A Low Noise Sub-Sampling PLL in Which Divider Noise Is Eliminated and PD-CP Noise Is not multiplied by N^2

This paper presents a 2.2-GHz low jitter sub-sampling based PLL. It uses a phase-detector/charge-pump (PD/CP)that sub-samples the VCO output with the reference clock. In contrast to what happens in a classical PLL, the PD/CP noise is not multiplied by N2 in this sub-sampling PLL, resulting in a low noise contribution from the PD/CP. Moreover, no frequency divider is needed in the locked state and hence divider noise and power can be eliminated. An added frequency locked loop guarantees correct frequency locking without degenerating jitter performance when in lock. The PLL is implemented in a standard 0.18- m CMOS process. It consumes 4.2 mA from a 1.8 V supply and occupies an active area of 0.4 X 0.45 m

A 2.2GHz Sub-Sampling PLL with 0.16psrms Jitter and -125dBc/Hz In-band Phase Noise at 700μW Loop-Components Power

A divider-less PLL exploits a phase detector that directly samples the VCO with a reference clock. No VCO sampling buffer is used while dummy samplers keep the VCO spur <;-56dBc. A modified inverter with low short-circuit current acts as a power efficient reference clock buffer. The 2.2 GHz PLL in 0.18 μm CMOS achieves -125dBc/Hz in-band phase noise with only 700 μW loop-components power

Characterization of the immune response induced by non-pathogenic mycobacteria in macrophages and dendritic cells

The capacity of the host to mount an effective immune response (IR) is crucial for the protection against invading pathogens. The apoptotic and proinflammatory responses of infected cells are important innate immune mechanisms. Consequently, the ability of persistent intracellular pathogens, such as the human pathogen Mycobacterium tuberculosis (Mtb), to inhibit infection-induced apoptosis of macrophages is important for its virulence in the host. Facultative-pathogenic mycobacterial species, like M. kansasii (Mkan), can cause disseminating disease in individuals with immune deficiencies. In contrast, non-pathogenic mycobacteria, like M. smegmatis (Msme), are not known to cause disseminating disease even in immunocompromised individuals. We hypothesized that this difference in phenotype could be explained by the strong induction of an innate IR by non-pathogenic mycobacteria. Here we analyze the mechanisms by which non-pathogenic mycobacteria induce a strong IR in their macrophage and dendritic cell (DC) host, specifically the induction of host cell apoptosis and the host inflammasome response via the secretion of IL-1&#946;. The comparison of two non-pathogenic mycobacterial species (Msme and Mkan) with two facultative-pathogenic mycobacterial species (M.kan and M. bovis BCG) demonstrated that only the non-pathogenic mycobacteria induce strong apoptosis in murine bone marrow derived macrophages (BMDM) and dendritic cells (BMDC), which was dependent upon caspase-3 activation and TNF secretion. Consistently, BMDMs responded by secreting relatively large amounts of TNF and by upregulating the expression of Il-12. We also demonstrated that Msme infection of BMDCs strongly induces the secretion of IL-1&#946;. This induction was dependent upon the presence of functional ASC and was partially independent of NLRP3. Interestingly this induction was also partially dependent on AIM2 and IFN-&#946;. This AIM2-dpendent induction was observed in infection with non-pathogenic and opportunistic mycobacteria, and attenuated but not virulent Mtb. Surprisingly, caspase-1/11 deficient BMDCs still secreted substantial but reduced amounts of IL-1&#946; upon Msme infection. In conclusion, we demonstrate a strong induction of the innate IR by non-pathogenic mycobacteria as measured by host cell apoptosis, and IL-12 / TNF / IL-1&#946; cytokine induction. We also demonstrate the partially caspase-1/11 and NLRP3 -independent, partially AIM2-dependent, but ASC-dependent IL-1&#946; secretion in Msme infected BMDCs. Our findings support the hypothesis that the strong induction of the innate IR is a major reason for the lack of pathogenicity in non-pathogenic mycobacteria

Statin intensity and postoperative mortality following open repair of intact abdominal aortic aneurysm.

BackgroundThere is a lack of evidence for the association between intensive statin therapy and outcomes following vascular surgery. The aim of this study was to evaluate the association between perioperative statin intensity and in-hospital mortality following open abdominal aortic aneurysm (AAA) repair.MethodsPatients undergoing open AAA repair between 2009 and 2015 were identified from the Premier Healthcare Database. Statin use was classified into low, moderate and high intensity, based on American College of Cardiology/American Heart Association guidelines. Supratherapeutic intensity was defined as doses higher than the recommended guidelines. Multivariable logistic regression analyses were undertaken to assess the association between statin intensity and postoperative major adverse events and in-hospital mortality.ResultsOf 6497 patients undergoing open AAA repair, 3217 (49·5 per cent) received perioperative statin. Statin users were more likely to present with three or more co-morbidities than non-users (26·5 versus 21·8 per cent; P &lt; 0·001). Unadjusted postoperative mortality was significantly lower in statin users (2·6 versus 6·3 per cent; P &lt; 0·001); however, there was no difference in the risk of developing major adverse events. Multivariable analysis showed that statin use was associated with lower odds of death (odds ratio 0·41, 95 per cent c.i. 0·31 to 0·54). Moderate, high and supratherapeutic statin intensities were not associated with lower odds of death or major adverse events compared with low-intensity statin therapy.ConclusionStatin use is associated with lower odds of death in hospital following open AAA repair. High-intensity statins were not associated with lower morbidity or mortality

Spur-reduction techniques for PLLs using sub-sampling phase detection

A low-spur sub-sampling PLL exploits an amplitude-controlled charge pump which is immune to current source mismatch. A DLL/PLL dual-loop architecture and buffering reduces the disturbance of the sampler to the VCO. The 2.2GHz PLL in 0.18-μm CMOS achieves -121dBc/Hz in-band phase noise at 200kHz and consumes 3.8mW. The worst-case reference spur measured on 20 samples is -80dBc.\u

Spur Reduction Techniques for Phase-Locked Loops Exploiting A Sub-Sampling Phase Detector

This paper presents phase-locked loop (PLL) reference-spur reduction design techniques exploiting a sub-sampling phase detector (SSPD) (which is also referred to as a sampling phase detector). The VCO is sampled by the reference clock without using a frequency divider and an amplitude controlled charge pump is used which is inherently insensitive to mismatch. The main remaining source of the VCO reference spur is the periodic disturbance of the VCO by the sampling at the reference frequency. The underlying VCO sampling spur mechanisms are analyzed and their effect is minimized by using dummy samplers and isolation buffers. A duty-cycle-controlled reference buffer and delay-locked loop (DLL) tuning are proposed to further reduce the worst case spur level. To demonstrate the effectiveness of the\ud proposed spur reduction techniques, a 2.21 GHz PLL is designed and fabricated in 0.18 m CMOS technology. While using a high loop-bandwidth-to-reference-frequency ratio of 1/20, the reference spur measured from 20 chips is 80 dBc. The PLL consumes 3.8 mW while the in-band phase noise is 121 dBc/Hz at 200 kHz and the output jitter integrated from 10 kHz to 100 MHz is 0.3 ps rms

A Cadaveric Study Validating in vitro Monitoring Techniques to Measure the Failure Mechanism of Glenoid Implants against Clinical CT

Definite glenoid implant loosening is identifiable on radiographs, however, identifying early loosening still eludes clinicians. Methods to monitor glenoid loosening in vitro have not been validated to clinical imaging. This study investigates the correlation between in vitro measures and CT images. Ten cadaveric scapulae were implanted with a pegged glenoid implant and fatigue tested to failure. Each scapulae were cyclically loaded superiorly and CT scanned every 20,000 cycles until failure to monitor progressive radiolucent lines. The superior and inferior rim displacements were also measured. A finite element (FE) model of one scapula was used to analyse the interfacial stresses at the implant/cement and cement/bone. All ten implants failed inferiorly at the implant-cement interface, two also failed at the cement-bone interface inferiorly, and three showed superior failure. Failure occurred at of 80,966 ± 53,729 (mean ± SD) cycles. CT scans confirmed failure of the fixation, and in most cases, was observed either before or with visual failure, indicating its capacity to detect loosening earlier for earlier intervention if needed. Significant correlations were found between both increasing inferior rim displacement (ASTM standard F2028-14), increasing vertical head displacement and failure of the glenoid implant. The FE model showed peak tensile stresses inferiorly and high compressive stresses superiorly, corroborating experimental findings. Similar failure modes have been cited in clinical and in vitro studies. In vitro monitoring methods correlated to failure progression in clinical CT images. Clinical Significance: The study highlights failure at the implant-cement interface and early signs of failure are identifiable in CT images

Failure mechanism of the all-polyethylene glenoid implant

Fixation failure of glenoid components is the main cause of unsuccessful total shoulder arthroplasties. The characteristics of these failures are still not well understood, hence, attempts at improving the implant fixation are somewhat blind and the failure rate remains high. This lack of understanding is largely due to the fundamental problem that direct observations of failure are impossible as the fixation is inherently embedded within the bone. Twenty custom made implants, reflecting various common fixation designs, and a specimen set-up was prepared to enable direct observation of failure when the specimens were exposed to cyclic superior loads during laboratory experiments. Finite element analyses of the laboratory tests were also carried out to explain the observed failure scenarios. All implants, irrespective of the particular fixation design, failed at the implant-cement interface and failure initiated at the inferior part of the component fixation. Finite element analyses indicated that this failure scenario was caused by a weak and brittle implant-cement interface and tensile stresses in the inferior region possibly worsened by a stress raiser effect at the inferior rim. The results of this study indicate that glenoid failure can be delayed or prevented by improving the implant/cement interface strength. Also any design features that reduce the geometrical stress raiser and the inferior tensile stresses in general should delay implant loosening

In vitro measurement of temperature changes during implantation of cemented glenoid components

Background and purpose It is unclear whether the increase in temperature during cement curing may cause osteonecrosis, leading to loosening of the glenoid component in shoulder arthroplasty. We therefore analyzed the temperature during implantation of cemented glenoid implants

Risk factors associated with intraoperative complications in primary shoulder arthroplasty

Background and purpose - Increasing numbers of shoulder arthroplasty are performed internationally. The predictors of intraoperative complications when implanting primary shoulder replacements are unknown. We determined the incidence of intraoperative complications during primary shoulder arthroplasty using the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man (NJR), and analyzed the associated risk factors for complications. Patients and methods - NJR data on primary shoulder arthroplasty were scrutinized for intraoperative complications. 2 analyses were performed: the first examined the incidence and predictors of any recorded complication; the second examined the incidence and predictors for intraoperative fractures specifically. Analysis of risk factors was performed using multivariable binary logistic regression modeling. Results - 12,559 primary shoulder arthroplasties were recorded, with an intraoperative complication rate of 2.5%, the majority being fractures (1.6% overall). The incidence of all complications was lower in men (RR vs. women =0.63 (95% CI 0.47-0.84)). Patients undergoing surgery for avascular necrosis (RR =2.3 (1.3-4.2)) or trauma sequelae (RR =1.6 (1.2-2.7)) had a higher risk of complications compared with OA. Patients undergoing a stemmed hemiarthroplasty (RR =1.8 (1.2-2.5)) and reverse shoulder arthroplasty (RR 1.6 (1.1-2.5)) had a higher risk of complications compared with total shoulder arthroplasty. The incidence of all complications was less in patients undergoing resurfacing arthroplasty (vs. total shoulder arthroplasty (RR 0.42 (0.24-0.73)) and when performing the superior approach (vs. deltopectoral (RR 0.56 (0.39-0.80)). Interpretation - This is the first study to use a national data set to examine risk factors for intraoperative complications during all types of primary shoulder arthroplasty, and identifies several previously unrecognized risk factors, such as surgical approach