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Background Professionalism is a core competency that is difficult to assess. We examined the incidence of publication inaccuracies in Electronic Residency Application Service applications to our training program as potential indicators of unprofessional behavior. Study Design We reviewed all 2019-2020 National Resident Matching Program applicants being considered for interview. Applicant demographic characteristics recorded included standardized examination scores, gender, medical school, and medical school ranking (2019 US News & World Report). Publication verification by a medical librarian was performed for peer-reviewed journal articles/abstracts, peer-reviewed book chapters, and peer-reviewed online publications. Inaccuracies were classified as “nonserious” (eg incorrect author order without author rank promotion) or “serious” (eg miscategorization, non-peer-reviewed journal, incorrect author order with author rank promotion, nonauthorship of cited existing publication, and unverifiable publication). Multivariate logistic regression analysis was performed for demographic characteristics to identify predictors of overall inaccuracy and serious inaccuracy. Results Of 319 applicants, 48 (15%) had a total of 98 inaccuracies; after removing nonserious inaccuracies, 37 (12%) with serious inaccuracies remained. Seven publications were reported in predatory open access journals. In the regression model, none of the variables (US vs non-US medical school, gender, or medical school ranking) were significantly associated with overall inaccuracy or serious inaccuracy. Conclusions One in 8 applicants (12%) interviewing at a general surgery residency program were found to have a serious inaccuracy in publication reporting on their Electronic Residency Application Service application. These inaccuracies might represent inattention to detail or professionalism transgressions.

Objective To perform a systematic review on the effects of testicular sparing surgery (TSS) on the oncological, functional, and hormonal outcomes of adults with testicular tumors. Methods A literature search was performed after PROSPERO registration (CRD42020200842) and reported in compliance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) methods. We conducted a systematic search of Medline (Ovid), Embase, Cochrane CENTRAL, CINAHL, Scopus, Web of Science, ClinicalTrials.gov, and the WHO/ICTRP from inception to November 20, 2020. Manuscripts and published abstracts were included if they involved testis‐sparing surgery (TSS) and contained data on any outcomes related to fertility, hormonal parameters, or oncological control, or if they evaluated surgical technique. Results Our initial search yielded 3,370 manuscripts, with 269 of these screened for full‐text eligibility. After our exclusion criteria were applied, 32 studies were included in the final analysis. Oncological outcomes were obtained from 12 studies (average follow‐up 57.8 months), functional data from 26 studies (average follow‐up 49.6 months), fertility information from 10 studies (average follow‐up 55.8 months), and data on nonpalpable tumors from 11 studies (average follow‐up 32.1 months). Oncological control appears to be excellent in studies that reported these outcomes. Presence of germ cell neoplasia in situ was controlled with adjuvant radiation in nearly all cases. Functional outcomes are also promising, as development of primary and compensated hypogonadism was rare. Semen parameters are poor preoperatively among men with benign and malignant testis tumors, with occasional decline after TSS. Frozen section analysis at the time of surgery appears to be very reliable, and the majority of nonpalpable tumors appear to be benign. Conclusions TSS is a safe and efficacious technique with regards to oncological control and postoperative hormonal function based on retrospective, noncontrolled studies. TSS avoids unnecessary removal of benign testicular tissue, and should be given serious consideration in cases of nonpalpable, small tumors under 2 cm. In cases of malignancy, TSS can safely avoid anorchia in men with bilateral tumors and in men with solitary testicles. The use of the operating microscope, while theoretically promising, does not necessarily lead to better outcomes, however data are limited.

We present the case of a 41-year-old female who underwent bilateral lung transplantation after the donor lungs were placed on a normothermic ex vivo lung perfusion and ventilation device and flown nearly 5000 miles from Honolulu, Hawaii to Durham, North Carolina. The patient experienced no primary graft dysfunction. One year after transplantation she has remained rejection-free and exhibits excellent pulmonary function. This case highlights the challenge that active organ preservation systems pose to questions of organ allocation and geographic sharing.

Focused cardiac ultrasound (FoCUS) has become a valuable tool to assess unexplained hypotension in critically ill patients. Due to increasing availability of transthoracic echocardiography (TTE) equipment in the operating room, there is a widespread interest in its usefulness for intraoperative diagnosis of hypotension as an alternative to transesophageal echocardiography (TEE). The objective of this systematic review is to evaluate the utility of intraoperative FoCUS to assess patients experiencing unexplained hypotension while undergoing noncardiac surgery. We performed a systematic literature search of multiple publication databases for studies that evaluated the utility of intraoperative FoCUS for assessment and management of unexplained hypotension in patients undergoing noncardiac surgery, including retro- and prospective clinical studies. A summary of the study findings, study quality, and assessment of level of evidence is presented. We identified 2227 unique articles from the literature search, of which 27 were potentially relevant, and 9 were included in this review. The number of patients pooled from these studies was 255, of whom 228 had intraoperative diagnoses with the aid of intraoperative FoCUS. The level of evidence of all studies included was very low according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. This systematic review has demonstrated that FoCUS may be a useful, noninvasive method to differentiate causes of intraoperative hypotension and guide correcting interventions, although the quality of evidence is very low. Further prospective high-quality studies are needed to investigate whether intraoperative FoCUS has a diagnostic utility that is associated with improved outcomes.

Nevus of Ota is cosmetically burdensome and often prompts patients to seek treatment. Lasers are commonly used in removing these lesions; however, no systemic analysis has been conducted to support a gold standard laser. To conduct a meta-analysis of the efficacy and safety of Q-switched Nd:YAG lasers (QSNL), Q-switched ruby lasers (QSRL), Q-switched alexandrite lasers (QSAL), and picosecond alexandrite lasers (PSAL) in removing nevus of Ota. Inclusion criteria were nevus of Ota patients treated with QSNL, QSRL, QSAL, or PSAL and documentation of percent clearance and the rate of at least one adverse event. Articles in English, Chinese, or Japanese were included. The prespecified outcome measures were efficacy (percent clearance) and safety (rates of hyperpigmentation, hypopigmentation, scarring, and recurrence). The review included 57 studies and 13,417 patients. The pooled success rate was 64% for QSNL (95% CI 52-76%), 54% for QSRL (95% CI 39-69%), 58% for QSAL (95% CI 44-72%), and 100% for PSAL (95% CI 98-102%). The pooled adverse event rate was 5% for QSNL (95% CI 4-6%), 14% for QSRL (95% CI 9-19%), 9% for QSAL (95% CI 6-12%), and 44% (95% CI 31-57%) for PSAL. QSNL has the most evidence for effectively and safely treating nevus of Ota. PSAL potentially has a superior efficacy; however, further studies are needed to elucidate its side effect profile when treating nevus of Ota.

Rationale: Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common...

Recent prescribing trends reflect government-led efforts undertaken in both the U.S. and Canada to decrease opioid use. These provisions reflect a reduction in the use of many potent opioids in favour of tramadol. Despite the purported benefits of tramadol over other opioids, little remains known about tramadol-associated hallucinations (TAH). We conducted a systematic literature search in Embase, Medline, Cochrane CENTRAL, CINAHL, PubMed, Scopus, PAHO Virtual Health Library, MedNar, and ClinicalTrials.gov to find reported cases of hallucinations associated with the use of tramadol. For all corresponding cases reporting hallucinations secondary to tramadol use, we extracted data on patient demographics, medical management, and the details on hallucinations. Cases were categorized as “probable TAH” if the evidence supported an association between hallucinations and tramadol use, or “possible TAH” if hallucinations were attributed to tramadol use but the supporting evidence was weak. The “probable TAH” cases were further classified as “isolated TAH” if hallucinations were the primary complaint, or “other existing medical condition” if concurrent signs and symptoms alluded to a diagnosis of an existing medical condition. We then conducted a narrative synthesis of the available literature to contextualize these results. A total of 941 articles were identified in the initial search. No observational studies or randomized clinical trials were identified with our systematic review; only case reports were found. After a thorough screening, 34 articles comprising 101 patients reported an association between tramadol use and hallucinations. Among these 101 cases, 31 were “probable TAH” and 70 were “possible TAH”. Of the 31 cases of “probable TAH”, 16 cases were “isolated TAH” while the remaining 15 cases belonged to “other existing medical condition”. Tramadol-associated hallucinations can result in auditory or visual disturbances, although multisensory symptoms have also been reported. The mechanism underlying TAH remains poorly understood and likely involves numerous receptor types. The relative risk of hallucinations from tramadol compared with other opioids remains unclear.

Objectives: Women who sell sex have a high prevalence of human papilloma virus, which may cause cervical cancer. The objective of this review was to collate findings on prevalence, associated factors, screening, service provision and utilization of services in relation to human papilloma virus and cervical cancer among women who sell sex in Eastern and Southern Africa. Methods: A scoping review methodology was employed. Inclusion criteria were as follows: (1) empirical papers, (2) of studies conducted in Eastern and Southern Africa, (3) published in the last 10 years, and (4) addressing women who sell sex in relation to (5) human papilloma virus and cervical cancer. A thorough search of a range of databases surfaced 66 papers. Both authors applied inclusion and exclusion criteria, resulting in 14 papers being reviewed. Results: The reported prevalence of high-risk human papillomavirus virus varied between 23.6% and 70.5%. HIV sero-positivity, other sexually transmitted infections and Epstein-Barr virus were associated with human papilloma virus and high-grade cervical lesions. High-risk human papilloma virus was associated with women who reported younger age at first intercourse, non-barrier contraceptive use, and no history of condom use. For screening, there was overall agreement between physician- and self-collected samples. Contradictory results were found for visual inspection with acetic acid. Screening services utilization was associated with provider’s recommendation, history of sexually transmitted infections, frequency of facility visit and history of vaginal examination. A diagonal programme led to an increase in screening, attributed to the targeted services. Conclusions: Context is important in planning cervical cancer services. There is a need for enhanced sexually transmitted infections and viral management within cervical cancer prevention. Women who sell sex should be empowered in self-collection of stored-dry specimens, especially in resource-constrained regions. Cervical cancer screening services should be honed to the needs of women who sell sex.

Background: Congenital heart disease (CHD) with single-ventricle (SV) physiology is now survivable with a three-stage surgical course ending with Fontan palliation. However, 10-year transplant-free survival remains at 39–50%, with ventricular dysfunction progressing to heart failure (HF) being a common sequela. For SV-CHD patients who develop HF, undergoing the surgical course would not be helpful and could even be detrimental. As HF risk cannot be predicted and metabolic defects have been observed in Ohia SV-CHD mice, we hypothesized that respiratory defects in peripheral blood mononuclear cells (PBMCs) may allow HF risk stratification in SV-CHD.Methods: SV-CHD (n = 20), biventricular CHD (BV-CHD; n = 16), or healthy control subjects (n = 22) were recruited, and PBMC oxygen consumption rate (OCR) was measured using the Seahorse Analyzer. Respiration was similarly measured in Ohia mouse heart tissue.Results: Post-Fontan SV-CHD patients with HF showed higher maximal respiratory capacity (p = 0.004) and respiratory reserve (p < 0.0001), parameters important for cell stress adaptation, while the opposite was found for those without HF (reserve p = 0.037; maximal p = 0.05). This was observed in comparison to BV-CHD or healthy controls. However, respiration did not differ between SV patients pre- and post-Fontan or between pre- or post-Fontan SV-CHD patients and BV-CHD. Reminiscent of these findings, heart tissue from Ohia mice with SV-CHD also showed higher OCR, while those without CHD showed lower OCR.Conclusion: Elevated mitochondrial respiration in PBMCs is correlated with HF in post-Fontan SV-CHD, suggesting that PBMC respiration may have utility for prognosticating HF risk in SV-CHD. Whether elevated respiration may reflect maladaptation to altered hemodynamics in SV-CHD warrants further investigation.

Importance Dermoscopy increases the diagnostic accuracy for melanoma. However, the accuracy of individual structures and patterns used in melanoma detection has not been systematically evaluated. Objective To assess the diagnostic accuracy of individual dermoscopic structures and patterns used in melanoma detection. Data sources A search of Ovid Medline, Embase, Cochrane CENTRAL, Scopus, and Web of Science was conducted from inception to July 2020. Study selection Studies evaluating the dermoscopic structures and patterns among melanomas in comparison with nonmelanoma lesions were included. Excluded were studies with fewer than 3 patients, studies in languages other than English or Spanish, studies not reporting dermoscopic structures per lesion type, and studies assessing only nail, mucosal, acral, facial, or metastatic melanomas or melanomas on chronically sun-damaged skin. Multiple reviewers applied these criteria, and 0.7% of studies met selection criteria. Data extraction and synthesis The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline and Meta-analysis of Observational Studies in Epidemiology reporting guideline were followed. Guidelines were applied via independent extraction by multiple observers. Data were pooled using a random-effects model. Main outcomes and measures The prespecified outcome measures were diagnostic accuracy (sensitivity and specificity) and risk (odds ratio [OR]) of melanoma for the following dermoscopic structures/patterns: atypical dots/globules, atypical network, blue-white veil, negative network, off-centered blotch, peripheral-tan structureless areas, atypical vessels (eg, linear irregular, polymorphous), pseudopods, streaks, regression (ie, peppering, scarlike areas), shiny white structures, angulated lines, irregular pigmentation, and a multicomponent pattern. Results A total of 40 studies including 22 796 skin lesions and 5736 melanomas were evaluated. The structures and patterns with the highest ORs were shiny white structures (OR, 6.7; 95% CI, 2.5-17.9), pseudopods (OR, 6.7; 95% CI, 2.7-16.1), irregular pigmentation (OR, 6.4; 95% CI, 2.0-20.5), blue-white veil (OR, 6.3; 95% CI, 3.7-10.7), and peppering (OR, 6.3; 95% CI, 2.4-16.1). The structures with the highest specificity were pseudopods (97.3%; 95% CI, 94.3%-98.7%), shiny white structures (93.6%; 95% CI, 85.6%-97.3%), peppering (93.4%; 95% CI, 81.9%-97.8%), and streaks (92.1%; 95% CI, 88.4%-94.7%), whereas features with the highest sensitivity were irregular pigmentation (62.3%; 95% CI, 31.2%-85.8%), blue-white veil (60.6%; 95% CI, 46.7%-72.9%), atypical network (56.8%; 95% CI, 43.6%-69.2%), and a multicomponent pattern (53.7%; 95% CI, 40.4%-66.4%). Conclusions and relevance The findings of this systematic review and meta-analysis support the diagnostic importance of dermoscopic structures associated with melanoma detection (eg, shiny white structures, blue-white veil), further corroborate the importance of the overall pattern, and may suggest a hierarchy in the significance of these structures and patterns.

SUMMARY Gastroesophageal reflux and esophageal dysmotility are common in patients with advanced lung disease and are associated with allograft dysfunction after lung transplantation. The effect of transplantation on reflux and esophageal motility is unclear. The aim of this study was to describe the changes in esophageal function occurring after lung transplantation. A retrospective cohort study was performed on lung transplant candidates evaluated at a tertiary care center between 2015 and 2016. A total of 76 patients who underwent lung transplantation had high-resolution manometry and ambulatory pH-metry before and after transplant. Demographic data, esophageal function testing results, and clinical outcomes such as pulmonary function testing were collected and analyzed using appropriate statistical tests and multivariable regression. Of the 76 patients, 59 (78%) received a bilateral transplant. There was a significant increase in esophageal contractility posttransplant, with an increase in median distal contractile integral from 1470 to 2549 mmHg cm s (P < 0.01). There were 19 patients with Jackhammer esophagus posttransplant, including 15 patients with normal motility pretransplant. Nine patients with ineffective or fragmented peristalsis pretransplant had normal manometry posttransplant. Abnormal pH-metry was observed in 35 (46%) patients pretransplant and 29 (38%) patients posttransplant (P = 0.33). Patients with gastroesophageal reflux disease posttransplant had less improvement in pulmonary function at one year, as measured by forced expiratory volume (P = 0.04). These results demonstrate that esophageal contractility increases significantly after lung transplantation, with an associated change in motility classification. In comparison, gastroesophageal reflux does not worsen, but is associated with worse pulmonary function, posttransplant.

