Recommendations for a core outcome set for measuring standing balance in adult populations: a consensus-based approach

Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally

Development of Social Vocalizations in Mice

Adult mice are highly vocal animals, with both males and females vocalizing in same sex and cross sex social encounters. Mouse pups are also highly vocal, producing isolation vocalizations when they are cold or removed from the nest. This study examined patterns in the development of pup isolation vocalizations, and compared these to adult vocalizations. In three litters of CBA/CaJ mice, we recorded isolation vocalizations at ages postnatal day 5 (p5), p7, p9, p11, and p13. Adult vocalizations were obtained in a variety of social situations. Altogether, 28,384 discrete vocal signals were recorded using high-frequency-sensitive equipment and analyzed for syllable type, spectral and temporal features, and the temporal sequencing within bouts. We found that pups produced all but one of the 11 syllable types recorded from adults. The proportions of syllable types changed developmentally, but even the youngest pups produced complex syllables with frequency-time variations. When all syllable types were pooled together for analysis, changes in the peak frequency or the duration of syllables were small, although significant, from p5 through p13. However, individual syllable types showed different, large patterns of change over development, requiring analysis of each syllable type separately. Most adult syllables were substantially lower in frequency and shorter in duration. As pups aged, the complexity of vocal bouts increased, with a greater tendency to switch between syllable types. Vocal bouts from older animals, p13 and adult, had significantly more sequential structure than those from younger mice. Overall, these results demonstrate substantial changes in social vocalizations with age. Future studies are required to identify whether these changes result from developmental processes affecting the vocal tract or control of vocalization, or from vocal learning. To provide a tool for further research, we developed a MATLAB program that generates bouts of vocalizations that correspond to mice of different ages

Lactate Regulates Metabolic and Proinflammatory Circuits in Control of T Cell Migration and Effector Functions

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Developmental learning impairments in a rodent model of nodular heterotopia

Developmental malformations of neocortex—including microgyria, ectopias, and periventricular nodular heterotopia (PNH)—have been associated with language learning impairments in humans. Studies also show that developmental language impairments are frequently associated with deficits in processing rapid acoustic stimuli, and rodent models have linked cortical developmental disruption (microgyria, ectopia) with rapid auditory processing deficits. We sought to extend this neurodevelopmental model to evaluate the effects of embryonic (E) day 15 exposure to the anti-mitotic teratogen methylazoxymethanol acetate (MAM) on auditory processing and maze learning in rats. Extensive cortical anomalies were confirmed in MAM-treated rats post mortem. These included evidence of laminar disruption, PNH, and hippocampal dysplasia. Juvenile auditory testing (P21–42) revealed comparable silent gap detection performance for MAM-treated and control subjects, indicating normal hearing and basic auditory temporal processing in MAM subjects. Juvenile testing on a more complex two-tone oddball task, however, revealed a significant impairment in MAM-treated as compared to control subjects. Post hoc analysis also revealed a significant effect of PNH severity for MAM subjects, with more severe disruption associated with greater processing impairments. In adulthood (P60–100), only MAM subjects with the most severe PNH condition showed deficits in oddball two-tone processing as compared to controls. However, when presented with a more complex and novel FM sweep detection task, all MAM subjects showed significant processing deficits as compared to controls. Moreover, post hoc analysis revealed a significant effect of PNH severity on FM sweep processing. Water Maze testing results also showed a significant impairment for spatial but not non-spatial learning in MAM rats as compared to controls. Results lend further support to the notions that: (1) generalized cortical developmental disruption (stemming from injury, genetic or teratogenic insults) leads to auditory processing deficits, which in turn have been suggested to play a causal role in language impairment; (2) severity of cortical disruption is related to the severity of processing impairments; (3) juvenile auditory processing deficits appear to ameliorate with maturation, but can still be elicited in adulthood using increasingly complex acoustic stimuli; and (4) malformations induced with MAM are also associated with generalized spatial learning deficits. These cumulative findings contribute to our understanding of the behavioral consequences of cortical developmental pathology, which may in turn elucidate mechanisms contributing to developmental language learning impairment in humans

Mice do not require auditory input for the normal development of their ultrasonic vocalizations

