OBJECTIVE:To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod.
METHODS:In ...this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24.
RESULTS:Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval CI) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 1.7–2.6) and 12-week WO groups (1.7 1.3–2.2) and higher in the 16-week WO group (8.2 7.3–9.1). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 0.2–0.6; 12 weeks, 2.1 1.6–2.6; 16 weeks, 3.6 3.0–4.2). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 5.67–22.53) than in the 12-week (21.3 1.41–41.19) or 16-week (18.5 8.40–28.60) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred.
CONCLUSIONS:Initiating fingolimod therapy 8–12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO.
CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods.
Abstract Background Left atrium (LA) dilation and P-wave duration are linked to the amount of endurance training and are risk factors for atrial fibrillation (AF). The aim of this study was to ...evaluate the impact of LA anatomical and electrical remodeling on its conduit and pump function measured by two-dimensional speckle tracking echocardiography (STE). Method Amateur male runners > 30 years were recruited. Study participants ( n = 95) were stratified in 3 groups according to lifetime training hours: low (< 1500 h, n = 33), intermediate (1500 to 4500 h, n = 32) and high training group (> 4500 h, n = 30). Results No differences were found, between the groups, in terms of age, blood pressure, and diastolic function. LA maximal volume (30 ± 5, 33 ± 5 vs. 37 ± 6 ml/m2 , p < 0.001), and conduit volume index (9 ± 3, 11 ± 3 vs. 12 ± 3 ml/m2 , p < 0.001) increased significantly from the low to the high training group, unlike the STE parameters: pump strain − 15.0 ± 2.8, − 14.7 ± 2.7 vs. − 14.9 ± 2.6%, p = 0.927; conduit strain 23.3 ± 3.9, 22.1 ± 5.3 vs. 23.7 ± 5.7%, p = 0.455. Independent predictors of LA strain conduit function were age, maximal early diastolic velocity of the mitral annulus, heart rate and peak early diastolic filling velocity. The signal-averaged P-wave (135 ± 11, 139 ± 10 vs. 148 ± 14 ms, p < 0.001) increased from the low to the high training group. Four episodes of non-sustained AF were recorded in one runner of the high training group. Conclusion The LA anatomical and electrical remodeling does not have a negative impact on atrial mechanical function. Hence, a possible link between these risk factors for AF and its actual, rare occurrence in this athlete population, could not be uncovered in the present study.
Introduction
Antivirals and occlusive lip patches are key treatments for cold sores. Additional therapeutic options, and validated methods to evaluate these, are needed.
Methods
This exploratory, ...double-blind, single-center study aimed to evaluate a novel lip patch containing the antiviral aciclovir (ACV) using noninvasive methods for measuring cold sore-associated inflammation. Healthy subjects with ultraviolet radiation (UVR)-induced cold sores were randomized to 10 days’ treatment with a lip patch containing ACV (
N
= 12) or without ACV (
N
= 13). Outcome measures included blood flux (field laser perfusion imaging, FLPI), skin temperature (thermography), and skin redness (high-resolution color photography, HRCP).
Results
Mean blood flux (in perfusion units) and skin temperature (in °C/pixel) were higher for cold sores versus intrasubject control regions. For ACV versus placebo patches, skin temperature was higher for ACV with total day 1–5 mean values of 2.6 versus 0.5 (
p
= 0.036) and day 1–10 mean values of 3.2 versus 0.8 (
p
= 0.049). Conversely, mean total episode blood flux values over days 1–5 were lower for ACV versus placebo patch (flux 2227 versus 2939,
p
= 0.340) and remained lower over days 1–10 (flux ACV 810 versus placebo 961,
p
= 0.404). HRCP failed to discriminate cold sores from control regions or between treatments. Subject-reported pain/soreness, itching, and burning were generally lower with ACV patch.
Conclusions
FLPI reliably measures cold sore-related inflammation and thermography heat radiating from the skin. HRCP was of little value.
Trial Registration
NCT01653509.
The Levantine high productivity sequence is a product of an extensive upwelling system that operated in the Late Cretaceous along the SE Tethyan margin. This system resulted in the deposition of a ...unique sequence of carbonate, chert, porcellanite, phosphorite and organic-rich (oil shale) sediments in a series of basins located proximally and marginally to the upwelling center. This study presents a detailed and updated chronostratigraphic framework for the high productivity sequence in Israel based on eight sections covering a N–S cross section of ∼90 km. The Shefela Basin (central Israel) represents the thickest and the most complete penetrated stratigraphic interval of the oil shale deposits in Israel. The newly drilled Aderet borehole in the Shefela Basin provided a continuous core record coupled with high quality geophysical well logs and was used in this study as a ‘type-section’ for the detailed chronostratigraphic scheme of the high productivity sequence. A total of 23 datum levels were recognized using planktic and benthic foraminiferal biostratigraphy, lithostratigraphy and gamma ray well log markers. The varying lithostratigraphic units (containing chert, phosphate, porcellanite and organic-rich carbonates) of the more proximal basins of southern Israel (Negev) were individually correlated to specific horizons within the monotonous organic-rich carbonates of the distal setting of the Shefela Basin.
The first occurrence of the Late Cretaceous organic-rich carbonates in Israel is documented in the Negev during the late Coniacian, within the upper Dicarinella concavata Zone, and corresponds chronologically to the upper part of the lower Menuha Formation. The regional unconformity around the Santonian/Campanian boundary was found to be less substantial at the distal localities in comparison to the proximal ones. The distinct appearance of the ‘Mishash Tongue’ chert in the Shefela was correlated to the massive Chert Member (Mishash Formation) in the Negev, and assigned to the middle Campanian. Deposition of the overlying phosphate series spans from the lower Contusotruncana plummerae to the base of the Pseudoguembelina palpebra Zones (78.3–71.7 Ma) and co-occurs in both proximal and deeper distal areas, although in a much lesser magnitude in the latter. The top of the phosphatic unit is marked by a regional unconformity. The oil shale deposits in southern Israel coincide with the 100 m richest TOC interval (average of 15.2 wt.% TOC) in the Shefela. The diminishing phase of organic-rich deposition occurred in a diachronous step-wise manner across Israel, from the top of the P. palpebra Zone to the upper part of the Abathomphalus mayaroensis Zone in southern and central Israel, respectively. This indicates that the full duration of the high productivity sequence in Israel spans approximately 19 myr.
Arabian Plate-wide maximum flooding surfaces (MFS) recorded during the Tectonic Mega-Sequence (TMS) AP9 timeframe (92–63 Ma) are identified here in the local sedimentary system of the Levant: K160 signifying the onset of organic-rich carbonates; K170 at the upper part of the massive and brecciated Chert Member; and K180 marking the diminishing phase of the high productivity sequence in Israel.
•Chronostratigraphy of the Upper Cretaceous strata in Israel was established.•The sequence spans ∼19 myr, from D. concavata to A. mayaroensis planktic biozones.•Sedimentation rates are affected by shore proximity and match lithologic shifts.•High oceanographic connectivity between southern and central Israel is deduced.•Eustatic influence is inferred by the correlation with the Arabian Plate.
BACKGROUND AND PURPOSE:Comparative studies of exercise interventions for people with Parkinson disease (PD) rarely considered how one should deliver the intervention. The objective of this study was ...to compare the success of exercise when administered by (1) home exercise program, (2) individualized physical therapy, or (3) a group class. We examined if common comorbidities associated with PD impacted success of each intervention.
METHODS:Fifty-eight people (age = 63.9 ± 8 years) with PD participated. People were randomized into (1) home exercise program, (2) individual physical therapy, or (3) group class intervention. All arms were standardized and based on the Agility Boot Camp exercise program for PD, 3 times per week for 4 weeks. The primary outcome measure was the 7-item Physical Performance Test. Other measures of balance, gait, mobility, quality of life, balance confidence, depressions, apathy, self-efficacy and UPDRS-Motor, and activity of daily living scores were included.
RESULTS:Only the individual group significantly improved in the Physical Performance Test. The individual exercise showed the most improvements in functional and balance measures, whereas the group class showed the most improvements in gait. The home exercise program improved the least across all outcomes. Several factors effected success, particularly for the home group.
DISCUSSION AND CONCLUSIONS:An unsupervised, home exercise program is the least effective way to deliver exercise to people with PD, and individual and group exercises have differing benefits. Furthermore, people with PD who also have other comorbidities did better in a program directly supervised by a physical therapist.Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A112).
While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of ...possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR).
VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic-pharmacodynamic modeling was performed with NONMEM.
Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope
increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response.
BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation.
Late Cretaceous sea surface temperatures (SSTs) were reconstructed based on TEX86 data from the unique high productivity upwelling system in the Southern Tethys margin, Israel. SSTs were determined ...from two oil shale sequences of the Santonian–early Maastrichtian (~85 to 68Ma) in southern (Efe Syncline) and central (Shefela basin) Israel (paleo latitude 8–15°N). These two sampling sites represent the inner and outer belts of the upwelling system. Our TEX86 data indicate a significant long-term SST cooling trend from 36.0 to 29.3°C during the late Santonian and the early Campanian in the Southern Tethys margin consistent with the opening of the Equatorial Atlantic Gateway (EAG).
Based on our data from the equatorial region and literature data from the polar region we reassessed the equator to pole SST gradient to 22°C. This value is closer to the modern ocean equator-to-pole SST gradient (30°C) than suggested from previous studies.
Furthermore, the SST data suggests the presence of cooler surface water in the inner belt (27.7°C) caused by the upwelling system and warmer surface water (29.2°C) further seaward in the outer belt.
•Late Santonian cooling trend recorded in the marine sediments of the Southern Tethys•Sea surface temperature profile of a Late Santonian to Maastrichtian upwelling system•Sea surface temperature gradient within a Late Cretaceous upwelling system•Reassessment of the Late Cretaceous equator to pole sea surface temperature gradient
To the Editor:
In the Halt Progression of Polycystic Kidney Disease (HALT-PKD) study, Schrier et al. (Dec. 11 issue)
1
randomly assigned patients with early-stage autosomal dominant polycystic kidney ...disease (ADPKD) to either a standard blood-pressure target or a low blood-pressure target. The low blood-pressure target was associated with a slower increase in total kidney volume, but not with an overall change in the estimated glomerular filtration rate (GFR). The latter finding might be viewed as being disappointing. However, we would caution that the institution of strict blood-pressure control will result in an acute, hemodynamic, but reversible decrease in the estimated . . .
Background. Previous studies suggest that the occurrence of pre-eclampsia is seasonally distributed. This retrospective study aims to determine whether there is a seasonal variation in the number of ...admissions and the prevalence of women with pre-eclampsia in Tygerberg Hospital, South Africa. Methods. The number of women admitted with a diagnosis of pre-eclampsia, eclampsia or haemolysis elevated liver enzymes low platelets (HELLP) syndrome (together called pre-eclampsia) was obtained from hospital records from 2002 to 2003 for each season and month. Associations were analysed with Odds Ratios (OR). Furthermore, these data was compared with the Cape Town temperatures recorded on each day over the period, as well as the total rainfall for each month. Bivariate logistic regression of the probability of pre-eclampsia on temperature and rainfall was performed. Results. Pre-eclampsia occurred in 11.5% of all admissions (1,329/11,585). The prevalence was highest in winter (13.6% pre-eclampsia patients from all admissions). Women admitted in winter had a higher risk of developing pre-eclampsia compared to those admitted in summer (OR =1.69, 95% CI: 1.07-1.53). The risk of developing pre-eclampsia in June was higher than in February (summer in South Africa, reference month) (OR =2.81, 95% CI: 2.06-3.83). There was a significant correlation between the number of admissions with pre-eclampsia and the minimum daily temperature (r=−0.620, p=0.032). Conclusions. Pre-eclampsia occurs more frequently in winter at Tygerberg Hospital, South Africa. The findings have implications for future research related to the aetiology of pre-eclampsia as well as for clinical care.
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