Search

PURPOSE: With onset of the COVID-19 pandemic, telehealth became the primary modality for health care appointments. This study examined patient experiences with and preferences for telehealth at a cancer genetic counseling clinic throughout the first 6 months of the pandemic (March-August 2020). METHODS: An anonymous survey assessed patient demographics; usage and prior experience with technology; emotional responses, technical experiences, and satisfaction with the telehealth appointment (via the Genetic Counseling Satisfaction Scale and Visit-Specific Satisfaction Questionnaire); preference for future telehealth; and recommendation of telehealth to others. RESULTS: Among 380 respondents, most were highly satisfied with the telehealth appointment (with 65.6% and 66.4% of participants completing the Genetic Counseling Satisfaction Scale and Visit-Specific Satisfaction Questionnaire, respectively). Multivariable analyses indicated several notable findings. Adjusting for relevant covariates, participants with less education felt significantly more concerned about telehealth than those with highest educational attainment. Participants age 40-69 years were generally more comfortable, relieved, and grateful that their appointment was scheduled as telehealth than were those older than 70 years. Women were marginally more relieved and grateful for telehealth appointments than men. As the pandemic progressed, significantly more participants were highly satisfied with their telehealth appointment and participants trended toward having greater preferences for future telehealth use. Most participants (78.6%) would recommend telehealth to others, although 50.8% preferred future in-person appointments. CONCLUSION: As the pandemic progressed, patients expressed increasing preferences for and satisfaction with telehealth. Service delivery models that incorporate individual patient preferences should be developed with special consideration to factors such as age, sex, and education level.

One purported benefit of the direct anterior approach (DAA) for total hip arthroplasty (THA) is a lower rate of postoperative dislocation.An institutional database was used to identify 8840 primary THAs performed from 2003 to 2020 including 5065 (57%) performed using the DAA and 3775 (43%) performed via the posterior approach (PA). Direction and mechanism of dislocation were determined from chart review. Outcomes were compared using Kaplan-Meier survivorship with dislocation as the endpoint and a Cox multivariate regression was used to investigate factors associated with dislocation. The mean follow-up was 1.7 ± 2.0 years for the DAA and 3.1 ± 3.3 years for the PA.The 0.5% (26/5065) incidence of dislocation among DAA hips was significantly less than the 3.3% (126/3775) among PA cases (P.001). The majority of dislocations were posterior (DAA 57%, PA 79%) and occurred during activities of daily living (DAA 82%, PA 77%). Five-year survivorship was significantly higher for the DAA group compared to the PA group (99.1% vs 95.4%, P.001). Dislocation risk was 4.9 times higher for the PA compared to the DAA (hazard ratio = 4.9, 95% confidence interval = 3.2-7.5, P.001). Increasing head diameter reduced the risk (hazard ratio = 0.70, 95% confidence interval = 0.57-0.86, P.001). The 0.2% incidence (10/5065) of revision for instability among the DAA group was significantly lower than the 1.1% (43/3775) rate for the PA group (P.001).Compared to primary THAs performed with the PA, DAA cases had a lower risk of dislocation, higher survivorship with dislocation as an endpoint, and a lower risk of revision for instability in this single institution cohort.

Introduction Modular component exchange can limit morbidity by retaining well-fixed hip arthroplasty components but dislocation has been a relatively frequent postoperative complication. This study evaluated the effect of surgical approach on dislocation rate in a modern revision cohort. Methods From 2010 to 2020, 248 aseptic head and liner exchanges were performed at a single institution including 54 done via the direct anterior (DA), 80 via the direct lateral (DL), and 114 via the posterolateral (PL) approach. The mean patient age at revision was 64.9±10.4 years and 50% (123/248) were performed among males. Indications for revision included 140 (56%) for polyethylene wear, 68 (27%) for failed metal-on-metal components, and 40 (16%) for instability. The mean follow-up after revision was 2.3 years. Results Thirty (12%) patients dislocated at a mean of 0.6 years (range, 0.01 to 4.6 years) postoperatively. The dislocation rate stratified by revision approach was 17% (9/54) for the DA, 6% (5/80) for the DL, and 14% (16/114) for the PL approach (p=0.13). Hips revised by the DA that dislocated were more abducted (51±8 vs. 45±8, p=0.05) and more anteverted (26±9 vs. 20±7, p=0.08) than non-dislocators. Among all 248 hips, cups with more than 48 degrees of abduction were 2.6 times more likely to dislocate (p=0.01). Head diameter, neck length, patient age, and sex were not associated with dislocation (p≥0.20). Discussion and Conclusion Dislocation remains a common complication after head and liner exchange regardless of approach. Cup position contributes to postoperative instability and must be critically evaluated during preoperative planning.