<p>Abstract</p> <p>Background</p> <p>Transgenic mice have become an important tool to elucidate the genetic foundation of the human language faculty. While learning is an essential prerequisite for the acquisition of human speech, it is still a matter of debate whether auditory learning plays any role in the development of species-specific vocalizations in mice. To study the influence of auditory input on call development, we compared the occurrence and structure of ultrasonic vocalizations from deaf otoferlin-knockout mice, a model for human deafness DFNB9, to those of hearing wild-type and heterozygous littermates.</p> <p>Results</p> <p>We found that the occurrence and structure of ultrasonic vocalizations recorded from deaf otoferlin-knockout mice and hearing wild-type and heterozygous littermates do not differ. Isolation calls from 16 deaf and 15 hearing pups show the same ontogenetic development in terms of the usage and structure of their vocalizations as their hearing conspecifics. Similarly, adult courtship 'songs' produced by 12 deaf and 16 hearing males did not differ in the latency to call, rhythm of calling or acoustic structure.</p> <p>Conclusion</p> <p>The results indicate that auditory experience is not a prerequisite for the development of species-specific vocalizations in mice. Thus, mouse models are of only limited suitability to study the evolution of vocal learning, a crucial component in the development of human speech. Nevertheless, ultrasonic vocalizations of mice constitute a valuable readout in studies of the genetic foundations of social and communicative behavior.</p

Genomic Signature-Based Identification of Influenza A Viruses Using RT-PCR/Electro-Spray Ionization Mass Spectrometry (ESI-MS) Technology

BACKGROUND: The emergence and rapid spread of the 2009 H1N1 pandemic influenza A virus (H1N1pdm) in humans highlights the importance of enhancing the capability of existing influenza surveillance systems with tools for rapid identification of emerging and re-emerging viruses. One of the new approaches is the RT-PCR electrospray ionization mass spectrometry (RT-PCR/ESI-MS) technology, which is based on analysis of base composition (BC) of RT-PCR amplicons from influenza "core" genes. Combination of the BC signatures represents a "genomic print" of an influenza A virus. METHODOLOGY/PRINCIPAL FINDINGS: Here, 757 samples collected between 2006 and 2009 were tested, including 302 seasonal H1N1, 171 H3N2, 7 swine triple reassortants, and 277 H1N1pdm viruses. Of the 277 H1N1pdm samples, 209 were clinical specimens (throat, nasal and nasopharyngeal swabs, nasal washes, blood and sputum). BC signatures for the clinical specimen from one of the first cases of the 2009 pandemic, A/California/04/2009, confirmed it as an unusual, previously unrecognized influenza A virus, with "core" genes related to viruses of avian, human and swine origins. Subsequent analysis of additional 276 H1N1pdm samples revealed that they shared the genomic print of A/California/04/2009, which differed from those of North American swine triple reassortant viruses, seasonal H1N1 and H3N2 and other viruses tested. Moreover, this assay allowed distinction between "core" genes of co-circulating groups of seasonal H1N1, such as clades 2B, 2C, and their reassortants with dual antiviral resistance to adamantanes and oseltamivir. CONCLUSIONS/SIGNIFICANCE: The RT-PCR/ESI-MS assay is a broad range influenza identification tool that can be used directly on clinical specimens for rapid and accurate detection of influenza virus genes. The assay differentiates the H1N1pdm from seasonal and other nonhuman hosts viruses. Although not a diagnostic tool, this assay demonstrates its usefulness and robustness in influenza virus surveillance and detection of novel and unusual viruses with previously unseen genomic prints

Consensus generation of a minimum set of outcome measures for auditing glaucoma surgery outcomes—a Delphi exercise

Purpose: To identify the key set of glaucoma surgery outcome measures considered most important and practical to collect by glaucoma specialists. Methods: One hundred two glaucoma specialists (57 members of the UK and Eire Glaucoma Society (UKEGS) and 45 members of the European Glaucoma society (EGS)) took part in an Online Delphi exercise. The RAND/UCLA appropriateness method was used analyse data from each round and generate a disagreement index. Results: Participants agreed on 13 baseline data points and 12 outcomes that were considered important and practical to collect. For intraocular pressure (IOP) percentage reduction in IOP from baseline (last three IOP readings pre-op) and reduction below a specified target were considered important. For visual fields, change in a global visual field index, e.g. MD, and development of progression as assessed by linear regression were considered important. From a safety perspective, any visual loss resulting in a doubling of the minimal angle of resolution, loss of 5 dB or more of visual field or development of advanced field loss (Hodapp Parrish Anderson Stage 4) was considered important. The importance of routinely using patient reported outcome measures (PROMs) was highlighted. Consensus suggested that outcomes of glaucoma treatments should be reported at 1, 5 and 10 years. Conclusions: There was broad consensus on a minimum dataset for reporting the outcomes of glaucoma surgery and outcome measurement intervals

