A Methodology for Successfully Producing Global Translations of Patient Reported Outcome Measures for Use in Multiple Countries

The production of accurate and culturally relevant translations of patient reported outcome (PRO) measures is essential for the success of international clinical trials. Although there are many reports in publication regarding the translation of PRO measures, the techniques used to produce single translations for use in multiple countries (global translations) are not well documented. This article addresses this apparent lack of documentation and presents the methodology used to create global translations of the Chronic Liver Disease Questionnaire—Hepatitis C Virus (CLDQ-HCV). The challenges of creating a translation for use in multiple countries are discussed, and the criteria for a global translation project explained. Based on a thorough translation and linguistic validation methodology including a concept elaboration, multiple forward translations, two back translations, reviews by in-country clinicians and the instrument developer, pilot testing in each target country and multiple sets of proofreading, the key concept of the global translation methodology is consistent international harmonization, achieved through the involvement of linguists from each target country at every stage of the process. This methodology enabled the successful resolution of the translation issues encountered, and resulted in consistent translations of the CLDQ-HCV that were linguistically and culturally appropriate for all target countries.     

Detection of mosaic variants using genome sequencing in a large pediatric cohort

The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.     

A pilot study of home-based genetic testing completion rate in telegenetics cancer clinics in West Virginia Appalachia

Telegenetics has shifted some genetic testing performance to the patient's own home, with the patient collecting his/her own sample. Little is known regarding the rate of test completion of such home-based genetic testing. This study compared the completion rate of home-based genetic tests before and after a reminder system was implemented. In the pre-reminder group, we reviewed medical records for patients who were seen via telegenetics and agreed to complete genetic testing using an at-home test kit. In the reminder group, a prospective analysis of the genetic test completion rate was performed taking a clinical quality improvement approach where three reminders were provided for patients who had not submitted their at-home genetic testing. Our study included 94 patients' records: 46 pre-reminders and 48 reminders. The lab received 24 patient samples (52.2%) in the pre-reminder group. In the reminder group, 30 patients returned their kits (62.5%). Despite a higher percentage of patients completing their test in the reminder group, there was no statistically significant difference between the pre-reminder and reminder groups. The rate of test completion in our pilot test was statistically similar between the two groups, but the reminder group was trending toward a higher percent of completion which may be clinically meaningful.     

Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals

Phelan-McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array-CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at-risk subjects and molecular targets for novel treatment approaches.     

Postoperative Urinary Retention after Benign Gynecologic Surgery with a Liberal versus Strict Voiding Protocol

Study ObjectiveSurgeons employ various methods for evaluating what is considered a common occurrence after gynecologic operations, postoperative urinary retention (POUR). Few have reported the incidence of POUR with a liberal voiding protocol (no requirement to void before discharge). The primary objective of this study was to evaluate the risk of POUR after benign gynecologic surgery, comparing a liberal voiding protocol with more strict voiding protocols. Secondary outcomes included length of hospital stay (LOS) and urinary tract infection (UTI).DesignRetrospective cohort study.SettingQuaternary-care academic hospital in the United States.PatientsPatients undergoing hysterectomy or myomectomy at Cedars-Sinai Medical Center from August 2017 through July 2018 (n = 652). Cases involving incontinence operations, correction of pelvic organ prolapse, malignancy, or peripartum hysterectomy were excluded.InterventionsHysterectomy, myomectomy.Measurements and Main ResultsPOUR, defined as the need for recatheterization within 24 hours of catheter removal, along with UTI and LOS were compared between liberal and strict voiding protocols. A subgroup analysis was performed for those undergoing minimally invasive surgery (MIS). A total of 303 (46.5%) women underwent surgery with a liberal postoperative voiding protocol and 349 (53.5%) women with a strict voiding protocol. Overall, the incidence of POUR was low at 3.8% and not different between the groups (2.6% liberal vs. 4.9% strict, p = .14). UTIs also occurred infrequently (2.8% overall, 2.6% liberal vs. 2.9% strict, p = .86). Similar results were seen specifically among those who underwent MIS: POUR (3.7% overall, 2.8% liberal vs. 5.3% strict, p = .17) and UTI (3.3% overall, 2.4% liberal vs. 4.7% strict, p = .28). The median LOS (interquartile range) was much shorter for MIS patients with a liberal voiding protocol (median 15 hours overall [interquartile range 15 hours], 9 [4] hours liberal vs. 36 [34] hours strict, p <.01). Among those discharged the same day (72.6% of the MIS cases), patients with a liberal voiding protocol had a significantly shorter LOS than those with strict (mean [standard deviation] 9.4 [2.5] hours vs. 10.6 [35] hours, p <.01). Postoperative complications occurred less frequently in those with MIS procedures (11.8% in MIS vs. 20.2% in laparotomies, p <.01) and those with liberal voiding protocols (11.2% liberal vs. 16.9% strict p = .04).ConclusionOverall, POUR occurs infrequently after major benign gynecologic surgery and does not differ between those with liberal and strict voiding protocols. Our data suggest that same-day discharge after MIS hysterectomy and myomectomy without a requirement to void does not increase the risk of POUR and shortens LOS. Eliminating voiding protocols after these procedures may facilitate greater efficiency in the postanesthesia recovery unit and may contribute to enhanced recovery after surgery protocols.     

