2024 Eastern publications
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Item Large-scale evaluation of outcomes after a genetic diagnosis in children with severe developmental disorders(Elsevier, 2024-10-14) Copeland, H.; Low, K. J.; Wynn, S. L.; Ahmed, A.; Arthur, V.; Balasubramanian, M.; Bennett, K.; Berg, J.; Bertoli, M.; Bryson, L.; Bucknall, C.; Campbell, J.; Chandler, K.; Chauhan, J.; Clarkson, A.; Coles, R.; Conti, H.; Costello, P.; Coupar, T.; Craig, A.; Dean, J.; Dillon, A.; Dixit, A.; Drew, K.; Eason, J.; Forzano, F.; Foulds, N.; Gardham, A.; Ghali, N.; Green, A.; Hanna, W.; Harrison, R.; Hegarty, M.; Higgs, J.; Holder, M.; Irving, R.; Jain, V.; Johnson, K.; Jolley, R.; Jones, W. D.; Jones, G.; Joss, S.; Kalinauskiene, R.; Kanani, F.; Kavanagh, K.; Khan, M.; Khan, N.; Kivuva, E.; Lahiri, N.; Lakhani, N.; Lampe, A.; Lynch, S. A.; Mansour, S.; Marsden, A.; Massey, H.; McKee, S.; Mohammed, S.; Naik, S.; Nesarajah, M.; Newbury-Ecob, R.; Osborne, F.; Parker, M. J.; Patterson, J.; Pottinger, C.; Prapa, M.; Prescott, K.; Quinn, S.; Radley, J. A.; Robart, S.; Ross, A.; Rosti, G.; Sansbury, F. H.; Sarkar, A.; Searle, C.; Shannon, N.; Shears, D.; Smithson, S.; Stewart, H.; Suri, M.; Tadros, S.; Theobald, R.; Thomas, R.; Tsoulaki, O.; Vasudevan, P.; Rodriguez, M. V.; Vittery, E.; Whyte, S.; Woods, E.; Wright, T.; Zocche, D.; Firth, H. V.; Wright, C. F.; Peninsula Clinical Genetics Service; Copeland, HarrietPURPOSE: We sought to evaluate outcomes for clinical management after a genetic diagnosis from the Deciphering Developmental Disorders study. METHODS: Individuals in the Deciphering Developmental Disorders study who had a pathogenic/likely pathogenic genotype in the DECIPHER database were selected for inclusion (n = 5010). Clinical notes from regional clinical genetics services notes were reviewed to assess predefined clinical outcomes relating to interventions, prenatal choices, and information provision. RESULTS: Outcomes were recorded for 4237 diagnosed probands (85% of those eligible) from all 24 recruiting centers across the United Kingdom and Ireland. Clinical management was reported to have changed in 28% of affected individuals. Where individual-level interventions were recorded, additional diagnostic or screening tests were started in 903 (21%) probands through referral to a range of different clinical specialties, and stopped or avoided in a further 26 (0.6%). Disease-specific treatment was started in 85 (2%) probands, including seizure-control medications and dietary supplements, and contra-indicated medications were stopped or avoided in a further 20 (0.5%). The option of prenatal/preimplantation genetic testing was discussed with 1204 (28%) families, despite the relatively advanced age of the parents at the time of diagnosis. Importantly, condition-specific information or literature was given to 3214 (76%) families, and 880 (21%) were involved in family support groups. In the most common condition (KBG syndrome; 79 [2%] probands), clinical interventions only partially reflected the temporal development of phenotypes, highlighting the importance of consensus management guidelines and patient support groups. CONCLUSION: Our results underscore the importance of achieving a clinico-molecular diagnosis to ensure timely onward referral of patients, enabling appropriate care and anticipatory surveillance, and for accessing relevant patient support groups.Item Hiding in plain sight: a partial deletion of BRCA1 exon 7 undetectable by MLPA is a Nepali founder variant(BMJ, 2024-12-11) Clowes, V.; Taylor, J. C.; Pagnamenta, A. T.; Institute of Biomedical and Clinical Science; Pagnamenta, Alistair TItem The Effect of Postoperative Analgesia on the Day-Case Rate of Laparoscopic Cholecystectomy: A Randomised Pilot Study of the Laparoscopic-Assisted Right Subcostal Transversus Abdominis Plane Block plus Local Anaesthetic Wound Infiltration versus Local Anaesthetic Wound Infiltration only(S Karger AG, 2024-08-19) Di Mauro, D.; Reece-Smith, A.; Njere, I.; Hubble, S.; Manzelli, A.; Upper GI Surgery (Department of); Mauro, Davide Di; Reece-Smith, Alex; Njere, Ikechukwu; Hubble, Sheena; Manzelli, AntonioOBJECTIVE: The transversus abdominis plane (TAP) block and local anaesthetic infiltration (LAI) of port sites provide adequate analgesia after laparoscopic cholecystectomy (LC). Little is known if the two techniques affect the day-case (DC) rate of LC. We tested the appropriateness of the research design in view of a larger randomised controlled trial (RCT) - laparoscopic-assisted right subcostal TAP block plus local anaesthetic wound infiltration (STALA) versus LAI. SUBJECTS AND METHODS: Sixty patients having DC LC were randomised into STALA and LAI. Participants received bupivacaine 0.5% 30 mL. Pain scores were evaluated with the Visual Analogue Scale (VAS) score, at 1 h post-surgery and at discharge. Need of postoperative intravenous (IV) opioids, DC rate, and Quality of Recovery-15 questionnaires were compared between groups and were considered as measures of efficacy of the interventions and follow-up in a definitive trial. RESULTS: Twenty-nine participants were randomised to STALA, and 31 to LAI. Subjects in LAI group were all women (p = 0.0007) and younger (43.8 vs. 37.7 years, p = 0.023). Median VAS scores were 0 versus 1 at 1 h (p = 0.60), 0 versus 1.5 at discharge (p = 0.55). The need of IV opioids was 15/29 (51.7%) versus 13/31 (41.9%; p = 0.60). The DC rate was 93.1% versus 93.5% (p = 0.39). Fifty (83.3%) participants responded the questionnaires. CONCLUSIONS: The laparoscopically guided right subcostal TAP block provided no additional benefit to LAI on pain control after LC and DC rate. Despite the appropriate design, our findings do not support a larger RCT.Item Comparison of standard-dose and reduced-dose treatment of metastatic prostate cancer with enzalutamide, apalutamide or darolutamide: a rapid review(BMJ Publishing Group, 2024-02-29) Bromley, H. L.; Varughese, M.; Gilbert, D. C.; Hoskin, P.; Tannock, I. F.; Reeves, K.; Choudhury, A.; Oncology; Varughese, MohiniOBJECTIVE: To review the efficacy and safety of low-dose versus standard-dose enzalutamide, apalutamide or darolutamide treatment for metastatic prostate cancer. METHODS AND ANALYSIS: Keyword searches in MEDLINE and EMBASE up to 1 June 2023, with forward and backward citation searches of potentially relevant studies. Studies were included if primary outcome data were reported for patients with metastatic prostate cancer who had received reduced doses of enzalutamide, apalutamide or darolutamide. Searches were limited to original full-text and English-language studies. Key outcomes included overall survival (OS), progression-free survival (PFS), prostate-specific antigen response and treatment-related adverse events. The review was performed in accordance with Cochrane Rapid Reviews Methods Group guidelines. RESULTS: Ten studies were identified that met the eligibility criteria: five phase I studies, two post-hoc analyses of phase III trials and three retrospective analyses. No consistent association between OS, PFS and drug dose was identified. Fewer severe treatment-related adverse events were observed at lower drug doses. CONCLUSION: This review provides evidence that enzalutamide, apalutamide or darolutamide could be given at a lower than the standard recommended dose without loss of antitumour activity. A prospective near-equivalence randomised trial should be undertaken to compare registered and lower doses of these agents. PROSPERO REGISTRATION NUMBER: CRD42023440371.Item Therapeutic modalities of deferiprone in Parkinson's disease: SKY and EMBARK studies(IOS Press, 2024-12-27) Devos, D.; Rascol, O.; Meissner, W. G.; Foubert-Samier, A.; Lewis, S.; Tranchant, C.; Anheim, M.; Maltête, D.; Remy, P.; Eggert, K.; Pape, H.; Geny, C.; Couratier, P.; Carroll, C.; Sheridan, R.; Burn, D.; Pavese, N.; Raw, J.; Berg, D.; Suchowersky, O.; Kalia, L. V.; Evans, A.; Drapier, S.; Danaila, T.; Schnitzler, A.; Corvol, J. C.; Defer, G.; Temin, N. T.; Fradette, C.; Tricta, F.; Moreau, C.; Healthcare for Older People (Department of); Sheridan, RayBACKGROUND: Reducing nigrostriatal iron overload reduces neuronal loss in Parkinson's disease (PD) models. OBJECTIVE: Examine the safety and efficacy of deferiprone in reducing motor disability progression in dopaminergic-treated and treatment-naïve patients with early-stage PD. METHODS: Two phase II, multicenter studies, SKY and EMBARK, enrolled patients diagnosed with early PD (<3 years from screening). In SKY, patients on stable dopaminergic therapy were randomized 1:1 to one of four dosage (or placebo-matching) cohorts (300, 600, 900, 1200 mg twice daily [BID]) for 9 months. EMBARK enrolled patients on stable dopaminergic therapy or treatment-naïve patients and received 15 mg/kg BID. For both studies, the primary outcome was the change from baseline to month 9 in motor examination score (Movement Disorder Society-Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III). ClinicalTrials.gov: NCT02728843; ANZCTR: ACTRN12617001578392. RESULTS: Overall, 140 patients were randomized in SKY (28 per cohort). Thirty-six patients enrolled in EMBARK (27 dopaminergic-treated; 9 treatment-naïve). In the SKY study, all doses showed the same worsening as the placebo group, with the exception of the 600 mg dose, which was associated with non-significant reductions in MDS-UPDRS Part III least-squares mean (LSM) between baseline and 9 months (-2-8 points versus placebo). In EMBARK, LSM (SE) changes from baseline in MDS-UPDRS Part III were nonsignificant (-1.6 [1.7]) and significant (8.3 [3.9]) for dopaminergic-treated and treatment-naïve patients, respectively, the latter indicating disease worsening. Adverse events possibly related to deferiprone were reported in 35.7%-88.9% across all deferiprone groups vs. 42.9% for placebo. CONCLUSIONS: SKY and EMBARK studies indicate that deferiprone combined with L-dopa does not provide significant motor function benefit, while the absence of L-dopa treatment worsens symptoms. Parkinson's disease is an age-related brain condition that can lead to problems with movement, muscle cramps, mental health, and pain. People with Parkinson's disease also struggle with activities of daily living that can reduce their well-being. Researchers have found that some people with Parkinson's disease have high levels of iron in their brain. Currently, we do not know if removing iron from the brain can help people with Parkinson's disease. In this study, we examined if a medicine that removes iron from the brain could improve symptoms of Parkinson's disease. This medicine is called deferiprone. Our study included 176 people with Parkinson's disease. People were then divided into 2 groups. In the first group, people were already being treated for Parkinson's disease and then were given deferiprone for 9 months. We found that a low or high dose of deferiprone did not improve disease symptoms. In the second group, people taking no other medication for their Parkinson's disease were given deferiprone for 9 months. In this group, deferiprone worsened Parkinson's symptoms. There are currently no arguments in favor of using deferiprone in Parkinson's disease. Deferiprone without L-dopa worsens symptoms. Research could potentially evaluate low doses of iron chelator in combination with L-dopa over the long term and in large numbers of people. eng