Microalbuminuria predicts graft loss and death in the renal transplant population. Measurement of the urinary albumin-to-creatinine ratio (UACR) is recommended for its detection. There is uncertainty ...regarding the optimal UACR cutoff values. Few studies have examined the accuracy of UACR in the general population and none have been conducted in renal transplant recipients. The aim of this study is to determine the performance of UACR in the renal transplant population.
Renal transplant recipients with a daily urinary albumin excretion rate of up to 300 mg accurately carried out a 24-hour urine collection and provided a morning urine sample for the measurement of albuminuria and UACR. The performance measures of UACR for the detection of microalbuminuria (30 to 300 mg/d) were calculated using different cutoffs.
Median albuminuria was 23 mg/d, and median UACR was 17 mg/g. The area under the receiver-operating characteristic curve was 0.94 in men and 0.98 in women. The optimal cutoff was 21 mg/g in men and 24 mg/g in women. In men, the 30-, 17-, and 21-mg/g cutoffs provided a sensitivity of 0.79, 0.89, and 0.87. In women, the 30-, 25-, and 24-mg/g cutoffs provided a sensitivity of 0.90, 0.97, and 1.0.
These data show that in the renal transplant population, lower gender-specific cutoffs should be used for the detection of microalbuminuria than the recommended 30-mg/g cutoff. These data support the need for a reappraisal of the 30-mg/g cutoff for the detection of microalbuminuria.
Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a ...role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.
•Ibrutinib induced a high rate of sustained responses for patients with cGVHD and inadequate response to corticosteroid-containing therapy.•This trial supported the approval of ibrutinib for treatment of adult patients with cGVHD after failure of ≥1 lines of systemic therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil–containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 ...and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval CI, 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
•Belumosudil, a selective ROCK2 inhibitor, was well tolerated in heavily pretreated subjects, with 44% continuing treatment beyond 1 year.•Belumosudil demonstrated efficacy in patients with SR cGVHD, with responses in all organs and after failure of ibrutinib/ruxolitinib.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
γδ T cells act as a first line of defense against invading pathogens. However, despite their abundance in mucosal tissue, little information is available about their functionality in this compartment ...in the context of HIV/SIV infection. In this study, we evaluated the frequency, phenotype, and functionality of Vδ1 and Vδ2 T cells from blood, rectum, and the female reproductive tract (FRT) of rhesus macaques to determine whether these cells contribute to control of SIV infection. No alteration in the peripheral Vδ1/Vδ2 ratio in SIV-infected macaques was observed. However, CD8
and CD4
CD8
Vδ1 T cells were expanded along with upregulation of NKG2D, CD107, and granzyme B, suggesting cytotoxic function. In contrast, Vδ2 T cells showed a reduced ability to produce the inflammatory cytokine IFN-γ. In the FRT of SIV
macaques, Vδ1 and Vδ2 showed comparable levels across vaginal, ectocervical, and endocervical tissues; however, endocervical Vδ2 T cells showed higher inflammatory profiles than the two other regions. No sex difference was seen in the rectal Vδ1/Vδ2 ratio. Several peripheral Vδ1 and/or Vδ2 T cell subpopulations expressing IFN-γ and/or NKG2D were positively correlated with decreased plasma viremia. Notably, Vδ2 CD8
T cells of the endocervix were negatively correlated with chronic viremia. Overall, our results suggest that a robust Vδ1 and Vδ2 T cell response in blood and the FRT of SIV-infected macaques contribute to control of viremia.
gamma delta T cells act as a first line of defense against invading pathogens. However, despite their abundance in mucosal tissue, little information is available about their functionality in this ...compartment in the context of HIV/SIV infection. In this study, we evaluated the frequency, phenotype, and functionality of V delta 1 and V delta 2 T cells from blood, rectum, and the female reproductive tract (FRT) of rhesus macaques to determine whether these cells contribute to control of SIV infection. No alteration in the peripheral V delta 1/V delta 2 ratio in SIV-infected macaques was observed. However, CD8+ and CD4+CD8+ V delta 1 T cells were expanded along with upregulation of NKG2D, CD107, and granzyme B, suggesting cytotoxic function. In contrast, V delta 2 T cells showed a reduced ability to produce the inflammatory cytokine IFN- gamma . In the FRT of SIV+ macaques, V delta 1 and V delta 2 showed comparable levels across vaginal, ectocervical, and endocervical tissues; however, endocervical V delta 2 T cells showed higher inflammatory profiles than the two other regions. No sex difference was seen in the rectal V delta 1/V delta 2 ratio. Several peripheral V delta 1 and/or V delta 2 T cell subpopulations expressing IFN- gamma and/or NKG2D were positively correlated with decreased plasma viremia. Notably, V delta 2 CD8+ T cells of the endocervix were negatively correlated with chronic viremia. Overall, our results suggest that a robust V delta 1 and V delta 2 T cell response in blood and the FRT of SIV-infected macaques contribute to control of viremia.
Floating-leaved rhizophytes and pleustophytes are the first barrier to Sun’s rays and significantly affect the light regime of the water column. To evaluate these effects on light attenuation, the ...reflectance and transmittance spectra variability were examined according to the leaf traits within three plant groups: (1) seed plants with green abaxial surfaces; (2) seed plants with red abaxial surfaces; and (3) ferns with trichomes. Specific leaf area (SLA), chlorophyll
a
and
b
, and UV-B and UV-A-absorbing substances differed between these three groups. The ‘spectral signatures’ of floating-leaved seed plants are similar to those of terrestrial seed plants, with a peak in the green region and a pronounced ‘red edge’. Ferns transmitted more light along the whole spectrum compared to other species. Most reflectance and transmittance spectra variability of the first group was explained by SLA. In the second group, 36% of the reflectance spectra variability was explained by tissue density and carotenoids, and 48% of the transmittance spectra variability by carotenoids, anthocyanins and SLA. In ferns, the reflectance spectra variability was mainly explained by chlorophylls, and partly by trichome length and mesophyll thickness, with the transmittance spectra variability significantly affected by chlorophyll
b
.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Twospotted spider mite (Tetranychus urticae Koch) is a cosmopolitan pest of numerous plants, including hop (Humulus lupulus L.). The most costly damage from the pest on hop results from infestation ...of cones, which are the harvested product, which can render crops unsalable if cones become discolored.We analyzed 14 yr of historical data from 312 individual experimental plots in western Oregon to identify risk factors associated with visual damage to hop cones from T. urticae. Logistic regression models were fit to estimate the probability of cone damage. The most predictive model was based on T. urticae-days during mid-July to harvest, which correctly predicted occurrence and nonoccurrence of cone damage in 91 and 93% of data sets, respectively, based onYouden's index. A second model based on the ratio of T. urticae to predatory arthropods late in the season correctly predicted cone damage in 92% of data sets and nonoccurrence of damage in 77% of data sets. The model based on T. urticae abundance performed similarly when validated in 23 commercial hop yards, whereas the model based on the predator:prey ratio was relatively conservative and yielded false-positive predictions in 11 of the 23 yards. Antecedents of these risk factors were explored and quantified by structural equation modeling. A simple path diagram was constructed that conceptualizes T. urticae invasion of hop cones as dependent on prior density of the pest on leaves in early spring and summer, which in turn influences the development of predatory arthropods that mediate late-season density of the pest. In summary, the biological insights and models developed here provide guidance to pest managers on the likelihood of visual cone damage from T. urticae that can inform late-season management based on both abundance of the pest and its important predators. This is critically important because a formal economic threshold for T. urticae on hop does not exist and current management efforts may be mistimed to influence the pest when crop damage is most probable. More broadly, this research suggests that current management practices that target T. urticae early in the season may in fact predispose yards to later outbreaks of the pest.
In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown ...an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes.
In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-to-treat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600.
Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41–70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI −2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis.
Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population.
US National Institutes of Health, US Food and Drug Administration, Thrasher Research Fund, Australian National Health and Medical Research Council, Health Technologies Assessment–National Institute for Health Research (UK), Australian and New Zealand College of Anaesthetists, Murdoch Children's Research Institute, Canadian Institutes of Health Research, Canadian Anesthesiologists Society, Pfizer Canada, Italian Ministry of Health, Fonds NutsOhra, UK Clinical Research Network, Perth Children's Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary Background Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an ...increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. Methods In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov , number NCT00756600. Findings Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean SD) was 98·6 (14·2) in the awake-regional group and 98·2 (14·7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0·169, 95% CI −2·30 to 2·64). The median duration of anaesthesia in the general anaesthesia group was 54 min. Interpretation For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. Funding Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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