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Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants’ clinical features and family history.

Secondary findings (SFs) identified through genomic sequencing (GS) can offer a wide range of health benefits to patients. Resource and capacity constraints pose a challenge to their clinical management; therefore, clinical workflows are needed to optimise the health benefits of SFs. In this paper, we describe a model we created for the return and referral of all clinically significant SFs, beyond medically actionable results, from GS. As part of a randomised controlled trial evaluating the outcomes and costs of disclosing all clinically significant SFs from GS, we consulted genetics and primary care experts to determine a feasible workflow to manage SFs. Consensus was sought to determine appropriate clinical recommendations for each category of SF and which clinician specialist would provide follow-up care. We developed a communication and referral plan for each category of SFs. This involved referrals to specialised clinics, such as an Adult Genetics clinic, for highly penetrant medically actionable findings. Common and non-urgent SFs, such as pharmacogenomics and carrier status results for non-family planning participants, were directed back to the family physician (FP). SF results and recommendations were communicated directly to participants to respect autonomy and to their FPs to support follow-up of SFs. We describe a model for the return and referral of all clinically significant SFs to facilitate the utility of GS and promote the health benefits of SFs. This may serve as a model for others returning GS results transitioning participants from research to clinical settings.

Electronic consultation (eConsult) is a freely-available secure online platform connecting primary care providers (PCPs) to geneticists. Our purpose was to determine whether eConsult is effective in improving genetics service delivery in primary care.

Alternative models of genetic counseling are needed to meet the rising demand for genomic sequencing. Digital tools have been proposed as a method to augment traditional counseling and reduce burden on professionals; however, their role in delivery of genetic counseling is not established. This study explored the role of the Genomics ADvISER, a digital decision aid, in delivery of genomic counseling.

Most secondary genomic findings (SFs) fall in the scope of primary care practice. However, primary care providers' (PCPs) capacity to manage these findings is not well understood. We explored PCPs’ views and experiences of managing SFs through a qualitative study. PCPs participated in semi-structured interviews about SFs from a patient in their practice or a hypothetical patient. The interpretive descriptive methodology was used to analyze transcripts thematically through constant comparison. Fifteen family physicians from Ontario, Canada participated (ten females; 6–40 years in practice across community and academic settings). PCPs made sense of SFs through the lens of actionability: they actively looked for clinical relevance by considering a wide range of immediate and future actions, including referrals, genetic testing, screening, lifestyle changes, counseling about family planning, informing family members, future medication choice, increased vigilance/surveillance, and managing results in the electronic medical record. PCPs saw clinical actionability as the main benefit mitigating the potential harms of learning SFs, namely patient anxiety and unnecessary investigations. PCPs conceptualized actionability more broadly than it is traditionally defined in medical genetics. Further research will be needed to determine if PCPs’ emphasis on actionability conflicts with patients’ expectations of SFs and if it leads to overutilization of healthcare resources.

To evaluate the effectiveness of the Genomics ADvISER (www.genomicsadviser.com) decision aid (DA) for selection of secondary findings (SF), compared with genetic counseling alone.

Widespread, quality genomics education for health professionals is required to create a competent genomic workforce. A lack of standards for reporting genomics education and evaluation limits the evidence base for replication and comparison. We therefore undertook a consensus process to develop a recommended minimum set of information to support consistent reporting of design, development, delivery, and evaluation of genomics education interventions.

Patient care involving genetics is challenging for nongenetics health-care providers. Clinical decision support (CDS) tools are a potential solution because they provide patient-specific risk assessments and/or management recommendations. This systematic review synthesized evidence on whether using CDS tools resulted in appropriate changes in genetics-related patient management made by nongenetics health-care providers.

To investigate associations of adolescents’ time spent on homework/studying with nocturnal time for sleep and depression symptoms, in a competitive academic environment.

