How is overall survival assessed in randomised clinical trials in cancer and are subsequent treatment lines considered? A systematic review

Background: Overall survival is the “gold standard” endpoint in cancer clinical trials. It plays a key role in determining the clinical- and cost-effectiveness of a new intervention and whether it is recommended for use in standard of care. The assessment of overall survival usually requires trial participants to be followed up for a long period of time. In this time, they may stop receiving the trial intervention and receive subsequent anti-cancer treatments, which also aim to extend survival, during trial follow-up. This can potentially change the interpretation of overall survival in the context of the clinical trial. This review aimed to determine how overall survival has been assessed in cancer clinical trials and whether subsequent anti-cancer treatments are considered. Methods: Two searches were conducted using MEDLINE within OVID© on the 9th of November 2021. The first sought to identify papers publishing overall survival results from randomised controlled trials in eight reputable journals and the second to identify papers mentioning or considering subsequent treatments. Papers published since 2010 were included if presenting or discussing overall survival in the context of treating cancer. Results: One hundred and thirty-four papers were included. The majority of these were presenting clinical trial results (98, 73%). Of these, 45 (46%) reported overall survival as a (co-) primary endpoint. A lower proportion of papers including overall survival as a (co-) primary endpoint compared to a secondary endpoint were published in recent years. The primary analysis of overall survival varied across the papers. Fifty-nine (60%) mentioned subsequent treatments. Seven papers performed additional analysis, primarily when patients in the control arm received the experimental treatment during trial follow-up (treatment switching). Discussion: Overall survival has steadily moved from being the primary to a secondary endpoint. However, it is still of interest with papers presenting overall survival results with the caveat of subsequent treatments, but little or no investigation into their effect. This review shows that there is a methodological gap for what researchers should do when trial participants receive anti-cancer treatment during trial follow-up. Future research will identify the stakeholder opinions, on how this methodological gap should be addressed

Anti-Guest Statutes and Marital Immunity for Torts in Conflict of Laws: Techniques for Resolving Ostensible True Conflict Cases and Constitutional Limitations

In the now historic case of Babcock v. Jackson, decided in 1963, the New York Court of Appeals introduced an apparently novel mode of analyzing tort choice-of-law issues that has achieved remarkable popularity with the judges of other states. It has been adopted in tort cases where the facts and issues were quite different from those of Babcock v. Jackson and in contract cases as well. Why does the Babcock v. Jackson methodology appeal so strongly to the judges of the highest state tribunals? The short answer is that this methodology is extremely realistic; it brings the judges directly to grips with the basic elements of the choice problem: two divergent rules of law producing divergent practical results and effectuating divergent policies. Of these two rules the judges must choose one. The new methodology emancipates them from the simplistic place of injury formula with its distracting and misleading escape devices. It enables them to base their choice upon a rational consideration of the policies and effects of each of the proffered rules in relation to the domiciles of the parties and the location of other significant facts in the case

Effects of adult aging on letter position coding in reading: evidence from eye movements

It is well-established that young adults encode letter position flexibly during natural reading. However, given the visual changes that occur with normal aging, it is important to establish whether letter position coding is equivalent across adulthood. In 2 experiments, young (18-25 years) and older (65 years) adults' were recorded while reading sentences with words containing transposed adjacent letters. Transpositions occurred at beginning (rpoblem), internal (porblem), or end (problme) locations in words. In Experiment 1, these transpositions were present throughout reading. By comparison, Experiment 2 used a gaze-contingent paradigm such that once the reader's gaze moved past a word containing a transposition, this word was shown correctly and did not subsequently change. Both age groups showed normal levels of comprehension for text including words with transposed letters. The pattern of letter transposition effects on eye movements was similar for the young and older adults, with greater increases in reading times when external relative to internal letters were transposed. In Experiment 1, however, effects of word beginning transpositions during rereading were larger for the older adults. In Experiment 2 there were no interactions, confirming that letter position coding is similar for both age groups at least during first-pass processing of words. These findings show that flexibility in letter position encoding during the initial processing of words is preserved across adulthood, although the interaction effect in rereading in Experiment 1 also suggests that older readers may use more stringent postlexical verification processes, for which the accuracy of word beginning letters is especially important

Vertical Mixing and Heat Fluxes Conditioned by a Seismically Imaged Oceanic Front

The southwest Atlantic gyre connects several distinct water masses, which means that this oceanic region is characterized by a complex frontal system and enhanced water mass modification. Despite its significance, the distribution and variability of vertical mixing rates have yet to be determined for this system. Specifically, potential conditioning of mixing rates by frontal structures, in this location and elsewhere, is poorly understood. Here, we analyze vertical seismic (i.e., acoustic) sections from a three-dimensional survey that straddles a major front along the northern portion of the Brazil-Falkland Confluence. Hydrographic analyses constrain the structure and properties of water masses. By spectrally analyzing seismic reflectivity, we calculate spatial and temporal distributions of the dissipation rate of turbulent kinetic energy, ε, of diapycnal mixing rate, K, and of vertical diffusive heat flux, FH. We show that estimates of ε, K, and FH are elevated compared to regional and global mean values. Notably, cross-sectional mean estimates vary little over a 6 week period whilst smaller scale thermohaline structures appear to have a spatially localized effect upon ε, K, and FH. In contrast, a mesoscale front modifies ε and K to a depth of 1 km, across a region of O(100) km. This front clearly enhances mixing rates, both adjacent to its surface outcrop and beneath the mixed layer, whilst also locally suppressing ε and K to a depth of 1 km. As a result, estimates of FH increase by a factor of two in the vicinity of the surface outcrop of the front. Our results yield estimates of ε, K and FH that can be attributed to identifiable thermohaline structures and they show that fronts can play a significant role in water mass modification to depths of 1 km.</jats:p

Eye movements during reading and topic scanning: effects of word frequency

The study examined the nature of eye movement control and word recognition during scanning for a specific topic, compared with reading for comprehension. Experimental trials included a manipulation of word frequency: the critical word was frequent (and orthographically familiar) or infrequent (2 conditions: orthographically familiar and orthographically unfamiliar). First-pass reading times showed effects of word frequency for both reading and scanning, with no interactions between word characteristics and task. Therefore, in contrast to the task of searching for a single specific word (Rayner and Fischer, 1996), there were immediate and localized influences of lexical processing when scanning for a specific topic, indicating that early word recognition processes are similar during reading and topic scanning. In contrast, there were interactions for later measures, with larger effects of word frequency during reading than scanning, indicating that reading goals can modulate later processes such as the integration of words into sentence context. Additional analyses of the distribution of first-pass single fixation durations indicated that first-pass fixations of all durations were shortened during scanning compared with reading, and reading for comprehension produced a larger subset of longer first-pass fixations compared with scanning. The implications for the nature of word recognition and eye movement control are discussed

Effects of aging, word frequency, and text stimulus quality on reading across the adult lifespan: evidence from eye movements

Reductions in stimulus quality may disrupt the reading performance of older adults more when compared with young adults because of sensory declines that begin early in middle age. However, few studies have investigated adult age differences in the effects of stimulus quality on reading, and none have examined how this affects lexical processing and eye movement control. Accordingly, we report two experiments that examine the effects of reduced stimulus quality on the eye movements of young (18-24 years), middle-aged (41-51 years), and older (65 years) adult readers. In Experiment 1, participants read sentences that contained a high-or low-frequency critical word and that were presented normally or with contrast reduced so that words appeared faint. Experiment 2 further investigated effects of reduced stimulus quality using a gaze-contingent technique to present upcoming text normally or with contrast reduced. Typical patterns of age-related reading difficulty (e.g., slower reading, more regressions) were observed in both experiments. In addition, eye movements were disrupted more for older than younger adults when all text (Experiment 1) or just upcoming text (Experiment 2) appeared faint. Moreover, there was an interaction between stimulus quality and word frequency (Experiment 1), such that readers fixated faint low-frequency words for disproportionately longer. Crucially, this effect was similar across all age groups. Thus, although older readers suffer more from reduced stimulus quality, this additional difficulty primarily affects their visual processing of text. These findings have important implications for understanding the role of stimulus quality on reading behavior across the lifespan

A multicentre, prospective, randomised, blinded clinical trial to compare some perioperative effects of buprenorphine or butorphanol premedication before equine elective general anaesthesia and surgery

REASONS FOR PERFORMING STUDY: Buprenorphine, a μ‐agonist opioid, has recently been licensed for equine use, but butorphanol, a κ‐agonist opioid, is more commonly used in horses. The effect of the 2 opioids has not previously been compared in a large clinical study. OBJECTIVES: To compare post operative analgesia and physiological variables in horses undergoing elective surgery following premedication with either buprenorphine or butorphanol in a conventional clinical setting. STUDY DESIGN: Multicentre, prospective, randomised, blinded clinical investigation. METHODS: Eighty‐nine healthy horses admitted for elective surgery to one of 6 UK equine veterinary clinics were premedicated with acepromazine, a nonsteroidal anti‐inflammatory drug, and romifidine followed by intravenous (i.v.) buprenorphine or butorphanol. Anaesthesia was induced with diazepam/ketamine and maintained with isoflurane in oxygen. A range of surgical procedures were performed and supplementary anaesthetic agents given as required. Physiological variables were monitored during anaesthesia and pain, ataxia, sedation and vital function were assessed post operatively. Data were analysed using t‐tests, ANOVA, Mann–Whitney U‐test and Chi‐squared test as appropriate and P<0.05 was regarded as significant, except for multiple comparisons, when P<0.01 was used. RESULTS: Surgery was carried out successfully in all cases and no mortality or serious morbidity occurred. Physiological variables remained within normal limits and all horses recovered successfully, most standing within 1 h of ceasing anaesthesia. There were no significant differences between groups in any variable except post operative pain when scores (simple descriptive scale) between 3 and 6 h were significantly lower after buprenorphine than after butorphanol. CONCLUSIONS: Horses experienced less post operative pain after buprenorphine than after butorphanol premedication. Compared with butorphanol, buprenorphine did not cause any different effects on vital function

Predicting participation in group parenting education in an Australian sample: The role of attitudes, norms, and control factors

We examined the theory of planned behavior (TPB) in predicting intentions to participate in group parenting education. One hundred and seventy-six parents (138 mothers and 38 fathers) with a child under 12 years completed TPB items assessing attitude, subjective norms, perceived behavioral control (PBC), and two additional social influence variables (self-identity and group norm). Regression analyses supported the TPB predictors of participation intentions with self-identity and group norm also significantly predicting intentions. These findings offer preliminary support for the TPB, along with additional sources of social influence, as a useful predictive model of participation in parenting education

Speech rhythm: a metaphor?

Is speech rhythmic? In the absence of evidence for a traditional view that languages strive to coordinate either syllables or stress-feet with regular time intervals, we consider the alternative that languages exhibit contrastive rhythm subsisting merely in the alternation of stronger and weaker elements. This is initially plausible, particularly for languages with a steep ‘prominence gradient’, i.e. a large disparity between stronger and weaker elements; but we point out that alternation is poorly achieved even by a ‘stress-timed’ language such as English, and, historically, languages have conspicuously failed to adopt simple phonological remedies that would ensure alternation. Languages seem more concerned to allow ‘syntagmatic contrast’ between successive units and to use durational effects to support linguistic functions than to facilitate rhythm. Furthermore, some languages (e.g. Tamil, Korean) lack the lexical prominence which would most straightforwardly underpin prominence alternation. We conclude that speech is not incontestibly rhythmic, and may even be antirhythmic. However, its linguistic structure and patterning allow the metaphorical extension of rhythm in varying degrees and in different ways depending on the language, and that it is this analogical process which allows speech to be matched to external rhythms