Newly formed dust within the circumstellar environment of SN Ia-CSM 2018evt.

Dust associated with various stellar sources in galaxies at all cosmic epochs remains a controversial topic, particularly whether supernovae play an important role in dust production. We report evidence of dust formation in the cold, dense shell behind the ejecta-circumstellar medium (CSM) interaction in the Type Ia-CSM supernova (SN) 2018evt three years after the explosion, characterized by a rise in mid-infrared emission accompanied by an accelerated decline in the optical radiation of the SN. Such a dust-formation picture is also corroborated by the concurrent evolution of the profiles of the Hα emission line. Our model suggests enhanced CSM dust concentration at increasing distances from the SN as compared to what can be expected from the density profile of the mass loss from a steady stellar wind. By the time of the last mid-infrared observations at day +1,041, a total amount of 1.2 ± 0.2 × 10-2 M⊙ of new dust has been formed by SN 2018evt, making SN 2018evt one of the most prolific dust factories among supernovae with evidence of dust formation. The unprecedented witness of the intense production procedure of dust may shed light on the perceptions of dust formation in cosmic history.

Performance demonstration of vacuum microwave components critical for the operation of the ITER low-field side reflectometer.

Final design studies in preparation for manufacturing have been performed for functional components of the vacuum portion of the ITER Low-Field Side Reflectometer (LFSR). These components consist of an antenna array, electron cyclotron heating (ECH) protection mirrors, phase calibration mirrors, and vacuum windows. Evaluation of these components was conducted at the LFSR test facility and DIII-D. The antenna array consists of six corrugated-waveguide antennas for simultaneous profile, fluctuation, and Doppler measurements. A diffraction grating, incorporated into the plasma-facing miter bend, provides protection of sensitive components from stray ECH at 170 GHz. For in situ phase calibration of the LFSR profile reflectometer, an embossed mirror is incorporated into the adjacent miter bend. Measurements of the radiated beam profile indicate that these components have a small, acceptable effect on mode conversion and beam quality. Baseline transmission characteristics of the dual-disk vacuum window are obtained and are used to guide ongoing developments. Preliminary simulations indicate that a surface-relief structure on the window surfaces can greatly improve transmission. The workability of real-time phase measurements was demonstrated on the DIII-D profile reflectometer. The new automated real-time analysis agrees well with the standard post-processing routine.

A kilonova as the electromagnetic counterpart to a gravitational-wave source.

Gravitational waves were discovered with the detection of binary black-hole mergers and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova. The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate. Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short γ-ray burst. The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 ± 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 ± 0.1 times light speed. The power source is constrained to have a power-law slope of -1.2 ± 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90-140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.

In vivo modulation of polo-like kinases supports a key role for PLK2 in Ser129 α-synuclein phosphorylation in mouse brain.

α-Synuclein is the major component of Lewy bodies. α-Synuclein phosphorylated at Ser 129 (Phospho-α-Syn) is the most common synuclein modification observed in Parkinson's disease pathology and transgenic animal models. Polo-like kinase 2 (PLK2) was previously proposed as an important kinase in α-synuclein phosphorylation at Ser129. To better understand the role of PLK2 in α-synuclein phosphorylation in vivo, we further evaluated the effect of PLK2 genetic knockdown and pharmacological inhibition on Phospho-α-Syn levels in different brain regions of PLK2 knockout (KO), heterozygous (Het) and wild-type (WT) mice. Whereas PLK2 knockdown had no effect on Total-α-synuclein brain levels, it resulted in a gene-dosage dependent, albeit incomplete, reduction of endogenous Phospho-α-Syn levels in all brain regions investigated. No compensatory induction of other α-synuclein kinases (PLK3, casein kinase-2, G-protein-coupled receptor kinase 5 (GRK5) and GRK6) was observed at the mRNA level in the PLK2 KO mouse brain. To determine whether increased activity of another PLK family member is responsible for the residual Phospho-α-Syn levels in the PLK2 KO mouse brain, the pan-PLK inhibitor BI 2536 was tested in PLK2 KO mice. Whereas BI 2536 reduced Phospho-α-Syn levels in WT mice, it did not further reduce the residual endogenous Phospho-α-Syn levels in PLK2 KO and Het mice, suggesting that a kinase other than PLK1-3 accounts for the remaining PLK inhibitor-resistant pool in the mouse brain. Moreover, PLK3 KO in mice had no effect on both Total- and Phospho-α-Syn brain levels. These results support a significant role for a PLK kinase in phosphorylating α-synuclein at Ser129 in the brain, and suggest that PLK2 is responsible for this activity under physiological conditions.

The operative correction of symptomatic flat foot deformities in children: the relationship between static alignment and dynamic loading.

At our institution surgical correction of symptomatic flat foot deformities in children has been guided by a paradigm in which radiographs and pedobarography are used in the assessment of outcome following treatment. Retrospective review of children with symptomatic flat feet who had undergone surgical correction was performed to assess the outcome and establish the relationship between the static alignment and the dynamic loading of the foot. A total of 17 children (21 feet) were assessed before and after correction of soft-tissue contractures and lateral column lengthening, using standardised radiological and pedobarographic techniques for which normative data were available. We found significantly improved static segmental alignment of the foot, significantly improved mediolateral dimension foot loading, and worsened fore-aft foot loading, following surgical treatment. Only four significant associations were found between radiological measures of static segmental alignment and dynamic loading of the foot. Weakness of the plantar flexors of the ankle was a common post-operative finding. Surgeons should be judicious in the magnitude of lengthening of the plantar flexors that is undertaken and use techniques that minimise subsequent weakening of this muscle group.

Confidence matters: a Self-Determination Theory study of factors determining engagement in self-management support practices of UK clinicians.

Within a national quality improvement programme for self-management of long-term conditions, we surveyed clinicians working with patients with diabetes, chronic obstructive pulmonary disease, musculoskeletal pain and depression. We applied the Self-Determination Theory framework to explore what factors can facilitate and impede the clinicians' engagement in clinical self-management support (SMS), patient centredness and organizational support for self-management. We also investigated whether attending professional training for clinicians in the practice of self-management (SM) increases motivation to support SM and reported use of SM practices. The study included 482 clinicians who were surveyed once (cross-sectional design) and 114 clinicians who were surveyed before and after training (longitudinal cohort). We found that the high level of satisfaction of competence need predicts practising SMS in all three areas (clinical SMS: beta coefficient = 0.21; p < 0.0001; patient centredness: beta coefficient = 0.50; p < 0.001; organizational SMS: coefficient = 0.20; p < 0.0001). Internalized regulation to support SMS increases engagement in clinical and organizational SMS. Upon comparing the two samples we explored the possible predictors of clinicians' self-referring to attend the training. Clinicians who volunteer to attend the training spend more time working directly with patients with long-term conditions (chi(2) = 4.8; df = 1; p = 0.02), had less previous relevant training (chi(2) = 4.77; df = 1; p = 0.02), and they have less autonomy to support SM (t = 5.0; df = 476; p < 0.0001). However, they report more engagement in patient-centred practices (t = 1.9; df = 585; p = 0.05). These factors are a good fit with the aims of the programme. We confirmed that attending the training had a significant, positive impact on clinicians' engagement in clinical SMS and patient centredness, as well as their overall confidence to support SM. We conclude that to facilitate clinicians to practice SMS it is very important to provide relevant professional training, professional support and incentives to foster clinicians' perceptions of their competence in relation to these practices. Organizations should develop a culture that values SMS, offer training to clinicians to enhance their sense of competence to effectively deliver SMS and support clinicians in finding their own way of supporting SM; in other words to create an optimal context to internalize regulation to support SM.

A faint type of supernova from a white dwarf with a helium-rich companion.

