Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks' gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks' gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. FINDINGS: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference -3·39%, 90% CI -8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. INTERPRETATION: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks' gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. FUNDING: UK Medical Research Council and Indian Department of Biotechnology.

Uncertainty and Communication Preferences Among Patients Undergoing Lung Transplant Evaluation: A Mixed-Methods Study.

OBJECTIVE: Higher uncertainty is associated with poorer quality of life and may be impacted by clinician communication about the future. We determined how patients undergoing lung transplant evaluation experience uncertainty and communication about the future from clinicians. METHODS: We performed a convergent parallel mixed-methods study using a cross-sectional survey and semistructured interviews. Patients undergoing lung transplant evaluation at the University of Colorado and the University of Washington answered questions about future communication and completed the Mishel Uncertainty in Illness Scale-Adult (MUIS-A; range 33-165, higher scores indicate more uncertainty). Interviews were analyzed using content analysis. Integration of survey and interview results occurred during data interpretation. RESULTS: A total of 101 patients completed the survey (response rate: 47%). Twelve survey participants completed interviews. In the survey, most patients identified changing family roles as important (76%), which was infrequently discussed with clinicians (31%). Most patients (86%) worried about the quality of their life in the future, and 74% said that not knowing what to expect in the future prevented them from making plans. The mean MUIS-A score was 85.5 (standard deviation 15.3). Interviews revealed three themes: (1) uncertainty of the future distresses participants; (2) participants want practical information from clinicians; and (3) communication preferences vary among participants. CONCLUSION: Participants experienced distressing uncertainty and wanted information about the future. Communication topics that were important to participants were not always addressed by physicians. Clinicians should address how chronic lung disease and lung transplant can directly impact patients' lives and support patients to cope with uncertainty.

Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Social and biologic determinants in lung transplant allocation.

PURPOSE OF REVIEW: Lung transplant is a life-saving intervention for many with end-stage lung disease. As usable donor lungs are a limited resource and the risk of death on the waitlist is not uniform among candidates, organ allocation must consider many variables in order to be equitable. RECENT FINDINGS: The lung allocation score (LAS) system, implemented in 2005, accounted for disease severity, risk of death without transplant, and 1-year survival estimates; however, recipient size, allosensitization, and blood type, biologic features that influence donor pool for a given recipient, do not impact allocation priority. Additionally, social determinants such as geography, socioeconomic status, race, and ethnicity can impact the likelihood of receiving a transplant. This has resulted in certain groups being transplanted at lower rates and at higher risk of dying on the waitlist. In order to address these disparities, lung organ allocation in the United States transitioned to a continuous distribution system using the composite allocation score (CAS) on 9 March 2023. SUMMARY: In this article, we will review some of the data demonstrating the impact that biologic and social determinants have had on lung allocation in order to provide background as to why these have been incorporated into the CAS.

Planned delivery or expectant management in preeclampsia: an individual participant data meta-analysis.

OBJECTIVE: Pregnancy hypertension is a leading cause of maternal and perinatal mortality and morbidity. Between 34+0 and 36+6 weeks gestation, it is uncertain whether planned delivery could reduce maternal complications without serious neonatal consequences. In this individual participant data meta-analysis, we aimed to compare planned delivery to expectant management, focusing specifically on women with preeclampsia. DATA SOURCES: We performed an electronic database search using a prespecified search strategy, including trials published between January 1, 2000 and December 18, 2021. We sought individual participant-level data from all eligible trials. STUDY ELIGIBILITY CRITERIA: We included women with singleton or multifetal pregnancies with preeclampsia from 34 weeks gestation onward. METHODS: The primary maternal outcome was a composite of maternal mortality or morbidity. The primary perinatal outcome was a composite of perinatal mortality or morbidity. We analyzed all the available data for each prespecified outcome on an intention-to-treat basis. For primary individual patient data analyses, we used a 1-stage fixed effects model. RESULTS: We included 1790 participants from 6 trials in our analysis. Planned delivery from 34 weeks gestation onward significantly reduced the risk of maternal morbidity (2.6% vs 4.4%; adjusted risk ratio, 0.59; 95% confidence interval, 0.36-0.98) compared with expectant management. The primary composite perinatal outcome was increased by planned delivery (20.9% vs 17.1%; adjusted risk ratio, 1.22; 95% confidence interval, 1.01-1.47), driven by short-term neonatal respiratory morbidity. However, infants in the expectant management group were more likely to be born small for gestational age (7.8% vs 10.6%; risk ratio, 0.74; 95% confidence interval, 0.55-0.99). CONCLUSION: Planned early delivery in women with late preterm preeclampsia provides clear maternal benefits and may reduce the risk of the infant being born small for gestational age, with a possible increase in short-term neonatal respiratory morbidity. The potential benefits and risks of prolonging a pregnancy complicated by preeclampsia should be discussed with women as part of a shared decision-making process.

