Despite many investigations concerning the outcomes of affective organizational commitment (AC) in the workplace, very few studies so far have analyzed the long-term development of AC within ...individuals over time. Existing research either focused on individuals’ initial employment stage or was restricted to a specific organizational context. To provide supplemental evidence, we examined the development of AC over 6 years in a group of employees that had passed their initial year of employment. Results from a factorial-invariant latent change score model with 1004 individuals from different organizations in Korea indicated an overall increase of AC over time. To further explore why individuals differ in their growth patterns, we related intra-individual changes of AC to individuals’ income in two aspects: levels and changes. Cross-lagged regression models firstly revealed positive reciprocal relationships between AC level and income level, showing an individual accumulation of AC over time. Furthermore, the study showed a significantly positive impact of income changes on AC changes, but not vice versa, illustrating the transition of AC at the individual level. Theoretical and practical implications of these findings are discussed, revealing future research on the development of commitment.
Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) ...cholesterol levels with infrequent dosing.
We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540.
A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval CI, 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent.
Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).
Oxymetazoline 0.1% is a novel ophthalmic agent for the treatment of acquired blepharoptosis in adults that has been shown to improve upper eyelid elevation and superior visual field deficits. This ...analysis characterized the rapid onset of upper eyelid elevation with once-daily oxymetazoline 0.1% and durability of this effect over 42 days.
Pooling data from two prospective, randomized, placebo-controlled, phase 3 studies, change in marginal reflex distance 1 (MRD-1) was evaluated at a range of post-instillation time points on treatment days 1, 14, and 42. Onset of effect was assessed beginning at 5 minutes post-administration (one study) and through 6 hours at the first two visits (both studies). Overall, 203 subjects received oxymetazoline 0.1% and 101 received vehicle.
Oxymetazoline 0.1% demonstrated a rapid onset of action on all days evaluated. Mean changes from baseline 5 and 15 minutes post-oxymetazoline 0.1% instillation on day 1 were 0.59 ± 0.72 mm and 0.93 ± 0.81 mm, respectively (vs 0.20 ± 0.57 mm and 0.32 ± 0.64 mm with vehicle; both p<0.001). On day 14, mean changes from baseline 5 and 15 minutes post-oxymetazoline 0.1% instillation were 0.77 ± 0.85 mm and 1.11 ± 0.92 mm, respectively (vs 0.42 ± 0.78 mm and 0.41 ± 0.83 mm with vehicle; both p<0.05). This effect was also observed immediately post-instillation on day 42, where mean increases 5 and 15 minutes post-oxymetazoline 0.1% instillation were 0.86 ± 0.85 mm and 1.04 ± 0.91 mm, respectively (vs 0.42 ± 0.80 mm and 0.47 ± 0.93 mm with vehicle; both p<0.005). Significant improvements vs vehicle (p<0.001) were also observed at 2-6 hours on days 1 and 14. At all time points, the proportion of subjects showing a positive response to treatment (>0% MRD-1 increase) was >15% greater in the oxymetazoline 0.1% group (range 16.6-36.1% more responders vs vehicle), with the largest differences observed 2 and 6 hours post-instillation.
Oxymetazoline 0.1% provided rapid and sustained upper eyelid elevation. Together with data demonstrating superior visual field improvement and a favorable safety profile, this analysis supports oxymetazoline 0.1% as an effective non-surgical treatment for acquired ptosis.
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•NGM282 is a first-in-class, engineered analogue of the gut hormone FGF19.•NGM282 therapy is associated with an elevation of blood cholesterol in patients with NASH.•Co-administration ...of rosuvastatin significantly reduces LDL-C, LDL particles, triglycerides and VLDL particles.•Co-administration of rosuvastatin results in increases in HDL-C and HDL particles.
NGM282, an engineered analogue of the gut hormone FGF19, improves hepatic steatosis and fibrosis biomarkers in patients with non-alcoholic steatohepatitis (NASH). However, NGM282 increases serum cholesterol levels by inhibiting CYP7A1, which encodes the rate-limiting enzyme in the conversion of cholesterol to bile acids. Herein, we investigate whether administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282.
In this phase II, open-label, multicenter study, patients with biopsy-confirmed NASH were treated with subcutaneous NGM282 once daily for 12 weeks. After 2 weeks, rosuvastatin was added in stepwise, biweekly incremental doses to a maximum of 40 mg daily. Both drugs were continued until the end of treatment at week 12. We evaluated plasma lipids, lipoprotein particles and liver fat content.
In 66 patients who received NGM282 0.3 mg (n = 23), NGM282 1 mg (n = 21), or NGM282 3 mg (n = 22), circulating cholesterol increased from baseline at week 2. Initiation of rosuvastatin resulted in rapid decline in plasma levels of total cholesterol and low-density lipoprotein cholesterol. At week 12, reductions from baseline in total cholesterol levels of up to 18% (p <0.001), low-density lipoprotein cholesterol of up to 28% (p <0.001), triglycerides of up to 34% (p <0.001) and an increase in high-density lipoprotein cholesterol of up to 16% (p <0.001), with similar changes in lipoprotein particles, were observed in these patients. Robust decreases from baseline in 7alpha-hydroxy-4-cholesten-3-one (p <0.001) and liver fat content (p <0.001) were also observed. Rosuvastatin was safe and well-tolerated when co-administered with NGM282 in patients with NASH.
In this multicenter study, NGM282-associated elevation of cholesterol was effectively managed with rosuvastatin. Co-administration of rosuvastatin with NGM282 may be a reasonable strategy to optimize the cardiovascular risk profile in patients with NASH.
Non-alcoholic steatohepatitis (NASH) represents a large and growing public health concern with no approved therapy. NGM282, an engineered analogue of the gut hormone FGF19, reduces liver fat, liver injury and inflammation in patients with NASH. However, NGM282 increases cholesterol levels. Here we show that co-administration of a statin can manage the cholesterol increase seen in patients with NASH receiving treatment with NGM282, producing a favorable overall lipid profile.
Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are common forms of dementia in the elderly. The neuropathology of AD and DLB is related to cholinergic dysfunctions, and both α4 and α7 ...nicotinic acetylcholine receptor (nAChR) subunits are decreased in several brain areas in both diseases. In this immunohistochemical study, we compared neuronal and astroglial α4 and α7 subunits in AD, DLB and age-matched controls in the hippocampal formation. The numbers of α4 reactive neurons were decreased in layer 3 of the entorhinal cortex of AD and DLB, whereas those of α7 reactive neurons were decreased in layer 2 of the subiculum of AD and DLB and in layer 3 of the entorhinal cortex of DLB. In contrast, the intensity of α7 reactive neuropil was significantly higher in AD than in controls or DLB in a number of areas of the hippocampus (CA3/4 and stratum granulosum), subiculum and entorhinal cortex. An increase in α7 immunoreactivity in AD was also associated with astrocytes. The number of astrocytes double-labelled with α7 and glial fibrillary acidic protein (GFAP) antibodies was increased in most areas of the hippocampus and entorhinal cortex in AD compared with controls and DLB. Increased astrocyte α7 nAChRs in AD may be associated with inflammatory mechanisms related to degenerative processes specific to this disease.
Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel superfamily composed of α and β subunits with specific structural, functional and pharmacological properties. In ...this study we have used immunohistochemistry to investigate the presence of nicotinic acetylcholine receptor subunits in human cerebellum. Tissue was obtained at autopsy from eight adult individuals (aged 36–56 years). Histological sections were prepared from formalin-fixed paraffin-embedded material. α3, α4, α6, α7, β2, and β4 subunits were present in this brain area associated with both neuronal and non-neuronal cell types. Most Purkinje cells were immunoreactive for all the above subunits, but most strongly for α4 and α7. A proportion of granule cell somata were immunoreactive for all subunits except α3. Punctate immunoreactivity in Purkinje cell and granule cell layers was evident with antibodies against α3, α4, α6, and α7 in parallel with synaptophysin immunoreactivity, suggesting the presence of these subunits on nerve terminals in the human cerebellum. All subunits were present in the dentate nucleus associated with neurones and cell processes. Strong immunoreactivity of neuropil in both the molecular and granule cell layers and within the dentate nucleus was noted with α4, α7 and β4 subunits. Astrocytes and astrocytic cell processes appeared to be immunoreactive for α7 and cell processes observed in white matter, also possibly astrocytic, were immunoreactive for β2. Immunoreactivity to all subunits was noted in association with blood vessels.
We suggest that nicotinic acetylcholine receptor subunits may be involved in the modulation of cerebellar activity. Further investigations are warranted to evaluate the participation of nicotinic acetylcholine receptors in cerebellar pathology associated with both developmental and age-related disorders.
Selecting provincial leaders is a fraught task for authoritarian regimes. Although central authorities more readily trust provincial leaders with close ties to the center, such loyalists may lack the ...local knowledge and connections necessary to govern adeptly. Using an original data set on the tenures and backgrounds of China’s provincial party standing committee members, this article explores how Beijing fine-tunes provincial leadership teams to resolve this dilemma. The analysis challenges the conventional wisdom that Beijing exerts its tightest personnel control in strategically important provinces. It shows that Beijing tolerates significant embeddedness of local leadership in provinces with complex governance challenges even when these provinces are important. Moreover, it finds that when the center reasserts control through appointments of loyalist personnel during times of crisis, it does so in a balanced manner. These calibrated personnel strategies highlight the extent to which authoritarian systems rely on local expertise and experience as well as top-down control.
The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in autopsy confirmed cases, ...and to determine pathological correlates of MTA in Alzheimer's disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI). We studied 46 individuals who had both antemortem MRI and an autopsy. Subjects were clinicopathologically classified as having Alzheimer's disease (n = 11), DLB (n = 23) or VCI (n = 12). MTA was rated visually using a standardized (Scheltens) scale blind to clinical or autopsy diagnosis. Neuropathological analysis included Braak staging as well as quantitative analysis of plaques, tangles and α-synuclein Lewy body-associated pathology in the hippocampus. Correlations between MTA and pathological measures were carried out using Spearman's rho, linear regression to assess the contributions of local pathologic changes to MTA. Receiver operator curve analysis was used to assess the diagnostic specificity of MTA for Alzheimer's disease among individuals with Alzheimer's disease, DLB and VCI. MTA was a highly accurate diagnostic marker for autopsy confirmed Alzheimer's disease (sensitivity of 91% and specificity of 94%) compared with DLB and VCI. Across the entire sample, correlations were observed between MTA and Braak stage (ρ = 0.50, P < 0.001), per cent area of plaques in the hippocampus (ρ = 0.37, P = 0.014) and per cent area of tangles in the hippocampus (ρ = 0.49, P = 0.001). Linear regression showed Braak stage (P = 0.022) to be a significant predictor of MTA but not percent area of plaques (P = 0.375), percent area of tangles (P = 0.330) or percent area of Lewy bodies (P = 0.086). MTA on MRI had robust discriminatory power for distinguishing Alzheimer's disease from DLB and VCI in pathologically confirmed cases. Pathologically, it is more strongly related to tangle rather than plaque or Lewy body pathology in the temporal lobe. It may have utility as a means for stratifying samples in vivo on the basis of putative differences in pathology.
Three new bioactive silver(I) coordination polymers formulated as Ag2(μ2-PTA)(μ3-PTA)(μ2-pga)(H2O)n·6H2O (1), Ag2(μ2-PTA)(μ3-PTA)(Hpmal)2n·2H2O (2), and Ag(μ3-PTA) (Hdmga)n (3) were self-assembled ...from Ag2O, 1,3,5-triaza-7-phosphaadamantane (PTA), and a substituted dicarboxylic acid (3-phenylglutaric acid (H2pga), phenylmalonic acid (H2pmal), or 3,3-dimethylglutaric acid (H2dmga)) as an ancillary ligand. Compounds 1-3 were fully characterized by IR and NMR spectroscopy, ESI-MS(±), elemental analysis, and single-crystal X-ray diffraction, revealing that their architectural and topological diversity is governed by structural modulation of a dicarboxylate building block. The structures vary from a 1D cyclic chain with the SP 1-periodic net (4,4)(0,2) topology in 2 to distinct 2D metal-organic layers with the cem-d and hcb topologies in 1 and 3, respectively. In addition, compounds 1-3 exhibit a notable antimicrobial efficiency against a panel of common Gram-negative (E. coli and P. aeruginosa) and Gram-positive (S. aureus) bacteria and yeast (C. albicans). The best normalized minimum inhibitory concentrations (normalized MIC) of 11-23 nmol mL(-1) (for bacterial strains) or 68 nmol mL(-1) (for a yeast strain) are shown by compound 2, and the eventual structure-bioactivity correlations are discussed.
Investigating correlates of tobacco smoking provides the only currently available opportunity of examining effects of long‐term exposure of nicotinic receptors on a specific nicotinic agonist in ...human. Alzheimer‐type pathology (Aβ and abnormally phosphorylated tau assessed on the basis of AT8 immunoreactivity) together with vascular markers has been compared in age‐matched groups of normal elderly smokers and non‐smokers in the entorhinal cortex, an area of noted age‐related pathology. The density of total Aβ and diffuse Aβ immunoreactivity, together with formic acid‐extractable Aβ42 but not Aβ40, was reduced in smokers (n = 10–18) compared with non‐smokers (n = 10–20) (P < 0.05). There was also a reduced percentage of cortical and leptomeningeal vessels with associated Aβ immunoreactivity in smokers (n = 13) compared with non‐smokers (n = 14) (P < 0.005 and 0.05, respectively). There was a significant inverse correlation between formic acid‐extractable Aβ42 and pack years (n = 34, r = −0.389, P = 0.025), with a similar trend for total Aβ immunoreactivity which did not reach statistical significance (n = 30, r = −0.323, P = 0.082). In contrast, there were no significant group differences for vascular markers (collagen IV, α‐actin or glucose transporter 1), AT8 immunoreactivity or phosphate‐buffered saline‐soluble Aβ peptides, and no significant associations with gender for any of the measured parameters. These findings are consistent with previously reported reductions in histologically assessed amyloid plaques in aged human brain associated with tobacco use and dramatic lessening of Aβ deposits in APPsw mice after nicotine treatment. Development of nicotinic drugs to protect against β‐amyloidosis as one of the principal pathological hallmarks of brain ageing and Alzheimer's disease is indicated.
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