Long term outcomes in lung transplant are limited by the development of chronic lung allograft dysfunction (CLAD). Within the past several decades, antibody-mediated rejection (AMR) has been recognized as a risk factor for CLAD. The presence of HLA antibodies in lung transplant candidates, “sensitized patients” may predispose patients to AMR, CLAD, and higher mortality after transplant. This review will discuss issues surrounding the sensitized patient, including mechanisms of sensitization, implications within lung transplant, and management strategies.

The histopathologic diagnosis of acute allograft injury is prognostically important in lung transplantation with evidence demonstrating a strong and consistent association between acute rejection (AR)(1–7), acute lung injury (ALI)(8, 9) and the subsequent development of chronic lung allograft dysfunction (CLAD). The pathogenesis of these allograft injuries however, remains poorly understood. CXCL9 and CXCL10 are CXC chemokines induced by interferon-γ and act as potent chemoattractants of mononuclear cells. We hypothesized that these chemokines are involved in the mononuclear cell recruitment associated with AR and ALI. We further hypothesized that the increased activity of these chemokines could be quantified as increased levels in the bronchoalveolar lavage fluid. In this prospective multicenter study, we evaluate the incidence of histopathologic allograft injury development during the first-year post-transplant and measure bronchoalveolar CXCL9 and CXCL10 levels at the time of the biopsy. In multivariable models, CXCL9 levels were 1.7-fold and 2.1-fold higher during AR and ALI compared with “normal” biopsies without histopathology. Similarly, CXCL10 levels were 1.6-fold and 2.2-fold higher during these histopathologies, respectively. These findings support the association of CXCL9 and CXCL10 with episodes of AR and ALI, and provide potential insight into the pathogenesis of these deleterious events.

Health systems analyses are touted as mechanisms through which health policy and planning may be implemented. An example is the WHO health systems approach that connects people (needs, rights, pers...

In this paper we describe the system design and capabilities of the Australian Square Kilometre Array Pathfinder (ASKAP) radio telescope at the conclusion of its construction project and commencement of science operations. ASKAP is one of the first radio telescopes to deploy phased array feed (PAF) technology on a large scale, giving it an instantaneous field of view that covers 31 square degrees at 800 MHz. As a two-dimensional array of 36x12m antennas, with baselines ranging from 22m to 6km, ASKAP also has excellent snapshot imaging capability and 10 arcsecond resolution. This, combined with 288 MHz of instantaneous bandwidth and a unique third axis of rotation on each antenna, gives ASKAP the capability to create high dynamic range images of large sky areas very quickly. It is an excellent telescope for surveys between 700 MHz and 1800 MHz and is expected to facilitate great advances in our understanding of galaxy formation, cosmology and radio transients while opening new parameter space for discovery of the unknown., 38 pages, 24 figures, accepted for publication in PASA

PurposeTo determine whether supplementation with turmeric or curcumin extract effects pain and physical function in individuals with knee osteoarthritis (OA). Second, we investigated the therapeutic response (pain and function) of turmeric compared with non-steroidal anti-inflammatory drugs (NSAIDs).MethodsA search was conducted in MEDLINE, Embase, CINAHL and Cochrane Review. Inclusion criteria included randomised controlled trials reporting pain and physical function in humans with knee OA comparing turmeric therapy with NSAIDs or no therapy. Two reviewers screened 5273 abstracts. Risk of bias and quality were assessed via Cochrane Collaboration tool and CONSORT (Consolidated Standards of Reporting Trials) 2010, respectively.ResultsTen studies were included in the final analysis. Eight had high methodological quality and two were categorised as good with a mean CONSORT quality score of 21.1. Nine studies had adequate sequence generation and six had adequate allocation concealment. Participants and outcome assessors were blinded in eight studies. Three of the studies compared turmeric therapy to NSAIDs. All 10 studies showed improvement in pain and function from baseline with turmeric therapy (p≤0.05). In three studies comparing turmeric to NSAIDs, there were no differences in outcome scores (p>0.05). In all studies there were no significant adverse events in the turmeric therapy group.ConclusionCompared with placebo, there appears to be a benefit of turmeric on knee OA pain and function. Based on a small number of studies the effects are similar to that of NSAIDs. Variables such as optimal dosing, frequency and formulation remain unclear at this time.

Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [

Supplemental Digital Content is available in the text., Background. Acute perivascular rejection (AR) is common in lung recipients and increases the risk for chronic lung allograft dysfunction (CLAD). Hyaluronan (HA), an extracellular matrix constituent, accumulates in experimental AR and can act as an innate immune agonist, breaking tolerance and potentiating alloimmunity. We previously demonstrated HA accumulates in CLAD after human-lung transplantation. We sought to determine if HA accumulates in the bronchoalveolar lavage fluid (BALF) concurrent with AR in lung recipients. Methods. The cohort consisted of 126 first adult lung recipients at 5 transplant centers with a total of 373 BALF samples collected within the first posttransplant year. All samples were paired with a lung biopsy from the same bronchoscopy. BALF HA (ng/mL) was quantified by ELISA and log-transformed for analysis. Linear-mixed effect models, adjusted for potential confounders, were used to estimate the association between BALF HA concentration and the presence of AR on biopsy. The association between early posttransplant BALF HA levels and the development of CLAD was explored utilizing tertiles of maximum BALF HA level observed within the first 6 months of transplant. Results. In analyses adjusted for potential confounders, BALF HA concentration was significantly increased in association with AR (change in means on log-scale 0.31; 95% CI, 0.01-0.60; P = 0.044). When considered on the original scale (ng/mL), BALF HA concentrations were 1.36 times (36%) higher, on average, among samples with, versus without, AR. The cumulative incidence of CLAD was numerically higher in individuals in the highest tertiles of BALF HA level within the first 6 months after transplant, as compared with those in the lowest tertile; however, this difference was not statistically significant (P = 0.32). Conclusions. These results demonstrate accumulation of HA in clinical AR and suggest a mechanism by which innate and adaptive immune activation might interact in the development of AR and CLAD.

OBJECTIVE. The purpose of this study was to assess the image quality and resource utilization of single-injection, split-bolus, dual-enhancement abdominopelvic CT angiography (hereafter referred to as dual-enhancement CTA) performed for combined vascular and solid organ assessment compared with those of single-injection, single-enhancement abdominopelvic CT angiography (hereafter referred to as single-enhancement CTA) for vascular assessment in combination with additional examinations (CT, MRI, and US) performed to assess for malignancy in lung transplant candidates. MATERIALS AND METHODS. We retrospectively reviewed 100 patients who underwent abdominopelvic CTA examinations before lung transplant. Cohort A (n = 50) underwent dual-enhancement CTA and cohort B (n = 50) underwent single-enhancement CTA. Contrast opacification of the vasculature was assessed along the abdominal aorta through the right femoral artery. Solid organ enhancement was assessed in the right lobe of the liver and the right renal cortex. Measurements of mean radiation dose, contrast exposure, and cost of the studies (in U.S. dollars) were compared. RESULTS. Mean (± SD) vascular enhancement on dual-enhancement CTA and single-enhancement CTA was 334.2 ± 26.5 HU (coefficient of variation, 8.3%) and 340.0 ± 21.6 HU (coefficient of variation, 6.5%) (p = 0.23), respectively. For dual-enhancement CTA and single-enhancement CTA, mean liver enhancement was 125.8 ± 30.5 HU and 60.4 ± 6.9 HU (p < 0.01), respectively, whereas mean renal cortical enhancement was 260.3 ± 62.2 HU and 133.4 ± 38.6 HU (p < 0.01), respectively. The mean IV contrast volume was 150 mL for dual-enhancement CTA and 75 mL for single-enhancement CTA. Cohort A underwent six additional imaging studies (one of which was a CT colonography study with an effective dose of 19.0 mSv) at a total cost of $9840 per patient. Cohort B underwent 44 additional imaging studies (mean effective dose, 12.7 ± 6.5 mSv) at a total cost of $12,846 per patient (resulting in a 30.6% reduction in cost for dual-enhancement CTA studies; p < 0.0001). CONCLUSION. Dual-enhancement abdominopelvic CTA allows combined vascular and abdominopelvic solid organ assessment with improved image quality and a lower cost compared with traditional imaging pathways.

In the United States, an overall national decline in organ transplants has accompanied the substantial burden of COVID-19. Amidst significant regional variations in COVID-19, lung transplantation (LTx) remains a critical life-saving operation. Our LTx practice during the early pandemic may provide a blueprint for managing LTx in an era of continued community prevalence. Patients who underwent LTx at our institution between March 1 and May 20, 2020 were included. Recipient, operative, and donor characteristics were compared to those from our program in 2019, and COVID-19 testing practices were evaluated for March, April, and May to understand how our practice adapted to the pandemic. Our program performed 36 LTx, 33% more than the same period in 2019. Recipient, operative, and donor characteristics during COVID-19 were similar to those in 2019. By April 1, all donors and recipients underwent pretransplant COVID-19 testing, all returning negative results. To date, no recipients have developed posttransplant COVID-19. At our institution, pretransplant COVID-19 testing, use of local donor lungs, and avoidance of donors from areas of increased community penetration supported a safe and effective LTx practice during the early COVID-19 pandemic. Continued follow-up is required to ensure the long-term safety of these newly transplanted patients.

Long-term survival after lung transplant lags behind that of other commonly transplanted organs, reflecting the current incomplete understanding of the mechanisms involved in the development of posttransplant lung injury, rejection, infection, and chronic allograft dysfunction. To address this unmet need, 2 ongoing National Institute of Allergy and Infectious Disease funded studies through the Clinical Trials in Organ Transplant Consortium (CTOT) CTOT-20 and CTOT-22 were dedicated to understanding the clinical factors and biological mechanisms that drive chronic lung allograft dysfunction and those that maintain cytomegalovirus polyfunctional protective immunity. The CTOT-20 and CTOT-22 studies enrolled 800 lung transplant recipients at 5 North American centers over 3 years. Given the number and complexity of subjects included, CTOT-20 and CTOT-22 utilized innovative data transfers and capitalized on patient-entered data collection to minimize site manual data entry. The data were coupled with an extensive biosample collection strategy that included DNA, RNA, plasma, serum, bronchoalveolar lavage fluid, and bronchoalveolar lavage cell pellet. This Special Article describes the CTOT-20 and CTOT-22 protocols, data and biosample strategy, initial results, and lessons learned through study execution.

We describe an ultra-wide-bandwidth, low-frequency receiver ("UWL") recently installed on the Parkes radio telescope. The receiver system provides continuous frequency coverage from 704 to 4032 MHz. For much of the band (~60%) the system temperature is approximately 22K and the receiver system remains in a linear regime even in the presence of strong mobile phone transmissions. We discuss the scientific and technical aspects of the new receiver including its astronomical objectives, as well as the feed, receiver, digitiser and signal-processor design. We describe the pipeline routines that form the archive-ready data products and how those data files can be accessed from the archives. The system performance is quantified including the system noise and linearity, beam shape, antenna efficiency, polarisation calibration and timing stability., submitted to PASA

Background Rituximab is used for resistant SLE, but clinical response varies. We previously validated two interferon-stimulated-gene expression scores (IFN-Score-A and IFN-Score-B) that improved prediction of clinical outcomes in SLE. IFN-Score-A included most reported ISGs and predicted flares and glucocorticoid requirements. IFN-Score-B included ISGs that respond to multiple IFN subtypes and predicted development of SLE in At-Risk individuals. Diagnosis of SLE was associated with both scores, while only IFN-Score-B was elevated in RA. The British Society for Rheumatology Biologics Registry (BILAG-BR) collects samples for RTX-treated patients in the UK. MASTERPLANS ISA consortium to identify predictors of drug response. Methods Patients were recruited if they were starting a first cycle of RTX for active SLE (BILAG A or 2xBILAG B) despite previous cyclophosphamide or mycophenolate mofetil. Disease activity was measured using BILAG-2004. Clinical response was defined as improvement by > =1 grade in active BILAG-2004 systems with no worsening in other systems. Whole blood was collected into TEMPUS tubes and RNA extracted. IFN-Scores were measured using a custom Taqman array as previously described [El Sherbiny et al., 2018]. Multivariate logistic regression was used to test IFN-Scores and baseline clinical covariates as predictors of BILAG response at 6 months. Results Samples were available from 147 patients, of whom 84 had complete baseline and 6-month clinical data available and were included in this analysis. 40/84 (47.6%) patients had BILAG response at 6 months. In univariate and multivariate analysis, high IFN-Score-B expression was significantly associated with clinical response (see Table 1). Conclusion This preliminary analysis suggests that assessment of IFN activity has a role in predicting response to RTX. A novel IFN score (Score B) was more predictive than classic ISGs (Score A). These results add to a body of work showing that IFN-Score-B predicts clinically significant outcomes independently of overall IFN activity. Future work will analyse this biomarker in a larger cohort of patients and integrate with other putative clinical and biological predictors of response. Disclosures A. Alase None. Z. Wigston None. A. Burska None. M. Md Yusof None. J. Reynolds None. M. Wittmann None. I. Bruce None. E.M. Vital None.

Objective Posttransplant depression has been linked to increased risk for adverse outcomes in lung transplant patients. Maintaining target serum immunosuppressant levels is also essential for optimal lung transplant clinical outcome and may be a crucial predictor of outcomes. Because depression could affect medication nonadherence, resulting in out-of-range immunosuppressant levels, we examined the relationship between posttransplant depression, immunosuppressant medication trough level variability, indexed by out-of-range values on clinical outcomes and coefficient of variability, and clinical outcomes. Method A consecutive series of 236 lung transplant recipients completed the Center for Epidemiological Studies-Depression two-month posttransplant. Immunosuppressant trough levels (i.e., tacrolimus or cyclosporine) within the range of individualized immunosuppressant targets were obtained at three-, six-, nine-month follow-up clinic visits. Clinical outcomes including hospitalizations and mortality were obtained from medical records. Results Fourteen percent of patients were classified as depressed (Center for Epidemiological Studies-Depression ≥16), 144 (61%) of patients had at least 25% out-of-range immunosuppressant values, and the average coefficient of variability was 36%. Over a median of 2.6 years (interquartile range = 1.2), 32 participants died (14%) and 144 (61%) had at least one unplanned, transplant-related hospitalization. Both depression (hazard ratio = 1.45 (1.19, 1.76), p Conclusions Early posttransplant depression was associated with significantly worse clinical outcomes. While immunosuppressant level variability is also related to adverse outcomes, such variability does not account for increased risk observed with depression.

Importance Inhaled nitric oxide (iNO) is commonly administered for selectively inhaled pulmonary vasodilation and prevention of oxidative injury after lung transplant (LT). Inhaled epoprostenol (iEPO) has been introduced worldwide as a cost-saving alternative to iNO without high-grade evidence for this indication. Objective To investigate whether the use of iEPO will lead to similar rates of severe/grade 3 primary graft dysfunction (PGD-3) after adult LT when compared with use of iNO. Design, setting, and participants This health system-funded, randomized, blinded (to participants, clinicians, data managers, and the statistician), parallel-designed, equivalence clinical trial included 201 adult patients who underwent single or bilateral LT between May 30, 2017, and March 21, 2020. Patients were grouped into 5 strata according to key prognostic clinical features and randomized per stratum to receive either iNO or iEPO at the time of LT via 1:1 treatment allocation. Interventions Treatment with iNO or iEPO initiated in the operating room before lung allograft reperfusion and administered continously until cessation criteria met in the intensive care unit (ICU). Main outcomes and measures The primary outcome was PGD-3 development at 24, 48, or 72 hours after LT. The primary analysis was for equivalence using a two one-sided test (TOST) procedure (90% CI) with a margin of 19% for between-group PGD-3 risk difference. Secondary outcomes included duration of mechanical ventilation, hospital and ICU lengths of stay, incidence and severity of acute kidney injury, postoperative tracheostomy placement, and in-hospital, 30-day, and 90-day mortality rates. An intention-to-treat analysis was performed for the primary and secondary outcomes, supplemented by per-protocol analysis for the primary outcome. Results A total of 201 randomized patients met eligibility criteria at the time of LT (129 men [64.2%]). In the intention-to-treat population, 103 patients received iEPO and 98 received iNO. The primary outcome occurred in 46 of 103 patients (44.7%) in the iEPO group and 39 of 98 (39.8%) in the iNO group, leading to a risk difference of 4.9% (TOST 90% CI, -6.4% to 16.2%; P = .02 for equivalence). There were no significant between-group differences for secondary outcomes. Conclusions and relevance Among patients undergoing LT, use of iEPO was associated with similar risks for PGD-3 development and other postoperative outcomes compared with the use of iNO. Trial registration ClinicalTrials.gov identifier: NCT03081052.

