Emerging roles of the brain's default network.
During periods of inactivity, global metabolism does not decrease in the brain, and small but consistent increases in activity occur in a specific set of regions called the "default network". Although much is known about the topological and connectional properties of the default network, its functions remain a matter of debate. Functional neuroimaging and electrophysiological studies have suggested two apparently contrasting functions for this network: spontaneous cognition and monitoring the environment. Spontaneous cognition, however, is by default situated in a given external context, an external milieu to which we align ourselves and which must be monitored. This review integrates recent literature suggesting that the two proposed functions of the default network functions need not to be mutually exclusive, and that spontaneous cognition and monitoring of the environment represent complementary instances of conscious experiences occurring during idle moments of daily life.


Material properties of and tissue reaction to the Slocum TPLO plate.
To determine the material properties of Slocum TPLO plates and assess the soft tissue reaction adjacent to these plates in dogs that had undergone tibial plateau leveling osteotomy (TPLO). 3 new TPLO plates, 8 retrieved TPLO plates, and 1 new Synthes dynamic compression plate. Metallurgic analyses were performed. Tissue samples were obtained from areas adjacent to retrieved plates and submitted for histologic examination. All of the TPLO plates had a 2-phase microstructure consisting of austenite and ferrite in various amounts. Residua, inclusions, and cavities were seen during microscopic examination of the plate surface. The major differences between new and retrieved TPLO plates were the presence of small gaps separating many inclusions from the surrounding matrix and the presence of various-sized pits on the surface of the retrieved plates. The dynamic compression plate had a nearly pure austenitic structure and was largely free from residua, inclusions, and cavities. Histologic examination of tissue samples obtained from areas adjacent to retrieved TPLO plates revealed intra- and extracellular particulate debris. Two types of particles (one consisting of chromium, nickel, molybdenum, and iron and the other consisting of aluminum and silicon) were seen. Results determined that new and retrieved TPLO plates were manufactured from 316L stainless steel and produced by a casting process, but not all plates met specifications for chemical composition of cast surgical implants (American Society for Testing Materials standard F745); tissues surrounding retrieved plates had evidence of adverse reactions, probably as a result of plate corrosion.


Is Early Definitive Fixation of Bicondylar Tibial Plateau Fractures Safe? An Observational Cohort Study.
The optimal treatment protocol for bicondylar plateau fractures remains controversial. Contrary to popular practice which favors a staged protocol in many high-energy fracture patterns, we have used early single-stage open reduction and internal fixation (ORIF) to treat these injuries whenever possible. The purpose of this study was to determine the complication rate and the functional and radiographic outcomes of this strategy. Retrospective cohort study and prospective data collection. Level I trauma center. One hundred one patients with 102 OTA/AO type 41-C bicondylar tibial plateau fractures were treated with early definitive ORIF, defined as nonstaged surgery performed within 72 hours from injury. A subset of patients was part of a longitudinal study and reported functional outcomes at 1 year. Early definitive ORIF. Primary outcome: reoperation rate, defined as any surgery within 12 months after the index operation; secondary outcomes: quality and stability of radiographic fracture reduction; and functional outcome [Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and short musculoskeletal functional assessment (SMFA)]. Nonstaged operative treatment of bicondylar plateau fractures was performed in 91.3% of the fractures during the study period. For those, early definitive ORIF (surgery within 72 hours from injury) was performed in 82.3% fractures. Mean time from injury to ORIF, for closed fractures, was 29.8 hours. Sixteen (15.7%) fractures, which were treated with early definitive ORIF, required an additional surgical procedure within 12 months. Complications included wound infection requiring surgical management, compartment syndrome requiring fasciotomies, nonunion, early fixation failure, and implant removal for discomfort. The reoperation rate was 12.7% if implant removal was excluded. At least 3 of the 4 radiographic criteria used to assess the adequacy of reduction were achieved in 95.1% of cases, and all 4 criteria were met in 59.8% of fractures. The Physical Component of the SF-36 at 12 months was 42.6, which is comparable to values reported in previous studies for operative treatment of bicondylar plateau fractures. In a model where surgery is performed without delay by experienced orthopaedic trauma surgeons, a large proportion of bicondylar tibial plateau fractures can be safely treated with early definitive ORIF. Early surgery was associated with satisfactory postoperative radiographic reductions. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Denosumab for Elderly Men with Osteoporosis: A Cost-Effectiveness Analysis from the US Payer Perspective.
Purpose. To evaluate the cost-effectiveness of denosumab versus other osteoporotic treatments in older men with osteoporosis from a US payer perspective. Methods. A lifetime cohort Markov model previously developed for postmenopausal osteoporosis (PMO) was used. Men in the model were 78 years old, with a BMD T-score of -2.12 and a vertebral fracture prevalence of 23%. During each 6-month Markov cycle, patients could have experienced a hip, vertebral or nonhip, nonvertebral (NHNV) osteoporotic fracture, remained in a nonfracture state, remained in a postfracture state, or died. Background fracture risks, mortality rates, persistence rates, health utilities, and medical and drug costs were derived from published sources. Previous PMO studies were used for drug efficacy in reducing fracture risk. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, risedronate, ibandronate, teriparatide, and zoledronate. Results. Denosumab had an incremental cost-effectiveness ratio (ICER) of $16,888 compared to generic alendronate and dominated all other treatments. Results were most sensitive to changes in costs of denosumab and the relative risk of hip fracture. Conclusion. Despite a higher annual treatment cost compared to other medications, denosumab is cost-effective compared to other osteoporotic treatments in older osteoporotic US men.


Expression of endothelial nitric oxide synthase and endothelin-1 in skin tissue from amputated limbs of patients with complex regional pain syndrome.
Impaired microcirculation during the chronic stage of complex regional pain syndrome (CRPS) is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Endothelial dysfunction is suggested to be the main cause of diminished blood flow. The aim of this study was to examine the distribution of endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) relative to vascular density represented by the endothelial marker CD31-immunoreactivity in the skin tissue of patients with chronic CRPS. We performed immunohistochemical staining on sections of skin specimens obtained from the amputated limbs (one arm and one leg) of two patients with CRPS. In comparison to proximal specimens we found an increased number of migrated endothelial cells as well as an increase of eNOS activity in distal dermis specimens. We found indications that endothelial dysfunction plays a role in chronic CRPS.


Heart Failure Pharmacotherapy and Supports in the Elderly - A Short Review.
Heart failure is predominantly a disease of the elderly with an increasing prevalence with increasing age. Increasing age is also associated with increased multi-morbidity such that elderly heart failure patients typically have five to six comorbidities in addition to heart failure. Elderly patients are also more likely to have heart failure with preserved ejection fraction (HFpEF), and there are fewer evidence-based treatments with proven efficacy in HFpEF. Hence the management of heart failure in these patients is largely about managing the symptoms of heart failure, along with the other cardiovascular and non-cardiovascular comorbidities. Any proposed treatments need to be considered for the potential for reduced benefit due to the competing risk of morbidity and mortality from the patient's other conditions. In patients with heart failure, health related quality of life is impacted by both comorbidities and frailty, and frailty is associated with an increased risk of emergency department visits and hospitalisation. Frailty may also be associated with increased adverse reactions to medications. Although newer guidelines have more information on the management of these comorbidities there are still many areas of uncertainty and potential treatment conflicts. Further research is required on the interactions between different comorbidities, their treatments and heart failure and its management.


Domain analysis of Kv6.3, an electrically silent channel.
The subunit Kv6.3 encodes a voltage-gated potassium channel belonging to the group of electrically silent Kv subunits, i.e. subunits that do not form functional homotetrameric channels. The lack of current, caused by retention in the endoplasmic reticulum (ER), was overcome by coexpression with Kv2.1. To investigate whether a specific section of Kv6.3 was responsible for ER retention, we constructed chimeric subunits between Kv6.3 and Kv2.1, and analysed their subcellular localization and functionality. The results demonstrate that the ER retention of Kv6.3 is not caused by the N-terminal A and B box (NAB) domain nor the intracellular N- or C-termini, but rather by the S1-S6 core protein. Introduction of individual transmembrane segments of Kv6.3 in Kv2.1 was tolerated, with the exception of S6. Indeed, introduction of the S6 domain of Kv6.3 in Kv2.1 was enough to cause ER retention, which was due to the C-terminal section of S6. The S4 segment of Kv6.3 could act as a voltage sensor in the Kv2.1 context, albeit with a major hyperpolarizing shift in the voltage dependence of activation and inactivation, apparently caused by the presence of a tyrosine in Kv6.3 instead of a conserved arginine. This study suggests that the silent behaviour of Kv6.3 is largely caused by the C-terminal part of its sixth transmembrane domain that causes ER retention of the subunit.


Comparison of the clinical and cost effectiveness of two management strategies (rehabilitation versus surgical reconstruction) for non-acute anterior cruciate ligament (ACL) injury: study protocol for the ACL SNNAP randomised controlled trial.
Anterior cruciate ligament (ACL) rupture is a common knee injury that can lead to poor quality of life, decreased activity and increased risk of secondary osteoarthritis of the knee. Management of patients with a non-acute ACL injury can include a non-surgical (rehabilitation) or surgical (reconstruction) approach. However, insufficient evidence to guide treatment selection has led to high variation in treatment choice for patients with non-acute presentation of ACL injury. The objective of the ACL SNNAP trial is to determine in patients with non-acute anterior cruciate ligament deficiency (ACLD) whether a strategy of non-surgical management (rehabilitation) (with option for later ACL reconstruction only if required) is more clinically effective and cost effective than a strategy of surgical management (reconstruction) without prior rehabilitation with all patients followed up at 18 months. The study is a pragmatic, multi-centre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Patients with a symptomatic non-acute ACL deficient knee will be randomised to either non-surgical management (rehabilitation) or surgical management (reconstruction). We aim to recruit 320 patients from approximately 30 secondary care orthopaedic units from across the United Kingdom. Randomisation will occur using a web-based randomisation system. Blinding of patients and clinicians to treatment allocation will not be possible because of the nature of the interventions. Participants will be followed up via self-reported questionnaires at 6, 12 and 18 months. The primary outcome is the Knee injury and Osteoarthritis Outcome Score (KOOS) at 18 months post randomisation. Secondary outcomes will include a return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee specific quality of life and resource usage. At present, no evidence-based treatment of non-acute ACL deficiency exists, particularly in the NHS. Moreover, little consensus exists on the management approach for these patients. The proposed trial will address this gap in knowledge regarding the clinical and cost effectiveness of ACL treatment and inform future standards of care for this condition. ISRCTN: 10110685. Registered on 16 November 2016. ClinicalTrials.gov: NCT02980367. Registered in December 2016.


