Patient Support Programmes (PSPs) are used by the pharmaceutical industry to provide education and support to consumers to overcome the challenges they face managing their condition and treatment. ...Whilst there is an increasing number of PSPs, limited information is available on whether these programmes contribute to safety signals. PSPs do not have a scientific hypothesis, nor are they governed by a protocol. However, by their nature, PSPs inevitably generate adverse event (AE) reports. The main goal of the research was to gather all Novartis-initiated PSPs for sacubitril/valsartan, followed by research in the company safety database to identify all AE reports emanating from these PSPs. Core data sheets (CDS) were reviewed to assess if these PSPs contributed to any new, regulatory-authority approved, validated signals. Overall, AEs entered into the safety database from PSPs confirmed no contribution to CDS updates. Detailed review of real-world data revealed tablet splitting or taking one higher dose tablet a day instead of twice daily. This research, and subsequent analyses, revealed that PSPs did not impact safety label changes for sacubitril/valsartan. It revealed an important finding concerning drug utilisation i.e. splitting of sacubitril/valsartan tablets to reduce cost. This finding suggests that PSPs may contribute important real-world data on patterns of medication usage. There remains a paucity of literature available on this topic, hence further research is required to assess if it would be worth designing PSPs for collecting data on drug utilisation and (lack of) efficacy. Such information from PSPs could be important for all stakeholders.
Abstract
Al
0.85
Ga
0.15
As
0.56
Sb
0.44
has recently attracted significant research interest as a material for 1550 nm low-noise short-wave infrared (SWIR) avalanche photodiodes (APDs) due to the ...very wide ratio between its electron and hole ionization coefficients. This work reports new experimental excess noise data for thick Al
0.85
Ga
0.15
As
0.56
Sb
0.44
PIN and NIP structures, measuring low noise at significantly higher multiplication values than previously reported (
F
= 2.2 at
M
= 38). These results disagree with the classical McIntyre excess noise theory, which overestimates the expected noise based on the ionization coefficients reported for this alloy. Even the addition of ‘dead space’ effects cannot account for these discrepancies. The only way to explain the low excess noise observed is to conclude that the spatial probability distributions for impact ionization of electrons and holes in this material follows a Weibull–Fréchet distribution function even at relatively low electric-fields. Knowledge of the ionization coefficients alone is no longer sufficient to predict the excess noise properties of this material system and consequently the electric-field dependent electron and hole ionization probability distributions are extracted for this alloy.
CONTEXT: Observational studies suggest that heavy alcohol consumption may increase the risk of stroke while moderate consumption may decrease the risk. OBJECTIVE: To examine the association between ...alcohol consumption and relative risk of stroke. DATA SOURCES: Studies published in English-language journals were retrieved by searching MEDLINE (1966–April 2002) using Medical Subject Headings alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke; Dissertation Abstracts Online using the keywords stroke and alcohol; and bibliographies of retrieved articles. STUDY SELECTION: From 122 relevant retrieved reports, 35 observational studies (cohort or case control) in which total stroke, ischemic stroke, or hemorrhagic (intracerebral or total) stroke was an end point; the relative risk or relative odds and their variance (or data to calculate them) of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and abstainers served as the reference group. DATA EXTRACTION: Information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, and risk estimates was abstracted independently by 3 investigators using a standardized protocol. DATA SYNTHESIS: A random-effects model and meta-regression analysis were used to pool data from individual studies. Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, 1.64 (95% confidence interval CI, 1.39-1.93); ischemic stroke, 1.69 (95% CI, 1.34-2.15); and hemorrhagic stroke, 2.18 (95% CI, 1.48-3.20), while consumption of less than 12 g/d was associated with a reduced relative risk of total stroke, 0.83 (95%, CI, 0.75-0.91) and ischemic stroke, 0.80 (95% CI, 0.67-0.96), and consumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, 0.72 (95%, CI, 0.57-0.91). The meta-regression analysis revealed a significant nonlinear relationship between alcohol consumption and total and ischemic stroke and a linear relationship between alcohol consumption and hemorrhagic stroke. CONCLUSIONS: These results indicate that heavy alcohol consumption increases the relative risk of stroke while light or moderate alcohol consumption may be protective against total and ischemic stroke.
The temperature dependence of the ionization coefficients of AlAsSb has been determined from 210 K to 335 K by measuring the avalanche multiplication in a series of three p + -i-n + and two n + -i-p ...+ diodes. Both electron and hole ionization coefficients reduce at approximately the same rate as the temperature increases but much less so than in InAlAs or InP. This results in a significantly smaller breakdown voltage variation with temperature of 13 mV/K in a 1.55 μm thick p + -i-n + structure and a calculated 15.58 mV/K for a 10 Gb/s InGaAs/AlAsSb separate absorption and multiplication avalanche photodiode (SAM-APD). Monte-Carlo modelling suggests that the primary reason for this reduced temperature dependence is the increased alloy scattering in the Sb containing alloy, reducing the impact of variation in phonon scattering rate with temperature.
Digital alloy and random alloy Al 0.85 Ga 0.15 As 0.56 Sb 0.44 avalanche photodiodes (APDs) exhibit low excess noise, comparable to Si APDs. Consequently, this material is a promising multiplication ...layer candidate for separate absorption, charge, and multiplication structure APDs with high gain-bandwidth product. Characterization of the impact ionization coefficients of electrons ( α ) and holes ( β ) plays an important role in the simulation of avalanche photodiodes. The multiplication gain curves of eight p + -i-n + and n + -i-p + APDs covering a wide range of avalanche widths have been used to determine the electric field dependence of the impact ionization coefficients of Al 0.85 Ga 0.15 As 0.56 Sb 0.44 . A large impact ionization coefficient ratio between that of electrons to holes was seen across a wide electric field range. Simulations of the avalanche multiplication in these structures using a random path length (RPL) model gave good agreement with experimental results over almost three orders of magnitude, and a mixed injection method was employed to verify the extracted impact ionization coefficients. Interestingly, no difference in the impact ionization coefficients was seen between digital alloy and random alloy Al 0.85 Ga 0.15 As 0.56 Sb 0.44 . This knowledge of impact ionization coefficients is beneficial for the future utilization of the Al x Ga 1-x As y Sb 1-y material system.
The impact ionization characteristics of (Al x Ga 1- x ) 0.52 In 0.48 P have been studied comprehensively across the full composition range. Electron and hole impact ionization coefficients ...(<inline-formula> <tex-math notation="LaTeX">\alpha </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">\beta </tex-math></inline-formula>, respectively) have been extracted from avalanche multiplication and excess noise data for seven different compositions and compared to those of Al x Ga 1- x As. While both <inline-formula> <tex-math notation="LaTeX">\alpha </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">\beta </tex-math></inline-formula> initially decrease gradually with increasing bandgap, a sharp decrease in <inline-formula> <tex-math notation="LaTeX">\beta </tex-math></inline-formula> occurs in (Al x Ga 1- x ) 0.52 In 0.48 P when <inline-formula> <tex-math notation="LaTeX">{x} > 0.61 </tex-math></inline-formula>, while <inline-formula> <tex-math notation="LaTeX">\alpha </tex-math></inline-formula> decreases only slightly. <inline-formula> <tex-math notation="LaTeX">\alpha </tex-math></inline-formula> and <inline-formula> <tex-math notation="LaTeX">\beta </tex-math></inline-formula> decrease minimally with further increases in <inline-formula> <tex-math notation="LaTeX">{x} </tex-math></inline-formula> and the breakdown voltage saturates. This behavior is broadly similar to that seen in Al x Ga 1- x As, suggesting that it may be related to the details of the conduction band structure as it becomes increasingly indirect in both alloy systems.
The goal of war is to defeat the enemy’s will to fight. But how this can be accomplished is a thorny issue. Nothing Less than Victory provocatively shows that aggressive, strategic military offenses ...can win wars and establish lasting peace, while defensive maneuvers have often led to prolonged carnage, indecision, and stalemate. Taking an ambitious and sweeping look at six major wars, from antiquity to World War II, John David Lewis shows how victorious military commanders have achieved long-term peace by identifying the core of the enemy’s ideological, political, and social support for a war, fiercely striking at this objective, and demanding that the enemy acknowledges its defeat.
Allogeneic blood transfusion (ABT) is associated with transfusion-related immune modulation (TRIM) and subsequent poorer patient outcomes including perioperative infection, multiple organ failure, ...and mortality. The precise mechanism(s) underlying TRIM remain largely unknown. During intraoperative cell salvage (ICS) a patient’s own (autologous) blood is collected, anticoagulated, processed, and reinfused. One impediment to understanding the influence of the immune system on transfusion-related adverse outcomes has been the inability to characterize immune profile changes induced by blood transfusion, including ICS. Dendritic cells and monocytes play a central role in regulation of immune responses, and dysfunction may contribute to adverse outcomes. During a prospective observational study (n = 19), an in vitro model was used to assess dendritic cell and monocyte immune responses and the overall immune response following ABT or ICS exposure. Exposure to both ABT and ICS suppressed dendritic cell and monocyte function. This suppression was, however, significantly less marked following ICS. ICS presented an improved immune competence. This assessment of immune competence through the study of intracellular cytokine production, co-stimulatory and adhesion molecules expressed on dendritic cells and monocytes, and modulation of the overall leukocyte response may predict a reduction of adverse outcomes ( i.e., infection) following ICS.
ObjectivesThere is little evidence guiding the management of grade I–II traumatic splenic injuries with contrast blush (CB). We aimed to analyze the failure rate of nonoperative management (NOM) of ...grade I–II splenic injuries with CB in hemodynamically stable patients.MethodsA multicenter, retrospective cohort study examining all grade I–II splenic injuries with CB was performed at 21 institutions from January 1, 2014, to October 31, 2019. Patients >18 years old with grade I or II splenic injury due to blunt trauma with CB on CT were included. The primary outcome was the failure of NOM requiring angioembolization/operation. We determined the failure rate of NOM for grade I versus grade II splenic injuries. We then performed bivariate comparisons of patients who failed NOM with those who did not.ResultsA total of 145 patients were included. Median Injury Severity Score was 17. The combined rate of failure for grade I–II injuries was 20.0%. There was no statistical difference in failure of NOM between grade I and II injuries with CB (18.2% vs 21.1%, p>0.05). Patients who failed NOM had an increased median hospital length of stay (p=0.024) and increased need for blood transfusion (p=0.004) and massive transfusion (p=0.030). Five patients (3.4%) died and 96 (66.2%) were discharged home, with no differences between those who failed and those who did not fail NOM (both p>0.05).ConclusionNOM of grade I–II splenic injuries with CB fails in 20% of patients.Level of evidenceIV.
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