Evolutionary Design of Self-Templated Supramolecular Fibrils Using M13 Bacteriophage for Tissue Engineering.

Biomaterials in nature form hierarchical structures and functions across various length scales through binding and assembly processes. Inspired by nature, we developed hierarchically organized tissue engineering materials through evolutionary screening and self-templating assembly. Leveraging the M13 bacteriophage (phage), we employed an evolutionary selection process against hydroxyapatite (HA) to isolate HA-binding phage (HAPh). The newly discovered phage exhibits a bimodal length, comprising 950 nm and 240 nm, where the synergistic effect of these dual lengths promotes the formation of supramolecular fibrils with periodic banded structures. The assembled HAPh fibrils show the capability of HA mineralization and the directional growth of osteoblast cells. When applied to a dentin surface, it induces the regeneration of dentin-like tissue structures, showcasing its potential applications as a scaffold in tissue engineering. The integration of evolutionary screening and self-templating assembly holds promise for the future development of hierarchically organized tissue engineering materials.

Impact of Prior Abdominal Procedures on Peritoneal Dialysis Catheter Outcomes: Findings From the North American Peritoneal Dialysis Catheter Registry.

RATIONALE & OBJECTIVE: A history of prior abdominal procedures may influence the likelihood of referral for peritoneal dialysis (PD) catheter insertion. To guide clinical decision making in this population, this study examined the association between prior abdominal procedures and outcomes in patients undergoing PD catheter insertion. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults undergoing their first PD catheter insertion between November 1, 2011, and November 1, 2020, at 11 institutions in Canada and the United States participating in the International Society for Peritoneal Dialysis North American Catheter Registry. EXPOSURE: Prior abdominal procedure(s) defined as any procedure that enters the peritoneal cavity. OUTCOMES: The primary outcome was time to the first of (1) abandonment of the PD catheter or (2) interruption/termination of PD. Secondary outcomes were rates of emergency room visits, hospitalizations, and procedures. ANALYTICAL APPROACH: Cumulative incidence curves were used to describe the risk over time, and an adjusted Cox proportional hazards model was used to estimate the association between the exposure and primary outcome. Models for count data were used to estimate the associations between the exposure and secondary outcomes. RESULTS: Of 855 patients who met the inclusion criteria, 31% had a history of a prior abdominal procedure and 20% experienced at least 1 PD catheter-related complication that led to the primary outcome. Prior abdominal procedures were not associated with an increased risk of the primary outcome (adjusted HR, 1.12; 95% CI, 0.68-1.84). Upper-abdominal procedures were associated with a higher adjusted hazard of the primary outcome, but there was no dose-response relationship concerning the number of procedures. There was no association between prior abdominal procedures and other secondary outcomes. LIMITATIONS: Observational study and cohort limited to a sample of patients believed to be potential candidates for PD catheter insertion. CONCLUSION: A history of prior abdominal procedure(s) does not appear to influence catheter outcomes following PD catheter insertion. Such a history should not be a contraindication to PD. PLAIN-LANGUAGE SUMMARY: Peritoneal dialysis (PD) is a life-saving therapy for individuals with kidney failure that can be done at home. PD requires the placement of a tube, or catheter, into the abdomen to allow the exchange of dialysis fluid during treatment. There is concern that individuals who have undergone prior abdominal procedures and are referred for a catheter might have scarring that could affect catheter function. In some institutions, they might not even be offered PD therapy as an option. In this study, we found that a history of prior abdominal procedures did not increase the risk of PD catheter complications and should not dissuade patients from choosing PD or providers from recommending it.

Extracellular Vesicle Analysis Allows for Identification of Invasive IPMN.

