Summary Prevalence and impact of metabolic disease is rising. In particular, overweight and obesity are at epidemic levels and are a leading health concern in the Western world. Shift work increases ...the risk of overweight and obesity, along with a number of additional metabolic diseases, including metabolic syndrome and type 2 diabetes (T2D). How shift work contributes to metabolic disease has not been fully elucidated. Short sleep duration is associated with metabolic disease and shift workers typically have shorter sleep durations. Short sleep durations have been shown to elicit a physiological stress response, and both physiological and psychological stress disrupt the healthy functioning of the intestinal gut microbiota. Recent findings have shown altered intestinal microbial communities and dysbiosis of the gut microbiota in circadian disrupted mice and jet lagged humans. We hypothesize that sleep and circadian disruption in humans alters the gut microbiota, contributing to an inflammatory state and metabolic disease associated with shift work. A research agenda for exploring the relationship between insufficient sleep, circadian misalignment and the gut microbiota is provided.
Summary Background Sleep deprivation and fatigue are common subjective complaints among astronauts. Previous studies of sleep and hypnotic drug use in space have been limited to post-flight ...subjective survey data or in-flight objective data collection from a small number of crew members. We aimed to characterise representative sleep patterns of astronauts on both short-duration and long-duration spaceflight missions. Methods For this observational study, we recruited crew members assigned to Space Transportation System shuttle flights with in-flight experiments between July 12, 2001, and July 21, 2011, or assigned to International Space Station (ISS) expeditions between Sept 18, 2006, and March 16, 2011. We assessed sleep–wake timing objectively via wrist actigraphy, and subjective sleep characteristics and hypnotic drug use via daily logs, in-flight and during Earth-based data-collection intervals: for 2 weeks scheduled about 3 months before launch, 11 days before launch until launch day, and for 7 days upon return to Earth. Findings We collected data from 64 astronauts on 80 space shuttle missions (26 flights, 1063 in-flight days) and 21 astronauts on 13 ISS missions (3248 in-flight days), with ground-based data from all astronauts (4014 days). Crew members attempted and obtained significantly less sleep per night as estimated by actigraphy during space shuttle missions (7·35 h SD 0·47 attempted, 5·96 h 0·56 obtained), in the 11 days before spaceflight (7·35 h 0·51, 6·04 h 0·72), and about 3 months before spaceflight (7·40 h 0·59, 6·29 h 0·67) compared with the first week post-mission (8·01 h 0·78, 6·74 h 0·91; p<0·0001 for both measures). Crew members on ISS missions obtained significantly less sleep during spaceflight (6·09 h 0·67), in the 11 days before spaceflight (5·86 h 0·94), and during the 2-week interval scheduled about 3 months before spaceflight (6·41 h SD 0·65) compared with in the first week post-mission (6·95 h 1·04; p<0·0001). 61 (78%) of 78 shuttle-mission crew members reported taking a dose of sleep-promoting drug on 500 (52%) of 963 nights; 12 (75%) of 16 ISS crew members reported using sleep-promoting drugs. Interpretation Sleep deficiency in astronauts was prevalent not only during space shuttle and ISS missions, but also throughout a 3 month preflight training interval. Despite chronic sleep curtailment, use of sleep-promoting drugs was pervasive during spaceflight. Because chronic sleep loss leads to performance decrements, our findings emphasise the need for development of effective countermeasures to promote sleep. Funding The National Aeronautics and Space Administration.
Delayed sleep-wake phase disorder (DSWPD) is commonly defined as an inability to fall asleep and wake at societal times resulting in excessive daytime sleepiness. Although the cause is multifaceted, ...delays in sleep time are largely driven by misalignment between the circadian pacemaker and the desired sleep-wake timing schedule. Current treatment approaches focus on correcting the circadian delay; however, there is a lack of data investigating combined therapies for treatment of DSWPD.
Summary Background Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove ...intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov , NCT00784134. Findings Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio RR 1·06 95% CI 0·88–1·28; p=0·554). A difference of 3·5% (RR 1·08 95% CI 0·90–1·29, p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 18% vs saline 73 29%, hazard ratio 0·60 95% CI 0·41–0·86, p=0·006), but a greater proportion with mRS 5 (42 17% vs 21 9%; RR 1·99 95% CI 1·22–3·26, p=0·007). Ventriculitis (17 7% alteplase vs 31 12% saline; RR 0·55 95% CI 0·31–0·97, p=0·048) and serious adverse events (114 46% alteplase vs 151 60% saline; RR 0·76 95% CI 0·64–0·90, p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six 2% in the alteplase group vs five 2% in the saline group; RR 1·21 95% CI 0·37–3·91, p=0·771) was similar. Interpretation In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. Funding National Institute of Neurological Disorders and Stroke.
Summary Background Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 ...trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. Methods We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65 -associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. Findings AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov , number NCT00516477. Interpretation The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Funding Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.
We conducted a prospective pilot study to evaluate safety and feasibility of TraceIT, a resorbable radiopaque hydrogel, to improve image guidance for bladder cancer radiation therapy (RT).
Patients ...with muscle invasive bladder cancer receiving definitive RT were eligible. TraceIT was injected intravesically around the tumor bed during maximal transurethral resection of bladder tumor. The primary endpoint was the difference between radiation treatment planning margin on daily cone beam computed tomography based on alignment to TraceIT versus standard-of-care pelvic bone anatomy. The Van Herk margin formula was used to determine the optimal planning target volume margin. TraceIT visibility, recurrence rates, and survival were estimated by Kaplan-Meier method. Toxicity was measured by Common Terminology Criteria for Adverse Events version 4.03.
The trial was fully accrued and 15 patients were analyzed. TraceIT was injected in 4 sites/patient (range, 4-6). Overall, 94% (95% confidence interval CI, 90%-98%) of injection sites were radiographically visible at RT initiation versus 71% (95% CI, 62%-81%) at RT completion. The median duration of radiographic visibility for injection sites was 106 days (95% CI, 104-113). Most patients were treated with a standard split-course approach with initial pelvic radiation fields, then midcourse repeat transurethral resection of bladder tumor followed by bladder tumor bed boost fields, and 14/15 received concurrent chemotherapy. Alignment to fiducials could allow for reduced planning target volume margins (0.67 vs 1.56 cm) for the initial phase of RT, but not for the boost (1.01 vs 0.96 cm). This allowed for improved target coverage (D95% 80%-83% to 91%-94%) for 2 patients retrospectively planned with both volumetric-modulated arc therapy and 3-dimensional conformal RT. At median follow-up of 22 months, no acute or late complications attributable to TraceIT placement occurred. No patients required salvage cystectomy.
TraceIT intravesical fiducial placement is safe and feasible and may facilitate tumor bed delineation and targeting in patients undergoing RT for localized muscle invasive bladder cancer. Improved image guided treatment may facilitate strategies to improve local control and minimize toxicity.
Portal vein embolization (PVE) is used to induce liver hypertrophy for surgical candidates with marginal future liver remnant (FLR) volumes. We compared the feasibility, safety, and effectiveness of ...a transarterial approach for PVE (TA-PVE) with those of a transhepatic approach for PVE (TH-PVE) in a swine model.
Ten experimental pigs (TA-PVE, n = 5; TH-PVE, n = 5) and six controls (TA, n = 3; TH, n = 3) were studied. For TA-PVE, a microcatheter was advanced into arteries supplying the left and left middle hepatic lobes. A 3 to 1 Ethiodol-ethanol mixture was infused into selected arteries to cross the arterioportal peribiliary plexus and remain within the portal veins (PVs). For TH-PVE, PVs in the same lobar distribution were embolized with 355- to 500-micro m polyvinyl alcohol particles and coils. Controls were similarly catheterized for saline infusion. Computed tomography with volumetry was performed before and 7, 14, 21, and 28 days after PVE to assess FLR hypertrophy (absolute FLR volume change and FLR/total liver volume TLV). Computed tomographic volumetry, laboratory data, and histopathology were compared between groups.
All procedures were technically successful. The increases in mean absolute FLR volume (TA-PVE, 148 +/- 84 cm(3); TH-PVE, 62 +/- 19 cm(3); P = .082), mean FLR hypertrophy (TA-PVE, 93.2%; TH-PVE, 48.4%; P = .178), and mean FLR/TLV (TA-PVE, 31.0%; TH-PVE, 16.2%; P = .130) from day 0 to day 28 between experimental groups were better for TA-PVE. Changes in laboratory data among all groups were minimal. Two complications occurred from TA-PVE (right gastric artery embolization n = 2 without sequela) and two from TH-PVE (acute segmental right PV thrombosis n = 1; death 3 weeks after PVE of unknown cause n = 1).
Transarterial portal vein embolization is feasible, safe, and effective for inducing future liver remnant hypertrophy in swine and may represent an improvement over previously reported transhepatic portal vein embolization methods.
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