Speech and language therapy versus placebo or no intervention for speech problems in Parkinson's disease

Parkinson's disease patients commonly suffer from speech and vocal problems including dysarthric speech, reduced loudness and loss of articulation. These symptoms increase in frequency and intensity with progression of the disease). Speech and language therapy (SLT) aims to improve the intelligibility of speech with behavioural treatment techniques or instrumental aids

Impact of breast cancer subtypes on 3-year survival among adolescent and young adult women.

IntroductionYoung women have poorer survival after breast cancer than do older women. It is unclear whether this survival difference relates to the unique distribution of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2)-defined molecular breast cancer subtypes among adolescent and young adult (AYA) women aged 15 to 39 years. The purpose of our study was to examine associations between breast cancer subtypes and short-term survival in AYA women, as well as to determine whether the distinct molecular subtype distribution among AYA women explains the unfavorable overall breast cancer survival statistics reported for AYA women compared with older women.MethodsData for 5,331 AYA breast cancers diagnosed between 2005 and 2009 were obtained from the California Cancer Registry. Survival by subtype (triple-negative; HR+/HER2-; HR+/HER2+; HR-/HER2+) and age-group (AYA versus 40- to 64-year-olds) was analyzed with Cox proportional hazards regression with follow-up through 2010.ResultsWith up to 6 years of follow-up and a mean survival time of 3.1 years (SD = 1.5 years), AYA women diagnosed with HR-/HER + and triple-negative breast cancer experienced a 1.6-fold and 2.7-fold increased risk of death, respectively, from all causes (HR-/HER + hazard ratio: 1.55; 95% confidence interval (CI): 1.10 to 2.18; triple-negative HR: 2.75; 95% CI, 2.06 to 3.66) and breast cancer (HR-/HER + hazard ratio: 1.63; 95% CI, 1.12 to 2.36; triple-negative hazard ratio: 2.71; 95% CI, 1.98 to 3.71) than AYA women with HR+/HER2- breast cancer. AYA women who resided in lower socioeconomic status neighborhoods, had public health insurance, and were of Black, compared with White, race/ethnicity experienced worse survival. This race/ethnicity association was attenuated somewhat after adjusting for breast cancer subtypes (hazard ratio, 1.33; 95% CI, 0.98 to 1.82). AYA women had similar all-cause and breast cancer-specific short-term survival as older women for all breast cancer subtypes and across all stages of disease.ConclusionsAmong AYA women with breast cancer, short-term survival varied by breast cancer subtypes, with the distribution of breast cancer subtypes explaining some of the poorer survival observed among Black, compared with White, AYA women. Future studies should consider whether distribution of breast cancer subtypes and other factors, including differential receipt of treatment regimens, influences long-term survival in young compared with older women

Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system

Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer’s disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination

Lee Silverman voice treatment versus standard NHS speech and language therapy versus control in Parkinson's disease (PD COMM pilot):study protocol for a randomized controlled trial

Background: Parkinson’s disease is a common movement disorder affecting approximately 127,000 people in the UK, with an estimated two thirds having speech-related problems. Currently there is no preferred approach to speech and language therapy within the NHS and there is little evidence for the effectiveness of standard NHS therapy or Lee Silverman voice treatment. This trial aims to investigate the feasibility and acceptability of randomizing people with Parkinson’s disease-related speech or voice problems to Lee Silverman voice treatment or standard speech and language therapy compared to a no-intervention control. Methods/Design: The PD COMM pilot is a three arm, assessor-blinded, randomized controlled trial. Randomization will be computer-generated with participants randomized at a ratio of 1:1:1. Participants randomized to intervention arms will be immediately referred to the appropriate speech and language therapist. The target population are patients with a confirmed diagnosis of idiopathic Parkinson’s disease who have problems with their speech or voice. The Lee Silverman voice treatment intervention group will receive the standard regime of 16 sessions between 50 and 60 minutes in length over four weeks, with extra home practice. The standard speech and language therapy intervention group will receive a dose determined by patients’ individual needs, but not exceeding eight weeks of treatment. The control group will receive standard care with no speech and language therapy input for at least six months post-randomization. Outcomes will be assessed at baseline (pre-randomization) and post- randomization at three, six, and 12 months. The outcome measures include patient-reported voice measures, quality of life, resource use, and assessor-rated speech recordings. The recruitment aim is at least 60 participants over 21 months from 11 sites, equating to at least 20 participants in each arm of the trial. This trial is ongoing and recruitment commenced in May 2012. Discussion: This study will provide information on the feasibility and acceptability of randomizing participants to different speech and language therapies or control/deferred treatment. The findings relating to recruitment, treatment compliance, outcome measures, and effect size will inform a future phase III randomized controlled trial

Lee Silverman Voice Treatment versus standard speech and language therapy versus control in Parkinson’s disease: preliminary cost-consequence analysis of the PD COMM pilot randomised controlled trial

Additional file 1: Table S1. Speech and language therapy (SLT) set-up costs. Table S2. Derivation of unit costs: sources and assumptions. Table S3. Resource use per patient over 12 months (NHS and social care funded). Table S4. Mean medication costs by drug type over 12 months, per patient (2014/15 costs). Table S5. Resource use per patient over 12 months (privately funded). Table S6. Patient funded care costs and out of pocket expenses over 12 months, per patient. Table S7. Convergence between index scores of EQ-5D-3L and ICECAP-O dimensions (Spearman’s rank correlation). Table S8. Convergence between index scores of PDQ39 dimensions and ICECAP-O responses (Spearman’s rank correlation). Table S9. Convergence between index scores of PDQ39 dimensions and EQ-5D-3L responses (Spearman’s rank correlation

Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods: We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings: Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation: Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding: Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative

Lee Silverman voice treatment versus NHS speech and language therapy versus control for dysarthria in people with Parkinson's disease (PD COMM): pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial

To assess the clinical effectiveness of two speech and language therapy approaches versus no speech and language therapy for dysarthria in people with Parkinson's disease. Pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial. The speech and language therapy interventions were delivered in outpatient or home settings between 26 September 2016 and 16 March 2020. 388 people with Parkinson's disease and dysarthria. Participants were randomly assigned to one of three groups (1:1:1): 130 to Lee Silverman voice treatment (LSVT LOUD), 129 to NHS speech and language therapy, and 129 to no speech and language therapy. LSVT LOUD consisted of four, face-to-face or remote, 50 min sessions each week delivered over four weeks. Home based practice activities were set for up to 5-10 mins daily on treatment days and 15 mins twice daily on non-treatment days. Dosage for the NHS speech and language therapy was determined by the local therapist in response to the participants' needs (estimated from prior research that NHS speech and language therapy participants would receive an average of one session per week over six to eight weeks). Local practices for NHS speech and language therapy were accepted, except for those within the LSVT LOUD protocol. Analyses were based on the intention to treat principle. The primary outcome was total score at three months of self-reported voice handicap index. People who received LSVT LOUD reported lower voice handicap index scores at three months after randomisation than those who did not receive speech and language therapy (-8.0 points (99% confidence interval -13.3 to -2.6); P<0.001). No evidence suggests a difference in voice handicap index scores between NHS speech and language therapy and no speech and language therapy (1.7 points (-3.8 to 7.1); P=0.43). Patients in the LSVT LOUD group also reported lower voice handicap index scores than did those randomised to NHS speech and language therapy (-9.6 points (-14.9 to -4.4); P<0.001). 93 adverse events (predominately vocal strain) were reported in the LSVT LOUD group, 46 in the NHS speech and language therapy group, and none in the no speech and language therapy group. No serious adverse events were recorded. LSVT LOUD was more effective at reducing the participant reported impact of voice problems than was no speech and language therapy and NHS speech and language therapy. NHS speech and language therapy showed no evidence of benefit compared with no speech and language therapy. ISRCTN registry ISRCTN12421382. [Abstract copyright: © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

From cheek swabs to consensus sequences : an A to Z protocol for high-throughput DNA sequencing of complete human mitochondrial genomes

Background: Next-generation DNA sequencing (NGS) technologies have made huge impacts in many fields of biological research, but especially in evolutionary biology. One area where NGS has shown potential is for high-throughput sequencing of complete mtDNA genomes (of humans and other animals). Despite the increasing use of NGS technologies and a better appreciation of their importance in answering biological questions, there remain significant obstacles to the successful implementation of NGS-based projects, especially for new users. Results: Here we present an ‘A to Z’ protocol for obtaining complete human mitochondrial (mtDNA) genomes – from DNA extraction to consensus sequence. Although designed for use on humans, this protocol could also be used to sequence small, organellar genomes from other species, and also nuclear loci. This protocol includes DNA extraction, PCR amplification, fragmentation of PCR products, barcoding of fragments, sequencing using the 454 GS FLX platform, and a complete bioinformatics pipeline (primer removal, reference-based mapping, output of coverage plots and SNP calling). Conclusions: All steps in this protocol are designed to be straightforward to implement, especially for researchers who are undertaking next-generation sequencing for the first time. The molecular steps are scalable to large numbers (hundreds) of individuals and all steps post-DNA extraction can be carried out in 96-well plate format. Also, the protocol has been assembled so that individual ‘modules’ can be swapped out to suit available resources