Context:
There is controversy as to whether papillary thyroid microcarcinoma (PTMC) represents more than one disease entity with different outcomes, requiring different treatment.
Objectives:
To ...compare characteristics, outcomes, and factors associated with prognosis of incidental and nonincidental PTMC.
Setting and Design:
Two reviewers performed searches of online databases (1966–2012), reference lists, and conference abstract books. Longitudinal studies of subjects >16 years old receiving any treatments for papillary thyroid cancer ≤10 mm in size were included. Two reviewers independently screened abstracts and articles, extracted data, and assessed quality of studies using National Institute of Clinical Excellence and PRISMA criteria.
Results:
Of 1102 abstracts identified, 262 studies were reviewed and 17 studies included, comprising 3523 subjects, with mean follow-up of 70 months and total follow-up of 21 329 person-years. This included 854 subjects with incidental PTMC (follow-up, 4800 person-years; mean tumor size, 4.6 mm range 3.3–6.7 mm) and 2669 nonincidental PTMC cases (follow-up, 16 529 person-years; mean tumor size, 6.9 mm range 5.6–8.0 mm). The recurrence rate in the incidental group (0.5%; 95% confidence interval CI, 0–1%, P < .001) was significantly lower than that in the nonincidental group PTMC (7.9%; 95% CI, 5–11%), with an OR of recurrence of 14.7 (95% CI, 5.6–54.8, P < .001) for nonincidental PTMC, compared with incidental PTMC. Lymph nodes were involved in 80% (126/157) of recurrences. On meta-regression, age, sex, size, tumor multifocality, lymph node involvement, and treatment modality were not significantly associated with recurrence.
Conclusions:
Our meta-analysis strongly suggests the existence of at least two distinct entities of PTMC. Incidental PTMC has different clinical characteristics and a much lower recurrence rate than nonincidental PTMC, suggesting that management protocols should be re-considered. Additional studies with standardized data collection are required to explore potential differences between subgroups of nonincidental PTMC.
Highly connected networks generally improve resilience in complex systems. We present a novel application of this paradigm and investigated the potential for anthropogenic structures in the ocean to ...enhance connectivity of a protected species threatened by human pressures and climate change. Biophysical dispersal models of a protected coral species simulated potential connectivity between oil and gas installations across the North Sea but also metapopulation outcomes for naturally occurring corals downstream. Network analyses illustrated how just a single generation of virtual larvae released from these installations could create a highly connected anthropogenic system, with larvae becoming competent to settle over a range of natural deep-sea, shelf and fjord coral ecosystems including a marine protected area. These results provide the first study showing that a system of anthropogenic structures can have international conservation significance by creating ecologically connected networks and by acting as stepping stones for cross-border interconnection to natural populations.
Patients and their families often have preferences for medical care that relate to wider considerations beyond the clinical effectiveness of the proposed interventions. Traditionally, these ...preferences have not been adequately considered in research. Research questions where patients and families have strong preferences may not be appropriate for traditional randomized controlled trials (RCTs) due to threats to internal and external validity, as there may be high levels of drop-out and non-adherence or recruitment of a sample that is not representative of the treatment population. Several preference-informed designs have been developed to address problems with traditional RCTs, but these designs have their own limitations and may not be suitable for many research questions where strong preferences and opinions are present.
In this paper, we propose a novel and innovative preference-informed complementary trial (PICT) design which addresses key weaknesses with both traditional RCTs and available preference-informed designs. In the PICT design, complementary trials would be operated within a single study, and patients and/or families would be given the opportunity to choose between a trial with all treatment options available and a trial with treatment options that exclude the option which is subject to strong preferences. This approach would allow those with strong preferences to take part in research and would improve external validity through recruiting more representative populations and internal validity. Here we discuss the strengths and limitations of the PICT design and considerations for analysis and present a motivating example for the design based on the use of opioids for pain management for children with musculoskeletal injuries.
PICTs provide a novel and innovative design for clinical trials with more than two arms, which can address problems with existing preference-informed trial designs and enhance the ability of researchers to reflect shared decision-making in research as well as improving the validity of trials of topics with strong preferences.
The purpose of this policy briefing is to examine our health care systems through the lens of the COVID-19 pandemic and identify how we can strengthen health care in Canada post-pandemic. The ...COVID-19 pandemic has provided compelling evidence that substantive changes to our health care systems are needed. Specifically, the pandemic has emphasized structural inequities on a broad scale within Canadian society. These include systemic racial and socioeconomic inequities that must be addressed broadly, including in the delivery of health care. We make recommendations about what we can do to emerge stronger from the pandemic. While these recommendations are not novel, how they are framed and contextualized differs because of the problems in our health care system that have been highlighted and exacerbated by the pandemic.The evidence is clear that socioeconomic circumstances, intergenerational trauma, adverse early life experiences, and educational opportunities are critical factors when it comes to health over the life course. Given the problems in the delivery of health care that the pandemic has revealed, we need a different approach. How health care was organized prior to the COVID-19 pandemic did not produce what people wanted and needed in terms of health care and outcomes. How do we emerge from COVID-19 with an effective, equitable, and resilient health care system for all Canadians?
To address health inequities and emerge from the pandemic with strengthened health care in Canada, we must consider how Amartya Sen's capabilities framework on social well-being can be operationalized to achieve better health care and health outcomes. Specifically, we address the need to: strengthen primary care and improve access to primary care; utilize a community-embedded approach to care; and implement better integration across the care continuum, including integration between primary care and public health.
Coherent governance and leadership that are charged with realizing benefits through collaboration will maximize outcomes and promote sustainability. Only when we provide access to high-quality culturally competent care that is centered around the individual and their needs will we be able to make true headway in addressing these long-standing health inequities.
The mammalian securin, pituitary tumor-transforming gene (PTTG), is overexpressed in several tumors and transforms cells in vitro and in vivo. To test the hypothesis that PTTG overexpression causes ...aneuploidy, enhanced green fluorescent protein (EGFP)-tagged PTTG (PTTG-EGFP) was expressed in human H1299 cancer cells (with undetectable endogenous PTTG expression) and mitosis of individual live cells observed. Untransfected cells and cells expressing EGFP alone exhibited appropriate mitosis. PTTG-EGFP markedly prolonged prophase and metaphase, indicating that PTTG blocks progression of mitosis to anaphase. In cells that underwent apparently normal mitosis (35 of 65 cells), PTTG-EGFP was degraded about 1 min before anaphase onset. Cells that failed to degrade PTTG-EGFP exhibited asymmetrical cytokinesis without chromosome segregation (18 of 65 cells) or chromosome decondensation without cytokinesis (9 of 65 cells), resulting in appearance of a macronucleus. Fifty-one of 55 cells expressing a nondegradable mutant PTTG exhibited asymmetrical cytokinesis without chromosome segregation, and some (4 of 55) decondensed chromosomes, both resulting in macronuclear formation. During this abnormal cytokinesis, all chromosomes and spindles and both centrosomes moved to one daughter cell, suggesting potential chaos in the subsequent mitosis. In conclusion, failure of PTTG degradation or enhanced PTTG accumulation, as a consequence of overexpression, inhibits mitosis progression and chromosome segregation but does not directly affect cytokinesis, resulting in aneuploidy. These results demonstrate that PTTG induces aneuploidy in single, live, human cancer cells.
Patients with the acute respiratory distress syndrome (ARDS) require artificial ventilation but this treatment may produce secondary lung damage. High-frequency oscillatory ventilation (HFOV) may ...reduce this damage.
To determine the clinical benefit and cost-effectiveness of HFOV in patients with ARDS compared with standard mechanical ventilation.
A parallel, randomised, unblinded clinical trial.
UK intensive care units.
Mechanically ventilated patients with a partial pressure of oxygen in arterial blood/fractional concentration of inspired oxygen (P : F) ratio of 26.7 kPa (200 mmHg) or less and an expected duration of ventilation of at least 2 days at recruitment.
Treatment arm HFOV using a Novalung R100(®) ventilator (Metran Co. Ltd, Saitama, Japan) ventilator until the start of weaning. Control arm Conventional mechanical ventilation using the devices available in the participating centres.
The primary clinical outcome was all-cause mortality at 30 days after randomisation. The primary health economic outcome was the cost per quality-adjusted life-year (QALY) gained.
One hundred and sixty-six of 398 patients (41.7%) randomised to the HFOV group and 163 of 397 patients (41.1%) randomised to the conventional mechanical ventilation group died within 30 days of randomisation (p = 0.85), for an absolute difference of 0.6% 95% confidence interval (CI) -6.1% to 7.5%. After adjustment for study centre, sex, Acute Physiology and Chronic Health Evaluation II score, and the initial P : F ratio, the odds ratio for survival in the conventional ventilation group was 1.03 (95% CI 0.75 to 1.40; p = 0.87 logistic regression). Survival analysis showed no difference in the probability of survival up to 12 months after randomisation. The average QALY at 1 year in the HFOV group was 0.302 compared to 0.246. This gives an incremental cost-effectiveness ratio (ICER) for the cost to society per QALY of £88,790 and an ICER for the cost to the NHS per QALY of £ 78,260.
The use of HFOV had no effect on 30-day mortality in adult patients undergoing mechanical ventilation for ARDS and no economic advantage. We suggest that further research into avoiding ventilator-induced lung injury should concentrate on ventilatory strategies other than HFOV.
Current Controlled Trials ISRCTN10416500.
Different mutations in the human Crumbs homolog-1 (CRB1) gene cause a variety of retinal dystrophies, such as Leber congenital amaurosis, early onset retinitis pigmentosa (e.g., RP12), RP with ...Coats-like exudative vasculopathy, and pigmented paravenous retinochoroidal atrophy. Loss of Crb1 leads to displaced photoreceptors and focal degeneration of all neural layers attributable to loss of adhesion between photoreceptors and Müller glia cells. To gain insight into genotype-phenotype relationship, we generated Crb1(C249W) mice that harbor an amino acid substitution (Cys249Trp) in the extracellular sixth calcium-binding epidermal growth factor domain of Crb1. Our analysis showed that Crb1(C249W) as wild-type protein trafficked to the subapical region adjacent to adherens junctions at the outer limiting membrane (OLM). Hence, these data suggest correct trafficking of the corresponding mutant CRB1 in RP12 patients. Crb1(C249W) mice showed loss of photoreceptors in the retina, relatively late compared with mice lacking Crb1. Scanning laser ophthalmoscopy revealed autofluorescent dots that presumably represent layer abnormalities after OLM disturbance. Gene expression analyses revealed lower levels of pituitary tumor transforming gene 1 (Pttg1) transcripts in Crb1(C249W/-) knock-in and Crb1(-/-) knock-out compared with control retinas. Exposure to white light decreased levels of Pttg1 in Crb1 mutant retinas. We hypothesize deregulation of Pttg1 expression attributable to a C249W substitution in the extracellular domain of Crb1.
Basic fibroblast growth factor promotes angiogenesis and mitogenesis in colon carcinomas. Pituitarytumour transforming gene (
PTTG
1
) causes in-vitro and in-vivo transformation, regulates secretion ...of basic fibroblast growth factor, and inhibits chromatid separation. Most normal tissues show little or no
PTTG
1
expression but cancer cells express the gene abundantly. We postulated that
PTTG
1
expression in colorectal tumours is related to tumour invasiveness.
PTTG
1
gene and protein expression were assessed in 68 colorectal tumours and compared with invasive characteristics, such as lymph-node invasion, evidence of metastases, tumour vessel density, and expression of basic fibroblast growth factor.
PTTG
1
expression is given in terms of the fold-increase over that in normal-adjacent colorectal tissue.
PTTG
1
was overexpressed in all of 48 colon carcinomas (median fold-increase 2·2 IQR 1·8–3·3) and in 19 of 20 colonic polyps (2·2 1·6–3·1) compared with normal colonic tissue. Invasion of surrounding lymph nodes was associated with higher
PTTG
1
expression than in carcinomas limited to the bowel wall (3·4 2·1–5·9
vs 1·9 1·7–2·4, p=0·007), and higher
PTTG
1
expression was seen in more vascular than in less vascular tumours (2·6 1·9–5·1
vs 1·9 1·8–2·5, p=0·04).
Increased tumour
PTTG
1
expression may be a marker of invasive colorectal carcinoma and could represent a new therapeutic target.
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