Introduction Precision oncology (PO) is a growing treatment approach in the era of next-generation sequencing (NGS) and matched therapies. Effective delivery of PO in the community has not been extensively studied. Our program developed a virtual molecular tumor board (MTB) strategy to help guide PO care. Materials and Methods Over 18 months, eligible adult patients with advanced, incurable solid tumor malignancies were enrolled in a molecular profiling (MP) study using the Foundation Medicine NGS panel. Results were reviewed through a weekly, videoconferenced MTB conducted across our largely rural integrated health system. Recommendations from the MTB were used to identify actionable alterations (AAs). Feasibility of PO care delivery was assessed as the primary outcome. Secondary outcomes included the frequency of AAs, genomic matched treatments, genomic matched clinical trial enrollment, and clinical outcomes. Results A total of 120 participants with a variety of advanced tumor types were enrolled. Of these, 109 (90.8%) had successful MP. Treatment on the basis of an AA was recommended by the MTB in 58% of patients (63 of 109) who had a successful MP result. For those completing MP, treatments included enrollment in a genomic matched clinical trial (n = 16; 14.6%) and genomic matched treatment with a Food and Drug Administration–approved agent (n = 23; 21.1%). Response and survival data were similar regardless of the matched treatment option chosen. Conclusion A video-conferenced MTB-facilitated NGS testing and treatment delivery system was implemented in our integrated community oncology program. Continued use of this model aims to increase understanding of the impact of PO in this setting.

Context: Dosing parameters are needed to ensure the best practice guidelines for knee osteoarthritis. Objective: To determine whether resistance training affects pain and physical function in individuals with knee osteoarthritis, and whether a dose-response relationship exists. Second, we will investigate whether the effects are influenced by Kellgren-Lawrence grade or location of osteoarthritis. Data Sources: A search for randomized controlled trials was conducted in MEDLINE, Embase, and CINAHL, from their inception dates, between November 1, 2018, and January 15, 2019. Keywords included knee osteoarthritis, knee joint, resistance training, strength training, and weight lifting. Study Selection: Inclusion criteria were randomized controlled trials reporting changes in pain and physical function on humans with knee osteoarthritis comparing resistance training interventions with no intervention. Two reviewers screened 471 abstracts; 12 of the 13 studies assessed were included. Study Design: Systematic review. Level of Evidence: Level 2. Data Extraction: Mean baseline and follow-up Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and standard deviations were extracted to calculate the standard mean difference. Articles were assessed for methodological quality using the CONSORT (Consolidated Standards of Reporting Trials) 2010 scale and Cochrane Collaboration tool for assessing risk of bias. Results: The 12 included studies had high methodological quality. Of these, 11 studies revealed that resistance training improved pain and/or physical function. The most common regimen was a 30- to 60-minute session of 2 to 3 sets of 8 to 12 repetitions with an initial resistance of 50% to 60% of maximum resistance that progressed over 3 sessions per week for 24 weeks. Seven studies reported Kellgren-Lawrence grade, and 4 studies included osteoarthritis location. Conclusion: Resistance training improves pain and physical function in knee osteoarthritis. Large effect sizes were associated with 24 total sessions and 8- to 12-week duration. No optimal number of repetitions, maximum strength, or frequency of sets or repetitions was found. No trends were identified between outcomes and location or Kellgren-Lawrence grade of osteoarthritis.

The UK Government is under growing pressure to improve the performance of public services whilst reducing costs. Services are under stress at a national and local level. This pressure to improve the value being delivered to citizens whilst reducing operational costs and risks is analogous to the pressure the financial service industry has been under since 2008. Financial services organisations are increasingly turning to Distributed Ledger Technology (DLT) to address these challenges. Distributed ledger technology is enabling a new paradigm in financial services where organisations collaborate and integrate at the infrastructure and transaction level, freeing up resources for innovation and competition at the application and value proposition level; what we are seeing is wholesale business model transformation. This paper explores how a new Public Value Network might enable Public Service Organisations to: 1. Retain their existing decentralised business models, (budgets, decision making, business, service design) yet optimise and synchronise locally and nationally 2. Collaborate in the design and delivery of frictionless human centric services 3. Automate- services, adherence to and auditing of regulation, policy and process 4. Improve financial transparency across public service value chain.

We examined practice patterns and surgical indications in the management of common shoulder procedures by surgeons practicing at physician-owned facilities.This study was a retrospective analysis of 501 patients who underwent arthroscopic shoulder procedures performed by five surgeons in our practice at one of five facilities during an 18-month period. Two of the facilities were physician-owned, and three of the five surgeons were shareholders. Demographics, insurance status, symptom duration, time from injury/symptom onset to the decision to perform surgery (at which time surgical consent is obtained), and time to schedule surgery were studied to determine the influence of facility type and physician shareholder status.Median duration of symptoms before surgery was significantly shorter in workers' compensation patients than in non-workers' compensation patients (47% less; P0.0001) and in men than in women (31% less; P0.001), but was not influenced by shareholder status or facility ownership (P0.05). Time between presentation and surgical consent was not influenced by facility ownership (P = 0.39) or shareholder status (P = 0.50). Time from consent to procedure was 13% faster in physician-owned facilities than in non-physician-owned facilities (P = 0.03) and 35% slower with shareholder physicians than with nonshareholder physicians (P0.0001).The role of physician investment in private healthcare facilities has caused considerable debate in the orthopaedic surgery field. To our knowledge, this study is the first to examine the effects of shareholder status and facility ownership on surgeons' practice patterns, surgical timing, and measures of nonsurgical treatment before shoulder surgery.Neither shareholder status nor facility ownership characteristics influenced the speed with which surgeons determined that shoulder surgery was indicated or surgeons' use of preoperative nonsurgical treatment. After the need for surgery was determined, patients underwent surgery sooner at physician-owned facilities than at non-physician-owned facilities and with nonshareholder physicians than with shareholder physicians.Level III.

Our objective was to examine variability in pain levels following lung transplantation, and examine individual biopsychosocial factors influencing changes in pain.We performed a retrospective study of a cohort of 150 patients transplanted and discharged from Duke University Hospital between January 2015 and September 2016. During hospitalization and at clinic visits up to two months after discharge, subjective pain ratings were obtained using a 0-10 Numeric Rating Scale. Psychiatric diagnoses of anxiety and depression and Center for Epidemiological Studies - Depression (CES-D) scores collected after hospital discharge were examined as predictors of post-surgery pain. Medical and surgical variables were examined as covariates.During hospitalization, pain ratings decreased over time (p0.001). Predictors of higher pain levels included pre-transplant history of depression (p=0.001) and anxiety (p=0.04), bilateral lung transplant (p=0.03), and lower six-minute walk distance (p=0.02). Two months after discharge, 18% of patients reported continued pain and 34% remained on opioid pain medications. Two months after discharge, more frequent post-operative complications predicted higher pain levels in a univariate analysis (p=0.02) although this relationship was attenuated after adjustment for depression. In a multivariate analysis, elevated CES-D scores (p=0.002), and greater opioid use (p=0.031) predicted higher pain levels 2-months post-discharge.We conclude that patients with psychiatric comorbidities may be at risk for greater pain, and may require additional strategies for more effective pain management.

Breakthrough Listen is a ten-year initiative to search for signatures of technologies created by extraterrestrial civilizations at radio and optical wavelengths. Here, we detail the digital data recording system deployed for Breakthrough Listen observations at the 64-m aperture CSIRO Parkes Telescope in New South Wales, Australia. The recording system currently implements two recording modes: a dual-polarization, 1.125 GHz bandwidth mode for single beam observations, and a 26-input, 308-MHz bandwidth mode for the 21-cm multibeam receiver. The system is also designed to support a 3 GHz single-beam mode for the forthcoming Parkes ultra-wideband feed. In this paper, we present details of the system architecture, provide an overview of hardware and software, and present initial performance results., v2, accepted to PASA

Purpose Acute cellular rejection (ACR) is a histopathologic diagnosis made by assessment of transbronchial biopsies (TBBX). Consensus guidelines recommend a minimum of 5 alveolated samples for histologic adequacy; it is not uncommon for samples to be inadequate for diagnosis. This study was designed to determine what factors impact the recovery of adequate specimens for ACR grading, as well as explore discrepancies in “sample calling” between the pathologist & bronchoscopist. Methods Observational, single center study including retrospective chart review of 142 bronchoscopies with TBBX performed on 128 lung transplant recipients (LTRs) who underwent surveillance bronchoscopy between May 2017 & May 2018. For the purpose of our study we defined inadequate samples as Results Of 142 TBBX procedures, 22 (15.5%), resulted in inadequate sampling. Of note, pathologists called less sample fragments than bronchoscopists 70% of the time. Characteristics associated with inadequate sampling included both LTR & procedural characteristics (Table 1 & 2). Conclusion Bronchoscopists may overestimate the number of total fragments obtained compared with pathologists. Both demographic & procedure characteristics may aid in identifying LTRs at higher risk for inadequate sampling during TBBx.

Purpose Gastroesophageal reflux disease is common in lung transplant recipients and is thought to cause lung graft injury through aspiration of gastric contents. Bile acids in bronchoalveolar lavage (BAL) are putative markers of gastric microaspiration and associated with inflammation and earlier chronic lung allograft dysfunction (CLAD). Microaspiration is thought to augment CLAD risk through potentiation of acute rejection (AR), although this has not been demonstrated. We hypothesized that BAL bile acid levels would be associated with AR presence and severity. Methods Among all adult, first, bilateral lung transplants, performed at two large lung transplant centers 2010-2015, transbronchial biopsies obtained within the first-year post-transplant were categorized as spirometrically-significant or stable based on the presence or absence of ≥10% concurrent drop in FEV1. AR diagnosis was based histology and biopsies with concurrent infection were excluded. BAL supernatant levels of bile acids (taurocholic acid (TCA), glycocholic acid (GCA), cholic acid), and inflammatory proteins (IL6, CXCL8, S100A8, CCL2, IL1β, CCL5, IL1α, RAGE, S100A12, IL12) were compared between patient groups. Association between BA levels and subsequent CLAD or death/retransplant was assessed using Cox Proportional Hazards models, adjusted for relevant peri-transplant clinical covariates and AR group. Endpoints We identified 42 patients with spirometrically-significant AR, 56 patients with stable AR, and 81 patients with stable no-AR with available BAL samples (one sample per patient). BAL at time of spirometrically-significant AR, compared to other groups, had elevated levels of TCA (ANOVA

Purpose In lung transplant candidates with a high-calculated panel reactive antibodies (cPRA), the waitlist time and risk of death are considerable. Additionally, the presence of post-transplant HLA antibodies is associated with chronic lung allograft dysfunction (CLAD) and mortality. Our center designed a post-transplant multimodal antibody management protocol (PMAMP) in an effort to alter immune response and minimize antibody development of highly sensitized recipients (cPRA > 80) with the goal of improving transplant outcomes. Methods This is a single center, retrospective evaluation of our PMAMP. Lung transplant recipients with cPRA >80% were eligible for our PMAMP (Table 1). From April 2019 to April 2020, there were 5 eligible patients who underwent transplant. For comparison, matched historical control data was collected from 7 highly sensitized patients who underwent transplant from March 2003 to September 2008 but did not receive PMAMP. Demographics and outcome data were collected. Results Demographics and outcomes are described in Table 2. To date, all 5 patients who underwent PMAMP are alive with CLAD-free survival and no episodes of rejection with a median transplant follow-up time of 427 days. Of note, all patients in both groups experienced at least one infectious complication following transplant. Conclusion Our PMAMP shows promise for mediating CLAD-free survival, rejection, and extending post-transplant survival in highly sensitized candidates undergoing lung transplant; however, more data and follow-up is needed to ensure the safety and efficacy of this protocol.

Purpose: Preclinical and clinical studies have shown that marginal bone loss can be secondary to repeated disconnection and reconnection of abutments that affect the peri-implant mucosal seal. The aim of this systematic review and meta-analysis was to evaluate the impact of abutment disconnections/reconnections on peri-implant marginal bone level changes. Materials and Methods: To address this question, two reviewers independently performed an electronic search of three major databases up to October 2015 complemented by manual searches. Eligible articles were selected on the basis of prespecified inclusion and exclusion criteria after a two-phase search strategy and assessed for risk of bias. A random-effects meta-analysis was performed for marginal bone loss. Results: The authors initially identified 392 titles and abstracts. After evaluation, seven controlled clinical studies were included. Qualitative assessment of the articles revealed a trend toward protective marginal bone level preservation for implants with final abutment placement (FAP) at the time of implant placement compared with implants for which there were multiple abutment placements (MAP). The FAP group exhibited a marginal bone level change ranging from 0.08 to 0.34 mm, whereas the MAP group exhibited a marginal bone level change ranging from 0.09 to 0.55 mm. Meta-analysis of the seven studies reporting on 396 implants showed significantly greater bone loss in cases of multiple abutment disconnections/reconnections. The weighted mean difference in marginal bone loss was 0.19 mm (95% confidence interval, 0.06-0.32 mm), favoring bone preservation in the FAP group. Conclusion: Within the limitations of this meta-analysis, abutment disconnection and reconnection significantly affected peri-implant marginal bone levels. These findings pave the way for revisiting current restorative protocols at the restorative treatment planning stage to prevent incipient marginal bone loss.

BACKGROUND Gastroesophageal reflux disease (GERD) is a risk factor for chronic lung allograft dysfunction. Bile acids—putative markers of gastric microaspiration—and inflammatory proteins in the bronchoalveolar lavage (BAL) have been associated with chronic lung allograft dysfunction, but their relationship with GERD remains unclear. Although GERD is thought to drive chronic microaspiration, the selection of patients for anti-reflux surgery lacks precision. This multicenter study aimed to test the association of BAL bile acids with GERD, lung inflammation, allograft function, and anti-reflux surgery. METHODS We analyzed BAL obtained during the first post-transplant year from a retrospective cohort of patients with and without GERD, as well as BAL obtained before and after Nissen fundoplication anti-reflux surgery from a separate cohort. Levels of taurocholic acid (TCA), glycocholic acid, and cholic acid were measured using mass spectrometry. Protein markers of inflammation and injury were measured using multiplex assay and enzyme-linked immunosorbent assay. RESULTS At 3 months after transplantation, TCA, IL-1β, IL-12p70, and CCL5 were higher in the BAL of patients with GERD than in that of no-GERD controls. Elevated TCA and glycocholic acid were associated with concurrent acute lung allograft dysfunction and inflammatory proteins. The BAL obtained after anti-reflux surgery contained reduced TCA and inflammatory proteins compared with that obtained before anti-reflux surgery. CONCLUSIONS Targeted monitoring of TCA and selected inflammatory proteins may be useful in lung transplant recipients with suspected reflux and microaspiration to support diagnosis and guide therapy. Patients with elevated biomarker levels may benefit most from anti-reflux surgery to reduce microaspiration and allograft inflammation.

BACKGROUND Respiratory syncytial virus (RSV) infection in lung transplant recipients (LTRs) causes mortality rates of 10%-20% despite antiviral therapy. Ribavirin (RBV) has been used to treat RSV-infected LTRs with limited data. METHODS A retrospective study including all LTRs at Duke Hospital during January 2013-May 2017 with positive RSV polymerase chain reaction respiratory specimens was performed. RESULTS Fifty-six of 70 patients in the oral RBV group and 29 of 32 in the inhaled RBV group had symptomatic RSV infection. One patient receiving oral RBV had to prematurely stop drug due to significant nausea and vomiting. While unadjusted all-cause 1-year mortality was significantly higher in the inhaled RBV group (24.1% versus 7.1% [oral RBV], P = 0.03), adjusted hazard ratio (HR) for death and oral RBV use (compared to inhaled RBV), accounting for oxygen requirement and need for mechanical ventilation, showed the HR for death and oral RBV use was 0.38 ([0.10, 1.46], P = 0.38). The HR for death in patients with supplemental oxygen >2 L/min at diagnosis was 6.18 ([1.33, 26.83], P = 0.02). Kaplan-Meier curves showed patients with forced expiratory volume in 1 second decline ≥5% and ≥10% at 90 days post-RSV infection had a higher 1-year mortality (P = 0.004 and P = 0.001, respectively). CONCLUSIONS Oral and inhaled RBV appear to be well tolerated in LTRs, and our data support the use of oral RBV as a safe alternative to inhaled ribavirin in LTRs. Oxygen requirement >2 L/min at diagnosis and forced expiratory volume in 1 second decline ≥5% postinfection may be markers for increased mortality.

