Multinational survey of treatment practices of clinicians managing subclinical hypothyroidism in older people in 2019

Background: International societies have recommended that levothyroxine should not routinely be prescribed in older individuals for the management of mild subclinical hypothyroidism (SCH). However, it is unknown whether clinicians managing people with SCH are either aware of or adhere to these guidelines. Methods: A web-based survey of members of several international thyroid associations and general practitioners in North-East England was conducted. Respondents were presented with a vignette of an 80-year-old gentleman with mild persistent SCH experiencing tiredness. Multivariable logistic regression analyses were performed to evaluate predictors of awareness of guidelines and responses to treatment. Results: The survey response rate was 21.9% (565/2,583). Only 7.6% of clinicians were unaware of guidelines regarding management of SCH in older people. Twenty percent of clinicians stated that they would treat the older patient with mild SCH, whereas 13% were unsure. Clinicians from North America were more likely to treat the older person with mild SCH than clinicians from elsewhere (OR 2.24 [1.25–3.98]). Likewise, non-endocrinologists were also more likely than endocrinologists to treat the older person with mild SCH (OR 3.26 [1.45–6.47]). Conclusion: The majority of clinicians are aware of guidelines regarding management of SCH in older individuals. However, a considerable proportion of clinicians would still treat an older person with non-specific symptoms and mild SCH. These guidelines need to be disseminated more widely and more research is required to understand barriers to adherence to international recommendations

Impact of residual disease as a prognostic factor for survival in women with advanced epithelial ovarian cancer after primary surgery

BACKGROUND: Ovarian cancer is the seventh most common cancer among women and a leading cause of death from gynaecological malignancies. Epithelial ovarian cancer is the most common type, accounting for around 90% of all ovarian cancers. This specific type of ovarian cancer starts in the surface layer covering the ovary or lining of the fallopian tube. Surgery is performed either before chemotherapy (upfront or primary debulking surgery (PDS)) or in the middle of a course of treatment with chemotherapy (neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS)), with the aim of removing all visible tumour and achieving no macroscopic residual disease (NMRD). The aim of this review is to investigate the prognostic impact of size of residual disease nodules (RD) in women who received upfront or interval cytoreductive surgery for advanced (stage III and IV) epithelial ovarian cancer (EOC). OBJECTIVES: To assess the prognostic impact of residual disease after primary surgery on survival outcomes for advanced (stage III and IV) epithelial ovarian cancer. In separate analyses, primary surgery included both upfront primary debulking surgery (PDS) followed by adjuvant chemotherapy and neoadjuvant chemotherapy followed by interval debulking surgery (IDS). Each residual disease threshold is considered as a separate prognostic factor. SEARCH METHODS: We searched CENTRAL (2021, Issue 8), MEDLINE via Ovid (to 30 August 2021) and Embase via Ovid (to 30 August 2021). SELECTION CRITERIA: We included survival data from studies of at least 100 women with advanced EOC after primary surgery. Residual disease was assessed as a prognostic factor in multivariate prognostic models. We excluded studies that reported fewer than 100 women, women with concurrent malignancies or studies that only reported unadjusted results. Women were included into two distinct groups: those who received PDS followed by platinum-based chemotherapy and those who received IDS, analysed separately. We included studies that reported all RD thresholds after surgery, but the main thresholds of interest were microscopic RD (labelled NMRD), RD 0.1 cm to 1 cm (small-volume residual disease (SVRD)) and RD > 1 cm (large-volume residual disease (LVRD)). DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Where possible, we synthesised the data in meta-analysis. To assess the adequacy of adjustment factors used in multivariate Cox models, we used the 'adjustment for other prognostic factors' and 'statistical analysis and reporting' domains of the quality in prognosis studies (QUIPS) tool. We also made judgements about the certainty of the evidence for each outcome in the main comparisons, using GRADE. We examined differences between FIGO stages III and IV for different thresholds of RD after primary surgery. We considered factors such as age, grade, length of follow-up, type and experience of surgeon, and type of surgery in the interpretation of any heterogeneity. We also performed sensitivity analyses that distinguished between studies that included NMRD in RD categories of 0 cm) and NMRD was also important. SVRD versus NMRD in a PDS setting In PDS studies, most showed an increased risk of death in all RD groups when those with macroscopic RD (MRD) were compared to NMRD. Women who had SVRD after PDS had more than twice the risk of death compared to women with NMRD (hazard ratio (HR) 2.03, 95% confidence interval (CI) 1.80 to 2.29; I2 = 50%; 17 studies; 9404 participants; moderate-certainty). The analysis of progression-free survival found that women who had SVRD after PDS had nearly twice the risk of death compared to women with NMRD (HR 1.88, 95% CI 1.63 to 2.16; I2 = 63%; 10 studies; 6596 participants; moderate-certainty). LVRD versus SVRD in a PDS setting When we compared LVRD versus SVRD following surgery, the estimates were attenuated compared to NMRD comparisons. All analyses showed an overall survival benefit in women who had RD < 1 cm after surgery (HR 1.22, 95% CI 1.13 to 1.32; I2 = 0%; 5 studies; 6000 participants; moderate-certainty). The results were robust to analyses of progression-free survival. SVRD and LVRD versus NMRD in an IDS setting The one study that defined the categories as NMRD, SVRD and LVRD showed that women who had SVRD and LVRD after IDS had more than twice the risk of death compared to women who had NMRD (HR 2.09, 95% CI 1.20 to 3.66; 310 participants; I2 = 56%, and HR 2.23, 95% CI 1.49 to 3.34; 343 participants; I2 = 35%; very low-certainty, for SVRD versus NMRD and LVRD versus NMRD, respectively). LVRD versus SVRD + NMRD in an IDS setting Meta-analysis found that women who had LVRD had a greater risk of death and disease progression compared to women who had either SVRD or NMRD (HR 1.60, 95% CI 1.21 to 2.11; 6 studies; 1572 participants; I2 = 58% for overall survival and HR 1.76, 95% CI 1.23 to 2.52; 1145 participants; I2 = 60% for progression-free survival; very low-certainty). However, this result is biased as in all but one study it was not possible to distinguish NMRD within the < 1 cm thresholds. Only one study separated NMRD from SVRD; all others included NMRD in the SVRD group, which may create bias when comparing with LVRD, making interpretation challenging. MRD versus NMRD in an IDS setting Women who had any amount of MRD after IDS had more than twice the risk of death compared to women with NMRD (HR 2.11, 95% CI 1.35 to 3.29, I2 = 81%; 906 participants; very low-certainty). AUTHORS' CONCLUSIONS: In a PDS setting, there is moderate-certainty evidence that the amount of RD after primary surgery is a prognostic factor for overall and progression-free survival in women with advanced ovarian cancer. We separated our analysis into three distinct categories for the survival outcome including NMRD, SVRD and LVRD. After IDS, there may be only two categories required, although this is based on very low-certainty evidence, as all but one study included NMRD in the SVRD category. The one study that separated NMRD from SVRD showed no improved survival outcome in the SVRD category, compared to LVRD. Further low-certainty evidence also supported restricting to two categories, where women who had any amount of MRD after IDS had a significantly greater risk of death compared to women with NMRD. Therefore, the evidence presented in this review cannot conclude that using three categories applies in an IDS setting (very low-certainty evidence), as was supported for PDS (which has convincing moderate-certainty evidence)

Photobiomodulation in the management of oral mucositis for adult head and neck cancer patients receiving irradiation: the LiTEFORM RCT.

BackgroundOral mucositis is a debilitating and painful complication of head and neck cancer irradiation that is characterised by inflammation of the mucous membranes, erythema and ulceration. Oral mucositis affects 6000 head and neck cancer patients per year in England and Wales. Current treatments have not proven to be effective. International studies suggest that low-level laser therapy may be an effective treatment.ObjectivesTo assess the clinical effectiveness and cost-effectiveness of low-level laser therapy in the management of oral mucositis in head and neck cancer irradiation. To identify barriers to and facilitators of implementing low-level laser therapy in routine care.DesignPlacebo-controlled, individually randomised, multicentre Phase III superiority trial, with an internal pilot and health economic and qualitative process evaluations. The participants, outcome assessors and therapists were blinded.SettingNine NHS head and neck cancer sites in England and Wales.ParticipantsA total of 87 out of 380 participants were recruited who were aged ≥ 18 years and were undergoing head and neck cancer irradiation with ≥ 60 Gy.InterventionRandom allocation (1 : 1 ratio) to either low-level laser therapy or sham low-level laser therapy three times per week for the duration of irradiation. The diode laser had the following specifications: wavelength 660 nm, power output 75 mW, beam area 1.5 cm2, irradiance 50 mW/cm2, exposure time 60 seconds and fluence 3 J/cm2. There were 20-30 spots per session. Sham low-level laser therapy was delivered in an identical manner.Main outcome measureThe mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks following the start of irradiation. Higher scores indicate a worse outcome.ResultsA total of 231 patients were screened and, of these, 87 were randomised (low-level laser therapy arm, n = 44; sham arm, n = 43). The mean age was 59.4 years (standard deviation 8.8 years) and 69 participants (79%) were male. The mean Oral Mucositis Weekly Questionnaire-Head and Neck Cancer score at 6 weeks was 33.2 (standard deviation 10) in the low-level laser therapy arm and 27.4 (standard deviation 13.8) in the sham arm.LimitationsThe trial lacked statistical power because it did not meet the recruitment target. Staff and patients willingly participated in the trial and worked hard to make the LiTEFORM trial succeed. However, the task of introducing, embedding and sustaining new low-level laser therapy services into a complex care pathway proved challenging. Sites could deliver low-level laser therapy to only a small number of patients at a time. The administration of low-level laser therapy was viewed as straightforward, but also time-consuming and sometimes uncomfortable for both patients and staff, particularly those staff who were not used to working in a patient's mouth.ConclusionsThis trial had a robust design but lacked power to be definitive. Low-level laser therapy is relatively inexpensive. In contrast with previous trials, some patients found low-level laser therapy sessions to be difficult. The duration of low-level laser therapy sessions is, therefore, an important consideration. Clinicians experienced in oral cavity work most readily adapt to delivering low-level laser therapy, although other allied health professionals can be trained. Blinding the clinicians delivering low-level laser therapy is feasible. There are important human resource, real estate and logistical considerations for those setting up low-level laser therapy services.Future workFurther well-designed randomised controlled trials investigating low-level laser therapy in head and neck cancer irradiation are needed, with similar powered recruitment targets but addressing the recruitment challenges and logistical findings from this research.Trial registrationThis trial is registered as ISRCTN14224600.FundingThis project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 46. See the NIHR Journals Library website for further project information

BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study

Background Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism. Methods The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data. Discussion This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

The impact of the Speech Systems Approach on intelligibility for children with cerebral palsy: a secondary analysis

Background The motor speech disorder, dysarthria, is common in cerebral palsy. The Speech Systems Approach therapy programme, which focuses on controlling breath supply and speech rate, has increased children’s intelligibility. Objective To ascertain if increased intelligibility is due to better differentiation of the articulation of individual consonants in words spoken in isolation and in connected speech. Design Secondary analysis. Setting University. Participants Forty-two children with cerebral palsy and dysarthria aged 5–18 years, Gross Motor Function Classification System I–V. Intervention The Speech Systems Approach is a motor learning therapy delivered to individuals by a speech and language therapist in 40-minute sessions, three times per week for 6 weeks. Intervention focuses on production of a strong, clear voice and speaking at a steady rate. Practice changes from single words to increasingly longer utterances in tasks with increasing cognitive load. Main outcome measures Unfamiliar listeners’ identification of singleton consonants (e.g. nap) and clusters of consonants (e.g. stair, end) at the start and end of words when hearing single words in forced choice tasks and connected speech in free transcription tasks. Acoustic measures of sound intensity and duration. Data sources Data collected at 1-week pre- and 1-week post-therapy from three studies: two interrupted time series design, one feasibility randomised controlled trial. Results Word initial and word final singleton consonants and consonant clusters were better identified post-therapy. The extent of improvement differed across word initial and word final singleton consonant subtypes. Improvement was greater for single words than connected speech. Change in sound identification varied across children, particularly in connected speech. Sound intensity and duration increases also were inconsistent. Limitations The small sample size did not allow for analysis of cerebral palsy type. Acoustic data were not available for all children, limiting the strength of conclusions that can be drawn. The different but phonetically balanced word lists, used in the original research, created variability in single words spoken across recordings analysed. Low frequencies of plosives, fricatives and affricates necessitated their combination for analysis preventing investigation of the effect of specific consonants. Connected speech was spontaneous, again creating variability within the data analysed. The estimated effects of therapy may therefore be partially explained by differences in the spoken language elicited. Conclusions The Speech Systems Approach helped children generate greater breath supply and a steady rate, leading to increased intensity and duration of consonant sounds in single words, thereby aiding their identification by listeners. Transfer of the motor behaviour to connected speech was inconsistent. Future work Refining the Speech Systems Approach to focus on connected speech early in the intervention. Personalisation of cues according to perceptual and acoustic speech measures. Creation of a battery of measures that can be repeated across children and multiple recordings. Study registration This trial is registered as Research Registry 6117. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR130967) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 4. See the NIHR Journals Library website for further project information. Plain language summary Some children with cerebral palsy have speech that sounds weak, slurred and difficult to understand, which seriously impacts their social life and education. We developed a therapy programme to help children control their breathing and how fast they speak. Having more breath should make children’s voices stronger. Speaking at a steady rate should give enough time for children to move their jaw, tongue and lips to produce each sound more precisely. Children’s speech was easier to understand after the therapy. This study aimed to find out if the therapy worked by helping children to say consonant sounds more clearly. We used recordings made in previous research to work out which consonants listeners heard correctly. We also looked at waveforms, which showed children’s speech as moving pictures, to find out how speech changed. After therapy, when children spoke in single words, listeners heard almost all types of consonant sounds at the start and end of words more clearly. No particular type of consonant sounds, such as ‘s’ in ‘so’ or ‘t’ in ‘tar’, led to better speech clarity. Waveforms showed that some children produced stronger speech sounds, some slowed their speech, and some did both. Listeners heard some children more clearly after therapy when they spoke in phrases, but found others more difficult to understand. Few consonants were easier to understand after therapy. We saw no clear patterns of change in speech waveforms. Overall, children produced stronger, more precise speech in single words, but not all transferred this skill to speaking in phrases. Children differed in how they achieved clearer speech. We used the findings to refine the therapy to focus on phrases early in the programme and to personalise instructions to children’s individual speech patterns. We will use waveforms to find where children have most difficulty and to measure improvement. Scientific summary Background and introduction The motor disorders of cerebral palsy (CP) often affect breath control and speech production, causing the speech disorder dysarthria. Dysarthria in CP typically affects all speech systems: respiration, phonation, resonance, prosody and articulation. Respiration is often shallow and lacks co-ordination with phonation, generating weak or inconsistent subglottal pressure. Vocal folds may vibrate slowly and irregularly; air may leak through the folds when they should be adducted, reducing the intraoral pressure and weakening the sound source. The velum may rise slowly or fail to close off the nasal passage during speech. The movements of the articulators (jaw, tongue and lips) may be slow and imprecise. They may also be weak, reducing children’s ability to constrict the vocal tract for consonant sounds. The combined effect of these limitations is that children often speak in short phrases, with inappropriate phrasing or rushes of speech if children run out of air. Their voice may sound weak, breathy and sometimes harsh. Speech is often slow with reduced melodic intonation and children may have a restricted range of consonants that they can produce clearly. Intervention focussing on breath support and speech rate is expected to aid with the co-ordination of three phases of speech production, mainly initiation, phonation and articulation. Greater breath supply and increased air pressure during exhalation should increase subglottal air pressure bringing firmer contact of the vocal folds during phonation to generate a stronger vocal note/sound source. The improved audibility and potential for greater intraoral air pressure arising from this will also help compensate for any weak closures of articulators and reduce ‘leakage’ of air during speech. A steady speech rate should allow children to move with precision from one articulatory place and manner to another. Thus, as a result of changes in breath supply and rate, phonemes should be acoustically differentiated and listeners better able to perceive the sounds that children are articulating (increased phonetic intelligibility). The Speech Systems Approach has been developed to focus on breath control and speech rate and has led to improvements in the intelligibility of children’s speech which have been maintained for up to 12 weeks without further intervention. What is not yet known is whether there is a differential effect on types of speech sounds, or whether this effect is moderated by CP type or severity of impairment. Establishing this can then help with further individualisation of therapy and further gains in intelligibility. Aims The aim of the study was to ascertain if therapy focusing on breath supply and speech rate is associated with increased differentiation of the articulation of individual phonemes, enabling listeners to better identify individual phonemes in words spoken in isolation and in connected speech (CS). Methods Design The study was a secondary analysis of previously collected data from two phase II studies using an interrupted time series design and one feasibility randomised controlled trial of the Speech Systems Approach. Participants Forty-two children and young people aged 5–18 years, who had a diagnosis of CP by a medical practitioner and moderate to severe dysarthria as assessed by their local speech language therapist, received the Speech Systems Approach in the original studies. Participants were excluded from the studies if they had hearing impairments >50 decibel HL, visual impairments that were not correctable with glasses, or were unable to follow simple verbal instructions. All 42 participants were included in this secondary analysis. Intervention Children received individual therapy following the Speech Systems Approach from a registered speech and language therapist three times a week for 6 weeks. Sessions lasted approximately 40 minutes. In two of the original studies the sessions were provided face-to-face, the third study session took place remotely using video conferencing software. In the first session the therapist tried several cues to find the best that elicited a strong, clear voice in an open vowel (ah). Cues included ‘strong, big, loud’ and a combination of these. For children who had difficulty initiating movement cues were ‘nice and easy’ or ‘smooth’. Once the most appropriate cue had been found for the child, that cue was used to elicit open vowels on command. Practice of the target voice then followed a hierarchy of increasing length of utterance and cognitive load. Children first practiced in single words (SWs), then short phrases and finally longer CS. At each stage they started with repetition, moved to picture naming and description, and then questions and answers and games. Children had to use their target voice 8/10 attempts to move to the next level in the hierarchy. Children were provided with knowledge of results on how their voice sounded and were encouraged to use bio feedback (‘How did that feel?’). Feedback was given frequently in the acquisition phase at each level of the hierarchy and then faded to aid retention. Sessions followed a set sequence for practice of the target voice: (1) 10 open vowels; (2) three repetitions of 10 self-selected phrases that children use in daily life; (3) 70–80 words and phrases from the speech task hierarchy; and (4) 10–20 utterances randomly selected from the three preceding tasks. Procedure Data were collected at 6- and 1-week pre-therapy and 1, 6- and 12-weeks post-therapy. The original studies suggested that gains in intelligibility were observed immediately after therapy (1 week) and were maintained at 6 and 12 weeks. For this study we analysed data from 1-week pre- and 1-week post-therapy. At each time point, participants’ speech was recorded on two separate days and elicited through two tasks. SWs were elicited using the Children’s Speech Intelligibility Measure (CSIM) which contains 200 lists of 50 words. The CSIM is a forced choice word recognition task. Listeners heard each word and selected the target word from a list of 12 phonetically similar words. CS was elicited by asking the participants to describe complex pictures and answer questions. The recordings were transcribed live by an expert speech and language therapist and then checked with the child, to create a gold standard transcription of target words. Up to 60 seconds of CS was presented to listeners in phrases separated by pauses of at least three seconds. The CS recognition task was open choice; listeners heard the recordings of CS and wrote down the words they perceived the child to say. Listeners were native speakers of English, aged 18–55 years, and had no hearing difficulties or regular experience of interacting with people with disabilities or speech disorders. In each of the original studies, listeners were randomly allocated three speech recordings, with the limitation that they did not hear the same child more than once. Each recording was heard by three listeners. Outcomes Perceptual data Each word produced by children in the SW and CS tasks was categorised by the single consonants and the clusters of consonants at the start and end of words. Consonants were categorised according to their voicing (voiced = vocal fold vibration; voiceless = vocal folds open), place of articulation (bilabial, labiodental, dental, alveolar, post-alveolar, velar, and glottal), and manner of articulation (plosives, fricatives, affricates, nasals and approximants). The words perceived by listeners were categorised in the same way. A review of the data showed that some manners and places of articulation rarely appeared in the SW lists. We therefore combined manners of articulation into obstruents, which demand constriction/closure of the vocal tract (plosives, fricative and affricates), and sonorants, which allow air to flow out of the mouth or nose (approximants and nasals) and places of articulation to labial (bilabial, labiodental), coronal (dental, alveolar, post-alveolar) and dorsal (velar). Consonants were then further categorised according to a combination of their voicing, place, and manner characteristics (e.g. voiced labial obstruent). This was done owing to dependencies between voice and manner such that consonants with a sonorant manner are never voiceless. Because of this, we were not able to separate the main effects of voice and manner from each other if they were added as individual explanatory variables in modelling. The perceptual data were multilevel such that children were level 2 units and each target word-and-listener combination was a level 1 unit. The primary outcome for the perceptual analysis was the identification of words and segments within them (binary outcomes). Words and sounds were identified if there was a match between the target and perceived word/consonant/cluster/voice/place/manner. Secondary outcomes include the percentage identification measures. We visually inspected radar plots profiling performance on six percentage identification measures comprising the voice, place and manner of word initial and word final singleton consonants at pre- and post-therapy. Acoustic data Recordings of 24 out of the 42 children were available pre- and post-therapy and were automatically transcribed and segmented, and manually corrected. Measures of intensity (dB), duration (ms) and speech rate (seconds per syllable) were made at word and segment level. Changes in intensity and/or speech rate were monitored post-therapy and examined as a function of consonant manner, intelligibility, and groups of children based on the perceptual analyses. Data analysis Perceptual data We used generalised linear mixed modelling (GLMM) with a logit link function and random effect of child to examine the effect of the Speech Systems Approach intervention (post-therapy vs. pre-therapy) on identification of word initial and word final singleton consonants and consonant clusters and whether there was evidence that certain types of consonants benefitted more from the therapy than others. We visually inspected radar plots of change in listeners’ identification of consonants to group children with similar profiles. Acoustic data Acoustic measurements made on SWs and CS, with mean differences and 95% confidence intervals (CIs) calculated between the post- and pre-therapy. Changes in the acoustic variables were then compared to changes in perceptual variables such as single and connected word intelligibility. These comparisons were made for each individual child and groupings derived from the radar plots from the perceptual data analysis. Results Perceptual analysis Using GLMM, we found evidence that the odds of word initial and word final singleton consonants being identified by listeners increased after therapy in both the SW [odds ratio (95% CI) = 1.54 (1.44 to 1.65) and 1.61 (1.51 to 1.73) respectively; all p < 0.01] and CS analyses [1.26 (1.15 to 1.39) and 1.27 (1.15 to 1.41) respectively; all p < 0.01], even after adjusting for potential confounders. There was also evidence for the effect of therapy on the identification of word initial consonant clusters and word final consonant clusters in the SW analyses [1.84 (1.60 to 2.12) and 1.42 (1.15 to 1.75) respectively; all p < 0.01]. Identification of consonant clusters was not examined in the CS data due to the infrequent use of clusters. Additionally, we found evidence of heterogeneity in the effect of therapy on word initial and word final singleton consonant identification between the subtypes of consonants, categorised according to their voicing, place, and manner, in both SW and CS analyses. Nearly all subtypes of consonants, as either word initial or word final singleton consonants, showed an improvement in the probability of being identified by a listener after therapy in the SW analyses, but only about a handful showed an improvement in the CS analyses. We identified six groups of children in the SW data and seven groups of children in the CS data. Each group categorised children according to their relative standing at pre-therapy, the direction and magnitude of change in percentage identification measures, and additionally which combination of the six measures displayed a change. Acoustic analysis Most of the children whose data were analysed acoustically produced slower speech post-therapy, regardless of gains in intelligibility. There was individual variability in the degree of change in speech rate, with a tendency for greater decreases in the speech rate of children whose initial performance was low. Most children also produced words with higher mean intensity post-therapy regardless of gains in intelligibility. However, the majority of the children with an increase in maximum intensity in initial and final word position had improved intelligibility post-therapy. This was particularly the case for the obstruent category. There was variation in changes to intensity across clusters, word position and manner categories, with more modest increases in the intensity of sonorant sounds pre- and post-therapy compared to obstruents. There were also more variable changes in speech rate, intensity and their relationship with intelligibility in CS compared with SWs. Conclusions and recommendations The Speech Systems Approach, which focusses on breath control and speech rate, improved the intelligibility of SWs. Our previous research suggests that gains were maintained for up to 12 weeks following the intensive burst of therapy. This type of intervention is now recommended by National Institute for Health and Care Excellence (NICE) to help address the interaction challenges faced by children with CP. Acoustic analysis of a subset of the data shows change for individuals in intensity and/or duration of individual speech segments. Findings suggest that increased intelligibility was achieved through a stronger vocal signal and allowing children to articulate individual sounds with greater precision. Changes in CS were more modest, suggesting that adaptations to the approach are warranted. The marked individual differences suggest a varying response to therapy between children but also within children across speech segments. Personalisation of the intervention, with cues adapted to the child’s performance, should be investigated. Acoustic analysis of speech during the intervention could aid personalisation, showing how speech changes in response to individual cues. Practice should move to CS quickly. Intelligibility, through listener identification of words and constituent sounds, should continue to be assessed in SWs and CS to investigate the impact of utterance length. Two matched lists of high frequency SWs could be used to facilitate comparison across children and time. Using one list at 6-weeks pre-therapy and immediately post-therapy, and a second list immediately pre-therapy and at follow-up would minimise learning effects. Acoustic change should be measured to help understand how change is achieved by individuals. Study registration This trial is registered as Research Registry 6117. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR130967) and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 4. See the NIHR Journals Library website for further project information

MET-PREVENT:metformin to improve physical performance in older people with sarcopenia and physical prefrailty/frailty-protocol for a double-blind, randomised controlled proof-of-concept trial

INTRODUCTION: Skeletal muscle dysfunction is central to both sarcopenia and physical frailty, which are associated with a wide range of adverse outcomes including falls and fractures, longer hospital stays, dependency and the need for care. Resistance training may prevent and treat sarcopenia and physical frailty, but not everyone can or wants to exercise. Finding alternatives is critical to alleviate the burden of adverse outcomes associated with sarcopenia and physical frailty. This trial will provide proof-of-concept evidence as to whether metformin can improve physical performance in older people with sarcopenia and physical prefrailty or frailty. METHODS AND ANALYSIS: MET-PREVENT is a parallel group, double-blind, placebo-controlled proof-of-concept trial. Trial participants can participate from their own homes, including completing informed consent and screening assessments. Eligible participants with low grip strength or prolonged sit-to-stand time together with slow walk speed will be randomised to either oral metformin hydrochloride 500 mg tablets or matched placebo, taken three times a day for 4 months. The recruitment target is 80 participants from two secondary care hospitals in Newcastle and Gateshead, UK. Local primary care practices will act as participant identification centres. Randomisation will be performed using a web-based minimisation system with a random element, balancing on sex and baseline walk speed. Participants will be followed up for 4 months post-randomisation, with outcomes collected at baseline and 4 months. The primary outcome measure is the four metre walk speed at the 4-month follow-up visit. ETHICS AND DISSEMINATION: The trial has been approved by the Liverpool NHS Research Ethics Committee (20/NW/0470), the Medicines and Healthcare Regulatory Authority (EudraCT 2020-004023-16) and the UK Health Research Authority (IRAS 275219). Results will be made available to participants, their families, patients with sarcopenia, the public, regional and national clinical teams, and the international scientific community. TRIAL REGISTRATION NUMBER: ISRCTN29932357