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Objective: To examine recent changes in the birth prevalence of cerebral palsy in Australia; to examine the functional mobility of children with cerebral palsy by residential remoteness., Study Design: Population-based register study; analysis of Australian Cerebral Palsy Register (ACPR) data., Setting, Participants: Children with cerebral palsy born in Australia, 1995-2016, and included in the ACPR at the time of the most recent state/territory data provision (31 July 2022)., Main Outcome Measures: Change in birth prevalence of cerebral palsy, of cerebral palsy acquired pre- or perinatally (in utero to day 28 after birth), both overall and by gestational age group (less than 28, 28-31, 32-36, 37 or more weeks), and of cerebral palsy acquired post-neonatally (day 29 to two years of age); gross motor function classification by residential remoteness., Results: Data for 10 855 children with cerebral palsy born during 1995-2016 were available, 6258 of whom were boys (57.7%). The birth prevalence of cerebral palsy in the three states with complete case ascertainment (South Australia, Victoria, Western Australia) declined from 2.1 (95% confidence interval [CI], 1.9-2.4) cases per 1000 live births in 1995-1996 to 1.5 (95% CI, 1.3-1.7) cases per 1000 live births in 2015-2016. The birth prevalence of pre- or perinatally acquired cerebral palsy declined from 2.0 (95% CI, 1.7-2.3) to 1.4 (95% CI, 1.2-1.6) cases per 1000 live births; statistically significant declines were noted for all gestational ages except 32-36 weeks. The decline in birth prevalence of post-neonatally acquired cerebral palsy, from 0.15 (95% CI, 0.11-0.21) to 0.08 (95% CI, 0.05-0.12) cases per 1000 live births, was not statistically significant. Overall, 3.4% of children with cerebral palsy (307 children) lived in remote or very remote areas, a larger proportion than for all Australians (2.0%); the proportion of children in these areas who required wheelchairs for mobility was larger (31.3%) than that of children with cerebral palsy in major cities or regional areas (each 26.1%)., Conclusions: The birth prevalence of cerebral palsy declined markedly in Australia during 1995-2016, reflecting the effects of advances in maternal and perinatal care. Our findings highlight the need to provide equitable, culturally safe access to antenatal services for women, and to health and disability services for people with cerebral palsy, across Australia., (© 2024 AMPCo Pty Ltd.)

A growing number of genes have been identified in individuals with cerebral palsy (CP); however, many of these studies have poor compliance with the cerebral palsy clinical description. This systematic review aimed to assess the quality of the cerebral palsy clinical description/phenotype in cerebral palsy genetic studies published between 2010 and 2024 and report clinically relevant genes based on the quality of the cerebral palsy phenotype. An expert panel developed 6 criteria to review the reported cerebral palsy phenotype/description for each included study. Clinically relevant genes were extracted from each study and stratified into 2 tiers based on the quality. Eighteen studies were included. There was high confidence in the reported cerebral palsy description/phenotype from 8 studies. Of the initial 373 clinically relevant genes, 85 were tier II genes. Individual cerebral palsy motor disorder and phenotype data were absent for 349 of these individuals, limiting further analysis. The tier I gene list was composed of 6 genes: ATL1 , COL4A1 , GNAO1 , KIF1A , SPAST , and TUBA1A . Bilateral spasticity was the most common motor disorder reported in individuals with variants in all 6 genes, and most individuals had accompanying conditions. Prioritizing the accurate reporting of motor and nonmotor phenotypes is crucial for future cerebral palsy genetic studies to further understand the underlying neurobiology., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic-ischaemic encephalopathy (HIE)., Method: This was a systematic review of randomized controlled trials (RCTs) (with meta-analysis) and non-RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long-term major neurodevelopmental disability)., Results: Twenty-five RCTs (2099 infants) and four non-RCTs (871 infants) were included, 23 in low- and middle-income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53-0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58-0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34-1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86-10.46; one RCT). No reduction in death or long-term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14-1.89; one RCT) but reductions in several short-term adverse outcomes were observed with magnesium sulphate. Evidence was low- to very-low certainty because of risk of bias and imprecision., Interpretation: Given the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high-quality studies to determine stand-alone effects in LMICs and effects with and after therapeutic hypothermia in high-income countries., (© 2024 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Objective: To determine whether we can safely and successfully transplant an ovary tissue allograft from a nonidentical donor to her Turner syndrome sister., Design: Transplantation of cryopreserved ovary tissue, as well as fresh transplantation of ovarian tissue between identical twins, is now well established with numerous reported successful cases. However, there have not yet been any ovary transplants between nonidentical women requiring immunosuppression (ovary allotransplant). This could be a much more common indication for ovary tissue transplantation if safe and reliable immunosuppression were available., Setting: Infertility Center of St. Louis., Patient(s): A 20-year-old amenorrheic woman with nonmosaic 45-XO Turner syndrome requested ovary tissue transplantation from her fertile 22-year-old 46-XX sister. They were an human leukocyte antigens match but were ABO incompatible, a well-known contra-indication to solid tissue or organ transplantation. The Turner syndrome sister strongly preferred to be able to become pregnant naturally without donor egg in vitro fertilization and to avoid hormone replacement therapy. In her religious group, that would also be important for finding a marital match. Despite the poor prognosis associated with ABO incompatibility, an ovary from her 22-year-old nonidentical fertile sister was transplanted to her employing the immunosuppression protocol now used for kidney transplant patients in our centers at Washington University and Johns Hopkins., Intervention(s): Not applicable., Main Outcome Measure(s): Post operatively at 5 months she developed normal monthly menstrual ovarian function, and she became spontaneously pregnant with a normal infant girl. The relation between her postoperation follicle stimulating hormone and antimüllerian hormone levels continue to support the theory that tissue pressure controls primordial follicle recruitment. The fact that ABO incompatibility did not prevent success suggests that diffusion and not revascularization may be all that is required for successful long-term ovarian cortex transplant survival with spontaneous pregnancy., Result(s): Ovary allotransplantation with safe immunosuppression allows natural conception, and also normal hormone function obviates the need for hormone replacement therapy. Orthotopic placement of the graft and surgical technique is critical for natural conception and a higher pregnancy rate., Conclusion(s): Allotransplantation requiring safe immunosuppression, if successful, maybe a much more commonly used indication for ovary transplantation in the future than frozen ovary grafts or grafts between identical twins., Competing Interests: Declaration of Interests S.J.S. has nothing to disclose. S.G. has nothing to disclose. B.R. has nothing to disclose. E.K. reports consulting fees from Silber Infertility Center of St. Louis as Embryology Laboratory Director. R.D.S. reports funding from Veloxis and CareDx, outside the submitted work; royalties from UpToDate, content writer; honoraria from National Kidney Foundation, symposium; leadership position, Transplant nephrology fellowship training accreditation program; and stocks in Pfizer. A.M. has nothing to disclose. D.B. reports royalties from UpToDate, Editor in Chief and Transplantation, Deputy Editor; and consulting fees from Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Idecabtagene vicleucel (ide-cel) has shown impressive efficacy in relapsed/refractory multiple myeloma (RRMM). This study aimed to investigate the impact of absolute lymphocyte count (ALC) on the survival outcomes of RRMM patients treated with standard of care (SOC) ide-cel. Data were collected retrospectively from 11 institutions in the U.S. Impact of ALC parameters including pre-apheresis (pre-A), pre-lymphodepletion (pre-LD), absolute and percent difference from pre-A to pre-LD on clinical outcomes after ide-cel were examined using survival analysis. A new ALC profile was created based on univariate analysis that comprises 3 groups: normal (≥1 × 10 9 /L) pre-LD ALC (LD N ), low (<1 × 10 9 /L) pre-LD ALC (LD L ) + percent reduction <37.5 (%R L ), and LD L ALC + percent reduction ≥37.5 (%R H ). A total of 214 SOC ide-cel recipients were included in this analysis. The median patient age was 64 years (interquartile range [IQR], 57 to 69 years), median number of prior therapies was 6 (IQR, 5 to 9), and median duration of follow-up was 5.4 months (IQR, 2.1 to 8.3 months). Most patients had both low pre-A ALC (75.3%) and pre-LD ALC (77.2%), and the reduction from pre-A to pre-LD (median, .65 to .55 × 10 9 /L) was statistically significant. Univariate analysis showed that the LD L + %R H group had significantly worse progression-free survival (PFS) and overall survival (OS) compared to the LD L + %R L and LD N ALC groups (6-month PFS: 40% versus 67.6% and 60.9%; 6-month OS: 69.5% versus 87% and 94.3%). In multivariable analysis, after adjusting for age, performance status, cytogenetic risk, use of bridging therapy, and extramedullary disease, PFS did not maintain its statistical significance; however, OS remained significantly worse for LD L + %R H group compared to the LD N ALC group (hazard ratio [HR], 4.3; 95% confidence interval [CI], 1.1 to 17), but the difference between the LD L + %R H versus %R L groups was not statistically significant (HR, 1.7; 95% CI, .8 to 4.0). Our findings indicate that low pre-LD ALC with high %R from pre-A to pre-LD was associated with inferior survival outcomes, particularly OS, in patients who received SOC ide-cel., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: To systematically review the evidence for the effectiveness and safety of magnesium sulfate as a fetal neuroprotective agent when given to individuals at risk of preterm birth., Data Sources: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov , the World Health Organization International Clinical Trials Registry Platform (through March 17, 2023), and reference lists of relevant studies., Methods of Study Selection: Randomized controlled trials (RCTs) assessing magnesium sulfate for fetal neuroprotection in pregnant participants at risk of imminent preterm birth were eligible. Two authors assessed RCTs for inclusion, extracted data, and evaluated risk of bias, trustworthiness, and evidence certainty (GRADE [Grading of Recommendations Assessment, Development and Evaluation])., Tabulation, Integration, and Results: We included six RCTs (5,917 pregnant participants and 6,759 fetuses at less than 34 weeks of gestation at randomization). They were conducted in high-income countries (two in the United States, two across Australia and New Zealand, and one each in Denmark and