Supernovae are thought to arise from two different physical processes. The cores of massive, short-lived stars undergo gravitational core collapse and typically eject a few solar masses during their explosion. These are thought to appear as type Ib/c and type II supernovae, and are associated with young stellar populations. In contrast, the thermonuclear detonation of a carbon-oxygen white dwarf, whose mass approaches the Chandrasekhar limit, is thought to produce type Ia supernovae. Such supernovae are observed in both young and old stellar environments. Here we report a faint type Ib supernova, SN 2005E, in the halo of the nearby isolated galaxy, NGC 1032. The 'old' environment near the supernova location, and the very low derived ejected mass ( approximately 0.3 solar masses), argue strongly against a core-collapse origin. Spectroscopic observations and analysis reveal high ejecta velocities, dominated by helium-burning products, probably excluding this as a subluminous or a regular type Ia supernova. We conclude that it arises from a low-mass, old progenitor, likely to have been a helium-accreting white dwarf in a binary. The ejecta contain more calcium than observed in other types of supernovae and probably large amounts of radioactive (44)Ti.

Initial description of the human NLRP3 promoter.

Mutations in NLRP3 (CIAS1) are identified in a continuum of related inflammatory disorders, known as cryopyrinopathies since NLRP3 codes for the protein cryopyrin. Approximately 40% of patients with classic presentation lack mutations in the coding region of NLRP3 suggesting heterogeneity or epigenetic factors. Cryopyrin is a key regulator of proinflammatory cytokine release. Therefore, variations in the NLRP3 promoter sequence may have effects on disease state in patients with cryopyrinopathies and other inflammatory diseases. In this report, we confirmed three 5'-untranslated region splice forms with two separate transcriptional start sites, and identified potential promoter regions and six new DNA promoter variants. One variant is unique to a mutation negative cryopyrinopathy patient and increases in vitro gene expression. Additional studies can now be performed to further characterize the NLRP3 promoter and sequence variants, which will lead to better understanding of the regulation of NLRP3 expression and its role in disease.

Tribo-mechanical properties of thin boron coatings deposited on polished cobalt alloy surfaces for orthopedic applications.

This paper presents experimental evidence that thin (< approximately 200 nm) boron coatings, deposited with a (vacuum) cathodic arc technique on pre-polished Co-Cr-Mo surfaces, could potentially extend the life of metal-on-polymer orthopedic devices using cast Co-Cr-Mo alloy for the metal component. The primary tribological test used a linear, reciprocating pin-on-disc arrangement, with pins made of ultra-high molecular weight polyethylene. The disks were cast Co-Cr-Mo samples that were metallographically polished and then coated with boron at a substrate bias of 500 V and at about 100 degrees C. The wear tests were carried out in a saline solution to simulate the biological environment. The improvements were manifested by the absence of a detectable wear track scar on the coated metal component, while significant polymer transfer film was detected on the uncoated (control) samples tested under the same conditions. The polymer transfer track was characterized with both profilometry and Rutherford Backscattering Spectroscopy. Mechanical characterization of the thin films included nano-indentation, as well as additional pin-on-disk tests with a steel ball to demonstrate adhesion, using ultra-high frequency acoustic microscopy to probe for any void occurrence at the coating-substrate interface.

Evaluation of the validity of the Quality of Well-being Scale in Trinidad and Tobago.

Both developing countries in the Caribbean and developed countries face resource allocation challenges. However, cost-effectiveness analysis instruments that may assist in allocation of resources have not been tested in Caribbean countries. Trinidad and Tobago is an advantageous location to test an instrument for potential use in the Caribbean. It has a single payer healthcare system and a literate population. Due to historical and current migration from other Caribbean countries, the population might be a fair representation of English-speaking Caribbean nations. We tested the validity of the Quality of Well-being Scale (QWB) on a sample of the non-institutionalized general population in Trinidad. The survey included reports of chronic conditions and items from the Trinidad and Tobago National Health Interview Survey. Data were analyzed using a multivariable regression model. One adult from each of 235 households consented to the interview. The results are consistent with results obtained in the United States of America. Being older female, more chronic conditions and more symptoms/problems were significantly associated with lower mean QWB scores. These results suggest that the QWB with US-derived weights show evidence of validity in Trinidad and Tobago. Thus, health decision makers can use the QWB to compare the effects of different health conditions and health interventions. In addition, investigators can make cross-cultural comparisons of QWB scores for diseases or health conditions.

Impact of Ménière's disease on quality of life.

OBJECTIVE: To describe health-related quality of life among patients with Ménière's disease in whom conventional therapy failed and who requested further medical intervention. STUDY DESIGN: Pretreatment interviews to establish baseline quality of life characteristics before medical intervention. SETTING: Tertiary referral center. PATIENTS: 19 adult patients, 12 women and 7 men, whose ages ranged from 32 to 83 years. INTERVENTIONS: Pretreatment baseline interviews. MAIN OUTCOME MEASURES: Quality of Well-being Scale, SF-12 Physical and SF-12 Mental scores, Center for Epidemiologic Studies-Depression Scale. RESULTS: The Quality of Well-being score (0.561) indicated a loss of well-being from 1 to 0.561 = 43.9% in patients with Ménière's disease as compared with people with no symptoms and full functional status. The hypothesis that Quality of Well-being scores on days on which patients had symptoms characteristic of acute Ménière's disease episodes were lower than Quality of Well-being scores on days on which they did not report such symptoms was supported (p = 0.000). The reported SF-12 Physical mean score (38.9) was greater than 1 standard deviation below the general mean of 50, and the SF-12 Mental score (44.2) was 0.5 standard deviation below the general mean of 50. The Center for Epidemiologic Studies-Depression Scale score was 23, with a score 16 or greater indicating clinically significant depression. CONCLUSIONS: The results suggest that the condition of patients with Ménière's disease may be measured by these instruments, that the instruments are in substantial agreement about the serious impairment in patients' quality of life, and that the days with acute episodes of Ménière's disease symptoms are significantly worse than the days without such symptoms. Treating physicians indicated surprise at the breadth and the level of debilitation characteristic of these patients with Ménière's disease.

Substitution model of sequence evolution for the human immunodeficiency virus type 1 subtype B gp120 gene over the C2-V5 region.

Phylogenetic analyses frequently rely on models of sequence evolution that detail nucleotide substitution rates, nucleotide frequencies, and site-to-site rate heterogeneity. These models can influence hypothesis testing and can affect the accuracy of phylogenetic inferences. Maximum likelihood methods of simultaneously constructing phylogenetic tree topologies and estimating model parameters are computationally intensive, and are not feasible for sample sizes of 25 or greater using personal computers. Techniques that initially construct a tree topology and then use this non-maximized topology to estimate ML substitution rates, however, can quickly arrive at a model of sequence evolution. The accuracy of this two-step estimation technique was tested using simulated data sets with known model parameters. The results showed that for a star-like topology, as is often seen in human immunodeficiency virus type 1 (HIV-1) subtype B sequences, a random starting topology could produce nucleotide substitution rates that were not statistically different than the true rates. Samples were isolated from 100 HIV-1 subtype B infected individuals from the United States and a 620 nt region of the env gene was sequenced for each sample. The sequence data were used to obtain a substitution model of sequence evolution specific for HIV-1 subtype B env by estimating nucleotide substitution rates and the site-to-site heterogeneity in 100 individuals from the United States. The method of estimating the model should provide users of large data sets with a way to quickly compute a model of sequence evolution, while the nucleotide substitution model we identified should prove useful in the phylogenetic analysis of HIV-1 subtype B env sequences.

The importance of gender on outcome after major trauma: functional and psychologic outcomes in women versus men.

BACKGROUND: Outcome after major trauma is an increasingly important focus of injury research. The effect of gender on functional and psychological outcomes has not been examined. The Trauma Recovery Project is a large, prospective, epidemiologic study designed to examine multiple outcomes after major trauma, including quality of life, functional outcome, and psychological sequelae such as depression and early symptoms of acute stress reaction. The specific objectives of the present report are to examine gender differences in short- and long-term functional and psychological outcomes in the Trauma Recovery Project population. METHODS: Between December 1, 1993, and September 1, 1996, 1,048 eligible trauma patients triaged to four participating trauma center hospitals in the San Diego Regionalized Trauma System were enrolled in the study. The enrollment criteria for the study included age 18 years and older, admission Glasgow Coma Scale score of 12 or greater, and length of stay greater than 24 hours. Quality of life was measured after injury using the Quality of Well-being scale, a sensitive index to the well end of the functioning continuum (range, 0 = death to 1.000 = optimum functioning). Depression was assessed using the Center for Epidemiologic Studies Depression scale and early symptoms of acute stress reaction were assessed using the Impact of Events scale. Patient outcomes were assessed at discharge and at 6, 12, and 18 months after discharge. RESULTS: Functional outcome was significantly worse at each follow-up time point in women (n = 313) versus men (n = 735). Quality of Well-being scale scores were markedly and significantly lower at 6-month follow-up in women compared with those in men (0.606 vs. 0.646, p < 0.0001). This association persisted at 12-month (0.637 vs. 0.6685, p < 0.0001) and 18-month (0.646 vs. 0.6696, p < 0.0001) follow-up. Women were also significantly more likely to be depressed at all follow-up time points (discharge odds ratio [OR] = 1.4, p < 0.05; 6-month follow-up OR = 2.2, p < 0.01; 12-month follow-up OR = 2.0, p < 0.01; 18-month follow-up OR = 2.2, p < 0.01) and to have early symptoms of acute stress reaction at discharge (OR = 1.4, p < 0.05). These differences remained significant and independent after adjusting for injury severity, mechanism, age, and sociodemographic factors. CONCLUSION: Women are at risk for markedly worse functional and psychological outcomes after major trauma than men, independent of injury severity and mechanism. Gender differences in short- and long-term trauma outcomes have important implications for future studies of recovery from trauma.

The impact of major in-hospital complications on functional outcome and quality of life after trauma.

BACKGROUND: Little is known about the impact of major in-hospital complications on functional outcome in the short- and long-term period after serious injury. The Trauma Recovery Project (TRP) is a large, prospective, epidemiologic study designed to examine multiple outcomes after major trauma, including quality of life and functional limitation. Patient outcomes were assessed at discharge and at 6, 12, and 18 months after discharge. The specific objectives of the present report are to examine the effect of postinjury complications on functional outcomes at discharge and at 6-, 12-, and 18-month follow-up time points in the TRP population. METHODS: Between December 1, 1993, and September 1, 1996, 1,048 eligible trauma patients triaged to four participating trauma center hospitals in the San Diego Regionalized Trauma System were enrolled in the study. The enrollment criteria for the study included age 18 years or older; admission Glasgow Coma Scale score of 12 or greater; and length of stay greater than 24 hours. Quality of life was measured after injury using the Quality of Well-being (QWB) scale, a sensitive index to the well end of the functioning continuum (range, 0 [death] to 1.000 [optimum functioning]). Major in-hospital complications were assessed for 820 patients and were coded as pulmonary, cardiovascular, gastrointestinal, hepatic, hematologic, infections, renal, musculoskeletal, neurologic, and vascular, on the basis of standardized codes used in the Trauma Registry. RESULTS: Major in-hospital complications were present in 83 (10.1%) patients. Discharge QWB scores were significantly lower in patients with major complications (0.394 vs. 0.402, p < 0.05). QWB scores were also significantly lower at 6-month follow-up in patients with major complications (0.575 vs. 0.637, p < 0.0001). Types of major complications with significantly lower 6-month follow-up QWB scores were pulmonary, gastrointestinal, infections, and musculoskeletal. Patients with major complications also had significantly lower 12-month (0.626 vs. 0.674, p < 0.01) and 18-month (0.646 vs. 0.681, p < 0.05) follow-up QWB scores. Pulmonary major complications and infections were associated with significantly lower QWB scores at 12-month follow-up. CONCLUSION: These results provide new evidence that major in-hospital complications may have an important impact on functional outcomes after major trauma.

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.

Coordinated plant defense responses in Arabidopsis revealed by microarray analysis.

Disease resistance is associated with a plant defense response that involves an integrated set of signal transduction pathways. Changes in the expression patterns of 2,375 selected genes were examined simultaneously by cDNA microarray analysis in Arabidopsis thaliana after inoculation with an incompatible fungal pathogen Alternaria brassicicola or treatment with the defense-related signaling molecules salicylic acid (SA), methyl jasmonate (MJ), or ethylene. Substantial changes (up- and down-regulation) in the steady-state abundance of 705 mRNAs were observed in response to one or more of the treatments, including known and putative defense-related genes and 106 genes with no previously described function or homology. In leaf tissue inoculated with A. brassicicola, the abundance of 168 mRNAs was increased more than 2.5-fold, whereas that of 39 mRNAs was reduced. Similarly, the abundance of 192, 221, and 55 mRNAs was highly (>2.5-fold) increased after treatment with SA, MJ, and ethylene, respectively. Data analysis revealed a surprising level of coordinated defense responses, including 169 mRNAs regulated by multiple treatments/defense pathways. The largest number of genes coinduced (one of four induced genes) and corepressed was found after treatments with SA and MJ. In addition, 50% of the genes induced by ethylene treatment were also induced by MJ treatment. These results indicated the existence of a substantial network of regulatory interactions and coordination occurring during plant defense among the different defense signaling pathways, notably between the salicylate and jasmonate pathways that were previously thought to act in an antagonistic fashion.

Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E.

The human immunodeficiency virus type 1 (HIV-1) epidemic in Southeast Asia has been largely due to the emergence of clade E (HIV-1E). It has been suggested that HIV-1E is derived from a recombinant lineage of subtype A (HIV-1A) and subtype E, with multiple breakpoints along the E genome. We obtained complete genome sequences of clade E viruses from Thailand (93TH057 and 93TH065) and from the Central African Republic (90CF11697 and 90CF4071), increasing the total number of HIV-1E complete genome sequences available to seven. Phylogenetic analysis of complete genomes showed that subtypes A and E are themselves monophyletic, although together they also form a larger monophyletic group. The apparent phylogenetic incongruence at different regions of the genome that was previously taken as evidence of recombination is shown to be not statistically significant. Furthermore, simulations indicate that bootscanning and pairwise distance results, previously used as evidence for recombination, can be misleading, particularly when there are differences in substitution or evolutionary rates across the genomes of different subtypes. Taken jointly, our analyses suggest that there is inadequate support for the hypothesis that subtype E variants are derived from a recombinant lineage. In contrast, many other HIV strains claimed to have a recombinant origin, including viruses for which only a single parental strain was employed for analysis, do indeed satisfy the statistical criteria we propose. Thus, while intersubtype recombinant HIV strains are indeed circulating, the criteria for assigning a recombinant origin to viral structures should include statistical testing of alternative hypotheses to avoid inappropriate assignments that would obscure the true evolutionary properties of these viruses.

Likelihood-based tests of topologies in phylogenetics.

Likelihood-based statistical tests of competing evolutionary hypotheses (tree topologies) have been available for approximately a decade. By far the most commonly used is the Kishino-Hasegawa test. However, the assumptions that have to be made to ensure the validity of the Kishino-Hasegawa test place important restrictions on its applicability. In particular, it is only valid when the topologies being compared are specified a priori. Unfortunately, this means that the Kishino-Hasegawa test may be severely biased in many cases in which it is now commonly used: for example, in any case in which one of the competing topologies has been selected for testing because it is the maximum likelihood topology for the data set at hand. We review the theory of the Kishino-Hasegawa test and contend that for the majority of popular applications this test should not be used. Previously published results from invalid applications of the Kishino-Hasegawa test should be treated extremely cautiously, and future applications should use appropriate alternative tests instead. We review such alternative tests, both nonparametric and parametric, and give two examples which illustrate the importance of our contentions.