Two-year follow-up of infant and maternal outcomes after planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): A randomised controlled trial.

OBJECTIVE: We evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes. DESIGN: Parallel-group, non-masked, randomised controlled trial. SETTING: Forty-six maternity units in the UK. POPULATION: Women with pre-eclampsia between 34+0 and 36+6  weeks of gestation, without severe disease, were randomised to planned delivery or expectant management. MAIN OUTCOME MEASURES: Infant neurodevelopmental outcome at 2 years of age, using the Parent Report of Children's Abilities - Revised (PARCA-R) composite score. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were enrolled in the trial, with 450 women allocated to planned delivery and 451 women allocated to expectant management. At the 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) allocated to expectant management. The mean composite standardised PARCA-R scores were 89.5 (SD 18.2) in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of -2.4 points (95% CI -5.4 to 0.5 points). CONCLUSIONS: In infants of women with late preterm pre-eclampsia, the average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management was pursued. With the lower than anticipated follow-up rate there was limited power to demonstrate that these scores did not differ, but the small between-group difference in PARCA-R scores is unlikely to be clinically important.

Discrete Virus Factories Form in the Cytoplasm of Cells Coinfected with Two Replication-Competent Tagged Reporter Birnaviruses That Subsequently Coalesce over Time.

The Birnaviridae family, responsible for major economic losses to poultry and aquaculture, is composed of nonenveloped viruses with a segmented double-stranded RNA (dsRNA) genome that replicate in discrete cytoplasmic virus factories (VFs). Reassortment is common; however, the underlying mechanism remains unknown given that VFs may act as a barrier to genome mixing. In order to provide new information on VF trafficking during dsRNA virus coinfection, we rescued two recombinant infectious bursal disease viruses (IBDVs) of strain PBG98 containing either a split GFP11 or a tetracysteine (TC) tag fused to the VP1 polymerase (PBG98-VP1-GFP11 and PBG98-VP1-TC). DF-1 cells transfected with GFP1-10 prior to PBG98-VP1-GFP11 infection or stained with a biarsenical derivative of the red fluorophore resorufin (ReAsH) following PBG98-VP1-TC infection, had green or red foci in the cytoplasm, respectively, that colocalized with VP3 and dsRNA, consistent with VFs. The average number of VFs decreased from a mean of 60 to 5 per cell between 10 and 24 h postinfection (hpi) (P < 0.0001), while the average area increased from 1.24 to 45.01 µm2 (P < 0.0001), and live cell imaging revealed that the VFs were highly dynamic structures that coalesced in the cytoplasm. Small VFs moved faster than large (average 0.57 µm/s at 16 hpi compared to 0.22 µm/s at 22 hpi), and VF coalescence was dependent on an intact microtubule network and actin cytoskeleton. During coinfection with PBG98-VP1-GFP11 and PBG98-VP1-TC viruses, discrete VFs initially formed from each input virus that subsequently coalesced 10 to 16 hpi, and we speculate that Birnaviridae reassortment requires VF coalescence.IMPORTANCE Reassortment is common in viruses with segmented double-stranded RNA (dsRNA) genomes. However, these viruses typically replicate within discrete cytoplasmic virus factories (VFs) that may represent a barrier to genome mixing. We generated the first replication competent tagged reporter birnaviruses, infectious bursal disease viruses (IBDVs) containing a split GFP11 or tetracysteine (TC) tag and used the viruses to track the location and movement of IBDV VFs, in order to better understand the intracellular dynamics of VFs during a coinfection. Discrete VFs initially formed from each virus that subsequently coalesced from 10 h postinfection. We hypothesize that VF coalescence is required for the reassortment of the Birnaviridae This study provides new information that adds to our understanding of dsRNA virus VF trafficking.

