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Treatment of antibiotic refractory chronic pouchitis with JAK inhibitors and S1P receptor modulators: an ECCO CONFER Multicentre Case Series.
No full textBACKGROUND AND AIMS
Data regarding effectiveness and safety of JAK inhibitors and S1P receptor modulators in antibiotic refractory chronic pouchitis (CARP) are lacking.
METHODS
This ECCO-CONFER project retrospectively collected JAK inhibitors or S1P receptor modulators treatments for CARP with at least 3-months follow up. The outcomes included corticosteroid and antibiotics-free clinical response and remission at three and twelve months, trend in mPDAI, endoscopic PDAI, CRP and calprotectin.
RESULTS
Seventeen treatments in 15 patients were collected. Previous pouchitis treatments included infliximab (5/15), adalimumab (4/15), vedolizumab (9/15), and ustekinumab (5/15). Pooling data on JAK inhibitors (8 tofacitinib, 1 filgotinib and 6 upadacitinib), after 3 months (T3), steroid and antibiotics-free clinical response was achieved in 53.3% (8/15), steroid and antibiotics-free clinical remission was achieved in 40% (6/15). Of the patients with at least 12 months of follow-up, steroid and antibiotics-free clinical response was achieved in 50% (3/6) and remission in one patient (16.7%), endoscopic response in 50% (3/6), endoscopic remission in 50% (3/6). Of the two ozanimod treatments at T3, steroid and antibiotics-free clinical response was achieved in one patient, without remission; both discontinued ozanimod before T12. No side effects reported.
CONCLUSIONS
Small molecules may represent a suitable option for CARP refractory to multiple biologics, deserving further investigation
LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the LumiThera Valeda Light Delivery System.
Get PDFPURPOSE
The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) AMD using the LumiThera Valeda® Light Delivery System.
METHODS
LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were treated with multiwavelength PBM (590, 660 and 850 nm) or Sham treatment delivered 9 treatments over 3-5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report.
RESULTS
A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy BCVA endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 - -0.1, p = 0.02)(PBM alone: 5.4 letters (SE 0.96), CI: 3.5 - 7.3, p < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7 - 5.2, p < 0.0001). The PBM group showed a significant decrease in new onset GA (p = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed.
CONCLUSIONS
LIGHTSITE III provides a prospective, randomized controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM
Cumulative Absolute Risk of Subsequent Colorectal Cancer After Abdominopelvic Radiotherapy Among Childhood Cancer Survivors: A PanCareSurFup Study.
No full textPURPOSE
Childhood cancer survivors are at the risk of developing subsequent colorectal cancers (CRCs), but the absolute risks by treatment modality are uncertain. We quantified the absolute risks by radiotherapy treatment characteristics using clinically accessible data from a Pan-European wide case-control study nested within a large cohort of childhood cancer survivors: the PanCareSurFup Study.
METHODS
Odds ratios (ORs) from a case-control study comprising 143 CRC cases and 143 controls nested within a cohort of 69,460 survivors were calculated. These, together with standardized incidence ratios for CRC for this cohort and European general population CRC incidence rates and survivors' mortality rates, were used to estimate cumulative absolute risks (CARs) by attained age for different categories of radiation to the abdominopelvic area.
RESULTS
Overall, survivors treated with abdominopelvic radiotherapy treatment (ART) were three times more likely to develop a subsequent CRC than those who did not receive ART (OR, 3.1 [95% CI, 1.4 to 6.6]). For male survivors treated with ART, the CAR was 0.27% (95% CI, 0.17 to 0.59) by age 40 years, 1.08% (95% CI, 0.69 to 2.34) by age 50 years (0.27% expected in the general population), and 3.7% (95% CI, 2.36 to 7.80) by age 60 years (0.95% expected). For female survivors treated with ART, the CAR was 0.29% (95% CI, 0.18 to 0.62) by age 40 years, 1.03% (95% CI, 0.65 to 2.22) by age 50 years (0.27% expected), and 3.0% (95% CI, 1.91 to 6.37) by age 60 years (0.82% expected).
CONCLUSION
We demonstrated that by age 40 years survivors of childhood cancer treated with ART already have a similar risk of CRC as those age 50 years in the general population for whom population-based CRC screening begins in many countries. This information should be used in the development of survivorship guidelines for the risk stratification of survivors concerning CRC risk
Long-term pulmonary outcome of children with congenital diaphragmatic hernia: functional lung MRI using matrix-pencil decomposition enables side-specific assessment of lung function.
