Physical Activity Is Associated with Slower Cognitive Decline in Older Adults with Type 2 Diabetes.

BACKGROUND: Physical activity is associated with slower cognitive decline in old age. Type 2 diabetes (T2d) is a risk factor for dementia and cognitive decline. Physical activity protects against several T2d complications. Yet, little is known about the contribution of physical activity to cognitive health among the elderly with T2d. OBJECTIVES: To examine the association between physical activity and cognitive decline in older adults with T2d. DESIGN: This is a prospective longitudinal study using data from the Israel Diabetes and Cognitive Decline (IDCD) study. SETTING: ICDC study (N=1,213), is a population-based cohort of adults over the age of 65, diagnosed with type 2 diabetes, who were cognitively normal at baseline and followed up every 18 months. PARTICIPANTS: Participants with at least one follow-up assessment who were in the same physical activity group consistently and had complete demographic data. MEASUREMENTS: Physical activity was measured using Minnesota Leisure Time Activity Questionnaire, cognitive functioning was measured using a broad neuropsychological assessment measuring Executive Functioning, Attention/Working Memory, Semantic Categorization and Episodic Memory. RESULTS: Participants were classified into physical activity groups based on self-reported physical activity at baseline and all follow ups: "active" - participation in recreational physical activity (n=286); "non-active"- the only physical activity was walking from place to place (n=93) and "sedentary" (n=19). Linear mixed effects models were applied to adjust for key demographic and cardiovascular risk factors. Participants were 72.4 (SD 4.6) years old, had 13.3 (SD 3.6) years of education, and 163 (41%) were female. In the fully adjusted model, compared to the non-active group the active group had significantly slower rate of decline in Global Cognition (p=0.005), Executive Functioning (p=.014), and Attention/Working Memory (p=.01). There were no significant group differences for Semantic Categorization (p=.17) and Episodic Memory (p=.88). CONCLUSIONS: Among initially cognitively normal and independent older adults with T2d, a physically active lifestyle was associated with a slower rate of cognitive decline. Future research should examine whether promoting physical activity may prevent or delay onset of dementia in this high-risk population.

A phase I study of panobinostat and ruxolitinib in patients with primary myelofibrosis (PMF) and post--polycythemia vera/essential thrombocythemia myelofibrosis (post--PV/ET MF).

Ruxolitinib, a selective JAK1/JAK2 inhibitor, is the current first line therapy for myelofibrosis (MF), which reduces symptomatology and splenomegaly, but does not clearly modify disease course. Panobinostat, a histone deacetylase inhibitor, was shown to be safe and tolerable in phase I and II trials and demonstrated clinical activity in approximately a third of treated patients. Combination therapy of ruxolitinib and panobinostat showed synergistic activity in a preclinical MF model, which prompted clinical evaluation of this combination in both ruxolitinib naïve and treated MF patients. Herein, we report the results of an investigator-initiated, dose escalation, phase I trial of ruxolitinib and panobinostat in 15 patients with primary MF and post-polycythemia vera/essential thrombocythemia MF. This combination treatment proved to be safe and tolerable without dose limiting thrombocytopenia and a maximum tolerated dose of both agents in combination was not determined. The majority of patients maintained stable disease with this combination treatment and 40 % attained a clinical improvement (spleen n = 5, anemia n = 1) by modified IWG-MRT at the end of 6 cycles. This is one of the first attempts of rationally designed, JAK inhibitor-based, combination therapy studies and exemplifies the feasibility of such an approach in patients with advanced MF.

Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients: The Quarterback trial.

BACKGROUND: Human Papillomavirus oropharyngeal carcinoma (HPVOPC) has better progression free (PFS) and overall survival (OS) than non-HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant acute toxicity and late morbidity. We hypothesized that after induction chemotherapy (IC), reduced dose chemoradiation (rdCRT) would result in equivalent PFS and OS compared to sdCRT plus IC in HPVOPC and would reduce toxicity. METHODS: Patients with p16+, previously untreated, locally advanced HPVOPC and ≤20 pack years smoking history received 3 cycles of IC with docetaxel, cisplatin and fluorouracil (TPF). Clinical responders who were HPV positive by type-specific PCR were randomized 1:2 to sdCRT (7000 cGy) or rdCRT (5600 cGy) with weekly carboplatin. The endpoints of the study were 3 year PFS and OS. RESULTS: 23 patients were enrolled, 22 were evaluable for TPF toxicity and 20 were randomized, 8 to sdCRT and 12 to rdCRT. Sixteen (80%) were HPV 16+ and 4 (20%) were other high risk (HR) variants. Fourteen (70%) had high risk features: T4, N2c, or N3. Median follow up was 56 months (range 42-70). Three-year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures are locoregional within 4 months of completion of CRT; 2 were in HR variants (50%). CONCLUSIONS: rdCRT after IC resulted in similar PFS/OS compared sdCRT. These data support Phase 3 clinical trials of radiation dose reduction after IC as a treatment strategy in HPVOPC. Molecular HPV with variant testing and smoking history are necessary for de-escalation trials.

Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: a sponsor-independent international study.

Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients. Thirty-three patients benefitting from PAC on clinical trial prior to the hold were allowed to resume therapy on an individual, compassionate-use basis. This study reports the detailed outcomes of 19 of these PAC retreatment patients with a median follow-up of 8 months. Despite a median platelet count of 49 × 109/L at restart of PAC, no significant change in hematologic profile was observed. Grade 3/4 adverse events of epistaxis (n = 1), asymptomatic QT prolongation (n = 1), and bradycardia (n = 1) occurred in three patients within the first 3 months of retreatment. One death due to catheter-associated sepsis occurred. The median time to discontinuation of PAC therapy on compassionate use for all 33 patients was 12.2 (95% CI 8.3-NR) months. PAC retreatment was associated with modest improvement in splenomegaly without progressive myelosuppression and supports the continued development of this agent for the treatment of MF second line to ruxolitinib or in the setting of treatment-limiting thrombocytopenia.

Neoadjuvant chemoradiation radiation dose levels for surgically resectable esophageal cancer: predictors of use and outcomes.

Neoadjuvant chemoradiation (CRT) followed by surgical resection is the standard of care for resectable, locally advanced esophageal cancer. There are promising results using 41.4 Gy relative to historical controls using higher doses, but the utilization and efficacy of lower neoadjuvant radiation dosing is unclear. This study uses the National Cancer Database (NCDB) to explore patterns of care for neoadjuvant CRT dose levels and outcomes. The NCDB was queried for localized invasive esophageal adenocarcinoma (AC) or squamous cell carcinoma (SCC) receiving neoadjuvant CRT with doses from 40 to 54 Gy followed by surgical resection. Patients were divided into radiation levels: 40-41.4, 45, 50.4, and 54 Gy, respectively. Factors predicting use of 40-41.4 Gy vs. all other dose levels were compared using multivariable logistic regression. Factors affecting overall survival (OS) were compared using univariate and multivariate modeling. A total of 6,274 patients with AC (n = 5,176) or SCC (n = 1,098) receiving neoadjuvant CRT and definitive resection were identified. Hispanic race (OR 2.67 [95% CI 1.22-5.81]) and treatment at an academic center (OR 2.72 [95% CI 1.15-6.41]) predicted for use of low-dose CRT. Lower dose CRT increased from 3.9% in 2004 to 7.2% in 2013. There was no difference in OS when stratified according to radiation dose level (P = 0.48). Multivariable analysis found private/government insurance, higher education, higher median income, and treatment at an academic center were associated with improved OS. Age, male gender, Charlson-Deyo comorbidity score, stage, tumor grade, and treatment in the South were associated with worse OS. Use of lower neoadjuvant CRT dose is more common at academic centers and shows possible increasing usage. Neoadjuvant radiation dose for esophageal cancer is not associated with differences in OS in this large database.

Detection and correlation of pre-operative, frozen section, and final pathology in high-risk endometrial cancer.

PURPOSE: To evaluate sensitivity and specificity of pre-operative and frozen section pathologic evaluation (FSA) in predicting high-risk (HR) histology endometrial cancer. MATERIALS AND METHODS: A retrospective analysis was performed on all patients diagnosed with endometrial cancer at a single institution. Medical records were abstracted for baseline characteristics, surgical reports for staging, and final histology was confirmed by a gynecologic pathologist. RESULTS: 868 patients were identified. Of these, 118 had Grade 3 endometrioid, 36 clear cell carcinoma (CCC), 47 carcinosarcoma (CS), and 84 uterine papillary serous carcinoma (UPSC) histology. Endometrial biopsy (EMB) had an overall sensitivity of 90%, 77% for low grade, 78% for HR, with a specificity of 0%. For dilation and curettage (D&C), overall sensitivity was 85%, 69% for low grade, and 77% for HR. Specificity was 33%. Sensitivities for combined pre-operative testing for G3 endometrioid, CCC, CS, and UPSC were: 56%, 28%, 72%, and 60%, respectively. For frozen section analysis (FSA), overall sensitivity was 77%, and 67% for low and high grade. For G3 endometrioid, CCC, CS, and UPSC, sensitivities were 57%, 20%, 74%, 32%, respectively. Specificity was 95%. FSA identified an additional six patients (8%) with UPSC, CCC or CS that were pre-operatively low risk, providing an 8% improvement in sensitivity but decreased specificity. CONCLUSIONS: Pre-operative EMB and D&C are overall very sensitive for detecting endometrial cancer; however, sensitivity decreases with HR histology. Pre-op testing will miss 28% of HR diagnoses and FSA provides an opportunity to identify some patients with UPSC, CCC, and CS. If pre-operative results suggest HR cancer, the surgeon should proceed with comprehensive surgical staging without an FSA.

Comparison of two classification systems for vesicovaginal fistula.

INTRODUCTION AND HYPOTHESIS: This study aims to compare the prognostic value of two obstetric fistula classification systems. METHODS: Prospective analysis of 202 patients evaluated for obstetric fistula (OF) at the General Referral Hospital of Panzi, Bukavu, DRC, from April through December 2009. Fistula classification using both Goh's and Waaldijk's systems, as well as preoperative, surgical, and follow-up assessment were included. Receiver operating characteristics (ROC) curves were used to compare the accuracy of the two systems to discriminate successful closure from persistent fistula. RESULTS: Two hundred two women underwent fistula repair. Ten were lost to follow-up. At longest follow-up, 181 patients (88.3%) had successful fistula closure. On multivariate analysis, the independent variables of multiparity and a primary or secondary repair were more likely to have a successful closure. In Waaldijk's system, no single component was more predictive of successful closure than another. In Goh's system, type 4 fistulae were more likely to have failed closure compared to those with type 1 or 2 (p = 0.0144). When comparing ROC curves, Goh's system had significantly better ability to predict successful closure than the Waaldijk's system, p = 0.0421. CONCLUSIONS: Waaldijk and Goh are the two most commonly used obstetric fistula classification systems. In this series of OF patients at Panzi Hospital in the Democratic Republic of Congo, Goh's classification system demonstrated a significantly better prediction of OF closure than the Waaldijk's system.

Antenatal antibiotic exposure in preterm infants with necrotizing enterocolitis.

OBJECTIVE: To determine whether an association exists between antenatal antibiotic exposure and incidence of necrotizing enterocolitis (NEC) in low birth weight infants. STUDY DESIGN: A retrospective case-control study was performed on all infants with a diagnosis of NEC born at our institition between 1988 and 2006. Medical histories of all infants with a diagnosis of NEC ≥Bell's stage IIA and matched controls without NEC were reviewed. Maternal and neonatal characteristics were compared using the Mantel-Haenszel chi-square procedure, and logistic regression models were constructed to account for confounding. RESULT: Clinical data for 97 matched pairs were analyzed. The adjusted odds ratio (OR) for antenatal exposure to ampicillin was significantly greater for infants who developed NEC (OR 2.3, 95% confidence interval 1.1, 4.8, P=0.003) than for control infants. CONCLUSION: Infants who developed NEC were more likely to have a history of in utero exposure to ampicillin in the immediate antepartum period than infants who did not develop NEC.

Intravaginal misoprostol versus Foley catheter for labour induction: a meta-analysis.

BACKGROUND: There are a number of agents used for cervical ripening prior to the induction of labour. Two commonly used agents are intravaginal misoprostol and a transcervical Foley catheter. OBJECTIVE: To review the evidence comparing misoprostol and transcervical Foley catheter placement for induction of labour, and perform a meta-analysis comparing these two induction agents. SEARCH STRATEGY: We conducted database searches of PubMed, Embase, the Cochrane Library Database, and the ClinicalTrials.gov website. Bibliographies of all relevant articles were reviewed. SELECTION CRITERIA: Prospective, randomised trials comparing the use of intravaginal misoprostol and transcervical Foley catheter for the purpose of cervical ripening and induction of labour were included. We excluded studies in which the patients in these two intervention groups also received other induction agents concurrently, such as oral misoprostol, oxytocin, or other prostaglandins. DATA COLLECTION AND ANALYSIS: The primary outcomes selected were time to delivery, and the rates of caesarean section, uterine tachysystole, and chorioamnionitis. Random-effects generalised linear models with a poisson distribution and log link function were used to compare the two induction agents across the studies. MAIN RESULTS: Nine studies (1603 patients) were identified as eligible to be included in this meta-analysis. There were no significant differences in the mean time to delivery (mean difference 1.08 ± 2.19 hours shorter for misoprostol, P = 0.2348), the rate of caesarean delivery (RR 0.991; 95% CI 0.768, 1.278), or in the rate of chorioamnionitis (RR 1.130; 95% CI 0.611, 2.089) between women who received misoprostol compared with transcervical Foley catheter. Patients who received misoprostol had significantly higher rates of tachysystole compared with women who received a transcervical Foley catheter (RR 2.844; 95% CI 1.392, 5.812). CONCLUSIONS: Intravaginal misoprostol and transcervical Foley catheter have similar effectiveness as induction agents. Transcervical Foley catheter is associated with a lower incidence of tachysystole.

Dyskinesias predict the onset of motor response fluctuations in patients with Parkinson's disease on L-dopa monotherapy.

The aim of the study was to investigate the relationship between dyskinesias and motor fluctuations in patients with Parkinson's disease on l-dopa monotherapy. We identified 116 patients on l-dopa monotherapy treated between 1965 and 1992 and followed until death. Dyskinesias occurred in 102 patients. Of these, 48 only developed dyskinesias while 54 had both dyskinesias and motor fluctuations. Among patients with both complications, 49 developed dyskinesias before fluctuations, and only five had dyskinesias after the onset of fluctuations. Our findings suggest that dyskinesias predict the onset of motor fluctuations, and may share a common pathophysiological mechanism.

Validation of X-ray fluorescence-measured Swine femur lead against atomic absorption spectrometry.

The aim of this study was to apply the technique of (109)Cd-based K-shell X-ray fluorescence (XRF) bone lead measurements to swine femurs and to validate the concentrations obtained therefrom against an independent chemical measurement of bone lead: atomic absorption spectrometry (AAS). The femurs ranged in lead concentration from 1.0 to 24.5 microg of lead per gram of ashed bone, as measured by AAS. On average, XRF overestimated AAS-measured femur lead by 2.6 microg/g [95% confidence interval (CI), 1.1-4.0 microg/g], approximately 2 microg/g poorer than that observed in studies of human tibiae. Measurements of swine femur and, by extension, of nonhuman bones may require adjustment of the XRF spectrum peak extraction method.

Individual variability in human tibia lead concentration.

Our aims in this study were to determine proximal-distal variability in adult human tibia lead concentration via electrothermal atomization atomic absorption spectrometry (ETAAS) and to determine whether there were any differences between core and surface tibia lead concentrations. We analyzed duplicate core and surface tibia samples for lead at multiple proximal-distal sections on 10 adult human cadaver legs. Dried bone samples were digested in nitric acid using microwave-assisted heating, and lead content was determined by ETAAS with Zeeman background correction. Lead concentrations in nine tibiae (one tibia was excluded because some of the data were compromised) ranged from 3.1 to 27.9 microg lead/g of dry bone. Both core and surface tibia lead concentrations were lower at the proximal and distal ends of the tibia. Surface tibia lead was approximately 5 microg/g greater than core tibia lead in six tibiae with relatively low lead concentration, and 8 microg/g greater in three tibiae with relatively high lead concentration. The difference between core and surface tibia lead was independent of proximal-distal tibia location. We conclude that these nine human tibiae showed a greater surface tibia lead concentration than core tibia lead concentration. This observation has consequences for the noninvasive measurement of tibia lead via K-shell and L-shell X-ray fluorescence.

Patella lead x-ray fluorescence measurements are independent of sample orientation.

In vivo x-ray fluorescence bone lead measurements assess long-term lead exposure. Tibia, calcaneus, and patella are the most commonly sampled bones. Patella measurements also include lead signals from the distal femur, proximal tibia, and synovium. It is therefore important to know whether the orientation of the patella relative to the measurement system substantially affects the measured patella lead concentrations and their measurement uncertainties. This study examined whether these parameters exhibited a dependence on the orientation of the patella with respect to the measurement system, a dependence that could arise from varying nonpatella contributions. There was no effect of orientation on measured patella lead concentration, but there was a highly significant effect of orientation on the measurement uncertainty. These data do not conclusively show that there are no nonpatella contributions to a patella lead measurement; rather, that any such contributions are not a function of measurement orientation over the range of orientations considered. Further study is required if the contribution of nonpatella tissues to a patella lead XRF-measured concentration is to be fully addressed. This study also filled a gap in the literature by quantifying the within-patella (29%) and between-patella (71%) variability of measured patella lead concentrations from replicate measures of nine patellae.

Tibia lead levels and methodological uncertainty in 12-year-old children.

In vivo bone lead measurements with 109Cd-based K-shell X-ray fluorescence (XRF) have been used to assess long-term lead exposure in adults. Tibia lead levels were measured in 210 children (106 boys, 104 girls) of 11-12(1/2) years of age in a lead smelter town and in a control (nonexposed) town. Tibia lead levels, methodological uncertainties, and models of some of the factors influencing them are presented. 109Cd-based K-shell XRF tibia lead methodological uncertainty in children is comparable to that in adults.

The effect of measurement location on tibia lead XRF measurement results and uncertainty.

The aims of this study were to determine whether the location on the tibia measured by 109Cd-based K-shell x-ray fluorescence (XRF) affected the measurement result and its uncertainty, and whether higher tibia lead levels at the extremities of the tibia and/or inhomogeneity in the distribution of lead in the tibia could be inferred therefrom. Replicate XRF measurements were performed at multiple locations on ten adult cadaver intact legs and on nine bare tibiae dissected from them. Mean lead levels in the bare tibiae ranged from 16 to 48 microg Pb per g of bone mineral. Bare tibia measurements showed that both the XRF result and its uncertainty increased towards the proximal and distal ends of the tibia. The XRF result decreased away from the medial-lateral mid-point of the tibia, but XRF uncertainty was not significantly affected. Intact leg measurements showed no effect of proximal distal location on XRF result but did show an effect on XRF uncertainty. We conclude that the XRF method used can determine the differences in bone lead level resulting from the more trabecular composition at the ends of the tibia, and we present limited evidence for localized regions of low tibia lead level.

Predictors of DMSA chelatable lead, tibial lead, and blood lead in 802 Korean lead workers.

OBJECTIVES: To examine the interrelations among chelatable lead (by dimercaptosuccinic acid, DMSA), tibial lead, and blood lead concentrations in 802 Korean workers with occupational exposure to lead and 135 employed controls with only environmental exposure to lead. METHODS: This was a cross sectional study wherein tibial lead, DMSA chelatable lead, and blood lead were measured. Linear regression was used to identify predictors of the three lead biomarkers, evaluating the influence of age, job duration, sex, education level, alcohol and tobacco use, creatinine clearance rate, and body mass index. RESULTS: DMSA chelatable lead concentrations ranged from 4.8 to 2102.9 microg and were positively associated with age, current smoking, and creatinine clearance rate. On average, women had 64 microg less DMSA chelatable lead than men. When blood lead and its square were added to a model with age, sex, current smoking, body mass index, and creatinine clearance rate, blood lead accounted for the largest proportion of the variance and sex became of borderline significance. Tibial lead concentrations ranged from -7 to 338 microg/g bone mineral and were positively associated with age, job duration, and body mass index. Women had, on average, 9.7 microg/g less tibial lead than men. Blood lead concentrations ranged from 4.3 to 85.7 microg/dl and were positively associated with age and tibial lead, whereas current smokers had higher blood lead concentrations and women had lower blood lead concentrations. CONCLUSIONS: The data suggest that age and sex are both predictors of DMSA chelatable lead, blood lead, and tibial lead concentrations and that tibial lead stores in older subjects are less bioavailable and may contribute less to blood lead concentrations than tibial lead stores in younger subjects. Although blood lead concentrations accounted for a large proportion of the variance in DMSA chelatable lead concentrations, suggesting that measurement of both in epidemiological studies may not be necessary, the efficacy of each measure in predicting health outcomes in epidemiological studies awaits further investigation.

Variability in XRF-measured tibia lead levels.

A few studies have examined the variability in 109Cd-based K-shell x-ray fluorescence (KXRF) bone lead measurements from replicate measurements made either at the same time or over a period of time, and one of these studies has shown that the uncertainty in an individual measurement is an underestimate of the standard deviation of replicate measurements. Variability in KXRF tibia lead measurements was assessed from ten cadaver intact legs, from the bare tibiae dissected from nine of these legs, and from four in vivo volunteers. Cadaver legs underwent replicate measurements on multiple occasions. In vivo volunteers underwent single measurements of the left tibia monthly for one year. Average tibia lead levels in the cadaver legs and in vivo volunteers ranged from 6 to 50 and from 6 to 13 microg Pb per g of bone mineral respectively. The factors influencing the standard deviation of replicate measurements were investigated. Both cadaver and in vivo measurements confirmed that the uncertainty in an individual measurement is an underestimate of the standard deviation of replicate measurements, suggesting a methodological deficiency probably shared by most current 109Cd-based K-shell XRF lead measurement systems.