BACKGROUND AND AIMS: Advances in cross-sectional imaging have resulted in increased detection of intraductal papillary mucinous neoplasms (IPMNs), and their management remains controversial. At present, there is no reliable noninvasive method to distinguish between indolent and high risk IPMNs. We performed extracellular vesicle (EV) analysis to identify markers of malignancy in an attempt to better stratify these lesions. METHODS: Using a novel ultrasensitive digital extracellular vesicle screening technique (DEST), we measured putative biomarkers of malignancy (MUC1, MUC2, MUC4, MUC5AC, MUC6, Das-1, STMN1, TSP1, TSP2, EGFR, EpCAM, GPC1, WNT-2, EphA2, S100A4, PSCA, MUC13, ZEB1, PLEC1, HOOK1, PTPN6, and FBN1) in EV from patient-derived cell lines and then on circulating EV obtained from peripheral blood drawn from patients with IPMNs. We enrolled a total of 133 patients in two separate cohorts: a clinical discovery cohort (n = 86) and a validation cohort (n = 47). RESULTS: From 16 validated EV proteins in plasma samples collected from the discovery cohort, only MUC5AC showed significantly higher levels in high-grade lesions. Of the 11 patients with invasive IPMN (inv/HG), 9 had high MUC5AC expression in plasma EV of the 11 patients with high-grade dysplasia alone, only 1 had high MUC5AC expression (sensitivity of 82%, specificity of 100%). These findings were corroborated in a separate validation cohort. The addition of MUC5AC as a biomarker to imaging and high-riskstigmata allowed detection of all cases requiring surgery, whereas imaging and high-risk stigmata alone would have missed 5 of 14 cases (36%). CONCLUSIONS: MUC5AC in circulating EV can predict the presence of invasive carcinoma within IPMN. This approach has the potential to improve the management and follow-up of patients with IPMN including avoiding unnecessary surgery.

Transcriptomic RNAseq drug screen in cerebrocortical cultures: toward novel neurogenetic disease therapies.

Rare monogenic diseases affect millions worldwide; although over 4500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases. Many genetic diseases result from increased or decreased protein activity and identification of clinically approved drugs which moderate this pathogenic dosage holds therapeutic potential. To identify such agents for neurogenetic diseases, we have generated genome-wide transcriptome profiles of mouse primary cerebrocortical cultures grown in the presence of 218 blood-brain barrier (BBB) penetrant clinic-tested drugs. RNAseq and differential expression analyses were used to generate transcriptomic profiles; therapeutically relevant drug-gene interactions related to rare neurogenetic diseases identified in this fashion were further analyzed by quantitative reverse transcriptase-polymerase chain reaction, western blot and immunofluorescence. We have created a transcriptome-wide searchable database for easy access to the gene expression data resulting from the cerebrocortical drug screen (Neuron Screen) and have mined this data to identify a novel link between thyroid hormone and expression of the peripheral neuropathy associated gene Pmp22. Our results demonstrate the utility of cerebrocortical cultures for transcriptomic drug screening, and the database we have created will foster further discovery of novel links between over 200 clinic-tested BBB penetrant drugs and genes related to diverse neurologic conditions.

Urate lowering therapy to improve renal outcomes in patients with chronic kidney disease: systematic review and meta-analysis.

BACKGROUND: Hyperuricemia may contribute to renal injury. We do not know whether use of treatments that lower urate reduce the progression of chronic kidney disease (CKD) and cardiovascular disease. We performed a systematic review and meta-analysis of randomized controlled trials to assess the benefits and risks of treatments that lower urate in patients with stages 3-5 CKD. METHODS: We searched MEDLINE, EMBASE, CENTRAL, Web of Science and trial registers for randomized controlled trials (RCTs) without language restriction. Two authors independently screened articles, assessed risk of bias and extracted data. Data obtained included serum uric acid, serum creatinine or other estimates of glomerular filtration rate, incidence of end-stage renal disease (ESRD), systolic and diastolic blood pressure, proteinuria, cardiovascular disease and adverse events. RESULTS: From the 5497 citations screened, 19 RCTs enrolling 992 participants met our inclusion criteria. Given significant heterogeneity in duration of follow-up and study comparators, only trials greater than 3 months comparing allopurinol and inactive control were meta-analyzed using random effects models. Pooled estimate for eGFR was in favour of allopurinol with a mean difference (MD) of 3.2 ml/min/1.73 m(2), 95% CI 0.16-6.2 ml/min/1.73 m(2), p = 0.039 and this was consistent with results for serum creatinine. Statistically significant reductions in serum uric acid, systolic and diastolic blood pressure were found, favouring allopurinol. There were insufficient data on adverse events, incidence of ESRD and cardiovascular disease for analysis. CONCLUSIONS: Adequately powered RCTs are needed to establish whether treatments that lower urate have beneficial renal and cardiovascular effects.

