The spectrum of cardiovascular complications related to immune-checkpoint inhibitor treatment : Including myocarditis and the new entity of non inflammatory left ventricular dysfunction.

BACKGROUND: The full range of cardiovascular complications related to the use of Immune checkpoint inhibitors (ICI) is not fully understood. We aim to describe the spectrum of cardiovascular adverse events (cvAEs) by presenting our real-world experience of the diagnosis and management of these complications. METHODS: Two thousand six hundred and forty-seven (2647) patients were started on ICI treatment between 2014 and 2020. Data from 110 patients referred to the cardio-oncology service with a suspected cvAE was collected prospectively and analysed. RESULTS: Eighty-nine patients (3.4%) were confirmed to have cvAEs while on ICI therapy. Myocarditis was the most frequent event (33/89), followed by tachyarrhythmia (27/89), non-inflammatory left ventricular dysfunction (NILVD) (15/89) and pericarditis (7/89). Results from myocarditis and non-inflammatory left ventricular dysfunction cohorts were compared. Myocarditis and NILVD showed significant differences in respect toof troponin elevation, cardiac magnetic resonance abnormalities and ventricular function. Dual ICI therapy and other immune related adverse events were more frequently associated with myocarditis than NILVD. There was a significant difference in the median time from starting ICI treatment to presentation with myocarditis versus NILVD (12 vs 26 weeks p = 0.049). Through early recognition of myocarditis, prompt treatment with steroids and interruption of ICI, there were no cardiovascular in-hospital deaths. NILVD did not require steroid treatment and ICI could be restarted safely. CONCLUSIONS: The full spectrum of cardiovascular complications in patients with immune checkpoint inhibitors is much broader than initially described. Myocarditis remains the most frequent cvAE related to ICI treatment. A novel type of myocardial injury was observed and defined as Atrial tachyarrhythmias and NILVD were also frequent in this cohort. NILVD has a This differs fromdifferent presentation from ICI-related myocarditis, mainly usually presenting afterby the lack of inflammatory features on CMR and biomarkers and a later presentation in time

Preserving the impossible: conservation of soft-sediment hominin footprint sites and strategies for three-dimensional digital data capture.

Human footprints provide some of the most publically emotive and tangible evidence of our ancestors. To the scientific community they provide evidence of stature, presence, behaviour and in the case of early hominins potential evidence with respect to the evolution of gait. While rare in the geological record the number of footprint sites has increased in recent years along with the analytical tools available for their study. Many of these sites are at risk from rapid erosion, including the Ileret footprints in northern Kenya which are second only in age to those at Laetoli (Tanzania). Unlithified, soft-sediment footprint sites such these pose a significant geoconservation challenge. In the first part of this paper conservation and preservation options are explored leading to the conclusion that to 'record and digitally rescue' provides the only viable approach. Key to such strategies is the increasing availability of three-dimensional data capture either via optical laser scanning and/or digital photogrammetry. Within the discipline there is a developing schism between those that favour one approach over the other and a requirement from geoconservationists and the scientific community for some form of objective appraisal of these alternatives is necessary. Consequently in the second part of this paper we evaluate these alternative approaches and the role they can play in a 'record and digitally rescue' conservation strategy. Using modern footprint data, digital models created via optical laser scanning are compared to those generated by state-of-the-art photogrammetry. Both methods give comparable although subtly different results. This data is evaluated alongside a review of field deployment issues to provide guidance to the community with respect to the factors which need to be considered in digital conservation of human/hominin footprints

Chromosomal imbalances associated with carcinoma in situ and associated testicular germ cell tumours of adolescents and adults

