Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

BACKGROUND: During a stimulated cycle of in vitro fertilisation or intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle-stimulating hormone (FSH) to induce multifollicular development in the ovaries. A normal response to stimulation (e.g. retrieval of 5 to 15 oocytes) is considered desirable. Generally, the number of eggs retrieved is associated with the dose of FSH. Both hyper-response and poor response are associated with an increased chance of cycle cancellation. In hyper-response, this is due to increased risk of ovarian hyperstimulation syndrome (OHSS), while poor response cycles are cancelled because the quantity and quality of oocytes is expected to be low. Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response. Traditionally, this meant women's age, but increasingly, clinicians use various ovarian reserve tests (ORTs). These include basal FSH (bFSH), antral follicle count (AFC), and anti-Müllerian hormone (AMH). It is unclear whether individualising FSH dose improves clinical outcomes. This review updates the 2018 version. OBJECTIVES: To assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, and two trial registers in February 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared (a) different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal, or high responders based on AMH, AFC, and/or bFSH) or (b) an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. MAIN RESULTS: We included 26 studies, involving 8520 women (6 new studies added to 20 studies included in the previous version). We treated RCTs with multiple comparisons as separate trials for the purpose of this review. Meta-analysis was limited due to clinical heterogeneity. Evidence certainty ranged from very low to low, with the main limitations being imprecision and risk of bias associated with lack of blinding. Direct dose comparisons according to predicted response in women Due to differences in dose comparisons, caution is required when interpreting the RCTs in predicted low responders. All evidence was low or very low certainty. Effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy. Similarly, in predicted normal responders (10 studies, 4 comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units (IU): odds ratio (OR) 0.88, 95% confidence interval (CI) 0.57 to 1.36; I2 = 0%; 2 studies, 522 women) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the OHSS outcome to enable inferences. In predicted high responders, lower doses may or may not affect live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; 1 study, 521 women), severe OHSS, and clinical pregnancy. It is also unclear whether lower doses reduce moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; 1 study, 521 participants). ORT-algorithm studies Eight trials compared an ORT-based algorithm to a non-ORT control group. It is unclear whether live birth/ongoing pregnancy and clinical pregnancy are increased using an ORT-based algorithm (live birth/ongoing pregnancy: OR 1.12, 95% CI 0.98 to 1.29; I2 = 30%; 7 studies, 4400 women; clinical pregnancy: OR 1.04, 95% CI 0.91 to 1.18; I2 = 18%; 7 studies, 4400 women; low-certainty evidence). However, ORT algorithms may reduce moderate or severe OHSS (Peto OR 0.60, 95% CI 0.42 to 0.84; I2 = 0%; 7 studies, 4400 women; low-certainty evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.74, 95% CI 0.42 to 1.28; I2 = 0%; 5 studies, 2724 women; low-certainty evidence). Our findings suggest that if the chance of live birth with a standard starting dose is 25%, the chance with ORT-based dosing would be between 25% and 31%. If the chance of moderate or severe OHSS with a standard starting dose is 5%, the chance with ORT-based dosing would be between 2% and 5%. These results should be treated cautiously due to heterogeneity in the algorithms: some algorithms appear to be more effective than others. AUTHORS' CONCLUSIONS: We did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT) affected live birth/ongoing pregnancy rates, but we could not rule out differences, due to sample size limitations. Low-certainty evidence suggests that it is unclear if ORT-based individualisation leads to an increase in live birth/ongoing pregnancy rates compared to a policy of giving all women 150 IU. The confidence interval is consistent with an increase of up to around six percentage points with ORT-based dosing (e.g. from 25% to 31%) or a very small decrease (< 1%). A difference of this magnitude could be important to many women. It is unclear if this is driven by improved outcomes in a particular subgroup. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU. However, the size of the effect is also unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates. It is likely that different ORT algorithms differ in their effectiveness. Current evidence does not provide a clear justification for adjusting the dose of 150 IU in poor or normal responders, especially as increased dose is associated with greater total FSH dose and cost. It is unclear whether a decreased dose in predicted high responders reduces OHSS, although this would appear to be the most likely explanation for the results.

Wellbeing After Stroke (WAterS): Feasibility Testing of a Co-developed Acceptance and Commitment Therapy Intervention to Support Psychological Adjustment After Stroke.

OBJECTIVE: Feasibility test a co-developed intervention based on Acceptance and Commitment Therapy to support psychological adjustment post-stroke, delivered by a workforce with community in-reach. DESIGN: Observational feasibility study utilising patient, carer, public involvement. SETTING: Online. UK. PARTICIPANTS: Stroke survivors with self-reported psychological distress 4 + months post-stroke. INTERVENTIONS: The co-developed Wellbeing After Stroke (WAterS) intervention includes: 9-weekly, structured, online, group sessions for stroke survivors, delivered via a training programme to upskill staff without Acceptance and Commitment Therapy experience, under Clinical Psychology supervision. MAIN MEASURES: Feasibility of recruitment and retention; data quality from candidate measures; safety. Clinical and demographic information at baseline; patient-reported outcome measures (PROMs) via online surveys (baseline, pre- and post-intervention, 3 and 6 months after intervention end) including Mood (hospital anxiety and depression scale (HADS)), Wellbeing (ONS4), Health-Related Quality of Life (EQ5D5L), Psychological Flexibility (AAQ-ABI) and Values-Based Living (VQ). RESULTS: We trained eight staff and recruited 17 stroke survivors with mild-to-moderate cognitive and communication difficulties. 12/17 (71%) joined three intervention groups with 98% attendance and no related adverse events. PROMS data were well-completed. The HADS is a possible future primary outcome (self-reported depression lower on average by 1.3 points: 8.5 pre-group to 7.1 at 3-month follow-up; 95% CI 0.4 to 3.2). CONCLUSION: The WAterS intervention warrants further research evaluation. Staff can be trained and upskilled to deliver. It appears safe and feasible to deliver online to groups, and study recruitment and data collection are feasible. Funding has been secured to further develop the intervention, considering implementation and health equality.

Do Stroke Care Processes Modify Clinical Outcomes in Patients with Stroke-Associated Pneumonia? A Registry Cohort Study in England and Wales.

INTRODUCTION: It is not known whether modern stroke unit care reduces the impact of stroke complications, such as stroke-associated pneumonia (SAP), on clinical outcomes. We investigated the relationship between SAP and clinical outcomes, adjusting for the confounding effects of stroke care processes and their timing. METHODS: The Sentinel Stroke National Audit Programme provided patient data for all confirmed strokes between April 2013 and December 2018. SAP was defined as new antibiotic initiation for suspected pneumonia within the first 7 days from stroke admission. We compared outcomes after SAP versus non-SAP in appropriate multilevel mixed models. Each model was adjusted for patient and clinical characteristics, as well as markers of stroke care and their timing within the first 72 h. The appropriate effect estimates and corresponding 95% confidence intervals (CIs) were reported. RESULTS: Of 201,778 patients, SAP was present in 14.2%. After adjustment for timing of acute stroke care processes and clinical characteristics, adverse outcomes remained for SAP versus non-SAP patients. In these adjusted analyses, patients with SAP maintained an increased risk of longer length of in-hospital stay (IRR of 1.27; 95% CI: 1.25, 1.30), increased odds of worse functional outcome at discharge (OR of 2.9; 95% CI: 2.9, 3.0), and increased risk of in-hospital mortality (HR of 1.78; 95% CI: 1.74, 1.82). CONCLUSION: We show for the first time that SAP remains associated with worse clinical outcomes, even after adjusting for processes of acute stroke care and their timing. These findings highlight the importance of continued research efforts aimed at preventing SAP.

A study of prisms and therapy in attention loss after stroke (SPATIAL): A feasibility randomised controlled trial.

OBJECTIVE: Investigate feasibility and acceptability of prism adaptation training for people with inattention (spatial neglect), early after stroke, during usual care. DESIGN: Phase II feasibility randomised controlled trial with 3:1 stratified allocation to standard occupational therapy with or without intervention, and nested process evaluation. SETTING: Ten hospital sites providing in-patient stroke services. PARTICIPANTS: Screened positive for inattention more than one-week post-stroke; informal carers. Occupational therapists participated in qualitative interviews. INTERVENTION: Adjunctive prism adaptation training at the start of standard occupational therapy sessions for three weeks. MAIN MEASURES: Feasibility measures included recruitment and retention rates, intervention fidelity and attrition. Outcomes collected at baseline, 3 weeks and 12 weeks tested measures including Nottingham Extended Activities of Daily Living Scale. Acceptability was explored through qualitative interviews and structured questions. RESULTS: Eighty (31%) patients were eligible, 57 (71%) consented, 54 randomised (40:13, +1 exclusion) and 39 (74%) completed 12-week outcomes. Treatment fidelity was good: participants received median eight intervention sessions (IQR: 5, 12) lasting 4.7 min (IQR: 4.1, 5.0). All six serious adverse events were unrelated. There was no signal that patients allocated to intervention did better than controls. Twenty five of 35 recruited carers provided outcomes with excellent data completeness. Therapists, patients and carers found prism adaptation training acceptable. CONCLUSIONS: It is feasible and acceptable to conduct a high-quality definitive trial of prism adaptation training within occupational therapy early after stroke in usual care setting, but difficult to justify given no sign of benefit over standard occupational therapy. CLINICAL TRIAL REGISTRATION: https://www.isrctn.com/ Ref ISRCTN88395268.