Severe acute respiratory virus syndrome 2 (SARS-CoV-2) has led to a worldwide pandemic. Early studies in solid organ transplant (SOT) recipients suggested a wide variety of presentations, however, there remains a paucity of robust data in this population. We conducted a systematic review and meta-analysis of SOT recipients with SARS-CoV-2 infection from January 1st t October 9th, 2020. Pooled incidence of symptoms, treatments and outcomes were assessed. Two hundred and fifteen studies were included for systematic review and 60 for meta-analysis. We identified 2,772 unique SOT recipients including 1,500 kidney, 505 liver, 141 heart and 97 lung. Most common presenting symptoms were fever and cough in 70.2% and 63.8% respectively. Majority (81%) required hospital admission. Immunosuppressive medications, especially antimetabolites, were decreased in 76.2%. Hydroxychloroquine and interleukin six antagonists were administered in59.5% and 14.9% respectively, while only few patients received remdesivir and convalescent plasma. Intensive care unit admission was 29% from amongst hospitalized patients. Only few studies reported secondary infections. Overall mortality was 18.6%. Our analysis shows a high incidence of hospital admission in SOT recipients with SARS-CoV-2 infection. As management of SARS-CoV-2 continues to evolve, long-term outcomes among SOT recipients should be assessed in future studies.

An emerging body of research has shown that there are large inequalities in access to higher education in South Africa. There remains a gap, however, in identifying how factors such as schooling background, academic performance, race and gender are linked with key higher education outcomes. In particular, the significance of these factors for first-choice degree attainment at university and in the subsequent transition to the labour market is of interest. This article addresses these questions by presenting a descriptive and multivariate analysis of data collected through a tracer study which interviewed graduates from two Eastern Cape universities. The results suggest that schooling background, race and gender are associated with study choices and unemployment. These findings have important implications both for equity and for the efficiency of higher education institutions. The article concludes with a discussion of potential policy responses and the implications for equity in higher education.

Medical institutions in industrial and developing countries are increasingly turning to functional foods as intervention in chronic disease. Advances in genetic engineering have provided methods of purposefully designing functional foods and bioactive compound-producing organisms. This literature review examines the recent history of biotechnological applications in functional food, the state of bioagricultural engineering for high-value compound production, and the challenges that developers face in promulgatingfunctional foods from biotechnological sources. Based on the literature reviewed, it is predicted that adding biotechnologically-produced compounds will be more successful in producing novel functional foods. Conclusion: Current functional food application is frequently hampered by a dearth of foods suitable to the purpose. The concurrent advent of biotechnology means that producers and clinicians are not constrained by limited and precarious natural development. Biotechnology has already produced altered dietary staples that can safely induce real health benefits, but the social approval of genetically modified foodstuffs is inconsistent at best. Modifying microalgae to produce micro and macronutrients, for harvest and incorporation into functional food products, provides the ideal specificity and reliability for bioactive compound use. However, its application in biomedical science is impeded by technical difficulty. It remains to be seen if microorganism engineering willbe able to meet the needs of its many stakeholders, including the functional food community. Nonetheless,the prospect of a flourishing functional food market, and the healthier population it will bring about, certainly makes it worth a try.

The focus of this article centers on three specific themes of disruption that are likely to affect the future of Christian higher education. The first theme examines the juxtaposition of faith-based institutional identity and its influence on a post-modern society. The second theme explores the disaggregation of traditional faculty functions and the impact on student learning and institutional effectiveness. The last theme addresses changing student demographics and the associated expectations of this post-traditional population. The magnitude and complexity of these themes requires dynamic and flexible leadership at the board, administrative, and faculty levels. This article distinguishes between disruptive and technical change, and identifies how each approach impacts the unique social concerns facing faith-based institutions today. The article concludes by proposing new models of institutional collaboration and innovative cultures of learning that will meet the pragmatic need for institutional ...

Purpose CLAD, mainly manifest as bronchiolitis obliterans syndrome (BOS), is the leading cause of late death in lung recipients. BOS develops despite routine immunosuppression and its pathogenesis is poorly understood. The histological correlate of BOS is bronchiolitis obliterans (BO), or airways fibrosis. We quantified over 700 immune-related genes in BO affected airways to better understand immune responses active in end-stage BOS. Methods Formalin fixed paraffin embedded lung tissue was procured at retransplantation for BOS (n=6). Unused donor tissue was used as normal control (n=5). Histologies of interest were isolated using laser capture microdissection (LCMD). Within each BOS lung, airways histologically affected by BO pathology, defined as intraluminal fibrous expansion, were isolated. Additionally, airways unaffected by evident fibrosis were isolated. Within each donor lung, histologically normal airways were isolated. Cellular RNA was extracted and multiplex gene expression analysis was performed using the NanoString PanCancer Immune Profiling Panel. Linear regression was used to compare gene expression among groups. The primary comparison was differential expression in BO affected vs. normal donor airways. We also compared expression in BO affected vs. unaffected airways within BOS explant lungs. P-values were corrected for multiple comparisons using Benjamini-Hochberg. Results Sixty-seven genes were significantly different between BO affected vs. normal donor airways, of which 52 had a fold change (FC) 2. Along with genes in adaptive immunity, several genes related to innate and humoral activation were significantly increased in BO affected airways. Among the innate immune genes with increased expression in BO were toll-like receptor 1 (FC 2.31) and its adaptor molecule CD14 (FC 5.26) in addition to the complement subcomponent C1s (FC 3.06), while those in humoral immunity included bone marrow stromal antigen 2 (FC 3.41), important to the growth and development of B-cells. No genes were significantly differentially expressed between BO affected vs. unaffected airways within BOS explant lungs. Conclusion Our results suggest innate and humoral immune responses are active in airways affected by BO pathology, and also in airways without evident fibrosis. Ongoing analyses of BO lesions through LCMD will provide new insights into CLAD pathogenesis.

Purpose The pulmonary microbiome modulates the immune milieu in the lung allograft and is in turn influenced by external factors such as microaspiration of oropharyngeal contents. A potential driver of microaspiration is gastroesophageal reflux disease (GERD), which has been associated with poor outcomes after lung transplantation. We aimed to compare the pulmonary microbiome in lung transplant recipients with and without GERD, and correlate microbial composition with concurrent lung inflammation. Methods We selected 22 GERD patients and 49 no-GERD controls from adult lung transplant recipients with 24-hour pH-impedance testing and bronchoalveolar lavage fluid (BAL) collection at 3 months post-transplant. BAL microbial communities were characterized by 16S rRNA gene sequencing. Ten inflammatory protein markers in BAL were measured by multiplex assay. Results Baseline patient characteristics including age, sex, primary disease, and transplant type were comparable between GERD and no-GERD groups. Shannon diversity index was lower (MD=-0.33, p=0.04), while Berger-Parker dominance index was higher (MD=0.10, p=0.03), in GERD patients compared to no-GERD controls. Hierarchical clustering of all samples by Bray-Curtis dissimilarity identified three distinct pneumotypes (Figure 1). GERD was significantly associated with one of these pneumotypes, PT1, which was enriched in multiple anaerobic oropharyngeal taxa including Prevotella and Veillonella. In GERD patients, the presence of PT1 compared to all others was associated with higher levels of IL-8 (p=0.03). Conclusion At time of GERD diagnosis, lung transplant recipients are more likely to have a pulmonary microbiome lower in diversity and enriched in oropharyngeal taxa. These perturbations are consistent with microaspiration and may contribute to allograft inflammation. Future studies are warranted to assess how the pulmonary microbiome changes over time in the context of GERD and its correlation with rejection and long-term outcomes.

