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Transplantation of any organ into a recipient requires a donor. Lung transplant has a long history of an inadequate number of suitable donors to meet demand, leading to deaths on the waiting list annually since national data was collected, and strict listing criteria. Before the Uniform Determination of Death Act (UDDA), passed in 1980, legally defined brain death in the U.S., all donors for lung transplant came from sudden death victims [uncontrolled Donation after Circulatory Death donors (uDCDs)] in the recipient's hospital emergency department. After passage of the UDDA, uDCDs were abandoned to Donation after Brain Death donors (DBDs)-perhaps prematurely. Compared to livers and kidneys, many DBDs have lungs that are unsuitable for transplant, due to aspiration pneumonia, neurogenic pulmonary edema, trauma, and the effects of brain death on lung function. Another group of donors has become available-patients with a devastating irrecoverable brain injury that do not meet criteria for brain death. If a decision is made by next-of-kin (NOK) to withdraw life support and allow death to occur by asphyxiation, with NOK consent, these individuals can have organs recovered if death occurs relatively quickly after cessation of mechanical ventilation and maintenance of their airway. These are known as controlled Donation after Circulatory Death donors (cDCDs). For a variety of reasons, in the U.S., lungs are recovered from cDCDs at a much lower rate than kidneys and livers. Ex-vivo lung perfusion (EVLP) in the last decade has had a modest impact on increasing the number of lungs for transplant from DBDs, but may have had a larger impact on lungs from cDCDs, and may be indispensable for safe transplantation of lungs from uDCDs. In the next decade, DCDs may have a substantial impact on the number of lung transplants performed in the U.S. and around the world.

Background Clinical trials generally each collect their own data despite routinely collected health data (RCHD) increasing in quality and breadth. Our aim is to quantify UK-based randomised controlled trials (RCTs) accessing RCHD for participant data, characterise how these data are used and thereby recommend how more trials could use RCHD. Methods We conducted a systematic review of RCTs accessing RCHD from at least one registry in the UK between 2013 and 2018 for the purposes of informing or supplementing participant data. A list of all registries holding RCHD in the UK was compiled. In cases where registries published release registers, these were searched for RCTs accessing RCHD. Where no release register was available, registries were contacted to request a list of RCTs. For each identified RCT, information was collected from all publicly available sources (release registers, websites, protocol etc.). The search and data extraction were undertaken between January and May 2019. Results We identified 160 RCTs accessing RCHD between 2013 and 2018 from a total of 22 registries; this corresponds to only a very small proportion of all UK RCTs (about 3%). RCTs accessing RCHD were generally large (median sample size 1590), commonly evaluating treatments for cancer or cardiovascular disease. Most of the included RCTs accessed RCHD from NHS Digital (68%), and the most frequently accessed datasets were mortality (76%) and hospital visits (55%). RCHD was used to inform the primary trial (82%) and long-term follow-up (57%). There was substantial variation in how RCTs used RCHD to inform participant outcome measures. A limitation was the lack of information and transparency from registries and RCTs with respect to which datasets have been accessed and for what purposes. Conclusions In the last five years, only a small minority of UK-based RCTs have accessed RCHD to inform participant data. We ask for improved accessibility, confirmed data quality and joined-up thinking between the registries and the regulatory authorities. Trial registration PROSPERO CRD42019123088.

BACKGROUND: Trial monitoring is an important component of good clinical practice to ensure the safety and rights of study participants, confidentiality of personal information, and quality of data. However, the effectiveness of various existing monitoring approaches is unclear. Information to guide the choice of monitoring methods in clinical intervention studies may help trialists, support units, and monitors to effectively adjust their approaches to current knowledge and evidence. OBJECTIVES: To evaluate the advantages and disadvantages of different monitoring strategies (including risk‐based strategies and others) for clinical intervention studies examined in prospective comparative studies of monitoring interventions. SEARCH METHODS: We systematically searched CENTRAL, PubMed, and Embase via Elsevier for relevant published literature up to March 2021. We searched the online 'Studies within A Trial' (SWAT) repository, grey literature, and trial registries for ongoing or unpublished studies. SELECTION CRITERIA: We included randomized or non‐randomized prospective, empirical evaluation studies of different monitoring strategies in one or more clinical intervention studies. We applied no restrictions for language or date of publication. DATA COLLECTION AND ANALYSIS: We extracted data on the evaluated monitoring methods, countries involved, study population, study setting, randomization method, and numbers and proportions in each intervention group. Our primary outcome was critical and major monitoring findings in prospective intervention studies. Monitoring findings were classified according to different error domains (e.g. major eligibility violations) and the primary outcome measure was a composite of these domains. Secondary outcomes were individual error domains, participant recruitment and follow‐up, and resource use. If we identified more than one study for a comparison and outcome definitions were similar across identified studies, we quantitatively summarized effects in a meta‐analysis using a random‐effects model. Otherwise, we qualitatively summarized the results of eligible studies stratified by different comparisons of monitoring strategies. We used the GRADE approach to assess the certainty of the evidence for different groups of comparisons. MAIN RESULTS: We identified eight eligible studies, which we grouped into five comparisons. 1. Risk‐based versus extensive on‐site monitoring: based on two large studies, we found moderate certainty of evidence for the combined primary outcome of major or critical findings that risk‐based monitoring is not inferior to extensive on‐site monitoring. Although the risk ratio was close to 'no difference' (1.03 with a 95% confidence interval [CI] of 0.81 to 1.33, below 1.0 in favor of the risk‐based strategy), the high imprecision in one study and the small number of eligible studies resulted in a wide CI of the summary estimate. Low certainty of evidence suggested that monitoring strategies with extensive on‐site monitoring were associated with considerably higher resource use and costs (up to a factor of 3.4). Data on recruitment or retention of trial participants were not available. 2. Central monitoring with triggered on‐site visits versus regular on‐site visits: combining the results of two eligible studies yielded low certainty of evidence with a risk ratio of 1.83 (95% CI 0.51 to 6.55) in favor of triggered monitoring intervention. Data on recruitment, retention, and resource use were not available. 3. Central statistical monitoring and local monitoring performed by site staff with annual on‐site visits versus central statistical monitoring and local monitoring only: based on one study, there was moderate certainty of evidence that a small number of major and critical findings were missed with the central monitoring approach without on‐site visits: 3.8% of participants in the group without on‐site visits and 6.4% in the group with on‐site visits had a major or critical monitoring finding (odds ratio 1.7, 95% CI 1.1 to 2.7; P = 0.03). The absolute number of monitoring findings was very low, probably because defined major and critical findings were very study specific and central monitoring was present in both intervention groups. Very low certainty of evidence did not suggest a relevant effect on participant retention, and very low‐quality evidence indicated an extra cost for on‐site visits of USD 2,035,392. There were no data on recruitment. 4. Traditional 100% source data verification (SDV) versus targeted or remote SDV: the two studies assessing targeted and remote SDV reported findings only related to source documents. Compared to the final database obtained using the full SDV monitoring process, only a small proportion of remaining errors on overall data were identified using the targeted SDV process in the MONITORING study (absolute difference 1.47%, 95% CI 1.41% to 1.53%). Targeted SDV was effective in the verification of source documents but increased the workload on data management. The other included study was a pilot study which compared traditional on‐site SDV versus remote SDV and found little difference in monitoring findings and the ability to locate data values despite marked differences in remote access in two clinical trial networks. There were no data on recruitment or retention. 5. Systematic on‐site initiation visit versus on‐site initiation visit upon request: very low certainty of evidence suggested no difference in retention and recruitment between the two approaches. There were no data on critical and major findings or on resource use. AUTHORS' CONCLUSIONS: The evidence base is limited in terms of quantity and quality. Ideally, for each of the five identified comparisons, more prospective, comparative monitoring studies nested in clinical trials and measuring effects on all outcomes specified in this review are necessary to draw more reliable conclusions. However, the results suggesting risk‐based, targeted, and mainly central monitoring as an efficient strategy are promising. The development of reliable triggers for on‐site visits is ongoing; different triggers might be used in different settings. More evidence on risk indicators that identify sites with problems or the prognostic value of triggers is needed to further optimize central monitoring strategies. In particular, approaches with an initial assessment of trial‐specific risks that need to be closely monitored centrally during trial conduct with triggered on‐site visits should be evaluated in future research.

Inflammatory skin conditions are common in all ages and races. These disorders can be disfiguring and cause great discomfort, leading to a negative impact on the patient’s quality of life. Inflammatory conditions can present atypically in skin of color. In darker skin, psoriasis plaques may be violaceous with gray scale, and erythema is sometimes difficult to appreciate. In skin of color, the classic purple color of lichen planus may be black, gray, brown, or violaceous. Lichen planus actinicus and lichen planus pigmentosus are variants that are more common in darker skin. Atypical forms of pityriasis rosea present more commonly in skin of color, including papular pityriasis rosea, and involvement of the face, scalp, and mouth. There is a higher incidence of sarcoidosis in African Americans compared to Caucasians, and African Americans seemed to be diagnosed at an earlier age and have more severe disease. If untreated, inflammatory conditions in patients with skin of color can lead to post-inflammatory hyperpigmentation, which can be very difficult to treat.

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Background and importance Intensive clinical pharmacy input from admission to discharge has been shown to improve patient outcomes. The clinical pharmacy service in our institution has historically been under-resourced. Aim and objectives The study aim was to develop a ward based clinical pharmacy service and to evaluate its impact using a number of clinical, safety and financial metrics. Material and methods A clinical pharmacist was assigned to provide pharmaceutical care to patients on a medicine for the older person ward. Over an 8 week period, the pharmacist prospectively recorded her interventions/activities. To assess impact on patient care, interventions were graded according to the Eadon criteria. The potential cost avoidance associated with interventions was estimated using two methods identified in the literature. Both define costs related to medication errors and calculate cost avoidance associated with clinical interventions based on prevention of harm. Medication incident reporting was analysed to assess the impact on patient safety. Results Eighty–four patients received a pharmacist review. Across a spectrum of activities, a total of 267 pharmacist interventions were recorded: 87% of patients had at least one pharmacist intervention. A total of 90% of interventions requiring follow–up with the medical team were accepted and resulted in a change to patient care. Eadon grading of interventions deemed that 81% of interventions improved the standard of patient care. Two different methods were used to estimate potential cost avoidance: one estimated annual savings of €154 103–€344 926; the other estimated these at €174 373. Given current pharmacist salary costs, this equates to a cost–benefit ratio of 2.8:1 to 6.3:1. (This does not include the 27% reduction in drug spend observed during the study period. However, more longitudinal data are required to confirm and characterise this phenomenon.) In the third quarter of 2018, 21 medication incidents were reported from the study ward compared with an average of 4 incident reports from the first and second quarters of 2018. This represents a fivefold increase in medication incident reporting, suggestive of an enhanced culture of patient safety. Conclusion and relevance This study assessed and quantified a wide spectrum of pharmacist contributions to medication management and safety. Costing of these contributions estimated the cost–benefit ratio of the clinical pharmacy service, providing compelling support for the extension of this service throughout the hospital. References and/or acknowledgements No conflict of interest.

Background: Small for gestational age (SGA) babies are at high risk of perinatal mortality. We aimed to determine the potential to reduce perinatal mortality by improving antenatal detection of SGA babies in Scotland. Methods: We conducted a retrospective population study of all singleton SGA babies born in the 15 Consultant-led maternity units in Scotland in a 3-month period (1st Dec 2014 to 28th Feb 2015 inclusive). Demographic and pregnancy outcome data were extracted from Scottish birth records for all pregnancies; case note review was performed for all SGA cases [defined as birthweight less than the 10th centile for their gestational age at delivery as defined by the appropriate sex-specific UK-WHO Child Growth Standards]. Results: The SGA rate in Scotland was 5.5% (673/12218; 95% confidence interval [CI] 5.1, 5.9) and 27.6% (186/673; 95% CI 24.3, 31.2) of SGA cases were identified prior to delivery. SGA was associated with 18.2% (12/66; 95% CI [10.1%, 30.0%) of all perinatal deaths. The majority (10/12, 83.3%) of SGA babies who died had been identified as SGA in the antenatal period. There was no difference in perinatal mortality whether SGA was detected or not (5.4% [10/186; 95% CI 2.8, 10.0] in the SGA detected group vs 0.4% [2/487 [95% CI 0.3, 2.2] in the non-detected group after adjusting for risk factors for SGA, gestation at delivery and birthweight centile (Adjusted odds ratio [AOR] 0.85 [95% CI 0.5, 1.5], p=0.556). Conclusions: Despite only around a quarter of SGA babies being identified antenatally, the potential to reduce perinatal mortality in the Scottish population by improving SGA detection is limited. Only a minority of perinatal deaths occurred in SGA babies; and in the majority of these SGA was detected antenatally.

BACKGROUND: The objective of this study was to review the international experience in lung transplantation using lung donation after circulatory death (DCD).METHODS: In this retrospective study, data from the International Society for Heart and Lung Transplantation (ISHLT) DCD Registry were analyzed. The study cohort included DCD lung transplants performed between January 2003 and June 2013, and reported to the ISHLT DCD Registry as of April 2014. The participating institutions included 10 centers in North America, Europe and Australia. The control group was a cohort of lung recipients transplanted using brain-dead donors (DBDs) during the same study period. The primary end-point was survival after lung transplantation.RESULTS: There were 306 transplants performed using DCD donors and 3,992 transplants using DBD donors during the study period. Of the DCD transplants, 94.8% were Maastricht Category whereas 4% were Category IV and 1.2% Category V (euthanasia). Heparin was given in 54% of the cases, donor extubation occurred in 90% of the cases, and normothermic ex vivo lung perfusion (EVLP) was used in 12%. The median time from withdrawal of life support therapy (WLST) to cardiac arrest was 15 minutes (5th to 95th percentiles of 5 to 55 minutes), and from WLST to cold flush was 33 minutes (5th to 95th percentiles of 19.5 to 79.5 minutes). Recipient age and medical diagnosis were similar in DCD and DBD groups (p = not significant ENS]). Median hospital length of stay was 18 days in DCD lung transplants and 16 days in DBD transplants (p = 0.016). Thirty-day survival was 96% in the DCD group and 97% in the DBD group. One-year survival was 89% in the DCD group and 88% in the DBD group (p = NS). Five-year survival was 61% in both groups (p = NS). The mechanism of donor death within the DCD group seemed to influence recipient early survival. The survival rates through 30 days were significantly different by donor mechanism of death (p = 0.0152). There was no significant correlation between the interval of WLST to pulmonary flush with survival (p = 0.11).CONCLUSION: This large study of international, multi-center experience demonstrates excellent survival after lung transplantation using DCD donors. It should be further evaluated whether the mechanism of donor death influences survival after DCD transplant. (C) 2015 International Society for Heart and Lung Transplantation. All rights reserved.

In this review, we discuss the current state of donation after circulatory death (DCD). We define the DCD donor and describe the current protocols in management of the DCD patient. We then discuss current techniques in organ procurement of the lung and abdominal organs.Although donation after brain death is preferable to DCD, recent data have demonstrated acceptable early outcomes in both thoracic and abdominal organ transplant. In spite of advancements in surgical techniques and organ preservation, much has yet to be learned to minimize warm ischemia time and reperfusion injury in the DCD population.In light of the continually growing disparity between organ supply and demand, DCD has regained traction as a means to increase the donor pool.

Aspiration of gastroesophageal refluxate has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the progression of bronchiolitis obliterans syndrome after lung transplantation. The goals of the present study were to identify lung transplant patients at the greatest risk of aspiration and to investigate the causative factors.From September 2009 to November 2011, 252 bronchoalveolar lavage fluid (BALF) samples were collected from 100 lung transplant patients. The BALF pepsin concentrations and the results of transbronchial biopsy, esophageal function testing, barium swallow, and gastric emptying scan were compared among those with the most common end-stage lung diseases requiring lung transplantation: IPF, chronic obstructive pulmonary disease, cystic fibrosis, and α1-antitrypsin deficiency.Patients with IPF had higher BALF pepsin concentrations and a greater frequency of acute rejection than those with α1-antitrypsin deficiency, cystic fibrosis, or chronic obstructive pulmonary disease (P = 0.037). Moreover, the BALF pepsin concentrations correlated negatively with a lower esophageal sphincter pressure and distal esophageal amplitude; negatively with distal esophageal amplitude and positively with total esophageal acid time, longest reflux episode, and DeMeester score in those with chronic obstructive pulmonary disease; and negatively with the upright acid clearance time in those with IPF.Our results suggest that patients with IPF after lung transplantation are at increased risk of aspiration and a greater frequency of acute rejection episodes, and that the risk factors for aspiration might be different among those with the most common end-stage lung diseases who have undergone lung transplantation. These results support the role of evaluating the BALF for markers of aspiration in assessing lung transplant patients as candidates for antireflux surgery.

OBJECTIVE To estimate the rates of early neonatal and maternal complications in a consecutive series of successful Kielland's rotational forceps deliveries. METHODS This was a retrospective cohort study of consecutive cases of successful rotational forceps deliveries performed in singleton pregnancies at 36 weeks of gestation or more in a tertiary referral center in Scotland, UK, from 2001 to 2008 (n=873). We also compared outcomes associated with successful rotational forceps deliveries in 2008 (n=150) with those of nonrotational forceps delivery (n=873), ventouse delivery (n=159), spontaneous vertex delivery (n=3,494), and emergency cesarean delivery (n=947). RESULTS There was one stillbirth associated with a rotational forceps delivery. This was diagnosed before application of forceps. After rotational forceps deliveries, 58 of 872 (6.7%) of live-born neonates were admitted to the neonatal unit. Twenty-seven of 872 (3.1%) neonates had one or more complications that could be attributable to traumatic delivery and seven neonates (0.8%) had a diagnosis of neonatal encephalopathy. When compared with alternative methods of delivery over a single year, neonatal admission rates after delivery by rotational forceps deliveries (5 of 150 [3.3%]) were not significantly different from spontaneous vertex delivery (128 of 3,494 [3.7%; P=1.00]) or ventouse delivery (6 of 159 [3.8%; P=1.00]) and lower than emergency cesarean delivery (106 of 947 [11.2%; P=.002). Postpartum hemorrhage rates after rotational forceps deliveries (8 of 150 [5.3%; P=.008]) were lower than those associated with emergency cesarean delivery (142 of 947 [15.0%; P=.008]). CONCLUSION Rates of short-term neonatal and maternal complications after successful rotational forceps deliveries are low. LEVEL OF EVIDENCE II.

Background: There is a paucity of information regarding the management of blunt thoracic aortic injury in the pediatric population compared to adults. This article adds three cases of blunt thoracic aortic injuries in pediatric patients to the literature and analyzes these in conjunction with several of the previous case series which have been published. Methods: Three cases were reviewed along with 38 previously reported cases in an attempt to identify trends in demographics and management. The three new cases presented over a four year period. All are male. A six year old and a 17-year-old were involved in motor vehicle crashes and a 10-year-old was struck by a vehicle while skateboarding. Results: The 6-year-old and the 17-year-old were treated non-interventionally due to severe closed head injuries. One received beta blockade. Both survived. The third, without head injury, underwent interposition graft and also survived. Conclusions: These findings are not greatly dissimilar from the adult experience. In reviewing all 41 pediatric cases, findings reveal a high mortality, predominantly due to head injury as well as the aortic injury. Open repair and interposition grafting continue to be the mainstay of management, with endovascular procedures and non-operative management becoming more prevalent recently. The role of beta-blockade is unclear in children with this injury. Further multicenter prospective studies of this rare pediatric injury may be useful.

Background Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM. Methods We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks’ gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic control, participant satisfaction and clinical outcomes. Results Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n = 13) or metformin and insulin (n = 10). Mean (SD) recruitment rate was 0.39 (0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6–90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic control to metformin and glibenclamide, with fewer blood glucose readings

A 35 year old Latina female presented with a several year history of discoloration of her chest, upper back, and arms. The discoloration started on her chest and slowly progressed to the arms. She has tried over the counter fade creams without success. There is minimal pruritus. She notes some improvement when she goes on vacation at the beach. She has no other associated systemic symptoms.

Diabet. Med. 29, e398–e401 (2012) Abstract Background We describe an unplanned pregnancy in a 19-year-old with lipodystrophic diabetes caused by a mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. The pregnancy was complicated by poor compliance with treatment, severe hypertriglyceridaemia and pancreatitis. Case report The patient presented at 6 weeks’ gestation with an HbA1c of 140 mmol/mol (15%), cholesterol 8.1 mmol/l and triglycerides 20.1 mmol/l. She wished to continue the pregnancy so lipid-lowering therapy was discontinued. She was severely insulin resistant and poorly compliant with diet and medication. A continuous subcutaneous insulin infusion was required for efficient delivery of large doses of basal insulin, alongside injected mealtime boluses, (up to 300 units insulin per day). At 17 weeks’ gestation she developed acute pancreatitis secondary to hypertriglyceridaemia (triglycerides > 100 mmol/l) and required plasmapheresis. Lipid-lowering therapy was reinstated in the third trimester and plasmapheresis was required repeatedly to maintain triglycerides

Background The prevalence of vitamin D deficiency in lung disease is greater than in the general population. Vitamin D deficiency may negatively affect immune and lung function. Accordingly, we hypothesized that lung transplant recipients with vitamin D deficiency are more susceptible to rejection and infections after transplantation. Methods Transplant outcomes were reviewed in a retrospective cohort of 102 lung transplant recipients who had 25-hydroxyvitamin D [25(OH)D] levels drawn during the near-transplant period (100 days pre- or post-transplant). Results In the near-transplant period, 80% of recipients were 25(OH)D-deficient and 20% were not 25(OH)D-deficient. Episodes of acute cellular rejection in the deficient group were more frequent than in the non-deficient group [mean 1.27 (0.99 to 1.55) vs 0.52 (0.12 to 0.93), p = 0.006]. The rejection rate in the deficient group was more than double that of the the non-deficient group [IRR 2.43 (1.30 to 4.52), p = 0.005]. Infectious episodes were also more frequent in the deficient group than in the non-deficient group [mean 4.01 (3.24 to 4.79) vs 2.71 (1.47 to 3.96), p = 0.04]. The mortality rate of recipients who remained 25(OH)D-deficient 1 year after transplant was almost 5-fold higher than in recipients who were not 25(OH)D-deficient [IRR 4.79 (1.06 to 21.63), p = 0.04]. Conclusions Low serum 25(OH)D levels in lung transplant recipients were associated with increased incidence of acute rejection and infection. The mortality of recipients who remained deficient 1 year post-transplant was higher than that of recipients who maintained normal vitamin D levels at 1 year post-transplant.

The prevalence of gastroesophageal reflux disease (GERD) in lung transplant patients is twice that of the general population, yet it is unclear which pathophysiological factors play a role in the development or exacerbation of GERD in these patients.1–4 It has been speculated that the lung transplantation itself might be causative in the pathogenesis of GERD after lung transplantation, probably by increasing the risk of esophageal or vagal nerve injury or by increasing the transdiaphragmatic gastroesophageal pressure gradient.1,2 For example, Young et al2 demonstrated that GERD worsens after lung transplantation, reporting that the mean esophageal acid contact time in the supine position before and after transplant doubled from 5.1% to 11.4%. However, they failed to demonstrate that the type of transplant may be responsible for the deterioration of the reflux profile in these patients. Conversely, in a small study that we conducted to determine the prevalence and extent of GERD, as well as the frequency of risk factors and complications of GERD in lung transplant patients, we incidentally found that GERD was more common after bilateral transplantation and retransplantation than after a unilateral lung transplant.1 Therefore, to understand if the type of transplant may lead more frequently to GERD and proximal reflux, we have investigated the prevalence of distal and proximal reflux, as well as the radiologic, endoscopic, and manometric characteristics, in a much larger series of lung transplant patients, which have been stratified according to the type of transplant received (unilateral, bilateral, or retransplant).

Lymphangioleiomyomatosis (LAM) leads to hyperproliferation of abnormal smooth muscle cells in the lungs, associated with diffuse pulmonary parenchymal cyst formation and progressive dyspnea on exertion. The disease targets women of child-bearing age. Complications include pneumothoraces and chylous pleural effusions. Ten-year survival is estimated at 70%, and lung transplantation remains the only validated treatment. It has been observed that LAM cells express markers associated with melanocytic differentiation, including gp100 and MART-1. Other melanocytic markers have also been observed. The same proteins are targeted by T cells infiltrating melanoma tumors as well as by T cells infiltrating autoimmune vitiligo skin, and these antigens are regarded as relatively immunogenic. Consequently, vaccines have been developed for melanoma targeting these and other immunogenic melanocyte differentiation proteins. Preliminary data showing susceptibility of LAM cells to melanoma-derived T cells suggest that vaccine...

Lung transplantation is now a well established treatment option for several end-stage respiratory diseases. Survival after lung transplantation has significantly improved over the last decade. The primary limitation to increased utilization of lung transplantation remains donor scarcity. Suitable allografts have been procured from donors after determination of neurologic death and from donors after determination of cardiac death (DDCD or DCD). Historically, the first human lung transplantation performed, utilized an allograft procured after cardiovascular death, also referred to as nonheart-beating donor.The experience at University of Wisconsin in 1993 reintroduced DCD lung transplantation with the first successful clinical case.A potential additional lung allograft source, DCD lung transplantation has been established with very acceptable outcomes observed by several centers. We provide the relevant background for the rationale of donor allograft expansion to include DCD lungs from controlled (Maastricht category III donors).This review considers the available evidence for DCD lung transplantation and compares reported primary graft dysfunction rates and current survival data available.

Long-term morbidity and mortality after lung transplantation are largely attributable to bronchiolitis obliterans syndrome (BOS), a form of chronic rejection.1,2 In turn, BOS and rejection have been associated with gastroesophageal reflux disease (GERD), although direct causality has not been established.3,4 The mechanism by which GERD may cause or exacerbate BOS is not known; however, it is thought that aspiration of gastroesophageal contents may trigger a nonallogenic injury to the transplanted lungs. The investigation of the causal relationship between GERD, aspiration, and BOS is important because GERD can be treated before lung function deteriorates.4–6 In fact, studies have shown that operative control of GERD may stabilize or improve lung function in some patients with BOS, especially when a laparoscopic fundoplication is performed early after lung transplantation.7–10 Control of reflux is key, because GERD may be a modifiable risk factor for the progression of BOS; GERD and aspiration of gastroduodenal substances, like pepsin, might be stopped by laparoscopic antireflux surgery (LARS). Nevertheless, the role and the indications for LARS in the management of patients with BOS or rejection is less clear because it is not known if aspiration can be prevented by LARS, or if aspiration of gastroesophageal refluxate indeed represents a nonallogenic injury to the transplanted lungs. The aim of this study was to determine if LARS after lung transplantation could represent an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF), and if aspiration of gastroesophageal refluxate is associated with a worse clinical outcome than patients without evidence of aspiration. We hypothesized that recovery of pepsin in the BALF confirms aspiration and that LARS could be protective against aspiration of pepsin.

Sirolimus (rapamycin) is a potent anti-proliferative agent with immunosuppressive properties that is increasingly being used in solid-organ and hematopoietic stem cell transplantation. In addition, this drug is being investigated for treatment of a broad range of disorders, including cardiovascular disease, malignancies, tuberous sclerosis, and lymphangeioleiomyomatosis. In this study, we found an increased risk of venous thromboembolism (VTE) in lung transplant recipients treated with a sirolimus (SIR)-based immunosuppressive regimen.One hundred eighty-one lung transplant recipients were enrolled in a prospective, multicenter, randomized, open-label trial comparing a tacrolimus (TAC)/SIR/prednisone immunosuppression regimen with a TAC/azathioprine (AZA)/prednisone immunosuppressive regimen. The differences in rates of VTE were examined.There was a significantly higher occurrence of VTE in the SIR cohort [15 of 87 (17.2%)] compared with the AZA cohort [3 of 94 (3.2%)] (stratified log-rank statistic = 7.44, p0.01). When adjusted for pre-transplant diagnosis and stratified by transplant center, this difference remained essentially unchanged (hazard ratio for SIR vs AZA = 5.2, 95% confidence interval 1.4 to 19.5, p = 0.01).Clinicians prescribing SIR should maintain a high level of vigilance for VTE, particularly among patients with other risk factors for this complication.

Lung transplantation is currently performed on selected patients with end-stage lung disease. However, the median survival of patients after lung transplantation is inferior to that of any other solid organ transplantation, only 5 years.1 This low survival rate is primarily due to the development of obliterative bronchiolitis, which clinically manifests as bronchiolitis obliterans syndrome (BOS).2 BOS develops in almost half of lung transplant recipients within 5 years and is a source of considerable morbidity because of its detrimental effect on lung function and quality of life.1 The pathophysiology of obliterative bronchiolitis is not fully understood. However, evidence suggests that obliterative bronchiolitis might represent a nonimmunologic aberrant response to a chronic stimulus injury.3–6 Recently, gastroesophageal reflux disease (GERD) has been proposed as a potential factor responsible for chronic injury. Several studies have indirectly shown that the presence of GERD in lung transplant recipients is a risk factor for the development and progression of BOS, because of the high prevalence of GERD demonstrated after lung transplantation and because operative control of GERD may control the decline in lung function characteristic of BOS.4–7 Despite the evidence that supports the detrimental effect of GERD before and after lung transplantation, the prevalence of risk factors of GERD, including esophageal dysmotility, hiatal hernia, and delayed gastric emptying, are still unknown. In addition, the prevalence of Barrett’s esophagus, a known complication of GERD, has not been determined in lung transplant patients. The purpose of this study was to determine the prevalence and extent of GERD, as well as the frequency of these risk factors and complications of GERD in lung transplant patients.

Objective We sought to examine long-term outcomes at the University of Wisconsin for all lung transplant recipients who received lungs from donation after cardiac death donors since the initiation of this program in 1993. Methods Eighteen (4.2%) of the 424 lung transplantations performed in 406 patients between January 1993 and April 2009 used lungs from donation after cardiac death donors. Outcomes for this recipient cohort were compared with those for recipients who received organs from brain-dead donors. Results Warm ischemic time (from withdrawal of support to reperfusion of organs) was 30 ± 17 minutes (11–93 minutes). The patient survival rates in the donation after cardiac death group (DCD group) at 1, 3, and 5 years were 88.1% ± 7.9%, 81.9% ± 9.5%, and 81.9% ± 9.5%, respectively. These survival rates were not different from those of the brain-dead donor group (BDD group, P = .66). The incidence of primary graft dysfunction in the DCD group was similar to that of the BDD group (P = .59). However, the incidence of airway complications was somewhat higher in the DCD group. Freedom from bronchiolitis obliterans syndrome at 1, 3, and 5 years in the DCD group was 80.4% ± 10.2%, 80.4% ± 10.2%, and 72.3% ± 11.9%, respectively, and did not differ from the incidence of bronchiolitis obliterans syndrome in the BDD group (P = .59). Conclusions Our data show that the long-term patient and graft survival rates after donation after cardiac death lung transplantation were equivalent to those after brain-dead donor lung transplantation. Our findings suggest that the use of donation after cardiac death donors can safely and substantially expand the donor pool for lung transplantation.

Davis CS, Gagermeier J, Dilling D, Alex C, Lowery E, Kovacs EJ, Love RB, Fisichella PM. A review of the potential applications and controversies of non-invasive testing for biomarkers of aspiration in the lung transplant population. Clin Transplant 2010: 24: E54–E61. © 2010 John Wiley & Sons A/S. Abstract: Despite improvements in one-yr survival following lung transplantation, five-yr survival lags significantly behind the transplantation of other solid organs. The contrast in survival persists despite advancements in anti-rejection regimens, suggesting a non-alloimmune mechanism to chronic lung transplant failure. Notably, markers of aspiration have been demonstrated in bronchoalveolar lavage (BAL) fluid concurrent with bronchiolitis obliterans syndrome (BOS). This recent evidence has underscored gastroesophageal reflux (GER) and its associated aspiration risk as a non-alloimmune mechanism of chronic lung transplant failure. Given the suggested safety and efficacy of laparoscopic anti-reflux procedures in the lung transplant population, identifying those at risk for aspiration is of prime importance, especially concerning the potential for long-term improvements in morbidity and mortality. Conventional diagnostic methods for GER and aspiration, such as pH monitoring and detecting pepsin and bile salts in BAL fluid, have gaps in their effectiveness. Therefore, we review the applications and controversies of a non-invasive method of defining reflux injury in the lung transplant population: the detection of biomarkers of aspiration in the exhaled breath condensate. Only by means of assay standardization and directed collaboration may such a non-invasive method be a realization in lung transplantation.

Bronchiolitis obliterans syndrome (BOS), a process of fibro-obliterative occlusion of the small airways in the transplanted lung, is the most common cause of lung transplant failure. We tested the role of cell-mediated immunity to collagen type V [col(V)] in this process. PBMC responses to col(II) and col(V) were monitored prospectively over a 7-year period. PBMCs from lung transplant recipients, but not from healthy controls or col(IV)-reactive Goodpasture's syndrome patients after renal transplant, were frequently col(V) reactive. Col(V)-specific responses were dependent on both CD4+ T cells and monocytes and required both IL-17 and the monokines TNF-alpha and IL-1beta. Strong col(V)-specific responses were associated with substantially increased incidence and severity of BOS. Incidences of acute rejection, HLA-DR mismatched transplants, and induction of HLA-specific antibodies in the transplant recipient were not as strongly associated with a risk of BOS. These data suggest that while alloimmunity initiates lung transplant rejection, de novo autoimmunity mediated by col(V)-specific Th17 cells and monocyte/macrophage accessory cells ultimately causes progressive airway obliteration.

Study Objective. To determine whether lung transplant recipients would have a less vigorous T-cell response to hepatitis B surface antigen (HBsAg) than that of patients awaiting lung transplantation and healthy subjects, we sought to measure and compare T-cell responses among these three groups. Design. Prospective study. Setting. Lung transplant clinic at a university hospital. Subjects. Twelve lung transplant recipients, 12 patients awaiting lung transplantation, and 15 healthy subjects. All participants had received the hepatitis B vaccine series and had a documented antibody response to it. Intervention. Blood samples were obtained from each participant. Measurements and Main Results. Participants' sex, age, time since lung transplantation (if applicable), and time since hepatitis B immunization were recorded. Peripheral blood mononuclear cells were isolated from the participants' blood samples for the trans vivo delayed-type hypersensitivity (DTH) assay. These cells were mixed with saline, tetanus toxoid, or HBsAg and injected into the footpads of immunodeficient mice. Resultant swelling of the footpad was used as an index of human T-cell response. The healthy subjects were younger than the patients in both transplant groups. However, we found no significant difference in DTH response elicited by HBsAg among the healthy subjects, patients awaiting lung transplantation, and lung transplant recipients (mean ± standard error [SE] 34.7 ± 4.3, 32.1 ± 3.1, and 33.5 ± 4.0 × 10−4 in., respectively, p>0.8) or when tetanus toxoid was used as a positive control (15.7 ± 2.8, 22.8 ± 6.5, and 21.7 ± 3.9 × 10−4 in., respectively, p>0.3). No correlation between age or time since immunization and DTH response was noted. Conclusion. Lung transplant recipients maintained a T-cell response to HBsAg that was similar in vigor to that of both patients awaiting transplantation and healthy subjects even though their antibody concentrations waned rapidly after transplantation. The role of these T cells as a correlate of protection from infection remains to be investigated.

Background Although new approaches to the treatment of patients with cystic fibrosis (CF) are significantly prolonging their lives, most patients will eventually develop respiratory failure due to progressive bronchiectasis caused by chronic lung infection and inflammation and die from to respiratory failure. We examined our center's (University of Wisconsin Hospital and Clinics) experience with lung transplantation for patients with CF and reviewed the literature to examine current and evolving approaches to transplantation for this indication. Methods We reviewed all published literature pertaining to lung transplantation for CF through 2006, and we reviewed all aspects of transplantation for patients with CF at our institution from 1994 to 2005. Results Major complications following lung transplantation include acute rejection, bacterial infection, and bronchiolitis obliterans. Five-year survival at UWHC (Kaplan–Meier) is 67%, and survival was not adversely affected by transplanting patients receiving mechanical ventilation. The major cause of death for transplant recipients was bronchiolitis obliterans syndrome (BOS). Conclusions Lung transplantion for CF is associated with acceptable survival rates and can improve quality of life. Lung transplant should be offered to all patients with advanced CF lung disease if they meet currently accepted inclusion and exclusion criteria.

Everolimus is an immunosuppressive agent that reduces cardiac allograft vasculopathy. This report presents the 24-month results of a multicenter trial of everolimus vs azathioprine in heart transplantation.A total of 634 patients were randomized to receive 1.5 mg everolimus, 3 mg everolimus or azathioprine, with cyclosporine and steroids. A 12-month, double-blind, double-dummy period was followed by a 12-month open-label period.At 24 months, the percentage of patients reaching the composite efficacy end-points was significantly lower with everolimus (1.5 mg: 45.9%, p = 0.016; 3 mg: 36.0%, p0.001) than with azathioprine (57.5%). The change in maximal intimal thickness from baseline to 24 months was significantly smaller with everolimus 1.5 mg (0.07 mm, p = 0.014) and 3 mg (0.06 mm, p = 0.004) compared with azathioprine (0.15 mm). The 24-month incidence of vasculopathy was 33.3% with everolimus 1.5 mg, 45.5% with everolimus 3 mg and 58.3% with azathioprine (p = 0.017 vs everolimus 1.5 mg). Incidence of cytomegalovirus infection was 3-fold lower in patients receiving everolimus compared with azathioprine (7.2% and 7.1% in the 1.5-mg and 3-mg everolimus cohorts, respectively, and 21% in the azathioprine group; p0.0001). Median serum creatinine levels at 24 months were higher with everolimus than with azathioprine, but decreased when cyclosporine exposure was reduced (everolimus 1.5 mg: baseline 167 micromol, after 6 months 157.5 micromol; everolimus 3 mg: baseline 185.6 micromol, after 6 months 160 micromol; azathioprine: baseline 123.3 micromol, after 6 months 127 micromol).Everolimus significantly reduced acute rejection and limited the progression of allograft vasculopathy at 24 months compared with azathioprine. Although graft and patient survival was comparable at 24 months, everolimus therapy may improve longer-term outcomes after heart transplantation.

A 30-year old African American woman presents with multiple scarred plaques on her scalp, ears, and neck. The lesions are occasionally pruritic and even painful, especially in the early stages when they first appear. She notes that outbreaks are worse during the summer, and she admits that she is very conscious of her appearance year-wide, often wearing her hair past her shoulders and clothing that covers her neck to help hide her skin. She denies joint pain, shortness of breath, chest pain, or ever noticing any ulcers in her mouth.

A 50 year old African American female presented with “moles” on her face. She began noticing them in her 30’s, but as she aged, they increased in number and size. They are asymptomatic. She notes that all of her sisters, as well as her mother, have these moles.

A 65 year old African-American female presents with a 1 year history of a scar on her lower leg that has been increasing in size. It is nontender, but occasionally pruritic and bleeds often. She grew up in Wisconsin and on further questioning, reported frequent use of well water.

Study Objective. To increase the response rate to hepatitis B vaccine in patients awaiting lung transplantation. Design. Historically controlled, open-label study. Setting. Lung transplant clinic at a university hospital. Subjects. Twenty-seven consecutive individuals with end-stage pulmonary disease who were enrolled to accrue 15 subjects who would complete the vaccine series before transplantation; and 27 lung transplant recipients who were immunized with the conventional dose before the study and served as historical controls. Intervention. Intramuscular injection of high-dose hepatitis B vaccine 40 μg at 0, 1, and 6 months. Measurements and Main Results. Hepatitis B surface antibody (anti-HBs) concentrations were measured 1–2 months after completing the high-dose series. Individuals with undetectable anti-HBs received additional vaccine to a maximum of six doses. The response rate to the series was compared with that in the control group. Seventeen individuals in the high-dose group and 14 controls met the study criterion of complete vaccine series before transplantation. The former had a much higher response rate than the latter (9 [53%] vs 1 [7%], p

Background: Mechanical ventilation for ventilatory failure has been considered a relative contraindication to subsequent lung transplantation. The purpose of this study was to test the hypothesis that patients with cystic fibrosis (CF) who are intubated and mechanically ventilated before transplantation have poorer post-transplant outcomes than do patients who are not ventilated. Methods: We compared the outcomes of 8 patients with CF who underwent mechanical ventilation for 62 ±20 days (range, 3–153 days) before bilateral lung transplantation with outcomes of 24 patients with CF who did not undergo pre-transplant mechanical ventilation. Results: Although time to extubation after transplantation was prolonged significantly (11 vs 4 days) for the pre-transplant ventilated group, days to hospital discharge, forced expiratory volume in 1 second (percent predicted) at 1 year after transplantation, and post-transplant survival as determined using the Kaplan-Meier method did not differ statistically between the 2 groups. Conclusions: Patients with CF who undergo pre-transplant endotracheal intubation and mechanical ventilation for respiratory failure have outcomes that do not differ significantly from those of patients with CF who do not require invasive ventilatory support before bilateral lung transplantation.

Study objectives To characterize Aspergillus infections in lung transplant recipients with cystic fibrosis (CF). Design A retrospective analysis of 32 consecutive lung transplant recipients with CF who underwent bilateral lung transplant at the University of Wisconsin from 1994 to 2000 to determine the incidence, risk factors, and consequences of Aspergillus infection. The findings were compared to 101 non-CF recipients of lung transplants (93) and heart-lung transplants (8) for other transplant indications. Setting A university hospital. Patients or participants Lung transplant recipients with CF or other indications for transplantation. Interventions None. Measurements and results Seventeen of 32 CF recipients (53%) had Aspergillus fumigatus isolated from their respiratory secretions prior to undergoing transplantation. Ten of these 17 (59%) recipients had A fumigatus persistently found in their respiratory secretions posttransplant vs 6 of 15 CF patients (40%) who had not been colonized pretransplant and 28 of 101 of the non-CF recipients (28%). Four of the preoperatively colonized CF recipients developed tracheobronchial aspergillosis (TBA) just distal to the bronchial anastomoses, and one recipient had dehiscence of the involved anastomosis. None of the CF recipients developed disseminated aspergillosis or pneumonia. Prophylactic antifungal therapy did not prevent TBA, and IV amphotericin B therapy was required to clear the infection in all four patients, with endobronchial debridement of necrotic tissue required in two of them. In contrast, 10 of the non-CF (10%) recipients developed Aspergillus infections posttransplant (TBA, 4 recipients; pneumonitis, 6 recipients), and only 3 patients had successful treatment and long-term survival (TBA, 2 patients; pneumonia, 1 patient). Donor lung ischemia time, cytomegalovirus infection or pneumonia, or pretransplant mechanical ventilation did not increase the risk of developing TBA in CF recipients. Conclusions The risk of TBA for patients receiving lung transplants for CF warrants early surveillance bronchoscopy to detect TBA, particularly in recipients with pretransplant colonization.

A consensus meeting to develop guidelines that would improve the recovery and transplantation of organs from the cadaver donor was held on 28–29 March 2001, in Crystal City, Virginia, sponsored by the American Society of Transplant Surgeons and the American Society of Transplantation. The crisis in organ supply persists and the continuing shortage presents a compelling responsibility for the transplant community to maximize the use of organs procured from cadaver donors.

To determine the frequency, clinical characteristics, and radiologic findings of bronchogenic carcinoma in patients surviving more than 1 month after lung transplantation.The study population was composed of 2,168 consecutive patients at seven lung transplantation centers who survived longer than 1 month after lung transplantation. Medical records, chest radiographs, and computed tomographic (CT) scans obtained at the time of diagnosis and prior images when available were reviewed for various items of information and imaging features.Twenty-four (1%) of the 2,168 patients, all with single-lung transplants, developed cancer in the native lung. Eighteen patients had emphysema, and six had pulmonary fibrosis. The frequencies of cancer in patients with emphysema and fibrosis were 2% (18 of 859 patients) and 4% (six of 147 patients), respectively. Twelve (50%) of their 24 cancers were detected at chest radiography. Fourteen (58%) patients had clinical symptoms. Twenty-one (88%) of the 24 patients had one (n = 11) or more (n = 10) nodules, and nine (38%) had one (n = 8) or more (n = 1) masses visible on CT scans. Nodules and masses were visible on 12 (50%) and seven (29%) of 24 chest radiographs, respectively. Eleven (48%) of 23 cancers for which prior chest radiographs were available were seen retrospectively on prior chest radiographs.Bronchogenic carcinoma develops in the native lung of transplant recipients with emphysema and pulmonary fibrosis with frequencies of 2% and 4%, respectively. The carcinomas most commonly manifest as a pulmonary nodule or mass on chest radiographs, with more nodules seen on CT scans.

The authors performed a multicenter, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of ondansetron (20 μg/day and 100 μg/day) in treating cognitive decline in 185 patients with Alzheimer disease. Although ondansetron was well tolerated without any serious drug-related side effects, the study failed to demonstrate any significant cognitive improvement.

Cutaneous toxoplasmosis is a rare and diagnostically challenging entity. Today, the acquired form occurs predominantly in immunocompromised patients with human immunodeficiency virus or after hematopoietic stem cell transplantation. We report a case of cutaneous toxoplasmosis in a 6-year-old girl after allogeneic stem cell transplantation for immune-mediated encephalopathy, first manifesting at 16 months of age. In the post-transplant setting, she developed a rash consisting of approximately 8 scattered 3–4-mm round, erythematous macules and papules on her back, abdomen, and right shoulder. Sections from a biopsy of a lesion on the back revealed numerous spherules tightly packed within small cystic structures in the epidermis. The diagnosis of cutaneous toxoplasmosis was confirmed by an immunohistochemical stain for Toxoplasma gondii and polymerase chain reaction on the peripheral blood for the T. gondii genome. This case should raise awareness that acquired toxoplasmosis with cutaneous involvement can occur in the pediatric population, particularly in immunocompromised patients after stem cell transplantation. Early diagnosis and treatment of this life-threatening opportunistic infection may improve patient outcomes.

Proteasomes appear to be involved in the pathophysiology of various acute and chronic lung diseases. Information on the human lung proteasome in health and disease, however, is sparse. Therefore, we studied whether end-stage pulmonary diseases are associated with alterations in lung 20S/26S proteasome content, activity and 20S subunit composition. Biopsies were obtained from donor lungs (n=7) and explanted lungs from patients undergoing lung transplantation because of end stage chronic obstructive pulmonary disease (COPD; n=7), idiopathic pulmonary fibrosis (IPF, n=7) and pulmonary sarcoidosis (n=5). 20S/26S proteasomes in lung extracts were quantified by ELISA, chymotrypsin-like proteasome peptidase activities measured and 20S proteasome β subunits analyzed by Western blot. As compared with donor lungs, proteasome content was increased in IPF and sarcoidosis, but not in COPD. The relative distribution of free 20S and 26S proteasomes was similar; 20S proteasome was predominant in all extracts. Proteasome peptidase activities in donor and diseased lungs were indistinguishable. All extracts contained a mixed composition of inducible 20S β immuno-subunits and their constitutive counterparts; a disease associated distribution could not be identified. A higher content of lung proteasomes in IPF and pulmonary sarcoidosis may contribute to the pathophysiology of human fibrotic lung diseases.

Lung transplantation is the only established therapeutic option for several end-stage respiratory diseases. Limited mostly by lack of suitable allografts, the results have measurably improved over the last decade. Numerous surgical and pharmaceutical improvements have had positive impact on outcomes. The potential for critical care issues and the need for interdisciplinary management remains paramount. Cardiac, renal, and metabolic complications are frequently encountered in the acute postoperative phase. Allograft rejection and infectious diseases as well as problems related to immunosuppressive regimen are seen later after lung transplantation. Neurologic manifestations with a range of etiologies are discussed here in this context.

The objective was to evaluate the safety and efficacy of video rollerbar endometrial ablation with patients under local anesthesia in the office operating room in the Women's Wellness Center, using only intravenous (IV) sedation and a paracervical block. Eleven patients underwent video office rollerbar endometrial ablation under local anesthesia and IV sedation per our protocol. Two other patients underwent rollerbar ablation under general anesthesia with a 27 French resectoscope in a local hospital. Diary scores for menorrhagia, premenstrual syndrome (PMS), dysmenorrhea, and their impact on life were obtained before and after the procedure. Six-, 12-, 24-, and 36-month followup of these patients is presented. Six- and 12-month followup of all 11 patients who underwent video rollerbar endometrial ablation in the office under local anesthesia and of the two hospital patients showed improvement in the number of bleeding days by 65%. Dysmenorrhea and PMS were improved by 66.67% and 78%, respectively. Seventy...

Lung volume reduction surgery (LVRS) is a palliative surgical procedure for patients with severe emphysema. Resection of nonfunctional emphysematous lung tissue has been reported to relieve breathlessness and to improve quality of life for many patients by improving lung elastic recoil, respiratory muscle function, and ventilation-perfusion matching. However, the risks and benefits of LVRS remain controversial, as mainly short-term data are available for carefully selected groups of LVRS patients and no prospective, randomized trials for LVRS with pulmonary rehabilitation versus optimal medical therapy plus pulmonary rehabilitation have been reported. Bilateral staple resection for LVRS appears to be superior to use of a laser or unilateral approach in the short term, but relatively little data exist on long-term outcomes. Additional clinical investigation is required to determine whether LVRS should be a widely accepted therapy for severe emphysema.

Remnant fallopian tube syndrome is a rare medical condition that may be easily overlooked. To the authors' best knowledge, this is the first documented case in medical literature. A 39-year-old woman with a history of a vaginal hysterectomy and bilateral salpingo-oophorectomy had experienced chronic pelvic pain for more than 6 years. Exploratory laparotomy revealed a right cystic mass. The pathology report determined the mass to be a fallopian tube remnant. Chronic pelvic pain should always be thoroughly investigated despite a history of adnexectomy. Inadequate removal of adnexa should be considered if other pathologic conditions of the organs have been ruled out as possible causes. (J GYNECOL SURG 16:47, 2000)

University of Wisconsin solution (UW) has been shown to be an effective preservative for the cardiac allograft. Recently, the high potassium content of UW has been implicated in causing coronary endothelial damage, allegedly contributing to development of cardiac allograft vasculopathy (CAV) and eventually to poorer survival.We examined our experience using UW for preservation of cardiac allografts between 1990 and 1994 (n = 94), and compared these to hearts preserved with the lower potassium-containing Stanford solution used at our center between 1986 and 1990 (n = 65). Indices of graft function, ischemic injury, CAV incidence, CAV severity, and survival were evaluated.The 2 groups were similar in age, gender, diagnosis, donor inotropic support, donor-recipient weight ratio, incidence of acute graft failure, and cytomegalovirus seroconversion. UW-preserved hearts came from older donors (30.5 vs 24.1 years, p.001), and were transplanted into more status 1 recipients (56% vs 22%, p.001), consistent with current trends. Mean ischemic time of UW-preserved hearts was significantly longer (184 vs 155 minutes, p.005) although time required to wean from bypass was less (45.5 vs 73.8 minutes, p.001) and there was a trend towards less inotropic requirement. CPK-MB release was less with UW preservation (63 vs 87 microg/ dL, p = .001). Three years after transplantation, both groups were similar in the incidence of CAV (UW, 27.3%; STNF, 37.5%; p = 0.27), and also the severity of CAV (p = 0.78). Deaths attributed to CAV were equal in each group (UW, 11.4% vs STNF, 10.7%; p = 0.79). Kaplan-Meier survival analysis revealed equivalent survival curves (p = 0.26).We conclude that UW is a safe and effective myocardial preservative, allowing longer ischemic times with equivalent graft function. Our data suggest that when UW is used for cardiac allograft preservation, both CAV and survival are comparable to the experience with other preservatives containing lower concentrations of potassium.

Background. The role of bone marrow-derived “passenger” leukocytes in the outcome of solid organ transplantation remains controversial. This study tested the relationship between high levels of donorderived leukocytes within the transplanted organ and clinical outcome after lung transplantation. Methods. Sequential bronchoalveolar lavage samples were obtained from human lung allograft recipients. Leukocytes of donor origin in the bronchoalveolar lavage fluid were detected using two-color immunofluorescence, and the results were correlated with multiple clinical parameters. Results. Mean donor leukocyte levels for the first 200 days after transplantation were higher in patients with a good transplantation outcome compared with those patients who lost their grafts due to acute rejection (AR) or developed bronchiolitis obliterans syndrome. The presence of low numbers of donor-derived leukocytes for the first 200 days after transplantation was found to be a significant risk factor for graft loss due to either acute or chronic rejection (P50.032). Nearly all patients (85%) experienced AR episodes. However, the time to onset of severe AR episodes was significantly longer (P50.049), and the incidence of these episodes reduced, in patients who maintained high numbers of donor-derived leukocytes for the first 200 days after transplantation. Conclusions. The presence of high numbers of donor-derived leukocytes, particularly macrophages, in the transplanted lung in the first 200 days after transplantation was associated with stable graft function. Donor-derived leukocytes were reduced or absent in patients with a poor transplantation outcome. These findings rule out a negative influence of persisting donor leukocytes and are consistent with the emerging two-way models of transplant tolerance.

Microlaparoscopes have been evaluated for minimally invasive laparoscopy using minimal anaesthesia or analgesia since our preliminary report on microlaparoscopy in 1993. This international multicentre report of safety and efficacy of diagnostic and operative microlaparoscopy was completed to evaluate the role of microlaparoscopy in a wide spectrum of gynaecological indications, diagnoses of pelvic and tubal disease, tubal occlusion and assisted reproduction. A total of 408 patients from seven centres around the world were included in this report. Of the 164 patients who underwent microlaparoscopy under local analgesia only three patients (1.8%) converted to i.v. sedation because of pain intolerance. All 71 patients who underwent microlaparoscopy under i.v. sedation as planned tolerated the procedure with acceptable pain level perception. Only one abdominal wall minor bleeding and one uterine wall minor bleeding were recorded in the remaining 173 patients who underwent microlaparoscopy under general anaesthesia. Visualization of the pelvic organs was sufficient in all 408 cases for diagnosis and treatment of selected pelvic pathology. We concluded, based on this sizeable microlaparoscopy series, that this outpatient procedure can replace large diameter laparoscopy for diagnosis and treatment of various pelvic conditions. Microlaparoscopy can safely replace large diameter laparoscopy in motivated patients who require minor operative procedures such as tubal occlusion, minor adhesiolysis, tubal gamete or embryo transfers and fulguration of endometriotic implants. This series demonstrated that operative microlaparoscopy can be carried out under general anaesthesia, reducing to nil the potential damage of a large diameter tracer. Future improvements in i.v. sedation in combination with i.p. local anaesthesia will potentially eliminate the need for general anaesthesia in some of the patients undergoing minor operative microlaparoscopy.

TOAST is a multicenter, randomized, placebo-controlled clinical trial testing the usefulness of a new antithrombotic drug in improving the outcome of persons with acute ischemic stroke. Until recently, no clinical trial testing a treatment for ischemic stroke had demonstrated efficacy in outcome. Design problems of previously conducted trials with inconclusive results may partly explain their failures. During the design of TOAST, the investigators addressed several issues so the trial could test the treatment accurately. We report the strategies used in designing, implementing, and coordinating the trial.

Myocardial stunning after heart surgery is associated with increased morbidity and mortality in patients with severe multivessel disease and reduced myocardial function. The purpose of this study was to evaluate the safety, tolerance, and efficacy of adenosine as a cardioprotective agent when added to blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard cold-blood cardioplegia, or cold-blood cardioplegia containing 1 of 5 adenosine doses (100 microM, 500 microM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 microg/kg/min of adenosine). Invasive and noninvasive measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours postbypass. Use of inotropic agents and vasoactive drugs pastoperatively was recorded; blood samples were collected for measurement of nucleoside levels. High-dose adenosine treatment was associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine (p0.05). Increasing doses of the adenosine additive were also associated with lower requirements of dopamine (p = 0.003) and nitroglycerine (p = 0.001). The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6-fold greater than their respective high-dose adenosine treatment cohorts. Finally, the placebo- and 100 microM-adenosine group was associated with a lower ejection fraction when compared to patients receiving the intermediate dose or high-dose treatment. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans.