Sex-Specific Effects of Blood Pressure Lowering Pharmacotherapy for the Prevention of Cardiovascular Disease: An Individual Participant-Level Data Meta-Analysis.

BACKGROUND: Whether the relative effects of blood pressure (BP)-lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain. METHODS: We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data. RESULTS: We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89-0.95] for women and 0.90 [0.88-0.93] for men; P for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all P for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all P for interaction, ≥0.14). CONCLUSIONS: The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment

Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis

Background: The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods: We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from <120 to ≥170 mm Hg). The primary outcome was a major cardiovascular event (defined as a composite of fatal and non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring admission to hospital), analysed as per intention to treat. Findings: Data for 344 716 participants from 48 randomised clinical trials were available for this analysis. Pre-randomisation mean systolic/diastolic blood pressures were 146/84 mm Hg in participants with previous cardiovascular disease (n=157 728) and 157/89 mm Hg in participants without previous cardiovascular disease (n=186 988). There was substantial spread in participants' blood pressure at baseline, with 31 239 (19·8%) of participants with previous cardiovascular disease and 14 928 (8·0%) of individuals without previous cardiovascular disease having a systolic blood pressure of less than 130 mm Hg. The relative effects of blood pressure-lowering treatment were proportional to the intensity of systolic blood pressure reduction. After a median 4·15 years' follow-up (Q1–Q3 2·97–4·96), 42 324 participants (12·3%) had at least one major cardiovascular event. In participants without previous cardiovascular disease at baseline, the incidence rate for developing a major cardiovascular event per 1000 person-years was 31·9 (95% CI 31·3–32·5) in the comparator group and 25·9 (25·4–26·4) in the intervention group. In participants with previous cardiovascular disease at baseline, the corresponding rates were 39·7 (95% CI 39·0–40·5) and 36·0 (95% CI 35·3–36·7), in the comparator and intervention groups, respectively. Hazard ratios (HR) associated with a reduction of systolic blood pressure by 5 mm Hg for a major cardiovascular event were 0·91, 95% CI 0·89–0·94 for partipants without previous cardiovascular disease and 0·89, 0·86–0·92, for those with previous cardiovascular disease. In stratified analyses, there was no reliable evidence of heterogeneity of treatment effects on major cardiovascular events by baseline cardiovascular disease status or systolic blood pressure categories. Interpretation: In this large-scale analysis of randomised trials, a 5 mm Hg reduction of systolic blood pressure reduced the risk of major cardiovascular events by about 10%, irrespective of previous diagnoses of cardiovascular disease, and even at normal or high–normal blood pressure values. These findings suggest that a fixed degree of pharmacological blood pressure lowering is similarly effective for primary and secondary prevention of major cardiovascular disease, even at blood pressure levels currently not considered for treatment. Physicians communicating the indication for blood pressure lowering treatment to their patients should emphasise its importance on reducing cardiovascular risk rather than focusing on blood pressure reduction itself. Funding: British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

Background: Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. Approach: An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. Content: In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A$_{1c}$ (HbA$_{1c}$) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA$_{1c}$. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. Summary: The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended

Investigating the stratified efficacy and safety of pharmacological blood pressure-lowering: an overall protocol for individual patient-level data meta-analyses of over 300 000 randomised participants in the new phase of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC)

Introduction Previous research from the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) and others has shown that pharmacological blood pressure (BP)- lowering substantially reduces the risk of major cardiovascular events, including ischaemic heart disease, heart failure and stroke. In this new phase, the aim is to conduct individual patient-level data (IPD) meta-analyses involving eligible BP-lowering randomised controlled trials (RCTs) to address uncertainties relating to efficacy and safety of BP-lowering treatment. Methods and analysis RCTs investigating the effect of pharmacological BP-lowering, with a minimum of 1000 patient-years of follow-up in each trial arm, are eligible. Our systematic review identified 100 potentially eligible trials. We requested their investigators/sponsors to contribute baseline, follow-up and outcomes data. As of June 2018, the collaboration has obtained data from 49 trials (n=315 046 participants), with additional data currently in the process of being transferred from four RCTs (n=34 642 participants). In addition, data harmonisation has commenced. Scientific activities of the collaboration are overseen by the Steering Committee with input from all collaborators. Detailed protocols for individual meta-analyses will be developed and registered on public platforms. Ethics and dissemination Ethics approval has been obtained for this new and extended phase of the BPLTTC, the largest collaboration of de-identified IPD from RCTs. It offers an efficient and ethical manner of re-purposing existing data to answer clinically important questions relating to BP treatment as well as methodological questions relating to IPD meta-analyses. Among the immediate impacts will include reliable quantification of effects of treatment modifiers, such as baseline BP, age and prior disease, on both vascular and non-vascular outcomes. Analyses will further assess the impact of BP-lowering on important, but less well understood, outcomes, such as new-onset diabetes and renal disease. Findings will be published in peer-reviewed medical journals on behalf of the collaboration

Extramission, Attribution, and the Speed of the Implicit Gaze Beam

The human brain devotes a notable amount of effort to process the gaze of other social agents as it is a fundamental aspect of social interactions and the prediction of other’s behavior. Eyes have been regarded as the “window into the soul” and have been associated with an ancient theory of vision, called extramission, whereby an invisible substance emanating from eyes interacts with objects before returning to the eyes spawning vision. Recent research has shown that the brain may implicitly and automatically model a social agent’s attention in a physically inaccurate representation as if it were emanating from the agent’s eyes and flowing through space towards an attended object while additionally shown to enact a pushing effect which biases the perceived weight of that object. This thesis will review the known mechanisms by which eye directed social attention is facilitated and will analyze the attention given to eyes from a historical and evolutionary perspective in addition to elucidating properties of the attribution and speed of the implicit gaze beam model of social attention. In Chapter 1, I review social attention and indicate the vital importance that eyes and eye gaze have on the communicative nature of humans before explaining the known neural mechanisms of eye gaze processing, followed by a review of the vast quantity of information that humans attribute to eyesight – including notions of the evil eye and theory of mind – before providing a historical review of the pervasive belief in extramission and its implications on social attention. In Chapter 2 – I describe two novel experiments performed using a tube-tilt paradigm where participants rate the angle at which a tube will topple over to determine that humans may model the mind of a group distinctly from that of an individual. In Chapter 3, I describe four novel experiments performed using a dot-motion paradigm where the effects of motion adaptation generated by facial stimuli reveal that humans likely model the minds of non-human species in a manner very similar to that of humans in addition to the determination that the speed at which the implicit gaze beam propagates is approximately 1.4 visual degrees per second. In Chapter 4, I will conclude this thesis and provide ideas for further experimentation to further elucidate the unknown properties of the implicit gaze beam model of social attention

Extramission, Attribution, and the Speed of the Implicit Gaze Beam

The human brain devotes a notable amount of effort to process the gaze of other social agents as it is a fundamental aspect of social interactions and the prediction of other’s behavior. Eyes have been regarded as the “window into the soul” and have been associated with an ancient theory of vision, called extramission, whereby an invisible substance emanating from eyes interacts with objects before returning to the eyes spawning vision. Recent research has shown that the brain may implicitly and automatically model a social agent’s attention in a physically inaccurate representation as if it were emanating from the agent’s eyes and flowing through space towards an attended object while additionally shown to enact a pushing effect which biases the perceived weight of that object. This thesis will review the known mechanisms by which eye directed social attention is facilitated and will analyze the attention given to eyes from a historical and evolutionary perspective in addition to elucidating properties of the attribution and speed of the implicit gaze beam model of social attention. In Chapter 1, I review social attention and indicate the vital importance that eyes and eye gaze have on the communicative nature of humans before explaining the known neural mechanisms of eye gaze processing, followed by a review of the vast quantity of information that humans attribute to eyesight – including notions of the evil eye and theory of mind – before providing a historical review of the pervasive belief in extramission and its implications on social attention. In Chapter 2 – I describe two novel experiments performed using a tube-tilt paradigm where participants rate the angle at which a tube will topple over to determine that humans may model the mind of a group distinctly from that of an individual. In Chapter 3, I describe four novel experiments performed using a dot-motion paradigm where the effects of motion adaptation generated by facial stimuli reveal that humans likely model the minds of non-human species in a manner very similar to that of humans in addition to the determination that the speed at which the implicit gaze beam propagates is approximately 1.4 visual degrees per second. In Chapter 4, I will conclude this thesis and provide ideas for further experimentation to further elucidate the unknown properties of the implicit gaze beam model of social attention

Extramission, Attribution, and the Speed of the Implicit Gaze Beam

The human brain devotes a notable amount of effort to process the gaze of other social agents as it is a fundamental aspect of social interactions and the prediction of other’s behavior. Eyes have been regarded as the “window into the soul” and have been associated with an ancient theory of vision, called extramission, whereby an invisible substance emanating from eyes interacts with objects before returning to the eyes spawning vision. Recent research has shown that the brain may implicitly and automatically model a social agent’s attention in a physically inaccurate representation as if it were emanating from the agent’s eyes and flowing through space towards an attended object while additionally shown to enact a pushing effect which biases the perceived weight of that object. This thesis will review the known mechanisms by which eye directed social attention is facilitated and will analyze the attention given to eyes from a historical and evolutionary perspective in addition to elucidating properties of the attribution and speed of the implicit gaze beam model of social attention. In Chapter 1, I review social attention and indicate the vital importance that eyes and eye gaze have on the communicative nature of humans before explaining the known neural mechanisms of eye gaze processing, followed by a review of the vast quantity of information that humans attribute to eyesight – including notions of the evil eye and theory of mind – before providing a historical review of the pervasive belief in extramission and its implications on social attention. In Chapter 2 – I describe two novel experiments performed using a tube-tilt paradigm where participants rate the angle at which a tube will topple over to determine that humans may model the mind of a group distinctly from that of an individual. In Chapter 3, I describe four novel experiments performed using a dot-motion paradigm where the effects of motion adaptation generated by facial stimuli reveal that humans likely model the minds of non-human species in a manner very similar to that of humans in addition to the determination that the speed at which the implicit gaze beam propagates is approximately 1.4 visual degrees per second. In Chapter 4, I will conclude this thesis and provide ideas for further experimentation to further elucidate the unknown properties of the implicit gaze beam model of social attention

Altered Sox9 and FGF signaling gene expression in Aga2 OI mice negatively affects linear growth.

Osteogenesis imperfecta (OI), or brittle bone disease, is a disorder characterized by bone fragility and increased fracture incidence. All forms of OI also feature short stature, implying an effect on endochondral ossification. Using the Aga2+/- mouse, which has a mutation in type I collagen, we show an affected growth plate primarily due to a shortened proliferative zone. We used single-cell RNA-Seq analysis of tibial and femoral growth plate tissues to understand transcriptional consequences on growth plate cell types. We show that perichondrial cells, which express abundant type I procollagen, and growth plate chondrocytes, which were found to express low amounts of type I procollagen, had ER stress and dysregulation of the same unfolded protein response pathway as previously demonstrated in osteoblasts. Aga2+/- proliferating chondrocytes showed increased FGF and MAPK signaling, findings consistent with accelerated differentiation. There was also increased Sox9 expression throughout the growth plate, which is expected to accelerate early chondrocyte differentiation but reduce late hypertrophic differentiation. These data reveal that mutant type I collagen expression in OI has an impact on the cartilage growth plate. These effects on endochondral ossification indicate that OI is a biologically complex phenotype going beyond its known impacts on bone to negatively affect linear growth