Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies?

Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Fetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on-going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (i) they often lack synucleinopathy, and (ii) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson's, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow-progressing, and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson's include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy. This article is protected by copyright. All rights reserved.</p

Spontaneous collapse as a prognostic marker for human blastocysts: A systematic review and meta-analysis

STUDY QUESTION: Is spontaneous collapse (SC) by human blastocysts a prognostic factor in IVF treatment? SUMMARY ANSWER: SC in human blastocyst is associated with reduced euploid embryo and pregnancy rates. WHAT IS KNOWN ALREADY: SC of the human blastocyst is a phenomenon that was revealed relatively recently following the clinical application of time-lapse monitoring in IVF laboratories. The ploidy and clinical prognosis of affected blastocysts are still poorly understood, with inconsistent reports. Systematic reviews and meta-analyses on this topic are currently absent in the literature but its potential as a marker of embryo viability holds great clinical value. In this study, we aimed to comprehensively evaluate the potential of SC as a prognostic factor in regard to ploidy status, and pregnancy, live birth and miscarriage rates. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis were performed according to PRISMA guidelines, with a protocol registered with PROSPERO (CRD42022373749). A search of MEDLINE, EMBASE, and the Cochrane Library for relevant studies was carried out on 10 October 2022, using key words relevant to \u27blastocyst collapse\u27 and \u27time-lapse imaging\u27. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two independent reviewers systematically screened and evaluated each study in terms of participants, exposure, comparator, and outcomes (PECO). The Quality In Prognosis Studies tool was used for quality assessment. Data were extracted according to Cochrane methods. Pregnancy, live birth, ploidy, or miscarriage data were summarized by risk ratios (RRs) or odds ratios and their 95% CIs. All meta-analyses were performed with random-effects models. MAIN RESULTS AND THE ROLE OF CHANCE: Following removal of duplicates, a total of 196 records were identified by the initial search. After screening according to PECO, 19 articles were included for further eligibility assessment. For meta-analysis, seven retrospective cohort studies were eventually included. After data pooling, the incidence of blastocyst SC was 37.0% (2516/6801) among seven studies (ranging from 17.4% to 56.2%). SC was associated with significantly lower clinical pregnancy rates (two studies, n = 736; RR = 0.77, 95% CI = 0.62-0.95; I 2 = 30%), ongoing pregnancy rates (five studies, n = 2503; RR = 0.66, 95% CI = 0.53-0.83; I 2 = 60%), and reduced euploidy rates (three studies, n = 3569; RR = 0.70, 95% CI = 0.59-0.83; I 2 = 69%). Nevertheless, live birth rates (two studies, n = 816; RR = 0.76, 95% CI = 0.55-1.04; I 2 = 56%) and miscarriage rate (four studies, n = 1358; RR = 1.31, 95% CI = 0.95-1.80; I 2 = 0%) did not differ between blastocysts with or without SC. There was, however, significant heterogeneity between the studies included for evaluation of ongoing pregnancy rates (I 2 = 60%, P = 0.04), live birth rates (I 2 = 56%, P = 0.13), and ploidy rates (I 2 = 69%, P = 0.04). Subgroup analyses were conducted according to different definitions of SC, number of collapse events, and whether the transferred blastocyst had undergone preimplantation genetic testing for aneuploidy; with inconclusive findings across subgroups. LIMITATIONS, REASONS FOR CAUTION: All studies in the meta-analysis were retrospective with varying levels of heterogeneity for different outcomes. Not all studies had accounted for potential confounding factors, therefore only unadjusted data could be used in the main meta-analysis. Studies employed slightly different strategies when defining blastocyst SC. Standardization in the definition for SC is needed to improve comparability between future studies. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that blastocyst SC has negative implications for a pregnancy. Such blastocysts should be given a low ranking when selecting from a cohort for intrauterine transfer. Blastocyst SC should be considered as a contributing variable when building blastocyst algorithms to predict pregnancy or live birth

Risk factors for mismatches in the ART laboratory: An analysis of 73,719 electronic witnessing points

Research question: What are the risk factors for mismatches (involving or not involving biological material) and critical mismatches (CMM; involving biological material) in an assisted reproductive technology laboratory equipped with an electronic witnessing system (EWS)? Design: In total, 73,719 witnessing points were extracted retrospectively from an EWS database, representing 11,210 consecutive treatment cycles performed at Fertility North between January 2016 and July 2023. Results: Overall, 138 (0.19%) mismatches and 16 (0.02%) CMM were identified during the study period. Significant differences were detected in both mismatch (P = 0.003) and CMM (P = 0.038) rates between different time periods of the day. The mismatch rate was highest between 12 pm and 2 pm (0.28%), whilst the CMM rate was highest after 4 pm (0.13%). Neither mismatches nor CMM were associated with a specific weekday or weekend day/public holiday (P = 0.886 and 0.183, respectively). Both mismatch (P \u3c 0.001) and CMM (P \u3c 0.001) rates differed significantly between eight laboratory processes. The mismatch rate was highest during embryo transfer (0.36%), and the CMM rate was highest during oocyte denudation (0.13%). Furthermore, the mismatch rate differed significantly between 20 operators (P \u3c 0.001), whereas the CMM rate did not (P = 0.216). Multivariate logistic regression found that six laboratory processes [in the order from higher to lower risk, oocyte denudation (P \u3c 0.001), embryo transfer (P \u3c 0.001), cryopreservation (P = 0.002), sperm preparation (P = 0.003), oocyte collection (P = 0.007) and insemination (P = 0.006)] and four individual operators (P = 0.005, 0.037, 0.010 and 0.048, respectively) were associated with mismatches. On univariate regression analysis, time after 4 pm (P = 0.020) and oocyte denudation (P \u3c 0.001) were the only risk factors associated with CMM. Conclusions: Mismatches are associated with specific laboratory processes and individual operators, while CMM are associated with time after 4 pm and oocyte denudation

Physiotherapy interventions for people with dementia and a hip fracture-a scoping review of the literature.

BACKGROUND: People with dementia are 2.7 times more likely to suffer a hip fracture than those without and their management is estimated to cost £0.92 billion per year. Yet there has been little focus on the effectiveness of interventions for this population. OBJECTIVE: The aim of this scoping review was to summarise the current available evidence for physiotherapy interventions for people with dementia who fracture their hip as well as to identify gaps in the literature that may require further research. DATA SOURCES: A systematic search of the following databases was undertaken-TRIP, CINAHL, Amed, Embase, PEDro, PsycINFO, Cochrane Library, Open Grey, Ethos, ISRCTN, Proquest, PROSPERO and UK Clinical Trials Gateway. STUDY SELECTION: Articles were included if they described an intervention which is considered within the scope of a physiotherapist and targeted those with both a hip fracture and dementia. SYNTHESIS METHODS: A narrative summary was then undertaken to describe the current state of the literature. RESULTS: Twenty six studies were included, of which thirteen were observational, six RCTs, two qualitative, two surveys and three systematic reviews. Only nine studies focused explicitly on physiotherapy interventions. CONCLUSION: The findings of this scoping review suggest there is limited evidence to guide physiotherapists in the management of people with dementia who fracture their hip. No evidence was found about perceptions or experiences of patients in this group or of the physiotherapists involved in their care. Further research is needed to develop and evaluate physiotherapy interventions for people with dementia who fracture their hip

Serum concentrations of the biomarkers CA125, CA15-3, CA72-4, tPSA and PAPP-A in natural and stimulated ovarian cycles

Objective Biomarkers associated with cancer screening (CA125, CA15‐3, CA72‐4, total prostate specific antigen [tPSA]) and the monitoring of pregnancy (pregnancy associated plasma protein‐A [PAPP‐A]) were measured during natural and stimulated ovarian cycles in disease‐free non-pregnant women to determine if they could reflect normal events relating to ovulation and/or endometrial changes. Methods A total of 73 blood samples (10 women) collected throughout the natural menstrual cycle, and 64 blood samples (11 women) taken during stimulated ovarian cycles, were analysed on the Roche Cobas e411 automated analyser. Results Detectable levels of tPSA were measured in at least one point in the cycle in 6/10 of women in the natural cycle and 10/11 of women in stimulated cycles, and CA72-4 was detected in only 12/21 women tested. Concentrations of CA125, tPSA, CA15‐3 and CA72‐4 showed no significant difference between the natural and stimulated ovarian cycle groups. On average the mean PAPP‐A of the natural group was (2.41±0.58) mIU/L higher than the stimulated group (t=4.10, P< 0.001). CA125 and CA15‐3 results were both significantly influenced by the stage of the cycle (P<0.0001), whereas tPSA and PAPP‐A concentrations revealed no significant changes (P≥0.65). CA72‐4 was not affected by the stage of the cycle nor ovarian stimulation. Conclusion Ovarian stimulation reduced serum PAPP‐A levels, CA125 and CA15‐3 levels were generally unaffected by ovarian stimulation but displayed cyclical changes throughout both natural and stimulated cycles, whilst tPSA and CA72-4 were not affected by the stage of the cycle or ovarian stimulation

Regional differences in prostaglandin E₂ metabolism in human colorectal cancer liver metastases

Background: Prostaglandin (PG) E₂ plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE₂ catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE₂ content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE₂ in human CRC cells in vitro. Methods: Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE₂ levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β. Results: PGE₂ levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE₂. Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo.Conclusions: There is significant intra-tumoral heterogeneity in PGE₂ content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE₂ metabolism should be targeted for novel treatment of advanced CRC

Dopaminergic Cell Replacement for Parkinson’s Disease: Addressing the Intracranial Delivery Hurdle

Parkinson's disease (PD) is an increasingly prevalent neurological disorder, affecting more than 8.5 million individuals worldwide. α-Synucleinopathy in PD is considered to cause dopaminergic neuronal loss in the substantia nigra, resulting in characteristic motor dysfunction that is the target for current medical and surgical therapies. Standard treatment for PD has remained unchanged for several decades and does not alter disease progression. Furthermore, symptomatic therapies for PD are limited by issues surrounding long-term efficacy and side effects. Cell replacement therapy (CRT) presents an alternative approach that has the potential to restore striatal dopaminergic input and ameliorate debilitating motor symptoms in PD. Despite promising pre-clinical data, CRT has demonstrated mixed success clinically. Recent advances in graft biology have renewed interest in the field, resulting in several worldwide ongoing clinical trials. However, factors surrounding the effective neurosurgical delivery of cell grafts have remained under-studied, despite their significant potential to influence therapeutic outcomes. Here, we focus on the key neurosurgical factors to consider for the clinical translation of CRT. We review the instruments that have been used for cell graft delivery, highlighting current features and limitations, while discussing how future devices could address these challenges. Finally, we review other novel developments that may enhance graft accessibility, delivery, and efficacy. Challenges surrounding neurosurgical delivery may critically contribute to the success of CRT, so it is crucial that we address these issues to ensure that CRT does not falter at the final hurdle

Abnormal cleavage up to day 3 does not compromise live birth and neonatal outcomes of embryos that have achieved full blastulation: A retrospective cohort study