Carcinoma in situ (CIS) or intratubular germ cell neoplasia is generally considered the precursor lesion of adult testicular germ cell tumours (TGCT). The chromosomal imbalances associated with CIS and the corresponding seminoma (SE) or nonseminoma (NS) have been determined by comparative genomic hybridization (CGH) analysis of microdissected material from seven cases. Significantly, the CIS showed no gain of 12p material whereas in the invasive components of all cases gain of 12p was found, in 2 cases associated with amplification of the 12p11.2–12.1 region. Interphase fluorescence in situ analysis was consistent with this and provided evidence for the i(12p) or 12p11.2–12.1 amplification in the SE and NS but not in the corresponding CIS. This suggests a role for these changes in progression of CIS to invasive testicular cancer or progression of the invasive disease. Other imbalances such as gain of material from chromosomes 1, 5, 7, 8, 12q and X and loss of material from chromosome 18 were frequently identified (> 40% of cases) in the CIS associated with both SE and NS as well as in the invasive components. Loss of material from chromosome 4 and 13 and gain of 2p were more frequently found in the invasive components. The results shed light on the genetic relationship between the non-invasive and invasive components of testicular cancer and the stage at which particular chromosomal changes may be important. © 2001 Cancer Research Campaign http://www.bjcancer.co

Predicting Outcomes in Men With Metastatic Nonseminomatous Germ Cell Tumors (NSGCT): Results From the IGCCCG Update Consortium

Purpose: The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. Materials and methods: Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set. Results: Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided (https://www.eortc.org/IGCCCG-Update). Conclusion: The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors

Palatal development of preterm and low birthweight infants compared to term infants – What do we know? Part 1: The palate of the term newborn

BACKGROUND: The evidence on prematurity as 'a priori' a risk for palatal disturbances that increase the need for orthodontic or orthognathic treatment is still weak. Further well-designed clinical studies are needed. The objective of this review is to provide a fundamental analysis of methodologies, confounding factors, and outcomes of studies on palatal development. One focus of this review is the analysis of studies on the palate of the term newborn, since knowing what is 'normal' is a precondition of being able to assess abnormalities. METHODS: A search profile based on Cochrane search strategies applied to 10 medical databases was used to identify existing studies. Articles, mainly those published before 1960, were identified from hand searches in textbooks, encyclopedias, reference lists and bibliographies. Sources in English, German, and French of more than a century were included. Data for term infants were recalculated if particular information about weight, length, or maturity was given. The extracted values, especially those from non-English paper sources, were provided unfiltered for comparison. RESULTS: The search strategy yielded 182 articles, of which 155 articles remained for final analysis. Morphology of the term newborn's palate was of great interest in the first half of the last century. Two general methodologies were used to assess palatal morphology: visual and metrical descriptions. Most of the studies on term infants suffer from lack of reliability tests. The groove system was recognized as the distinctive feature of the infant palate. The shape of the palate of the term infant may vary considerably, both visually and metrically. Gender, race, mode of delivery, and nasal deformities were identified as causes contributing to altered palatal morphology. Until today, anatomical features of the newborn's palate are subject to a non-uniform nomenclature. CONCLUSION: Today's knowledge of a newborn's 'normal' palatal morphology is based on non-standardized and limited methodologies for measuring a three-dimensional shape. This shortcoming increases bias and is the reason for contradictory research results, especially if pathologic conditions like syndromes or prematurity are involved. Adequate measurement techniques are needed and the 'normal palatal morphology' should be defined prior to new clinical studies on palatal development

Population of Merging Compact Binaries Inferred Using Gravitational Waves through GWTC-3

We report on the population properties of compact binary mergers inferred from gravitational-wave observations of these systems during the first three LIGO-Virgo observing runs. The Gravitational-Wave Transient Catalog 3 (GWTC-3) contains signals consistent with three classes of binary mergers: binary black hole, binary neutron star, and neutron star-black hole mergers. We infer the binary neutron star merger rate to be between 10 and 1700 Gpc-3 yr-1 and the neutron star-black hole merger rate to be between 7.8 and 140 Gpc-3 yr-1, assuming a constant rate density in the comoving frame and taking the union of 90% credible intervals for methods used in this work. We infer the binary black hole merger rate, allowing for evolution with redshift, to be between 17.9 and 44 Gpc-3 yr-1 at a fiducial redshift (z=0.2). The rate of binary black hole mergers is observed to increase with redshift at a rate proportional to (1+z)κ with κ=2.9-1.8+1.7 for z≲1. Using both binary neutron star and neutron star-black hole binaries, we obtain a broad, relatively flat neutron star mass distribution extending from 1.2-0.2+0.1 to 2.0-0.3+0.3M⊙. We confidently determine that the merger rate as a function of mass sharply declines after the expected maximum neutron star mass, but cannot yet confirm or rule out the existence of a lower mass gap between neutron stars and black holes. We also find the binary black hole mass distribution has localized over- and underdensities relative to a power-law distribution, with peaks emerging at chirp masses of 8.3-0.5+0.3 and 27.9-1.8+1.9M⊙. While we continue to find that the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above approximately 60M⊙, which would indicate the presence of a upper mass gap. Observed black hole spins are small, with half of spin magnitudes below χi≈0.25. While the majority of spins are preferentially aligned with the orbital angular momentum, we infer evidence of antialigned spins among the binary population. We observe an increase in spin magnitude for systems with more unequal-mass ratio. We also observe evidence of misalignment of spins relative to the orbital angular momentum

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

The population of merging compact binaries inferred using gravitational waves through GWTC-3

We report on the population properties of 76 compact binary mergers detected with gravitational waves below a false alarm rate of 1 per year through GWTC-3. The catalog contains three classes of binary mergers: BBH, BNS, and NSBH mergers. We infer the BNS merger rate to be between 10 $\rm{Gpc^{-3} yr^{-1}}$ and 1700 $\rm{Gpc^{-3} yr^{-1}}$ and the NSBH merger rate to be between 7.8 $\rm{Gpc^{-3}\, yr^{-1}}$ and 140 $\rm{Gpc^{-3} yr^{-1}}$ , assuming a constant rate density versus comoving volume and taking the union of 90% credible intervals for methods used in this work. Accounting for the BBH merger rate to evolve with redshift, we find the BBH merger rate to be between 17.9 $\rm{Gpc^{-3}\, yr^{-1}}$ and 44 $\rm{Gpc^{-3}\, yr^{-1}}$ at a fiducial redshift (z=0.2). We obtain a broad neutron star mass distribution extending from $1.2^{+0.1}_{-0.2} M_\odot$ to $2.0^{+0.3}_{-0.3} M_\odot$. We can confidently identify a rapid decrease in merger rate versus component mass between neutron star-like masses and black-hole-like masses, but there is no evidence that the merger rate increases again before 10 $M_\odot$. We also find the BBH mass distribution has localized over- and under-densities relative to a power law distribution. While we continue to find the mass distribution of a binary's more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above $\sim 60 M_\odot$. The rate of BBH mergers is observed to increase with redshift at a rate proportional to $(1+z)^{\kappa}$ with $\kappa = 2.9^{+1.7}_{-1.8}$ for $z\lesssim 1$. Observed black hole spins are small, with half of spin magnitudes below $\chi_i \simeq 0.25$. We observe evidence of negative aligned spins in the population, and an increase in spin magnitude for systems with more unequal mass ratio

All-sky search for long-duration gravitational-wave bursts in the third Advanced LIGO and Advanced Virgo run

After the detection of gravitational waves from compact binary coalescences, the search for transient gravitational-wave signals with less well-defined waveforms for which matched filtering is not well suited is one of the frontiers for gravitational-wave astronomy. Broadly classified into “short” ≲1  s and “long” ≳1  s duration signals, these signals are expected from a variety of astrophysical processes, including non-axisymmetric deformations in magnetars or eccentric binary black hole coalescences. In this work, we present a search for long-duration gravitational-wave transients from Advanced LIGO and Advanced Virgo’s third observing run from April 2019 to March 2020. For this search, we use minimal assumptions for the sky location, event time, waveform morphology, and duration of the source. The search covers the range of 2–500 s in duration and a frequency band of 24–2048 Hz. We find no significant triggers within this parameter space; we report sensitivity limits on the signal strength of gravitational waves characterized by the root-sum-square amplitude hrss as a function of waveform morphology. These hrss limits improve upon the results from the second observing run by an average factor of 1.8