Perioperative anidulafungin combined with triazole prophylaxis for the prevention of early invasive candidiasis in lung transplant recipients.

BACKGROUND: Invasive candidiasis (IC) is a substantial cause of morbidity and mortality among lung transplant recipients (LTRs). Postoperative factors include prolonged hospital stay, central lines, delayed chest closure, and dehiscence increase IC risk. Correspondingly, current guidelines propose targeted IC coverage early posttransplant with fluconazole or an echinocandin. METHODS: This retrospective analysis was performed on LTRs from January 2016 to January 2020 and evaluated effectiveness of a recent protocol utilizing perioperative anidulafungin for early IC prevention in addition to long-term triazole antifungal prophylaxis. Prior to this protocol, patients were primarily established on itraconazole prophylaxis alone. The primary endpoint was proven or probable IC within 90 days after transplant. Multivariable logistic regression modeling was used to assess risk factors for invasive fungal infection (IFI). RESULTS: Among 144 LTRs, there was a numerically lower incidence of IC in the protocol group, although not statistically significant (6% vs. 13%, p = 0.16). Incidence of proven or probable IFI was 7.5% in the protocol cohort and 19.5% in the pre-protocol cohort (p = 0.038). In multivariable analysis, when controlling for lung allocation score (OR 1.04, 95% CI 1.01-1.08), donor perioperative culture with fungal growth (OR 2.92, 95% CI 1.02-8.92), and dehiscence (OR 3.54, 95% CI 1.14-10.85), protocol cohort was not significantly associated with IFI (OR 0.41, 95% CI 0.12-1.23). CONCLUSIONS: To our knowledge, this is the first study investigating combination triazole/echinocandin use in the early post-lung transplant period. These findings demonstrate that in-hospital anidulafungin offers unclear benefit for early IC prevention when used in combination with triazole prophylaxis.

Planned early delivery for late preterm pre-eclampsia in a low- and middle-income setting: a feasibility study.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity globally. Planned delivery between 34+0 and 36+6 weeks may reduce adverse pregnancy outcomes but is yet to be evaluated in a low and middle-income setting. Prior to designing a randomised controlled trial to evaluate this in India and Zambia, we carried out a 6-month feasibility study in order to better understand the proposed trial environment and guide development of our intervention. METHODS: We used mixed methods to understand the disease burden and current management of pre-eclampsia at our proposed trial sites and explore the acceptability of the intervention. We undertook a case notes review of women with pre-eclampsia who delivered at the proposed trial sites over a 3-month period, alongside facilitating focus group discussions with women and partners and conducting semi-structured interviews with healthcare providers. Descriptive statistics were used to analyse audit data. A thematic framework analysis was used for qualitative data. RESULTS: Case notes data (n = 326) showed that in our settings, 19.5% (n = 44) of women with pre-eclampsia delivering beyond 34 weeks experienced an adverse outcome. In women delivering between 34+0 and 36+6 weeks, there were similar numbers of antenatal stillbirths [n = 3 (3.3%)] and neonatal deaths [n = 3 (3.4%)]; median infant birthweight was 2.2 kg and 1.9 kg in Zambia and India respectively. Lived experience of women and healthcare providers was an important facilitator to the proposed intervention, highlighting the serious consequences of pre-eclampsia. A preference for spontaneous labour and limited neonatal resources were identified as potential barriers. CONCLUSIONS: This study demonstrated a clear need to evaluate the intervention and highlighted several challenges relating to trial context that enabled us to adapt our protocol and design an acceptable intervention. Our study demonstrates the importance of assessing feasibility when developing complex interventions, particularly in a low-resource setting. Additionally, it provides a unique insight into the management of pre-eclampsia at our trial settings and an understanding of the knowledge, attitudes and beliefs underpinning the acceptability of planned early delivery.