France) and commenced between 1995 and 2018. Primary outcomes: up to 2 years of corrected age, magnesium sulfate compared with placebo reduced the risk of cerebral palsy (risk ratio [RR] 0.71, 95% CI, 0.57-0.89; six RCTs, 6,107 children) and death or cerebral palsy (RR 0.87, 95% CI, 0.77-0.98; six RCTs, 6,481 children) (high-certainty evidence). Magnesium sulfate had little or no effect on death up to 2 years of corrected age (moderate-certainty evidence) or these outcomes at school age (low-certainty evidence). Although there was little or no effect on death or cardiac or respiratory arrest for pregnant individuals (low-certainty evidence), magnesium sulfate increased adverse effects severe enough to stop treatment (RR 3.21, 95% CI, 1.88-5.48; three RCTs, 4,736 participants; moderate-certainty evidence). Secondary outcome: magnesium sulfate reduced the risk of severe neonatal intraventricular hemorrhage (moderate-certainty evidence)., Conclusion: Magnesium sulfate for preterm fetal neuroprotection reduces cerebral palsy and death or cerebral palsy for children. Further research is required on longer-term benefits and harms for children, effect variation by participant and treatment characteristics, and the generalizability of findings to low- and middle-income countries., Systematic Review Registration: The review protocol was based on a standard Cochrane Pregnancy and Childbirth template and our previous Cochrane Systematic Review (doi: 10.1002/14651858.CD004661.pub3 ; published before the introduction of PROSPERO)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: To provide a description of cerebral palsy (CP) registers globally, identify which aim to report on CP epidemiology, and report similarities and differences across topics of importance for the sustainability and collaboration between registers., Method: Representatives of all known CP registers globally (n = 57) were invited to participate. The online survey included 68 questions across aims, methodologies, output/impact, and stakeholder involvement. Responses were analysed using descriptive statistics., Results: Forty-five registers participated, including three register networks. Twenty were newly established or under development, including 12 in low- and middle-income countries (LMICs). An epidemiological aim was reported by 91% of registers. Funding is received by 85% of registers, most often from not-for-profit organizations. CP definitions are comparable across registers. While the minimum data set of a register network is used by most registers, only 25% of identified items are collected by all three register networks. Ninety per cent of registers measure research activities/output, and 64% measure research impact. People with lived experience are involved in 62% of registers., Interpretation: There has been a recent surge in CP registers globally, particularly in LMICs, which will improve understanding of CP epidemiology. Ongoing efforts to address identified methodological differences are essential to validate comparison of results and support register collaboration., What This Paper Adds: Cerebral palsy (CP) registers represent an increasing number of regions, including low- and middle-income, worldwide. Most registers collect the minimum data set of a CP register network. Research activities/output and impact are measured by most registers. The majority of registers involve people with lived experience in operation or research., (© 2023 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version., Objectives: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth., Search Methods: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies., Selection Criteria: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia., Data Collection and Analysis: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach., Main Results: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4) (RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported., Authors' Conclusions: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered., (Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

This paper will review a remarkable new approach to in vitro maturation "IVM" of oocytes from ovarian tissue, based on our results with in vitro oogenesis from somatic cells. As an aside benefit we also have derived a better understanding of ovarian longevity from ovary transplant. We have found that primordial follicle recruitment is triggered by tissue pressure gradients. Increased pressure holds the follicle in meiotic arrest and prevents recruitment. Therefore recruitment occurs first in the least dense inner tissue of the cortico-medullary junction. Many oocytes can be obtained from human ovarian tissue and mature to metaphase 2 in vitro with no need for ovarian stimulation. Ovarian stimulation may only be necessary for removing the oocyte from the ovary, but this can also be accomplished by simple dissection at the time of ovary tissue cryopreservation. By using surgical dissection of the removed ovary, rather than a needle stick, we can obtain many oocytes from very small follicles not visible with ultrasound. A clearer understanding of ovarian function has come from in vitro oogenesis experiments, and that explains why IVM has now become so simple and robust. Tissue pressure (and just a few "core genes" in the mouse) direct primordial follicle recruitment and development to mature oocyte, and therefore also control ovarian longevity. There are three distinct phases to oocyte development both in vitro and in vivo: in vitro differentiation "IVD" which is not gonadotropin sensitive (the longest phase), in vitro gonadotropin sensitivity "IVG" which is the phase of gonadotropin stimulation to prepare for meiotic competence, and IVM to metaphase II. On any given day 35% of GVs in ovarian tissue have already undergone "IVD" and "IVG" in vivo, and therefore are ready for IVM., (© 2023. The Author(s).)

