Pulmonary artery pressure monitoring in chronic heart failure: effects across clinically relevant subgroups in the MONITOR-HF trial.

BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronisation therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life, clinical, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were nonsignificant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = 0.03; adjusted Pinteraction = 0.33) and diabetics (Pinteraction = 0.01; adjusted Pinteraction = 0.06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.

Characteristics and outcomes of COVID-19 in heart transplantation recipients in the Netherlands.

BACKGROUND: Immunocompromised patients are at high risk of complicated severe acute respiratory coronavirus 2 infection. The aim of this retrospective study was to describe the characteristics and outcomes of heart transplantation (HTx) recipients with coronavirus disease 2019 (COVID-19) in the Netherlands. METHODS: HTx patients from one of the three HTx centres in the Netherlands with COVID-19 (proven by positive reverse-transcription polymerase chain reaction or serology test result) between February 2020 and June 2021 were included. The primary endpoint was all-cause mortality and the secondary endpoint was disease severity. RESULTS: COVID-19 was diagnosed in 54/665 HTx patients (8%), with a mean (±â€¯standard deviation (SD)) time after HTx of 11 ± 8 years. Mean (±â€¯SD) age was 53 ± 14 years and 39% were female. Immunosuppressive therapy dosage was reduced in 37% patients (20/54). Hospitalisation was required in 39% patients (21/54), and 13% patients (7/54) had severe COVID-19 (leading to intensive care unit (ICU) admission or death). In-hospital mortality was 14% (3/21), and all-cause mortality was 6%. Compared with patients with moderate COVID-19 (hospitalised without ICU indication), severe COVID-19 patients tended to be transplanted earlier and had a significantly higher mean (±â€¯SD) body mass index (26 ± 3 vs 30 ± 3 kg/m2, p = 0.01). Myocardial infarction, cellular rejection and pulmonary embolism were observed once in three different HTx patients. CONCLUSION: HTx patients were at increased risk of complicated COVID-19 with frequent hospitalisation, but the all-cause mortality was substantially lower than previously described (7-33%).

On the mechanism of mechanochemical molecular encapsulation in peptidic capsules.

Molecular encapsulation of C60 inside a hydrogen-bond-sealed semi-flexible peptidic capsule is hindered in solution, yet it proceeds effectively after mechanical milling of a solid sample. We show that the molecular mechanism involves the generation of non-covalently disordered forms that are active in guest uptake. We also show that the solvent-free mechanochemical covalent synthesis of capsules directly results in obtaining disordered, active forms.

A chiral member of the family of organic hexameric cages.

A cubic nanocage (O symmetry) that exhibits inherent chirality and has a covalent, rigid skeleton with molecule-sized entrance portals was obtained by means of dynamic covalent chemistry using a reaction between aldehyde-functionalized resorcin[4]arene and hydrazine.

The frequency of snowline-region planets from four-years of OGLE-MOA-Wise second-generation microlensing.

We present a statistical analysis of the first four seasons from a "second-generation" microlensing survey for extrasolar planets, consisting of near-continuous time coverage of 8 deg2 of the Galactic bulge by the OGLE, MOA, and Wise microlensing surveys. During this period, 224 microlensing events were observed by all three groups. Over 12% of the events showed a deviation from single-lens microlensing, and for ~1/3 of those the anomaly is likely caused by a planetary companion. For each of the 224 events we have performed numerical ray-tracing simulations to calculate the detection efficiency of possible companions as a function of companion-to-host mass ratio and separation. Accounting for the detection efficiency, we find that 55 - 22 + 34 % of microlensed stars host a snowline planet. Moreover, we find that Neptunes-mass planets are ~ 10 times more common than Jupiter-mass planets. The companion-to-host mass ratio distribution shows a deficit at q ~ 10-2, separating the distribution into two companion populations, analogous to the stellar-companion and planet populations, seen in radial-velocity surveys around solar-like stars. Our survey, however, which probes mainly lower-mass stars, suggests a minimum in the distribution in the super-Jupiter mass range, and a relatively high occurrence of brown-dwarf companions.

Extremely metal-poor stars from the cosmic dawn in the bulge of the Milky Way.

The first stars are predicted to have formed within 200 million years after the Big Bang, initiating the cosmic dawn. A true first star has not yet been discovered, although stars with tiny amounts of elements heavier than helium ('metals') have been found in the outer regions ('halo') of the Milky Way. The first stars and their immediate successors should, however, preferentially be found today in the central regions ('bulges') of galaxies, because they formed in the largest over-densities that grew gravitationally with time. The Milky Way bulge underwent a rapid chemical enrichment during the first 1-2 billion years, leading to a dearth of early, metal-poor stars. Here we report observations of extremely metal-poor stars in the Milky Way bulge, including one star with an iron abundance about 10,000 times lower than the solar value without noticeable carbon enhancement. We confirm that most of the metal-poor bulge stars are on tight orbits around the Galactic Centre, rather than being halo stars passing through the bulge, as expected for stars formed at redshifts greater than 15. Their chemical compositions are in general similar to typical halo stars of the same metallicity although intriguing differences exist, including lower abundances of carbon.

Non-paraganglioma tumors of the jugular foramen - Growth patterns, radiological presentation, differential diagnosis.

OBJECTIVE: Most common tumors of the jugular foramen are paragangliomas. However, other lesions, also malignant, may involve the jugular foramen and mimic radiographic presentation of paragangliomas. Therefore, a correct preoperative diagnosis is crucial for best treatment planning. This study analyzes imaging characteristics of non-paraganglioma neoplasms involving the jugular foramen, with attention given to features helpful in differential diagnosis. STUDY DESIGN: A retrospective chart search. SETTING: Teritary referral university centre. SUBJECTS AND METHODS: During the years 1997-2010, 11 cases of jugular foramen tumors other than paragangliomas, with available imaging studies, were identified. Histopathology revealed: 3 schwannomas, 1 malignant schwannoma, 2 meningiomas, 1 hemangiopericytoma, 1 ependymoma, 1 endolymphatic sac carcinoma (ELST) and 2 nasopharyngeal carcinoma metastases. CT, MRI and angiography were assessed to determine tumor growth directions, bone involvement, tumor morphology and vascular composition. RESULTS: Schwannomas were characterized by parapharyngeal space involvement, jugular foramen expansion, preservation of cortical margins, irregular contrast enhancement. Meningiomas presented diffuse bone infiltration, sclerotic changes, erosion of the cortical bone. Ependymoma showed diffuse skull base infiltration, permeative erosion, heterogeneity, abundant vascularization. Hemangiopericytoma radiologically imitated paraganglioma. ELST showed permeative/geographic bony destruction, heterogeneity, intratumoral bony fragments. Metastases were lytic, solid lesions characterized by circumferential growth, internal carotid artery encasement and stenosis. CONCLUSIONS: A combination of certain radiological features including tumor epicenter, growth vectors, skull base infiltration, bony changes and tumor morphology help establish correct preoperative diagnosis and differentiate less common jugular foramen tumors, from most common paragangliomas. Hemangiopericytoma may radiologically mimic paraganglioma.

Exoplanet detection. A terrestrial planet in a ~1-AU orbit around one member of a ~15-AU binary.

Using gravitational microlensing, we detected a cold terrestrial planet orbiting one member of a binary star system. The planet has low mass (twice Earth's) and lies projected at ~0.8 astronomical units (AU) from its host star, about the distance between Earth and the Sun. However, the planet's temperature is much lower, <60 Kelvin, because the host star is only 0.10 to 0.15 solar masses and therefore more than 400 times less luminous than the Sun. The host itself orbits a slightly more massive companion with projected separation of 10 to 15 AU. This detection is consistent with such systems being very common. Straightforward modification of current microlensing search strategies could increase sensitivity to planets in binary systems. With more detections, such binary-star planetary systems could constrain models of planet formation and evolution.

Fiber Bragg gratings in hole-assisted multicore fiber for space division multiplexing.

