Novel assessment of leukocyte-rich platelet-rich plasma on functional and patient-reported outcomes in knee osteoarthritis: a pilot study.

Background: Leukocyte-rich platelet-rich plasma (LR-PRP) has demonstrated to be beneficial for patients with knee osteoarthritis (KOA); however, reliable objective end points to accurately assess its therapeutic effects is lacking. Aim: To investigate the efficacy of LR-PRP as assessed by functional and patient-reported outcomes at early time points (6 weeks). Materials & methods: We conducted a prospective cohort study in 12 patients with diagnosed KOA (Kellgren Lawrence score of II-III), who underwent a single ultrasound-guided LR-PRP injection. Results: There was significant improvement in timed up and go, pain and quality of life scales and balance parameters. There were nonsignificant improvements in range of motion and gait parameters. Conclusion: LR-PRP demonstrates efficacy in meaningful end points for functional and patient-reported outcomes at early time points in patients with KOA.

Assessment of longitudinal bone growth in osteogenesis imperfecta using metacarpophalangeal pattern profiles.

OBJECTIVE: Osteogenesis imperfecta (OI) is commonly associated with short stature, but it is unclear whether this is exclusively secondary to fractures and bone deformities or whether there is a primary defect in longitudinal bone growth. As metacarpal and phalangeal bones are rarely affected by fractures and deformities, any length deficits in these bones should reflect a direct disease effect on longitudinal growth. This study therefore assessed the relationship of hand bone length with clinical OI type and genotype. STUDY DESIGN: Prospective study. RESULTS: The length of all 19 tubular hand bones were measured in 144 individuals (age 6 to 57 years; 68 female) who had OI caused by COL1A1 or COL1A2 variants. Measurements of bone length were converted to z-scores using published reference data. Bone length was mostly normal in OI type I but was significantly decreased in OI types III and IV. Mean hand bone length z-score (i.e., the average length z-score of all 19 bones of a hand) was -0.2 for OI type I, -2.9 for OI type III and -1.2 for OI type IV. Mean hand bone length z-score was positively associated with height z-score (r2 = 0.65, P < 0.001). Regarding genotype-phenotype correlations, mean hand bone length z-score was close to 0 in individuals with COL1A1 mutations leading to haploinsufficiency but were significantly lower in the presence of mutations leading to triple-helical glycine substitutions in either the alpha 1 or alpha 2 chain of collagen type I. CONCLUSION: COL1A1 and COL1A2 mutations affect bone growth not only by inducing fractures and bone deformities, but also through longitudinal growth deficits in bones that do not fracture or deform.

Clinical Application of Genome and Exome Sequencing as a Diagnostic Tool for Pediatric Patients: a Scoping Review of the Literature.

PURPOSE: Availability of clinical genomic sequencing (CGS) has generated questions about the value of genome and exome sequencing as a diagnostic tool. Analysis of reported CGS application can inform uptake and direct further research. This scoping literature review aims to synthesize evidence on the clinical and economic impact of CGS. METHODS: PubMed, Embase, and Cochrane were searched for peer-reviewed articles published between 2009 and 2017 on diagnostic CGS for infant and pediatric patients. Articles were classified according to sample size and whether economic evaluation was a primary research objective. Data on patient characteristics, clinical setting, and outcomes were extracted and narratively synthesized. RESULTS: Of 171 included articles, 131 were case reports, 40 were aggregate analyses, and 4 had a primary economic evaluation aim. Diagnostic yield was the only consistently reported outcome. Median diagnostic yield in aggregate analyses was 33.2% but varied by broad clinical categories and test type. CONCLUSION: Reported CGS use has rapidly increased and spans diverse clinical settings and patient phenotypes. Economic evaluations support the cost-saving potential of diagnostic CGS. Multidisciplinary implementation research, including more robust outcome measurement and economic evaluation, is needed to demonstrate clinical utility and cost-effectiveness of CGS.

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.

BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives.