Pre-eclampsia is a complication of pregnancy and is one of the major causes of pregnancy-related death and serious illness for women and babies around the world. Most of these deaths occur in lower income countries in Africa and Asia. Signs of pre-eclampsia include high blood pressure and protein in the urine. It is unpredictable and may affect different organs within the woman, leading to seizures, stroke and even death if not well managed. It can also affect the baby's growth and in severe cases lead to stillbirth. We know that birth of the baby (and placenta) is the only cure for pre-eclampsia. Currently, it is recommended by the World Health Organisation that all women with pre-eclampsia are offered planned early birth once they reach 37 weeks of pregnancy, unless they develop severe complications needing intervention sooner than this. However, research from higher income countries has shown that planned early birth from 34 weeks of pregnancy may reduce serious complications in the woman, without causing harm to the baby. We are designing a clinical trial to find out whether, in women with pre-eclampsia between 34 and 37 weeks of pregnancy, it is better to offer planned early birth or to offer close monitoring until either they reach 37 weeks, or a complication develops requiring emergency intervention. Before designing this trial, we carried out a study in order to establish whether the main trial would be possible, and acceptable to the local community, at our potential trial sites in India and Zambia.

Split-Bolus, Single-Acquisition, Dual-Phase Abdominopelvic CT Angiography for the Evaluation of Lung Transplant Candidates: Image Quality and Resource Utilization.

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.

The cost effectiveness of vaginal versus abdominal repair of vesicovaginal fistulae.

INTRODUCTION AND HYPOTHESIS: The objective was to assess the comparative provider costs of vaginal and open abdominal repair of vesicovaginal fistula (VVF) and to determine the most cost-effective means of managing VVF. METHODS: A prospectively acquired database of all women undergoing VVF repair by a single surgeon between 2007 and 2015 was retrospectively reviewed to determine operating time, perioperative complications, inpatient stay and 30-day readmissions. The success and cost of the VVF repair were identified. Statistical analysis was by unpaired t test, Chi-squared test and Mann-Whitney U test. RESULTS: Forty-seven consecutive women of mean age 51 years (range 21-88) undergoing a first attempt at VVF repair at our institution were included; 32(68%) had vaginal repair with Martius fat pad interposition and 15 (32%) had open abdominal repair with omental interposition. There were no perioperative complications or 30-day readmissions in either group. Mean operative time was longer for open abdominal (223.4 min) than vaginal repair (196.9 min). Median inpatient stay was longer for an open abdominal (8 days) than for a vaginal approach (4 days). Successful anatomical closure was achieved in 91% of vaginal and 86% of open abdominal repairs at first attempt, and in 100% after second repair, where required. Mean/median costs for an abdominal repair were significantly higher, at £4,608.69/£4,169.20 than for vaginal repair at £3,381.50/£3,009.24 (P<0.05). CONCLUSIONS: Vesicovaginal fistulae were successfully repaired in 89% of cases at first attempt. The success rate did not differ between approaches. Vaginal repair is significantly more cost-effective than abdominal repair owing to the shorter operative time and length of stay.

Depression, Immunosuppressant Levels, and Clinical Outcomes in Postlung Transplant Recipients.

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 < . 01) and immunosuppressant variation (immunosuppressant out-of-range: hazard ratio = 1.41 (1.10, 1.81), p < .01) independently predicted more frequent hospitalizations and higher mortality. 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.

Parenteral administration of oral medications in lung transplant recipients: An underrecognized problem.

Microcrystalline cellulose (MCC) is an insoluble material commonly used as a binder and filler in oral medications. Identification of pulmonary intravascular deposition of MCC in transbronchial biopsies from lung transplant (LT) recipients following parenteral injection of oral medications has only been reported once. A search of our surgical pathology electronic database was performed from January 1, 2000 to November 1, 2017 using the text "transplant transbronchial." The diagnosis field for all cases retrieved was then searched for the text "cellulose." These cases were queried for patient demographics and outcomes. Between January 1, 2000 and November 1, 2017, 1558 lung transplants were performed in 1476 individual patients at our institution; 12 were identified to have MCC in their lung tissue. Patients with MCC identified on biopsies were more likely to be transplanted for cystic fibrosis versus other indications and younger versus older. MCC identified in 2 of our cases was favored to be donor derived. Of the 12 patients, 6 (50%) are deceased. MCC within the pulmonary vasculature may be an indicator of increased complications, mortality, or shortened survival in LT recipients. Detecting intravascular MCC and distinguishing it from aspirated foreign material can be challenging. Awareness of the differential diagnosis for pulmonary foreign material is of paramount importance for the pathologist.

Early experience with the use of hepatitis C antibody-positive, nucleic acid testing-negative donors in lung transplantation.

Historically, potential lung donors who have detectable antibodies to hepatitis C virus have been declined by most centers due to concern for possible disease transmission. We sought to evaluate hepatitis C viral transmission rates from donors who were known to be HCV Ab positive but HCV NAT negative. We performed a single-center retrospective review of a prospectively collected database for lung transplant recipients at our center including HCV Ab+NAT- donors (approved January 2017). Donor and recipient demographic data were compiled, and records were queried to ascertain rate of seroconversion. During the study period (1/1/17 to 8/9/17), a total of 64 recipients underwent lung transplantation. Thirteen (20%) donors were HCV Ab+NAT-. All recipients of HCV Ab+NAT- grafts were HCV Ab- at the time of transplant. Recipients of grafts from HCV Ab+NAT- donors underwent protocol NAT at 2 and 12 months and all are NAT- to date. One recipient developed reactive HCV Ab at 6 months post-transplant. Follow-up NAT showed HCV RNA to be undetectable. To date, use of HCV Ab+NAT- donors in lung transplantation has yielded favorable outcomes, with evidence of one transient seroconversion suggesting this practice may increase access to life-saving transplantation to those in need.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Survival after lung transplantation of cystic fibrosis patients infected with Burkholderia dolosa (genomovar VI).

Cystic fibrosis (CF) with severe lung disease is a well-recognized indication for lung transplantation. Colonization with various organisms in CF patients may impact post-transplant morbidity and mortality. Burkholderia cepacia complex (BCC) is made up of distinct genomovars with significant morbidity and mortality associated with B. cenocepacia (genomovar III) following lung transplant. The outcomes of patients infected with genomovar B. dolosa (genomovar VI) have yet to be described in the literature. We performed a retrospective chart review of all cystic fibrosis patients colonized with B. dolosa from our center who underwent lung transplantation (n = 11) at various medical centers across the US between 2000 and 2014. Survival rates were 73%, 53%, and 30% for 1, 3, and 5 years, respectively. Median survival was 44 months (95% CI = 11.1-76.8). CF patients with B. dolosa that have undergone lung transplantation have decreased one-year survival when compared to all patients transplanted with cystic fibrosis. Conditional 5-year survival for B. dolosa-infected patients was 43% in patients that survived the first year post-transplant, suggesting that this first year is crucial in managing the infection. Importantly, the survival of the B. dolosa patients was higher than compared to previously reported survival rates of B. cenocepacia patients post-transplant.

Differential gene expression in chicken primary B cells infected ex vivo with attenuated and very virulent strains of infectious bursal disease virus (IBDV).