In this Letter we present, for the first time to our knowledge, the results of fiber Bragg grating (FBG) inscription in a novel microstructured multicore fiber characterized by seven single-mode isolated cores. A clear Bragg reflection peak can be observed in all of the 7 cores after one inscription process with a KrF nanosecond laser in a Talbot interferometer set up. We furthermore perform a numerical analysis of the effective refractive indices of the particular modes and compare it with the FBG inscription results. An experimental analysis of the strain and temperature sensitivities of all of the Bragg peaks is also included.

An eclipsing-binary distance to the Large Magellanic Cloud accurate to two per cent.

In the era of precision cosmology, it is essential to determine the Hubble constant to an accuracy of three per cent or better. At present, its uncertainty is dominated by the uncertainty in the distance to the Large Magellanic Cloud (LMC), which, being our second-closest galaxy, serves as the best anchor point for the cosmic distance scale. Observations of eclipsing binaries offer a unique opportunity to measure stellar parameters and distances precisely and accurately. The eclipsing-binary method was previously applied to the LMC, but the accuracy of the distance results was lessened by the need to model the bright, early-type systems used in those studies. Here we report determinations of the distances to eight long-period, late-type eclipsing systems in the LMC, composed of cool, giant stars. For these systems, we can accurately measure both the linear and the angular sizes of their components and avoid the most important problems related to the hot, early-type systems. The LMC distance that we derive from these systems (49.97 ± 0.19 (statistical) ± 1.11 (systematic) kiloparsecs) is accurate to 2.2 per cent and provides a firm base for a 3-per-cent determination of the Hubble constant, with prospects for improvement to 2 per cent in the future.

Standardisation of metalloimmunoassay protocols for assessment of silver nanoparticle antibody conjugates.

The application of silver nanoparticles to electrochemical metalloimmunoassays has previously been reported (Szymanski et al., 2009) and is now used in the electrochemical Argento immunoassay platform via UK Patent No. 2458420. The development of an immunoassay in this format requires the optimisation of the antibody to silver nanoparticle conjugation process. Issues such as pH, antibody concentration and other factors can affect the assay performance. In order to determine the effect of these variables it is necessary to understand and control the effects of other factors that may affect the assay signal. In this study a number of conditions which affect the assay signal were identified and methods developed to minimise variability in the assay signal, resulting in a standardised method allowing easy comparisons of silver nanoparticle conjugates prepared and assayed at different times.

Increased cardiovascular risk in rats with primary renal dysfunction; mediating role for vascular endothelial function.

Primary chronic kidney disease is associated with high cardiovascular risk. However, the exact mechanisms behind this cardiorenal interaction remain unclear. We investigated the interaction between heart and kidneys in novel animal model for cardiorenal interaction. Normal Wistar rats and Munich Wistar Fromter rats, spontaneously developing renal dysfunction, were subjected to experimental myocardial infarction to induce cardiac dysfunction (CD) and combined cardiorenal dysfunction (CRD), respectively (N = 5-10). Twelve weeks later, cardiac- and renal parameters were evaluated. Cardiac, but not renal dysfunction was exaggerated in CRD. Accelerated cardiac dysfunction in CRD was indicated by decreased cardiac output (CD 109 ± 10 vs. CRD 79 ± 8 ml/min), diastolic dysfunction (E/e') (CD 26 ± 2 vs. CRD 50 ± 5) and left ventricular overload (LVEDP CD 10.8 ± 2.8 vs. CRD 21.6 ± 1.7 mmHg). Congestion in CRD was confirmed by increased lung and atrial weights, as well as exaggerated right ventricular hypertrophy. Absence of accelerated renal dysfunction, measured by increased proteinuria, was supported by absence of additional focal glomerulosclerosis or further decline of renal blood flow in CRD. Only advanced peripheral endothelial dysfunction, as found in CRD, appeared to correlate with both renal and cardiac dysfunction parameters. Thus, proteinuric rats with myocardial infarction showed accelerated cardiac but not renal dysfunction. As parameters mimic the cardiorenal syndrome, these rats may provide a clinically relevant model to study increased cardiovascular risk due to renal dysfunction. Peripheral endothelial dysfunction was the only parameter that correlated with both renal and cardiac dysfunction, which may indicate a mediating role in cardiorenal interaction.

