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How Low Can I Go

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How Low Can I Go


The phrase "How low can you go" is not usually encountered in conversation; it's an allusion, a line in Chubby Checker's 1962 recording Limbo Rock. It refers to a challenge dance called the limbo which requires the dancers to pass under a progressively lower bar on their feet while leaning backward, so "How low can you go?" is the literal challenge.

In Ludacris' 2009 recording How Low that surface meaning of the phrase shows up at a couple of points in the video, where one or more of the girls are actually performing limbo moves; but in the context of the song it's wrapped in several layers of double-entendre, such as low meaning 'vulgar', get down (and dirty) meaning 'participate enthusiastically in pleasurable or erotic activity', go down (on) meaning 'perform oral sex (on)', and doubtless more that I've missed.

"How Low" was officially released as the lead single from Ludacris' Battle of the Sexes album on December 8, 2009. Prior to the single's release, Ludacris performed the song live on October 10, 2009 at the BET Hip Hop Awards in Atlanta, Georgia. The track samples Public Enemy's "Bring the Noise" as the primary vocals in the chorus, additional vocals by Carla Henderson.

The video begins with three girls in a bedroom for a sleepover. They begin by talking directly into a camcorder, in which they reveal that there is a rumor that if you "go low" enough in front of a mirror, Ludacris will appear. They begin dancing to the song in front of a mirror, and Ludacris' face appears in the reflection and starts rapping. The girls are visibly excited at the sight and continue dancing. The video progresses with shots of Ludacris in a club with a black light. Back in the bedroom, Ludacris, backup dancers and masked men burst out of the mirror and into the room. The girls, scared, run downstairs and into another room to hide. Ludacris and his dancers come down the stairs and eventually find the girls. Ludacris magically tears off the girls' clothing and changes them into erotic dancers. More people begin to appear and throw a party in the house as all of the girls dance. The video then changes over to different girls, changing in a locker room. Similarly to the original girls, the girls in the locker room also state the rumor and decide to test it by dancing low in front of the mirror in the same hopes of seeing Ludacris. The following scene shows Ludacris at the original party, rapping in front of the dancing girls outside of the house. However, because the girls in the locker room have started to "go low", Ludacris begins to fade, while giving off some type of electrostatic discharge. He then appears in the mirror inside the locker room and the whole concept of the video apparently restarts. The video features a cameo from Disturbing tha Peace artist Lil Fate.

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Compiled by Lance Ledbetter and Dick Spottswood, this three-CD box set, the first ever anthology of the upright bass, explores the earliest recorded history of the instrument. Without it, the revolutionary sound of American mongrel music of the last century would have been thin gruel indeed.

Universally, however, everyone digesting the first large clinical outcomes trial for a PCSK9 inhibitor had their eyes on a different set of numbers: the massive reduction in LDL cholesterol achieved with this new class of drug.

Not to be outdone, similar reductions in LDL cholesterol have also been observed with alirocumab (Praluent, Sanofi/Regeneron), although the clinical outcomes data is still not yet available. In pooled data from multiple clinical trials, researchers recently showed that among 3,440 patients treated with alirocumab, 25% achieved an LDL cholesterol level of less than 25 mg/dL and approximately 10% went lower than 15 mg/dL.

In the GLAGOV trial, an intravascular ultrasound study led by Nissen and Stephen Nicholls, MBBS (University of Adelaide, Australia), patients with coronary artery disease who received evolocumab for 18 months also had dramatic reductions in LDL cholesterol levels, down from 93 mg/dL at baseline to 36.6 mg/dL. Some patients, such as those who started with an LDL cholesterol less than 70 mg/dL, achieved on-treatment LDL cholesterol levels as low as 24 mg/dL.

Two years later, the FDA asked Sanofi/Regeneron to monitor for adverse neurocognitive events in their long-term phase III clinical trials testing alirocumab, including ODYSSEY Outcomes. The recommendation to monitor for cognitive changes emerged with a signal showing numerically higher number of cognitive adverse events among evolocumab- and alirocumab-treated patients in case series and different studies, including ODYSSEY Long-Term and OSLER, respectively.

Fueled by concerns and the potential for harm, Amgen sponsored the EBBINGHAUS trial, a substudy of FOURIER that included 1,204 patients who underwent baseline and follow-up cognitive testing. As reported by TCTMD, the EBBINGHAUS researchers observed no differences between evolocumab- and placebo-treated patients in terms of performance on a battery of neuropsychological tests, and they saw no impairment of memory and executive function among patients who achieved LDL cholesterol levels less than 25 mg/dL with evolocumab.

Alirocumab has also been scrutinized for neurocognitive side effects. In a pooled analysis of the 3,240 patients who received alirocumab as part of the ODYSSEY development program, PCSK9-inhibitor treatment did not increase the risk of neurocognitive adverse events, even among patients who achieved LDL targets of less than 15 mg/dL. The pooled analysis included 14 studies, ranging in duration from 8 to 104 weeks.

In addition to the neurocognitive concerns, there have been worries about the potential development of diabetes and cataracts with very low LDL cholesterol levels. Neither of these adverse effects, however, were observed in the FOURIER trial, with adjudicated cases similar between patients who received evolocumab or placebo.

Similarly, in the pooled Odyssey analysis evaluating alirocumab there was also no increased risk of new-onset diabetes, although the risk of cataracts was higher among patients who achieved LDL cholesterol levels less than 25 mg/dL compared with those with higher LDL levels (2.0% vs 0.6%; P = 0.0018).

Regarding the risk of cataracts with LDL lowering, Everett noted that the HOPE-3 study also showed a higher risk of cataract surgery amongst rosuvastatin-treated patients compared with placebo (3.8 vs 3.1%; P = 0.02).

Underberg said that the clinical question of importance is not whether patients should be treated to a specific low value, but rather when to intervene with a second agent, such as ezetimibe (Zetia, Merck/Schering-Plough) or a PCSK9 inhibitor, in someone already taking a statin. Some patients might be adequately controlled with an LDL cholesterol level around 70 mg/dL, while other secondary-prevention patients will continue to have events.

Figure 1. T2-weighted MR brain images acquired at 1.5 T in (A) 1986. Image reused, with permission, from Zimmerman et al. [8] and (B) 2009 (authors' database).

Figure 2. MRI images of the mouse acquired at 0.1 T using a FISP sequence and dedicated coils for the whole-body and tail. (Top) Whole body: field-of-view (FoV) of 110 mm and in plane resolution of 430 430 μm2. The acquisition time was 30 min for 30 slices of 1 mm thickness. (Bottom) Tail: field-of-view (FoV) of 6.4 mm and in plane resolution of 100 100 μm2. The acquisition time was 1 h 30 min for 26 slices of 750 μm thickness. Images modified, with permission, from Choquet et al. [9].

Figure 3. Summary of the current landscape of low-field MR imaging in phantoms. (A) Shows the major achievements obtained at ultra-low field (micro tesla range) in combination with SQUID detectors, and (B) the images obtained in the mT range (from 1 to 199 mT). MSR, magnetically shielded room; CMSB, compact magnetically shielded box; Bp, polarization field; NA, number of signal averaging. Images reused with permission from Cooley et al. [21], O'Reilly et al. [23], McDaniel et al. [24], Greer et al. [25], Lother et al. [28], Benli et al. [32], Ujihara et al. [33], Kawagoe et al. [48], Demachi et al. [49], Liu et al. [50], Hilschenz et al. [55]. Images reused from Galante et al. [56], held under Creative Commons License CC-BY 4.0.

Figure 4. Summary of the current landscape of low-field MR imaging in vivo. (A) Shows the major achievements obtained at ultra-low field (micro tesla range) in combination with SQUID detectors, and (B) the images obtained in the mT range (from 1 to 199 mT). MSR, magnetically shielded room; CMSB, compact magnetically shielded box; Bp, polarization field; NA, number of signal averaging. Images reused, with permission, from Espy et al. [38], Hömmen et al. [45], Oyama et al. [47], McDaniel et al. [58]. Images reused from Sarracanie et al. [29], held under Creative Common License CC-BY 4.0.

Figure 5. Relative T1 contrast in human brain samples as a function of Larmor frequency. The green dotted line shows that the relative contrast between gray and white matter is higher when operating between 10 mT and 1.5 T (shaded blue box) and decreases dramatically at very high to ultra-high field strengths (shaded red box). Modified, with permission, from Fischer et al. [78]. 350c69d7ab


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