Early mobilisation is associated with lower subacute blood pressure and variability in ICH: A retrospective cohort study✰.

BACKGROUND: Very early rehabilitation after stroke appears to worsen outcome, particularly in intracerebral haemorrhage (ICH). Plausible mechanisms include increased mean blood pressure (BP) and BP variability. AIMS: To test associations between early mobilisation, subacute BP and survival, in observational data of ICH patients during routine clinical care. METHODS: We collected demographic, clinical and imaging data from 1372 consecutive spontaneous ICH patients admitted between 2 June 2013 and 28 September 2018. Time to first mobilisation (defined as walking, standing, or sitting out-of-bed) was extracted from electronic records. We evaluated associations between early mobilisation (within 24 h of onset) and both subacute BP and death by 30 days using multifactorial linear and logistic regression analyses respectively. RESULTS: Mobilisation at 24 h was not associated with increased odds of death by 30 days when adjusting for key prognostic factors (OR 0.4, 95% CI 0.2 to 1.1, p = 0.07). Mobilisation at 24 h was independently associated with both lower mean systolic BP (-4.5 mmHg, 95% CI -7.5 to -1.5 mmHg, p = 0.003) and lower diastolic BP variability (-1.3 mmHg, 95% CI -2.4 to -0.2 mg, p = 0.02) during the first 72 h after admission. CONCLUSIONS: Adjusted analysis in this observational dataset did not find an association between early mobilisation and death by 30 days. We found early mobilisation at 24 h to be independently associated with lower mean systolic BP and lower diastolic BP variability over 72 h. Further work is needed to establish mechanisms for the possible detrimental effect of early mobilisation in ICH.

Nailfold capillaroscopy: a survey of current UK practice and 'next steps' to increase uptake among rheumatologists.

OBJECTIVES: To identify barriers to the use of nailfold capillaroscopy as a diagnostic tool for patients presenting with Raynaud's phenomenon in UK rheumatology centres and to obtain rheumatologists' views on a proposed internet-based standardized system for clinical reporting of nailfold capillaroscopy images. METHODS: An online survey was developed using expert opinion from clinicians, scientists and health service researchers. The survey was piloted and sent to UK-based rheumatologists using established electronic mailing lists between October 2020 and March 2021. Survey data were analysed using descriptive statistics. RESULTS: A total of 104 rheumatologists representing rheumatology centres across the UK responded to the survey. Wide variations in terms of workloads and practices were described. Thirty-four (33%) respondents reported using nailfold capillaroscopy only at their own centre, 33 (32%) referred to other centres, 9 (9%) did both and 28 (27%) did not use capillaroscopy at all. Of the 43 respondents using capillaroscopy on site, 25 (58%) used either a dermatoscope or universal serial bus microscope and 9 (21%) used videocapillaroscopy. Among the 61 respondents not undertaking capillaroscopy on site, barriers included lack of equipment (85%), lack of experience in acquiring images (69%) and lack of expertise in interpreting images (67%). Sixty-six respondents (63%) expressed interest in an internet-based, standardized automated system for reporting images. CONCLUSION: Most UK rheumatologists currently do not perform nailfold capillaroscopy on site. An internet-based nailfold capillaroscopy system for use with low-cost microscopes as well as with videocapillaroscopy could help increase uptake of capillaroscopy and thereby facilitate early diagnosis of SSc across the UK.

Does PGT-A improve assisted reproduction treatment success rates: what can the UK Register data tell us?

PURPOSE: To show how naïve analyses of aggregated UK ART Register data held by the Human Fertilisation and Embryology Authority to estimate the effects of PGT-A can be severely misleading and to indicate how it may be possible to do a more credible analysis. Given the limitations of the Register, we consider the extent to which such an analysis has the potential to answer questions about the real-world effectiveness of PGT-A. METHODS: We utilise the publicly available Register datasets and construct logistic regression models for live birth events (LBE) which adjust for confounding. We compare all PGT-A cycles to control groups of cycles that could have had PGT-A, excluding cycles that did not progress to having embryos for biopsy. RESULTS: The primary model gives an odds ratio for LBE of 0.82 (95% CI 0.68-1.00) suggesting PGT-A may be detrimental rather than beneficial. However, due to limitations in the availability of important variables in the public dataset, this cannot be considered a definitive estimate. We outline the steps required to enable a credible analysis of the Register data. CONCLUSION: If we compare like with like groups, we obtain estimates of the effect of PGT-A that suggest an overall modest reduction in treatment success rates. These are in direct contrast to an invalid comparison of crude success rates. A detailed analysis of a fuller dataset is warranted, but it remains to be demonstrated whether the UK Register data can provide useful estimates of the impact of PGT-A when used as a treatment add-on.