Orienting asymmetries and lateralized processing of sounds in humans

<p>Abstract</p> <p>Background</p> <p>Lateralized processing of speech is a well studied phenomenon in humans. Both anatomical and neurophysiological studies support the view that nonhuman primates and other animal species also reveal hemispheric differences in areas involved in sound processing. In recent years, an increasing number of studies on a range of taxa have employed an orienting paradigm to investigate lateralized acoustic processing. In this paradigm, sounds are played directly from behind and the direction of turn is recorded. This assay rests on the assumption that a hemispheric asymmetry in processing is coupled to an orienting bias towards the contralateral side. To examine this largely untested assumption, speech stimuli as well as artificial sounds were presented to 224 right-handed human subjects shopping in supermarkets in Germany and in the UK. To verify the lateralized processing of the speech stimuli, we additionally assessed the brain activation in response to presentation of the different stimuli using functional magnetic resonance imaging (fMRI).</p> <p>Results</p> <p>In the naturalistic behavioural experiments, there was no difference in orienting behaviour in relation to the stimulus material (speech, artificial sounds). Contrary to our predictions, subjects revealed a significant left bias, irrespective of the sound category. This left bias was slightly but not significantly stronger in German subjects. The fMRI experiments confirmed that the speech stimuli evoked a significant left lateralized activation in BA44 compared to the artificial sounds.</p> <p>Conclusion</p> <p>These findings suggest that in adult humans, orienting biases are not necessarily coupled with lateralized processing of acoustic stimuli. Our results – as well as the inconsistent orienting biases found in different animal species – suggest that the orienting assay should be used with caution. Apparently, attention biases, experience, and experimental conditions may all affect head turning responses. Because of the complexity of the interaction of factors, the use of the orienting assay to determine lateralized processing of sound stimuli is discouraged.</p

Expression signatures of TP53 mutations in serous ovarian cancers

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>TP53 </it>gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease.</p> <p>Methods</p> <p>The <it>TP53 </it>coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage.</p> <p>Results</p> <p>Missense or chain terminating (null) mutations in <it>TP53 </it>were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict <it>TP53 </it>status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers.</p> <p>Conclusions</p> <p>This represents the first attempt to define a genomic signature of <it>TP53 </it>mutation in ovarian cancer. Patterns of gene expression characteristic of <it>TP53 </it>mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of <it>TP53 </it>mutation in breast cancer.</p

NG2 and phosphacan are present in the astroglial scar after human traumatic spinal cord injury

BACKGROUND: A major class of axon growth-repulsive molecules associated with CNS scar tissue is the family of chondroitin sulphate proteoglycans (CSPGs). Experimental spinal cord injury (SCI) has demonstrated rapid re-expression of CSPGs at and around the lesion site. The pharmacological digestion of CSPGs in such lesion models results in substantially enhanced axonal regeneration and a significant functional recovery. The potential therapeutic relevance of interfering with CSPG expression or function following experimental injuries seems clear, however, the spatio-temporal pattern of expression of individual members of the CSPG family following human spinal cord injury is only poorly defined. In the present correlative investigation, the expression pattern of CSPG family members NG2, neurocan, versican and phosphacan was studied in the human spinal cord. METHODS: An immunohistochemical investigation in post mortem samples of control and lesioned human spinal cords was performed. All patients with traumatic SCI had been clinically diagnosed as having "complete" injuries and presented lesions of the maceration type. RESULTS: In sections from control spinal cord, NG2 immunoreactivity was restricted to stellate-shaped cells corresponding to oligodendrocyte precursor cells. The distribution patterns of phosphacan, neurocan and versican in control human spinal cord parenchyma were similar, with a fine reticular pattern being observed in white matter (but also located in gray matter for phosphacan). Neurocan staining was also associated with blood vessel walls. Furthermore, phosphacan, neurocan and versican were present in the myelin sheaths of ventral and dorsal nerve roots axons. After human SCI, NG2 and phosphacan were both detected in the evolving astroglial scar. Neurocan and versican were detected exclusively in the lesion epicentre, being associated with infiltrating Schwann cells in the myelin sheaths of invading peripheral nerve fibres from lesioned dorsal roots. CONCLUSION: NG2 and phosphacan were both present in the evolving astroglial scar and, therefore, might play an important role in the blockade of successful CNS regeneration. Neurocan and versican, however, were located at the lesion epicentre, associated with Schwann cell myelin on regenerating peripheral nerve fibres, a distribution that was unlikely to contribute to failed CNS axon regeneration. The present data points to the importance of such correlative investigations for demonstrating the clinical relevance of experimental data