Three tools for managing vertigo in the frontline

Vertigo is a challenging symptom in general practice. With access to three tools – a focused history, eye examination and a management algorithm – a large proportion of vertiginous patients could be managed effectively by GPs. This practical guide seeks to increase the skills and confidence of frontline practitioners when managing vertigo

Prognosis and Survival of Older Patients With Dizziness in Primary Care:a 10-year prospective cohort study

Purpose: The prognosis of dizzy older patients in primary care is unknown. Our objective was to determine the prognosis and survival of patients with different subtypes and causes of dizziness. Methods: In a primary care prospective cohort study, 417 older adults with dizziness (mean age 75.5 years) received a full diagnostic workup in 2006-2008. A panel of physicians classified their dizziness subtype and primary cause of dizziness. Presyncope was the most common dizziness subtype (69.1%), followed by vertigo (41.0%), disequilibrium (39.8%), and other dizziness (1.7%). The most common primary causes of dizziness were cardiovascular disease (56.8%) and peripheral vestibular disease (14.4%). Main outcome measures were mortality and dizziness-related impairment assessed at 10-year follow-up.Results: At 10-year follow-up 169 patients (40.5%) had died. Multivariable adjusted Cox models showed a lower mortality rate for patients with the subtype vertigo compared to other subtypes (HR 0.62 (95% CI 0.40 to 0.96)), and for peripheral vestibular disease versus cardiovascular disease as primary cause of dizziness (HR 0.46 (95% CI 0.25 to 0.84)). After 10 years, 47.7% of patients who filled out the follow-up measurement experienced substantial dizziness-related impairment. No significant difference in substantial impairment was seen between different subtypes and primary causes of dizziness. Conclusions: The 10-year mortality rate was lower for the dizziness subtype vertigo compared to other subtypes. Patients with dizziness primarily caused by peripheral vestibular disease had a lower mortality rate than patients with cardiovascular disease. Substantial dizziness-related impairment in older dizzy patients 10 years later is high, and indicates that current treatment strategies by FPs may be suboptimal.<br/

Improving gene function predictions using independent transcriptional components

The interpretation of high throughput sequencing data is limited by our incomplete functional understanding of coding and non-coding transcripts. Reliably predicting the function of such transcripts can overcome this limitation. Here we report the use of a consensus independent component analysis and guilt-by-association approach to predict over 23,000 functional groups comprised of over 55,000 coding and non-coding transcripts using publicly available transcriptomic profiles. We show that, compared to using Principal Component Analysis, Independent Component Analysis-derived transcriptional components enable more confident functionality predictions, improve predictions when new members are added to the gene sets, and are less affected by gene multi-functionality. Predictions generated using human or mouse transcriptomic data are made available for exploration in a publicly available web portal. Our understanding of the function of many transcripts is still incomplete, limiting the interpretability of transcriptomic data. Here the authors use consensus-independent component analysis, together with a guilt-by-association approach, to improve the prediction of gene function

Establishment and characterisation of testicular cancer patient-derived xenograft models for preclinical evaluation of novel therapeutic strategies

Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients' response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer

Internet based vestibular rehabilitation with and without physiotherapy support for adults aged 50 and older with a chronic vestibular syndrome in general practice:three armed randomised controlled trial

Objective: To investigate the clinical effectiveness and safety of stand alone and blended internet based vestibular rehabilitation (VR) in the management of chronic vestibular syndromes in general practice.Design: Pragmatic, three armed, parallel group, individually randomised controlled trial.Setting: 59 general practices in the Netherlands.Participants: 322 adults aged 50 and older with a chronic vestibular syndrome.Interventions: Stand alone VR comprising a six week, internet based intervention with weekly online sessions and daily exercises (10-20 minutes a day). In the blended VR group, the same internet based intervention was supplemented by face-to-face physiotherapy support (home visits in weeks 1 and 3). Participants in the usual care group received standard care from a general practitioner, without any restrictions.Main outcome measures: The primary outcome was vestibular symptoms after six months as measured by the vertigo symptom scale-short form (VSS-SF range 0-60, clinically relevant difference ≥3 points). Secondary outcomes were dizziness related impairment, anxiety, depressive symptoms, subjective improvement of vestibular symptoms after three and six months, and adverse events.Results: In the intention-to-treat analysis, participants in the stand alone and blended VR groups had lower VSS-SF scores at six months than participants in the usual care group (adjusted mean difference −4.1 points, 95% confidence interval −5.8 to −2.5; and −3.5 points, −5.1 to −1.9, respectively). Similar differences in VSS-SF scores were seen at three months follow-up. Participants in the stand alone and blended VR groups also experienced less dizziness related impairment, less anxiety, and more subjective improvement of vestibular symptoms at three and six months. No serious adverse events related to online VR occurred during the trial.Conclusion: Stand alone and blended internet based VR are clinically effective and safe interventions to treat adults aged 50 and older with a chronic vestibular syndrome. Online VR is an easily accessible form of treatment, with the potential to improve care for an undertreated group of patients in general practice.Trial registration: Netherlands Trial Register NTR5712

