People aged 85 and over are often excluded from research on the grounds of being difficult to recruit and problematic to retain. The Newcastle 85+ study successfully recruited a cohort of 854 ...85-year-olds to detailed health assessment at baseline and followed them up over 3 phases spanning 5 years. This paper describes the effectiveness of its retention strategies.
Primary retention strategies involved meticulous management of contact information and active maintenance of contact with participants between research visits and between phases of the study. For statistical analysis, data on post-inclusion attrition over the 3 follow-up phases was separated into 'death' and 'withdrawal' categories, with sub-categories 'health' and 'non-health' reasons created for 'withdrawal'. Multinomial logistic regression was used to determine if particular socio-demographic and health characteristics were associated with post-inclusion attrition due to withdrawal at each of the 3 phase-to-phase transition points.
For both sexes, at successive follow-up phases there was a decrease in attrition due to withdrawal and an increase due to death. Withdrawal was most prevalent between baseline and phase 2. Across the 5 years of the study total post-inclusion (post-baseline) attrition due to death accounted for a 40% (344/854) loss to cohort and total post-inclusion attrition due to withdraw a 19% (166/854) loss to cohort, with health reasons for withdrawal becoming more dominant over time. Adjusting for sex, parsimonious modelling showed only occupational class (National Statistics Socio-economic Classification) to be associated with withdrawal and only between baseline and phase 2 (routine/manual compared to managerial (OR 3.41; 95% CI 1.23 to 9.44).
Following successful recruitment, we retained a high proportion of participants from a very old age group over 5 years of longitudinal research. No strong predictors of post-inclusion attrition due to withdrawal were found, suggesting the general effectiveness of our retention strategies.
Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, ...cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4α expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4α resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4α1 and Hnf4α2, we showed that HNF4α2 is the main osseous Hnf4α isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4α2 prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.
In the present study, a model of antecedents and outcomes of ethical behavior in work organizations was developed and tested. Antecedents included are corporate ethical values, organizational ...justice, and organizational commitment. The outcome of organizational citizenship behaviors was also examined. Data were gathered from 489 members of a regional chapter of the National Association of Purchasing Managers (NAPM). Structural equation modeling was used to test the model. Results indicated the data fit the model well. Implications for managers and directions for future research are discussed.
AFN-1252 is a novel inhibitor of FabI, an essential enzyme in Staphylococcus spp. This study was undertaken to assess the safety, tolerability and pharmacokinetic properties of AFN-1252, following ...oral administration in an ascending dose trial.
This was a double-blind, randomized, placebo-controlled, two-part study. In Part I, single doses (QD) of 100, 200, 300, or 400 mg AFN-1252 were administered. In Part II, subjects received 200, 400, 600, or 800 mg (total daily dose) where 100, 200 and 400-mg doses were given twice in one day.
AFN-1252 was well-absorbed with Cmax at 3-4 h when given once per day and 2.5-9 h when dosed twice in a single dosing day. T½ ranged from 8 to 11 h. Total and peak exposures of AFN-1252 increased nonlinearly. Adverse events were primarily mild and resolved promptly.
Oral doses of AFN-1252 were safe and well tolerated. AFN-1252 has the potential for once or twice-a-day dosing for treatment of staphylococcal infections.
Background The superior cavo-pulmonary connection was introduced at our institution in 1988 for infants undergoing surgery for hypoplastic left heart syndrome. Patients with hypoplastic left heart ...syndrome remain at high risk for mortality in the time period between the Norwood procedure and the superior cavo-pulmonary connection. The primary objectives of this study were to compare interstage mortality across 4 eras and analyze factors that may impact interstage mortality. Methods and Results Patients with hypoplastic left heart syndrome who underwent the Norwood procedure, were discharged from the hospital, and were eligible for superior cavo-pulmonary connection between January 1, 1988, and December 31, 2017, were included. The study period was divided into 4 eras based on changes in operative or medical management. Mortality rates were estimated with 95% CIs. Adjusted and unadjusted logistic regression models were used to identify risk factors for mortality. There were 1111 patients who met the inclusion criteria. Overall, interstage mortality was 120/1111 (10.8%). Interstage mortality was significantly lower in era 4 relative to era 1 (4.6% versus 13.4%;
=0.02) during the time that age at the superior cavo-pulmonary connection was the lowest (135 days;
<0.01) and the interstage monitoring program was introduced. In addition, use of the right ventricle to pulmonary artery shunt was associated with decreased interstage mortality (
=0.02) and was more routinely practiced in era 4. Conclusions During this 30-year experience, the risk of interstage mortality decreased significantly in the most recent era. Factors that coincide with this finding include younger age at superior cavo-pulmonary connection, introduction of an interstage monitoring program, and increased use of the right ventricle to pulmonary artery shunt.
For neuropathic pain, current therapies do not provide relief for most patients; less than half achieve a 50% pain reduction. Current analgesics have adverse effects. We present 2 Phase I studies of ...LX9211, a new small-molecule AP2-associated kinase 1 inhibitor with preclinical effectiveness in pain relief.
Both randomized, placebo-controlled studies’ primary objectives evaluated the tolerability and pharmacokinetic properties of oral LX9211. In the single-ascending dose (SAD) study, single, oral, liquid doses of 5, 10, 15, 20, 30, 40, 80, 120, 160, 200, and 300 mg of LX9211 or placebo were administered in the fasted state and 40 mg in a fed group. In the multiple-ascending dose (MAD) study, a loading dose was administered on day 1 and maintenance doses were administered daily on days 2 to 14. The treatment groups were designated as: 25/2.5, 50/5.0, 100/10, 150/15, and 200/20 mg. The secondary objectives included ECG evaluation.
The SAD study enrolled 96 participants 19 to 61 years of age (86.5% male) in 12 cohorts (2:6 placebo:LX9211), and the MAD study enrolled 50 participants 20 to 63 years of age (78% male) in 5 cohorts (2:8 placebo:LX9211). Both studies had a good LX9211 safety profile. No deaths or serious adverse events occurred. All treatment-emergent adverse events (TEAEs) were mild, except for moderate nausea and vomiting reported in 1 participant in the SAD 300-mg cohort. All TEAEs were considered recovered or resolved, except for blurred vision (n = 1 in the SAD 300-mg group), which was ongoing at the last visit. One participant in the MAD study (50/5 mg group) discontinued participation in the study early because of TEAEs (angioedema, dermatitis allergic, and urticaria). Headache, dizziness, constipation, and nausea were the most common TEAEs. In the SAD study, 4 participants in the 200-mg cohort developed headache approximately 24 hours after dosing, lasting 24 to 48 hours. Only 1 required treatment (acetaminophen). No notable ECG changes from baseline were found in either study. After both single- and multiple-dose administration, plasma exposure of LX9211 was approximately dose proportional. Steady-state LX9211 plasma concentrations were rapidly attained and maintained by a dosing regimen of a loading dose, followed by daily maintenance doses (1/10 the loading dose). No accumulation was as seen after multiple dosing.
These studies found that LX9211 was safe and well tolerated in healthy participants. These findings suggest it is appropriate to take LX9211 forward into Phase II studies of patients with diabetic peripheral neuropathic pain and postherpetic neuralgia. LX9211 has received fast track designation by the US Food and Drug Administration.
We investigated the incidence and predictors of failure to undergo the Fontan in children with hypoplastic left heart syndrome who survived superior cavopulmonary connection.
The cohort consists of ...all patients with hypoplastic left heart syndrome who survived to hospital discharge after superior cavopulmonary connection between 1988 and 2017. The primary outcome was attrition, which was defined as death, nonsuitability for the Fontan, or cardiac transplantation before the Fontan. Subjects were excluded if they were awaiting the Fontan, were lost to follow-up, or underwent biventricular repair. The study period was divided into 4 eras based on changes in operative or medical management. Attrition was estimated with 95% confidence intervals, and predictors were identified using adjusted, logistic regression models.
Of the 856 hospital survivors after superior cavopulmonary connection, 52 died, 7 were deemed unsuitable for Fontan, and 12 underwent or were awaiting heart transplant. Overall attrition was 8.3% (71/856). Attrition rate did not change significantly across eras. A best-fitting multiple logistic regression model was used, adjusting for superior cavopulmonary connection year and other influential covariates: right ventricle to pulmonary artery shunt at Norwood (P < .01), total support time at superior cavopulmonary connection (P < .01), atrioventricular valve reconstruction at superior cavopulmonary connection (P = .02), performance of other procedures at superior cavopulmonary connection (P = .01), and length of stay after superior cavopulmonary connection (P < .01).
In this study spanning more than 3 decades, 8.3% of children with hypoplastic left heart syndrome failed to undergo the Fontan after superior cavopulmonary connection. This attrition rate has not decreased over 30 years. Use of a right ventricle to pulmonary artery shunt at the Norwood procedure was associated with increased attrition.
Background
Omadacycline is a semisynthetic aminomethylcycline antibacterial derived from the tetracycline class. It is approved in the USA to treat adults with acute bacterial skin and skin-structure ...infections and community-acquired bacterial pneumonia.
Objectives
This phase I, open-label study evaluated the effect of a potential drug–drug interaction of verapamil—a known P-glycoprotein (P-gp) inhibitor—with omadacycline on the pharmacokinetic profile of omadacycline in healthy adults. The safety and tolerability of omadacycline taken alone and in combination with verapamil were also evaluated.
Methods
A single oral dose of 240 mg verapamil extended release (ER) was given 2 h prior to a single oral dose of 300 mg omadacycline.
Results
Ten (83.3%) of the 12 participants enrolled in the study completed the study, and all enrolled participants were included in the safety and pharmacokinetic populations. An increase of 14–25% in systemic exposure to omadacycline was seen when administered following a single oral dose of 240 mg verapamil ER compared with omadacycline alone, as measured by the area under the concentration–time curve (AUC) from time 0 to 24 h after dosing (AUC
0–24
), from time 0 to the last quantifiable concentration (AUC
0–t
), from time 0 extrapolated to infinity (AUC
0–inf
), and by maximum (peak) observed plasma concentration (
C
max
). Treatment-emergent adverse events were reported by one participant (nausea and headache).
Conclusions
These findings suggest that, if given with a known P-gp inhibitor, dose adjustment of oral omadacycline is not warranted based on small increases in absorption and systemic exposure. No safety signals were identified.
Abstract
OBJECTIVES
The objective of this study was to estimate hospital mortality and length of stay (LOS) for children with hypoplastic left heart syndrome undergoing superior cavopulmonary ...connection (SCPC).
METHODS
All hypoplastic left heart syndrome interstage survivors who underwent SCPC between 1 January 1988 and 31 December 2017 were included. The study period was divided into 4 eras based on changes in operative or medical management. Mortality rates were estimated using standard binomial proportions. Adjusted and unadjusted logistic regression models were used to identify risk factors for mortality and LOS.
RESULTS
The most common procedures for the cohort (n = 958) were Hemi-Fontan (57.3%) or Bidrectional Glenn shunt (35.7%). The mortality was 4.1% overall and decreased in all 3 later eras compared to era 1. Factors associated with mortality in a multiple covariate model included longer total support time, earlier gestational age, longer LOS at the Norwood Procedure and need for additional procedures. Overall, the median LOS was 7.0 days with a decrease from eras 1 to 2 and plateaued in eras 3 and 4. Predictors of longer LOS included genetic anomaly, longer Norwood LOS, additional procedures, lower weight at surgery and longer total support time. The type of SCPC was not associated with mortality or LOS.
CONCLUSIONS
In this large cohort of patients with hypoplastic left heart syndrome undergoing SCPC, hospital mortality has decreased significantly. LOS initially declined but plateaued in recent eras. The risk factors for mortality and longer LOS are related to patient and procedural complexity, especially the need for additional procedures at the time of SCPC.
A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in ...4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP) to potentially enhance protection. This was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method. In both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-gamma FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection. This study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.
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