There is growing impetus to include measures of personal utility, the nonmedical value of information, in addition to clinical utility in health technology assessment (HTA) of genomic tests such as genomic sequencing (GS). However, personal utility and clinical utility are challenging to define and measure. This study aimed to explore what drives patients’ preferences for hypothetically learning medically actionable and non-medically actionable secondary findings (SF), capturing clinical and personal utility; this may inform development of measures to evaluate patient outcomes following return of SF. Semi-structured interviews were conducted with adults with a personal or family cancer history participating in a trial of a decision aid for selection of SF from genomic sequencing (GS) (www.GenomicsADvISER.com). Interviews were analyzed thematically using constant comparison. Preserving health-related and non-health-related quality of life was an overarching motivator for both learning and not learning SF. Some participants perceived that learning SF would help them “have a good quality of life” through informing actions to maintain physical health or leading to psychological benefits such as emotional preparation for disease. Other participants preferred not to learn SF because results “could ruin your quality of life,” such as by causing negative psychological impacts. Measuring health-related and non-health-related quality of life may capture outcomes related to clinical and personal utility of GS and SF, which have previously been challenging to measure. Without appropriate measures, generating and synthesizing evidence to evaluate genomic technologies such as GS will continue to be a challenge, and will undervalue potential benefits of GS and SF.

•Adolescents are not immune to sleep loss-induced neurobehavioral impairment.•Daytime napping can alleviate neurobehavioral deficits during chronic sleep loss.•What constitutes optimal sleep may vary across individuals.•Personalized sleep recommendations may be facilitated by smartphones and wearables.

Purpose: To evaluate the effectiveness of the Genomics ADvISER (www.genomicsadviser.com) decision aid (DA) for selection of secondary findings (SF), compared with genetic counseling alone. Methods: A randomized controlled trial (RCT) was conducted to evaluate whether the Genomics ADvISER is superior to genetic counseling when hypothetically selecting SF. Participants were randomized to use the DA followed by discussion with a genetic counselor, or to genetic counseling alone. Surveys were administered at baseline and post-intervention. Primary outcome was decisional conflict. Secondary outcomes were knowledge, preparation for, and satisfaction with decision-making, anxiety, and length of counseling session. Results: Participants (n?=?133) were predominantly White/European (74%), female (90%), and =50 years old (60%). Decisional conflict (mean difference 0.05; P?=?0.60), preparation for decision-making (0.17; P?=?0.95), satisfaction with decision (–2.18; P?=?0.06), anxiety (0.72; P?=?0.56), and knowledge of sequencing limitations (0.14; P?=?0.70) did not significantly differ between groups. However, intervention participants had significantly higher knowledge of SF (0.39; P?<?0.001) and sequencing benefits (0.97; P?=?0.01), and significantly shorter counseling time (24.40?minutes less; P?<?0.001) Conclusions: The Genomics ADvISER did not decrease decisional conflict but reduced counseling time and improved knowledge. This decision aid could serve as an educational tool, reducing in-clinic time and potentially health care costs.

Shortened sleep has negative consequences on adolescents’ well-being. The present study evaluated an interactive school-based sleep education program (SEP) aimed at increasing adolescent sleep duration.

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Guidelines recommend that providers engage patients in shared decision-making about receiving incidental results (IR) prior to genomic sequencing (GS), but this can be time-consuming, given the myriad of IR and variation in patients’ preferences. We aimed to develop patient profiles to inform pre-test counseling for IR. We conducted semi-structured interviews with participants as a part of a randomized trial of the GenomicsADvISER.com, a decision aid for selecting IR. Interviews explored factors participants considered when deliberating over learning IR. Interviews were analyzed by thematic analysis and constant comparison. Participants were mostly female (28/31) and about half of them were over the age of 50 (16/31). We identified five patient profiles that reflect common contextual factors, attitudes, concerns, and perceived utility of IR. Information Enthusiasts self-identified as “planners” and valued learning most or all IR to enable planning and disease prevention because “knowledge is power”. Concerned Individuals defined themselves as “anxious,” and were reluctant to learn IR, anticipating negative psychological impacts from IR. Contemplators were discerning about the value and limitations of IR, weighing health benefits with the impacts of not being able to “un-know” information. Individuals of Advanced Life Stage did not consider IR relevant for themselves and primarily considered their implications for family members. Reassurance Seekers were reassured by previous negative genetic test results which shaped their expectations for receiving no IR: “hopefully [GS will] be negative, too. And then I can rest easy”. These profiles could inform targeted counseling for IR by providing a framework to address common values, concerns. and misconceptions.

Background: Peptide-based therapeutics offer a unique avenue for the development of novel agents for the treatment of diabetes mellitus including α-glucosidase inhibitors. The peptide, SQSPA, was reported to possess to α -glucosidase inhibitory activity in addition to resistance to Gastrointestinal Tract (GIT) digestion. Methods: In this study, the in silico and in vitro structure-activity analyses of the peptide was conducted using alanine scanning to identify key amino acid residues. Results: The alanine scanning led to four analogs viz; AQSPA, SASPA, SQAPA and SQSAA which were GIT stable. Initially, the peptides were subjected to molecular docking on human α- glucosidase and α -amylase where the binding affinities to the enzymes were in the order; AQSPA>SASPA>SQSPA>SQAPA> SQSAA and AQSPA>SQSAA>SASPA>SQSPA> SQAPA, respectively. Hydrogen bond were important for the binding of all peptides but SASPA and AQSPA had the highest hydrogen bonds interactions with the α-glucosidase and α-amylase, respectively. In vitro analysis revealed that the α -glucosidase and α-amylase inhibitory activities of the peptides were in the order AQSPA>SQSPA>SQAPA>SASPA>SQSAA and AQSPA>SASPA> SQAPA>SQSPA>SQSAA, respectively. Using inhibition kinetics, SQSPA was a mixed inhibitor of α-glucosidase while AQSPA, SQAPA and SQSAA showed non-competitive inhibition. For α- amylase inhibition, SQSPA was a non-competitive inhibitor while AQSPA and SQSAA were mixed inhibitors; SASPA and SQAPA showed uncompetitive inhibition. Conclusion: The results indicated that P4 and Q2 are important requirements for the α-glucosidase and α-amylase inhibitory activities of the parent peptide, SQSPA. Furthermore, alanine scanning has led to the design of a novel α-glucosidase inhibitory peptide, AQSPA, with increased activities.

Digital tools are increasingly incorporated into genetics practice to address challenges with the current model of care. Yet, genetics providers’ perspectives on digital tool use are not well characterized.

We sought to explore patient-reported utility of all types of cancer results from genomic sequencing (GS).

Prospective consecutively enrolled cohort.

In spinal deformity surgery, posterior column osteotomies (PCOs) are used to increase spinal flexibility and permit greater deformity correction, while avoiding the morbidity of anterior column surgery. Complications related to use of PCOs have been well characterized in adults; however, there is a paucity of information in the pediatric population.

Study Design: Prospective consecutively enrolled cohort. Objectives: To evaluate paraspinal muscle concentration of intravenously administered vancomycin, at predetermined time points, during posterior spinal fusion (PSF) with instrumentation in neuromuscular scoliosis (NMS). Summary: Surgical site infection (SSI) after PSF for NMS can be a devastating complication, which may lead to prolonged antibiotic use, multiple additional surgical procedures, pseudarthroses, and sepsis. Because of significant morbidity of SSIs in NMS, the prophylactic use of vancomycin has been adopted at our institution as standard wound prophylaxis, despite any high-level evidence of its efficacy. Methods: A prospective study of 20 patients who underwent definitive PSF for NMS and received vancomycin infusion preoperatively per institutional protocol. Serum levels were obtained immediately after infusion, at surgical incision, and then at 1, 2, and 4 hours post incision. Muscle tissue samples were simultaneously obtained at incision and at 1, 2, and 4 hours post incision. Samples were analyzed by a validated liquid chromatography–tandem mass spectrometry method. Results: 10 males and 10 females with a mean age of 14+11 years (9–20 years) received a mean infusion of 15.0 mg/kg vancomycin. Mean serum levels were 26.7 µg/mL after infusion, 18.1 at incision, 13.2 at 1 hour, 11.8 at 2 hours, and 7.6 at 4 hours post infusion. Mean muscle levels were 0.5 µg/mL at incision, 0.6 at 1 hour, 0.5 at 2 hours, and 0.7 at 4 hours post infusion. Mean serum levels reached minimum inhibitory concentration (MIC) for Staphylococcus aureusat incision and at all timepoints during surgery. Mean muscle vancomycin levels never reached MIC. No patients had any cardiac or kidney disease, and all patients had normal kidney function according to their preoperative laboratory values. Conclusions: Using accepted guidelines for the administration of intravenous vancomycin preoperatively, serum levels reached MIC at incision and at all timepoints tested during PSF for neuromuscular scoliosis. At no timepoint tested did muscle levels reach MIC. Level of Evidence: Level II.

Background: In spinal deformity surgery, posterior column osteotomies (PCOs) are used to increase spinal flexibility and permit greater deformity correction, while avoiding the morbidity of anterior column surgery. Complications related to use of PCOs have been well characterized in adults; however, there is a paucity of information in the pediatric population. Methods: A single-surgeon retrospective analysis was completed of 484 PCOs in 142 patients (average age: 14.5 years) undergoing spinal deformity surgery. All surgeries were completed by a standard posterior approach using a midline incision and dual-rod, pedicle screw constructs. PCO-related complications were recorded (intraoperative monitoring alerts, postoperative neurologic deficit, dural tear/violations, cerebrospinal fluid [CSF] leak, pseudarthrosis, etc.) and analyzed by diagnosis (idiopathic, congenital, neuromuscular, syndromic). Results: The diagnoses for the 142 patients were idiopathic (103 patients), neuromuscular (23 patients), syndromic (14 patients), and congenital (2 patients). In a subset of 87 patients with 2-year radiographic follow-up, the preoperative major coronal Cobb measurement was 75.5° ± 17.6°, which corrected to 34.9° ± 17.5° postoperatively and 37.8° ± 17.9° at last follow-up (p < .0001, p < .0001). Complications evaluated were postoperative neurologic deficit (0% of patients, 0/142), dural tears/violations at site of PCO (0.4% of PCOs, 2/484), CSF leak (0% of patients, 0/142), and pseudoarthrosis at site of PCO (0% of PCOs, 0/290). Conclusion: The overall frequency of complications related to PCOs was 0.4% (0.4% dural tears/violations) with 0% postoperative neurologic deficit, CSF leak, or pseudarthrosis. Based on these data, PCOs appear to be a safe technique in pediatric spine deformity surgery, with a low rate of technique-related complications. Study Design: Retrospective case series. Objectives: To report the frequency of posterior column osteotomy complications (neurologic deficit, dural tear, cerebrospinal fluid leak, and pseudarthrosis) in pediatric patients undergoing spinal deformity surgery. Level of Evidence: Level IV.

Thymic regulatory T cells (tTregs) and induced regulatory T cells (iTregs) suppress murine acute graft‐versus‐host disease (GVHD). Previously, we demonstrated that the plasmacytoid dendritic cell indoleamine 2,3‐dioxygenase (IDO) fosters the in vitrodevelopment of human iTregs via tryptophan depletion and kynurenine (Kyn) metabolites. We now show that stimulation of naïve CD4+T cells in low tryptophan (low Trp) plus Kyn supports human iTreg generation. In vitro, low Trp + Kyn iTregs and tTregs potently suppress T effector cell proliferation equivalently but are phenotypically distinct. Compared with tTregs or T effector cells, bioenergetics profiling reveals that low Trp + Kyn iTregs have increased basal glycolysis and oxidative phosphorylation and use glutaminolysis as an energy source. Low Trp + Kyn iTreg viability was reliant on interleukin (IL)‐2 in vitro. Although in vivo IL‐2 administration increased low Trp + Kyn iTreg persistence on adoptive transfer into immunodeficient mice given peripheral blood mononuclear cells to induce GVHD,IL‐2–supported iTregs did not improve recipient survival. We conclude that low Trp + Kyn create suppressive iTregs that have high metabolic needs that will need to be addressed before clinical translation. This work defines the clinical‐scale production of Tregs induced via in vitroexpansion of effector T cells under conditions of low tryptophan plus kynurenines that are as suppressive in vitroas thymic Tregs, but have high metabolic demands that hinder in vivoefficacy.

Retrospective review of a multicenter database.

Purpose:Population-based reflex testing of colorectal tumors can identify individuals with Lynch syndrome (LS), but there is debate regarding the type of patient discretion such a program warrants. We examined health-care providers’ views and experiences to inform the design of a reflex-testing program and their perspectives regarding an opt-out option.Methods:We interviewed providers managing LS or colorectal cancer patients, including surgeons, genetic counselors, oncologists, primary-care physicians, and gastroenterologists. Qualitative data were analyzed thematically using constant comparison techniques.Results:Providers supported a reflex-testing program because of the current lack of coordinated immunohistochemistry (IHC) testing and underascertainment of LS patients as well as the opportunity to standardize the increasing use of genomic tests in practice. Most supported an opt-out after reflex testing because they felt that IHC is akin to other pathology tests, which are not optional. Some favored an opt-out before testing because of concern for patients experiencing distress, insurance discrimination, or a diagnostic odyssey that may be inconclusive.Conclusion:Providers support a reflex-testing program to improve the identification and management of suspected LS patients. However, how to support meaningful information provision to enable an opt-out without jeopardizing testing uptake and the anticipated public health benefits remains a policy challenge.Genet Med advance online publication 06 October 2016

Purpose:Newborn screening (NBS) for cystic fibrosis (CF) can identify carriers, which is considered a benefit that enables reproductive planning. We examined the reproductive impact of carrier result disclosure of NBS for CF.Methods:We surveyed mothers of carrier infants after NBS (Time 1) and 1 year later (Time 2) to ascertain intended and reported communication of their infants’ carrier results to relatives, carrier testing for themselves/other children, and reproductive decisions. A sub-sample of mothers was also interviewed at Time 1 and Time 2.Results:The response rate was 54%. A little more than half (55%) of mothers underwent carrier testing at Time 1; another 40% of those who intended to undergo testing at Time 1 underwent testing at Time 2. Carrier result communication to relatives was high (92%), but a majority of participants did not expect the results to influence family planning (65%). All interviewed mothers valued learning their infants’ carrier results. Some underwent carrier testing and then shared results with family. Others did not use the results or used them in unintended ways.Conclusion:Although mothers valued learning carrier results from NBS, they reported moderate uptake of carrier testing and limited influence on family planning. Our study highlights the secondary nature of the benefit of disclosing carrier results of NBS.Genet Med 19 4, 403–411.

Newborn screening (NBS) for cystic fibrosis (CF) can identify carriers, which is considered a benefit that enables reproductive planning. We examined the reproductive impact of carrier result disclosure of NBS for CF.

Evidence indicates that many barriers exist to the integration of genetic case finding into primary care. We conducted an exploratory study of the determinants of three specific behaviours related to using breast cancer genetics referral guidelines effectively: ‘taking a family history’, ‘making a risk assessment’, and ‘making a referral decision’. We developed vignettes of primary care consultations with hypothetical patients, representing a wide range of genetic risk for which different referral decisions would be appropriate. We used the Theory of Planned Behavior to develop a survey instrument to capture data on behavioural intention and its predictors (attitude, subjective norm, and perceived behavioural control) for each of the three behaviours and mailed it to a sample of Canadian family physicians. We used correlation and regression analyses to explore the relationships between predictor and dependent variables. The response rate was 96/125 (77%). The predictor variables explained 38–83% of the variance in intention across the three behaviours. Family physicians’ intentions were lower for ‘making a risk assessment’ (perceived as the most difficult) than for the other two behaviours. We illustrate how understanding psychological factors salient to behaviour can be used to tailor professional educational interventions; for example, considering the approach of behavioural rehearsal to improve confidence in skills (perceived behavioural control), or vicarious reinforcement as where participants are sceptical that genetics is consistent with their role (subjective norm).

The ability to recall facts is improved when learning takes place at spaced intervals, or when sleep follows shortly after learning. However, many students cram for exams and trade sleep for other activities. The aim of this study was to examine the interaction of study spacing and time in bed (TIB) for sleep on vocabulary learning in adolescents.

The article focuses on the Watermark Engaged, a program created by Jack Herklotz, Watermark Retirement Communities' information technology director, which aim to bridge technology divide in he U.S. by providing opportunities among participants to explore technology. Topics discussed include the collaboration with technology giant Google, the technological need of the adults who were the target of the program, and the challenges and barriers in the adoption of technology among adults.

To review the use of preoperative screening for Staphylococcus aureusfor all pediatric spine procedures that was instituted at our facility in a multimodal approach to decrease the frequency of postoperative wound infections.

Objectives: To review the use of preoperative screening for Staphylococcus aureusfor all pediatric spine procedures that was instituted at our facility in a multimodal approach to decrease the frequency of postoperative wound infections. Summary of Background Data: Four years ago at our facility, a multimodal approach to decrease the frequency of postoperative infections after pediatric spine surgery was instituted. Methods: A single-center, single-surgeon pediatric spine surgery database was queried to identify all patients who had preoperative S. aureusnasal swab screening. Data collected included demographic data, diagnoses, methicillin-resistant S. aureus(MRSA) swab findings, bacterial antibiotic sensitivities, and outcome of the spine surgery. Results: A total of 339 MRSA screenings were performed. Twenty (5.9%) were MRSA positive, and 55 (16.2%) were methicillin-sensitive S. aureus(MSSA) positive. In the MRSA-positive group, 13 were neuromuscular, 5 were adolescent idiopathic scoliosis (AIS), 1 congenital, and 1 infantile idiopathic scoliosis. Of the MRSA-positive screenings, 13 (65.0% of MRSA-positive screenings; 3.8% of entire cohort) of were newly identified cases (9 neuromuscular, 3 AIS, and 1 congenital diagnoses). In the 55 MSSA-positive, 6 documented resistance to either cefazolin or clindamycin. Hence, in up to 22 of the preoperative screenings (6.5% of entire cohort; 16 MRSA and 6 MSSA showed antibiotic resistance), the preoperative antibiotic regimen could be altered to appropriately cover the identified bacterial resistances. During the study period, there were 11 patients who were diagnosed with a postoperative deep wound infection, none of them having positive screenings. Conclusion: The use of preoperative nasal swab MRSA screening permitted adjustment of the preoperative antibiotic regimen in up to 6.5% of patients undergoing pediatric spine surgery. This inexpensive, noninvasive tool can be used in preoperative surgical planning for all patients undergoing spinal procedures. Level of Evidence: Level IV.

To investigate sleep EEG changes in adolescents across 7 nights of sleep restriction to 5 h time in bed [TIB]) and 3 recovery nights of 9 h TIB.

To investigate the effects of sleep restriction (7 nights of 5 h time in bed [TIB]) on cognitive performance, subjective sleepiness, and mood in adolescents.