K(2P)18.1 translates T cell receptor signals into thymic regulatory T cell development

It remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca2+) is the most important second messenger, for which the potassium channel K(2P)18.1 is a relevant regulator. Here, we identify K(2P)18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-kappa B-mediated K(2P)18.1 upregulation in tTreg progenitors. K(2P)18.1 provided the driving force for sustained Ca2+ influx that facilitated NF-kappa B- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K(2P)18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K(2P)18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K(2P)18.1 variant that is associated with poor clinical outcomes indicate that K(2P)18.1 also plays a role in human Treg development. Pharmacological modulation of K(2P)18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K(2P)18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K(2P)18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders.Peer reviewe

Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

Background: Genetic studies of human lung function and Chronic Obstructive Pulmonary Disease have identified a highly significant and reproducible signal on 4q24. It remains unclear which of the two candidate genes within this locus may regulate lung function: GSTCD, a gene with unknown function, and/or INTS12, a member of the Integrator Complex which is currently thought to mediate 3'end processing of small nuclear RNAs.Results: We found that, in lung tissue, 4q24 polymorphisms associated with lung function correlate with INTS12 but not neighbouring GSTCD expression. In contrast to the previous reports in other species, we only observed a minor alteration of snRNA processing following INTS12 depletion. RNAseq analysis of knockdown cells instead revealed dysregulation of a core subset of genes relevant to airway biology and a robust downregulation of protein synthesis pathways. Consistent with this, protein translation was decreased in INTS12 knockdown cells. In addition, ChIPseq experiments demonstrated INTS12 binding throughout the genome, which was enriched in transcriptionally active regions. Finally, we defined the INTS12 regulome which includes genes belonging to the protein synthesis pathways.Conclusion: INTS12 has functions beyond the canonical snRNA processing. We show that it regulates translation by regulating the expression of genes belonging to protein synthesis pathways. This study provides a detailed analysis of INTS12 activities on a genome-wide scale and contributes to the biology behind the genetic association for lung function at 4q24.</p

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Phoenicopteriella mirabilis Fain 1970

&lt;i&gt;Phoenicopteriella mirabilis&lt;/i&gt; Fain, 1970 &lt;p&gt;(Fig. 8)&lt;/p&gt; &lt;p&gt; &lt;i&gt;Phoenicopteriella mirabilis&lt;/i&gt; Fain, 1970: 323, figs. 25&ndash;27. Holotype in RBINS, examined.&lt;/p&gt; &lt;p&gt; Type host: &lt;i&gt;Phoenicopterus ruber&lt;/i&gt; Linnaeus (Phoenicopteriformes: Phoenicopteridae) from North Africa.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Diagnosis.&lt;/b&gt; Palp tarsus with 2 setae (dorsal seta Sa-type, seta situated apically mushroom-like), solenidion absent; palp tibia without setae, solenidion present. Hypostome with 2 pairs of setae (Sa-type). Setae &lt;i&gt;vi&lt;/i&gt; situated anterior to level of setae &lt;i&gt;si&lt;/i&gt;. Setae &lt;i&gt;vi&lt;/i&gt;, &lt;i&gt;se&lt;/i&gt;, &lt;i&gt;c2&lt;/i&gt; Sa-type, sensillae &lt;i&gt;si&lt;/i&gt; Na-type, genital setae Bd-type, other idiosomal setae (including coxal setae) Db-type. Agenital series with 1 pair of setae. Genital series with 3 pairs of setae. Number of leg setae: coxae 1&ndash;0&ndash;1&ndash;1, femora 7&ndash;4&ndash;3&ndash;4.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Host and distribution.&lt;/b&gt; Phoenicopteriformes (Phoenicopteridae): &lt;i&gt;PhOenicOpterus ruber&lt;/i&gt; Linnaeus from North Africa (Fain 1970).&lt;/p&gt;Published as part of &lt;i&gt;Skoracki, Maciej, Schmidt, Karl-Heinz, Marciniak, Natalia &amp; Marciniak, Martyna, 2018, A review of mites of the subfamily Speleognathinae (Acariformes: Ereynetidae) parasitizing respiratory tracts of birds in the Afrotropical region, pp. 401-440 in Zootaxa 4403 (3)&lt;/i&gt; on page 412, DOI: 10.11646/zootaxa.4403.3.1, &lt;a href="http://zenodo.org/record/1212849"&gt;http://zenodo.org/record/1212849&lt;/a&gt

Picinyssus buccanodon Fain 1969

&lt;i&gt;Picinyssus buccanodon&lt;/i&gt; Fain, 1969 &lt;p&gt;(Fig. 9)&lt;/p&gt; &lt;p&gt; &lt;i&gt;Picinyssus buccanodon&lt;/i&gt; Fain, 1969: 370, figs. 1&ndash;2. Holotype in RMCA, examined.&lt;/p&gt; &lt;p&gt; Type host: &lt;i&gt;Buccanodon duchaillui&lt;/i&gt; (Cassin) (Piciformes: Ramphastidae) from Democratic Republic of Congo.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Diagnosis.&lt;/b&gt; Palp tarsus with 2 setae (Ba-type) and solenidion. All dorsal setae Db-type, except sensillae &lt;i&gt;si&lt;/i&gt; SC-type, and &lt;i&gt;ve&lt;/i&gt; Bd-type. All ventral setae (including coxal setae) Db-type.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Host and distribution.&lt;/b&gt; Piciformes (Ramphastidae): &lt;i&gt;BuccanOdOn duchaillui&lt;/i&gt; (Cassin) from Democratic Republic of Congo [Virunga National Park] (Fain 1969).&lt;/p&gt;Published as part of &lt;i&gt;Skoracki, Maciej, Schmidt, Karl-Heinz, Marciniak, Natalia &amp; Marciniak, Martyna, 2018, A review of mites of the subfamily Speleognathinae (Acariformes: Ereynetidae) parasitizing respiratory tracts of birds in the Afrotropical region, pp. 401-440 in Zootaxa 4403 (3)&lt;/i&gt; on page 414, DOI: 10.11646/zootaxa.4403.3.1, &lt;a href="http://zenodo.org/record/1212849"&gt;http://zenodo.org/record/1212849&lt;/a&gt

