May 2017. Human clinical trials, prospective cohort studies, and retrospective cohort studies related to tonsillectomy, ibuprofen use, and posttonsillectomy hemorrhage among pediatric patients were selected. Electronic searches revealed 151 studies, of which 12 were deemed eligible for analysis. Studies were weighted according to level of evidence and risk of bias. RESULTS: Pooling of results across all studies showed a statistically significant increase in PTH among the patients taking ibuprofen (odds ratio, 1.38; 95% confidence interval, 1.11-1.72). The I2 statistic of 20.8% demonstrates overall low study heterogeneity and good comparability of the results. CONCLUSION: Our meta-analysis of available cohort studies and randomized controlled trials (RCTs) shows possible increased tendency to PTH with the use of ibuprofen. This has not been demonstrated in other studies and systematic reviews because their analyses were limited by use of multiple nonsteroidal anti-inflammatory drugs and inclusion of studies limited to the perioperative period and low sample size. However, the current analysis is limited due to inclusion of many retrospective cohort studies with unclear follow-up and no blinding. Further RCTs will be required to investigate this trend toward increased PTH.

Heritable disorders of connective tissue: Description of a data repository and initial cohort characterization.

We describe a data repository on heritable disorders of connective tissue (HDCT) assembled by the National Institutes of Health's National Institute on Aging (NIA) Intramural Research Program between 2001 and 2013. Participants included affected persons with a wide range of heritable connective tissue phenotypes, and unaffected family members. Elements include comprehensive history and physical examination, standardized laboratory data, physiologic measures and imaging, standardized patient-reported outcome measures, and an extensive linked biorepository. The NIA made a commitment to make the repository available to extramural investigators and deposited samples at Coriell Tissue Repository (N = 126) and GenTAC registry (N = 132). The clinical dataset was transferred to Penn State University College of Medicine Clinical and Translational Science Institute in 2016, and data elements inventoried. The consented cohort of 1,009 participants averaged 39 ± 18 years (mean ± SD, range 2-95) at consent; gender distribution is 71% F and 83% self-report Caucasian ethnicity. Diagnostic categories include Ehlers-Danlos syndrome (classical N = 50, hypermobile N = 99, vascular N = 101, rare types and unclassified N = 178), Marfan syndrome (N = 33), Stickler syndrome (N = 60), fibromuscular dysplasia (N = 135), Other HDCT (N = 72). Unaffected family members (N = 218) contributed DNA for the molecular archive only. We aim to develop further discrete data from unstructured elements, analyze multisymptom HDCT manifestations, encourage data use by other researchers and thereby better understand the complexity of these high-morbidity conditions and their multifaceted effects on affected persons.