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Update This article was updated on January 14, 2020, because of a previous error. On page 1, in the Abstract and the section entitled “Case Reports,” the word that had read “Genentech“ now reads “Genetech.” An erratum has been published: JBJS Case Connect. 2020 Feb 5;10(1):e0363ER. Case: The use of biologics is rapidly expanding. Over the past decade, there has been a significant increase in the number of cash-based “stem cell”/regenerative medicine clinics in the United States. These clinics provide cash-based services touting stem cell injections to cure a myriad of conditions. Largely, these clinics are unregulated and using injections in a non–Food and Drug Administration–approved manner. We report on 2 patients who presented with symptoms suggestive of septic arthritis following stem cell injections by cash-based local stem cell clinics. Case 1 involved a patient who developed septic arthritis following an injection of umbilical cord blood–derived cellular products (Genetech) and required an antibiotic spacer followed by a total hip arthroplasty. Case 2 involved a patient who developed a likely immune-mediated reaction following an injection of morselized human placental allograft tissue by a local chiropractic office at a cost of approximately $8,000. Conclusions: We present these cases to bring increased awareness to the issue and call for increased regulation of this practice.

Rationale: GWAS (Genome-Wide Association Studies) have identified hundreds of genetic loci associated with atrial fibrillation (AF). However, these loci explain only a small proportion of AF heritability. Objective: To develop an approach to identify additional AF-related genes by integrating multiple omics data. Methods and Results: Three types of omics data were integrated: (1) summary statistics from the AFGen 2017 GWAS; (2) a whole blood EWAS (Epigenome-Wide Association Study) of AF; and (3) a whole blood TWAS (Transcriptome-Wide Association Study) of AF. The variant-level GWAS results were collapsed into gene-level associations using fast set-based association analysis. The CpG-level EWAS results were also collapsed into gene-level associations by an adapted SNP-set Kernel Association Test approach. Both GWAS and EWAS gene-based associations were then meta-analyzed with TWAS using a fixed-effects model weighted by the sample size of each data set. A tissue-specific network was subsequently constructed using the NetWAS (Network-Wide Association Study). The identified genes were then compared with the AFGen 2018 GWAS that contained more than triple the number of AF cases compared with AFGen 2017 GWAS. We observed that the multiomics approach identified many more relevant AF-related genes than using AFGen 2018 GWAS alone (1931 versus 206 genes). Many of these genes are involved in the development and regulation of heart- and muscle-related biological processes. Moreover, the gene set identified by multiomics approach explained much more AF variance than those identified by GWAS alone (10.4% versus 3.5%). Conclusions: We developed a strategy to integrate multiple omics data to identify AF-related genes. Our integrative approach may be useful to improve the power of traditional GWAS, which might be particularly useful for rare traits and diseases with limited sample size.

Abstract Aims As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. Methods and results Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. Conclusion Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

Objective: There is a lack of evidence regarding tapering opioid medications in patients with chronic non-cancer pain. The purpose of this survey was to gather perspectives on future research into opioid tapering from utilizers of chronic opioid therapy (COT) or other people affected by chronic noncancer pain. Methods: The survey was distributed in paper form to patients on COT and via an online platform to patients self-enrolled in the chronic pain patient engagement group. The survey included a layman’s description of a possible tapering trial of opioid medications and elicited binary responses regarding willingness to participate and reasoning as well as qualitative freeform responses. Thematic analysis was performed to identify themes in narrative responses. Results: A total of 190 surveys were returned with 72.1% of all respondents answering positively regarding their willingness to participate in a proposed study. The most common reasons for participating in the study included concerns regarding opioid dependence, adding to society’s knowledge of opioid medications, and determining if the respondent would personally receive benefit from opioid medications. Patients recently on COT felt it was important to be able to withdraw from the study and return to usual care at any time (41.8% for recent COT and 15.5% for no recent COT, P < .05). The most common reason for unwillingness to participate was that respondents did not feel they had enough information to feel comfortable participating. The narrative responses showed a group of respondents felt COT was the only answer to their or their loved ones’ chronic pain and that a study would demonstrate the need to continue these medications long-term. There were also stories of side effects and dependence with decreasing effectiveness of opioids for pain control. When prompted to comment on study design, respondents indicated the study should include alternative pain management options. This was accompanied by responses with the assumption that pain will worsen as opioid medications are decreased. Conclusion: Patient concerns regarding opioid medications and discontinuation reflect the lack of evidence available to prescribers. There appears to be patient support for future research into the effects of tapering opioid medications.