Background: Administrative health data, such as hospital admission data, are often used in research to identify children/young people with cerebral palsy (CP)., Objectives: To compare sociodemographic, clinical details and mortality of children/young people identified as having CP in either a CP population registry or hospital admission data., Methods: We identified two cohorts of children/young people (birth years 2001-2010, age at study end or death 2 months to 19 years 6 months) with a diagnosis of CP from either (i) the New South Wales (NSW)/Australian Capital Territory (ACT) CP Register or (ii) NSW hospital admission data (2001-2020). Using record linkage, these data sources were linked to each other and NSW Death, Perinatal, and Disability datasets. We determined the sensitivity and positive predictive value (PPV) of CP diagnosis in hospital admission data compared with the NSW/ACT CP Register (gold standard). We then compared the sociodemographic and clinical characteristics and mortality of the two cohorts available through record linkage using standardised mean difference (SMD)., Results: There were 1598 children/young people with CP in the NSW/ACT CP Register and 732-2439 children/young people with CP in hospital admission data, depending on the case definition used. The sensitivity of hospital admission data for diagnosis of CP ranged from 0.40-0.74 and PPV 0.47-0.73. Compared with children/young people with CP identified in the NSW/ACT CP Register, a greater proportion of those identified in hospital admission data (one or more admissions with G80 case definition) were older, lived in major cities, had comorbidities including epilepsy, gastrostomy use, intellectual disability and autism, and died during the study period (SMD > 0.1)., Conclusions: Sociodemographic and clinical characteristics differ between cohorts of children/young people with CP identified using a CP register or hospital admission data. Those identified in hospital admission data have higher rates of comorbidities and death, suggesting some may have progressive conditions and not CP. These differences should be considered when planning and interpreting research using various data sources., (© 2023 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT., Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP., Design, Setting, and Participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more)., Main Outcomes and Measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT., Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia)., Conclusion and Relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

Despite strong empirical support for treatments of eating disorders, research has demonstrated a trend of clinicians deviating from protocols outlined in empirically supported manuals. The present study used a convergent mixed-methods design to understand clinicians' use of and drift from empirically supported treatments in a sample of 114 licensed clinicians in the US who had substantial experience (i.e. one-third of caseload) working with patients with eating disorders and training in cognitive-behavioral therapy (CBT), family-based therapy (FBT), and/or interpersonal therapy (IPT) for eating disorders. Results revealed that 63.7-76.3% of clinicians drift from empirically supported treatments and 71.8% were aware they deviated from empirically supported treatments. Qualitative analyses identified client differences (57.2%) to be the primary reason why clinicians drift, with less participants describing therapist factors (20.4%), treatment shortcomings (12.6%), treatment setting (11.7%), logistic constraints (4.9%) and family factors (4.9%) as reasons why they drift. These findings suggest that drift for most clinicians may be better explained under the umbrella of evidence-based practice. Clinicians also identified a number of ways in which treatment and access to treatment can be improved. This broadened understanding of the use of empirically supported treatments within evidence-based practice may serve to help bridge the gap between research and practice.

Importance: Adverse life experiences have been proposed to contribute to diverse mental health problems through an association with corticolimbic functioning. Despite compelling evidence from animal models, findings from studies in humans have been mixed; activation likelihood estimation (ALE) meta-analyses have failed to identify a consistent association of adverse events with brain function., Objective: To investigate the association of adversity exposure with altered brain reactivity using multilevel kernel density analyses (MKDA), a meta-analytic approach considered more robust than ALE to small sample sizes and methodological differences between studies., Data Sources: Searches were conducted using PsycInfo, Medline, EMBASE, and Web of Science from inception through May 4, 2022. The following search term combinations were used for each database: trauma, posttraumatic stress disorder (PTSD), abuse, maltreatment, poverty, adversity, or stress; and functional magnetic resonance imaging (fMRI) or neuroimaging; and emotion, emotion regulation, memory, memory processing, inhibitory control, executive functioning, reward, or reward processing., Study Selection: Task-based fMRI studies within 4 domains (emotion processing, memory processing, inhibitory control, and reward processing) that included a measure of adverse life experiences and whole-brain coordinate results reported in Talairach or Montreal Neurological Institute space were included. Conference abstracts, books, reviews, meta-analyses, opinions, animal studies, articles not in English, and studies with fewer than 5 participants were excluded., Data Extraction and Synthesis: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline, 2 independent reviewers assessed abstracts and full-text articles for entry criteria. A third reviewer resolved conflicts and errors in data extraction. Data were pooled using a random-effects model and data analysis occurred from August to November 2022., Main Outcomes and Measures: Peak activation x-axis (left-right), y-axis (posterior-anterior), and z-axis (inferior-superior) coordinates were extracted from all studies and submitted to MKDA meta-analyses., Results: A total of 83 fMRI studies were included in the meta-analysis, yielding a combined sample of 5242 participants and 801 coordinates. Adversity exposure was associated with higher amygdala reactivity (familywise error rate corrected at P < .001; x-axis = 22; y-axis = -4; z-axis = -17) and lower prefrontal cortical reactivity (familywise error rate corrected at P < .001; x-axis = 10; y-axis = 60; z-axis = 10) across a range of task domains. These altered responses were only observed in studies that used adult participants and were clearest among those who had been exposed to severe threat and trauma., Conclusions and Relevance: In this meta-analysis of fMRI studies of adversity exposure and brain function, prior adversity exposure was associated with altered adult brain reactivity to diverse challenges. These results might better identify how adversity diminishes the ability to cope with later stressors and produces enduring susceptibility to mental health problems.