High dose genistein in Sanfilippo syndrome: A randomised controlled trial.

The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P = .26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P = .0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.

Non-pharmacological interventions for spatial neglect or inattention following stroke and other non-progressive brain injury.

BACKGROUND: People with spatial neglect after stroke or other brain injury have difficulty attending to one side of space. Various rehabilitation interventions have been used, but evidence of their benefit is unclear. OBJECTIVES: The main objective was to determine the effects of non-pharmacological interventions for people with spatial neglect after stroke and other adult-acquired non-progressive brain injury. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched October 2020), the Cochrane Central Register of Controlled Trials (CENTRAL; last searched October 2020), MEDLINE (1966 to October 2020), Embase (1980 to October 2020), the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1983 to October 2020), and PsycINFO (1974 to October 2020). We also searched ongoing trials registers and screened reference lists. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any non-pharmacological intervention specifically aimed at spatial neglect. We excluded studies of general rehabilitation and studies with mixed participant groups, unless separate neglect data were available. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Review authors categorised the interventions into eight broad types deemed to be applicable to clinical practice through iterative discussion: visual interventions, prism adaptation, body awareness interventions, mental function interventions, movement interventions, non-invasive brain stimulation, electrical stimulation, and acupuncture. We assessed the quality of evidence for each outcome using the GRADE approach. MAIN RESULTS: We included 65 RCTs with 1951 participants, all of which included people with spatial neglect following stroke. Most studies measured outcomes using standardised neglect assessments. Fifty-one studies measured effects on ADL immediately after completion of the intervention period; only 16 reported persisting effects on ADL (our primary outcome). One study (30 participants) reported discharge destination, and one (24 participants) reported depression. No studies reported falls, balance, or quality of life. Only two studies were judged to be entirely at low risk of bias, and all were small, with fewer than 50 participants per group. We found no definitive (phase 3) clinical trials. None of the studies reported any patient or public involvement. Visual interventions versus any control: evidence is very uncertain about the effects of visual interventions for spatial neglect based on measures of persisting functional ability in ADL (2 studies, 55 participants) (standardised mean difference (SMD) -0.04, 95% confidence interval (CI) -0.57 to 0.49); measures of immediate functional ability in ADL; persisting standardised neglect assessments; and immediate neglect assessments. Prism adaptation versus any control: evidence is very uncertain about the effects of prism adaptation for spatial neglect based on measures of persisting functional ability in ADL (2 studies, 39 participants) (SMD -0.29, 95% CI -0.93 to 0.35); measures of immediate functional ability in ADL; persisting standardised neglect assessments; and immediate neglect assessments. Body awareness interventions versus any control: evidence is very uncertain about the effects of body awareness interventions for spatial neglect based on measures of persisting functional ability in ADL (5 studies, 125 participants) (SMD 0.61, 95% CI 0.24 to 0.97); measures of immediate functional ability in ADL; persisting standardised neglect assessments; immediate neglect assessments; and adverse events. Mental function interventions versus any control: we found no trials of mental function interventions for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of mental function interventions on spatial neglect based on measures of immediate functional ability in ADL and immediate neglect assessments. Movement interventions versus any control: we found no trials of movement interventions for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of body awareness interventions on spatial neglect based on measures of immediate functional ability in ADL and immediate neglect assessments. Non-invasive brain stimulation (NIBS) versus any control: evidence is very uncertain about the effects of NIBS on spatial neglect based on measures of persisting functional ability in ADL (3 studies, 92 participants) (SMD 0.35, 95% CI -0.08 to 0.77); measures of immediate functional ability in ADL; persisting standardised neglect assessments; immediate neglect assessments; and adverse events. Electrical stimulation versus any control: we found no trials of electrical stimulation for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of electrical stimulation on spatial neglect based on immediate neglect assessments. Acupuncture versus any control: we found no trials of acupuncture for spatial neglect reporting on measures of persisting functional ability in ADL. Evidence is very uncertain about the effects of acupuncture on spatial neglect based on measures of immediate functional ability in ADL and immediate neglect assessments. AUTHORS' CONCLUSIONS: The effectiveness of non-pharmacological interventions for spatial neglect in improving functional ability in ADL and increasing independence remains unproven. Many strategies have been proposed to aid rehabilitation of spatial neglect, but none has yet been sufficiently researched through high-quality fully powered randomised trials to establish potential or adverse effects. As a consequence, no rehabilitation approach can be supported or refuted based on current evidence from RCTs. As recommended by a number of national clinical guidelines, clinicians should continue to provide rehabilitation for neglect that enables people to meet their rehabilitation goals. Clinicians and stroke survivors should have the opportunity, and are strongly encouraged, to participate in research. Future studies need to have appropriate high-quality methodological design, delivery, and reporting to enable appraisal and interpretation of results. Future studies also must evaluate outcomes of importance to patients, such as persisting functional ability in ADL. One way to improve the quality of research is to involve people with experience with the condition in designing and running trials.

