Chemical and Cellular Formation of Reactive Oxygen Species from Secondary Organic Aerosols in Epithelial Lining Fluid.

INTRODUCTION: Oxidative stress mediated by reactive oxygen species (ROS) is a key process for adverse aerosol health effects. Secondary organic aerosols (SOA) account for a major fraction of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5). PM2.5 inhalation and deposition into the respiratory tract causes the formation of ROS by chemical reactions and phagocytosis of macrophages in the epithelial lining fluid (ELF), but their relative contributions are not well quantified and their link to oxidative stress remains uncertain. The specific aims of this project were (1) elucidating the chemical mechanism and quantifying the formation kinetics of ROS in the ELF by SOA; (2) quantifying the relative importance of ROS formation by chemical reactions and macrophages in the ELF. METHODS: SOA particles were generated using reaction chambers from oxidation of various precursors including isoprene, terpenes, and aromatic compounds with or without nitrogen oxides (NOx). We collected size-segregated PM at two highway sites in Anaheim, CA, and Long Beach, CA, and at an urban site in Irvine, CA, during two wildfire events. The collected particles were extracted into water or surrogate ELF that contained lung antioxidants. ROS generation was quantified using electron paramagnetic resonance (EPR) spectroscopy with a spin-trapping technique. PM oxidative potential (OP) was also quantified using the dithiothreitol assay. In addition, kinetic modeling was applied for analysis and interpretation of experimental data. Finally, we quantified cellular superoxide release by RAW264.7 macrophage cells upon exposure to quinones and isoprene SOA using a chemiluminescence assay as calibrated with an EPR spin-probing technique. We also applied cellular imaging techniques to study the cellular mechanism of superoxide release and oxidative damage on cell membranes. RESULTS: Superoxide radicals (·O2-) were formed from aqueous reactions of biogenic SOA generated by hydroxy radical (·OH) photooxidation of isoprene, ß-pinene, α-terpineol, and d-limonene. The temporal evolution of ·OH and ·O2- formation was elucidated by kinetic modeling with a cascade of aqueous reactions, including the decomposition of organic hydroperoxides (ROOH), ·OH oxidation of primary or secondary alcohols, and unimolecular decomposition of α-hydroxyperoxyl radicals. Relative yields of various types of ROS reflected the relative abundance of ROOH and alcohols contained in SOA, which generated under high NOx conditions, exhibited lower ROS yields. ROS formation by SOA was also affected by pH. Isoprene SOA had higher ·OH and organic radical yields at neutral than at acidic pH. At low pH ·O2- was the dominant species generated by all types of SOA. At neutral pH, α-terpineol SOA exhibited a substantial yield of carbon-centered organic radicals (R·), while no radical formation was observed by aromatic SOA.Organic radicals in the ELF were formed by mixtures of Fe2+ and SOA generated from photooxidation of isoprene, α-terpineol, and toluene. The molar yields of organic radicals by SOA were 5-10 times higher in ELF than in water. Fe2+ enhanced organic radical yields by a factor of 20-80. Ascorbate mediated redox cycling of iron ions and sustained organic peroxide decomposition, as supported by kinetic modeling reproducing time- and concentration-dependence of organic radical formation, as well as by additional experiments observing the formation of Fe2+ and ascorbate radicals in mixtures of ascorbate and Fe3+. ·OH and superoxide were found to be efficiently scavenged by antioxidants.Wildfire PM mainly generated ·OH and R· with minor contributions from superoxide and oxygen-centered organic radicals (RO·). PM OP was high in wildfire PM, exhibiting very weak correlation with radical forms of ROS. These results were in stark contrast with PM collected at highway and urban sites, which generated much higher amounts of radicals dominated by ·OH radicals that correlated well with OP. By combining field measurements of size-segregated chemical composition, a human respiratory tract model, and kinetic modeling, we quantified production rates and concentrations of different types of ROS in different regions of the ELF by considering particle-size-dependent respiratory deposition. While hydrogen peroxide (H2O2) and ·O2- production were governed by Fe and Cu ions, ·OH radicals were mainly generated by organic compounds and Fenton-like reactions of metal ions. We obtained mixed results for correlations between PM OP and ROS formation, providing rationale and limitations of the use of oxidative potential as an indicator for PM toxicity in epidemiological and toxicological studies.Quinones and isoprene SOA activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in macrophages, releasing massive amounts of superoxide via respiratory burst and overwhelming the superoxide formation by aqueous chemical reactions in the ELF. The threshold dose for macrophage activation was much smaller for quinones compared with isoprene SOA. The released ROS caused lipid peroxidation to increase cell membrane fluidity, inducing oxidative damage and stress. Further increases of doses led to the activation of antioxidant response elements, reducing the net cellular superoxide production. At very high doses and long exposure times, chemical production became comparably important or dominant if the escalation of oxidative stress led to cell death. CONCLUSIONS: The mechanistic understandings and quantitative information on ROS generation by SOA particles provided a basis for further elucidation of adverse aerosol health effects and oxidative stress by PM2.5. For a comprehensive assessment of PM toxicity and health effects via oxidative stress, it is important to consider both chemical reactions and cellular processes for the formation of ROS in the ELF. Chemical composition of PM strongly influences ROS formation; further investigations are required to study ROS formation from various PM sources. Such research will provide critical information to environmental agencies and policymakers for the development of air quality policy and regulation.

Patient experiences of left-sided colorectal resection by robotic, conventional laparoscopic and open approaches: a qualitative study.

BACKGROUND: Robotic surgery (RS) is increasingly employed in colorectal surgical practice, widening the range of surgical techniques offered to patients. We investigated the perceptions of patients with colorectal cancer in relation to RS, open surgery (OS) and conventional laparoscopic surgery (CLS), to identify ideas or assumptions which, in the context of shared surgeon-patient decision-making, may affect the resultant choice of surgical technique. We also investigated salient factors affecting patients' perioperative experience, including those of RS patients, to guide improvements in care and preoperative patient preparation. METHODS: This study was conducted on patients who underwent resection of left-sided colorectal cancer at a large UK teaching hospital from November 2020 to July 2021. Purposive sampling was used to ensure a roughly equal proportion of patients who underwent RS, CLS and OS. The patients included in the study participated in semi-structured interviews six weeks postoperatively. The interview schedule allowed discussion around patients' experience of their surgery and postoperative recovery, and their perceptions of surgical techniques. Interview transcripts were coded manually using inductive thematic analysis, and analyst triangulation was employed to refine coding schemes and ensure reliability of emerging themes. RESULTS: Twenty-seven patients were recruited to the study; RS n = 9 (median age 69 [range 60-80] years); CLS n = 10 (median age 72 [range 32-82] years; OS n = 8 (median age 71 [range 60-75] years). Patients understood the technological benefits of RS but were concerned by a risk of technological failure causing patient harm. OS was understood to be associated with more pain and longer recovery than RS or CLS. Patients perceived CLS to be more technically challenging compared with OS. Less pain and smaller wounds than expected were significant positive factors in the experience of RS and CLS patients specifically. Complications and emotional impact were significant factors in the experience of all groups, for which many patients felt underprepared. CONCLUSIONS: Patients generally have a positive view of RS and technical innovation in surgery. Concerns mostly centred around failure of technology. Many patients felt unprepared for significant factors in their perioperative experience. Surgeons and healthcare providers should be prepared to address patients' perceptions and expectations of colorectal surgery preoperatively.

Medical publishing: a flawed model in dire need of reform.

Recently, in the midst of the Covid-19 pandemic, high-profile retractions of some papers published in prestigious medical journals have highlighted the necessity for structural reform to the current model of medical publishing. We discuss what ails the current system and what can be done to remedy it.

Association of CRP Haplotypes in Rheumatoid Arthritis and their Correlation with Severity of the Disease.

BACKGROUND: Rheumatoid arthritis is a heterogenous autoimmune disorder of unknown cause with variable clinical expression. Genetic factors play an important role and likely account for about 60% of disease susceptibility and expression. The aim of this study to find out the association of CRP haplotypes in rheumatoid arthritis and their correlation with severity of the disease. MATERIAL AND METHODS: This was case control study where in all available patients and volunteers (only for blood samples) were recruited. Peripheral blood samples of patients were collected at Rheumatology Clinic and Medicine Department of S.P. Medical College, Bikaner in collaboration with Department of Biological Sciences, BITS, Pilani-Hyderabad during July 2009 to January 2012. 100 control subjects with no known history of disease and 135 cases were recruited as per pre-decided inclusion and exclusion criteria. A tag SNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. RESULTS: Cases comprised of 98 females (Mean age 43.01+13.23 yrs) and 37 (mean age 47.4+14.9 years) males. The Control group comprised of 100 unrelated healthy controls. The cases and controls did not differ significantly for any of the clinical parameters, except for serum CRP levels. The allele distribution of rs1205 polymorphism among the studied cases and controls, which was statistical non-significant. The rs3093066 polymorphism located at the 3` position of the gene in the UTR at position number 157949723. The rs3116640 polymorphism located at 157948938 position on chromosome1 and the allele distribution of rs3116637 polymorphism among cases and controls which was also found to be monomorphic respectively. CONCLUSION: Extending the studies to a larger cohort will also allow genetic analyses of clinically defined endophenotypes observed in the patients of this chronic metabolic disease with attributes of autoimmune disorder and multiple symptoms in patients. Genetic studies can also impact strategies adopted for effective personalized treatment for this progressively debilitating disease.

Renal impairment after ileostomy formation: a frequent event with long-term consequences.

AIM: High stoma output and dehydration is common following ileostomy formation. However, the impact of this on renal function, both in the short term and after ileostomy reversal, remains poorly defined. We aimed to assess the independent impact on kidney function of an ileostomy after rectal cancer surgery and subsequent reversibility after ileostomy closure. METHODS: This retrospective single-site cohort study identified patients undergoing rectal cancer resection from 2003 to 2017, with or without a diverting ileostomy. Renal function was calculated preoperatively, before ileostomy closure, and 6 months after ileostomy reversal (or matched times for patients without ileostomy). Demographics, oncological treatments and nephrotoxic drug prescriptions were assessed. Outcome measures were deterioration from baseline renal function and development of moderate/severe chronic kidney disease (CKD ≥ 3). Multivariate analysis was performed to assess independent risk factors for postoperative renal impairment. RESULTS: Five hundred and eighty-three of 1213 patients had an ileostomy. Postoperative renal impairment occurred more frequently in ileostomates (9.5% absolute increase in rate of CKD ≥ 3; P < 0.0001) vs no change in patients without an ileostomy (P = 0.757). Multivariate analysis identified ileostomy formation, age, anastomotic leak and renin-angiotensin system inhibitors as independently associated with postoperative renal decline. Despite stoma closure, ileostomates remained at increased risk of progression to new or worse CKD [74/438 (16.9%)] compared to patients without an ileostomy [36/437 (8.2%), P = 0.0001, OR 2.264 (1.49-3.46)]. CONCLUSIONS: Ileostomy formation is independently associated with kidney injury, with an increased risk persisting after stoma closure. Strategies to protect against kidney injury may be important in higher risk patients (elderly, receiving renin-angiotensin system antihypertensives, or following anastomotic leakage).

Does intra-operative flexible endoscopy reduce anastomotic complications following left-sided colonic resections? A systematic review and meta-analysis.

AIM: Postoperative anastomotic leakage (AL) or bleeding (AB) significantly impacts on patient outcome following colorectal resection. To minimize such complications, surgeons can utilize different techniques perioperatively to assess anastomotic integrity. We aim to assess published anastomotic complication rates following left-sided colonic resection, comparing the use of intra-operative flexible endoscopy (FE) against conventional tests used to assess anastomotic integrity. METHODS: PubMed/MEDLINE and Embase online databases were searched for non-randomized and randomized case-control studies that investigated postoperative AL and/or AB rates in left-sided colonic resections, comparing intra-operative FE against conventional tests. Data from eligible studies were pooled, and a meta-analysis using Review Manager 5.3 software was performed to assess for differences in AL and AB rates. RESULTS: Data from six studies were analysed to assess the impact of FE on postoperative AL and AB rates (1084 and 751 patients respectively). Use of FE was associated with reduced postoperative AL and AB rates, from 6.9% to 3.5% and 5.8% to 2.4% respectively. Odds ratios favoured intra-operative FE: 0.37 (95% CI 0.21-0.68, P = 0.001) for AL and 0.35 (95% CI 0.15-0.82, P = 0.02) for AB. CONCLUSION: This meta-analysis showed that the use of intra-operative FE is associated with a reduced rate of postoperative AL and AB, compared to conventional anastomotic testing methods.