One or more bound planets per Milky Way star from microlensing observations.

Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M(⊕) and M(⊕) is Earth's mass). Cool Neptunes (10-30 M(⊕)) and super-Earths (5-10 M(⊕)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.

Alzheimer's risk variants in the clusterin gene are associated with alternative splicing.

Genetic variation in CLU encoding clusterin has been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. Following earlier reports that tightly regulated CLU alternative transcripts have different functions, we tested CLU single nucleotide polymorphisms (SNPs) including those associated with AD for quantitative effects on individual alternative transcripts. In 190 temporal lobe samples without pathology we found that the risk allele of the AD associated SNP rs9331888 increases the relative abundance of transcript NM_203339 (P=4.3×10(-12)). Using an independent set of 115 AD and control samples, we replicated this result (p=0.0014) and further observed that multiple CLU transcripts are at higher levels in AD compared to controls. The AD SNP rs9331888 is located in the first exon of NM_203339 and therefore, it is a functional candidate for the observed effects. We tested this hypothesis by in vitro dual luciferase assays using SK-N-SH cells and mouse primary cortical neurons and found allelic effects on enhancer function, consistent with our results on post-mortem human brain. These results suggest a biological mechanism for the genetic association of CLU with AD risk and indicate that rs9331888 is one of the functional DNA variants underlying this association.

Relation between the concentration of zinc in maternal whole blood and the risk of an infant being born with an orofacial cleft.

We investigated the relation between concentrations of maternal zinc and copper and the risk of an infant being born with an orofacial cleft. We did a case-control study using 116 mothers of children with isolated cleft lip with or without cleft palate (cleft group), and 64 mothers of unaffected children (control group). Mothers with a whole blood zinc concentration of 47.1 micromol/L or less had a risk 2.5 times higher of having a child with an orofacial cleft than those with a higher concentration (or level) (95% CI 1.03-6.23; p<0.05). A low zinc concentration combined with a high copper concentration was seen only in the cleft group. This evidence suggests an association between concentrations of maternal zinc and the risk of orofacial clefts in offspring.

Microvessel density and CpG island methylation of the THBS2 gene in malignant ovarian tumors.

We aimed to investigate the role of thrombospondin-2 (THBS2) related angiogenic activity in malignant ovarian tumors and to determine if aberrant methylation associated inactivation is involved in down-regulating THBS2 expression in ovarian cancer. The methylation status of the THBS2 promoter region and microvessel density (MVD) was studied in 70 malignant ovarian tumors and in 15 control ovarian samples. A methylation specific PCR (MSP) method was used to distinguish methylated from unmethylated DNA in the promoter regions of the THBS2 gene. MVD was assessed with anti-CD34 antibodies and the results were compared between tumors with average (AVD) and high (HVD) microvessel density. Alterations in the expression of trombospondin-2 were more often seen in early (FIGO stage I and II ) than in late stage tumors (66% vs. 30%, p=0.01). Age, menopausal status, the histological type and tumor grade did not correlate with thrombospondin-2 expression, however, silencing of THBS2 gene was more often seen in higher rather than in lower grade (50% vs. 28%) cancers and in nonserous rather than in serous (43% vs. 32%) tumors. In 81% of THBS2 mRNA-negative tumors, ahypermethylated promoter region of THBS2 was found (p=0.00003). An unmethylated product of the MSP reaction was more often detected in high grade tumors (93% vs. 76%, p=0.04). The incidence of THBS2 hypermethylation was not related to the tumor histological type, but unmethylated THBS2 was more often found in serous rather than in nonserous tumor (96% vs. 74%, p=0.01). The median MVD in malignant the tumor samples was 21,7 (range: 7.6-55.2). In the group with HVD, 54% were THBS2 mRNAnegative, conversely, in the group with AVD tumors only 26% of the cases had undetectable THSB2 mRNA. A significant correlation between microvessel density and the expression of trombospondin-2 (p=0.009) was found. In the samples with HVD, 51% had hypermethylated THBS2, however methylation pattern had no significant influence on microvessel density. In conclusion, hypermethylation might be responsible for altered expression of thrombospondin-2 in ovarian cancer. The THSB2 methylation pattern had no significant influence on microvessel density.