Quality of Life after Laparoscopic and Open Abdominal Myomectomy

Study ObjectiveTo evaluate the baseline and postoperative changes in quality of life and symptom-severity scores in women undergoing laparoscopic or open abdominal myomectomy for symptomatic myomas.DesignProspective cohort study of patients choosing myomectomy for symptomatic uterine myomas.SettingAcademic medical center.PatientsA total of 143 women enrolled in the study. Of these, 80 women completed both a preoperative questionnaire and at least 1 postoperative questionnaire between 6 and 27 months after surgery.InterventionsA total of 52 women had open abdominal myomectomy, and 28 had laparoscopic myomectomy between October 2014 and September 2017.Measurements and Main ResultsThe results of the Uterine Fibroid Symptom and Health-Related Quality-of-Life Questionnaire were compared before and after laparoscopic or open myomectomy. Women undergoing open abdominal myomectomy had larger and more numerous myomas than women undergoing laparoscopic myomectomy. Baseline quality-of-life scores were less adversely affected for women having laparoscopic myomectomy (mean [standard deviation], 57 [24] laparoscopic vs 43 [19] open abdominal, p = .01). However, baseline symptom-severity scores were statistically similar (49 [22] for laparoscopic and 57 [20] for open abdominal, p = .08) approaches. Six to 12 months after surgery, both open abdominal and laparoscopic surgeries provided excellent and similar improvements in symptom-severity and quality of life (postoperative symptoms severity scores, mean [standard deviation], 20 [14] laparoscopic vs 13 [11] open abdominal, p = .24 and quality-of-life scores, mean [standard deviation], 91 [16] laparoscopic vs 88 [17] open abdominal, p = .49). These improvements were sustained for women who returned questionnaires up to 27 months of follow-up.ConclusionWomen with symptomatic myomas have a compromised quality of life, and they experience a similarly dramatic improvement in quality of life and decrease in symptom-severity after both laparoscopic and open abdominal myomectomies.     

针刺治疗疼痛

1997年,美国国立卫生研究院共识委员会作出针刺疗法可有效缓解术后牙痛的结论,但未得出该疗法在其他类型疼痛治疗中有效的结论。在过去10年,美国人对针刺疗法的兴趣和应用大大增加,并开展了很多有关针刺疗法有效性的研究。     

Assessment of immunotoxicity in female Fischer 344/N and Sprague Dawley rats and female B6C3F1 mice exposed to hexavalent chromium via the drinking water

Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B₆C₃F₁ mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516?ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250?ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250?ppm B₆C₃F₁ mice and 516?ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516?ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5–7%) decreased in 250?ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on the immune system in both rats and mice.     

PulmoStent: <Emphasis Type="Italic">In Vitro</Emphasis> to <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of a Tissue Engineered Endobronchial Stent

Currently, there is no optimal treatment available for end stage tumour patients with airway stenosis. The PulmoStent concept aims on overcoming current hurdles in airway stenting by combining a nitinol stent with a nutrient-permeable membrane, which prevents tumour ingrowth. Respiratory epithelial cells can be seeded onto the cover to restore mucociliary clearance. In this study, a novel hand-braided dog bone stent was developed, covered with a polycarbonate urethane nonwoven and mechanically tested. Design and manufacturing of stent and cover were improved in an iterative process according to predefined requirements for permeability and mechanical properties and finally tested in a proof of concept animal study in sheep for up to 24 weeks. In each animal two stents were implanted, one of which was cell-seeded by endoscopic spraying in situ. We demonstrated the suitability of this membrane for our concept by glucose transport testing and in vitro culture of respiratory epithelial cells. In the animal study, no migration occurred in any of the twelve stents. There was only mild granulation tissue formation and tissue reaction; no severe mucus plugging was observed. Thus, the PulmoStent concept might be a step forward for palliative treatment of airway stenosis with a biohybrid stent device.