Internet based vestibular rehabilitation with and without physiotherapy support for adults aged 50 and older with a chronic vestibular syndrome in general practice:three armed randomised controlled trial

OBJECTIVE: To investigate the clinical effectiveness and safety of stand alone and blended internet based vestibular rehabilitation (VR) in the management of chronic vestibular syndromes in general practice. DESIGN: Pragmatic, three armed, parallel group, individually randomised controlled trial. SETTING: 59 general practices in the Netherlands. PARTICIPANTS: 322 adults aged 50 and older with a chronic vestibular syndrome. INTERVENTIONS: Stand alone VR comprising a six week, internet based intervention with weekly online sessions and daily exercises (10-20 minutes a day). In the blended VR group, the same internet based intervention was supplemented by face-to-face physiotherapy support (home visits in weeks 1 and 3). Participants in the usual care group received standard care from a general practitioner, without any restrictions. MAIN OUTCOME MEASURES: The primary outcome was vestibular symptoms after six months as measured by the vertigo symptom scale-short form (VSS-SF range 0-60, clinically relevant difference ≥3 points). Secondary outcomes were dizziness related impairment, anxiety, depressive symptoms, subjective improvement of vestibular symptoms after three and six months, and adverse events. RESULTS: In the intention-to-treat analysis, participants in the stand alone and blended VR groups had lower VSS-SF scores at six months than participants in the usual care group (adjusted mean difference -4.1 points, 95% confidence interval -5.8 to -2.5; and -3.5 points, -5.1 to -1.9, respectively). Similar differences in VSS-SF scores were seen at three months follow-up. Participants in the stand alone and blended VR groups also experienced less dizziness related impairment, less anxiety, and more subjective improvement of vestibular symptoms at three and six months. No serious adverse events related to online VR occurred during the trial. CONCLUSION: Stand alone and blended internet based VR are clinically effective and safe interventions to treat adults aged 50 and older with a chronic vestibular syndrome. Online VR is an easily accessible form of treatment, with the potential to improve care for an undertreated group of patients in general practice. TRIAL REGISTRATION: Netherlands Trial Register NTR5712

Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa

<p>Abstract</p> <p>Background</p> <p>The choice of appropriate artemisinin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate and simplicity of administration). To assess whether the combination dihydroartemisinin-piperaquine (DP) could be an alternative to artemether-lumefantrine (AL), the efficacy and the tolerability of the two products for the treatment of uncomplicated falciparum malaria in sub-Saharan Africa have been compared.</p> <p>Methods</p> <p>A multicentric open randomized controlled clinical trial of three-day treatment of DP against AL for the treatment of two parallel groups of patients aged two years and above and suffering from uncomplicated falciparum malaria was carried out in Cameroon, Côte d'Ivoire and Senegal. Within each group, patients were randomly assigned supervised treatment. DP was given once a day for three days and AL twice a day for three days. Follow-up visits were performed on day 1 to 4 and on day 7, 14, 21, 28 to evaluate clinical and parasitological results. The primary endpoint was the recovery rate by day 28.</p> <p>Results</p> <p>Of 384 patients enrolled, 197 were assigned DP and 187 AL. The recovery rates adjusted by genotyping, 99.5% in the DP group and 98.9% in the AL group, were not statistically different (p = 0.538). No Early Therapeutic Failure (ETF) was observed. At day 28, two patients in the DP group and five in AL group had recurrent parasitaemia with <it>Plasmodium falciparum</it>. In the DP group, after PCR genotyping, one of the two recurrences was classified as a new infection and the other as recrudescence. In AL group, two recurrences were classified after correction by PCR as recrudescence. All cases of recrudescence were classified as Late Parasitological Failure (LPF). In each group, a rapid recovery from fever and parasitaemia was noticed. More than 90% of patients did no longer present fever or parasitaemia 48 hours after treatment. Both drugs were well tolerated. Indeed, no serious adverse events were reported during the follow-up period. Most of the adverse events which developed were moderate and did not result in the treatment being stopped in either treatment group.</p> <p>Conclusions</p> <p>Dihydroartemisinin-piperaquine was as effective and well-tolerated as artemether-lumefantrine in the treatment of uncomplicated falciparum malaria. In addition, dihydroartemisinin-piperaquine, a single daily dose, could be an advantage over artemether-lumefantrine in Africa because of better treatment observance.</p

The Chromosomal Passenger Complex Activates Polo Kinase at Centromeres

INCENP acts as a protein scaffold that integrates the functions of two crucial mitotic kinases, Aurora B and Polo, at centromeres of mitotic chromosomes

The Chromosomal Passenger Complex Activates Polo Kinase at Centromeres

INCENP acts as a protein scaffold that integrates the functions of two crucial mitotic kinases, Aurora B and Polo, at centromeres of mitotic chromosomes

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology