ABSTRACT
Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral ...fractures (AFF). Recent published studies examining this potential association are conflicting regarding the existence and strength of this association. We conducted a systematic review and meta‐analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random‐effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta‐analysis: five case‐control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF, with adjusted RR of 1.70 (95% confidence interval CI, 1.22–2.37). Subgroup analysis of studies using the American Society for Bone and Mineral Research criteria to define AFF suggests a higher risk of AFF, with bisphosphonate use with RR of 11.78 (95% CI, 0.39–359.69) as compared to studies using mainly diagnosis codes (RR, 1.62; 95% CI, 1.18–2.22), although there is a wide confidence interval and severe heterogeneity (I2 = 96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI, 1.29–2.04). This meta‐analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long‐term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear.
Zika, a mosquito-borne viral disease that emerged in South America in 2015, was declared a Public Health Emergency of International Concern by the WHO in February of 2016. We developed a ...climate-driven R₀ mathematical model for the transmission risk of Zika virus (ZIKV) that explicitly includes two key mosquito vector species: Aedes aegypti and Aedes albopictus. The model was parameterized and calibrated using the most up to date information from the available literature. It was then driven by observed gridded temperature and rainfall datasets for the period 1950–2015. We find that the transmission risk in South America in 2015 was the highest since 1950. This maximum is related to favoring temperature conditions that caused the simulated biting rates to be largest and mosquito mortality rates and extrinsic incubation periods to be smallest in 2015. This event followed the suspected introduction of ZIKV in Brazil in 2013. The ZIKV outbreak in Latin America has very likely been fueled by the 2015–2016 El Niño climate phenomenon affecting the region. The highest transmission risk globally is in South America and tropical countries where Ae. aegypti is abundant. Transmission risk is strongly seasonal in temperate regions where Ae. albopictus is present, with significant risk of ZIKV transmission in the southeastern states of the United States, in southern China, and to a lesser extent, over southern Europe during the boreal summer season.
In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor ...activity, overall survival (OS) and safety data (additional 46.2months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001.
ROS1 status was determined by FISH or reverse transcriptase–polymerase chain reaction. All patients received crizotinib at a starting dose of 250mg twice daily.
Fifty-three patients received crizotinib, with a median duration of treatment of 22.4months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% 95% confidence interval (CI), 58% to 83%, including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7months; 95% CI, 15.2–45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3months (95% CI, 15.2–39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment.
These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup.
ClinicalTrials.gov identifier NCT00585195
The National Aeronautics and Space Administration Global‐scale Observations of the Limb and Disk ultraviolet spectrograph has been imaging the equatorial ionization anomaly (EIA), regions of the ...ionosphere with enhanced electron density north and south of the magnetic equator, since October 2018. The initial 3 months of observations was during solar minimum conditions, and they included observations in December solstice of unanticipated variability and depleted regions. Depletions are seen on most nights, in contrast to expectations from previous space‐based observations. The variety of scales and morphologies also pose challenges to understanding of the EIA. Abrupt changes in the EIA location, which could be related to in situ measurements of large‐scale depletion regions, are observed on some nights. Such synoptic‐scale disruptions have not been previously identified.
Plain Language Summary
In this study, ultraviolet images of emissions from the Earth's nighttime ionosphere were examined to determine the location of the equatorial ionization anomaly, regions of enhanced ionization that result in bands of nighttime airglow emission that typically appear parallel to the magnetic equator near +15° and −15° magnetic latitude. We found that gaps in the anomaly are observed much more frequently in these observations than in previous space‐based observations. These gaps, sometimes referred to as ionospheric bubbles or depletions, are important because they are associated with ionospheric changes that can cause disruptions in communications and satellite navigation that depend on satellites, such as GPS. The location of the anomaly was also observed to vary significantly, by as much as 15°, from the typical latitudes. The observed level of variability seen during the unusually quiet geomagnetic conditions during which the observations occurred suggests that accurate predictions of the location and variability of the equatorial ionization anomaly requires significant advances in understanding the causes of this variability.
Key Points
During geomagnetically quiet solar minimum conditions, significant temporal and spatial variability is observed in the equatorial ionosphere
At solar minimum, depleted ionospheric regions are observed on most nights, at varying longitudes, and with evident meridional symmetry
Synoptic‐scale disruptions of the ionization crests are seen on several nights, possibly associated with large‐scale plasma instabilities
Aims
We tested the hypothesis that candesartan improves outcomes in heart failure (HF) with mid‐range ejection fraction HFmrEF; ejection fraction (EF) 40–49%.
Methods and results
In 7598 patients ...enrolled in the CHARM Programme (HF across the spectrum of EF), we assessed characteristics, outcomes and treatment effect of candesartan according to EF. Patients with HFmrEF (n = 1322, 17%) were similar to those with HF with reduced EF (HFrEF; n = 4323, 57%) with respect to some characteristics, and intermediate between HFrEF and HF with preserved EF (HFpEF; n = 1953, 26%) with respect to others. Over a mean follow‐up of 2.9 years, the incidence rates for the primary outcome of cardiovascular death or HF hospitalization were 15.9, 8.5 and 8.9 per 100 patient‐years in HFrEF, HFmrEF and HFpEF. In adjusted analyses, the rates of the primary outcome declined with increasing EF up to 50%. For treatment effect, the incidence rates for the primary outcome for candesartan vs. placebo were 14.4 vs. 17.5 per 100 patient‐years in HFrEF hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75–0.91; P < 0.001, 7.4 vs. 9.7 per 100 patient‐years in HFmrEF (HR 0.76, 95% CI 0.61–0.96; P = 0.02), and 8.6 vs. 9.1 per 100 patient‐years in HFpEF (HR 0.95, 95% CI 0.79–1.14; P = 0.57). For recurrent HF hospitalization, the incidence rate ratios were 0.68 in HFrEF (95% CI 0.58–0.80; P < 0.001), 0.48 in HFmrEF (95% CI 0.33–0.70; P < 0.001), and 0.78 in HFpEF (95% CI 0.59–1.03; P = 0.08). With EF as a continuous spline variable, candesartan significantly reduced the primary outcome until EF well over 50% and recurrent HF hospitalizations until EF well over 60%.
Conclusion
Candesartan improved outcomes in HFmrEF to a similar degree as in HFrEF.
ClinicalTrials.gov: CHARM Alternative NCT00634400, CHARM Added NCT00634309, CHARM Preserved NCT00634712
Initial Observations by the GOLD Mission Eastes, R. W.; McClintock, W. E.; Burns, A. G. ...
Journal of geophysical research. Space physics,
July 2020, Letnik:
125, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The NASA Global‐scale Observations of the Limb and Disk (GOLD) mission has flown an ultraviolet‐imaging spectrograph on SES‐14, a communications satellite in geostationary orbit at 47.5°W longitude. ...That instrument observes the Earth's far ultraviolet (FUV) airglow at ~134–162 nm using two identical channels. The observations performed include limb scans, stellar occultations, and images of the sunlit and nightside disk from 6:10 to 00:40 universal time each day. Initial analyses reveal interesting and unexpected results as well as the potential for further studies of the Earth's thermosphere‐ionosphere system and its responses to solar‐geomagnetic forcing and atmospheric dynamics. Thermospheric composition ratios for major constituents, O and N2, temperatures near 160 km, and exospheric temperatures are retrieved from the daytime observations. Molecular oxygen (O2) densities are measured using stellar occultations. At night, emission from radiative recombination in the ionospheric F region is used to quantify ionospheric density variations in the equatorial ionization anomaly (EIA). Regions of depleted F region electron density are frequently evident, even during the current solar minimum. These depletions are caused by the “plasma fountain effect” and are associated with the instabilities, scintillations, or “spread F” seen in other types of observations, and GOLD makes unique observations for their study.
Plain Language Summary
The NASA Global‐scale Observations of the Limb and Disk (GOLD) mission has flown a dual‐channel, ultraviolet‐imaging spectrograph on SES‐14, a communications satellite in geostationary orbit at 47.5°W longitude. That instrument observes the Earth's far ultraviolet (FUV) airglow at ~134–162 nm. The observations performed include images of the Earth's sunlit and nightside disk, limb scans, and stellar occultations, from 6:10 to 00:40 universal time each day. Initial analyses reveal interesting and unexpected results as well as the potential for further studies of the Earth's thermosphere‐ionosphere system and its responses to solar‐geomagnetic forcing and atmospheric dynamics. Thermospheric temperatures and composition ratios for major constituents, O and N2, near 160‐km altitude and exospheric temperatures are retrieved from the daytime observations. Molecular oxygen (O2) densities are measured using stellar occultations. At night, emission from radiative recombination in the ionospheric F region is used to quantify ionospheric density variations in the equatorial ionization anomaly (EIA). Regions of depleted F region electron density are frequently evident in the EIA, even during the current solar minimum.
Key Points
GOLD makes global‐scale, synoptic measurements of the temperature, composition, and densities in the thermosphere‐ionosphere system
Most measurements by the GOLD instrument are made in one of four modes
The observations are providing new and surprising insights into the characteristics and behavior of the thermosphere and ionosphere
The idea that synchronous neural activity underlies cognition has driven an extensive body of research in human and animal neuroscience. Yet, insufficient data on intracranial electrical connectivity ...has precluded a direct test of this hypothesis in a whole-brain setting. Through the lens of memory encoding and retrieval processes, we construct whole-brain connectivity maps of fast gamma (30-100 Hz) and slow theta (3-8 Hz) spectral neural activity, based on data from 294 neurosurgical patients fitted with indwelling electrodes. Here we report that gamma networks desynchronize and theta networks synchronize during encoding and retrieval. Furthermore, for nearly all brain regions we studied, gamma power rises as that region desynchronizes with gamma activity elsewhere in the brain, establishing gamma as a largely asynchronous phenomenon. The abundant phenomenon of theta synchrony is positively correlated with a brain region's gamma power, suggesting a predominant low-frequency mechanism for inter-regional communication.
The Whole Atmosphere Community Climate Model version 6 (WACCM6) is a major update of the whole atmosphere modeling capability in the Community Earth System Model (CESM), featuring enhanced physical, ...chemical and aerosol parameterizations. This work describes WACCM6 and some of the important features of the model. WACCM6 can reproduce many modes of variability and trends in the middle atmosphere, including the quasi‐biennial oscillation, stratospheric sudden warmings, and the evolution of Southern Hemisphere springtime ozone depletion over the twentieth century. WACCM6 can also reproduce the climate and temperature trends of the 20th century throughout the atmospheric column. The representation of the climate has improved in WACCM6, relative to WACCM4. In addition, there are improvements in high‐latitude climate variability at the surface and sea ice extent in WACCM6 over the lower top version of the model (CAM6) that comes from the extended vertical domain and expanded aerosol chemistry in WACCM6, highlighting the importance of the stratosphere and tropospheric chemistry for high‐latitude climate variability.
Plain Language Summary
This manuscript describes the Whole Atmosphere Community Climate Model Version 6 (WACCM6), a chemistry and climate model which extends up to 140 km in the upper atmosphere. WACCM6 reproduces many important features of the climate system, and the addition of detailed chemistry and the higher than normal model top produces slightly improved simulations of the Arctic region.
Key Points
WACCM6 is a major upgrade to previous versions
WACCM6 can reproduce many modes of variability and trends in the middle atmosphere
WACCM6 provides improvements in high‐latitude climate variability at the surface and sea ice extent over a low top model
The Earth’s thermosphere and ionosphere constitute a dynamic system that varies daily in response to energy inputs from above and from below. This system can exhibit a significant response within an ...hour to changes in those inputs, as plasma and fluid processes compete to control its temperature, composition, and structure. Within this system, short wavelength solar radiation and charged particles from the magnetosphere deposit energy, and waves propagating from the lower atmosphere dissipate.
Understanding the global-scale response of the thermosphere-ionosphere
(
T-I
)
system to these drivers is essential to advancing our physical understanding of coupling between the space environment and the Earth’s atmosphere
. Previous missions have successfully determined how the “climate” of the T-I system responds. The Global-scale Observations of the Limb and Disk (GOLD) mission will determine how the “weather” of the T-I responds, taking the next step in understanding the coupling between the space environment and the Earth’s atmosphere. Operating in geostationary orbit, the GOLD imaging spectrograph will measure the Earth’s emissions from 132 to 162 nm. These measurements will be used image two critical variables—thermospheric temperature and composition, near 160 km—on the dayside disk at half-hour time scales. At night they will be used to image the evolution of the low latitude ionosphere in the same regions that were observed earlier during the day. Due to the geostationary orbit being used the mission observes the same hemisphere repeatedly, allowing the unambiguous separation of spatial and temporal variability over the Americas.
Summary
Background
Serum pepsinogen 1 (SPG1) and anti‐Helicobacter pylori serology have been used for gastric risk stratification in Asia.
Aim
To assess utility of these markers in a Western ...population.
Methods
SPG1 measurements were available for 21 895 Finnish male smokers in the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study. We used Cox proportional hazards models adjusted for potential confounders to estimate gastric cancer hazard ratios (HR) and 95% confidence intervals (95% CI) for low SPG1 (<25 μg/L). In a subset (n = 3555) with anti‐H. pylori serology, these markers jointly defined the following: Group A (H. pylori−, SPG1normal; reference group), Group B (H. pylori+, SPG1normal), Group C (H. pylori+, SPG1low) and Group D (H. pylori−, SPG1low). Odds ratios (ORs) and 95% CI were calculated using multivariate logistic regression.
Results
There were 329 gastric cancers diagnosed an average of 13.9 years after baseline. Pre‐diagnostic low SPG1 was significantly associated with increased gastric cancer risk (HR 2.68, 95% CI 1.99‐3.61). Among subjects with both SPG1 and H. pylori serology, groups B, C and D had increased gastric cancer ORs (95% CI) of 1.79 (1.21‐2.64), 3.85 (2.36‐6.28) and 6.35 (2.20‐18.34), respectively. CagA seropositives had significantly higher ORs than CagA seronegatives within group B (Pheterogeneity = 0.01). For groups B and C, repeat SPG1 level at 3 years did not further stratify gastric cancer risk.
Conclusions
Low SPG1 was associated with increased gastric cancer risk in our large Finnish cohort. A single measurement of SPG1 along with H. pylori whole cell and CagA serology provides potentially useful prediction of gastric cancer risk.
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