Infectious bursal disease virus (IBDV) belongs to the family Birnaviridae and is economically important to the poultry industry worldwide. IBDV infects B cells in the bursa of Fabricius (BF), causing immunosuppression and morbidity in young chickens. In addition to strains that cause classical Gumboro disease, the so-called 'very virulent' (vv) strain, also in circulation, causes more severe disease and increased mortality. IBDV has traditionally been controlled through the use of live attenuated vaccines, with attenuation resulting from serial passage in non-lymphoid cells. However, the factors that contribute to the vv or attenuated phenotypes are poorly understood. In order to address this, we aimed to investigate host cell-IBDV interactions using a recently described chicken primary B-cell model, where chicken B cells are harvested from the BF and cultured ex vivo in the presence of chicken CD40L. We demonstrated that these cells could support the replication of IBDV when infected ex vivo in the laboratory. Furthermore, we evaluated the gene expression profiles of B cells infected with an attenuated strain (D78) and a very virulent strain (UK661) by microarray. We found that key genes involved in B-cell activation and signalling (TNFSF13B, CD72 and GRAP) were down-regulated following infection relative to mock, which we speculate could contribute to IBDV-mediated immunosuppression. Moreover, cells responded to infection by expressing antiviral type I IFNs and IFN-stimulated genes, but the induction was far less pronounced upon infection with UK661, which we speculate could contribute to its virulence.

Antibody depletion strategy for the treatment of suspected antibody-mediated rejection in lung transplant recipients: Does it work?

BACKGROUND: Donor-specific antibodies (DSAs) after lung transplantation correlate with poor outcomes. The ideal treatment strategy for antibody-mediated rejection AMR is not defined. Our institution implemented an aggressive multimodality protocol for the treatment of suspected AMR. METHODS: Lung transplant recipients with suspected AMR were treated with a standardized protocol of plasma exchange, steroids, bortezomib, rituximab, and intravenous immune globulin. Primary outcome was DSA clearance at 6 months in those alive. Secondary endpoints included preserved allograft function at 6 months, survival at 6 and 12 months and complications due to the protocol. RESULTS: Sixteen lung transplant recipients with documented DSA and allograft dysfunction were included in the analysis. Of the 16 patients, 11 survived to 6 months. Three of those 11 patients (27%) cleared all DSAs within 6 months of the protocol. Four of the 11 patients (36%) had preserved allograft function at 6 months. Overall 12-month patient survival was 56%. Complications included thrombocytopenia (50%) and abdominal pain or gastrointestinal discomfort (18.7%). CONCLUSIONS: This multimodality protocol resulted in clearance of DSAs and preserved lung function in a minority of lung transplant recipients with suspected AMR surviving to 6 months after therapy. There were significant side effects of the protocol.

Does the Goh classification predict the outcome of vesico-vaginal fistula repair in the developed world?

INTRODUCTION AND HYPOTHESIS: The Goh Vesico-Vaginal Fistula (VVF) classification has prognostic value in VVF in the developing world (predominantly obstetric), with chances of successful closure decreasing from type 1 to type 4. We evaluated the prognostic value of the Goh classification for VVF of the developed world (predominantly iatrogenic). METHODS: A retrospective review was performed of 63 consecutive patients with a mean age of 53 years (range 21-88) undergoing VVF repair under a single surgeon between 2006 and 2014. Demographic data, aetiology, operative data and final outcome (anatomical and functional) were recorded. Fistulae were classified according to Goh's system and outcomes correlated with this classification. RESULTS: Successful closure at first repair was achieved in 90 % of type 1, 83 % of type 2, 100 % of type 3 and 100 % of type 4 fistulae. At second repair success was achieved in 100 % of all fistulae, irrespective of type. Continence post-anatomical closure was achieved in 100 % of type 1, 83 % of type 2, 83 % of type 3 and 75 % of type 4 fistulae. Fistula size and patient age were significant determinants of successful outcome. CONCLUSION: Anatomical closure was obtained in 90 % of VVF of the developed world at first attempt, 100 % overall, and was not affected by the Goh classification. Continence post-anatomical closure of VVF was 94 % overall and deteriorated with increasing Goh classification type. The Goh classification has no prognostic value regarding anatomical closure in VVF of the developed world, but may be useful in determining the risk of post-anatomical closure urinary incontinence. Smaller fistula size and younger patient age are significant determinants of success.