OBJECTIVES: Dietary elimination for treatment of eosinophilic esophagitis (EoE) is limited by lack of accuracy in current allergy tests. We aimed to develop an immunologic approach to identify dietary triggers and prospectively test allergen-specific immune signature-guided dietary elimination therapy. METHODS: In the first phase, we developed and assessed 2 methods for determining selected food triggers using samples from 24 adults with EoE: a CD4+ T-cell proliferation assay in peripheral blood and food-specific tissue IgG4 levels in esophageal biopsies. In the second phase, we clinically tested elimination diets created from these methods in a prospective cohort treated for 6 weeks (NCT02722148). Outcomes included peak eosinophil counts (eos/hpf), endoscopic findings (measured by the EoE Endoscopic Reference Score), and symptoms (measured by the EoE Symptom Activity Index). RESULTS: Parameters were optimized with a positive test on either assay, yielding agreements of 60%, 75%, 53%, 58%, and 53% between predicted and known triggers of peanut, egg, soy, wheat, and milk, respectively. In clinical testing, the mean number of foods eliminated based on the assays was 3.4, and 19 of 22 subjects were compliant with treatment. After treatment, median peak eosinophil counts decreased from 75 to 35 ( P = 0.007); there were 4 histologic responders (21%). The EoE Endoscopic Reference Score and EoE Symptom Activity Index score also decreased after treatment (4.6 vs 3.0; P = 0.002; and 32.5 vs 25.0; P = 0.06, respectively). DISCUSSION: We successfully developed a new testing approach using CD4 + T-cell proliferation and esophageal food-specific IgG4 levels, with promising accuracy rates. In clinical testing, this led to improvement in eosinophil counts, endoscopic severity, and symptoms of dysphagia, but a smaller than expected number of patients achieved histologic remission.

Objective The aim of this study was to quantitatively demonstrate radiation dose reduction for sinus and temporal bone examinations using high-resolution photon-counting detector (PCD) computed tomography (CT) with an additional tin (Sn) filter. Materials and Methods A multienergy CT phantom, an anthropomorphic head phantom, and a cadaver head were scanned on a research PCD-CT scanner using ultra-high-resolution mode at 100-kV tube potential with an additional tin filter (Sn-100 kV) and volume CT dose index of 10 mGy. They were also scanned on a commercial CT scanner with an energy-integrating detector (EID) following standard clinical protocols. Thirty patients referred to clinically indicated sinus examinations, and two patients referred to temporal bone examinations were scanned on the PCD-CT system after their clinical scans on an EID-CT. For the sinus cohort, PCD-CT scans were performed using Sn-100 kV at 4 dose levels at 10 mGy (n = 9), 8 mGy (n = 7), 7 mGy (n = 7), and 6 mGy (n = 7), and the clinical EID-CT was performed at 120 kV and 13.7 mGy (mean CT volume dose index). For the temporal bone scans, PCD-CT was performed using Sn-100 kV (10.1 mGy), and EID-CT was performed at 120 kV and routine clinical dose (52.6 and 66 mGy). For both PCD-CT and EID-CT, sinus images were reconstructed using H70 kernel at 0.75-mm slice thickness, and temporal bone images were reconstructed using a U70 kernel at 0.6-mm slice thickness. In addition, iterative reconstruction with a dedicated sharp kernel (V80) was used to obtain high-resolution PCD-CT images from a sinus patient scan to demonstrate improved anatomic delineation. Improvements in spatial resolution from the dedicated sharp kernel was quantified using modulation transfer function measured with a wire phantom. A neuroradiologist assessed the H70 sinus images for visualization of critical anatomical structures in low-dose PCD-CT images and routine-dose EID-CT images using a 5-point Likert scale (structural detection obscured and poor diagnostic confidence, score = 1; improved anatomic delineation and diagnostic confidence, score = 5). Image contrast and noise were measured in representative regions of interest and compared between PCD-CT and EID-CT, and the noise difference between the 2 acquisitions was used to estimate the dose reduction in the sinus and temporal bone patient cohorts. Results The multienergy phantom experiment showed a noise reduction of 26% in the Sn-100 kV PCD-CT image, corresponding to a total dose reduction of 56% compared with EID-CT (clinical dose) without compromising image contrast. The PCD-CT images from the head phantom and the cadaver scans demonstrated a dose reduction of 67% and 83%, for sinus and temporal bone examinations, respectively, compared with EID-CT. In the sinus cohort, PCD-CT demonstrated a mean dose reduction of 67%. The 10- and 8-mGy sinus patient images from PCD-CT were significantly superior to clinical EID-CT for visualization of critical sinus structures (median score = 5 ± 0.82 and P = 0.01 for lesser palatine foramina, median score = 4 ± 0.68 and P = 0.039 for nasomaxillary sutures, and median score = 4 ± 0.96 and P = 0.01 for anterior ethmoid artery canal). The 6- and 7-mGy sinus patient images did not show any significant difference between PCD-CT and EID-CT. In addition, V80 (sharp kernel, 10% modulation transfer function = 18.6 cm −1 ) PCD-CT images from a sinus patient scan increased the conspicuity of nasomaxillary sutures compared with the clinical EID-CT images. The temporal bone patient images demonstrated a dose reduction of up to 85% compared with clinical EID-CT images, whereas visualization of inner ear structures such as the incudomalleolar joint were similar between EID-CT and PCD-CT. Conclusions Phantom and cadaver studies demonstrated dose reduction using Sn-100 kV PCD-CT compared with current clinical EID-CT while maintaining the desired image contrast. Dose reduction was further validated in sinus and temporal bone patient studies. The ultra-high resolution capability from PCD-CT allowed improved anatomical delineation for sinus imaging compared with current clinical standard.