Congenital disorders resulting in pathological protein deficiencies are most often treated postnatally with protein or enzyme replacement therapies. However, treatment of these disorders in utero before irreversible disease onset could significantly minimize disease burden, morbidity, and mortality. One possible strategy for the prenatal treatment of congenital disorders is in utero delivery of messenger RNA (mRNA). mRNA is a nucleic acid therapeutic that has previously been investigated as a platform for protein replacement therapies and gene editing technologies. While viral vectors have been explored to induce intracellular expression of mRNA, they are limited in their clinical application due to risks associated with immunogenicity and genomic integration. As an alternative to viral vectors, safe and efficient in utero mRNA delivery can be achieved using ionizable lipid nanoparticles (LNPs). While LNPs have demonstrated potent in vivo mRNA delivery to the liver following intravenous administration, intra-amniotic delivery has the potential to deliver mRNA to cells and tissues beyond those in the liver, such as in the skin, lung, and digestive tract. However, LNP stability in fetal amniotic fluid and how this stability affects mRNA delivery has not been previously investigated. Here, we engineered a library of LNPs using orthogonal design of experiments (DOE) to evaluate how LNP structure affects their stability in amniotic fluid ex utero and whether a lead candidate identified from these stability measurements enables intra-amniotic mRNA delivery in utero. We used a combination of techniques including dynamic light scattering (DLS), transmission electron microscopy (TEM), and chromatography followed by protein content quantification to screen LNP stability in amniotic fluids. These results identified multiple lead LNP formulations that are highly stable in amniotic fluids ranging from small animals to humans, including mouse, sheep, pig, and human amniotic fluid samples. We then demonstrate that stable LNPs from the ex utero screen in mouse amniotic fluid enabled potent mRNA delivery in primary fetal lung fibroblasts and in utero following intra-amniotic injection in a murine model. This exploration of ex utero stability in amniotic fluids demonstrates a means by which to identify novel LNP formulations for prenatal treatment of congenital disorders via in utero mRNA delivery.

Purpose: To address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pre-test patient education, and genetic counselors delivered results and post-test genetic counseling via telephone. Methods: Among 1203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three-weeks and three-months following result return) of this mainstreaming model. Results: Only 10% of eligible patients declined participation. Among 1054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: Those with NV experienced a temporary increase in depression (pTime

Lay abstract ‘Precision oncology' has gained momentum as a term to describe cancer care that is optimized for an individual patient based on her/his unique characteristics. However, clinicians may encounter challenges with communication when delivering precision oncology care to patients and their families. We conducted three focus groups, or structured discussions, with breast, melanoma and thoracic oncology clinicians regarding their precision oncology communication experiences. Narrative transcripts of these discussions were analyzed by the research team to identify common themes. We identified four themes: varied definitions of precision oncology exist, clinicians and patients face unique challenges to precision oncology implementation, patient communication challenges engendered or heightened by precision oncology implementation, and clinician communication solutions and training needs. This study elucidated clinicians’ perspectives on delivering precision oncology and related communication challenges. Understanding these challenges and developing strategies to help clinicians navigate these discussions are critical for ensuring that patients reap the full benefits of precision oncology.

Viral engineered chimeric antigen receptor (CAR) T cell therapies are potent, targeted cancer immunotherapies, but their permanent CAR expression can lead to severe adverse effects. Nonviral messenger RNA (mRNA) CAR T cells are being explored to overcome these drawbacks, but electroporation, the most common T cell transfection method, is limited by cytotoxicity. As a potentially safer nonviral delivery strategy, here, sequential libraries of ionizable lipid nanoparticle (LNP) formulations with varied excipient compositions were screened in comparison to a standard formulation for improved mRNA delivery to T cells with low cytotoxicity, revealing B10 as the top formulation with a 3-fold increase in mRNA delivery. When compared to electroporation in primary human T cells, B10 LNPs induced comparable CAR expression with reduced cytotoxicity while demonstrating potent cancer cell killing. These results demonstrate the impact of excipient optimization on LNP performance and support B10 LNPs as a potent mRNA delivery platform for T cell engineering.

We tested a conceptual model that describes the relationship between individuals’ understanding of the multifactorial nature of cancer and their self-reported colorectal cancer screening. We collected cross-sectional survey data from 205 men and women age 50–75. Data were analyzed using structural equation modeling. The proposed model had reasonable fit (RMSEA = 0.09, CFI = 0.65). Multifactorial causal beliefs were associated with cancer risk perceptions (β = 0.16, p = 0.019) and more optimistic cancer cognitions (β = 0.17, p = 0.013). However, these constructs were not associated with colorectal cancer screening ( p’s > 0.05). Further testing could reveal whether this model can be applied to other cancer-related health behaviors including lifestyle changes and genetic testing.