Objective: To report the prevalence of cerebral palsy (CP) in children with severe congenital heart defects (sCHD) and the outcome/severity of the CP., Methods: Population-based, data linkage study between CP and congenital anomaly registers in Europe and Australia. The EUROCAT definition of severe CHD (sCHD) was used. Linked data from 4 regions in Europe and 2 in Australia were included. All children born in the regions from 1991 through 2009 diagnosed with CP and/or sCHD were included. Linkage was completed locally. Deidentified linked data were pooled for analyses., Results: The study sample included 4989 children with CP and 3684 children with sCHD. The total number of livebirths in the population was 1 734 612. The prevalence of CP was 2.9 per 1000 births (95% CI, 2.8-3.0) and the prevalence of sCHD was 2.1 per 1000 births (95% CI, 2.1-2.2). Of children with sCHD, 1.5% (n = 57) had a diagnosis of CP, of which 35 (61%) children had prenatally or perinatally acquired CP (resulting from a brain injury at ≤28 days of life) and 22 (39%) children had a postneonatal cause (a brain injury between 28 days and 2 years). Children with CP and sCHD more often had unilateral spastic CP and more intellectual impairments than children with CP without congenital anomalies., Conclusions: In high-income countries, the proportion of children with CP is much higher in children with sCHD than in the background population. The severity of disease in children with CP and sCHD is milder compared with children with CP without congenital anomalies., Competing Interests: Declaration of Competing Interest Funding support received for the overarching Comprehensive CA-CP Study: the Cerebral Palsy Alliance Research Foundation (The Comprehensive CA-CP Study PG1215 and PG2816 and salary support from Cerebral Palsy Alliance Research Foundation (S.G., S.M., H.S.S., N.B.). The study sponsors played no role in the study or the paper. The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Low muscle mass has been correlated with adverse outcomes in patients who are critically ill. Methods to identify low muscularity such as computed tomography scans or bioelectrical impedance analyses are impractical for admission screening. Urinary creatinine excretion (UCE) and creatinine height index (CHI) are associated with muscularity and outcomes but require a 24-h urine collection. The estimation of UCE from patient variables avoids the need for a 24-h urine collection and may be clinically useful., Methods: Variables of age, height, weight, sex, plasma creatinine, blood urea nitrogen (BUN), glucose, sodium, potassium, chloride, and carbon dioxide from a deidentified data set of 967 patients who had UCE measured were used to develop models to predict UCE. The model identified with the best predictive ability was validated and then retrospectively applied to a separate sample of 120 veterans who were critically ill to examine if UCE and CHI predicted malnutrition or were associated with outcomes., Results: A model was identified that included variables of plasma creatinine, BUN, age, and weight and was found to be highly correlated, moderately predictive of UCE, and statistically significant. Patients with model-estimated CHI  ≤  60% had significantly lower body weight, body mass index, plasma creatinine, and sera albumin and prealbumin levels; were 8.0 times more likely to be diagnosed with malnutrition; and were 2.6 times more likely to be readmitted in 6 months., Conclusion: A model that predicts UCE offers a novel method to identify patients with low muscularity and malnutrition on admission without the use of invasive tests., (© 2023 American Society for Parenteral and Enteral Nutrition. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF)., Methods: Healthy adults (Parts A/B) and HF patients (Part C) aged 18-85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C)., Primary Endpoint: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function., Results: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler)., Conclusions: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule., Trial Registration Number: ClinicalTrials.gov NCT03276728., Date of Registration: September 8, 2017., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n = 50, 62%) or in combination with a Bruton tyrosine kinase inhibitor (BTKi) (n = 16, 20%), an anti-CD20 monoclonal antibody (n = 11, 14%), or other active agents at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTKis in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index score before receiving venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in patients with MCL who are at high risk, and may have a better role in earlier lines of treatment and/or in conation with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large-scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies., Aims: We evaluated the accuracy of an electronic health records-based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk., Methods and Results: Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD-9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6 months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD-9 code in the records of 40 randomly selected and chart review-confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M-) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above). The positive predictive value (PPV) for the ICD-9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M-protein test results, 88% also had the ICD-9 diagnosis code., Conclusion: The diagnosis code-based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Aim: To determine trends and current estimates in regional and global prevalence of cerebral palsy (CP)., Method: A systematic analysis of data from participating CP registers/surveillance systems and population-based prevalence studies (from birth year 1995) was performed. Quality and risk of bias were assessed for both data sources. Analyses were conducted for pre-/perinatal, postnatal, neonatal, and overall CP. For each region, trends were statistically classified as increasing, decreasing, heterogeneous, or no change, and most recent prevalence estimates with 95% confidence intervals (CI) were calculated. Meta-analyses were conducted to determine current birth prevalence estimates (from birth year 2010)., Results: Forty-one regions from 27 countries across five continents were represented. Pre-/perinatal birth prevalence declined significantly across Europe and Australia (11 out of 14 regions), with no change in postneonatal CP. From the limited but increasing data available from regions in low- and middle-income countries (LMICs), birth prevalence for pre-/perinatal CP was as high as 3.4 per 1000 (95% CI 3.0-3.9) live births. Following meta-analyses, birth prevalence for pre-/perinatal CP in regions from high-income countries (HICs) was 1.5 per 1000 (95% CI 1.4-1.6) live births, and 1.6 per 1000 (95% CI 1.5-1.7) live births when postneonatal CP was included., Interpretation: The birth prevalence estimate of CP in HICs declined to 1.6 per 1000 live births. Data available from LMICs indicated markedly higher birth prevalence., What This Paper Adds: • Birth prevalence of pre-/perinatal cerebral palsy (CP) in high-income countries (HICs) is decreasing. • Current overall CP birth prevalence for HICs is 1.6 per 1000 live births. • Trends in low- and middle-income countries (LMICs) cannot currently be measured. • Current birth prevalence in LMICs is markedly higher than in HICs. • Active surveillance of CP helps to assess the impact of medical advancements and social/economic development. • Population-based data on prevalence and trends of CP are critical to inform policy., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Human induced pluripotent stem cells (hiPSCs) enable reproductive diseases to be studied when the reproductive health of the participant is known. In this study, monozygotic (MZ) monoamniotic (MA) twins discordant for primary ovarian insufficiency (POI) consent to research to address the hypothesis that discordant POI is due to a shared primordial germ cell (PGC) progenitor pool. If this is the case, reprogramming the twin's skin cells to hiPSCs is expected to restore equivalent germ cell competency to the twins hiPSCs. Following reprogramming, the infertile MA twin's cells are capable of generating human PGC-like cells (hPGCLCs) and amniotic sac-like structures equivalent to her fertile twin sister. Using these hiPSCs together with genome sequencing, our data suggest that POI in the infertile twin is not due to a genetic barrier to amnion or germ cell formation and support the hypothesis that during gestation, amniotic PGCs are likely disproportionately allocated to the fertile twin with embryo splitting., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: To determine factors that influence non-attendance at outpatient clinics by children with cerebral palsy (CP)., Method: This was a retrospective cohort study of 1395 children with CP (59.6% male; born 2005 to 2017) identified from the New South Wales (NSW)/Australian Capital Territory CP Register, who had scheduled appointments at outpatient clinics at two NSW tertiary paediatric hospitals between 2012 and 2019. Associations between sociodemographic, clinical, and process-of-care factors and non-attendance were examined using multivariate logistic regression with generalized estimating equations., Results: A total of 5773 (12%) of 50 121 scheduled outpatient days were not attended. Non-attendance increased over time (average increase 5.6% per year, 95% confidence interval [CI]: 3.7-7.3). Older children aged 5 to 9 years (adjusted odds ratio [aOR] 1.11; 95% CI: 1.02-1.22) and 10 to 14 years (aOR 1.17; 95% CI: 1.03-1.34), socioeconomic disadvantage (aOR 1.29; 95% CI: 1.11-1.50), previous non-attendance (aOR 1.38; 95% CI: 1.23-1.53), and recent rescheduled or cancelled appointments (aOR 1.08; 95% CI: 1.01-1.16) were associated with increased likelihood of non-attendance., Interpretation: One in eight outpatient appointments for children with CP were not attended. Non-attendance was associated with increasing age, socioeconomic disadvantage, previous non-attendance, and recent rescheduled or cancelled appointments. Identifying specific barriers and interventions to improve access to outpatient services for these groups is needed., What This Paper Adds: Twelve per cent of scheduled appointments for children with cerebral palsy are not attended. Proportions of appointments not attended has increased over the last decade. Increasing age and socioeconomic disadvantage increase the likelihood of non-attendance. Previous non-attendance and recent cancelled or rescheduled appointments increase the likelihood of further non-attendance., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Aim: To investigate temporal trends in birth prevalence, disability severity, and motor type for singletons with prenatal or perinatally acquired cerebral palsy (CP)., Method: Numerator data, number of children with CP born a singleton between 1995 and 2014, confirmed at 5 years of age, were drawn from three state registers with population-level ascertainment. Birth prevalence estimates and 95% confidence intervals (CI) were calculated per 1000 singleton live births for the three states combined, overall, by gestational age group, by dichotomized disability severity, and spastic laterality. Poisson regression models were used to analyse trends. Using data from all eight registers, trends in the proportional distribution of CP subtypes overall and stratified by gestational age were examined., Results: Birth prevalence of CP declined from 1.8 (95% CI 1.6-2.0) in 1995 to 1996 to 1.2 (95% CI 1.1-1.4) in 2013 to 2014 (average 5% per 2-year epoch, p < 0.001). Declines in birth prevalence were observed across all gestational age groups with the largest decline in children born at <28 weeks (average 8% per epoch, p < 0.001). Prevalence of moderate-severe disability declined for children born at <28 and ≥37 weeks (average 11% and 7% per epoch respectively, p < 0.001). The proportions of bilateral spastic CP declined (p < 0.001) at <28 weeks (p = 0.014) and ≥37 weeks (p < 0.001). The proportion of children with dyskinesia increased (28-31 weeks: p = 0.021, 32-36 weeks: p = 0.001, and ≥37 weeks: p < 0.001)., Interpretation: Birth prevalence of CP and moderate-severe disability (<28 and ≥37 weeks) declined in Australian singletons between 1995 and 2014, reflecting changes in prenatal and perinatal care over time., What This Paper Adds: Declines in birth prevalence of prenatal or perinatally acquired cerebral palsy were observed for singletons born in Australia between 1995 and 2014. These declines were evident across all gestational age groups. Declines in birth prevalence of moderate-severe disability were observed for children born at <28 weeks and ≥37 weeks., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Objective: To systematically review and synthesize evidence of determinants associated with hospital-based health service utilization among individuals with cerebral palsy (CP)., Data Sources: Electronic databases MEDLINE, Embase, APA Psycinfo were searched from January 2000 to April 2020., Study Selection: Observational studies were included that described people