UNLABELLED: Patients and families living with metabolic disorders face challenging dietary and drug treatment regimens. On the hypothesis that poor palatability, volume and frequency of drug/formula administration contribute to treatment non-adherence and hyperammonemic episodes, a survey was conducted of patient, caregiver (CG) and physician perspectives on treatments used in urea cycle disorders (UCD). METHODS: A paper and online survey assessed experience with UCD medications, medical foods and dietary supplements. RESULTS: 25 physicians, 52 adult patients and 114 CG responded. In 2009, the most common UCD-specific intervention reported by patients included sodium phenylbutyrate (60%), followed by l-citrulline (46%), amino acid medical foods (15%), l-arginine preparations (18%), and sodium benzoate (8%). Only 36% of patients reported experiencing no hyperammonemic episodes in the last 2 years. The most commonly reported cause of hyperammonemic episodes was infection or other acute illnesses, followed by dietary indiscretion, side effects of medications, and drug non-adherence. Most patients, caregivers and physicians (> 75%) ranked nitrogen-scavenging medications, l-citrulline, l-arginine, and medical foods as "effective" or "very effective." Non-adherence was common (e.g. 18% of patients admitted to missing sodium phenylbutyrate "at least once a week" and "at least one a day"). Barriers to adherence included taste of medications, frequency of drug administration, number of pills, difficulty swallowing pills, side effects, forgetting to take medications, and high cost. Strategies to mitigate the gastrointestinal side effects of medications included the use of gastric tubes and acid reflux medications. Physicians indicated that 25% and 33% of pediatric and adult patients, respectively, were given less than the recommended dose of sodium phenylbutyrate due to concerns of tolerance, administration, and cost. CONCLUSIONS: Despite positive views of their effectiveness, respondents found medications, medical foods and dietary supplements difficult to take and viewed adherence as inadequate, thus contributing to hyperammonemic episodes.

Genotype-phenotype correlation--promiscuity in the era of next-generation sequencing.

Newly cost-effective next-generation sequencing has led to an explosion of discoveries of novel genetic mutations that reveal the rampant "promiscuity" of genotype-phenotype relationships. Such discoveries should ultimately revolutionize clinical care.

Assessment of bone mineral status in children with Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with skeletal involvement. It is caused by mutations in fibrillin1 (FBN1) gene resulting in activation of TGF-ß, which developmentally regulates bone mass and matrix properties. There is no consensus regarding bone mineralization in children with MFS. Using dual-energy X-ray absorptiometry (DXA), we evaluated bone mineralization in 20 children with MFS unselected for bone problems. z-Scores were calculated based on age, gender, height, and ethnicity matched controls. Mean whole body bone mineral content (BMC) z-score was 0.26±1.42 (P=0.41). Mean bone mineral density (BMD) z-score for whole body was -0.34±1.4 (P=0.29) and lumbar spine was reduced at -0.55±1.34 (P=0.017). On further adjusting for stature, which is usually higher in MFS, mean BMC z-score was reduced at -0.677±1.37 (P=0.04), mean BMD z-score for whole body was -0.82±1.55 (P=0.002) and for lumbar spine was -0.83±1.32 (P=0.001). An increased risk of osteoporosis in MFS is controversial. DXA has limitations in large skeletons because it tends to overestimate BMD and BMC. By adjusting results for height, age, gender, and ethnicity, we found that MFS patients have significantly lower BMC and BMD in whole body and lumbar spine. Evaluation of diet, exercise, vitamin D status, and bone turnover markers will help gain insight into pathogenesis of the reduced bone mass. Further, larger longitudinal studies are required to evaluate the natural history, incidence of fractures, and effects of pharmacological therapy.

Supporting business continuity during a highly pathogenic avian influenza outbreak: a collaboration of industry, academia, and government.

Since 2006, a collaborative group of egg industry, state, federal, and academia representatives have worked to enhance preparedness in highly pathogenic avian influenza (HPAI) planning. The collaborative group has created a draft egg product movement protocol, which calls for realistic, science-based contingency plans, biosecurity assessments, commodity risk assessments, and real-time reverse transcriptase-PCR testing to support the continuity of egg operations while also preventing and eradicating an HPAI outbreak. The work done by this group serves as an example of how industry, government, and academia can work together to achieve better preparedness in the event of an animal health emergency. In addition, in the event of an HPAI outbreak in domestic poultry, U.S. consumers will be assured that their egg products come from healthy chickens.