Consensus and evidence suggest that cascade testing is critical to achieve the promise of cancer genetic testing. However, barriers to cascade testing include effective family communication of genetic risk information and family members’ ability to cope with genetic risk. These barriers are further complicated by the developmental needs of unaffected family members during critical windows for family communication and adaptation. Peer support could address these barriers. We provide two illustrative examples of ongoingBRCA1/2-related clinical trials that apply a peer support model to improve family communication and functioning. Peer support can augment currently available genetic services to facilitate adjustment to and effective use of cancer genetic risk information. Importantly, this scalable approach can address the presence of cancer risk within families across multiple developmental stages. This applies a family-centered perspective that accommodates all potentially at-risk relatives. This peer support model can be further applied to emerging topics in clinical genetics to expand reach and impact.

Periprosthetic femur fracture (PFF) remains a common reason for failure after total hip arthroplasty (THA). For over 10 years, our institution has performed both anterior approach (AA) and posterolateral (PL) approaches for primary THA with multiple stem designs. The aim of this study is to determine the 90-day relative risk of PFF with regard to approach and stem design.A retrospective review of our institutional database was performed on all patients undergoing primary THA from 2007 to 2018 using AA or PL approaches. Five surgeons performing 6309 THAs (AA = 4510; PL = 1799) using single-wedge taper (n = 2417) or fit-and-fill (n = 3892) stems were included. PFF occurring within 90 days of the index procedure were analyzed. Differences in PFF rates, fracture location, stem type, and treatment method were assessed. Comparisons were made using a Cox regression analysis.The 90-day revision rate for fracture was 0.3%. Clinically significant fractures requiring cerclage cabling, stem change, revision, or open reduction internal fixation occurred in 0.9% of patients (intraoperative = 37, 0.6%; postoperative = 17, 0.3%). Cox regression found PFF risk was significant for female patients (P = .008), patients older than age 65 (P.01), single-wedge taper stems (P = .05), and for cases with collarless stems (P = .04). Among PFF cases that required surgical intervention, risk factors were female sex, age older than 65, and body mass index under 25 (P.05). Collarless stems were 2.6 times more likely to result in PFF than collared stems (P = .04). Single-wedge taper stems were 2.3 times more likely to result in PFF than fit-and-fill stems (P = .05). Approach was not found to be an independent risk factor for PFF (P = .85).Our single-center experience demonstrates the risk of periprosthetic fracture within 90 days of surgery is significantly lower with collared stems and fit-and-fill stem designs. Female sex, age over 65, and body mass index below 25 nearly double the PFF risk. Surgical approach did not influence fracture rates.

Circulating tumor DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-Seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-Seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the parts-per-million range in patient samples. We profiled 678 specimens from 213 patients with B-cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B-cell lymphoma. In patients with undetectable ctDNA by CAPP-Seq after two cycles of therapy, an additional 25% have ctDNA detectable by PhasED-Seq and have worse outcomes. Finally, we demonstrate the application of PhasED-Seq to solid tumors., Editorial summary The sensitivity of circulating tumor DNA detection is improved by identifying sequences with two or more mutations.

Understanding the behaviors that lead to sunburn is an important objective toward developing intervention strategies to reduce risk for skin cancers. Our cross-sectional study surveyed 400 college students aged 18 and older at a public state university in the northeastern US in 2018 to assess tanning behaviors, outdoor activities, sun protection, and sunburn over the past year. Sunburn was exceedingly common; over half reported one or more sunburns in the past 12 months. Outdoor intentional and unintentional tanning were also common. Male sex, White race, sun sensitive skin type, and outdoor intentional and unintentional tanning were independently associated with increased odds of sunburn. Water and non-water sports, sunbathing, and vacations were also associated with sunburn. These results indicate that tanning and outdoor activities such as sports are important behaviors on which to focus for sunburn prevention among college students. Understanding the behaviors that are associated with sunburn provides useful opportunities to prevent skin cancer among young people.

BACKGROUND: College students participate in high levels of tanning, a skin cancer risk behavior due to ultraviolet radiation exposure, yet little is known about Asian college students’ behavior. This study examined the relationship between tanning attitudes, acculturation to the USA (cultural assimilation), and tanning behavior. METHOD: An online survey was used to recruit 211 Asian college students in the northeastern USA (47.4% born outside of the USA) to respond to questions about recent tanning behavior, sun protection strategies, attitudes about tanning, and acculturation to the USA. RESULTS: Attitudes about tanning, particularly desire for a darker skin tone and social norms, along with acculturation to the USA, were predictive of intentional tanning. The sample reported high levels of sun protection, which was associated with low acculturation. CONCLUSION: The significant role of acculturation in this study indicates that it may be a useful factor to include in future tanning intervention studies of relevant populations.

In recent years, immune cell-based cancer therapeutics have been utilized broadly in the clinic. Through advances in cellular engineering, chimeric antigen receptor (CAR) T-cell therapies have demonstrated substantial success in treating hematological tumors and have become the most prominent cell-based therapy with three commercialized products in the market. However, T-cell-based immunotherapies have certain limitations, including a restriction to autologous cell sources to avoid severe side-effects caused by human leukocyte antigen (HLA) mismatch. This necessity for personalized treatment inevitably results in tremendous manufacturing and time costs, reducing accessibility for many patients. As an alternative strategy, natural killer (NK) cells have emerged as potential candidates for improved cell-based immunotherapies. NK cells are capable of killing cancer cells directly without requiring HLA matching. Furthermore, NK cell-based therapies can use various allogeneic cell sources, allowing for the possibility of "off-the-shelf" immunotherapies with reduced side-effects and shortened manufacturing times. Here we provide an overview of the use of NK cells in cancer immunotherapy, their current status in clinical trials, as well as the design and implementation of delivery technologies-including viral, non-viral, and nanoparticle-based approaches-for engineering NK cell-based immunotherapies.

Allergic reactions occur when IgE molecules become crosslinked by antigens such as food proteins. Here we create the ‘AllerScan’ programmable phage display system to characterize the binding specificities of anti-allergen IgG and IgE antibodies in serum against thousands of allergenic proteins from hundreds of organisms at peptide resolution. Using AllerScan, we identify robust anti-wheat IgE reactivities in wheat allergic individuals but not in wheat-sensitized individuals. Meanwhile, a key wheat epitope in alpha purothionin elicits dominant IgE responses among allergic patients, and frequent IgG responses among sensitized and non-allergic patients. A double-blind, placebo-controlled trial shows that alpha purothionin reactivity, among others, is strongly modulated by oral immunotherapy in tolerized individuals. AllerScan may thus serve as a high-throughput platform for unbiased analysis of anti-allergen antibody specificities., A diverse array of antigens can trigger allergic reactions. Here the authors present the ‘AllerScan’ programmable phage display library, which is an efficient and unbiased approach for profiling anti-allergen antibody reactivities at cohort scale, with which a key wheat epitope is found to distinguish between wheat allergy and tolerance.

In 2015, the Accreditation Council for Graduate Medical Education published the Physical Medicine and Rehabilitation Milestones 1.0 as part of the Next Accreditation System. This was the culmination of more than 20 yrs of work on the part of the Accreditation Council for Graduate Medical Education to improve graduate medical education competency assessments. The six core competencies were patient care, medical knowledge, systems-based practice, practice-based learning and improvement, professionalism, and interpersonal and communication skills. While providing a good foundation for resident assessment, the Physical Medicine and Rehabilitation Milestones 1.0 was not without faults. With input from program directors, national organizations, and the public, the Physical Medicine and Rehabilitation Milestones 2.0 strives to further advance resident assessment, providing improvements through the integration of the harmonized Milestones and the addition of a supplemental guide.

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) have become widely used to manage perioperative pain following total joint arthroplasty (TJA). The purpose of our study is to evaluate the efficacy and safety of NSAIDs in support of the combined clinical practice guidelines of the American Association of Hip and Knee Surgeons, American Academy of Orthopaedic Surgeons, Hip Society, Knee Society, and American Society of Regional Anesthesia and Pain Management. Methods Databases including MEDLINE, EMBASE, and the Cochrane Central Registry of Controlled Trials were searched for studies published prior to November 2018 on NSAIDs in TJA. Studies included after a systematic review evaluated through direct comparisons and/or meta-analysis, including qualitative and quantitative heterogeneity testing, to evaluate effectiveness and safety of NSAIDs. Results After critical appraisal of 2921 publications, 25 articles represented the best available evidence for inclusion in the analysis. Oral selective cyclooxygenase (COX)-2 and non-selective NSAIDs and intravenous ketorolac safely reduce postoperative pain and opioid consumption during the hospitalization for primary TJA. Administration of an oral selective COX-2 NSAID reduced postoperative opioid consumption after discharge from TKA. Conclusion Strong evidence supports the use of an oral selective COX-2 or non-selective NSAID and intravenous ketorolac as adjunctive medications to manage postoperative pain during the hospitalization for TJA. Although no safety concerns were observed, prescribers need to remain vigilant when prescribing NSAIDs.