Genetic profile and mutation spectrum of Leber congenital amaurosis in a larger Indian cohort using high throughput targeted re-sequencing.

To provide a comprehensive data on the prevalence of mutations in Leber congenital amaurosis (LCA) candidate genes from a larger Indian cohort. Ninety-two unrelated subjects were recruited after complete ophthalmic examination and informed consent. Targeted re-sequencing of 20 candidate genes was performed using Agilent HaloPlex target enrichment assay and sequenced on Illumina MiSeq platform. The data were analyzed using standard bioinformatics pipeline, variants annotated, validated and segregated. Genotype-phenotype correlation was performed for the mutation-positive cases. Targeted next generation sequencing (NGS) for the 20 candidate genes generated data with an average sequence coverage and depth of 99.03% and 134X, respectively. Mutations were identified in 61% (56/92) of the cases, which were validated, segregated in the families and absent in 200 control chromosomes. These mutations were observed in 14/20 candidate genes and 39% (21/53) were novel. Distinct phenotypes were observed with respect to genotypes. To our knowledge, this study presents the first comprehensive mutation spectrum of LCA in a large Indian cohort. The mutation-negative cases indicate scope for finding novel candidate gene(s) although mutations in deep intronic and regulatory regions cannot be ruled out.

The Incremental Cost of Incompatible Living Donor Kidney Transplantation: A National Cohort Analysis.

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation.

Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial.

BACKGROUND: Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. METHODS: A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models. RESULTS: In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning. CONCLUSIONS: As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.

Optimizing the Bioavailability of Subcutaneously Administered Biotherapeutics Through Mechanochemical Drivers.

The subcutaneous route offers myriad benefits for the administration of biotherapeutics in both acute and chronic diseases, including convenience, cost effectiveness and the potential for automation through closed-loop systems. Recent advances in parenteral administration devices and the use of additives which enhance drug dispersion have generated substantial additional interest in IV to SQ switching studies. Designing pre-clinical and clinical studies using SQ mediated delivery however requires deep understanding of complex inter-related physiologies and transport pathways governing the interstitial matrix, vascular system and lymphatic channels. This expert review will highlight key structural features which contribute to transport and biodistribution in the subcutaneous space and also assess the impact of drug formulations. Based on the rapidly growing interest in the SQ delivery route, a number of potential areas for future development are highlighted, which are likely to allow continued evolution and innovation in this important area.

The effect of sodium nitroprusside on psychotic symptoms and spatial working memory in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia. METHOD: This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18-60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 µg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later. RESULTS: SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo. CONCLUSIONS: Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.

Chronic exposure to haloperidol and olanzapine leads to common and divergent shape changes in the rat hippocampus in the absence of grey-matter volume loss.

BACKGROUND: One of the most consistently reported brain abnormalities in schizophrenia (SCZ) is decreased volume and shape deformation of the hippocampus. However, the potential contribution of chronic antipsychotic medication exposure to these phenomena remains unclear. METHOD: We examined the effect of chronic exposure (8 weeks) to clinically relevant doses of either haloperidol (HAL) or olanzapine (OLZ) on adult rat hippocampal volume and shape using ex vivo structural MRI with the brain retained inside the cranium to prevent distortions due to dissection, followed by tensor-based morphometry (TBM) and elastic surface-based shape deformation analysis. The volume of the hippocampus was also measured post-mortem from brain tissue sections in each group. RESULTS: Chronic exposure to either HAL or OLZ had no effect on the volume of the hippocampus, even at exploratory thresholds, which was confirmed post-mortem. In contrast, shape deformation analysis revealed that chronic HAL and OLZ exposure lead to both common and divergent shape deformations (q = 0.05, FDR-corrected) in the rat hippocampus. In particular, in the dorsal hippocampus, HAL exposure led to inward shape deformation, whereas OLZ exposure led to outward shape deformation. Interestingly, outward shape deformations that were common to both drugs occurred in the ventral hippocampus. These effects remained significant after controlling for hippocampal volume suggesting true shape changes. CONCLUSIONS: Chronic exposure to either HAL or OLZ leads to both common and divergent effects on rat hippocampal shape in the absence of volume change. The implications of these findings for the clinic are discussed.