Background and objectives Although high spinal anesthesia (HSA) has been used in cardiac surgery, the technique has not yet been widely accepted. This retrospective study was designed to investigate the impact of HSA technique on fast-track strategy in cardiac surgery. Methods Elective cardiac surgery cases (n=1025) were divided into two groups: cases with HSA combined with general anesthesia (GA) (HSA group, n=188) and cases with GA only (GA group, n=837). In the HSA group, bupivacaine and morphine were intrathecally administered immediately before GA was induced. Outcomes included fast-track extubation (less than 6 hours), extubation in the operating room, fast-track discharge from the intensive care unit (ICU) (less than 48 hours) and hospital (less than 7 days). Results In the HSA group, 60.1% were extubated in less than 6 hours after ICU admission, as compared with 39.9% in the GA group (p<0.001). In the HSA group, 33.0% were extubated in the operating room, as compared with 4.4% in the GA group (p<0.001). LOS in the ICU was less than 48 hours in 67.6% in the HSA group, as compared with 57.2% of those in the GA group (p=0.033). LOS in the hospital was less than 7 days in 63.3% in the HSA group, as compared with 53.5% in the GA group (p=0.084). Conclusions HSA technique combined with GA in cardiac surgery increased the rate of fast-track extubation (less than 6 hours) when compared with GA only.

SummaryBackgroundImproved knowledge of the molecular pathophysiology and immunopathogenesis of cholestatic liver diseases in recent years has led to an increased interest in developing novel therapies. Patients with cholestatic liver disease often require different approaches to assessment and management of suspected drug‐induced liver injury (DILI) compared to those with healthy livers and those with parenchymal liver diseases. At present, there are no regulatory guidelines or society position papers, that systematically address best practices pertaining to detection of DILI in these patients.AimsTo outline best practices for detection, assessment and management of suspected acute DILI during clinical trials in adults with the cholestatic liver diseases – Primary Biliary Cholangitis (PBC) and Primary Sclerosing Cholangitis (PSC).MethodsThis is one of the several papers developed by the IQ DILI Initiative, which is comprised of members from 16 pharmaceutical companies, in collaboration with DILI experts from academia and regulatory agencies. The contents are the result of an extensive literature review, as well as in‐depth discussions among industry, regulatory and academic DILI experts, to achieve consensus recommendations on DILI‐related issues occurring during clinical trials for cholestatic liver diseases.ResultsRecommended best practices are outlined pertaining to hepatic eligibility criteria, monitoring of liver tests, approach to a suspected DILI signal, and hepatic discontinuation rules.ConclusionsThis paper provides a framework for the approach to detection, assessment and management of suspected acute DILI occurring during clinical trials in adults with cholestatic liver disease.

Objectives: To longitudinally measure LV diastolic function in HIV-exposed but uninfected (HEU) children perinatally exposed to ART. Design: HEU children who were perinatally exposed to antiretroviral therapy (ART) may be at risk for adverse cardiac effects. We have previously reported that those children have decreased left ventricular (LV) mass, dimension, and septal thickness with increased contractility. Methods: Serial echocardiograms were obtained at specific times from birth to 48 months from two groups of HIV-uninfected children: 148 HIV-negative children who were perinatally exposed to ART and 130 non-ART-exposed HIV-unexposed healthy controls. The following LV diastolic indices were obtained: mitral valve early and late diastolic velocity (E and A), tissue Doppler-derived LV-free wall and septal early diastolic velocity (LV e′ and sep e′). Results: All echocardiographic indices were significantly different in ART-exposed children compared with ART-unexposed healthy controls. Both E and A were overall lower at all ages by 8.28 cm/s (P = 0.0002) and 13.46 cm/s (P < 0.0001) respectively. E/A ratio was higher by 0.27, 0.46, and 0.28 units at birth, 1 year and 2 years of age, respectively (all P ≤ 0.01). Moreover, LV e′ and sep e′ were overall lower at all ages by 0.84 cm/s (P = 0.01) and 0.47 cm/s (P = 0.02), respectively. Conclusion: Children who were exposed to ART in utero have subclinical yet significant differences in specific LV diastolic indices. Follow-up with serial echocardiograms are recommended in this population to further assess the potential cardiac toxicity of perinatal exposure to ART.