Total knee arthroplasty (TKA) is associated with increased risk of prolonged narcotic requirement compared to total hip arthroplasty (THA). This study aims to compare acute postoperative narcotic consumption between the 2 procedures and quantify amount of narcotics used by opioid prescribed.From October 2017 to August 2019, patients were surveyed at 4-week follow-up to determine amount and duration of opioids used and whether they continued to require narcotics. Among 1332 patients who self-identified as opioid naïve, 670 underwent THA and 662 underwent TKA. Descriptive analysis was performed based on data type.The total morphine equivalent dose (MED) used in the postoperative period was lower in THA than in TKA (143 ± 160 vs 259 ± 250 MED, P.001). The duration of use was shorter, total amount of pills consumed was lower, and refill rates were less in THA compared to TKA regardless of which opioid was prescribed. A smaller proportion of patients required narcotics at 4-week follow-up in THA compared to TKA. A postoperative prescription of 45 pills of any one type of narcotic was sufficient for nearly 90% of THA patients, and 60 pills of any one type of narcotic was appropriate for over 75% of TKA patients.THA is associated with less total narcotic consumption, shorter duration of use, less refills, and lower likelihood of requiring narcotics at 4-week follow-up. Percentiles of total narcotics consumed are provided to promote judicious postoperative prescribing patterns, and one could consider further reducing narcotics when utilizing our protocol, particularly for THA patients.This is a level III retrospective cohort study reviewing narcotic use in over 900 consecutive opioid-naïve patients undergoing total hip and knee arthroplasty.

Genetic structure in host species is often used to predict disease spread. However, host and pathogen genetic variation may be incongruent. Understanding landscape factors that have either concordant or divergent influence on host and pathogen genetic structure is crucial for wildlife disease management. Devil facial tumour disease (DFTD) was first observed in 1996 and has spread throughout almost the entire Tasmanian devil geographic range, causing dramatic population declines. Whereas DFTD is predominantly spread via biting among adults, devils typically disperse as juveniles, which experience low DFTD prevalence. Thus, we predicted little association between devil and tumour population structure and that environmental factors influencing gene flow differ between devils and tumours. We employed a comparative landscape genetics framework to test the influence of environmental factors on patterns of isolation by resistance (IBR) and isolation by environment (IBE) in devils and DFTD. Although we found evidence for broad-scale costructuring between devils and tumours, we found no relationship between host and tumour individual genetic distances. Further, the factors driving the spatial distribution of genetic variation differed for each. Devils exhibited a strong IBR pattern driven by major roads, with no evidence of IBE. By contrast, tumours showed little evidence for IBR and a weak IBE pattern with respect to elevation in one of two tumour clusters we identify herein. Our results warrant caution when inferring pathogen spread using host population genetic structure and suggest that reliance on environmental barriers to host connectivity may be ineffective for managing the spread of wildlife diseases. Our findings demonstrate the utility of comparative landscape genetics for identifying differential factors driving host dispersal and pathogen transmission.

Total knee arthroplasty (TKA) is associated with increased risk of prolonged narcotic requirement compared to unicompartmental knee arthroplasty (UKA). The purpose of the current study is to compare acute postoperative narcotic consumption between the 2 procedures and quantify narcotic consumption.From October 2017 to August 2019 patients were surveyed for four weeks to determine the amount and duration of opioids consumed and requirement for continued narcotics. Among 976 opioid naïve patients, 314 (32%) underwent UKA and 662 (68%) underwent TKA. Patients were analyzed according to specific narcotic prescribed. Total morphine equivalent dose (MED), number of pills, duration, refill percentage, and usage percentage for 4 weeks were calculated for each procedure.MED used in the postoperative period was lower in patients undergoing UKA than TKA (200 ± 195 vs 259 ± 250 MED, P = .002). Total number of pills consumed and duration of use was less in UKA compared to TKA regardless of which opioid was prescribed. A smaller proportion of patients required narcotics for 4 weeks after UKA (32% vs 43%, P.001), and fewer UKA patients required narcotic refills (14% vs 27%, P.001). Sixty pills of any 1 type of narcotic was sufficient for 90% of UKA patients and over 75% of TKA patients.UKA is associated with less narcotic consumption, shorter duration of use, less refills, and lower likelihood of narcotic requirement for 4 weeks. We report narcotic consumption patterns for both procedures to aid surgeons in judicious postoperative prescribing.This is a level III retrospective cohort study reviewing narcotic use in over 900 consecutive opioid naïve patients undergoing UKA or TKA.