Purpose Frailty is gaining increased recognition in the evaluation of lung transplant (LTx) candidates. The Fried Frailty Phenotype (FFP) index has been the most commonly used instrument and is associated with pre- and post-transplant morbidity and mortality. A novel, alternative approach to assessing frailty is the Cumulative Deficits Frailty Index (CFI), which evaluates health deficits across multiple domains that may aid in refining candidacy evaluation. As a preliminary assessment, we aimed to understand the distribution of frailty scores among LTx candidates and assess agreement between the FFP and the CFI. Methods This was a prospective, multi-center study of a subset of participants in the Clinical Trials in Organ Transplantation-20 cohort who completed both the FFP and CFI assessments pre-transplant. FFP was characterized using 5 criteria (unintentional weight loss, grip strength, energy levels, gait speed and physical activity), with FFP frailty defined (≥3 criteria frail; 1-2 pre-frail; and 0 not frail). The CFI was comprised of 40 health items abstracted from medical records with frailty defined as >10/40 (score of 0.25) deficits. Agreement between total FFP and CFI scores was assessed using Cohen's Kappa statistic and we also evaluated the distribution of CFI scores by each sub-component of the FFP. Results The cohort was comprised of 124 LTx candidates (median age 62 years, 56% male, median LAS 39) with 57% having restrictive lung disease. 11 (9%) LTx candidates were frail on the FFP, whereas 85 (69%) were pre-frail (grouped as non-frail). The median CFI score for the cohort was 0.23 (IQR 0.15-0.28) with 48 (39%) deemed frail. 79 (64%) had matching frail and non-frail statuses between the indices with agreement assessed as poor [Kappa 0.11 95% CI (-0.02 to 0.24)]. The median CFI scores were more concordant with FFP domains of weight loss [Frail FFP: 0.26 (IQR 0.20-0.29) vs. Not Frail FFP: 0.21 (0.15-0.28)], physical activity [0.25 (0.21-0.28) vs. 0.21 (0.15-0.28)], and gait speed [0.25 (0.19-0.33) vs. 0.21 (0.15-0.28)], but not with grip strength or energy levels. Conclusion In this multi-center study, agreement between frailty indices was poor suggesting the CFI potentially captures a different construct than FFP. The study is ongoing evaluating the prognostic utility of these indices with early post-transplant outcomes.

Purpose The occurrence of acute allograft injuries remains one of the most important factors responsible for the development of early chronic lung allograft dysfunction. We and others have previously demonstrated a consistent association between acute lung injury (ALI), acute perivascular rejection (AR) and lymphocytic bronchiolitis (LB) and the subsequent development of CLAD. However, the pathogenesis of these allograft injuries remains poorly understood. CXCL9, CXCL10, and CXCL11 are CXC chemokines induced by interferon-γ and act as potent chemoattractants of mononuclear cells (e.g., activated T-cells and NK cells). We hypothesized that episodes of ALI, AR and LB would be associated with increased activity of these CXCR3 chemokines, as measured in the BAL at the time of the injury. Methods The study cohort consisted of the first 200 lung transplant recipients enrolled in Clinical Trials in Organ Transplantation-20 (NCT02631720), a prospective multi-center observational study collecting serial clinical data and biologic samples from 5 North American transplant centers. Recipients received a median (Q1,Q3) of 5 (3, 6) bronchoscopies during the first-year post-transplant. Transbronchial biopsies (TBBXs) with no histopathologic evidence of allograft injury were classified as “healthy”. BALF CXCL9, CXCL10 and CXCL11 mean fluorescence intensities (MFIs) were measured using luminex bead assays. To evaluate differences in CXCR3 chemokine levels between allograft injuries and healthy biopsies, multivariable linear mixed effects models were constructed taking into account repeated measurements from recipients. Results There were 844 TBBXs with 249(30%) episodes of allograft injury observed. There were 173(20%) episodes of AR, 30(4%) episodes of LB and 42(5%) episodes of ALI. Biopsies with AR, LB or ALI were associated with significant elevations in all three chemokines compared with healthy biopsies (p Conclusion We demonstrate for the first time in a multicenter study, CXCR3 chemokine elevations during episodes of acute allograft injury. These findings support the association of CXCR3 chemokines during episodes of AR, LB and ALI, and may potentially offer novel therapeutic targets to prevent and treat these deleterious events.

Purpose Diagnosis of CLAD after lung transplantation (LT) requires sustained decline in lung function and exclusion of other etiologies for the decline. The limitations of relying primarily on pulmonary function test (PFT) decline to define CLAD onset for large cohort studies are not well characterized. Using a large, prospective, multicenter cohort of LT recipients, we sought to implement a rigorous approach to identify and confirm CLAD using automated analysis of serial PFT trajectory combined with local site adjudication to rule out exclusionary conditions. Methods The CTOT-20 cohort consists of 803 adult first LT recipients enrolled between 2015 and 2018 from 5 North American centers. PFT data transfers occurred monthly from sites to the data coordinating center, which applied an automated process using SAS code to identify potential CLAD in subjects who survived at least 90 days and had at least 5 PFTs. Potential CLAD cases, defined by sustained PFT decline per ISHLT definition, were sent to the local site to either identify alternative reasons for the decline or confirm CLAD. The site adjudication process included systematic assessment of clinical findings, bronchoscopy, microbiology, pathology, and radiographic information. Results 746 subjects were included in the analysis and had on average 18.9 (range 5-77) PFTs. Potential CLAD was identified a total of 379 times in 195 subjects based on PFT decline. CLAD was confirmed by the local site PI in 108/195 subjects (55.4%) and the mean time to CLAD onset was 14.8 (range 3.6-39.6) months. CLAD was confirmed even less frequently during earlier timepoints (28% in months 0-6, 43% in months 7-12, and 52% in months 13-18). The most frequent concurrent conditions excluding CLAD diagnosis were active infection (34.4%), airways stenosis (16.0%), pleural effusion/disease (14.9%), and acute rejection (14.1%). Conclusion Utilizing an automated approach to identify potential CLAD supplemented by local site adjudication, we found that the majority of potential CLAD qualifying events by PFT decline had evident alternative explanations. Our results indicate that CLAD adjudication utilizing a broad spectrum of clinical information is critical. This approach was used effectively across multiple centers and provides a robust strategy that can be leveraged in future multicenter CLAD studies.

Background Lung transplant recipients commonly develop invasive fungal infections (IFIs), but the most effective strategies to prevent IFIs following lung transplantation are not known. Methods We prospectively collected clinical data on all patients who underwent lung transplantation at a tertiary care academic hospital from January 2007–October 2014. Standard antifungal prophylaxis consisted of aerosolized amphotericin B lipid complex during the transplant hospitalization. For the first 180 days after transplant, we analyzed prevalence rates and timing of IFIs, risk factors for IFIs, and data from IFIs that broke through prophylaxis. Results In total, 156 of 815 lung transplant recipients developed IFIs (prevalence rate, 19.1 IFIs per 100 surgeries, 95% confidence interval [CI] 16.4–21.8%). The prevalence rate of invasive candidiasis (IC) was 11.4% (95% CI 9.2–13.6%), and the rate of non-Candida IFIs was 8.8% (95% CI 6.9–10.8%). First episodes of IC occurred a median of 31 days (interquartile range [IQR] 16–56 days) after transplant, while non-Candida IFIs occurred later, at a median of 86 days (IQR 40–121 days) after transplant. Of 169 IFI episodes, 121 (72%) occurred in the absence of recent antifungal prophylaxis; however, IC and non-Candida breakthrough IFIs were observed, most often representing failures of micafungin (n = 16) and aerosolized amphotericin B (n = 24) prophylaxis, respectively. Conclusions Lung transplant recipients at our hospital had high rates of IFIs, despite receiving prophylaxis with aerosolized amphotericin B lipid complex during the transplant hospitalization. These data suggest benefit in providing systemic antifungal prophylaxis targeting Candida for up to 90 days after transplant and extending mold-active prophylaxis for up to 180 days after surgery.

BACKGROUND Chronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD. METHODS We performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC). RESULTS Differential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell–mediated cytotoxicity, and cytokine–cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29–4.53). CONCLUSIONS BAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD.