Summary Background Previous analyses of the International Subarachnoid Aneurysm Trial (ISAT) cohort have reported on the risks of recurrent subarachnoid haemorrhage and death or dependency for a ...minimum of 5 years and up to a maximum of 14 years after treatment of a ruptured intracranial aneurysm with either neurosurgical clipping or endovascular coiling. At 1 year there was a 7% absolute and a 24% relative risk reduction of death and dependency in the coiling group compared with the clipping group, but the medium-term results showed the increased need for re-treatment of the target aneurysm in the patients given coiling. We report the long-term follow-up of patients in this UK cohort. Methods In ISAT, patients were randomly allocated to either neurosurgical clipping or endovascular coiling after a subarachnoid haemorrhage, assuming treatment equipoise, between Sept 12, 1994, and May 1, 2002. We followed up 1644 patients in 22 UK neurosurgical centres for death and clinical outcomes for 10·0–18·5 years. We assessed dependency as self-reported modified Rankin scale score obtained through yearly questionnaires. Data for recurrent aneurysms and rebleeding events were collected from questionnaires and from hospital and general practitioner records. The Office for National Statistics supplied data on deaths. This study is registered, number ISRCTN49866681. Findings At 10 years, 674 (83%) of 809 patients allocated endovascular coiling and 657 (79%) of 835 patients allocated neurosurgical clipping were alive (odds ratio OR 1·35, 95% CI 1·06–1·73). Of 1003 individuals who returned a questionnaire at 10 years, 435 (82%) patients treated with endovascular coiling and 370 (78%) patients treated with neurosurgical clipping were independent (modified Rankin scale score 0–2; OR 1·25; 95% CI 0·92–1·71). Patients in the endovascular treatment group were more likely to be alive and independent at 10 years than were patients in the neurosurgery group (OR 1·34, 95% CI 1·07–1·67). 33 patients had a recurrent subarachnoid haemorrhage more than 1 year after their initial haemorrhage (17 from the target aneurysm). Interpretation Although rates of increased dependency alone did not differ between groups, the probability of death or dependency was significantly greater in the neurosurgical group than in the endovascular group. Rebleeding was more likely after endovascular coiling than after neurosurgical clipping, but the risk was small and the probability of disability-free survival was significantly greater in the endovascular group than in the neurosurgical group at 10 years. Funding UK Medical Research Council.
Objectives
Life expectancy is an important indicator informing decision making in policies relating to HIV‐infected people. Studies estimating life expectancy after starting combination ...antiretroviral therapy (cART) have noted differences between income regions. The objective of our study was to perform a meta‐analysis to assess life expectancy of HIV‐positive people after starting cART, and to quantify differences between low/middle‐ and high‐income countries.
Methods
Eight cohort studies estimating life expectancy in HIV‐positive people initiating cART aged ≥ 14 years using the abridged life table method were identified. Random effects meta‐analysis was used to pool estimated outcomes, overall and by income region. Heterogeneity between studies was assessed with the I2 statistic. We estimated additional years of life expected after starting cART at ages 20 and 35 years.
Results
Overall life expectancy in high‐income countries was an additional 43.3 years 95% confidence interval (CI) 42.5–44.2 years and 32.2 years (95% CI 30.9–33.5 years) at ages 20 and 35 years, respectively, and 28.3 (95% CI 23.3–33.3) and 25.6 (95% CI 22.1–29.2) additional years, respectively, in low/middle‐income countries. In low/middle‐income countries, life expectancy after starting cART at age 20 years was an additional 22.9 years (95% CI 18.4–27.5 years) for men and 33.0 years (95% CI 30.4–35.6 years) for women, but was similar in the two sexes in high‐income countries. In all income regions, life expectancy after starting cART increased over calendar time.
Conclusions
Our results suggest that the life expectancy of HIV‐positive people after starting cART has improved over time. Monitoring life expectancy into the future is important to assess how changes to cART guidelines will affect patient long‐term outcomes.
Neurons affected in Alzheimer’s disease (AD) experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and promotes the disease-defining amyloid beta peptide (Aβ) and Tau ...pathologies. Emerging findings suggest that the autophagy/lysosome pathway that removes damaged mitochondria (mitophagy) is also compromised in AD, resulting in the accumulation of dysfunctional mitochondria. Results in animal and cellular models of AD and in patients with sporadic late-onset AD suggest that impaired mitophagy contributes to synaptic dysfunction and cognitive deficits by triggering Aβ and Tau accumulation through increases in oxidative damage and cellular energy deficits; these, in turn, impair mitophagy. Interventions that bolster mitochondrial health and/or stimulate mitophagy may therefore forestall the neurodegenerative process in AD.
Post-surgical opioid prescribing intended for the short-term management of acute pain may lead to long-term opioid use. This study was undertaken to determine the prevalence of persistent ...post-surgical opioid use and patient-related factors associated with post-surgical opioid use. One thousand and thirteen opioid-naive patients awaiting elective surgery in a tertiary private hospital in Sydney were enrolled. Preoperatively, patients completed a questionnaire comprising potential predictors of persistent post-surgical opioid use. Patients underwent surgery with routine perioperative care, and were followed up at 90 to 120 days after surgery to determine opioid use. Factors associated with opioid use were assessed with logistic regression. We had an overall response rate of 95.8% (n=970) of patients, of whom 10.5% (n=102) continued to use opioids at >90 days after surgery. On surgical subtype analysis, the prevalence of persistent opioid use was 23.6% after spinal surgery, and 13.7% after orthopaedic surgery. Four factors were independently associated with persistent post-surgical opioid use in a multivariate model: having orthopaedic (odds ratio OR 4.6, 95% confidence interval CI 2.0 to 10.8, P <0.001) or spinal surgery (OR 4.0, 95% CI 1.7 to 9.2, P <0.001), anxiety (OR 2.1, 95% CI 1.1 to 4.1, P=0.03), attending pre-admission clinic (OR 3.7, 95% CI 1.6 to 8.6, P=0.002), and higher self-reported pain score at >90 days after surgery (P <0.001). More than 10% of opioid-naive patients undergoing elective surgery experience persistent post-surgical opioid use. Identification of factors associated with persistent post-surgical opioid use may allow development of a risk stratification tool to predict those at highest risk.
Almost everything you do on the Internet is governed by Terms of Service. The language in Terms of Service typically gives Internet providers broad rights to address potential account misuse. But do ...these Terms alter Fourth Amendment rights, either diminishing or even eliminating constitutional rights in Internet accounts? In the last five years, many courts have ruled that they do. These courts treat Terms of Service like a rights contract: by agreeing to use an Internet account subject to broad Terms of Service, you give up your Fourth Amendment rights. This article argues that the courts are wrong. Terms of Service have little or no effect on Fourth Amendment rights. Fourth Amendment rights are rights against the government, not private parties. Terms of Service can define relationships between private parties, but private contracts cannot define Fourth Amendment rights. This is true across the range of Fourth Amendment doctrines, including the "reasonable expectation of privacy" test, consent, abandonment, third-party consent, and the private search doctrine. Courts that have linked Terms of Service and Fourth Amendment rights are mistaken, and their reasoning should be rejected.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fourth Amendment law is often considered a theoretical embarrassment. The law consists of dozens of rules for very specific situations that seem to lack a coherent explanation. Constitutional ...protection varies dramatically based on seemingly arcane distinctions. This Article introduces a new theory that explains and justifies both the structure and content of Fourth Amendment rules: the theory of equilibrium-adjustment. The theory of equilibrium-adjustment posits that the Supreme Court adjusts the scope of Fourth Amendment protection in response to new facts in order to restore the status quo level of protection. When changing technology or social practice expands government power, the Supreme Court tightens Fourth Amendment protection; when it threatens government power, the Supreme Court loosens constitutional protection. Existing Fourth Amendment law therefore reflects many decades of equilibrium-adjustment as facts have changed over time. This simple argument explains a wide range of puzzling Fourth Amendment doctrines, including the automobile exception; rules on using sense-enhancing devices; the decline of the mere evidence rule; how the Fourth Amendment applies to the telephone network; undercover investigations; the law of aerial surveillance; rules for subpoenas; and the special Fourth Amendment protection for the home. The Article then offers a normative defense of equilibrium-adjustment. Equilibriumadjustment maintains interpretive fidelity while permitting Fourth Amendment law to respond to changing facts. Its wide appeal and focus on deviations from the status quo facilitates coherent decisionmaking amidst empirical uncertainty and yet also gives Fourth Amendment law significant stability. The Article concludes by arguing that judicial delay is an important precondition to successful equilibrium-adjustment.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, PRFLJ, SAZU, UILJ, UKNU, UL, UM, UPUK
Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. ...These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q
10
(CoQ
10
; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ
10
), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ
10
), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.
ABSTRACT We use radiation hydrodynamic simulations to examine two models of solar flare chromospheric heating: Alfvén wave dissipation and electron beam collisional losses. Both mechanisms are ...capable of strong chromospheric heating, and we show that the distinctive atmospheric evolution in the mid-to-upper chromosphere results in Mg ii k-line emission that should be observably different between wave-heated and beam-heated simulations. We also present Ca ii 8542 profiles that are formed slightly deeper in the chromosphere. The Mg ii k-line profiles from our wave-heated simulation are quite different from those from a beam-heated model and are more consistent with Interface Region Imaging Spectrograph observations. The predicted differences between the Ca ii 8542 in the two models are small. We conclude that careful observational and theoretical study of lines formed in the mid-to-upper chromosphere holds genuine promise for distinguishing between competing models for chromospheric heating in flares.
The Interface Region Imaging Spectrograph has routinely observed the flaring Mg ii near-ultraviolet (NUV) spectrum, offering excellent diagnostic potential and a window into the location of energy ...deposition. A number of studies have forward-modeled both the general properties of these lines and specific flare observations. Generally these have forward-modeled radiation via post-processing of snapshots from hydrodynamic flare simulations through radiation transfer codes. There has, however, not been a study of how the physics included in these radiation transport codes affects the solution. A baseline setup for forward-modeling Mg ii in flares is presented and contrasted with approaches that add or remove complexity. It is shown for Mg ii that (1) partial frequency distribution (PRD) is still required during flare simulations despite the increased densities; (2) using full angle-dependent PRD affects the solution but takes significantly longer to process a snapshot; (3) including Mg i in non-LTE (NLTE) results in negligible differences to the Mg ii lines but does affect the NUV quasi-continuum; (4) only hydrogen and Mg ii need to be included in NLTE; (5) ideally the nonequilibrium hydrogen populations, with nonthermal collisional rates, should be used rather than the statistical equilibrium populations; (6) an atom consisting of only the ground state, h and k upper levels, and continuum level is insufficient to model the resonance lines; and (7) irradiation from a hot, dense flaring transition region can affect the formation of Mg ii. We discuss modifications to the RH code allowing straightforward inclusion of the transition region and coronal irradiation in flares.
In the Supreme Court's recent decision on GPS surveillance, United States v. Jones, five justices authored or joined concurring opinions that applied a new approach to interpreting Fourth Amendment ...protection. Before Jones, Fourth Amendment decisions had always evaluated each step of an investigation individually. Jones introduced what we might call a "mosaic theory "of the Fourth Amendment, by which courts evaluate a collective sequence of government activity as an aggregated whole to consider whether the sequence amounts to a search. This Article considers the implications of a mosaic theory of the Fourth Amendment. It explores the choices and puzzles that a mosaic theory would raise, and it analyzes the merits of the proposed new method of Fourth Amendment analysis. The Article makes three major points. First, the mosaic theory represents a dramatic departure from the basic building block of existing Fourth Amendment doctrine. Second, adopting the mosaic theory would require courts to answer a long list of novel and challenging questions. Third, courts should reject the theory and retain the traditional sequential approach to Fourth Amendment analysis. The mosaic approach reflects legitimate concerns, but implementing it would be exceedingly difficult in light of rapid technological change. Courts can better respond to the concerns animating the mosaic theory within the traditional parameters of the sequential approach to Fourth Amendment analysis.
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