Background Evidence is needed regarding effective incentive strategies to increase clinician survey response rates. Cash cards are increasingly used as survey incentives; they are appealing because of their convenience and because in some cases their value can be reclaimed by investigators if not used. However, their effectiveness in clinician surveys is not known. In this study within the BRCA Founder OutReach (BFOR) study, a clinical trial of population-based BRCA1/2 mutation screening, we compared the use of upfront cash cards requiring email activation versus checks as clinician survey incentives. Methods Participants receiving BRCA1/2 testing in the BFOR study could elect to receive their results from their primary care provider (PCP, named by the patient) or from a geneticist associated with the study. In order to understand PCPs’ knowledge, attitudes, experiences and willingness to disclose results we mailed paper surveys to the first 501 primary care providers (PCPs) in New York, Boston, Los Angeles and Philadelphia who were nominated by study participants to disclose their BRCA1/2 mutation results obtained through the study. We used alternating assignment stratified by city to assign the first 303 clinicians to receive a $50 up-front incentive as a cash card (N = 155) or check (N = 148). The cash card required PCPs to send an activation email in order to be used. We compared response rates by incentive type, adjusting for PCP characteristics and study site. Results In unadjusted analyses, PCPs who received checks were more likely to respond to the survey than those who received cash cards (54.1% versus 41.9%, p = 0.046); this remained true when we adjusted for provider characteristics (OR for checks 1.61, 95% CI 1.01, 2.59). No other clinician characteristics had a statistically significant association with response rates in adjusted analyses. When we included an interaction term for incentive type and city, the favorable impact of checks on response rates was evident only in Los Angeles and Philadelphia. Conclusions An up-front cash card incentive requiring email activation may be less effective in eliciting clinician responses than up-front checks. However, the benefit of checks for clinician response rates may depend on clinicians’ geographic location. Trial registration ClinicalTrials.gov (NCT03351803), November 24, 2017.

Aims The purpose of this study was to use pharmacogenetics to determine the frequency of genetic variants in our total knee arthroplasty (TKA) patients that could affect postoperative pain medications. Pharmacogenetic testing evaluates patient DNA to determine if a drug is expected to have a normal clinical effect, heightened effect, or no effect at all on the patient. It also predicts whether patients are likely to experience side effects from medicine. We further sought to determine if changing the multimodal programme based on these results would improve pain control or reduce side effects. Methods In this pilot study, buccal samples were collected from 31 primary TKA patients. Pharmacogenetics testing examined genetic variants in genes OPRM1, CYP1A2, CYP2B6, CYP2C19, CYP3A4, CYP2C9, and CYP2D6. These genes affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and opioids. We examined the frequency of genetic variants to any of the medications we prescribed including celecoxib, hydrocodone, and tramadol. Patients were randomized to one of two groups: the control group received the standard postoperative pain regimen, and the study group received a customized regimen based on the pharmacogenetic results. For the first ten postoperative days, patients recorded pain scores, medication, and side effects. Results Genetic variants involving one or more medications in the multimodal pain protocol occurred in 13 of the 31 patients (42%). In total, eight patients (26%) had variants affecting more than one of the medications. For the 25 patients who recorded pain and medication logs, the mean pain levels and morphine equivalents (MEQs) consumed in the first ten days were higher in the control group than in the custom-guided group (p = 0.019 for pain and p = 0.655 for MEQ). Conclusion Overall, 42% of patients had a variant involving one of the pain medications prescribed in our perioperative pain program for TKA. Ongoing research will help determine if using these data to modify a patient’s medication will improve outcomes. Cite this article: Bone Joint J 2020;102-B(6 Supple A):73–78.

PURPOSEDespite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information.METHODSUsing a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size.RESULTSThe time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations.CONCLUSIONPeridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

OBJECTIVEThe number of children with complex medical conditions surviving to adulthood is increasing. A planned transition to adult care systems is essential to the health maintenance of these patients. Guidance has been established for the general health care transition (HCT) from adolescence to adulthood. No formal assessment of the performance of pediatric neurosurgeons in HCT has been previously performed. No “best practice” for this process in pediatric neurosurgery currently exists. The authors pursued two goals in this paper: 1) define the current state of HCT in pediatric neurosurgery through a survey of the membership of the American Society of Pediatric Neurosurgeons (ASPN) on current methods of HCT, and 2) develop leadership-endorsed best-practice guidelines for HCT from pediatric to adult neurosurgical health care.METHODSCompletion of the Current Assessment of Health Care Transition Activities survey was requested of 178 North American pediatric neurosurgeons by using a web-based questionnaire to capture HCT practices of the ASPN membership. The authors concurrently conducted a PubMed/MEDLINE–based literature review of HCT for young adults with special health care needs, surgical conditions, and/or neurological conditions for the period from 1990 to 2018. Selected articles were assembled and reviewed by subject matter experts and members of the ASPN Quality, Safety, and Advocacy Committee. Best-practice recommendations were developed and subjected to peer review by external expert groups.RESULTSSeventy-six responses to the survey (43%) were received, and 62 respondents (82%) answered all 12 questions. Scores of 1 (lowest possible score) were recorded by nearly 60% of respondents on transition policy, by almost 70% on transition tracking, by 85% on transition readiness, by at least 40% on transition planning as well as transfer of care, and by 53% on transition completion. Average responses on all core elements were < 2 on the established 4-point scale. Seven best-practice recommendations were developed and endorsed by the ASPN leadership.CONCLUSIONSThe majority of pediatric neurosurgeons have transition practices that are poor, do not meet the needs of patients and families, and should be improved. A structured approach to transition, local engagement with adult neurosurgical providers, and national partnerships between pediatric and adult neurosurgery organizations are suggested to address current gaps in HCT for patients served by pediatric neurosurgeons.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Background Angiotensin converting enzyme 2 (ACE2) is expressed in the human myocardium and blood vessels and degrades the vasoconstrictor peptide angiotensin (Ang) II. Plasma ACE2 activity is elevated in patients with cardiovascular disease (CVD) and is a predictor of major adverse cardiovascular events (MACE) in obstructive coronary artery disease. However, it is unknown whether acute coronary syndrome (ACS) causes dynamic changes in plasma ACE2 activity. Purpose We investigated dynamic changes in serial troponin-T and plasma ACE2 activity in patients presenting with ACS who underwent invasive coronary angiography (ICA). Methods Consecutive patients admitted with ACS from October-November 2019 were screened. Those meeting the Fourth Universal Definition of Myocardial Infarction who had both ICA and serial troponin-T testing were included. The study was approved by the hospitals Human Research Ethics Committee. All patients had routine plasma samples taken over 3 time-points for measurement of troponin-T; the same sample was used to measure plasma ACE2 activity. Catalytic ACE2 activity was measured using a validated, sensitive quenched fluorescent substrate-based assay. Serial median troponin and ACE2 activity levels were analysed using the Friedman test for repeated measures. Results Forty-nine patients were included. The mean age of participants was 63.9±11.0 years, and 36 (74%) patients were male. Overall, 16 (36%) patients presented with ST-elevation myocardial infarction (STEMI) and 29 (74%) with non-ST-elevation myocardial infarction (NSTEMI). Twenty-nine (59%) patients had a history of hypertension and 14 (29%) a history of ischaemic heart disease; 13 (27%) with priorMI, 11 (22%) had previous PCI and 2 (4%) had prior coronary artery bypass grafting. Over the 3 time points, there was a clear rise in median troponin-T levels representing myocardial injury (p Conclusions Patients with ACS had higher plasma ACE2 levels compared to levels previously reported in healthy controls. There were no dynamic changes in ACE2 activity in the setting of ACS, despite a significant rise in troponin-T. These results suggest that plasma ACE2 levels reflect underlying endothelial dysfunction rather than acute myocardial injury or infarction. Studies are now underway to assess if plasma ACE2 activity in ACS predicts MACE. Funding Acknowledgement Type of funding sources: None. Table 1

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy-number changes. We applied Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy-number alterations (CNA). We analyzed 64 prospectively collected plasma samples from 17 patients with pediatric sarcoma. Translocations were detected in the pretreatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy-number changes in the pretreatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and CNAs in the plasma of patients with pediatric sarcoma. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.

Background Transmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are particularly useful for identifying the molecular basis of phenotypic variation. In oncology, transcriptomics studies, which characterize the expression of thousands of genes, have identified processes leading to heterogeneity in cancer phenotypes and individual prognoses. More generally, transcriptomics studies of infectious diseases characterize interactions between host, pathogen, and environment to better predict population-level outcomes. Tasmanian devils have been impacted dramatically by a transmissible cancer (devil facial tumor disease; DFTD) that has led to widespread population declines. Despite initial predictions of extinction, populations have persisted at low levels, due in part to heterogeneity in host responses, particularly between sexes. However, the processes underlying this variation remain unknown. Results We sequenced transcriptomes from healthy and DFTD-infected devils, as well as DFTD tumors, to characterize host responses to DFTD infection, identify differing host-tumor molecular interactions between sexes, and investigate the extent to which tumor gene expression varies among host populations. We found minimal variation in gene expression of devil lip tissues, either with respect to DFTD infection status or sex. However, 4088 genes were differentially expressed in tumors among our sampling localities. Pathways that were up- or downregulated in DFTD tumors relative to normal tissues exhibited the same patterns of expression with greater intensity in tumors from localities that experienced DFTD for longer. No mRNA sequence variants were associated with expression variation. Conclusions Expression variation among localities may reflect morphological differences in tumors that alter ratios of normal-to-tumor cells within biopsies. Phenotypic variation in tumors may arise from environmental variation or differences in host immune response that were undetectable in lip biopsies, potentially reflecting variation in host-tumor coevolutionary relationships among sites that differ in the time since DFTD arrival.

Background Peanut allergy diagnosis relies on clinical reactivity to peanut supported by detection of specific IgE (sIgE) antibodies. Extract-based sIgE tests have low specificity, so component-resolved diagnostics may complement whole-extract testing. Methods We systematically collected peanut allergen component data in seven databases and studied the diagnostic accuracy of peanut storage proteins (Arah1, 2, 3) and cross-reactive peanut proteins (Arah8 PR-10 and Arah9 lipid transfer protein) through meta-analyses. The systematic literature review included studies employing peanut components and oral food challenge (OFC) as reference standard in patients suspected of peanut allergy. Data for component sIgE at pre-defined detection thresholds were extracted and combined in random-effects bivariate meta-analyses. Risk of bias was assessed as recommended by Cochrane, with two additional quality items of importance for this review. Results Nineteen eligible studies presented data suitable for meta-analysis. In cross-sectional pediatric studies, the pooled sensitivity of Arah2-sIgE at 0.35 kUA /L cutoff was 83.3% [95% CI 75.6, 88.9] and specificity in diagnosing objective peanut allergy was 83.6% [95% CI 77.4, 88.4]. Compared with 0.1 and 1.0 kUA /L, this threshold provided the best diagnostic accuracy. At 0.35 kUA /L, Arah1 and Arah3 had comparable specificity (86.0% and 88.0%, respectively) but significantly lower sensitivity compared with Arah2 (37.0% and 39.1%, respectively; P Conclusion sIgE to Arah2 can enhance the certainty of diagnosis and reduce the number of OFC necessary to rule out clinical peanut allergy in unclear cases.

International audience; Superior cavopulmonary circulation (SCPC) can be achieved by either the Hemi-Fontan (hF) or Bidirectional Glenn (bG) connection. Debate remains as to which results in best hemodynamic results. Adopting patient-specific multiscale computational modeling, we examined both the local dynamics and global physiology to determine if surgical choice can lead to different hemodynamic outcomes. Six patients (age: 3-6 months) underwent cardiac magnetic resonance imaging and catheterization prior to SCPC surgery. For each patient: (1) a finite 3-dimensional (3D) volume model of the preoperative anatomy was constructed to include detailed definition of the distal branch pulmonary arteries, (2) virtual hF and bG operations were performed to create 2 SCPC 3D models, and (3) a specific lumped network representing each patient's entire cardiovascular circulation was developed from clinical data. Using a previously validated multiscale algorithm that couples the 3D models with lumped network, both local flow dynamics, that is, power loss, and global systemic physiology can be quantified. In 2 patients whose preoperative imaging demonstrated significant left pulmonary artery (LPA) stenosis, we performed virtual pulmonary arterioplasty to assess its effect. In one patient, the hF model showed higher power loss (107%) than the bG, while in 3, the power losses were higher in the bG models (18-35%). In the remaining 2 patients, the power loss differences were minor. Despite these variations, for all patients, there were no significant differences between the hF and bG models in hemodynamic or physiological outcomes, including cardiac output, superior vena cava pressure, right-left pulmonary flow distribution, and systemic oxygen delivery. In the 2 patients with LPA stenosis, arterioplasty led to better LPA flow (5-8%) while halving the power loss, but without important improvements in SVC pressure or cardiac output. Despite power loss differences, both hF and bG result in similar SCPC hemodynamics and physiology outcome. This suggests that for SCPC, the pre-existing patient-specific physiology and condition, such as pulmonary vascular resistance, are more deterministic in the hemodynamic performance than the type of surgical palliation. Multiscale modeling can be a decision-assist tool to assess whether an extensive LPA reconstruction is needed at the time of SCPC for LPA stenosis.