The efficiency of dentin sialoprotein-phosphophoryn processing is affected by mutations both flanking and distant from the cleavage site.

Normal dentin mineralization requires two highly acidic proteins, dentin sialoprotein (DSP) and phosphophoryn (PP). DSP and PP are synthesized as part of a single secreted precursor, DSP-PP, which is conserved in marsupial and placental mammals. Using a baculovirus expression system, we previously found that DSP-PP is accurately cleaved into DSP and PP after secretion into medium by an endogenous, secreted, zinc-dependent Sf9 cell activity. Here we report that mutation of conserved residues near and distant from the G(447)↓D(448) cleavage site in DSP-PP(240) had dramatic effects on cleavage efficiency by the endogenous Sf9 cell processing enzyme. We found that: 1) mutation of residues flanking the cleavage site from P(4) to P(4)' blocked, impaired, or enhanced DSP-PP(240) cleavage; 2) certain conserved amino acids distant from the cleavage site were important for precursor cleavage; 3) modification of the C terminus by appending a C-terminal tag altered the pattern of processing; and 4) mutations in DSP-PP(240) had similar effects on cleavage by recombinant human BMP1, a candidate physiological processing enzyme, as was seen with the endogenous Sf9 cell activity. An analysis of a partial TLR1 cDNA from Sf9 cells indicates that residues that line the substrate-binding cleft of Sf9 TLR1 and human BMP1 are nearly perfectly conserved, offering an explanation of why Sf9 cells so accurately process mammalian DSP-PP. The fact that several mutations in DSP-PP(240) significantly modified the amount of PP(240) product generated from DSP-PP(240) precursor protein cleavage suggests that such mutation may affect the mineralization process.

Site specificity of DSP-PP cleavage by BMP1.

Bone morphogenic protein 1 (BMP1), a metalloproteinase, is known to cleave a wide variety of extracellular matrix proteins, suggesting that a consensus substrate cleavage amino acid sequence might exist. However, while such a consensus sequence has been proposed based on P4 to P4' (i.e. the four amino acids flanking either side of the BMP1 cleavage site; P4P3P2P1|P1'P2'P3'P4') sequence homologies between two BMP1 substrates, dentin matrix protein 1 and dentin sialoprotein phosphophoryn (DSP-PP) (i.e. xMQx|DDP), no direct testing has so far been attempted. Using an Sf9 cell expression system, we have been able to produce large amounts of uncleaved DSP-PP. Point mutations introduced into this recombinant DSP-PP were then tested for their effects on DSP-PP cleavage by either Sf9 endogenous tolloid-related protein 1 (TLR-1) or by its human homolog, BMP1. Here, we have measured DSP-PP cleavage efficiencies after modifications based on P4-P4' sequence comparisons with dentin matrix protein 1, as well as for prolysyl oxidase and chordin, two other BMP1 substrates. Our results demonstrate that any mutations within or outside of the DSP-PP P4 to P4' cleavage site can block, impair or accelerate DSP-PP cleavage, and suggest that its BMP1 cleavage site is highly conserved in order to regulate its cleavage efficiency, possibly with additional assistance from its conserved exosites. Thus, BMP1 cleavage cannot be based on a consensus substrate cleavage site.

The Association of Intra-Abdominal Adhesions with Peritoneal Dialysis Catheter-Related Complications.

