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SEE PDF] Longitudinal PB CAR-T phenotyping in P1 illustrates circulating naïve/central memory (Tn/Tcm) CAR-T subsets, whereas terminally differentiated (Te/Tte) and senescent populations (CD27-/CD28-) predominate in P2 (Figure 2C; Table S4). The effect of therapeutic IS on CAR-T manufacturing success and phenotype/expansion/persistence in vivo is sparsely reported in the literature [12, 13]. A. J. Portuguese, J. Gauthier, S. S. Tykodi, et al., “CD19 CAR‐T Therapy in Solid Organ Transplant Recipients: Case Report and Systematic Review,” Bone Marrow Transplantation 58, no. 4 (2023): 353–359. S. Yamshon, C. Gribbin, Z. Chen, et al., “Efficacy and Toxicity of CD19 Chimeric Antigen Receptor T Cell Therapy for Lymphoma in Solid Organ Transplant Recipients: A Systematic Review and Meta‐Analysis,” Transplantation and Cellular Therapy 30, no. 1 (2024): 73.e1–73.e12.

Amateur choral singing is a common pastime and worthy of study, possibly conferring benefits to health and social behaviour. Participants might be expected to possess musical ability and share some behavioural characteristics. Polymorphisms in genes concerned with serotonergic neurotransmission are associated with both behaviour and musical aptitude. Those investigated previously include the variable number tandem repeats RS1, RS3 and AVR in the AVPR1A (arginine vasopressin receptor 1a) gene and STin2 in the SLC6A4 (solute carrier family 6 [neurotransmitter transporter, serotonin], member 4) gene, as well as the SLC6A4 promoter region polymorphism, 5-HTTLPR. We conducted a genetic association study on 523 participants to establish whether alleles at these polymorphisms occur more commonly in choral singers than in those not regularly participating in organised musical activity (non-musicians). We also analysed tagging single nucleotide polymorphisms (SNPs) for AVPR1A and SLC6A4 to determine whether other variants in these genes were associated with singer/non-musician status. At the STin2 polymorphism, overall association with singer/non-musician status was evident at P = 0.006. The 9-repeat (P = 0.04) and 12-repeat (P = 0.04) alleles were more common in singers and the 10-repeat allele less so (P = 0.009). Odds ratios were 0.73 (95% CI 0.57-0.94) for the 10-repeat allele and 2.47 (95% CI 0.88-6.94) for the rarer 9-repeat allele. No overall association was detected at P<0.05 between any other polymorphism and singer/non-musician status. Our null findings with respect to RS3, RS1 and AVR, polymorphisms associated with musical ability by other authors, suggest that choir membership may depend partly on factors other than musical ability. In a related musical project involving one participating choir, a new 40-part unaccompanied choral work, \"Allele\", was composed and broadcast on national radio. In the piece, each singer's part incorporated their personal RS3 genotype.

Aims We present a single‐centre retrospective experience using oral milrinone in patients with a left ventricular assist device (LVAD) and concurrent refractory right ventricular failure. Methods and results All patients implanted with LVAD between January 2013 and July 2021 from a high‐volume advanced heart failure service were reviewed. Eight patients were initiated on oral milrinone during this period. Oral milrinone was started 1.5 [inter‐quartile range (IQR) 1–2.3] years after LVAD implantation and continued for 1.2 (IQR 0.5–2.8) years. Therapeutic milrinone levels were achieved (232.2 ± 153.4 ng/mL) with 62.4 ± 18% of time within the therapeutic range. Two patients had adverse events (non‐sustained ventricular tachycardia and ventricular fibrillation effectively treated by internal cardioverter defibrillator) but did not require milrinone discontinuation. Four deaths occurred, one after transplant and three from disease progression determined to be unrelated to oral milrinone use. Three patients continue oral milrinone therapy in the community. There was no significant difference found after the initiation of oral milrinone on any of the physiological measures; however, there were trends in reduction of New York Heart Association class from 3.4 ± 0.5 to 3.0 ± 0.8 (P = 0.08), reduction of right atrial/wedge pressure from 0.9 ± 0.3 to 0.5 ± 0.2 (P = 0.08), and improvement of right ventricular stroke work index from 3.8 ± 2 to 5.8 ± 2.7 (P = 0.16). Conclusions Oral milrinone appears safe for long‐term use in the outpatient setting when combined with therapeutic monitoring in this complex medical cohort with limited management options. Further study is needed to ascertain whether this treatment is effective in reducing heart failure symptoms and admissions.

BackgroundCorrection of mitral regurgitation (MR) at the time of left ventricular assist device (LVAD) implantation remains controversial. There is conflicting evidence regarding the clinical impact of residual MR, and studies have not examined whether MR aetiology or right heart function impacts the likelihood of residual MR.MethodsThis is a retrospective single-centre study of 155 consecutive patients with LVAD implantation from January 2011 to March 2020. Exclusion criteria were no MR pre-LVAD (n=8), inaccessible echocardiography (n=9), duplicate records (n=10) and concomitant mitral valve repair (n=1). Statistical analysis was performed using STATA V.16 and SPSS V.24.ResultsCarpentier IIIb MR aetiology was associated with more severe MR pre-LVAD (severe 18/27 (67%) vs non-severe 32/91 (35%), p=0.004) and a higher likelihood of residual MR (8/11 (72%) vs 30/74 (41%), p=0.045). Of 95 patients with significant MR pre-LVAD, 15 (16%) had persistent significant MR, which was associated with higher mortality (p=0.006), post-LVAD right ventricle (RV) dilatation (10/15 (67%) vs 28/80 (35%), p=0.022) and RV dysfunction (14/15 (93%) vs 35/80 (44%), p<0.001). Aside from ischaemic aetiology, other pre-LVAD parameters that were associated with significant residual MR included left ventricular end-systolic diameter (LVESD) (6.9 cm (5.7–7.2) vs 5.9 cm (5.5–6.5), p=0.043), left atrial volume index (LAVi) (78 mL/m2 (56–88) vs 57 mL/m2 (47–77), p=0.021), posterior leaflet displacement (2.5 cm (2.3–2.9) vs 2.3 cm (1.9–2.7), p=0.042) and basal right ventricular end-diastolic diameter (RVEDD) (5.1±0.8 cm vs 4.5±0.8 cm, p=0.010).ConclusionLVAD therapy improves MR and tricuspid regurgitation severity in the majority, but 14% have persistent significant residual MR, associated with right ventricular dysfunction and higher long-term mortality. This may be predicted pre-LVAD by greater LVESD, RVEDD and LAVi and by ischaemic aetiology.

Diagnosing sleep-disordered breathing in children with suspected sleep-disordered breathing Sleep questionnaires, combined sleep questionnaires and ‘protocol-driven’ clinical assessments, sleep video recordings and sleep audio recordings Children without comorbidities Recommendations The Sleep-Related Breathing Disorder scale of the Paediatric Sleep Questionnaire (SRBD-PSQ), with a cut-off of ≥0.33, or Obstructive Sleep Apnoea-18 item questionnaire (OSA-18), with a cut-off of ≥0.60, can be considered for diagnosing moderate-to-severe SDB in children of at least 2 years of age with no comorbidities. While pulse oximetry is non-discriminatory at all ages, particular caution is required in using oximetry to diagnose OSA in children under 2 years of age as children in this age group are predisposed to central sleep apnoea (CSA) (as a result of developmental immaturity) and oxygen desaturations cannot discriminate between obstructive and central events. If hypoventilation is suspected, please refer to the ‘Pulse oximetry and carbon dioxide (CO2) monitoring’ recommendations and GPPs below. The American Academy of Sleep Medicine (AASM) recommends scoring hypoventilation during sleep when >25% of the total sleep time, as measured by either the arterial PCO2 or surrogate (transcutaneous or end tidal which is more relevant in paediatrics), is spent with a PCO2 >50 mm Hg/6.7 kPa.3 Home monitoring (pulse oximetry or CRSS) Recommendation Home CRSS can be considered for diagnosing SDB in children without comorbidities where the patients and/or carers are deemed appropriate for implementing a home sleep study.

The search strategy is available for review in Online supplement appendix 12 of the full guideline.1 Critical appraisal and GRADE analysis of the evidence After an initial screening to determine relevance to the clinical questions, each paper was assessed to determine if it addressed: Following data extraction from the ‘accepted’ papers, evidence profiles were generated for each of the clinical questions and the quality of the evidence was assessed using the GRADE principles.5 Where GRADE analysis was not possible, but the evidence was deemed important enough to be included in the guideline, the evidence has been listed as (Ungraded), denoting that inclusion was reached by consensus of the Guideline Development Group (GDG). A definition of the GRADE scores is shown in table 1.Table 1 GRADE score definitions GRADE Definition High High confidence that the true effect is close to the estimated effect Moderate Moderate confidence that the true effect is close to the estimated effect Low Low confidence that the true effect is close to the estimated effect Very low Very low confidence that the true effect is close to the estimated effect Ungraded GRADE analysis not possible, but evidence deemed important GRADE, Grading of Recommendations, Assessment, Development and Evaluation. GRADE specifies two categories of strength for a recommendation as shown in table 2.Table 2 Explanation of the terminology used in BTS recommendations Strength Benefits and risks Implications Strong Recommended, so ‘offer’ Benefits appear to outweigh the risks (or vice versa) for the majority of the target group Most service users would want to, or should receive this intervention Conditional Suggested, so ‘consider’ Risks and benefits are more closely balanced, or there is more uncertainty in likely service users’ values and preferences Service users should be supported to arrive at a decision based on their values and preferences BTS, British Thoracic Society.

IntroductionPositron Emission Tomography/Computed Tomography (PET/CT) has many advantages over Single Photon Emission Computed Tomography in Myocardial Perfusion Imaging (MPI). However, UK availability, has been limited. We describe a new Rubidium (Rb) PET MPI service; the third in the National Health Service in England.MethodsAudit of the first 100 patients from November 2019 to January 2020. 66 men, 34 women, mean age 65 ±11, mean Body Mass Index 28.3 ±6.8. Imaging comprised CT for attenuation correction, CT for Agatston scoring if no known Coronary Artery Disease (CAD) or prior intervention, and PET with and without adenosine vasodilation.ResultsThe commonest indication was symptoms post-revascularization (36%). 31% had had previous percutaneous intervention, 15% had had previous coronary surgery. 21% had had prior cardiac CT. The mean wait from request to scan was 30 days. 98% were reported the same or next working day. 96% received 140 mcg/kg/min adenosine, 4% received 210 mcg/kg/min. Two patients did not show adequate vasodilation. All PET MPI scans were diagnostic quality. 43% had Agatston scoring. The mean total Agatston score was 511. The normalcy rate for PET MPS was 60%. The prevalence of infarction was 20%. The mean Myocardial Flow Reserve was 2.3 ±0.8.ConclusionRb PET MPI is feasible and high quality in a new service. It provides detailed coronary assessment, with plaque burden, relative perfusion and absolute myocardial blood flow quantification. It will be an essential contributor to patient diagnosis, treatment response and risk stratification.

This paper describes the development of a computer simulation tool, NEOSim, capable of modelling small NEO impacts and their effect on the global population. The development of the tool draws upon existing models for the atmospheric passage and impact processes. Simulation of the land and ocean impact effects, combined with a population density model, leads to casualty estimation at both a regional and global level. Casualty predictions are based upon the intensity of each impact effect on the local population density, with consideration given to the population inside or outside local infrastructure. Two case studies are presented. The first evaluates the potential threat to the UK, and highlights coastal locations as being at greatest risk. Locations around Cornwall demonstrate an increase in casualties above the local average. The second case study concerns the potential impact of asteroid (99942) Apophis in 2036. Propagation of the possible orbits along the line of variance leads to an extensive path of risk on the Earth. Deflection of the asteroid, by a variety of means, will move the projected impact site along this path. Results generated by NEOSim for the path indicate that South American countries such as Colombia and Venezuela are at a greatest risk with estimated casualty figures in excess of 10 million. Applications of this software to the NEO threat are discussed, along with the next stage of NEO impact simulation development.

BackgroundSevere secondary mitral regurgitation (MR) worsens prognosis in patients with medically managed heart failure (HF). In patients treated by left ventricular assist device (LVAD), it is unclear whether severe MR should be corrected at time of LVAD implantation.PurposeTo evaluate impact of LVAD therapy on severe MR and non-severe MR over 1 year.MethodsRetrospective single centre study of consecutive patients who underwent Heartmate (HM) 2 or HM3 LVAD implantation between January 2011 and March 2020.ResultsOf 155 patients, 20 were excluded due to LVAD exchange (n=10), mitral valve repair (n=1), or inaccessible pre-LVAD echocardiography (n=9). Based on multiparametric grading, 29 patients had severe secondary MR and 106 non-severe secondary MR (including none). Severe MR patients were more often female (10/29 (34%) vs 11/106 (10%); p=0.002) but were of similar age (54±12 vs 55±9 years; p=0.624), size (27±5 vs 27±4 kg/m2; p=1.0), with equivalent renal function (53±22 vs 55±20 ml/min/1.73m2; p=0.641) and median pre-operative NT-proBNP [4076 (IQR 206-5438) vs 4914 (IQR 2706-7518) pg/L; p=0.488]. There were similar proportions of patients with ischaemic aetiology [16/29 (55%) vs 66/106 (62%); p=0.488) and those receiving HM2 [11/29 (38%) vs 32/106 (30%)] and HM3 [18/29 (62%) vs 74/106 (70%); p=0.575] LVAD. Echocardiography before LVAD implantation demonstrated similar LV size (LV end-diastolic volume: 133±44 vs 118±50ml/m2; p=0.145, LV end-systolic volume: 107±41 vs 96±59ml/m2; p=0.348) and LV ejection fraction (17±9 vs 17±7%; p=1.0). Severe MR patients had significantly greater (p<0.001) MR by proximal isovolumetric surface area (0.93±0.27 vs 0.60±0.16cm), vena contracta (0.79±0.32 vs 0.57±0.18 cm), regurgitant volume (47±25 vs 24±12ml), and fraction (54±15 vs 37±13%). Follow-up echocardiography was performed at a median 222 days (range 356 days). Patients who received cardiac transplantation were excluded. Relative severities of MR at follow-up were: none=12 (46%), mild=8 (31%), moderate=5 (19%), severe=1 (4%) amongst patients with severe MR pre-LVAD, and none=55 (58%), mild=26 (27%), moderate=13 (14%), severe=1 (1%) amongst patients with non-severe MR pre-LVAD (figure 1). Within 12m, after excluding patients who underwent cardiac transplantation (severe MR n=4; non-severe MR n=2), rates of HF hospitalisation [5/25 (20%) vs 16/104 (15%); p=0.575] and all-cause mortality [2/25 (18%) vs 22/104 (21%); p=0.129)] were similar, irrespective of pre-LVAD MR severity. No patient who died during follow-up had severe MR prior to death.Abstract 4 Figure 1Abstract 4 Figure 2ConclusionLVAD improves severe MR in 96% of cases, resulting in 1-year rates of HF hospitalisation and mortality similar to patients without severe MR pre-LVAD. These data suggest mitral valve surgery at time of LVAD implantation is not warranted.Conflict of InterestNone

Background Rejection is a major cause of mortality and morbidity in heart transplant (HTx) recipients. Current methods for diagnosing rejection have limitations. Imaging methods to map the entire left ventricle and reliably identify potential sites of rejection is lacking. Animal studies suggest FDG PET-CT (FDG PET) could have potential application in human HTx recipients. Methods Between December 2020 and February 2022, all HTx recipients at Harefield Hospital, London, with definite or suspected rejection underwent FDG PET in addition to routine work-up. Results Thirty HTx recipients (12 with definite and 18 with suspected rejection) underwent FDG PET scans. Overall, 12 of the 30 patients had FDG PET with increased myocardial avidity, of whom 2 died (17%). Eighteen patients of the 30 patients had FDG PET with no myocardial avidity and all are alive (100%, p  = 0.15). All patients with definite rejection, scanned within 2 weeks of starting anti-rejection treatment, showed increased myocardial avidity. In 5 cases, FDG PET showed myocardial avidity beyond 6 weeks despite pulsed steroid treatment, suggesting unresolved myocardial rejection. Conclusion Preliminary findings suggest FDG PET may have a role in diagnosing cardiac transplant rejection. Future blinded studies are needed to help further validate this.