Shift work is a risk factor for inflammation, hypertension, and cardiovascular disease. This increased risk cannot be fully explained by classical risk factors. Shift workers’ behavioral and ...environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in shift workers, independent of differences in work stress, food quality, and other factors that are likely to differ between night and day shifts. Thus, our objectives were to determine the independent effect of circadian misalignment on 24-h high-sensitivity C-reactive protein (hs-CRP; a marker of systemic inflammation) and blood pressure levels—cardiovascular disease risk factors—in chronic shift workers. Chronic shift workers undertook two 3-day laboratory protocols that simulated night work, comprising 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment), using a randomized, crossover design. Circadian misalignment increased 24-h hs-CRP by 11% (p < 0.0001). Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 1.4 mmHg and 0.8 mmHg, respectively (both p ≤ 0.038). The misalignment-mediated increase in 24-h SBP was primarily explained by an increase in SBP during the wake period (+1.7 mmHg; p = 0.017), whereas the misalignment-mediated increase in 24-h DBP was primarily explained by an increase in DBP during the sleep opportunity (+1.8 mmHg; p = 0.005). Circadian misalignment per se increases hs-CRP and blood pressure in shift workers. This may help explain the increased inflammation, hypertension, and cardiovascular disease risk in shift workers.
Porous MFM-202a (MFM = Manchester Framework Material, replacing the NOTT designation) shows an exceptionally high uptake of acetylene, 18.3 mmol g–1 (47.6 wt %) at 195 K and 1.0 bar, representing the ...highest value reported to date for a framework material. However, at 293 K and 10 bar C2H6 uptake (9.13 mmol g–1) is preferred. Dual-site Langmuir-Freundlich (DSLF)- and Numerical Integration (NI)-based IAST methods have been used to analyze selectivities for C1 to C3 hydrocarbons. MFM-202a exhibits broadly hysteretic desorption of acetylene; such behavior is important for practical gas storage since it allows the gas to be adsorbed at high pressure but stored at relatively low pressure. Stepwise uptake and hysteretic release were also observed for adsorption of other unsaturated light hydrocarbons (ethane and propene) in MFM-202a but not for saturated hydrocarbons (methane, ethane, and propane). MFM-202a has been studied by in situ synchrotron X-ray powder diffraction to reveal the possible phase transition of the framework host as a function of gas loading. A comprehensive analysis for the selectivities between these light hydrocarbons has been conducted using both IAST calculation and dual-component mixed-gas adsorption experiments, and excellent agreement between theory and experiment was achieved.
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•Device characterization of sub-micron thin NiTi SMA bimorph actuators created using standard MEMS processing in cleanroom.•New fabrication method greatly reduces heat capacity and ...radius of curvature for NiTi SMA bimorph actuators (from several mm’s down to 100 μm radius).•Miniaturized SMA devices can be actuated optically using green laser with as little as 2 W/cm2 in less than 30 ms.•Lower power, reversible actuation using nanoscale SMA thin films enables applications in passive sensing and actuation using optical sources and circumvents the need for any power sources (battery, capacitor), wiring, or circuitry.
NiTi SMA thermal bimorph actuators have potential as high-force, high-displacement MEMS actuators. Historically, even microscale SMA actuation response has been limited to a maximum of ˜100 Hz. As NiTi film and device dimensions are scaled down into the micro and nano scales, heat transfer, and thus device cycling speeds can be significantly improved upon. We have used an in-situ annealed nickel-titanium (NiTi) shape memory alloy (SMA) sputter deposition process to sputter equiatomic NiTi films at 600 °C. We characterized our thin film (270 nm NiTi – 1.6 μm NiTi) material and verified its reversible shape memory effects (SME) using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and wafer bow versus temperature measurements. Upon release, the NiTi material exhibited a reversible phase change around 60 °C with a hysteresis of ˜3 °C. For the substrate confined case (i.e. NiTi on Si or Pt), hysteresis was much larger (i.e. ˜40 °C) with the phase change completed at ˜80 °C. In addition to SMA material characterization, we fabricated NiTi/Pt bimorph actuators at several (100 nm to 1.2 μm) NiTi and Pt thicknesses. Free-standing bimorph actuators were produced via a dry etch release, and temperature dependent curvature of these cantilevers was investigated. To address the low power, and high response time aspects, we performed a dynamic characterization using a 440 mW, 532 nm “green” laser to irradiate devices from 2 to 24 W/cm2 while measuring actuation response times that varied from 3 ms at the highest irradiation fluxes to 240 ms at the lowest. Our results showed decreased actuation powers and faster heating or actuation times compared to past works with NiTi microactuators. The NiTi films with 600 nm thickness on top of 20 nm Pt films exhibited the greatest change in curvature from 200 μm to flat states, and actuated in under 3 ms due to the very small volume of SMA requiring to be heated. These results suggest that NiTi/Pt bimorphs have potential applications as lower-power, faster-response, laser-activated micro shutters or thermal switches without needing a traditional wired power source.
Objective
Diet‐induced thermogenesis (DIT) is lower in the evening and at night than in the morning. This may help explain why meal timing affects body weight regulation and why shift work is a risk ...factor for obesity. The separate effects of the endogenous circadian system—independent of behavioral cycles—and of circadian misalignment on DIT are unknown.
Methods
Thirteen healthy adults undertook a randomized crossover study with two 8‐day laboratory visits: three baseline days followed either by repeated simulated night shifts including 12‐h inverted behavioral cycles (circadian misalignment) or by recurring simulated day shifts (circadian alignment). DIT was determined for up to 114 min (hereafter referred to as “early DIT”) following identical meals given at 8AM and 8PM in both protocols.
Results
During baseline days, early DIT was 44% lower in the evening than morning. This was primarily explained by a circadian influence rather than any behavioral cycle effect; early DIT was 50% lower in the biological evening than biological morning, independent of behavioral cycle influences. Circadian misalignment had no overall effect on early DIT.
Conclusions
The circadian system plays a dominating role in the morning/evening difference in early DIT and may contribute to the effects of meal timing on body weight regulation.
To compare dosimetric endpoints between proton therapy (PT) and conventional radiation and determine the feasibility of PT for regional nodal irradiation (RNI) in women with breast cancer.
From 2012 ...to 2014, 18 women (stage IIA-IIIB) requiring RNI prospectively enrolled on a pilot study. Median age was 51.8 years (range, 42-73 years). The cohort included breast-conserving therapy (BCT) and mastectomy patients and right- and left-sided cancers. Treatment targets and organs at risk were delineated on computed tomography scans, and PT and conventional plans were developed. Toxicity was prospectively recorded using Common Terminology Criteria for Adverse Events version 4.0. A Wilcoxon signed-rank sum test compared the dose-volume parameters. The primary endpoint was a reduction in cardiac V5.
Median follow-up was 20 months (range, 2-31 months). For all patients, the PT plan better met the dosimetric goals and was used for treatment. Proton therapy alone was used for 10 patients (9 postmastectomy, 1 after BCT) and combined proton-photon in 8 (6 BCT, 2 postmastectomy with immediate expander reconstruction). Proton therapy improved coverage of level 2 axilla (P=.0005). Adequate coverage of internal mammary nodes was consistently achieved with PT (median D95, 50.3 Gy; range, 46.6-52.1 Gy) but not with conventional radiation therapy (median D95, 48.2 Gy; range, 40.8-55 Gy; P=.0005). Median cardiac V5 was 0.6% with PT and 16.3% with conventional radiation (P<.0001). Median ipsilateral lung V5 and V20 were improved with PT (median V5 35.3% vs 60.5% P<.0001; and median V20, 21.6% vs 35.5% P<.0001). Grade 3 dermatitis developed in 4 patients (22%), which was the only grade 3 toxicity. No grade 4+ toxicities developed.
Proton therapy for RNI after mastectomy or BCT significantly improves cardiac dose, especially for left-sided patients, and lung V5 and V20 in all patients without excessive acute toxicity. Proton therapy simultaneously improves target coverage for the internal mammary nodes and level 2 axilla, which may positively impact long-term survival in breast cancer patients.
Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB ...is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies.
To report clinical outcomes in patients treated with image guided proton therapy (PT) for localized prostate cancer.
The medical records of 1327 men were reviewed. Each man was enrolled on an ...outcomes tracking study. Dual enrollment on a prospective clinical trial was allowed. Each patient was treated for localized prostate cancer with PT at our institution between 2006 and 2010. Ninety-eight percent of patients received 78 Gy (radiobiological equivalent RBE) or higher; 18% received androgen deprivation therapy (ADT). The 5-year freedom from biochemical progression (FFBP), distant metastasis-free survival, and cause-specific survival rates are reported for each risk group. Data on patient-reported quality of life and high-grade toxicities were prospectively collected and reported. A multivariate analysis was performed to identify clinical predictors of biochemical failure and urologic toxicity.
The median follow-up time was 5.5 years. The 5-year FFBP rates were 99%, 94%, and 74% in low-risk, intermediate-risk, and high-risk patients, respectively. The actuarial 5-year rates of late grade 3+ Common Terminology Criteria for Adverse Events, version 4.0, gastrointestinal (GI) and genitourinary (GU) toxicity were 0.6% and 2.9%, respectively. Multivariate analysis showed a significant correlation between grade 3+ GU toxicity and pretreatment prostate reductive procedures (P<.0001), prostate volume (P=.0085), pretreatment α-blockers (P=.0067), diabetes (P=.0195), and dose–volume histogram parameters (P=.0208). The median International Prostate Symptom Scores pretreatment scores and scores at 5 years after treatment were 7 and 7, respectively. The mean Expanded Prostate Cancer Index Composite (EPIC) scores significantly declined for sexual summary for patients not receiving ADT (from 67 to 53) between baseline and 5 years.
Image guided PT provided excellent biochemical control rates for patients with localized prostate cancer. The actuarial rates of high-grade toxicity were low after PT. From pretreatment to 5 years of follow-up, a significant decline was found only in mean EPIC sexual summary scores. Prospective clinical studies are needed to determine the comparative effectiveness of PT and other radiation treatment strategies.
The discovery of molecules that bind tightly and selectively to desired proteins continues to drive innovation at the interface of chemistry and biology. This paper describes the binding of human ...insulin by the synthetic receptor cucurbit7uril (Q7) in vitro. Isothermal titration calorimetry and fluorescence spectroscopy experiments show that Q7 binds to insulin with an equilibrium association constant of 1.5 × 10(6) M(-1) and with 50-100-fold selectivity versus proteins that are much larger but lack an N-terminal aromatic residue, and with >1000-fold selectivity versus an insulin variant lacking the N-terminal phenylalanine (Phe) residue. The crystal structure of the Q7·insulin complex shows that binding occurs at the N-terminal Phe residue and that the N-terminus unfolds to enable binding. These findings suggest that site-selective recognition is based on the properties inherent to a protein terminus, including the unique chemical epitope presented by the terminal residue and the greater freedom of the terminus to unfold, like the end of a ball of string, to accommodate binding. Insulin recognition was predicted accurately from studies on short peptides and exemplifies an approach to protein recognition by targeting the terminus.
There is growing evidence for the role of systemic inflammation in Alzheimer's disease (AD) and other neurodegenerative diseases; however the systemic inflammatory profile in dementia with Lewy ...bodies (DLB) has never before been investigated. This study aimed to characterise systemic inflammatory mediators in established DLB and AD, as well as in their prodromal, mild cognitive impairment (MCI) phases.
We obtained plasma samples from patients with DLB (n=37), AD (n=20), MCI with DLB profile (n=38), MCI with AD profile (n=20) and healthy control subjects (n=20). The following inflammatory biomarkers were measured using Roche cobas c702 and Meso Scale Discovery V-Plex Plus: high-sensitivity C-reactive protein, interferon-gamma, interleukin (IL)-10, IL-12p70, IL-13, IL-1beta, IL-2, IL-4, IL-6, IL-8 and tumour necrosis factor-alpha.
We found significantly higher levels of IL-10, IL-1beta, IL-4 and IL-2 in both MCI groups (P<0.001), while there was no significant difference in inflammatory markers between dementia groups and controls. Furthermore, increased disease severity was associated with lower levels of IL-1beta, IL-2 and IL-4 (P<0.05).
We have shown for the first time that in both DLB and AD, increased peripheral inflammation occurs early at the MCI disease stages. These data support a role for inflammation early in the disease process, and have important implications for the stage of disease where trials of anti-inflammatory medication should be focused.
Shift work is associated with increased human operational errors, presumably due to the circadian timing system that inhibits optimal cognitive function during the night. Circadian misalignment, ...which is the misalignment between the circadian pacemaker and behavioral/environmental cycles, impairs cognitive performance in non-shift workers. However, it remains uncertain whether the adverse cognitive consequences of circadian misalignment are also observed in chronic shift workers. Thus, we investigated the effects of circadian misalignment on cognitive performance in chronic shift workers. Using a randomized, cross-over design that simulated day shift work (circadian alignment) and night shift work (circadian misalignment), we show that circadian misalignment increases cognitive vulnerability on sustained attention, information processing and visual-motor performance, particularly after more than 10 hours of scheduled wakefulness. Furthermore, their increased levels of subjective sleepiness and their decreased sleep efficiency were significantly associated with impaired sustained attention and visual-motor performance. Our data suggest that circadian misalignment dramatically deteriorates cognitive performance in chronic shift workers under circadian misalignment. This increased cognitive vulnerability may have important safety consequences, given the increasing number of nighttime jobs that crucially rely on the availability of cognitive resources.
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