BACKGROUND: This study investigated the association of intra-abdominal adhesions with the risk of peritoneal dialysis (PD) catheter complications. METHODS: Individuals undergoing laparoscopic PD catheter insertion were prospectively enrolled from eight centers in Canada and the United States. Patients were grouped based on the presence of adhesions observed during catheter insertion. The primary outcome was the composite of PD never starting, termination of PD, or the need for an invasive procedure caused by flow restriction or abdominal pain. RESULTS: Seven hundred and fifty-eight individuals were enrolled, of whom 201 (27%) had adhesions during laparoscopic PD catheter insertion. The risk of the primary outcome occurred in 35 (17%) in the adhesion group compared with 58 (10%) in the no adhesion group (adjusted HR, 1.64; 95% confidence interval [CI], 1.05 to 2.55) within 6 months of insertion. Lower abdominal or pelvic adhesions had an adjusted HR of 1.80 (95% CI, 1.09 to 2.98) compared with the no adhesion group. Invasive procedures were required in 26 (13%) and 47 (8%) of the adhesion and no adhesion groups, respectively (unadjusted HR, 1.60: 95% CI, 1.04 to 2.47) within 6 months of insertion. The adjusted odds ratio for adhesions for women was 1.65 (95% CI, 1.12 to 2.41), for body mass index per 5 kg/m 2 was 1.16 (95% CI, 1.003 to 1.34), and for prior abdominal surgery was 8.34 (95% CI, 5.5 to 12.34). Common abnormalities found during invasive procedures included PD catheter tip migration, occlusion of the lumen with fibrin, omental wrapping, adherence to the bowel, and the development of new adhesions. CONCLUSIONS: People with intra-abdominal adhesions undergoing PD catheter insertion were at higher risk for abdominal pain or flow restriction preventing PD from starting, PD termination, or requiring an invasive procedure. However, most patients, with or without adhesions, did not experience complications, and most complications did not lead to the termination of PD therapy.

Machine Learning and Real-World Data to Predict Lung Cancer Risk in Routine Care.

BACKGROUND: This study used machine learning to develop a 3-year lung cancer risk prediction model with large real-world data in a mostly younger population. METHODS: Over 4.7 million individuals, aged 45 to 65 years with no history of any cancer or lung cancer screening, diagnostic, or treatment procedures, with an outpatient visit in 2013 were identified in Optum's de-identified Electronic Health Record (EHR) dataset. A least absolute shrinkage and selection operator model was fit using all available data in the 365 days prior. Temporal validation was assessed with recent data. External validation was assessed with data from Mercy Health Systems EHR and Optum's de-identified Clinformatics Data Mart Database. Racial inequities in model discrimination were assessed with xAUCs. RESULTS: The model AUC was 0.76. Top predictors included age, smoking, race, ethnicity, and diagnosis of chronic obstructive pulmonary disease. The model identified a high-risk group with lung cancer incidence 9 times the average cohort incidence, representing 10% of patients with lung cancer. Model performed well temporally and externally, while performance was reduced for Asians and Hispanics. CONCLUSIONS: A high-dimensional model trained using big data identified a subset of patients with high lung cancer risk. The model demonstrated transportability to EHR and claims data, while underscoring the need to assess racial disparities when using machine learning methods. IMPACT: This internally and externally validated real-world data-based lung cancer prediction model is available on an open-source platform for broad sharing and application. Model integration into an EHR system could minimize physician burden by automating identification of high-risk patients.

Plasma protein biomarkers for early prediction of lung cancer.

BACKGROUND: Individual plasma proteins have been identified as minimally invasive biomarkers for lung cancer diagnosis with potential utility in early detection. Plasma proteomes provide insight into contributing biological factors; we investigated their potential for future lung cancer prediction. METHODS: The Olink® Explore-3072 platform quantitated 2941 proteins in 496 Liverpool Lung Project plasma samples, including 131 cases taken 1-10 years prior to diagnosis, 237 controls, and 90 subjects at multiple times. 1112 proteins significantly associated with haemolysis were excluded. Feature selection with bootstrapping identified differentially expressed proteins, subsequently modelled for lung cancer prediction and validated in UK Biobank data. FINDINGS: For samples 1-3 years pre-diagnosis, 240 proteins were significantly different in cases; for 1-5 year samples, 117 of these and 150 further proteins were identified, mapping to significantly different pathways. Four machine learning algorithms gave median AUCs of 0.76-0.90 and 0.73-0.83 for the 1-3 year and 1-5 year proteins respectively. External validation gave AUCs of 0.75 (1-3 year) and 0.69 (1-5 year), with AUC 0.7 up to 12 years prior to diagnosis. The models were independent of age, smoking duration, cancer histology and the presence of COPD. INTERPRETATION: The plasma proteome provides biomarkers which may be used to identify those at greatest risk of lung cancer. The proteins and the pathways are different when lung cancer is more imminent, indicating that both biomarkers of inherent risk and biomarkers associated with presence of early lung cancer may be identified. FUNDING: Janssen Pharmaceuticals Research Collaboration Award; Roy Castle Lung Cancer Foundation.

Cancer-associated fibroblasts facilitate breast cancer progression through exosomal circTBPL1-mediated intercellular communication.

Breast cancer is the major common malignancy worldwide among women. Previous studies reported that cancer-associated fibroblasts (CAFs) showed pivotal roles in regulating tumor progression via exosome-mediated cellular communication. However, the detailed mechanism underlying the exosomal circRNA from CAFs in breast cancer progression remains ambiguous. Here, exosomal circRNA profiling of breast cancer-derived CAFs and normal fibroblasts (NFs) was detected by high-throughput sequencing, and upregulated circTBPL1 expression was identified in CAF exosomes. The exosomal circTBPL1 from CAFs could be transferred to breast cancer cells and promoted cell proliferation, migration, and invasion. Consistently, circTBPL1 knockdown in CAFs attenuated their tumor-promoting ability. Further exploration identified miR-653-5p as an inhibitory target of circTBPL1, and ectopic expression of miR-653-5p could partially reverse the malignant phenotypes induced by circTBPL1 overexpression in breast cancer. Additionally, TPBG was selected as a downstream target gene, and circTBPL1 could protect TPBG from miR-653-5p-mediated degradation, leading to enhanced breast cancer progression. Significantly, the accelerated tumor progression triggered by exosomal circTBPL1 from CAFs was confirmed in xenograft models. Taken together, these results revealed that exosomal circTBPL1 derived from CAFs contributed to cancer progression via miR-653-5p/TPBG pathway, indicating the potential of exosomal circTBPL1 as a biomarker and novel therapeutic target for breast cancer.

HPV-associated head and neck cancer: molecular and nano-scale markers for prognosis and therapeutic stratification.

Over the last 10 years, it has become clear that patients with head and neck cancer can be stratified into two distinct subgroups on the basis of the etiology of their disease. Patients with human papillomavirus-related cancers have significantly better survival rates and may necessitate different therapeutic approaches than those with tobacco and/or alcohol related cancers. This review discusses the various biomarkers currently in use for identification of patients with HPV-positive cancers with a focus on the advantages and limitations of molecular and nano-scale markers.

Large-scale Analyses of Disease Biomarkers and Apremilast Pharmacodynamic Effects.

Finding biomarkers that provide shared link between disease severity, drug-induced pharmacodynamic effects and response status in human trials can provide number of values for patient benefits: elucidating current therapeutic mechanism-of-action, and, back-translating to fast-track development of next-generation therapeutics. Both opportunities are predicated on proactive generation of human molecular profiles that capture longitudinal trajectories before and after pharmacological intervention. Here, we present the largest plasma proteomic biomarker dataset available to-date and the corresponding analyses from placebo-controlled Phase III clinical trials of the phosphodiesterase type 4 inhibitor apremilast in psoriasis (PSOR), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from 526 subjects overall. Using approximately 150 plasma analytes tracked across three time points, we identified IL-17A and KLK-7 as biomarkers for disease severity and apremilast pharmacodynamic effect in psoriasis patients. Combined decline rate of KLK-7, PEDF, MDC and ANGPTL4 by Week 16 represented biomarkers for the responder subgroup, shedding insights into therapeutic mechanisms. In ankylosing spondylitis patients, IL-6 and LRG-1 were identified as biomarkers with concordance to disease severity. Apremilast-induced LRG-1 increase was consistent with the overall lack of efficacy in ankylosing spondylitis. Taken together, these findings expanded the mechanistic knowledge base of apremilast and provided translational foundations to accelerate future efforts including compound differentiation, combination, and repurposing.

Quantifying the risk of insertion-related peritoneal dialysis catheter complications following laparoscopic placement: Results from the North American PD Catheter Registry.

BACKGROUND: Peritoneal dialysis (PD) is a more cost-effective therapy to treat kidney failure than in-center hemodialysis, but successful therapy requires a functioning PD catheter that causes minimal complications. In 2015, the North American Chapter of the International Society for Peritoneal Dialysis established the North American PD Catheter Registry to improve practices and patient outcomes following PD catheter insertion. AIMS: The objective of this study is to propose a methodology for defining insertion-related complications that lead to significant adverse events and report the risk of these complications among patients undergoing laparoscopic PD catheter insertion. METHODS: Patients undergoing laparoscopic PD catheter insertion were enrolled at 14 participating centers in Canada and the United States and followed using a Web-based registry. Insertion-related complications were defined as flow restriction, exit-site leak, or abdominal pain at any point during follow-up. We also included infections or bleeding within 30 days of insertion, and any immediate postoperative complications. Adverse events were categorized as PD never starting or termination of PD therapy, delay in the start of PD therapy or interruption of PD therapy, an emergency department visit or hospitalization, or need for invasive procedures. Cause-specific cumulative incidence functions were used to estimate risk. RESULTS: Five hundred patients underwent laparoscopic PD catheter insertion between 10 November 2015 and 24 July 2018. The cumulative risk of insertion-related complications 6 months from the date of insertion that led to an adverse event was 24%. The risk of flow restriction, exit-site leak, and pain at 6 months was 10.2%, 5.7%, and 5.3%, respectively. PD was never started or terminated in 6.4% of patients due to an insertion-related complication. Leaks and flow restrictions were most likely to delay or interrupt PD therapy. Flow restrictions were the primary cause of invasive procedures. Fifty percent of the complications occurred before the start of PD therapy. CONCLUSIONS: Insertion-related complications leading to significant adverse events following laparoscopic placement of PD catheters are common. Many complications occur before the start of PD. Insertion-related complications are an important area of focus for future research and quality improvement efforts.

Outcomes of Adopting Endoscopic Tympanoplasty in an Academic Teaching Hospital.

OBJECTIVES: To compare the outcomes of endoscopic versus microscopic tympanoplasty during the initial period of a surgeon adopting the new endoscopic technique and teaching the surgical approach to residents assisting in surgery. METHODS: Retrospective medical chart review of 60 consecutive operations for repair of isolated tympanic membrane perforations from 2011 to 2016 performed by a single surgeon assisted by residents in an academic teaching hospital. The outcomes of 20 ears repaired microscopically before the senior author adopted endoscopic ear surgery (Group A) were compared with the outcomes of the first 20 ears that were attempted with endoscopic surgery (Group B) and the next 20 ears performed endoscopically (Group C). Sixty ear operations were performed on 52 patients as 8 patients had bilateral ear surgery. RESULTS: The tympanic membrane closure rate was 80% for Group A, 80% for Group B, and 95% for Group C. Mean air-bone gap improvement was 12.8 dB in Group A, 8.3 dB in Group B, and 12.1 dB in Group C. Mean duration of surgery was 99.2 minutes in Group A, 91.3 minutes in Group B, and 90.5 minutes in Group C. In Group B, 20% of the ears (4/20) were converted to a microscopic approach; in Group C, none required conversion. CONCLUSIONS: Maintenance of good outcomes and similar results can be maintained during a surgeon's transition to adopting endoscopic tympanoplasty and teaching it to residents.

Clinico-radiologic features and management of hematological tumors in the breast: a case series.

Hematological tumors arising in the breast are uncommon and require different treatment modalities dependent upon tumor type. Current treatment options include surgical excision, chemotherapy, and radiotherapy. Management of these breast malignancies are poorly outlined in the literature. The purpose of this case series is to report five cases consisting of extranodal marginal zone lymphoma, lymphoplasmacytic lymphoma, and extramedullary plasmacytoma occurring in the breast. The cases illustrate heterogeneous radiologic findings and varying management approaches to these tumors. The case series underscores the importance of having a wide differential at diagnosis and recognizes management of disease should be taken on an individual basis with consideration of prognosis and first-line treatment options.

16S rRNA gene sequencing reveals site-specific signatures of the upper and lower airways of cystic fibrosis patients.

BACKGROUND: Metastasis of upper airway microbiota may have significant implications in the development of chronic lung disease. Here, we compare bacterial communities of matched sinus and lung mucus samples from cystic fibrosis (CF) subjects undergoing endoscopic surgery for treatment of chronic sinusitis. METHODS: Mucus from one maxillary sinus and expectorated sputum were collected from twelve patients. 16S rRNA gene sequencing was then performed on sample pairs to compare the structure and function of CF airway microbiota. RESULTS: Bacterial diversity was comparable between airway sites, though sinuses harbored a higher prevalence of dominant microorganisms. Ordination analyses revealed that samples clustered more consistently by airway niche rather than by individual. Finally, predicted metagenomes suggested that anaerobiosis was enriched in the lung. CONCLUSIONS: Our findings indicate that while the lung may be seeded by individual sinus pathogens, airway microenvironments harbor distinct bacterial communities that should be considered in selecting antimicrobial therapies.

Meta-analysis: risk for hypertension in living kidney donors.

BACKGROUND: The risk for hypertension after kidney donation remains uncertain. PURPOSE: To see whether normotensive adults who donate a kidney develop higher blood pressure and risk for hypertension compared with nondonor adults acting as control participants. DATA SOURCES: MEDLINE, EMBASE, and Science Citation Index were searched from 1966 until November 2005 for articles published in any language. Reference lists of pertinent articles were also reviewed. STUDY SELECTION: The authors selected studies involving 10 or more healthy normotensive adults who donated a kidney and in whom blood pressure was assessed at least 1 year later. DATA EXTRACTION: Two reviewers independently abstracted data on study and donor characteristics, blood pressure measurements, outcomes, and prognostic features. Comparison data were abstracted from donor studies with control participants. Thirty primary authors provided additional data. DATA SYNTHESIS: Forty-eight studies from 28 countries followed a total of 5145 donors. Before surgery, the average age of donors was 41 years, the average systolic blood pressure was 121 mm Hg, and the average diastolic blood pressure was 77 mm Hg for all studies. In controlled studies in which the average follow-up was at least 5 years after donation (range, 6 to 13 years), blood pressure was 5 mm Hg higher in donors than in control participants (the weighted mean for systolic blood pressure using 4 studies involving 157 donors and 128 control participants was 6 mm Hg [95% CI, 2 to 11 mm Hg], and the weighted mean for diastolic blood pressure using 5 studies involving 196 donors and 161 control participants was 4 mm Hg [CI, 1 to 7 mm Hg]). There was statistical heterogeneity among the 6 controlled studies that assessed hypertension; an increase in risk was noted in 1 study (relative risk, 1.9 [CI, 1.1 to 3.5]). LIMITATIONS: Most studies were retrospective and did not include control groups that were assembled and followed along with donors. Approximately one third of the donors had incomplete follow-up information. CONCLUSIONS: On the basis of the limited studies conducted to date, kidney donors may have a 5-mm Hg increase in blood pressure within 5 to 10 years after donation over that anticipated with normal aging. Future controlled, prospective studies with long periods of follow-up will better delineate safety and identify donors at lowest risk for long-term morbidity.

Current Canadian initiatives to reimburse live organ donors for their non-medical expenses.

Living organ donors frequently incur non-medical expenses for travel, accommodation, prescription drugs, loss of income, and child care in conjunction with organ donation. Despite international precedent and widespread public support, Canada currently lacks a unified strategy to reimburse donors for these expenses. In 2005, we communicated with 78 individuals within the field of Canadian transplantation to identify which initiatives for reimbursement of living donors existed in each province. Saskatchewan was the only province in which public employees were granted paid leave for organ donation. Six provincial governments partially reimbursed travel and accommodation. At the federal level, other expenses could be partially reimbursed through an income tax credit, while the Employment Insurance program and the Canada Pension Plan provided funding for donors who become unemployed or develop long-term disability as a result of donation. Charities helped a limited number of patients in financial need through grants and no-interest loans, but funding was generally limited by contributions received. While reimbursing living donors for their non-medical expenses is considered just, existing programs only partially reimburse expenses and are not available in all provinces. Developing future reimbursement policies will remove a disincentive faced by some potential donors, and may increase rates of transplantation in Canada.