Phoenicopteriella womersleyi

&lt;i&gt;Phoenicopteriella womersleyi&lt;/i&gt; (Fain, 1955) &lt;p&gt; &lt;i&gt;Speleognathus womersleyi&lt;/i&gt; Fain, 1955b: 695, 1956a: 21, figs. 5&ndash;6, 23, 26; Clark 1958: 84, figs. 3&ndash;4, 9&ndash;12. Holotype in RMCA, examined.&lt;/p&gt; &lt;p&gt; &lt;i&gt;Trispeleognathus womersleyi&lt;/i&gt;, Fain 1958b: 178, 1962a: 9; Fain &amp; Hyland 1975: 205.&lt;/p&gt; &lt;p&gt; &lt;i&gt;Trispeleognathus (Trispeleognathus) womersleyi&lt;/i&gt;, Fain 1963d: 23.&lt;/p&gt; &lt;p&gt; &lt;i&gt;Ophthalmognathus womersleyi&lt;/i&gt;, Domrow 1969: 390; Spicer 1977: 498.&lt;/p&gt; &lt;p&gt; &lt;i&gt;Phoenicopteriella womersleyi&lt;/i&gt;, Fain 1985a: 152, 1985b: 254, fig. 19.&lt;/p&gt; &lt;p&gt; Type host: &lt;i&gt;Dendrocygna viduata&lt;/i&gt; (Linnaeus) (Anseriformes: Anatidae) from Rwanda.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Diagnosis.&lt;/b&gt; Palp tarsus with 3 setae (Be-type) and solenidion; palp tibia without setae. Hypostome with 1 pair of setae (Bb-type). Setae &lt;i&gt;vi&lt;/i&gt; situated posterior to level of &lt;i&gt;si&lt;/i&gt;. All dorsal setae Dd-type, except sensillae &lt;i&gt;si&lt;/i&gt; SC-type, genital setae Bf-type. Agenital series with 2 pairs of setae. Genital series with 2 pairs of setae. Number of leg setae: coxae 2&ndash;1&ndash;1&ndash;1, femora 5&ndash;4&ndash;3&ndash;3.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Hosts and distribution.&lt;/b&gt; Anseriformes (Anatidae): &lt;i&gt;DendrOcygna viduata&lt;/i&gt; (Linnaeus) and &lt;i&gt;SarkidOrnis melanOtOs&lt;/i&gt; (Pennant) both from Rwanda [Southern Prov., Butare] (Fain 1956a).&lt;/p&gt; &lt;p&gt; &lt;b&gt;Non-African hosts and distribution.&lt;/b&gt; Anatidae: &lt;i&gt;Anas acuta&lt;/i&gt; Linnaeus, &lt;i&gt;A. clypeata&lt;/i&gt; (Linnaeus), &lt;i&gt;A. discOrs&lt;/i&gt; (Linnaeus), &lt;i&gt;A. strepera&lt;/i&gt; Linnaeus, &lt;i&gt;Aythia affinis&lt;/i&gt; (Eyton), all from USA (Clark 1958; Fain &amp; Hyland 1975; Spicer 1977).&lt;/p&gt;Published as part of &lt;i&gt;Skoracki, Maciej, Schmidt, Karl-Heinz, Marciniak, Natalia &amp; Marciniak, Martyna, 2018, A review of mites of the subfamily Speleognathinae (Acariformes: Ereynetidae) parasitizing respiratory tracts of birds in the Afrotropical region, pp. 401-440 in Zootaxa 4403 (3)&lt;/i&gt; on pages 412-413, DOI: 10.11646/zootaxa.4403.3.1, &lt;a href="http://zenodo.org/record/1212849"&gt;http://zenodo.org/record/1212849&lt;/a&gt

Coboydaia Fain. They 1985

Genus &lt;i&gt;Coboydaia&lt;/i&gt; Fain, 1985 &lt;p&gt; &lt;i&gt;Coboydaya&lt;/i&gt; Fain, 1971: 98 (as subgenus of &lt;i&gt;Boydaia&lt;/i&gt;), 1985a: 146 (genus rank). Type species: &lt;i&gt;Boydaia trochila&lt;/i&gt; Fain, 1958 by original designation.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Diagnosis.&lt;/b&gt; Hypostome with 2 pairs of setae. Propodonotal region with 5&ndash;6 pairs of setae (&lt;i&gt;ve&lt;/i&gt; present or absent). Each agenital and pseudanal setal series with 1&ndash;2 pairs. Trochanter I and II without setae.&lt;/p&gt; &lt;p&gt; &lt;b&gt;Remarks.&lt;/b&gt; The members of this genus are associated mainly with passerines, however two species have been recorded from non-passeriform host orders: Apodiformes and Columbiformes (Fain &lt;i&gt;et al&lt;/i&gt;. 1985; Skoracki &lt;i&gt;et al&lt;/i&gt;. 2012). The Afrotropical fauna comprises three of the five described species in this genus: &lt;i&gt;CObOydaia amandavae&lt;/i&gt; Fain 1962, &lt;i&gt;C. clavata&lt;/i&gt; Fain, 1956, and &lt;i&gt;C. nigra&lt;/i&gt; Fain, 1955.&lt;/p&gt;Published as part of &lt;i&gt;Skoracki, Maciej, Schmidt, Karl-Heinz, Marciniak, Natalia &amp; Marciniak, Martyna, 2018, A review of mites of the subfamily Speleognathinae (Acariformes: Ereynetidae) parasitizing respiratory tracts of birds in the Afrotropical region, pp. 401-440 in Zootaxa 4403 (3)&lt;/i&gt; on page 427, DOI: 10.11646/zootaxa.4403.3.1, &lt;a href="http://zenodo.org/record/1212849"&gt;http://zenodo.org/record/1212849&lt;/a&gt