Get PDFOBJECTIVES
In patients with congenital diaphragmatic hernia (CDH) the exact functional outcome of the affected lung side is still unknown, mainly due to the lack of spatially resolved diagnostic tools. Functional matrix-pencil decomposition (MP-) lung MRI fills this gap as it measures side-specific ventilation and perfusion. We aimed to assess the overall and side-specific pulmonary long-term outcomes of patients with CDH using lung function tests and MP-MRI.
METHODS
Thirteen school-aged children with CDH (seven with small and six with large defect-sized CDH, defined as > 50% of the chest wall circumference being devoid of diaphragm tissue) and thirteen healthy matched controls underwent spirometry, multiple-breath washout, and MP-MRI. The main outcomes were forced expiratory volume in 1 second (FEV1), lung clearance index (LCI2.5), ventilation defect percentage (VDP), and perfusion defect percentage (QDP).
RESULTS
Patients with a large CDH showed significantly reduced overall lung function compared to healthy controls (mean difference [95%-CIadjusted]: FEV1 (z-score) -4.26 [-5.61, -2.92], FVC (z-score) -3.97 [-5.68, -2.26], LCI2.5 (TO) 1.12 [0.47, 1.76], VDP (%) 8.59 [3.58, 13.60], QDP (%) 17.22 [13.16, 21.27]) and to patients with a small CDH. Side-specific examination by MP-MRI revealed particularly reduced ipsilateral ventilation and perfusion in patients with a large CDH (mean difference to contralateral side [95%-CIadjusted]: VDP (%) 14.80 [10.50, 19.00], QDP (%) 23.50 [1.75, 45.20]).
CONCLUSIONS
Data indicate impaired overall lung function with particular limitation of the ipsilateral side in patients with a large CDH. MP-MRI is a promising tool to provide valuable side-specific functional information in the follow-up of patients with CDH.
CLINICAL RELEVANCE STATEMENT
In patients with congenital diaphragmatic hernia, easily applicable MP-MRI allows specific examination of the lung side affected by the hernia and provides valuable information on ventilation and perfusion with implications for clinical practice, making it a promising tool for routine follow-up.
KEY POINTS
• Functional matrix pencil decomposition (MP) MRI data from a small sample indicate reduced ipsilateral pulmonary ventilation and perfusion in children with large congenital diaphragmatic hernia (CDH). • Easily applicable pencil decomposition MRI provides valuable side-specific diagnostic information on lung ventilation and perfusion. This is a clear advantage over conventional lung function tests, helping to comprehensively follow up patients with congenital diaphragmatic hernia and monitor therapy effects
Identification of genomic regions associated with differences in fleece type in Huacaya and Suri alpacas (Vicugna pacos).
Get PDFThe difference in fleece type is the distinguishing trait between the two types of alpacas (Vicugna pacos), Huacaya and Suri. The Suri fleece type has been found to be inherited dominantly over the Huacaya type, resulting in offspring with the Suri phenotype. The aim of our study was to map genomic regions associated with the two different fleece types. In this study, 91 alpacas (54 Huacayas and 37 Suris) from Germany and Switzerland were genotyped using the 76k alpaca SNP array. Only 59k chromosome-localised markers map to the alpaca reference assembly VicPac3.1, and after quality control 49 866 SNPs, were retained for population structure assessment and to conduct a genome-wide association study. Both principal component and neighbour-joining tree analysis showed that the two fleece-type cohorts overlapped rather than forming two distinct clusters. Genome-wide significantly associated markers were observed in the scaffold region of chromosome 16 (NW_021964192.1), which contains a cluster of keratin genes. A haplotype predominantly found in Suri alpacas has been identified which supports dominant inheritance. Variant filtering of nine whole-genome sequenced alpacas from both fleece types in the critical interval of 0.4 Mb did not reveal perfect segregation of either fleece type for specific variants. To our knowledge, this is the first study to use the recently developed species-specific SNP array to identify genomic regions associated with differences in fleece type in alpacas. There are still some limitations, such as the preliminary status of the reference assembly and the incomplete annotation of the alpaca genome
Dual mode of action of IP3-dependent SR-Ca2+ release on local and global SR-Ca2+ release in ventricular cardiomyocytes.
Get PDFIn heart muscle, the physiological function of IP3-induced Ca2+ release (IP3ICR) from the sarcoplasmic reticulum (SR) is still the subject of intense study. A role of IP3ICR may reside in modulating Ca2+-dependent cardiac arrhythmogenicity. Here we observe the propensity of spontaneous intracellular Ca2+ waves (SCaW) driven by Ca2+-induced Ca2+ release (CICR) in ventricular myocytes as a correlate of arrhythmogenicity on the organ level. We observe a dual mode of action of IP3ICR on SCaW generation in an IP3R overexpression model. This model shows a mild cardiac phenotype and mimics pathophysiological conditions of increased IP3R activity. In this model, IP3ICR was able to increase or decrease the occurrence of SCaW depending on global Ca2+ activity. This IP3ICR-based regulatory mechanism can operate in two "modes" depending on the intracellular CICR activity and efficiency (e.g. SCaW and/or local Ryanodine Receptor (RyR) Ca2+ release events, respectively): a) in a mode that augments the CICR mechanism at the cellular level, resulting in improved excitation-contraction coupling (ECC) and ultimately better contraction of the myocardium, and b) in a protective mode in which the CICR activity is curtailed to prevent the occurrence of Ca2+ waves at the cellular level and thus reduce the probability of arrhythmogenicity at the organ level
Implications of the COVID-19 trajectory for the evaluation of hand hygiene interventions: Secondary analysis of the Soapp trial.
Get PDFHand hygiene behavior is crucial to counter the spread of infectious diseases. However, its adoption during the early stages of the Coronavirus disease (COVID-19) pandemic showed temporal fluctuations associated with the trajectory of the pandemic (e.g. new COVID-19 infections). Such associations can confound conclusions about the effectiveness of interventions aimed at promoting hand hygiene during a pandemic. In this study, we performed a secondary analysis of a dataset from the optimization phase of Soapp, an app to promote hand hygiene during the COVID-19 pandemic. We used a longitudinal study design to test whether the associations between the pandemic trajectory and hand hygiene behavior were still present one year after the outbreak (primary outcome) and whether they impacted conclusions about the effectiveness of Soapp (secondary outcome). Participants (N = 216) were randomized to different versions of Soapp and used an electronic diary to self-report their hand hygiene behavior multiple times during the study. We considered the following indicators of the COVID-19 pandemic from the country of Switzerland in the period between March and August 2021: total cases/deaths, increases in recent new cases/deaths, new cases/deaths, and number of administered doses of vaccine. Data were analyzed using a multilevel approach. Results suggested that there were no significant associations between hand hygiene and the indicators of the pandemic trajectory. However, models including total cases/deaths impacted the conclusions about Soapp's effectiveness. Implications from this study are that the development and evaluation of hand hygiene interventions during a pandemic context should account for the trajectory indicators to maximize their effectiveness and control for confounding effects
Development of chemical tools based on GSK-7975A to study store-operated calcium entry in cells.
Get PDFMany physiological functions, such as cell differentiation, proliferation, muscle contraction, neurotransmission and fertilisation, are regulated by changes of Ca2+ levels. The major Ca2+ store in cells is the endoplasmic reticulum (ER). Certain cellular processes induce ER store depletion, e.g. by activating IP3 receptors, that in turn induces a store refilling process known as store-operated calcium entry (SOCE). This refilling process entails protein-protein interactions between Ca2+ sensing stromal interaction molecules (STIM) in the ER membrane and Orai proteins in the plasma membrane. Fully assembled STIM/Orai complexes then form highly selective Ca2+ channels called Ca2+ release-activated Ca2+ Channels (CRAC) through which Ca2+ ions flow into the cytosol and subsequently are pumped into the ER by the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Abnormal SOCE has been associated with numerous human diseases and cancers, and therefore key players STIM and Orai have attracted significant therapeutic interest. Several potent experimental and clinical candidate compounds have been developed and have helped to study SOCE in various cell types. We have synthesized multiple novel small-molecule probes based on the known SOCE inhibitor GSK-7975A. Here we present GSK-7975A derivatives, which feature photo-caging, photo-crosslinking, biotin and clickable moieties, and also contain deuterium labels. Evaluation of these GSK-7975A probes using a fluorometric imaging plate reader (FLIPR)-Tetra-based Ca2+ imaging assay showed that most synthetic modifications did not have a detrimental impact on the SOCE inhibitory activity. The photo-caged GSK-7975A was also used in patch-clamp electrophysiology experiments. In summary, we have developed a number of active, GSK-7975A-based molecular probes that have interesting properties and therefore are useful experimental tools to study SOCE in various cells and settings
Impact of pulmonary valve replacement on ventricular function and cardiac events in patients with tetralogy of Fallot. A retrospective cohort study.
Get PDFINTRODUCTION AND OBJECTIVES
Our aim was to assess the impact of prosthetic pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF) on changes in biventricular volumes and function and on adverse cardiac events.
METHODS
Adults with rTOF were identified from the SACHER-registry. Data from serial cardiac magnetic resonance imaging, echocardiography, exercise capacity and n-terminal pro b-type natriuretic peptide (NT-proBNP) were collected. The primary endpoint was right ventricular ejection fraction (RVEF) as measured by cardiac magnetic resonance. Secondary endpoints were biventricular volumes, left ventricular ejection fraction, exercise capacity and NT-proBNP levels, and time to adverse cardiac outcomes (atrial and ventricular arrhythmia, endocarditis). Associations between previous PVR and longitudinal changes in functional outcomes and time to adverse cardiac outcomes were analyzed using linear mixed-effects models and Cox proportional hazards models, respectively.
RESULTS
A total of 308 patients (153 with and 155 without PVR) with 887 study visits were analyzed. Previous PVR was not significantly associated with changes in RVEF (CE, --1.33; 95%CI, -5.87 to 3.21; P = .566). Previous PVR was associated with lower right ventricular end-diastolic volume but had no significant effect on left ventricular ejection fraction, exercise capacity, or NT-proBNP-levels. Previous PVR was associated with an increased hazard of atrial arrhythmias (HR, 2.09; 95%CI, 1.17-3.72; P = .012) and infective endocarditis (HR, 12.72; 95%CI, 4.69-34.49; P < .0001) but not with an increased hazard of sustained ventricular arrhythmias (HR, 0.64; 95%CI, 0.18-2.27; P = .490).
CONCLUSIONS
Previous PVR was not significantly associated with changes in RVEF but was associated with an increased risk of atrial arrhythmias and infective endocarditis
Millimeter accuracy SLR bias determination using independent multi-LEO DORIS and GPS-based precise orbits
No full textSatellite Laser Ranging (SLR) has become an invaluable core technique in numerous geodetic applications. SLR measurements to passive spherical satellites essentially contribute to the determination of geocenter coordinates and global scale in the International Terrestrial Reference Frame (ITRF) realizations. In addition, SLR measurements to active satellites in Low Earth Orbit (LEO) are up to now mostly used for an independent validation of orbit solutions, usually derived by microwave tracking techniques based on Doppler Orbitography and Radiopositioning Integrated by Satellite (DORIS) or Global Navigation Satellite Systems (GNSS). This allows for the analysis of systematic orbit errors (e.g., originating from poorly known non-gravitational perturbations or sensor offsets) not only in the radial direction (key to satellite altimetry missions), but in three dimensions.
Major obstacles to reach the millimeter accuracy and stability goals of
(at decadal time scales) of the Global Geodetic Observing System (GGOS) are station-satellite measurement biases and on-ground/board coordinate offsets. Among the observatories of the International Laser Ranging Service (ILRS) a large diversity of measurement qualities exists, and the calibration of station-dependent errors is now necessary to further exploit SLR data for present and future climate-driven needs.
We demonstrate that the analysis of SLR data to active LEO satellites equipped with DORIS or GNSS receivers is a promising means to characterize SLR biases and their stability. Using two independent selections of Earth observation missions in LEOs (consisting of six altimetry, three magnetic field and two gravity field satellites) with three different analysis software packages (Bernese, ZOOM, Napeos), we estimate SLR range biases for all involved tracking stations on a yearly basis. We find that for many of the stations independently estimated sets of biases agree on a few-mm level and that the inclusion of satellites from multiple missions allows rendering the bias estimation more robust and in particular less prone to geographically correlated orbit errors. This shows that microwave-derived orbits of active LEO satellites, nowadays of very high quality due to numerous advances in modeling and analysis techniques, can serve as interesting sources for SLR station calibration in demanding climate applications
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