Associations between bovine, human, and raw milk, and beef isolates of non-O157 Shiga toxigenic Escherichia coli within a restricted geographic area of the United States.

A survey for Shiga toxigenic Escherichia coli in raw milk and beef was conducted within a defined geographic region of the United States. Prevalence rates based on detection of Shiga toxin gene (stx) were 36% for retail beef, 23% for beef carcasses, and 21% for raw milk samples, which were significantly higher than were Shiga toxigenic E. coli isolation rates of 7.5, 5.8, and 3.2%, respectively. Seasonal prevalence differences were significant for stx positivity among ground beef and milk samples. Distribution of stx subtypes among isolates varied according to sample type, with stx1 predominating in milk, stx2 on carcasses, and the combination of both stx1 and stx2 in beef. Ancillary virulence markers eae and ehx were evident in 23 and 15% of isolates, respectively. Pulsed-field gel electrophoresis demonstrated associations between food isolates and sympatric bovine fecal, and human clinical isolates. These data demonstrate that non-O157 Shiga toxigenic E. coli is present in the food chain in the Pacific Northwest, and its risk to health warrants critical assessment.

Discovery of a Jupiter/Saturn analog with gravitational microlensing.

Searches for extrasolar planets have uncovered an astonishing diversity of planetary systems, yet the frequency of solar system analogs remains unknown. The gravitational microlensing planet search method is potentially sensitive to multiple-planet systems containing analogs of all the solar system planets except Mercury. We report the detection of a multiple-planet system with microlensing. We identify two planets with masses of approximately 0.71 and approximately 0.27 times the mass of Jupiter and orbital separations of approximately 2.3 and approximately 4.6 astronomical units orbiting a primary star of mass approximately 0.50 solar mass at a distance of approximately 1.5 kiloparsecs. This system resembles a scaled version of our solar system in that the mass ratio, separation ratio, and equilibrium temperatures of the planets are similar to those of Jupiter and Saturn. These planets could not have been detected with other techniques; their discovery from only six confirmed microlensing planet detections suggests that solar system analogs may be common.

Experimental study on heat transmission to the vestibule during CO2 laser use in revision stapes surgery.

We studied the transmission of heat to the vestibule during revision stapes surgery with a piston in situ, using a CO2 laser, in an in vitro model. A type K thermocouple was placed around the medial end of stainless steel and fluoroplastic wire pistons in a 'vestibule' filled with saline. The effect of laser hits on fluoroplastic wire and stainless steel stapes prostheses was investigated. The effect of introducing a vein graft to seal the stapedotomy was also examined. Greater temperature rises occurred with stainless steel than with fluoroplastic wire pistons. The addition of the vein graft reduced heat transmission. Application of the CO2 laser to fluoroplastic wire pistons, using the power settings suggested by the manufacturer, is not likely to damage the inner-ear structures. Application of 6 W laser energy to stainless steel pistons can potentially disturb the inner-ear function.

Regulatory RNAs in mammals.

Recent years have brought a dramatic change in our understanding of the role of ribonucleic acids (RNAs) within the cell. In addition to the already well-known classes of RNAs that take part in the transmission of genetic information from DNA to proteins, a new highly heterogeneous group of RNA molecules has emerged. The regulatory nonprotein-coding RNAs (npcRNAs) have been shown to be involved in modulation of gene expression on both the transcriptional and post-transcriptional level. They participate in mechanisms of chromatin modification, regulation of transcription factor activity, and influencing mRNA stability, processing, and translation. npcRNAs are key factors in genetic imprinting, dosage compensation of X-chromosome-linked genes, and many processes of differentiation and development.