Intravenous stem cell dose and changes in quantitative lung fibrosis and DLCO in the AETHER trial: a pilot study.

OBJECTIVE: Our purpose was to compare quantitative CT-derived changes in lung fibrosis with pulmonary function, including DLCO, in human subjects with idiopathic pulmonary fibrosis who received an injection of one of two different intravenous doses of human bone-marrow-derived mesenchymal stem cells. PATIENTS AND METHODS: Two three-subject cohorts from the AETHER trial (Allogeneic Human Cells in subjects with Idiopathic Pulmonary Fibrosis via Intravenous Delivery) underwent high-resolution CT and clinical testing at baseline, 24 weeks, and 48 weeks after injection. Cohort 1 received 2x107 stem cells, and cohort 2 received 1x108 stem cells. CT scans were quantitatively analyzed for lung fibrosis using 510K cleared validated software. The percent predicted DLCO and other pulmonary function studies were obtained. RESULTS: The cohorts were well matched in lung fibrosis at baseline as assessed by CT scan and lung function. The mean QLF in cohort 1 increased from 13.1% at baseline to 17.1% at 48 weeks, while mean QLF in cohort 2 increased from 15.4% at baseline to 16.5% at 48 weeks. The subjects in cohort 2 progressed more slowly in whole lung fibrosis by a mean of 2.87% compared with cohort 1 (p=0.001 with adjustment of baseline covariates) during the baseline to the 48-week interval. The baseline DLCO was lower in cohort 2 than in cohort 1 (p<0.0001). Over 48 weeks of the study, cohort 2 subjects demonstrated a mean DLCO decline of only 2% compared with a decline of 17% in cohort 1 subjects (p=0.02). CONCLUSIONS: In this pilot study, the subjects receiving 1x108 stem cells demonstrated slower progression in quantitative lung fibrosis and a smaller decrease in DLCO than subjects receiving 2x107 stem cells.

Rhinological interventions for obstructive sleep apnoea - a systematic review and descriptive meta-analysis.

OBJECTIVES: Obstructive sleep apnoea is a common chronic sleep disorder characterised by collapse of the upper airway during sleep. The nasal airway forms a significant part of the upper airway and any obstruction is thought to have an impact on obstructive sleep apnoea. A systematic review was performed to determine the role of rhinological surgical interventions in the management of obstructive sleep apnoea. METHODS: A systematic review of current literature was undertaken; studies were included if they involved comparison of a non-surgical and/or non-rhinological surgical intervention with a rhinological surgical intervention for treatment of obstructive sleep apnoea. RESULTS: Sixteen studies met the selection criteria. The pooled data suggest that there are reductions in the apnoea/hypopnea index and respiratory disturbance index following nasal surgery. However, the current body of studies is too heterogeneous for statistically significant meta-analysis to be conducted. CONCLUSION: Nasal surgery may have limited benefit for a subset of patients based on current evidence.

Infection in Organ Transplantation.

The prevention, diagnosis, and management of infectious disease in transplantation are major contributors to improved outcomes in organ transplantation. The risk of serious infections in organ recipients is determined by interactions between the patient's epidemiological exposures and net state of immune suppression. In organ recipients, there is a significant incidence of drug toxicity and a propensity for drug interactions with immunosuppressive agents used to maintain graft function. Thus, every effort must be made to establish specific microbiologic diagnoses to optimize therapy. A timeline can be created to develop a differential diagnosis of infection in transplantation based on common patterns of infectious exposures, immunosuppressive management, and antimicrobial prophylaxis. Application of quantitative molecular microbial assays and advanced antimicrobial therapies have advanced care. Pathogen-specific immunity, genetic polymorphisms in immune responses, and dynamic interactions between the microbiome and the risk of infection are beginning to be explored. The role of infection in the stimulation of alloimmune responses awaits further definition. Major hurdles include the shifting worldwide epidemiology of infections, increasing antimicrobial resistance, suboptimal assays for the microbiologic screening of organ donors, and virus-associated malignancies. Transplant infectious disease remains a key to the clinical and scientific investigation of organ transplantation.

A systematic review of the surgical techniques for the treatment of internal nasal valve collapse: where do we stand?

BACKGROUND: A myriad of interventions have been described to address the restoration or preservation of the internal nasal valve, the narrowest portion of nasal airway. OBJECTIVE OF REVIEW: To review systematically available knowledge and evidence about management options of the collapse of the internal nasal valve area. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: A MEDLINE, EMBASE, Cochrane Library and CENTRAL database search, followed by extensive hand searching for the identification of relevant studies. EVALUATION METHOD: Review of all English-language studies addressing the treatment of the internal nasal valve collapse. RESULTS: Fifty-three studies were eventually identified and systematically reviewed. The majority (50 of 53) of the included articles are graded as level IV evidence and only one randomised trial was identified. The included randomised study reported no significant difference in improvement between the intervention group (autospreader flap) and placebo arms. The majority of the included studies presented in this systematic review provide level IV evidence concerning the optimal approach for cases of nasal valve collapse. Current research is driven more by reports of techniques than patient outcomes. CONCLUSIONS: Proper evaluation and identification of the cause of the internal nasal valve collapse is paramount prior to selection of the preferred surgical solution. The three-dimensional construction of the nasal valve implies that many pathologies cannot be restored by a single solution. Treatment approaches should be directed at specific involved sites. Present systematic review of the literature revealed that the available evidence is based on low-level studies and focuses more on the description of various surgical techniques rather than on patient-reported outcome measures. Future studies are needed, including homogenous patient groups, comparing different surgical techniques and incorporating patient-reported outcome measures.

Mitotic phosphorylation of Bloom helicase at Thr182 is required for its proteasomal degradation and maintenance of chromosomal stability.

Mutations in Bloom helicase (BLM) lead to Bloom Syndrome (BS). BS is characterized by multiple clinical manifestations including predisposition to a wide spectrum of cancers. Studies have revealed the mechanism of BLM recruitment after stalled replication and its role during the repair of DNA damage. We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3ß- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. Consequently lack of Thr182 phosphorylation leads to multiple manifestations of chromosomal instability including increased levels of DNA damage, lagging chromatin, micronuclei formation, breaks and quadriradials. Hence Thr182 phosphorylation on BLM has two functions-it regulates BLM turnover during mitosis and also helps to maintain the chromosomal stability.

Regenerative medicine in otorhinolaryngology.

BACKGROUND: Tissue engineering using biocompatible scaffolds, with or without cells, can permit surgeons to restore structure and function following tissue resection or in cases of congenital abnormality. Tracheal regeneration has emerged as a spearhead application of these technologies, whilst regenerative therapies are now being developed to treat most other diseases within otolaryngology. METHODS AND RESULTS: A systematic review of the literature was performed using Ovid Medline and Ovid Embase, from database inception to 15 November 2014. A total of 561 papers matched the search criteria, with 76 fulfilling inclusion criteria. Articles were predominantly pre-clinical animal studies, reflecting the current status of research in this field. Several key human research articles were identified and discussed. CONCLUSION: The main issues facing research in regenerative surgery are translation of animal model work into human models, increasing stem cell availability so it can be used to further research, and development of better facilities to enable implementation of these advances.

High incidence of xenogenic bone marrow engraftment in pig-to-baboon intra-bone bone marrow transplantation.

Previous attempts of α-1,3-galactocyltransferase knockout (GalTKO) pig bone marrow (BM) transplantation (Tx) into baboons have demonstrated a loss of macro-chimerism within 24 h in most cases. In order to achieve improved engraftment with persistence of peripheral chimerism, we have developed a new strategy of intra-bone BM (IBBM) Tx. Six baboons received GalTKO BM cells, with one-half of the cells transplanted into the bilateral tibiae directly and the remaining cells injected intravenously (IBBM/BM-Tx) with a conditioning immunosuppressive regimen. In order to assess immune responses induced by the combined IBBM/BM-Tx, three recipients received donor SLA-matched GalTKO kidneys in the peri-operative period of IBBM/BM-Tx (Group 1), and the others received kidneys 2 months after IBBM/BM-Tx (Group 2). Peripheral macro-chimerism was continuously detectable for up to 13 days (mean 7.7 days; range 3-13) post-IBBM/BM-Tx and in three animals, macro-chimerism reappeared at days 10, 14 and 21. Pig CFUs, indicating porcine progenitor cell engraftment, were detected in the host BM in four of six recipients on days 14, 15, 19 and 28. In addition, anti-pig unresponsiveness was observed by in vitro assays. GalTKO/pCMV-kidneys survived for extended periods (47 and 60 days). This strategy may provide a potent adjunct for inducing xenogeneic tolerance through BM-Tx.

From the classic concepts to modern practice.

Transplant infectious disease is a field in evolution. For most allograft recipients, immunosuppressive therapies are more potent and have reduced the incidence of acute allograft rejection. At the same time, these therapies have increased susceptibility to many opportunistic infections and virally-mediated malignancies. Immunological tolerance has been achieved in only small numbers of patients who avoid drug toxicities and infection for as long as tolerance persists. The traditional timeline of post-transplant infections remains useful in the development of a differential diagnosis for patients with infectious syndromes. However, patterns of infection in the post-transplant period have changed over the past decade. Recipients are derived from a broader range of socioeconomic and geographical backgrounds. Infections are diagnosed more often, with improved microbiological assays (e.g. nucleic acid testing, NAT) used routinely in the diagnosis and management of common infections and increasingly in the screening of organ donors. Patterns of opportunistic infection have been altered by the increased identification of organisms demonstrating antimicrobial resistance and by the broader use of strategies to prevent viral, bacterial and fungal (including Pneumocystis) infections. Newer techniques are being applied (e.g. HLA-linked tetramer binding, intracellular cytokine staining) to assess pathogen-specific immunity. These are being integrated into clinical practice to assess individual susceptibility to specific infections. Infection, inflammation and the human microbiome are recognized as playing a central role in shaping innate and adaptive immune responses, graft rejection and autoimmunity. The full impact of infection on transplantation is only beginning to be appreciated.

Overview: cytomegalovirus and the herpesviruses in transplantation.

Herpesviruses infect most animal species. Infections due to the eight human herpesviruses (HHV) are exacerbated by immunosuppression in organ transplantation. The special features of the herpesvirus life cycle include the ability to establish latent, nonproductive infection and the life-long capacity for reactivation to productive, lytic infection. Interactions between latent virus and the immune system determine the frequency and severity of symptomatic infections. The immunologic and cellular effects of herpesvirus infections contribute to risk for opportunistic infections and graft rejection. Among the most important advances in transplantation are laboratory assays for the diagnosis and monitoring of herpesvirus infections and antiviral agents with improved efficacy in prophylaxis and therapy. For herpes simplex virus, varicella zoster virus and cytomegalovirus, these advances have significantly reduced the morbidity of infection. The syndromes of EBV-associated posttransplant lymphoproliferative disorders (PTLD) and Kaposi's sarcoma remain important complications of immunosuppression. The epidemiology and essential biology of human herpesvirus is reviewed.

Achieving flying colours in surgical safety: audit of World Health Organization 'Surgical Safety Checklist' compliance.

OBJECTIVE: The World Health Organization 'Surgical Safety Checklist' has been adopted by UK surgical units following National Patient Safety Agency guidance. Our aim was to assess compliance with our local version of this Checklist. METHODS: Otolaryngology trainee doctors prospectively assessed compliance with the local Checklist over a six-week period. A staff educational intervention was implemented and the audit was repeated 12 months later. RESULTS: A total of 72 cases were assessed. The initial audit found that: 44 per cent of procedures were undocumented at 'Sign in'; 'Time out' was inappropriately interrupted in 39 per cent of cases; the procedure started before Checklist completion in 33 per cent of cases; and the 'Sign out' was not read out in 94 per cent of cases and was not fully documented in 42 per cent of cases. Following education, re-audit indicated that overall compliance had improved from 63.7 per cent (± 8.9 per cent standard error of the mean) to 90.4 per cent (± 2.7 per cent standard error of the mean). CONCLUSION: Our completed audit cycle demonstrated a significant improvement in Checklist compliance following educational intervention. We discuss barriers to compliance, as well as strategies for quality improvement, and we call for other surgeons to similarly publish their Checklist experience and assess its impact on surgical outcomes.

The first 5-year follow up of distal antegrade continence enema stomas.

AIM: We investigated 5-year results of distal sites for antegrade continence enemas (DACE). METHODS: Patients with DACE sites placed more than 5 years previously were identified. Details of procedures were obtained. Parents, and patients over 18, were telephoned and asked to answer a standardised questionnaire. RESULTS: 31 patients were identified. Median age at DACE placement was 7 years (range 3-20). Median follow up was 92 months (range 66-145). 22 tubes were placed endoscopically, 7 were placed at open surgery and 2 at laparoscopic surgery. 28 responses to the telephone questionnaire were obtained. Of these, 15 were still using their DACE and 13 had stopped. Of those who had ceased washouts: 7 reported resolution of symptoms, 4 had a colostomy, 1 an ileostomy and 1 patient had abandoned their DACE. In patients using their stoma, washouts took a median of 5 min, with a median time to result of 25 min. 10 patients reported no soiling, 4 monthly and 1 daily soiling. Median satisfaction score was 8/10 (range 1-10/10). 24 (85%) said that they would recommend a DACE. CONCLUSIONS: This is the first report of 5-year follow up of a series of patients performing DACE washouts. The results are encouraging.

New technologies for infectious screening of organ donors.

Viral, bacterial, parasitic, prion, and fungal infections, although uncommon, have been transmitted via organ and tissue allografts. Improved screening techniques for infectious diseases in organ donors have helped to reduce disease transmission. Reports of clusters of donor-derived infections illustrate the need to improve the screening of tissue and organ donors. Available microbiologic assays, including molecular tests, are generally designed for use as diagnostic tools in individuals believed to have a specific infection based on clinical or epidemiological criteria. These assays are frequently unsuitable in the screening of deceased organ donors. Nucleic acid testing may reduce the risk of disease transmission by detecting early-stage infection, including those from human immunodeficiency virus, hepatitis B virus, and hepatitis C virus in the "window" period before antibody seroconversion can be documented. Screening of organ donors for potential pathogens cannot completely exclude the risk of disease transmission. The process of donor screening must continue to evolve with advances in diagnostic technologies for infectious diseases.

Prospective, randomised controlled trial comparing intense endoscopic cleaning versus minimal intervention in the early post-operative period following functional endoscopic sinus surgery.

OBJECTIVE: There is currently no standardised management protocol following functional endoscopic sinus surgery. This study assessed frequent endoscopic cleaning versus minimal intervention in the early post-operative period following such surgery. STUDY DESIGN: Prospective, randomised controlled, single-blinded, within-subject trial involving 24 patients with bilateral chronic rhinosinusitis undergoing bilateral functional endoscopic sinus surgery. MAIN OUTCOME MEASURE: The primary outcome measure was ethmoid cavity healing, based on endoscopic appearance, graded using a modified Lund-MacKay endoscopic score. SECONDARY OUTCOME MEASURE: Lund-MacKay symptom score before and after surgery. RESULTS: There was no overall statistically significant difference between the two groups (p = 0.37). Subgroup analysis revealed a significant effect of regular suction clearance on adhesions at three months (p = 0.048), but not on oedema, polyps, granulation, discharge or crusting. CONCLUSION: There is no evidence from this study to support frequent endoscopic cleaning in the early post-operative period after functional endoscopic sinus surgery. Less intensive post-operative management is recommended, resulting in decreased patient morbidity and fewer post-operative follow-up appointments.

UK incidence of achalasia: an 11-year national epidemiological study.

AIM: To determine the incidence and examine the epidemiology of achalasia before the age of 16 years in the UK from 1998 to 2008. METHODS: 25 regional paediatric surgery referral centres were asked to provide demographic and epidemiological data on cases of childhood achalasia from 1998 to 2008. Incidence rates were calculated from national population estimates. The data collection method was validated in one centre. RESULTS: 228 patients from 24 centres were diagnosed with achalasia before 16 years in the UK from 1998 to 2008. The mean incidence from 1998 to 2008 was 0.18/10(5) children/year. Where additional data was provided (69-81% of cases) 56% of children were male and the mean age of diagnosis was 10.9 years. Logistic regression analysis showed a rising incidence, with an OR of 1.12 (95% CI 1.06 to 1.16) for having achalasia in each successive year. The validation of this methodology showed that 95% of true cases and no false cases were identified. CONCLUSIONS: The mean incidence of childhood achalasia in the UK from 1998 to 2008 is at least 0.18/10(5) children/year; this has risen over the last 11 years and compared to the only other study published in 1988.

Recommended curriculum for subspecialty training in transplant infectious disease on behalf of the American Society of Transplantation Infectious Diseases Community of Practice Educational Initiatives Working Group.

The American Society of Transplantation Infectious Diseases (ID) Community of Practice has established an education workgroup to identify core components of a curriculum for training specialists in transplant ID. Clinical, laboratory, and research training form the triad of components on which an additional year of ID training, dedicated to the care of solid organ and hematopoietic stem cell transplant recipients, should be based. The recommended training environment would have access to adequate numbers of transplant patients, along with qualified faculty committed to teaching specialized fellows in this area. The learning objectives for both inpatient and outpatient clinical training are presented. The laboratory component requires trainees to attain expertize in utilizing and interpreting cutting-edge diagnostics used in transplant medicine. The research component may involve basic science, and translational or clinical research individualized to the trainee. Finally, suggestions for evaluation of both the fellows and the training program are provided.

Retroviral restriction factors and infectious risk in xenotransplantation.

The clinical application of xenotransplantation poses immunologic, ethical, and microbiologic challenges. Significant progress has been made in the investigation of each of these areas. Among concerns regarding infectious risks for human xenograft recipients is the identification in swine of infectious agents including porcine endogenous retroviruses (PERV) that are capable of replication in some human cell lines. PERV replication has, however, been difficult to demonstrate in primate-derived cell lines and in preclinical studies of non-human primates receiving porcine xenografts. Endogenous 'retroviral restriction factors' are intracellular proteins and components of the innate immune system that act at various steps in retroviral replication. Recent studies suggest that some of these factors may have applications in the management of endogenous retroviruses in xenotransplantation. The risks of PERV infection and the potential role of retroviral restriction factors in xenotransplantation are reviewed in detail.

Pulmonary arteriovenous fistula within a pulmonary cyst - evaluation with CT pulmonary angiography.

Pulmonary arteriovenous malformations (PAVMs) are abnormal direct communications between pulmonary arteries and pulmonary veins. These abnormal communications result in an anatomical right-to-left shunt that reduces the arterial oxygen saturation and may cause hypoxaemia and dyspnoea. Although PAVMs frequently remain undiagnosed, they are associated with severe morbidity in the form of ischaemic strokes and brain abscesses. We report a case of incidental CT angiography depiction of a PAVM within a pulmonary cyst. To the best of our knowledge, no such case has been described previously. On the basis of its appearance and lack of typical clinical features of hereditary haemorrhagic telangiectasia (HHT), we suggest that this PAVM actually represents an acquired fistula from a previously unrecognised focal pulmonary insult, such as trauma or infection, that simultaneously evolved into a pulmonary arteriovenous fistula (PAVF) within a traumatic pulmonary cyst or pneumatocele.

Development and validation of a disease-specific quality-of-life measure for children with achalasia.

BACKGROUND: Achalasia is an uncommon oesophageal motility disorder occasionally affecting children. Children with achalasia can experience significant morbidity, and quality-of- life (QoL) has never been studied in this population. AIM: The aim was to develop a disease-specific quality-of-life (DS-QoL) measure for children with achalasia. METHODS: Item response theory methods were used to develop the DS-QoL measure. The construct validity of this measure was assessed by comparing items and domains with the generic PedsQL questionnaire. Reliability was assessed using Cronbach's alpha coefficient for internal consistency. RESULTS: 17 children completed the final DS-QoL measure, which consisted of 20 items in three domains. The completion rate for items was 99%. "Floor and ceiling effects" ranged from 0-19%. Construct validity was good with significant correlation between 2 domains and 2 items on the PedsQL. Reliability was excellent, with Cronbach's alpha coefficient ranging from 0.78-0.93. CONCLUSIONS: This DS-QoL measure is appropriate for use in children with achalasia and has shown good results in this validation study. Further work in higher numbers is necessary to determine discriminant validity and test-retest reliability.

Central nervous system involvement in cryptococcal infection in individuals after solid organ transplantation or with AIDS.

BACKGROUND: Cryptococcus neoformans is an important pathogen of immunocompromised hosts. Manifestations of cryptococcal infection have not been compared between populations based on the nature of the underlying immune deficiencies. METHODS: The Prospective Antifungal Therapy Alliance (PATH) is a registry that collects clinical data from patients with invasive fungal infections from medical centers in North America. Univariate analyses and group comparisons were conducted from the PATH registry for cases of infection due to Cryptococcus species occurring between March 2004 and April 2008. RESULTS: A total 235 cases of proven infection due to Cryptococcus species were documented, all of which were due to C. neoformans (52 in solid organ transplant [SOT] recipients, 107 in patients infected with the human immunodeficiency virus [HIV], and 76 with neither HIV nor organ transplantation). A total of 140 cases manifested as meningitis (25 in SOT recipients, 88 in HIV-positive patients, and 27 in those with neither risk factor). Of individuals with cryptococcal infection, 44.2% of SOT recipients had central nervous system (CNS) disease, while 84.1% of those with HIV infection presented with CNS involvement (P=0.0265). SOT recipients receiving calcineurin inhibitors (CNIs) were less likely to have CNS involvement in cryptococcal infection (40.1% versus 66.7%). Overall, 12-week mortality for patients with cryptococcal infection in the PATH Alliance registry was 22.6% (21.2% for SOT, 15.9% for HIV-infected patients, and 32.9% for patients with risk factors other than HIV infection or organ transplantation). CONCLUSIONS: In a prospectively assembled cohort of individuals with proven infection due to C. neoformans, CNS involvement was more common in individuals with HIV infection than in SOT recipients. The role of CNIs in the reduction of risk for CNS cryptococcosis remains to be defined. Overall survival of patients with cryptococcal infection in immunocompromised hosts has improved over time. Observed differences in the context of various host immune deficits provide a basis for further investigation of cryptococcosis and other opportunistic infections.

Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry.

BACKGROUND: With use of data from the Prospective Antifungal Therapy (PATH) Alliance registry, we performed this multicenter, prospective, observational study to assess the epidemiologic characters and outcomes of invasive fungal infection (IFI) in hematopoietic stem cell transplant (HSCT) recipients. METHODS: Sixteen medical centers from North America reported data on adult HSCT recipients with proven or probable IFI during the period July 2004 through September 2007. The distribution of IFIs and rates of survival at 6 and 12 weeks after diagnosis were studied. We used logistic regression models to determine risk factors associated with 6-week mortality for allogeneic HSCT recipients with invasive aspergillosis (IA). RESULTS: Two hundred thirty-four adult HSCT recipients with a total of 250 IFIs were included in this study. IA (59.2%) was the most frequent IFI, followed by invasive candidiasis (24.8%), zygomycosis (7.2%), and IFI due to other molds (6.8%). Voriconazole was the most frequently administered agent (68.4%); amphotericin B deoxycholate was administered to a few patients (2.1%). Ninety-three (46.7%) of 199 HSCT recipients with known outcome had died by week 12. The 6-week survival rate was significantly greater for patients with IA than for those with invasive candidiasis and for those with IFI due to the Zygomycetes or other molds (P < .07). The 6-week mortality rate for HSCT recipients with IA was 21.5%. At 6 weeks, there was a trend toward a worse outcome among allogeneic HSCT recipients with IA who received myeloablative conditioning (P = .07); absence of mechanical ventilation or/and hemodialysis (P = .01) were associated with improved survival. CONCLUSIONS: IA remains the most commonly identified IFI among HSCT recipients, but rates of survival in persons with IA appear to have improved, compared with previously reported data. Invasive candidiasis and IFI due to molds other than Aspergillus species remain a significant problem in HSCT recipients.