Stroke impairment categories: A new way to classify the effects of stroke based on stroke-related impairments.

OBJECTIVE: To create a classification system based on stroke-related impairments. DATA SOURCE: All adults with stroke admitted for at least 72 hours in England, Wales and Northern Ireland from July 2013 to July 2015 extracted from the Sentinel Stroke National Audit Programme. ANALYSIS: Impairments were defined using the National Institute of Health Stroke Scale scores at admission. Common combinations of impairments were identified based on geometric coding and expert knowledge. Validity of the classification was assessed using standard descriptive statistics to report and compare patients' characteristics, therapy received and outcomes in each group. RESULTS: Data from 94,905 patients were extracted. The items of the National Institute of Health Stroke Scale (on admission) were initially grouped into four body systems: Cognitive, Motor, Sensory and Consciousness. Seven common combinations of these impairments were identified (in order of stroke severity); Patients with Loss of Consciousness (n = 6034, 6.4%); those with Motor + Cognitive + Sensory impairments (n = 28,226, 29.7%); Motor + Cognitive impairments (n = 16,967, 17.9%); Motor + Sensory impairments (n = 9882, 10.4%); Motor Only impairments (n = 20,471, 21.6%); Any Non-Motor impairments (n = 7498, 7.9%); and No Impairments (n = 5827, 6.1%). There was a gradation of age, premorbid disability, mortality and disability on discharge. People with the most and least severe categories were least likely to receive therapy, and received least therapy (-20 minutes/day of stay) compared to -35 minutes/day of stay for the moderately severe categories. CONCLUSIONS: A classification system of seven Stroke Impairment Categories has been presented.

Current clinical practice in the screening and diagnosis of spatial neglect post-stroke: Findings from a multidisciplinary international survey.

Spatial neglect has profound implications for quality of life after stroke, yet we lack consensus for screening/diagnosing this heterogeneous syndrome. Our first step in a multi-stage research programme aimed to determine which neglect tests are used (within four categories: cognitive, functional, neurological and neuroimaging/neuromodulation), by which stroke clinicians, in which countries, and whether choice is by professional autonomy or institutional policy. 454 clinicians responded to an online survey: 12 professions (e.g., 39% were occupational therapists) from 33 countries (e.g., 38% from the UK). Multifactorial logistic regression suggested inter-professional differences but fewer differences between countries (Italy was an outlier). Cognitive tests were used by 82% (particularly by psychologists, cancellation and drawing were most popular); 80% used functional assessments (physiotherapists were most likely). 20% (mainly physicians, from Italy) used neuroimaging/ neuromodulation. Professionals largely reported clinical autonomy in their choices. Respondents agreed on the need for a combined approach to screening and further training. This study raises awareness of the translation gap between theory and practice. These findings lay an important foundation to subsequent collaborative action between clinicians, researchers and stroke survivors to reach consensus on screening and diagnostic measures. The immediate next step is a review of the measures' psychometric properties.

Use of Pulmonary Computed Tomography for Evaluating Suspected Stroke-Associated Pneumonia.

OBJECTIVES: Accurate and timely diagnosis of pneumonia complicating stroke remains challenging and the diagnostic accuracy of chest X-ray (CXR) in the setting of stroke-associated pneumonia (SAP) is uncertain. The overall objective of this study was to evaluate the use of pulmonary computed tomography (CT) in diagnosis of suspected SAP. MATERIALS AND METHODS: Patients with acute ischemic stroke (IS) or intracerebral hemorrhage (ICH) were recruited within 24h of clinically suspected SAP and underwent non-contrast pulmonary CT within 48h of antibiotic initiation. CXR and pulmonary CT were reported by two radiologists. Pulmonary CT was used as the reference standard for final diagnosis of SAP. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and diagnostic odds ratio (OR) for CXR were calculated. RESULTS: 40 patients (36 IS, 4 ICH) with a median age of 78y (range 44y-90y) and a median National Institute of Health Stroke Scale score of 13 (range 3-31) were included. All patients had at least one CXR and 35/40 patients (88%) underwent pulmonary CT. Changes consistent with pneumonia were present in 15/40 CXRs (38%) and 12/35 pulmonary CTs (34%). 9/35 pulmonary CTs (26%) were reported normal. CXR had a sensitivity of 58.3%, specificity of 73.9%, PPV of 53.8 %, NPV of 77.2 %, diagnostic OR of 3.7 (95% CI 0.7 - 22) and an accuracy of 68.5% (95% CI 50.7% -83.1%). DISCUSSION: CXR has limited diagnostic accuracy in SAP. The majority of patients started on antibiotics had no evidence of pneumonia on pulmonary CT with potential implications for antibiotic stewardship. CONCLUSIONS: Pulmonary CT could be applied as a reference standard for evaluation of clinical and biomarker diagnostic SAP algorithms in multi-center studies.

How do patients pass through stroke services? Identifying stroke care pathways using national audit data.

OBJECTIVE: To map and describe how patients pass through stroke services. METHODS: Data from 94,905 stroke patients (July 2013-July 2015) who were still inpatients 72 hours after hospital admission were extracted from a national stroke register and were used to identify the routes patients took through hospital and community stroke services. We sought to categorize these routes through iterative consultations with clinical experts and to describe patient characteristics, therapy provision, outcomes and costs within each category. RESULTS: We identified 874 routes defined by the type of admitting stroke team and subsequent transfer history. We consolidated these into nine distinct routes and further summarized these into three overlapping 'pathways' that accounted for 99% of the patients. These were direct discharge (44%), community rehabilitation (47%) and inpatient transfer (19%) with 12% of the patients receiving both inpatient transfer and community rehabilitation. Patients with the mildest and most severe strokes were more likely to follow the direct discharge pathway. Those perceived to need most therapy were more likely to follow the inpatient transfer pathway. Costs were lowest and mortality was highest for patients on the direct discharge pathway. Outcomes were best for patients on the community rehabilitation pathway and costs were highest where patients underwent inpatient transfers. CONCLUSION: Three overarching stroke care pathways were identified which differ according to patient characteristics, therapy needs and outcomes. This pathway mapping provides a benchmark to develop and plan clinical services, and for future research.

Factors influencing the amount of therapy received during inpatient stroke care: an analysis of data from the UK Sentinel Stroke National Audit Programme.

OBJECTIVES: To understand why most stroke patients receive little therapy. We investigated the factors associated with the amount of stroke therapy delivered. METHODS: Data regarding adults admitted to hospital with stroke for at least 72 hours (July 2013-July 2015) were extracted from the UK's Sentinel Stroke National Audit Programme. Descriptive statistics and multilevel mixed effects regression models explored the factors that influenced the amount of therapy received while adjusting for confounding. RESULTS: Of the 94,905 patients in the study cohort (mean age: 76 (SD: 13.2) years, 78% had a mild or moderate severity stroke. In all, 92% required physiotherapy, 87% required occupational therapy, 57% required speech therapy but only 5% were considered to need psychology. The average amount of therapy ranged from 2 minutes (psychology) to 14 minutes (physiotherapy) per day of inpatient stay. Unmodifiable characteristics (such as stroke severity) dominated the variation in the amount of therapy. However important, modifiable organizational factors were the day and time of admission, type of stroke team, timely therapy assessments, therapy and nursing staffing levels (qualified and support staff), and presence of weekend or early supported discharge services. CONCLUSION: The amount of stroke therapy is associated with unmodifiable patient-related characteristics and modifiable organizational factors in that more therapy was associated with higher therapy and nurse staffing levels, specialist stroke rehabilitation services, timely therapy assessments, and the presence of weekend and early discharge services.

Environmental Factors and Hyperacute Stroke Care Activity During the COVID-19 Pandemic: An Interrupted Time-Series Analysis.

BACKGROUND AND AIMS: Concerns have arisen regarding patient access and delivery of acute stroke care during the COVID-19 pandemic. We investigated key population level events on activity of the three hyperacute stroke units (HASUs) within Greater Manchester and East Cheshire (GM & EC), whilst adjusting for environmental factors. METHODS: Weekly stroke admission & discharge counts in the three HASUs were collected locally from Emergency Department (ED) data and Sentinel Stroke National Audit Programme core dataset prior to, and during the emergence of the COVID-19 pandemic (Jan 2020 to May 2020). Whilst adjusting for local traffic-related air pollution and ambient measurement, an interrupted time-series analysis using a segmented generalised linear model investigated key population level events on the rate of stroke team ED assessments, admissions for stroke, referrals for transient ischaemic attack (TIA), and stroke discharges. RESULTS: The median total number of ED stroke assessments, admissions, TIA referrals, and discharges across the three HASU sites prior to the first UK COVID-19 death were 150, 114, 69, and 76 per week. The stable weekly trend in ED assessments and stroke admissions decreased by approximately 16% (and 21% for TIAs) between first UK hospital COVID-19 death (5th March) and the implementation of the Act-FAST campaign (6th April) where a modest 4% and 5% increase per week was observed. TIA referrals increased post Government intervention (23rd March), without fully returning to the numbers observed in January and February. Trends in discharges from stroke units appeared unaffected within the study period reported here. CONCLUSION: Despite adjustment for environmental factors stroke activity was temporarily modified by the COVID-19 pandemic. Underlying motivations within the population are still not clear. This raises concerns that patients may have avoided urgent health care risking poorer short and long-term health outcomes.

Prevention of mood disorder after stroke: a randomised controlled trial of problem solving therapy versus volunteer support.

BACKGROUND: Mood disorder after stroke is common but drug and psychosocial treatments have been assessed with disappointing results. Preventing mood disorder from developing in the first place could be a better approach and might reduce the need for pharmacotherapy in this predominantly older patient group. We used a brief problem-solving therapy and evaluated its effect in reducing mood disorder in the 12 months after stroke. METHODS: A 3-group, parallel, randomised controlled trial. Four hundred fifty patients with stroke were randomised within 1 month of hospital admission to problem-solving therapy from a psychiatric nurse, non-specific support given by volunteers or treatment-as-usual. Follow up took place at 6 and 12 months after stroke. Standardised measures of mood (Present State Examination, GHQ-28), cognitive state (mini-mental state examination) and function (Barthel ADL index, Frenchay Activities Index) were taken at baseline, 6 and 12 months after randomisation. Satisfaction with care was recorded at follow up. RESULTS: At 6 months, all psychological and activity measures favoured problem-solving therapy. At 12 months, patients in the problem-solving therapy group had significantly lower GHQ-28 scores and lower median Present State Examination symptom scores. There were no statistically significant differences in activity. The problem-solving therapy group were more satisfied with some aspects of care. CONCLUSIONS: The results are encouraging and suggest it is possible to prevent mood disorder in stroke patients using a psychological intervention. The differences between the groups at 12 months may indicate a sustained impact of psychological therapies, by comparison with non-specific support. TRIAL REGISTRATION: ISRCTN: ISRCTN33773710 Registered: 23/01/2004 (Retrospectively).

Microbiological Etiologies of Pneumonia Complicating Stroke: A Systematic Review.

BACKGROUND AND PURPOSE: Identifying the causal pathogens of pneumonia complicating stroke is challenging, and antibiotics used are often broad spectrum, without recourse to the microbiological cause. We aimed to review existing literature to identify organisms responsible for pneumonia complicating stroke, before developing a consensus-based approach to antibiotic treatment. METHODS: A systematic literature review of multiple electronic databases using predefined search criteria was undertaken, in accordance with Cochrane and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance. Published studies of hospitalized adults with ischemic stroke, intracerebral hemorrhage, or both, which identified microbiological etiologies for pneumonia complicating stroke up to January 1, 2017, were considered. Analysis included summary statistics and random-effects meta-analysis where appropriate. RESULTS: Fifteen studies (40% ischemic stroke, 60% ischemic stroke and intracerebral hemorrhage) involving 7968 patients were included. Reported occurrence of pneumonia varied considerably between studies (2%-63%) with a pooled frequency of 23% (95% confidence interval, 14%-34%; I2=99%). Where reported (60%), the majority of pneumonia occurred within 1 week of stroke (78%). Reported frequency of positive culture data (15%-88%) varied widely. When isolated, aerobic Gram-negative bacilli (38%) and Gram-positive cocci (16%) were most frequently cultured; commonly isolated organisms included Enterobacteriaceae (21.8%: Klebsiella pneumoniae, 12.8% and Escherichia coli, 9%), Staphylococcus aureus (10.1%), Pseudomonas aeruginosa (6%), Acinetobacter baumanii (4.6%), and Streptococcus pneumoniae (3.5%). Sputum was most commonly used to identify pathogens, in isolation (40%) or in conjunction with tracheal aspirate (15%) or blood culture (20%). CONCLUSIONS: Although the analysis was limited by small and heterogeneous study populations, limiting determination of microbiological causality, this review suggests aerobic Gram-negative bacilli and Gram-positive cocci are frequently associated with pneumonia complicating stroke. This supports the need for appropriately designed studies to determine microbial cause and a consensus-based approach in antibiotic usage and further targeted antibiotic treatment trials for enhanced antibiotic stewardship.

SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke): A Randomized Controlled Phase 2 Trial.

BACKGROUND AND PURPOSE: The proinflammatory cytokine IL-1 (interleukin-1) has a deleterious role in cerebral ischemia, which is attenuated by IL-1 receptor antagonist (IL-1Ra). IL-1 induces peripheral inflammatory mediators, such as interleukin-6, which are associated with worse prognosis after ischemic stroke. We investigated whether subcutaneous IL-1Ra reduces the peripheral inflammatory response in acute ischemic stroke. METHODS: SCIL-STROKE (Subcutaneous Interleukin-1 Receptor Antagonist in Ischemic Stroke) was a single-center, double-blind, randomized, placebo-controlled phase 2 trial of subcutaneous IL-1Ra (100 mg administered twice daily for 3 days) in patients presenting within 5 hours of ischemic stroke onset. Randomization was stratified for baseline National Institutes of Health Stroke Scale score and thrombolysis. Measurement of plasma interleukin-6 and other peripheral inflammatory markers was undertaken at 5 time points. The primary outcome was difference in concentration of log(interleukin-6) as area under the curve to day 3. Secondary outcomes included exploratory effect of IL-1Ra on 3-month outcome with the modified Rankin Scale. RESULTS: We recruited 80 patients (mean age, 72 years; median National Institutes of Health Stroke Scale, 12) of whom 73% received intravenous thrombolysis with alteplase. IL-1Ra significantly reduced plasma interleukin-6 (P<0.001) and plasma C-reactive protein (P<0.001). IL-1Ra was well tolerated with no safety concerns. Allocation to IL-1Ra was not associated with a favorable outcome on modified Rankin Scale: odds ratio (95% confidence interval)=0.67 (0.29-1.52), P=0.34. Exploratory mediation analysis suggested that IL-1Ra improved clinical outcome by reducing inflammation, but there was a statistically significant, alternative mechanism countering this benefit. CONCLUSIONS: IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further experimental studies are required to investigate efficacy and possible interactions of IL-1Ra with thrombolysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN74236229.

Bespoke versus off-the-shelf ankle-foot orthosis for people with stroke: randomized controlled trial.

OBJECTIVE: The aim of the study was to compare the effect of two designs of ankle-foot orthosis on people with stroke. DESIGN: The study design was an assessor-blind, multicentre randomized controlled trial. SETTING: The setting was community stroke services. PARTICIPANTS: A total of 139 community-dwelling stroke survivors with limited mobility were recruited. INTERVENTIONS: The two most commonly used types of ankle-foot orthosis (bespoke and off-the-shelf) were chosen. MAIN MEASURES: The main measures of the study were as follows: short- (6 weeks) and long-term (12 weeks) effects on stroke survivors' satisfaction; adverse events; mobility (Walking Handicap Scale); fear of falling (Falls Efficacy Scale-International (FES-I)) and walking impairments (gait speed and step length using the 5-m walk test). RESULTS: Long-term satisfaction was non-significantly higher in the off-the-shelf group: 72% versus 64%; OR (95% CI) = 0.64 (0.31 to 1.3); P = 0.21. No statistically significant differences were found between the orthoses except that the off-the-shelf group had less fear of falling at short-term follow-up than the bespoke group: mean difference (95% CI) = -4.6 (-7.6 to -1.6) points on the FES-I; P = 0.003. CONCLUSION: No differences between off-the-shelf and bespoke ankle-foot orthoses were found except that participants in the off-the-shelf orthosis group had less fear of falling at short-term follow-up.

Adjuncts in the IVF laboratory: where is the evidence for 'add-on' interventions?

Globally, IVF patients are routinely offered and charged for a selection of adjunct treatments and tests or 'add-ons' that they are told may improve their chance of a live birth, despite there being no clinical evidence supporting the efficacy of the add-on. Any new IVF technology claiming to improve live birth rates (LBR) should, in most cases, first be tested in an appropriate animal model, then in clinical trials, to ensure safety, and finally in a randomized controlled trial (RCT) to provide high-quality evidence that the procedure is safe and effective. Only then should the technique be considered as 'routine' and only when applied to the similar patient population as those studied in the RCT. Even then, further pediatric and long-term follow-up studies will need to be undertaken to examine the long-term safety of the procedure. Alarmingly, there are currently numerous examples where adjunct treatments are used in the absence of evidence-based medicine and often at an additional fee. In some cases, when RCTs have shown the technique to be ineffective, it is eventually withdrawn from the clinic. In this paper, we discuss some of the adjunct treatments currently being offered globally in IVF laboratories, including embryo glue and adherence compounds, sperm DNA fragmentation, time-lapse imaging, preimplantation genetic screening, mitochondria DNA load measurement and assisted hatching. We examine the evidence for their safety and efficacy in increasing LBRs. We conclude that robust studies are needed to confirm the safety and efficacy of any adjunct treatment or test before they are offered routinely to IVF patients.