Genetic engineering and molecular characterization of yeast strain expressing hybrid human-yeast squalene synthase as a tool for anti-cholesterol drug assessment.

AIMS: The main objective of the study is molecular and biological characterization of the human-yeast hybrid squalene synthase (SQS), as a promising target for treatment of hypercholesterolaemia. METHODS AND RESULTS: The human-yeast hybrid SQS, with 67% amino acids, including the catalytic site derived from human enzyme, was expressed in Saccharomyces cerevisiae strain deleted of its own SQS gene. The constructed strain has a decreased level of sterols compared to the control strain. The mevalonate pathway and sterol biosynthesis genes are induced and the level of triacylglycerols is increased. Treatment of the strain with rosuvastatin or zaragozic acid, two mevalonate pathway inhibitors, decreased the amounts of squalene, lanosterol and ergosterol, and up-regulated expression of several genes encoding enzymes responsible for biosynthesis of ergosterol precursors. Conversely, expression of the majority genes implicated in the biosynthesis of other mevalonate pathway end products, ubiquinone and dolichol, was down-regulated. CONCLUSIONS: The S. cerevisiae strain constructed in this study enables to investigate the physiological and molecular effects of inhibitors on cell functioning. SIGNIFICANCE AND IMPACT OF THE STUDY: The yeast strain expressing hybrid SQS with the catalytic core of human enzyme is a convenient tool for efficient screening for novel inhibitors of cholesterol-lowering properties.

Impaired subjective well-being in schizophrenia is associated with reduced anterior cingulate activity during reward processing.

BACKGROUND: Patients with schizophrenia have substantially reduced subjective well-being (SW) compared to healthy individuals. It has been suggested that diminished SW may be related to deficits in the neural processing of reward but this has not been shown directly. We hypothesized that, in schizophrenia, lower SW would be associated with attenuated reward-related activation in the reward network. METHOD: Twenty patients with schizophrenia with a range of SW underwent a functional magnetic resonance imaging (fMRI) reward task. The brain activity underlying reward anticipation and outcome in schizophrenia was examined and compared to that of 12 healthy participants using a full factorial analysis. Region of interest (ROI) analyses of areas within the reward network and whole-brain analyses were conducted to reveal neural correlates of SW. RESULTS: Reward-related neural activity in schizophrenia was not significantly different from that of healthy participants; however, the patients with schizophrenia showed significantly diminished SW. Both ROI and whole-brain analyses confirmed that SW scores in the patients correlated significantly with activity, specifically in the dorsal anterior cingulate cortex (dACC), during both reward anticipation and reward outcome. This association was not seen in the healthy participants. CONCLUSIONS: In patients with schizophrenia, reduced activation of the dACC during multiple aspects of reward processing is associated with lower SW. As the dACC has been widely linked to coupling of reward and action, and the link to SW is apparent over anticipation and outcome, these findings suggest that SW deficits in schizophrenia may be attributable to reduced integration of environmental rewarding cues, motivated behaviour and reward outcome.

A randomized, prospective, parallel group study of laparoscopic versus laparoendoscopic single site donor nephrectomy for kidney donation.

Few prospective, randomized studies have assessed the benefits of laparoendoscopic single site donor nephrectomy (LESS-DN) over laparoscopic donor nephrectomy (LDN). Our center initiated such a trial in January 2011, following subjects randomized to LESS-DN versus LDN from surgery through 5 years postdonation. Subjects complete recovery/satisfaction questionnaires at 2, 6 and 12 months postdonation; transplant recipient outcomes are also recorded. One hundred subjects (49 LESS-DN, 51 LDN) underwent surgery; donor demographics were similar between groups, and included a predominance of female, living-unrelated donors, mean age of 47 years who underwent left donor nephrectomy. Operative parameters (overall time, time to extraction, warm ischemia time, blood loss) were similar between groups. Conversion to hand-assist laparoscopy was required in 3 LESS-DN (6.1%) versus 2 LDN (3.9%; p = 0.67). Questionnaires revealed that 97.2% of LESS-DN versus 79.5% of LDN (p = 0.03) were 100% recovered by 2 months after donation. No significant difference was seen in satisfaction scores between the groups. Recipient outcomes were similar between groups. Our randomized trial comparing LESS donor nephrectomy to LDN confirms that LESS-DN offers a safe alternative to conventional LDN in terms of intra- and post-operative complications. LDN and LESS-DN offer similar recovery and satisfaction after donation.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

Copy number variants and therapeutic response to antidepressant medication in major depressive disorder.