STUDY QUESTION: Do embryos displaying abnormal cleavage (ABNCL) up to Day 3 have compromised live birth rates and neonatal outcomes if full blastulation has been achieved prior to transfer? SUMMARY ANSWER: ABNCL is associated with reduced full blastulation rates but does not impact live birth rates and neonatal outcomes once full blastulation has been achieved. WHAT IS KNOWN ALREADY?: It is widely accepted that ABNCL is associated with reduced implantation rates of embryos when transferred at the cleavage stage. However, evidence is scarce in the literature reporting birth outcomes from blastocysts arising from ABNCL embryos, likely because they are ranked low priority for transfer. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 1562 consecutive autologous in vitro fertilization cycles (maternal age 35.1 ± 4.7 years) performed at Fertility North, Australia between January 2017 and June 2022. Fresh transfers were performed on Day 3 or 5, with remaining embryos cultured up to Day 6 before vitrification. A total of 6019 embryos were subject to blastocyst culture, and a subset of 664 resulting frozen blastocysts was included for live birth and neonatal outcome analyses following single transfers. PARTICIPANTS/MATERIALS, SETTING, METHODS: ABNCL events were annotated from the first mitotic division up to Day 3, including direct cleavage (DC), reverse cleavage (RC) and \u3c6 intercellular contact points at the 4-cell stage (\u3c6ICCP). For DC and RC in combination, the ratios of affected blastomeres over the total number of all blastomeres up to Day 3 were also recorded. All pregnancies were followed up until birth with gestational age, birthweight, and sex of the baby being recorded. MAIN RESULTS AND THE ROLE OF CHANCE: Full blastulation rates for embryos showing DC (19.5%), RC (41.7%), \u3c6ICCP (58.8%), and mixed (≥2) ABNCL types (26.4%) were lower than the rates for those without ABNCL (67.2%, P \u3c 0.01 respectively). Subgroup analysis showed declining full blastulation rates with increasing ratios of combined DC/RC affected blastomeres over all blastomeres up to the 8-cell stage (66.2% when 0 affected, 47.0% when 0.25 affected, 27.4% when 0.5 affected, 14.5% when 0.75 affected, and 7.7% when all affected, P \u3c 0.01). However, once full blastulation had been achieved, no difference was detected between DC, RC, \u3c6ICCP, and no ABNCL blastocysts following single frozen transfers in subsequent live birth rates (25.9%, 33.0%, 36.0% versus 30.8%, P \u3e 0.05, respectively), gestational age (38.7 ± 1.6, 38.5 ± 1.2, 38.3 ± 3.5 versus 38.5 ± 1.8 weeks, P \u3e 0.05, respectively) and birthweight (3343.0 ± 649.1, 3378.2 ± 538.4, 3352.6 ± 841.3 versus 3313.9 ± 509.6 g, P \u3e 0.05, respectively). Multiple regression (logistic or linear as appropriate) confirmed no differences in all of the above measures after accounting for potential confounders. LIMITATIONS, REASONS FOR CAUTION: Our study is limited by its retrospective nature, making it impossible to control every known or unknown confounder. Embryos in our dataset, being surplus after selection for fresh transfer, may not represent the general embryo population. WIDER IMPLICATIONS OF THE FINDINGS: Our findings highlight the incremental impact of ABNCL, depending on the ratio of affected blastomeres up to Day 3, on subsequent full blastulation. The reassuring live birth and neonatal outcomes of ABNCL blastocysts imply a potential self-correction mechanism among those embryos reaching the blastocyst stage, which provides valuable guidance for clinical practice and patient counseling. STUDY FUNDING/COMPETTING INTEREST(S): This research is supported by an Australian Government Research Training Program (RTP) Scholarship. All authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A

Impacts of double biopsy and double vitrification on the clinical outcomes following euploid blastocyst transfer: A systematic review and meta-analysis

STUDY QUESTION: Compared to the \u27single biopsy + single vitrification\u27 approach, do \u27double biopsy + double vitrification\u27 or \u27single biopsy + double vitrification\u27 arrangements compromise subsequent clinical outcomes following euploidy blastocyst transfer? SUMMARY ANSWER: Both \u27double biopsy + double vitrification\u27 and \u27single biopsy + double vitrification\u27 led to reduced live birth/ongoing pregnancy rates and clinical pregnancy rates. WHAT IS KNOWN ALREADY?: It is not uncommon to receive inconclusive results following blastocyst biopsy and preimplantation genetic testing for aneuploidy (PGT-A). Often these blastocysts are warmed for re-test after a second biopsy, experiencing \u27double biopsy + double vitrification\u27. Furthermore, to achieve better workflow, IVF laboratories may choose to routinely vitrify all blastocysts and schedule biopsy at a preferred timing, involving \u27single biopsy + double vitrification\u27. However, in the current literature, there is a lack of systematic evaluation of both arrangements regarding their potential clinical risks in reference to the most common \u27single biopsy + single vitrification\u27 approach. STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis were performed, with the protocol registered in PROSPERO (CRD42023469143). A search in PUBMED, EMBASE, and the Cochrane Library for relevant studies was carried out on 30 August 2023, using the keywords \u27biopsy\u27 and \u27vitrification\u27 and associated variations respectively. Only studies involving frozen transfers of PGT-A tested euploid blastocysts were included, with those involving PGT-M or PGT-SR excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study groups included blastocysts having undergone \u27double biopsy + double vitrification\u27 or \u27single biopsy + double vitrification\u27, with a \u27single biopsy + single vitrification\u27 group used as control. The primary outcome was clinical pregnancy, while secondary outcomes included live birth/ongoing pregnancy, miscarriage, and post-warming survival rates. Random effects meta-analysis was performed with risk ratios (RR) and 95% CIs were used to present outcome comparisons. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 607 records were identified through the initial search and nine studies (six full articles and three abstracts) were eventually included. Compared to \u27single biopsy + single vitrification\u27, \u27double biopsy + double vitrification\u27 was associated with reduced clinical pregnancy rates (six studies, n = 18 754; RR = 0.80, 95% CI = 0.71-0.89; I2 = 0%) and live birth/ongoing pregnancy rates (seven studies, n = 20 964; RR = 0.72, 95% CI = 0.63-0.82; I2 = 0%). However, no significant changes were seen in miscarriage rates (seven studies, n = 22 332; RR = 1.40, 95% CI = 0.92-2.11; I2 = 53%) and post-warming survival rates (three studies, n = 13 562; RR = 1.00, 95% CI = 0.99-1.01; I2 = 0%) following \u27double biopsy + double vitrification\u27. Furthermore, \u27single biopsy + double vitrification\u27 was also linked with decreased clinical pregnancy rates (six studies, n = 13 284; RR = 0.84, 95% CI = 0.76-0.92; I2 = 39%) and live birth/ongoing pregnancy rates (seven studies, n = 16 800; RR = 0.79, 95% CI = 0.69-0.91; I2 = 70%), and increased miscarriage rates (five studies, n = 15 781; RR = 1.48, 95% CI = 1.31-1.67; I2 = 0%), but post-warming survival rates were not affected (three studies, n = 12 452; RR = 0.99, 95% CI = 0.97-1.01; I2 = 71%) by \u27single biopsy + double vitrification\u27. LIMITATIONS, REASONS FOR CAUTION: All studies included in this meta-analysis were retrospective with varying levels of heterogeneity for different outcomes. Not all studies had accounted for potential confounding factors. Only one study reported neonatal outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Our data indicated adverse impacts of \u27double biopsy + double vitrification\u27 and \u27single biopsy + double vitrification\u27 on clinical outcomes following euploid blastocyst transfers. Patients should be carefully consulted about the risks when offered such approaches. The biopsy process should be carried out as carefully and competently as possible to minimize an inconclusive diagnosis. STUDY FUNDING/COMPETING INTEREST(S): R.W. is supported by a National Health and Medical Research Council Emerging Leadership Investigator Grant (2009767). There is no other external funding to report. All authors report no conflict of interest. REGISTRATION NUMBER: CRD42023469143