Prevalence of gaming disorder in East Asia: A comprehensive meta-analysis.
Asian countries are deemed to be high prevalence areas for gaming disorder (GD). This meta-analysis is the first to synthesize the overall prevalence of GD in East Asia and investigate characteristics that influence prevalence estimates. Systematic and independent searches were conducted across PubMed, Web of Science, Embase, PsycINFO, and the Cochrane Library since their inception to January 27, 2021. The Agency for Healthcare Research and Quality scale was used for quality assessment. A random effect model was used to calculate the overall GD prevalence and 95% confidence intervals (CIs). In total, 22 articles (26 studies) comprising 51,525 participants were included in this meta-analysis. The overall pooled prevalence of GD in East Asia was 12%, 95% CI (10%-15%); this figure was adjusted to 6%, 95% CI (3%-9%) for a representative sample. Higher prevalence was observed in males than in females (16% vs. 8%, respectively, P < 0.05). Subgroup and meta-regression analyses revealed that studies among gamers or those without random sampling reported significantly higher prevalence rates. There were no significant differences between countries/regions, sample size, quality score, proportion of males, and scale used. The prevalence of GD in East Asia is higher than that in other world regions. Future studies should extend such epidemiological research to other regions to calculate the accurate prevalence of GD to benefit the local identification, prevention, policy formulation, and treatment efforts. Considering its negative effects, effective preventive and treatment measures for GD in East Asia need greater attention.


Smoking cessation after surgery. A randomized trial.
Cigarette smoking is the greatest cause of preventable mortality in the United States. Because most smokers would like to quit and most hospitals are smoke free, surgical admissions represent a window of opportunity for tobacco cessation interventions. A total of 324 patients (98% men), aged 25 to 82 years, who were current smokers and who underwent noncardiac surgery were enrolled in a randomized controlled trial at the Veterans Affairs Medical Center, San Francisco, Calif. One hundred sixty-eight participants (52%) received a multicomponent intervention designed to increase self-efficacy and coping skills that included face-to-face in-hospital counseling, viewing a smoking cessation videotape, self-help literature, nicotine replacement therapy, and 3 months of telephone follow-up. One hundred fifty-six participants (48%) received self-help literature and brief counseling lasting 10 minutes. Serum or saliva cotinine levels were measured to confirm self-reported smoking cessation. At 12 months of follow-up, the self-reported quit rate was 27% among the intervention group and 13% among the comparison group (relative risk, 2.1; 95% confidence interval, 1.2-3.5; P < .01). Based on biochemical confirmation, 15% of the intervention group, compared with 8% of the comparison group, quit smoking at 12 months (relative risk, 2.0; 95% confidence interval, 1.0-3.9; P = .04). A smoking cessation intervention targeted at smokers hospitalized for noncardiac surgery can increase long-term quit rates. Surgical hospitalizations provide an opportunity to reach smokers who want to quit smoking.


Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility.
A1 adenosine receptors in the rat prepiriform cortex play an important role in the inhibition of bicuculline methiodide-induced convulsions. In the present study we evaluated manipulation of endogenous adenosine in this brain area as a strategy to effect seizure suppression. All compounds evaluated were unilaterally microinjected into the rat prepiriform cortex. Administration of exogenous adenosine afforded a dose-dependent protection (ED50 = 48.1 +/- 8.4 nmol) against bicuculline methiodide-induced seizures, and these anticonvulsant effects were significantly potentiated by treatment with an adenosine kinase inhibitor, 5'-amino-5'-deoxyadenosine; by the adenosine transport blockers, dilazep or nitrobenzylthioinosine 5'-monophosphate; and by an adenosine deaminase inhibitor, 2'-deoxycoformycin. When administered alone, 5'-amino-5'-deoxyadenosine, 5'-iodotubercidin and dilazep were found to be highly efficacious as anticonvulsants with respective ED50 values of 2.6 +/- 0.8, 4.0 +/- 2.7 and 5.6 +/- 1.5 nmol. In contrast, 2'-deoxycoformycin was both less potent and less efficacious. These results suggest that accumulation of endogenous adenosine may contribute to seizure suppression, and that adenosine kinase and adenosine transport may play a pivotal role in the regulation of extracellular levels of adenosine in the central nervous system. The adenosine antagonist, 8-(p-sulfophenyl)theophylline, increased markedly the severity of bicuculline methiodide-induced seizures. Moreover, reduction of extracellular adenosine formation by a focal injection of an ecto-5'-nucleotidase inhibitor, alpha, beta-methyleneadenosine diphosphate, produced generalized seizures (ED50 = 37.3 +/- 22.7 nmol). Together the proconvulsant effect of an adenosine receptor antagonist and the convulsant action of an ecto-5'-nucleotidase inhibitor further support the role of endogenous adenosine as a tonically active antiepileptogenic substance in the rat prepiriform cortex.


Challenging Ancient DNA Results About Putative HLA Protection or Susceptibility to Yersinia pestis.
In a recent article, Immel et al. (Immel A, Key FM, Szolek A, Barquera R, Robinson MK, Harrison GF, Palmer WH, Spyrou MA, Susat J, Krause-Kyora B, et al. 2021. Analysis of genomic DNA from medieval plague victims suggests long-term effect of Yersinia pestis on human immunity genes. Mol Biol Evol. 38:4059-4076) extracted DNA from 36 individuals dead from plague in Ellwangen, Southern Germany, during the 16th century. By comparing their human leukocyte antigen (HLA) genotypes with those of 50 present-day Ellwangen inhabitants, the authors reported a significant decrease of HLA-B*51:01 and HLA-C*06:02 and a significant increase of HLA-DRB1*13:01/13:02 frequencies from ancient to modern populations. After comparing these frequencies with a larger sample of 8,862 modern Germans and performing simulations of natural selection, they concluded that these changes had been driven by natural selection. In an attempt to provide more evidence on such stimulating results, we explored the HLA frequency patterns over all of Europe, we predicted binding affinities of HLA-B/C/DRB1 alleles to 106,515 Yersinia pestis-derived peptides, and we performed forward simulations of HLA genetic profiles under neutrality. Our analyses do not sustain the conclusions of HLA protection or susceptibility to plague based on ancient DNA.


Gait Asymmetry Post-Stroke: Determining Valid and Reliable Methods Using a Single Accelerometer Located on the Trunk.
Asymmetry is a cardinal symptom of gait post-stroke that is targeted during rehabilitation. Technological developments have allowed accelerometers to be a feasible tool to provide digital gait variables. Many acceleration-derived variables are proposed to measure gait asymmetry. Despite a need for accurate calculation, no consensus exists for what is the most valid and reliable variable. Using an instrumented walkway (GaitRite) as the reference standard, this study compared the validity and reliability of multiple acceleration-derived asymmetry variables. Twenty-five post-stroke participants performed repeated walks over GaitRite whilst wearing a tri-axial accelerometer (Axivity AX3) on their lower back, on two occasions, one week apart. Harmonic ratio, autocorrelation, gait symmetry index, phase plots, acceleration, and jerk root mean square were calculated from the acceleration signals. Test-retest reliability was calculated, and concurrent validity was estimated by comparison with GaitRite. The strongest concurrent validity was obtained from step regularity from the vertical signal, which also recorded excellent test-retest reliability (Spearman's rank correlation coefficients (rho) = 0.87 and Intraclass correlation coefficient (ICC21) = 0.98, respectively). Future research should test the responsiveness of this and other step asymmetry variables to quantify change during recovery and the effect of rehabilitative interventions for consideration as digital biomarkers to quantify gait asymmetry.


Ceftriaxone versus combined gentamicin and clindamycin for polymicrobial surgical sepsis.
During a 7 month trial for therapy of polymicrobial surgical sepsis, intravenous antibiotic treatment was randomized between gentamicin (1 mg/kg every 8 hours) plus clindamycin (8 mg/kg every 6 hours), and the cephalosporin, ceftriaxone (1 g every 12 hours) in 197 patients, of whom 99 were being treated for peritonitis, 93 for soft tissue sepsis, and 5 for other forms of infection. No significant differences were noted in patient demographics, type of sepsis, associated disease states, surgical procedure, or causative aerobic or anaerobic pathogens. Results demonstrated approximately equivalent efficacy, although cure rates obtained with ceftriaxone in patients with soft tissue sepsis or intraabdominal abscess were superior to those achieved with combination gentamicin and clindamycin. There were no significant side effects with ceftriaxone therapy, such as the renal failure noted in six of the patients treated with gentamicin and clindamycin. We conclude that single agent treatment with ceftriaxone is preferable because of the greater safety and the longer dosing intervals.


Oxidative stress induces nuclear loss of DNA repair proteins Ku70 and Ku80 and apoptosis in pancreatic acinar AR42J cells.
Cell death linked to oxidative DNA damage has been implicated in acute pancreatitis. The severe DNA damage, which is beyond the capacity of the DNA repair proteins, triggers apoptosis. It has been hypothesized that oxidative stress may induce a decrease in the Ku70 and Ku80 levels and apoptosis in pancreatic acinar cells. In this study, it was found that oxidative stress caused by glucose oxidase (GO) acting on beta-d-glucose, glucose/glucose oxidase (G/GO), induced slight changes in cytoplasmic Ku70 and Ku80 but drastically induced a decrease in nuclear Ku70 and Ku80 both time- and concentration-dependently in AR42J cells. G/GO induced apoptosis determined by poly(ADP-ribose) polymerase cleavage, an increase in expression of p53 and Bax, and a decrease in Bcl-2 expression. G/GO-induced apoptosis was in parallel with the loss of nuclear Ku proteins in AR42J cells. Caspase-3 inhibitor prevented G/GO-induced nuclear Ku loss and cell death. G/GO did not induce apoptosis in the cells transfected with either the Ku70 or Ku80 expression gene but increased apoptosis in those transfected with the Ku dominant negative mutant. Pulse and pulse-chase results show that G/GO induced Ku70 and Ku80 syntheses, even though Ku70 and Ku80 were degraded both in cytoplasm and nucleus. G/GO-induced decrease in Ku binding to importin alpha and importin beta reflects possible modification of nuclear import of Ku proteins. The importin beta level was not changed by G/GO. These results demonstrate that nuclear decrease in Ku70 and Ku80 may result from the decrease in Ku binding to nuclear transporter importins and the degradation of Ku proteins. The nuclear loss of Ku proteins may underlie the mechanism of apoptosis in pancreatic acinar cells after oxidative stress.


The plant-specific protein FEHLSTART controls male meiotic entry, initializing meiotic synchronization in Arabidopsis.
Meiosis marks the transition from the sporophyte to the gametophyte generation in the life cycle of flowering plants, and creates genetic variations through homologous recombination. In most flowering plants, meiosis is highly synchronized within each anther, which is significant for efficient fertilization. To date, little is known about the molecular mechanisms of entry into meiosis and exit from it, and only a few genes in Arabidopsis have been characterized with a role in regulating meiotic progression. In this study, we report the functional characterization of a plant-specific basic helix-loop-helix (bHLH) protein, FEHLSTART (FST), a defect in which leads to premature meiotic entry and asynchronous meiosis, and results in decreased seed yield. Investigation of the time course of meiosis showed that the onset of leptotene, the first stage of prophase I, frequently occurred earlier in fst-1 than in the wild type. Asynchronous meiosis followed, which could manifest in the disruption of regular spindle structures and symmetric cell divisions in fst-1 mutants during the meiosis I/II transition. In accordance with frequently accelerated meiotic entry, whole-transcriptome analysis of fst-1 anthers undergoing meiosis revealed that 19 circadian rhythm genes were affected and 47 pollen-related genes were prematurely expressed at a higher level. Taken together, we propose that FST is required for normal meiotic entry and the establishment of meiotic synchrony.


Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia.
Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood. We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.


Screening for postnatal depression in primary care: cost effectiveness analysis.
To evaluate the cost effectiveness of routine screening for postnatal depression in primary care. Cost effectiveness analysis with a decision model of alternative methods of screening for depression, including standardised postnatal depression and generic depression instruments. The performance of screening instruments was derived from a systematic review and bivariate meta-analysis at a range of instrument cut points; estimates of other relevant parameters were derived from literature sources and relevant databases. A decision tree considered the full treatment pathway from the possible onset of postnatal depression through identification, treatment, and possible relapse. Primary care. A hypothetical population of women assessed for postnatal depression either via routine care only or supplemented by use of formal identification methods six weeks postnatally, as recommended in recent guidelines. Costs expressed in 2006-7 prices and impact on health outcomes expressed in terms of quality adjusted life years (QALYs). The time horizon of the analysis was one year. The routine application of either postnatal or general depression questionnaires did not seem to be cost effective compared with routine care only. The Edinburgh postnatal depression scale (at a cut point of 16) had an incremental cost effectiveness ratio (ICER) of pound 41,103 (euro 45,398, $67,130) per QALY compared with routine care only. The ICER for all other strategies ranged from pound 49,928 to pound 272,463 per QALY versus routine care only, while the probability that no formal identification strategy was cost effective was 88% (59%) at a cost effectiveness threshold of pound 20,000 ( pound 30,000) per QALY. While sensitivity analysis indicated that the cost of managing incorrectly identified depression (false positive result) was an important driver of the model, formal identification approaches did not seem to be cost effective at any feasible estimate of this cost. Formal identification methods for postnatal depression do not seem to represent value for money for the NHS. The major determinant of cost effectiveness seems to be the potential additional costs of managing women incorrectly diagnosed as depressed. Formal identification methods for postnatal depression do not currently satisfy the National Screening Committee's criteria for the adoption of a screening strategy as part of national health policy.


Mevalonate signaling, COPD and cancer: the statins and beyond.
Evidence suggests that smoking confers a persistent and/or exaggerated inflammatory response in the lungs that, with underlying genetic susceptibility, may result in lung remodeling and impaired repair. The innate immune response to smoking described above, which is modified by the mevalonate pathway, provides a plausible pathogenic link between the development of chronic obstructive pulmonary disease and lung cancer. The mevalonate pathway modifies innate responsiveness through important intracellular signaling molecules called guanine phosphate transferases (GTPases) such as Rho-A. Smoke exposure activates cell surface proteins which, through the mediating influence of GTPases, then modifies the activation of nuclear factor kappa -light-chain-enhancer of activated B cells (NFĸB) its downstream effects on genes underlying innate immunity, neutrophilic inflammation and carcinogenesis. The mevalonate pathway is modifiable through the enzyme 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMGCo-A) reductase. This enzyme controls the rate limiting step of the mevalonate pathway and is subject to inhibition by statin drugs (HMGCo-A reductase inhibitors) and small chain fatty acids derived from high dietary fiber intake. Ths, inhibitory effect dampens the innate immune response to smoking and may modify pulmonary inflammation and lung remodeling. This article is a symposia summary outlining the preclinical and clinical data suggesting that statins and a high-fiber diet may have a chemopreventive effect on lung cancer.


Interference from filled delays on visual change detection.
Failure to detect changes to salient visual input across a brief interval has popularized the use of change detection, a paradigm that plays important roles in recent studies of visual perception, short-term memory, and consciousness. Much research has focused on the nature of visual representation for the pre- and postchange displays, yet little is known about how visual change detection is interfered with by events inserted between the pre- and postchange displays. To address this question, we tested change detection of colors, spatial locations, and natural scenes, when the interval between changes was (1) blank, (2) filled with a visual scene, or (3) filled with an auditory word. Participants were asked to either ignore the filled visual or auditory event or attend to it by categorizing it as animate or inanimate. Results showed that the ability to detect visual changes was dramatically impaired by attending to a secondary task during the delay. This interference was significant for auditory as well as for visual interfering events and was invariant to the complexity of the prechange displays. Passive listening produced no interference, whereas passive viewing produced small but significant interference. We conclude that visual change detection relies significantly on central, amodal attention.


Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa.
We report here the crystal structure of the Pseudomonas aeruginosa multidrug exporter MexB, an intensively studied member of the resistance-nodulation-cell division family of secondary active transporters, at 3.0 A. MexB forms an asymmetric homotrimer where each subunit adopts a different conformation representing three snapshots of the transport cycle similar to the recently determined structures of its close homologue AcrB from Escherichia coli, so far the sole structurally characterized member of the superfamily. As for AcrB, the conformations of two subunits can be clearly assigned to either the binding step or the extrusion step in the transport process. Unexpectedly, a remarkable conformational shift in the third subunit is observed in MexB, which has potential implications for the assembly of the tripartite MexAB-OprM drug efflux system. Furthermore, an n-dodecyl-d-maltoside molecule was found bound to the internal multidrug-binding cavity, which might indicate that MexB binds and transports detergent molecules as substrates. As the only missing piece of the puzzle in the MexAB-OprM system, the X-ray structure of MexB completes the molecular picture of the major pump mediating intrinsic and acquired multidrug resistance in P. aeruginosa.


Cost comparison of the laparoscopic burch colposuspension, laparoscopic two-team sling procedure, and the transobturator tape procedure for the treatment of stress urinary incontinence.
To compare medical costs of three surgical procedures for the treatment of primary stress urinary incontinence: the laparoscopic Burch colposuspension procedure, the laparoscopic two-team sling procedure, and the transobturator tape (TOT) procedure. We performed a retrospective observational study of isolated minimally invasive surgical procedures (no concomitant surgery) in 18 women with primary stress incontinence. Six women underwent a laparoscopic Burch colposuspension procedure, six underwent a laparoscopic two-team sling, and six underwent a TOT procedure. The main outcome measure was the mean aggregated medical cost per patient treated. Itemized calculations were made for (1) equipment costs; (2) surgeon, surgical assistant, and anaesthesiologist reimbursements; (3) nursing costs; (4) operating and recovery room costs; and (5) costs of stay in hospital. The mean cost per patient undergoing a TOT procedure was $2547 (95% CI $2260 to $2833); for a laparoscopic Burch colposuspension it was $4354 (95% CI $3465 to $5244); and for a laparoscopic two-team sling procedure it was $5393 (95% CI $4959 to $5826). Significant differences were found across procedures using a one-way ANOVA. A TOT was lower in cost than both a Burch procedure, with a mean cost difference of $1807.88 (P < 0.001), and a sling procedure, with a mean cost difference of $2834.73 (P < 0.001). A transobturator tape procedure has less direct medical costs than a laparoscopic Burch colposuspension or a laparoscopic two-team sling procedure in the surgical treatment of stress urinary incontinence.


Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth.
Although in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus. The nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. We, therefore, identify Amotl1, which is not present in flies, as a mammalian intermediate for non-canonical Hippo signalling, downstream of Fat4. This work uncovers a mechanism for the restriction of heart growth at birth, a process which impedes the regenerative potential of the mammalian heart.


Prostration and the prognosis of death in African children with severe malaria.
Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain. Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration. Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P <0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambaréné Organ Dysfunction Score. Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes.


Ultrasound-targeted transfection of tissue-type plasminogen activator gene carried by albumin nanoparticles to dog myocardium to prevent thrombosis after heart mechanical valve replacement.
There are more than 300,000 prosthetic heart valve replacements each year worldwide. These patients are faced with a higher risk of thromboembolic events after heart valve surgery and long-term or even life-long anticoagulative and antiplatelet therapies are necessary. Some severe complications such as hemorrhaging or rebound thrombosis can occur when the therapy ceases. Tissue-type plasminogen activator (t-PA) is a thrombolytic agent. One of the best strategies is gene therapy, which offers a local high expression of t-PA over a prolonged time period to avoid both systemic hemorrhaging and local rebound thrombosis. There are some issues with t-PA that need to be addressed: currently, there is no up-to-date report on how the t-PA gene targets the heart in vivo and the gene vector for t-PA needs to be determined. To fabricate an albumin nano-t-PA gene ultrasound-targeted agent and investigate its targeting effect on prevention of thrombosis after heart mechanic valve replacement under therapeutic ultrasound. A dog model of mechanical tricuspid valve replacement was constructed. A highly expressive t-PA gene plasmid was constructed and packaged by nanoparticles prepared with bovine serum albumin. This nanopackaged t-PA gene plasmid was further cross-linked to ultrasonic microbubbles prepared with sucrose and bovine serum albumin to form the ultrasonic-targeted agent for t-PA gene transfection. The agent was given intravenously followed by a therapeutic ultrasound treatment (1 MHz, 1.5 w/cm(2), 10 minutes) of the heart soon after valve replacement had been performed. The expression of t-PA in myocardium was detected with multiclonal antibodies to t-PA by the indirect immunohistochemical method. Venous blood t-PA and D-dimer contents were tested before and 1, 2, 4, and 8 weeks after the operation. The high expression of t-PA could be seen in myocardium with increases in blood t-PA and D-dimer contents and thrombosis was prevented 8 weeks after operation. We successfully fabricated an albumin nano-t-PA gene ultrasound-targeted agent that could prevent dog thrombosis after mechanical heart valve replacement. Our study provides an experimental basis for prevention of human thrombosis-related diseases.


Prevention of dislocation of the hip in children with cerebral palsy: 20-year results of a population-based prevention programme.
In 1994 a cerebral palsy (CP) register and healthcare programme was established in southern Sweden with the primary aim of preventing dislocation of the hip in these children. The results from the first ten years were published in 2005 and showed a decrease in the incidence of dislocation of the hip, from 8% in a historical control group of 103 children born between 1990 and 1991 to 0.5% in a group of 258 children born between 1992 and 1997. These two cohorts have now been re-evaluated and an additional group of 431 children born between 1998 and 2007 has been added. By 1 January 2014, nine children in the control group, two in the first study group and none in the second study group had developed a dislocated hip (p < 0.001). The two children in the first study group who developed a dislocated hip were too unwell to undergo preventive surgery. Every child with a dislocated hip reported severe pain, at least periodically, and four underwent salvage surgery. Of the 689 children in the study groups, 91 (13%) underwent preventive surgery. A population-based hip surveillance programme enables the early identification and preventive treatment, which can result in a significantly lower incidence of dislocation of the hip in children with CP.


Expression of fgf23 and αklotho in developing embryonic tissues and adult kidney of the zebrafish, Danio rerio.
Fibroblast growth factor 23 (FGF23) is an endocrine hormone that is secreted by bone and acts on the kidney and parathyroid glands to regulate phosphate homeostasis. The effects of FGF23 on phosphate homeostasis are mediated by binding to FGF receptors and their coreceptor, αklotho, which are abundantly expressed in the kidney and parathyroid glands. However, the mechanisms of how FGF23 regulates phosphate handling in the proximal tubule are unclear because αklotho is primarily expressed in the distal nephron in humans and rodents. The purpose of this study was to gain additional insight into the FGF23-αklotho system by investigating the spatial and temporal aspects of the expression of fgf23 and αklotho in the zebrafish, Danio rerio. Here, we report that zebrafish fgf23 begins to be expressed after organogenesis and is continually expressed into adulthood in the corpuscles of Stannius, which are endocrine glands that lie in close proximity to the nephron and are thought to contribute to calcium and phosphate homeostasis in fish. Zebrafish αklotho expression can be detected by 24-h postfertilization in the brain, pancreas and the distal pronephros, and by 56-h postfertilization in liver. Expression in the distal pronephros persists throughout development, and by Day 5, there is also strong expression in the proximal pronephros. αklotho continues to be expressed in the tubules of the metanephros of the adult kidney. These data indicate conservation of the FGF23-αklotho system across species and suggest a likely role for αklotho in the proximal and distal tubules.


Incorporation of personal single nucleotide polymorphism (SNP) data into a national level electronic health record for disease risk assessment, part 1: an overview of requirements.
Personalized medicine approaches provide opportunities for predictive and preventive medicine. Using genomic, clinical, environmental, and behavioral data, tracking and management of individual wellness is possible. A prolific way to carry this personalized approach into routine practices can be accomplished by integrating clinical interpretations of genomic variations into electronic medical records (EMRs)/electronic health records (EHRs). Today, various central EHR infrastructures have been constituted in many countries of the world including Turkey. The objective of this study was to concentrate on incorporating the personal single nucleotide polymorphism (SNP) data into the National Health Information System of Turkey (NHIS-T) for disease risk assessment, and evaluate the performance of various predictive models for prostate cancer cases. We present our work as a miniseries containing three parts: (1) an overview of requirements, (2) the incorporation of SNP into the NHIS-T, and (3) an evaluation of SNP incorporated NHIS-T for prostate cancer. For the first article of this miniseries, the scientific literature is reviewed and the requirements of SNP data integration into EMRs/EHRs are extracted and presented. In the literature, basic requirements of genomic-enabled EMRs/EHRs are listed as incorporating genotype data and its clinical interpretation into EMRs/EHRs, developing accurate and accessible clinicogenomic interpretation resources (knowledge bases), interpreting and reinterpreting of variant data, and immersing of clinicogenomic information into the medical decision processes. In this section, we have analyzed these requirements under the subtitles of terminology standards, interoperability standards, clinicogenomic knowledge bases, defining clinical significance, and clinicogenomic decision support. In order to integrate structured genotype and phenotype data into any system, there is a need to determine data components, terminology standards, and identifiers of clinicogenomic information. Also, we need to determine interoperability standards to share information between different information systems of stakeholders, and develop decision support capability to interpret genomic variations based on the knowledge bases via different assessment approaches.


Catalytic mechanism and mode of action of the periplasmic alginate epimerase AlgG.
Pseudomonas aeruginosa is an opportunistic pathogen that forms chronic biofilm infections in the lungs of cystic fibrosis patients. A major component of the biofilm during these infections is the exopolysaccharide alginate, which is synthesized at the inner membrane as a homopolymer of 1-4-linked β-D-mannuronate. As the polymer passages through the periplasm, 22-44% of the mannuronate residues are converted to α-L-guluronate by the C5-epimerase AlgG to produce a polymer of alternating β-D-mannuronate and α-L-guluronate blocks and stretches of polymannuronate. To understand the molecular basis of alginate epimerization, the structure of Pseudomonas syringae AlgG has been determined at 2.1-Å resolution, and the protein was functionally characterized. The structure reveals that AlgG is a long right-handed parallel β-helix with an elaborate lid structure. Functional analysis of AlgG mutants suggests that His(319) acts as the catalytic base and that Arg(345) neutralizes the acidic group during the epimerase reaction. Water is the likely catalytic acid. Electrostatic surface potential and residue conservation analyses in conjunction with activity and substrate docking studies suggest that a conserved electropositive groove facilitates polymannuronate binding and contains at least nine substrate binding subsites. These subsites likely align the polymer in the correct register for catalysis to occur. The presence of multiple subsites, the electropositive groove, and the non-random distribution of guluronate in the alginate polymer suggest that AlgG is a processive enzyme. Moreover, comparison of AlgG and the extracellular alginate epimerase AlgE4 of Azotobacter vinelandii provides a structural rationale for the differences in their Ca(2+) dependence.


How might acupuncture work? A systematic review of physiologic rationales from clinical trials.
Scientific interest in acupuncture has led numerous investigators to conduct clinical trials to test the efficacy of acupuncture for various conditions, but the mechanisms underlying acupuncture are poorly understood. The author conducted a PubMed search to obtain a fair sample of acupuncture clinical trials published in English in 2005. Each article was reviewed for a physiologic rationale, as well as study objectives and outcomes, experimental and control interventions, country of origin, funding sources and journal type. Seventy-nine acupuncture clinical trials were identified. Twenty-six studies (33%) offered no physiologic rationale. Fifty-three studies (67%) posited a physiologic basis for acupuncture: 33 (62% of 53) proposed neurochemical mechanisms, 2 (4%) segmental nervous system effects, 6 (11%) autonomic nervous system regulation, 3 (6%) local effects, 5 (9%) effects on brain function and 5 (9%) other effects. No rationale was proposed for stroke; otherwise having a rationale was not associated with objective, positive or negative findings, means of intervention, country of origin, funding source or journal type. The dominant explanation for how acupuncture might work involves neurochemical responses and is not reported to be dependent on treatment objective, specific points, means or method of stimulation. Many acupuncture trials fail to offer a meaningful rationale, but proposing a rationale can help investigators to develop and test a causal hypothesis, choose an appropriate control and rule out placebo effects. Acupuncture may stimulate self-regulatory processes independent of the treatment objective, points, means or methods used; this would account for acupuncture's reported benefits in so many disparate pathologic conditions.


Nephelometric measurement of human serum prealbumin and correlation with acute-phase proteins CRP and SAA: results in familial amyloid polyneuropathy.
Prealbumin, a negative acute-phase reactant, has a role as a clinical index of patient status after inflammation, trauma, or surgery that is gaining recognition. We developed a rate nephelometric assay that allows quantitation of prealbumin levels in a large number of samples to be performed quickly, efficiently, and reproducibly. The generation of data by this method is more rapid and precise than the alternative measurement techniques of radioimmunoassay, radial immunodiffusion, and electroimmunoassay. Nephelometric analysis of serum prealbumin in 33 patients with familial amyloidosis showed significantly depressed concentrations compared with levels in normal individuals and in patients with primary and secondary amyloidosis. Prealbumin levels were compared with corresponding amounts of the acute-phase proteins C-reactive protein and serum amyloid A in the three amyloid groups. Lowered prealbumin concentrations corresponded to elevated levels of C-reactive protein and serum amyloid A in the sera from patients with primary and secondary amyloidosis. In the group with familial amyloidosis, however, the lower than normal levels of prealbumin did not correspond to elevations in C-reactive protein and serum amyloid A. Our data suggest that depressed plasma prealbumin concentrations noted in individuals with familial amyloidosis are not simply reflections of a negative acute-phase response.


Occurrence of cognitive and neurological symptoms in norwegian dentists.
Previous investigations have presented some evidence of late cognitive effects in dental personnel exposed to metallic mercury. We wanted to examine if Norwegian dentists have an increased prevalence of symptoms consistent with neurological and/or cognitive malfunction. The study group consisted of 406 dentists from central Norway and 217 controls from the general population, all under the age of 70. They had responded to a standardised postal questionnaire (Euroquest) inquiring about seven symptoms in regard to neurology, psychosomatics, memory, concentration, mood, sleep disturbances, and fatigue. A score was calculated for each symptom based on 4 to 15 single questions scored on a scale from 1 (seldom or never) to 4 (very often). The dentists and controls had a participation rate of 57.2% and 42.9% respectively. The dentists reported no more cognitive symptoms than the controls, with low average symptom scores from 1.16 for neurological symptoms in males to 1.73 for fatigue in females. Corresponding figures for the controls were 1.22 and 1.77. There were a total of 1.2% of the dentists and 1.8% of the controls who reported having three or more of the seven symptoms "often" or more frequently. Norwegian dentists do not report more cognitive and neurological symptoms than controls from the general population.


Meisetz and the birth of the KRAB motif.
The largest family of transcription factors in mammals is of Cys(2)His(2) zinc finger-proteins, each with an NH(2)-terminal KRAB motif. Extensive expansions of this family have occurred in separate mammalian lineages, with approximately 400 such genes known in the human genome. Despite their widespread occurrence, the evolutionary provenance of the KRAB motif is unclear since previously it has not been found outside of the tetrapod vertebrates. Here, we show that homologues of the histone methyltransferase Meisetz are present within the sea urchin (Strongylocentrotus purpuratus) genome. Sea urchin and mammalian Meisetz sequences each contain an N-terminal KRAB motif, which thereby establishes an early origin of the KRAB motif prior to the divergence of echinoderm and chordate lineages. Finally, we present evidence that KRAB motifs derive from a novel family of KRI (KRAB Interior) motifs that were present in the last common ancestor of animals, plants and fungi.


Identifying Familial Hypercholesterolemia Using a Blood Donor Screening Program With More Than 1 Million Volunteer Donors.
Familial hypercholesterolemia is an autosomal-dominant disorder that often causes premature coronary artery disease. Unfortunately, familial hypercholesterolemia remains largely undiagnosed. To estimate the prevalence of familial hypercholesterolemia in a population of blood donors. This analysis of deidentified data from blood donors 16 years and older who donated to Carter BloodCare, one of the largest independent blood programs in the United States, between January 2002 and December 2016. Carter BloodCare, which serves a population of about 8 million in Texas, routinely measures total nonfasting serum cholesterol levels as part of a donor health screening program. Data analysis occurred from October 2017 to March 2019. Blood donation. Familial hypercholesterolemia was defined using the Make Early Diagnosis to Prevent Early Death general population criteria, with total nonfasting serum cholesterol thresholds of 270, 290, 340, and 360 mg/dL for donors younger than 20 years, 20 to 29 years, 30 to 39 years, and 40 years or older, respectively (to convert cholesterol values to mmol/L, multiply by 0.0259). For repeated donors, the maximum observed total cholesterol level was used for analyses. The study included 1 178 102 individual donors with a total of 3 038 420 blood donations. Of all individual donors (median total cholesterol level, 183 [interquartile range (IQR), 157-212] mg/dL; median age, 32 [IQR, 19-47] years; 619 583 [52.6%] women), a total of 3473 individuals (or 1 in every 339) met criteria for familial hypercholesterolemia. This group had a median (IQR) total cholesterol of 332 (297-377) mg/dL. Estimated prevalence was higher at younger ages (<30 years: 1:257) compared with older ages (≥30 years: 1:469; P < .001) and in men (1:327) compared with women (1:351; P = .03). Among 2219 repeated donors who met familial hypercholesterolemia criteria at least once, 3116 of 10 833 total donations (28.8%) met FH criteria. The prevalence of familial hypercholesterolemia using the Make Early Diagnosis to Prevent Early Death criteria in a large cohort of blood donors was similar to the estimated prevalence of this disorder in the general population. The blood donor screening program could be a novel strategy to detect and notify individuals with potential familial hypercholesterolemia, particularly younger individuals in whom early detection and treatment is especially helpful, as well as guide cascade screening.


A public-private partnership develops and externally validates a 30-day hospital readmission risk prediction model.
Preventing the occurrence of hospital readmissions is needed to improve quality of care and foster population health across the care continuum. Hospitals are being held accountable for improving transitions of care to avert unnecessary readmissions. Advocate Health Care in Chicago and Cerner (ACC) collaborated to develop all-cause, 30-day hospital readmission risk prediction models to identify patients that need interventional resources. Ideally, prediction models should encompass several qualities: they should have high predictive ability; use reliable and clinically relevant data; use vigorous performance metrics to assess the models; be validated in populations where they are applied; and be scalable in heterogeneous populations. However, a systematic review of prediction models for hospital readmission risk determined that most performed poorly (average C-statistic of 0.66) and efforts to improve their performance are needed for widespread usage. The ACC team incorporated electronic health record data, utilized a mixed-method approach to evaluate risk factors, and externally validated their prediction models for generalizability. Inclusion and exclusion criteria were applied on the patient cohort and then split for derivation and internal validation. Stepwise logistic regression was performed to develop two predictive models: one for admission and one for discharge. The prediction models were assessed for discrimination ability, calibration, overall performance, and then externally validated. The ACC Admission and Discharge Models demonstrated modest discrimination ability during derivation, internal and external validation post-recalibration (C-statistic of 0.76 and 0.78, respectively), and reasonable model fit during external validation for utility in heterogeneous populations. The ACC Admission and Discharge Models embody the design qualities of ideal prediction models. The ACC plans to continue its partnership to further improve and develop valuable clinical models.


Small airways dysfunction in asthma: evaluation and management to improve asthma control.
The small airways have been neglected for many years, but interest in the topic has been rekindled with recent advances in measurement techniques to assess this region and also the ability to deliver therapeutics to the distal airways. Current levels of disease control in asthmatic patients remain poor and there are several contributory factors including; poor treatment compliance, heterogeneity of asthma phenotypes and associated comorbidities. However, the proposition that we may not be targeting all the inflammation that is present throughout the whole respiratory tree may also be an important factor. Indeed decades ago, pathologists and physiologists clearly identified the importance of small airways dysfunction in asthmatic patients. With improved inhaler technology to deliver drug to target the whole respiratory tree and more sensitive measures to assess the distal airways, we should certainly give greater consideration to treating the small airway region when seeing our asthmatic patients in clinic. The aim of this review is to address the relevance of small airways dysfunction in the daily clinical management of patients with asthma. In particular the role of small particle aerosols in the management of patients with asthma will be explored.


Predicting multipulse laser-induced failure for molybdenum metal mirrors.
In combination with known thermomechanical-fatigue data for Mo, we have conducted transient photothermal deflection (TPD) measurements to develop a model for the multipulse laser damage of Mo mirrors to predict their lifetimes. In laser-damage experiments to verify the model, Mo mirrors were irradiated with 10-ns Nd:YAG laser pulses at 1064 nm at a 10-Hz repetition rate. Digitized TPD waveforms indicated peak surface angular deflection that could then be converted into surface displacement. Numerical modeling of the vertical heat distribution enabled the peak surface-deflection signal to be converted into peak surface temperature. The thermomechanical model was verified by both the experimental and the numerical results. Conventional mechanical-fatigue data for Mo were used to derive a predictive equation for the laser-accumulation lifetime of Mo mirrors. Experiments were performed with 1-10(4) pulses per site, yielding laser-damage thresholds and accumulation curves. The accumulation behavior predicted from measurements of mechanical fatigue was in excellent agreement with the measured behavior. Thus a single-pulse TPD measurement of peak deformation at a subthreshold laser fluence, in conjunction with mechanical-fatigue data, may be used to estimate the safe operating fluence for a component in a multipulse laser environment.


Yolk androgens and the development of avian immunity: an experiment in jackdaws (Corvus monedula).
Maternally derived androgens have been shown to influence offspring phenotype in various ways. In birds, the benefits of prenatal androgen exposure, such as increased competitiveness and accelerated growth in nestlings, have been suggested to be balanced by costs, such as reduced immune function. In this study, we used an integrative approach to examine the influence of yolk androgens on the development of immune function in jackdaw (Corvus monedula) nestlings. Specifically, we tested whether the effects of yolk androgens on offspring immunity may extend over the first few days of life and be detectable even after several weeks. We manipulated yolk androgen concentrations in jackdaw eggs and estimated immune responsiveness by challenging the young with different pathogens at different stages of the nestling period. Six-day-old chicks hatched from eggs with elevated yolk androgen levels had lower pre-challenge antibody titres against lipopolysaccharide (LPS) than control chicks. However, antibody titres against LPS did not differ between treatment groups eight days after a challenge with LPS. During the late nestling phase, both humoral (towards diphtheria/tetanus antigens) and cell-mediated (towards phytohaemagglutinin) immune responsiveness were lower in chicks from yolk androgen-treated eggs compared with control chicks. Our experimental study on jackdaw chicks shows that elevated yolk androgen levels result in a general immunosuppression in offspring; this conclusion was based on results for several immunological tests of both humoral and cell-mediated immunity conducted at 1-2 and 3-4 weeks of age.


Arthroscopic treatment of full-thickness rotator cuff tears: 2- to 7-year follow-up study.
This study analyzes the midterm follow-up results of 40 full-thickness rotator cuff tears treated by arthroscopic subacromial decompression and debridement. Patients were selected for this prospective study based on a variety of factors, including physiologic age, handedness, activity level in occupation or avocation, and preoperative estimate of repairability. Patients were divided into three groups based on the size of the tear as measured during surgery; results were evaluated on the UCLA shoulder rating scale. This study emphasizes the importance of patient selection when applying arthroscopic treatment for full-thickness rotator cuff tears. Small (0-2 cm) tears (n = 10) in older individuals not involved in strenuous activities did well (90% satisfactory). Patients with larger (2-4 cm) repairable tears (n = 8) did poorly (50% satisfactory) in comparison with our previous study of the results of open repair (84% satisfactory). Arthroscopic treatment in patients with massive, irreparable tears (n = 22) did not restore lost strength or range of motion, but there was significant pain relief, and 86% were satisfied with the results on a limited-goals basis. The study concludes that with proper patient selection, arthroscopic treatment has a valuable, but limited, role in the treatment of full-thickness rotator cuff tears.


Digital transcriptome profiling from attomole-level RNA samples.
Accurate profiling of minute quantities of RNA in a global manner can enable key advances in many scientific and clinical disciplines. Here, we present low-quantity RNA sequencing (LQ-RNAseq), a high-throughput sequencing-based technique allowing whole transcriptome surveys from subnanogram RNA quantities in an amplification/ligation-free manner. LQ-RNAseq involves first-strand cDNA synthesis from RNA templates, followed by 3' polyA tailing of the single-stranded cDNA products and direct single molecule sequencing. We applied LQ-RNAseq to profile S. cerevisiae polyA+ transcripts, demonstrate the reproducibility of the approach across different sample preparations and independent instrument runs, and establish the absolute quantitative power of this method through comparisons with other reported transcript profiling techniques and through utilization of RNA spike-in experiments. We demonstrate the practical application of this approach to define the transcriptional landscape of mouse embryonic and induced pluripotent stem cells, observing transcriptional differences, including over 100 genes exhibiting differential expression between these otherwise very similar stem cell populations. This amplification-independent technology, which utilizes small quantities of nucleic acid and provides quantitative measurements of cellular transcripts, enables global gene expression measurements from minute amounts of materials and offers broad utility in both basic research and translational biology for characterization of rare cells.


Exaggerated displays do not improve mounting success in male seaweed flies Fucellia tergina (Diptera: Anthomyiidae).
Signals of individual quality are assumed to be difficult to exaggerate, either because they are directly linked to underlying traits (indices) or because they are costly to perform (handicaps). In practise advertisement displays may consist of conventional and costly components, for instance where a morphological structure related to body size is used in visual displays. In this case, there is the potential for dishonest displays, due to the population level variance around the relationship between body size and display structures. We examine the use of wing flicking displays that we observed in situ in a strandline dwelling seaweed fly Fucellia tergina, using overall body size and the size of their eyes as underlying indicators of condition. Males displayed far more frequently than females, and were also observed to frequently mount other flies, a behaviour that was rare in females. The rate of display was greater for males that had positive residual values from relationships between wing length and body length. In other words those males with larger than expected wings for their underlying quality displayed more frequently, indicating that these displays are open to exaggeration. Males with larger than expected wings (for the size of their body or eyes), however, mounted less frequently. We suggest that small bodied males are less successful in terms of mounting, but that those small males with relatively large wings may attempt to compensate for this through increased display effort.


Molecular Basis for Control of Diverse Genome Stability Factors by the Multi-BRCT Scaffold Rtt107.
BRCT domains support myriad protein-protein interactions involved in genome maintenance. Although di-BRCT recognition of phospho-proteins is well known to support the genotoxic response, whether multi-BRCT domains can acquire distinct structures and functions is unclear. Here we present the tetra-BRCT structures from the conserved yeast protein Rtt107 in free and ligand-bound forms. The four BRCT repeats fold into a tetrahedral structure that recognizes unmodified ligands using a bi-partite mechanism, suggesting repeat origami enabling function acquisition. Functional studies show that Rtt107 binding of partner proteins of diverse activities promotes genome replication and stability in both distinct and concerted manners. A unified theme is that tetra- and di-BRCT domains of Rtt107 collaborate to recruit partner proteins to chromatin. Our work thus illustrates how a master regulator uses two types of BRCT domains to recognize distinct genome factors and direct them to chromatin for constitutive genome protection.


Calcium-binding proteins in the vorticellid spasmoneme.
The proteins of the contractile spasmoneme from Vorticella convallaria, Carcheslium polypinum, and Zoothamnium geniculatum have been extracted in the detergent, sodium dodecyl sulfate (SDS), as well as urea and guanidine hydrochloride (GuCl). After SDS extraction, the molecular weight distribution of the proteins was examined by means of SDS-polyacrylamide gel electrophoresis. Significant amounts of material corresponding to the contractile proteins actin and tubulin are not present. The contractile organelles in the three species examined contain a group of closely related proteins of molecular weight near 20,000, which constitute a major part (40-60%) of the dry mass. The 20,000 mol wt proteins in Zoothamnium bind calcium with high affinity (pK congruent to 6) and are termed "spasmins." By means of urea polyacrylamide gel electrophorsis, it is demonstrated that in Carchesium and Zoothamnium certain spasmin components bind calcium even in the presence of 6 M urea. The binding of calcium in 6 M urea suggests a functional relationship between the spasmins and the calcium-binding proteins of striated muscle which behave similarly. The calcium binding in urea also indicates that the spasmins within a single spasmoneme have different calcium affinities, and this difference in calcium-binding properties may be an important factor in the physiological function of the organelle.


Use of intervention mapping to adapt a health behavior change intervention for endometrial cancer survivors: the shape-up following cancer treatment program.
About 80% of endometrial cancer survivors (ECS) are overweight or obese and have sedentary behaviors. Lifestyle behavior interventions are promising for improving dietary and physical activity behaviors, but the constructs associated with their effectiveness are often inadequately reported. The aim of this study was to systematically adapt an evidence-based behavior change program to improve healthy lifestyle behaviors in ECS. Following a review of the literature, focus groups and interviews were conducted with ECS (n = 16). An intervention mapping protocol was used for the program adaptation, which consisted of six steps: a needs assessment, formulation of matrices of change objectives, selection of theoretical methods and practical applications, program production, adoption and implementation planning, and evaluation planning. Social Cognitive Theory and Control Theory guided the adaptation of the intervention. The process consisted of eight 90-min group sessions focusing on shaping outcome expectations, knowledge, self-efficacy, and goals about healthy eating and physical activity. The adapted performance objectives included establishment of regular eating, balanced diet, and portion sizes, reduction in sedentary behaviors, increase in lifestyle and organized activities, formulation of a discrepancy-reducing feedback loop for all above behaviors, and trigger management. Information on managing fatigue and bowel issues unique to ECS were added. Systematic intervention mapping provided a framework to design a cancer survivor-centered lifestyle intervention. ECS welcomed the intervention and provided essential feedback for its adaptation. The program has been evaluated through a randomized controlled trial.


The Effect of Wnt Pathway Modulators on Human iPSC-Derived Pancreatic Beta Cell Maturation.
Current published protocols for targeted differentiation of human stem cells toward pancreatic β-cells fail to deliver sufficiently mature cells with functional properties comparable to human islet β-cells. We aimed to assess whether Wnt-modulation could promote the final protocol stages of β-cell maturation, building our hypothesis on our previous findings of Wnt activation in immature hiPSC-derived stage 7 (S7) cells compared to adult human islets and with recent data reporting a link between Wnt/PCP and in vitro β-cell maturation. In this study, we stimulated canonical and non-canonical Wnt signaling in hiPSC-derived S7 cells using syntetic proteins including WNT3A, WNT4, WNT5A and WNT5B, and we inhibited endogenous Wnt signaling with the Tankyrase inhibitor G007-LK (TKi). Whereas neither canonical nor non-canonical Wnt stimulation alone was able to mature hiPSC-derived S7 cells, WNT-inhibition with TKi increased the fraction of monohormonal cells and global proteomics of TKi-treated S7 cells showed a proteomic signature more similar to adult human islets, suggesting that inhibition of endogenous Wnt contributes toward final β-cell maturation.


Hidden photoinduced reactivity of the blue fluorescent protein mKalama1.
Understanding the photoinduced dynamics of fluorescent proteins is essential for their applications in bioimaging. Despite numerous studies on the ultrafast dynamics, the delayed response of these proteins, which often results in population of kinetically trapped dark states of various origins, is largely unexplored. Here, by using transient absorption spectroscopy spanning the time scale from picoseconds to seconds, we reveal a hidden reactivity of the bright blue-light emitting protein mKalama1 previously thought to be inert. This protein shows no excited-state proton transfer during its nanosecond excited-state lifetime; however, its tyrosine-based chromophore undergoes deprotonation coupled to non-radiative electronic relaxation. Such deprotonation causes distinct optical absorption changes in the broad UV-to-NIR spectral range (ca. 300-800 nm); the disappearance of the transient absorption signal has a complex nature and spans the whole microsecond-to-second time scale. The mechanisms underlying the relaxation kinetics are disclosed based on the X-ray structural analysis of mKalama1 and the high-level electronic structure calculations of proposed intermediates in the photocycle. We conclude that the non-radiative excited-state decay includes two major branches: internal conversion coupled to intraprotein proton transfer, where a conserved residue E222 serves as the proton acceptor; and ionization induced by two consecutive resonant absorption events, followed by deprotonation of the chromophore radical cation to bulk solvent through a novel water-mediated proton-wire pathway. Our findings open up new perspectives on the dynamics of fluorescent proteins as tracked by its optical transient absorption in the time domain extending up to seconds.


Modelling the molecular mechanisms of aging.
The aging process is driven at the cellular level by random molecular damage that slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the aging process. The complexity of the aging process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards and discusses many specific examples of models that have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field.


Prophylactic extraction of non-impacted third molars: is it necessary?
The decision of removing a non-impacted 3rd molar, unlike extraction of an impacted 3rd molar, is challenging for dentists as well as patients. This study investigates the pathologies affecting second molars situated adjacent to asymptomatic non-impacted 3rd molars. This retrospective study included digital radiographs of 749 patients taken between April to October 2015. Panoramic radiographs were evaluated for the presence of erupted asymptomatic non-impacted 3rd molars and pathologies on adjacent second molars. The patients were reviewed according to age and gender. A total of 2342 asymptomatic 3rd molars were assessed in the study based on the inclusion and exclusion criteria, and 2112 of them were found to be non-impacted. The second molars adjacent to non-impacted 3rd molars were shown to be significantly associated with distal caries (25.2%), mesial bone loss (10.5%) and total bone loss (37.2%), i.e., mesial as well as distal bone loss. Pathologies of the 3rd molars and teeth adjacent to 3rd molars can occur as a result of multiple factors. Caries and periodontal disease may also occur due to the inaccessibility to maintain oral hygiene. With a regular follow-up schedule, reinforced by the dentist and good oral hygiene, several pathologies that are significantly associated with non-impacted 3rd molars can be prevented and may not require prophylactic extraction.


Screening and prevention measures for melanoma: is there a survival advantage?
Controversy has emerged over the past decades regarding the value and impact of melanoma screening to detect early stage disease for improved prognosis. Those questioning the benefits of prevention efforts base their arguments on the absence of prospective, randomized studies demonstrating decreased melanoma mortality to justify the cost associated with screening and educational campaigns. For those in favor of melanoma screening, the lack of proven survival benefit is not a justification to abandon this approach, but rather a reflection of the lack of resources necessary to conduct a long-term trial. In 2009, the US Preventive Services Task Force (USPSTF)report did not recommend routine primary care screening for the general population given the absence of evidence. However, since the USPSTF report, a series of new studies are available, which support the potential benefit of screening and have the potential to significantly impact current policies regarding skin cancer screening, particularly for melanoma.


Understanding the role of welfare state characteristics for health and inequalities - an analytical review.
The past decade has witnessed a growing body of research on welfare state characteristics and health inequalities but the picture is, despite this, inconsistent. We aim to review this research by focusing on theoretical and methodological differences between studies that at least in part may lead to these mixed findings. Three reviews and relevant bibliographies were manually explored in order to find studies for the review. Related articles were searched for in PubMed, Web of Science and Google Scholar. Database searches were done in PubMed and Web of Science. The search period was restricted to 2005-01-01 to 2013-02-28. Fifty-four studies met the inclusion criteria. Three main approaches to comparative welfare state research are identified; the Regime approach, the Institutional approach, and the Expenditure approach. The Regime approach is the most common and regardless of the empirical regime theory employed and the amendments made to these, results are diverse and contradictory. When stratifying studies according to other features, not much added clarity is achieved. The Institutional approach shows more consistent results; generous policies and benefits seem to be associated with health in a positive way for all people in a population, not only those who are directly affected or targeted. The Expenditure approach finds that social and health spending is associated with increased levels of health and smaller health inequalities in one way or another but the studies are few in numbers making it somewhat difficult to get coherent results. Based on earlier reviews and our results we suggest that future research should focus less on welfare regimes and health inequalities and more on a multitude of different types of studies, including larger analyses of social spending and social rights in various policy areas and how these are linked to health in different social strata. But, we also need more detailed evaluation of specific programmes or interventions, as well as more qualitative analyses of the experiences of different types of policies among the people and families that need to draw on the collective resources.


Mammary Stem Cells and Tumor-Initiating Cells Are More Resistant to Apoptosis and Exhibit Increased DNA Repair Activity in Response to DNA Damage.
Adult stem cells and tumor-initiating cells (TICs) often employ different mechanisms of DNA damage response (DDR) as compared to other tissue cell types. However, little is known about how mammary stem cells (MaSCs) and mammary TICs respond to DNA damage. Using the mouse mammary gland and syngeneic p53-null tumors as models, we investigated the molecular and physiological consequences of DNA damage in wild-type MaSCs, p53-null MaSCs, and p53-null TICs. We showed that wild-type MaSCs and basal cells are more resistant to apoptosis and exhibit increased non-homologous end joining (NHEJ) activity. Loss of p53 in mammary epithelium affected both cell-cycle regulation and DNA repair efficiency. In p53-null tumors, we showed that TICs are more resistant to ionizing radiation (IR) due to decreased apoptosis, elevated NHEJ activity, and more-rapid DNA repair. These results have important implications for understanding DDR mechanisms involved in both tumorigenesis and therapy resistance.


Prediction of relapse in schizophrenia.
Despite the proven efficacy of neuroleptic drugs in the acute and maintenance pharmacotherapy of schizophrenia, practical methods for identifying patients who require neuroleptic treatment to prevent relapse are lacking. This study evaluated the use of a methylphenidate challenge test to predict the outcome in 34 stable outpatients with schizophrenia receiving neuroleptic treatment. Patients received two infusions, one of methylphenidate and one of placebo, in randomized order one week apart while receiving neuroleptic treatment and again three weeks after drug withdrawal. Behavioral, cardiovascular, and neurologic responses were evaluated before and after infusion under double-blind conditions. Patients were then followed up without medication for 52 weeks or until symptom recurrence. The results indicate that specific measures, including behavioral response to methylphenidate, presence of tardive dyskinesia, and, under specific pharmacologic conditions, tardive dyskinesia, blink-rate, and pulse-rate responses to methylphenidate, are associated with time and propensity to relapse following neuroleptic withdrawal. These measures may be potentially useful in the identification of candidates for neuroleptic withdrawal and/or dosage-reduction treatment strategies.


Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes.
Hydatidiform mole (HM) is an aberrant human pregnancy characterized by excessive trophoblastic proliferation and abnormal embryonic development. HM has two morphological types, complete (CHM) and partial (PHM), and non-recurrent ones have three genotypic types, androgenetic monospermic, androgenetic dispermic, and triploid dispermic. Most available studies on risk factors predisposing to different types of HM and their malignant transformation mainly suffer from the lack of comprehensive genotypic analysis of large cohorts of molar tissues combined with accurate postmolar hCG follow-up. Moreover, 10-20% of patients with one HM have at least one non-molar miscarriage, which is higher than the frequency of two pregnancy losses in the general population (2-5%), suggesting a common genetic susceptibility to HM and miscarriages. However, the underlying causes of the miscarriages in these patients are unknown. Here, we comprehensively analyzed 204 HM, mostly from patients referred to the Quebec Registry of Trophoblastic Diseases and for which postmolar hCG monitoring is available, and 30 of their non-molar miscarriages. We revisited the risk of maternal age and neoplastic transformation across the different HM genotypic categories and investigated the presence of chromosomal abnormalities in their non-molar miscarriages. We confirm that androgenetic CHM is more prone to gestational trophoblastic neoplasia (GTN) than triploid dispermic PHM, and androgenetic dispermic CHM is more prone to high-risk GTN and choriocarcinoma (CC) than androgenetic monospermic CHM. We also confirm the association between increased maternal age and androgenetic CHM and their malignancies. Most importantly, we demonstrate for the first time that patients with an HM and miscarriages are at higher risk for aneuploid miscarriages [83.3%, 95% confidence interval (CI): 0.653-0.944] than women with sporadic (51.5%, 95% CI: 50.3-52.7%, p value = 0.0003828) or recurrent miscarriages (43.8%, 95% CI: 40.7-47.0%, p value = 0.00002). Our data suggest common genetic female germline defects predisposing to HM and aneuploid non-molar miscarriages in some patients.


Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types.
Allelic loss is a hallmark of tumor suppressor gene (TSG) inactivation. We have allelotyped 29 paired lymphoblastoid and lung cancer cell lines derived from 11 patients with small cell (SCLC) and 18 patients with non-small cell lung carcinomas (NSCLC). Statistical analysis indicated that a threshold of 30% separated non-random allelic loss from the random genetic deletions of malignancy. We have identified non-random allelic loss at 42 of 54 (78%) specific chromosomal regions examined, with 22 regions (52%) common between the two major lung cancer histologic types. There were 3 regions (7%) with allelic loss specific for SCLC and 17 regions (41%) specific for NSCLC. Furthermore, there were significant differences in loss of heterozygosity (LOH) frequencies between NSCLC and SCLC at 13 regions on eight chromosome arms (3p, 5q, 6q, 9p, 10q, 11p, 13q, and 19p). Eight homozygous deletions were present in seven cell lines at four regions, 3p12, 3p14.2, 9p21, and 10q23-25. We have also identified novel sites of chromosomal deletions. In particular, there was frequent loss at 11p13 in SCLC and loss at 6p21.3 and 13q12.3 in NSCLC. In this study, we demonstrate that a) non-random allelic losses in lung cancer involve multiple regions; b) some losses are common to both NSCLC and SCLC subtypes, whereas others are subtype specific; c) there are genetic deletions at novel chromosomal regions; and d) several homozygous deletions have been noted. Our studies demonstrate the usefulness of continuous cell lines for detailed allelotyping, for comparing genetic abnormalities between SCLC and NSCLC, and for identifying homozygous deletions.


Intra-arterial mechanical thrombectomy stent retrievers and aspiration devices in the treatment of acute ischaemic stroke: A systematic review and meta-analysis with trial sequential analysis.
Intra-arterial mechanical thrombectomy combined with appropriate patient selection (image-based selection of acute ischaemic stroke patients with large artery occlusion) yields improved clinical outcomes. We conducted a systematic review and meta-analysis, with trial sequential analysis to understand the benefits, risks and impact of new trials reporting in 2016 on the magnitude/certainty of the estimates for clinical effectiveness and safety of mechanical thrombectomy. Random effects' models were conducted of randomised clinical trials comparing mechanical thrombectomy (stent retriever or aspiration devices) with/without adjuvant intravenous thrombolysis with intravenous thrombolysis and other forms of best medical/supportive care in the treatment of acute ischaemic stroke. Study inclusion and risk of bias were assessed independently by two reviewers. Functional independence (modified Rankin Scale 0-2) and mortality at 90 days, including symptomatic intracranial haemorrhage rate were extracted. Trial sequential analysis established the strength of the evidence derived from the meta-analyses. Eight trials of mechanical thrombectomy with a total sample size of 1841 (916 patients treated with mechanical thrombectomy and 925 treated without mechanical thrombectomy) fulfilled review inclusion criteria. The three most recent trials more precisely defined the effectiveness of mechanical thrombectomy (modified Rankin Scale 0 to 2; OR = 2.07, 95% CI = 1.70 to 2.51 based on data from eight trials versus OR = 2.39, 95% CI = 1.88 to 3.04 based on data from five trials). Meta-analyses showed no effect on mortality (OR = 0.81, 95% CI = 0.61 to 1.07) or symptomatic intracranial haemorrhage (OR = 1.22, 95% CI = 0.80 to 1.85) as found in analysis of first five trials. Trial sequential analysis indicated that the information size requirement was fulfilled to conclude the evidence for mechanical thrombectomy is robust. The impact of three recent trials on effectiveness and safety of mechanical thrombectomy was a more precise pooled effect size for functional independence. Trial sequential analysis demonstrated sufficient evidence for effectiveness and safety of mechanical thrombectomy. No further trials of mechanical thrombectomy versus no mechanical thrombectomy are indicated to establish clinical effectiveness. Uncertainty remains as to whether mechanical thrombectomy reduces mortality or increases risk of symptomatic intracranial haemorrhage.


Changing topography of the RPE resulting from experimentally induced rapid eye growth.
The retinal pigment epithelium (RPE) of the quokka wallaby. Setonix brachyurus, grows and changes throughout life. To investigate factors that determine changes in the quokka RPE, we have examined topography of this tissue in experimentally enlarged eyes. Unilateral eyelid suture was conducted at the time of normal eye opening, postnatal day (P) 110, and animals were examined at 1 or 1 1/2 years of age. The numbers and densities of RPE cells and the extent of multinucleation were compared with those in normal animals. Eyelid suture resulted in a 9.8% and 17.4% increase in retinal area at 1 and 1 1/2 years, respectively; a significant degree of myopia was associated with this enlargement. Cell density topography in experimental eyes was not the same as in controls. Cells from central retina were disproportionately larger in the experimental than control eyes. However, the RPE cell topography in sutured eyes was not the same as that of aged retinae of a similar size. Notably, in sutured eyes there was no development of the high or highest cell densities seen in equatorial and temporal central RPE in aged retinae, respectively. Furthermore, the degree of cell enlargement in peripheral regions was slight compared with that observed in similar-sized, aged retinae. There was no increase in RPE cell number; rather, average cell area increased accompanied by no change or a slight decrease in RPE thickness. Consequently, overall volume of cells did not change significantly. The large number of multinucleate cells normally seen in aged animals was not observed in experimentally enlarged eyes, implying that an increase in cell volume may be the trigger for multinucleation.


Prognostic factors in metaplastic carcinoma of the breast: a multi-institutional study.
Metaplastic breast carcinoma (MBC) is a rare type of breast cancer that has basal-like characteristics and is perceived to have poorer prognosis when compared with conventional no specific type/ductal carcinomas (ductal/NST). However, current data on MBC are largely derived from small case series or population-based reports. This study aimed to assess the clinicopathological features and outcome of MBC identified through an international multicentre collaboration. A large international multicentre series of MBC (no=405) with histological confirmation and follow-up information has been included in this study. The prognostic value of different variables and outcome has been assessed and compared with grade, nodal status and ER/HER2 receptor-matched ductal/NST breast carcinoma. The outcome of MBC diagnosed in Asian countries was more favourable than those in Western countries. The outcome of MBC is not different from matched ductal/NST carcinoma but the performance of the established prognostic variables in MBC is different. Lymph node stage, lymphovascular invasion and histologic subtype are associated with outcome but tumour size and grade are not. Chemotherapy was associated with longer survival, although this effect was limited to early-stage disease. In this study no association between radiotherapy and outcome was identified. Multivariate analysis of MBC shows that histologic subtype is an independent prognostic feature. This study suggests that MBC is a heterogeneous disease. Although the outcome of MBC is not different to matched conventional ductal/NST breast carcinoma, its behaviour is dependent on the particular subtype with spindle cell carcinoma in particular has an aggressive biological behaviour. Management of patients with MBC should be based on validated prognostic variables.


Survival analysis for high-dimensional, heterogeneous medical data: Exploring feature extraction as an alternative to feature selection.
In clinical research, the primary interest is often the time until occurrence of an adverse event, i.e., survival analysis. Its application to electronic health records is challenging for two main reasons: (1) patient records are comprised of high-dimensional feature vectors, and (2) feature vectors are a mix of categorical and real-valued features, which implies varying statistical properties among features. To learn from high-dimensional data, researchers can choose from a wide range of methods in the fields of feature selection and feature extraction. Whereas feature selection is well studied, little work focused on utilizing feature extraction techniques for survival analysis. We investigate how well feature extraction methods can deal with features having varying statistical properties. In particular, we consider multiview spectral embedding algorithms, which specifically have been developed for these situations. We propose to use random survival forests to accurately determine local neighborhood relations from right censored survival data. We evaluated 10 combinations of feature extraction methods and 6 survival models with and without intrinsic feature selection in the context of survival analysis on 3 clinical datasets. Our results demonstrate that for small sample sizes - less than 500 patients - models with built-in feature selection (Cox model with ℓ1 penalty, random survival forest, and gradient boosted models) outperform feature extraction methods by a median margin of 6.3% in concordance index (inter-quartile range: [-1.2%;14.6%]). If the number of samples is insufficient, feature extraction methods are unable to reliably identify the underlying manifold, which makes them of limited use in these situations. For large sample sizes - in our experiments, 2500 samples or more - feature extraction methods perform as well as feature selection methods.


Effect of patient-ventilator asynchrony on lung and diaphragmatic injury in experimental acute respiratory distress syndrome in a porcine model.
Patient-ventilator asynchrony during mechanical ventilation may exacerbate lung and diaphragm injury in spontaneously breathing subjects. We investigated whether subject-ventilator asynchrony increases lung or diaphragmatic injury in a porcine model of acute respiratory distress syndrome (ARDS). ARDS was induced in adult female pigs by lung lavage and injurious ventilation before mechanical ventilation by pressure assist-control for 12 h. Mechanically ventilated pigs were randomised to breathe spontaneously with or without induced subject-ventilator asynchrony or neuromuscular block (n=7 per group). Subject-ventilator asynchrony was produced by ineffective, auto-, or double-triggering of spontaneous breaths. The primary outcome was mean alveolar septal thickness (where thickening of the alveolar wall indicates worse lung injury). Secondary outcomes included distribution of ventilation (electrical impedance tomography), lung morphometric analysis, inflammatory biomarkers (gene expression), lung wet-to-dry weight ratio, and diaphragmatic muscle fibre thickness. Subject-ventilator asynchrony (median [interquartile range] 28.8% [10.4] asynchronous breaths of total breaths; n=7) did not increase mean alveolar septal thickness compared with synchronous spontaneous breathing (asynchronous breaths 1.0% [1.6] of total breaths; n=7). There was no difference in mean alveolar septal thickness throughout upper and lower lung lobes between pigs randomised to subject-ventilator asynchrony vs synchronous spontaneous breathing (87.3-92.2 μm after subject-ventilator asynchrony, compared with 84.1-95.0 μm in synchronised spontaneous breathing;). There were also no differences between groups in wet-to-dry weight ratio, diaphragmatic muscle fibre thickness, atelectasis, lung aeration, or mRNA expression levels for inflammatory cytokines pivotal in ARDS pathogenesis. Subject-ventilator asynchrony during spontaneous breathing did not exacerbate lung injury and dysfunction in experimental porcine ARDS.