It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant.

Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it?

Patients with mental disorders show many biological abnormalities which distinguish them from normal volunteers; however, few of these have led to tests with clinical utility. Several reasons contribute to this delay: lack of a biological 'gold standard' definition of psychiatric illnesses; a profusion of statistically significant, but minimally differentiating, biological findings; 'approximate replications' of these findings in a way that neither confirms nor refutes them; and a focus on comparing prototypical patients to healthy controls which generates differentiations with limited clinical applicability. Overcoming these hurdles will require a new approach. Rather than seek biomedical tests that can 'diagnose' DSM-defined disorders, the field should focus on identifying biologically homogenous subtypes that cut across phenotypic diagnosis--thereby sidestepping the issue of a gold standard. To ensure clinical relevance and applicability, the field needs to focus on clinically meaningful differences between relevant clinical populations, rather than hypothesis-rejection versus normal controls. Validating these new biomarker-defined subtypes will require longitudinal studies with standardized measures which can be shared and compared across studies--thereby overcoming the problem of significance chasing and approximate replications. Such biological tests, and the subtypes they define, will provide a natural basis for a 'stratified psychiatry' that will improve clinical outcomes across conventional diagnostic boundaries.

Risk factors associated with Clostridium difficile infection after kidney and pancreas transplantation.

BACKGROUND: Clostridium difficile infection (CDI) is a common cause of nosocomial antibiotic-associated diarrhea with an increased incidence reported in solid organ transplant recipients. We sought to determine if kidney and/or pancreas transplant recipients possess unique risk factors for CDI. METHODS: Between January 2009 and February 2011, 942 kidney and 56 pancreas transplants were performed at the 2 centers. Of these, 28 recipients (kidney, n = 24; pancreas, n = 4) developed CDI. Cases were matched to controls (n = 56) in a 1:2 ratio. RESULTS: Those with CDI were mostly male patients (82% vs. 48%, P = 0.003), deceased-donor organ recipients (86% vs. 64%, P = 0.045), more likely to have leukopenia (18% vs. 4%, P = 0.038), and had undergone a gastrointestinal procedure within 3 months preceding CDI diagnosis (18% vs. 4%, P = 0.038). Cases had higher cumulative and restricted antimicrobial exposure in days (37 ± 79 vs. 8 ± 12, P = 0.009 and 27 ± 69 vs. 7 ± 10, P = 0.032). Cephalosporin use was more common among cases (43% vs. 16%, P = 0.008). CONCLUSION: Careful antimicrobial selection and assurance of optimal treatment duration in the kidney and pancreas transplant population is prudent. Clinicians should have a heightened awareness of CDI risk particularly during periods of leukopenia and in the setting of gastrointestinal procedures.

Predicting a 'combined treatment outcome' in chronic schizophrenia: the role of demographics, symptomatology, functioning and subjective well-being.

OBJECTIVES: The aim of this study was to determine what variables predict a 'combined treatment outcome' (COMBOUT) in patients with chronic schizophrenia. METHODS: This analysis (n=522) was based on a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients diagnosed with schizophrenia or a related disorder. COMBOUT was assessed using the PANSS for symptoms, CGI-S for overall clinical status, MADRS for depressive symptoms, QLS for functioning/QOL, and SWN-K for subjective well-being. Possible predictors included demographics as well as baseline scores (Model I), and early change (week 2) scores (Model II). RESULTS: Model I: significantly better outcome (higher COMBOUT score) was observed in patients with lower MADRS (T= - 6.36; p<0.001) or higher QLS (T=5.05; p<0.001) scores at baseline. Model II: significantly better COMBOUT was observed in patients with early improvement of QLS (T=4.93; p<0.001), SWN-K (T=3.88; p<0.001), PANSS (T= - 2.32; p=0.021) and CGI-S scores (T= - 2.22; p=0.027). Changes in EPS were not predictors of COMBOUT in the models tested. CONCLUSION: COMBOUT at endpoint was predicted by lower depressive symptom score and higher QOL at baseline and by early improvement in psychopathology, quality of life and subjective well-being.