with CP, reported quantitative measures of hospital-based health service utilization (inpatient, outpatient, emergency department), and based in high-income countries. We excluded studies that included only subsets of people with CP, or those that only reported therapy service utilization., Data Extraction: After initial screen, 2 reviewers reviewed full texts for inclusion and performed data extraction and risk of bias assessment using the Newcastle-Ottawa scale. Determinants of health service utilization were identified and categorized using the Andersen behavioral model., Data Synthesis: Seventeen studies met inclusion criteria. Study quality was high. Twenty-six determinants were reported across 8 Andersen model characteristics. Individual predisposing factors such as sex showed no difference in health service utilization; inpatient admissions decreased with increasing age during childhood and was lower in adults. Increased health service utilization was associated with "individual need" including severe gross motor disability, epilepsy, developmental/ intellectual disability and gastrostomy-use across inpatient, outpatient and emergency department settings. There was little information reported on socio-demographic and health system contextual determinants., Conclusions: CP health service utilization is associated with age, severity and comorbidities. Improved understanding of determinants of health service utilization can support health service access for people with CP., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: Studies on cerebral palsy among children and adolescents in Arabic-speaking countries are scarce. In this systematic review, we aimed to describe the epidemiology of cerebral palsy among children and adolescents in Arabic-speaking countries in terms of prevalence, risk factors, motor types, and rehabilitation., Methods: Six key bibliographic databases were searched for relevant literature published to 17 July 2021. Titles and abstracts were screened for potential inclusion and two independent reviewers screened the full texts of potential articles following pre-defined inclusion/exclusion criteria. The included studies were evaluated independently by three reviewers. The risk of bias was assessed, and data were extracted and analysed., Results: A total of 32 studies from 7 countries met our inclusion criteria. The prevalence of cerebral palsy in Arabic-speaking countries was 1.8/1000 live births (95% CI: 1.2-2.5). Spastic cerebral palsy was the most common motor type, representing 59.8% (95% CI: 46.2-72.7) of pooled estimates. This included children with spastic quadriplegia, diplegia, and hemiplegia; 25.1% (95% CI: 18.2-32.8), 16.2% (95% CI: 11.4-23.3), and 10.4% (95% CI: 7.3-13.8), respectively. Consanguinity was high and represented 37.7% (95% CI: 29.3-46.6). Only one included study reported the types of rehabilitation received (e.g., physiotherapy and assistance devices)., Conclusions: This paper provides a summary of the epidemiology of cerebral palsy in Arabic-speaking countries and highlights areas for future research. There is still a substantial knowledge gap on the epidemiology of cerebral palsy in these regions. Countries in the Arab region should follow examples of countries that have successfully established cerebral palsy registries to generate evidence on epidemiology of cerebral palsy and opportunities for prevention.

Research Question: Is it possible to use experience gained from 24 years of frozen ovarian transplantation, and from recent experience with in-vitro gametogenesis to accomplish simple and robust in-vitro maturation (IVM) of oocytes from human ovarian tissue?, Design: A total of 119 female patients between age 2 and 35 years old underwent ovary cryopreservation (as well as in-vitro maturation of oocytes and IVM in the last 13 individuals) over a 24-year period. Up to 22 years later, 17 returned to have their ovary tissue thawed and transplanted back., Results: Every woman had a return of ovarian function 5 months after transplant, similar to previous observations. As observed before, anti-Müllerian hormone (AMH) concentration rose as FSH fell 4 months later. The grafts continued to work up to 8 years. Of the 17, 13 (76%) became pregnant with intercourse at least once, resulting in 19 healthy live births, including six live births from three women who had had leukaemia. Of the harvested germinal vesicle oocytes, 35% developed with simple culture media into mature metaphase II oocytes., Conclusions: The authors concluded the following. First, ovary tissue cryopreservation is a robust method for preserving fertility even for women with leukaemia, without a need to delay cancer treatment. Second, many mature oocytes can often be obtained from ovary tissue with simple media and no need for ovarian stimulation. Third, ovarian stimulation only be necessary for removing the oocyte from the ovary, which can also be accomplished by simple dissection at the time of ovary freezing. Finally, pressure and just eight 'core genes' control primordial follicle recruitment and development., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Telomere length regulation is essential for cell viability in eukaryotes. While many pathways that affect telomere length are known, we do not yet have a complete understanding of the mechanism of length regulation. To identify new pathways that might regulate telomere length, we carried out a genetic screen in yeast and identified the cyclin-dependent kinase complex Bur1/2 as a regulator of telomere length. Mutations in either BUR1 cyclin-dependent kinase or the associated BUR2 cyclin resulted in short telomeres. This regulation did not function through the known role of BUR1 in regulating histone modification as bur1∆ set2∆ and bur2∆ set2∆ double mutants rescued cell growth but did not rescue the telomere shortening effects. We found that both bur1∆ and bur2∆ set2∆ were also defective in de novo telomere addition, and deletion of SET2 did also not rescue this elongation defect. The Bur1/2 cyclin-dependent kinase regulates transcription of many genes. We found that TLC1 RNA levels were reduced in bur2∆ set2∆ mutants; however, overexpression of TLC1 restored the transcript levels but did not restore de novo telomere elongation or telomere length. These data suggest that the Bur1/2 kinase plays a role in telomere elongation separate from its role in transcription of telomerase components. Dissecting the role of the Bur1/2 kinase pathway at telomeres will help complete our understanding of the complex network of telomere length regulation., (© 2021 The Authors. Yeast published by John Wiley & Sons Ltd.)

Background: There has been increasing use of hospital discharge data to identify congenital anomalies, with limited information about the accuracy of these data., Objectives: To evaluate the accuracy of hospital discharge data in ascertaining major congenital anomalies in infants., Methods: All liveborn infants with major congenital anomalies born between 2004 and 2009 in New South Wales, Australia were included. They were separated into two study groups: (a) infants identified from the Register of Congenital Conditions with a corresponding record in linked hospital discharge data; and (b) infants with a recorded congenital anomaly in hospital data, but without a register record. For the first group, we assessed agreement (concordant diagnoses) and the proportion of anomalies with discrepant diagnoses in each dataset. For the second group, we determined the number of anomalies recorded only in hospital data and applied specific conditions restricting to those recorded in the birth admission, excluding nonspecific diagnoses, or those with relevant surgical procedures to minimize potential false positives or over-reporting., Results: The first study group included 9,346 infants with an average 84% agreement in the ascertainment of major anomalies between hospital and registry data, and >93% agreement for cardiac, abdominal wall, and gastrointestinal anomalies. Discrepant diagnoses occurred on average in 20% of cases from hospital data and 17% from registry data, and were slightly reduced with the use of diagnoses recorded only in tertiary pediatric hospitals. The second group included 25,893 infants where anomalies were only recorded in hospital data, most commonly skin and unspecified anomalies. Excluding unspecified cases, those only diagnosed at the birth admission and restricting to surgical procedures reduced over-reporting by up to 96%., Conclusions: Hospital discharge data provide an acceptable means to ascertain congenital anomalies, but with variable accuracy for different anomalies. Application of specific conditions and limited to surgical procedures improves the utility of using hospital discharge data to ascertain congenital anomalies., (© 2021 Wiley Periodicals LLC.)

Isatuximab is an IgG1 monoclonal antibody targeting CD38 that has received regulatory approval in combination regimens for patients with relapsed/refractory multiple myeloma. CD38 is an antigen with high surface expression on multiple myeloma cells. While daratumumab holds most of the market share for this drug class, isatuximab offers several unique aspects including a mechanism of action that may involve more direct myeloma-cell inhibition and killing and less reliance on cross-linking and immune effector cells, as well as subgroup data from pivotal trials showing notable efficacy in populations with renal impairment, high-risk cytogenetics and the elderly. While the administration of the drug remains intravenous, studies of fixed-volume infusion and rapid infusion may improve drug administration convenience. Ongoing studies are examining isatuximab in combination with other immune therapies and cellular therapies, conventional chemotherapy and across other disease entities., (Copyright 2021 Clarivate Analytics.)

Since its initial approval in 2015, daratumumab has had a tremendous impact on the treatment of multiple myeloma. It is a monoclonal antibody that targets CD38, an antigen with high surface expression on multiple myeloma cells. While it initially received approval as a monotherapy for multiply relapsed multiple myeloma, its favorable toxicity profile allowed for combinations with other novel myeloma therapies leading to numerous indications as a component of triplet and quadruplet regimens. These indications now span relapsed/refractory populations and both transplant-eligible and transplant-ineligible patients with newly diagnosed myeloma. Further investigations are underway to continue to expand the reach of daratumumab, including large phase III collaborative trials to assess the efficacy of daratumumab as part of post-transplant maintenance and its impact on smoldering myeloma. The recent introduction of a subcutaneous formulation of daratumumab with proven noninferiority will improve the convenience and accessibility of the drug. In this review, we examine the preclinical development of daratumumab, its pharmacology and clinical investigations that demonstrated its safety and efficacy. Furthermore, we discuss the outstanding questions related to daratumumab and ongoing clinical trials seeking to answer them., (Copyright 2021 Clarivate Analytics.)

Objectives: This study aimed to evaluate whether the falls prevention programme Dance to Health provides the health system with an effective and cost-effective means to address the issue of older people's falls., Study Design: This study used a pre-post design; that is, the same assessment measures were used both before and after the programme., Methods: Analysis and modelling were conducted using monitoring data (frequencies including session attendance, falls, general practitioner (GP) and hospital visits), comprehensive financial information (including all costs related to the delivery of Dance to Health), and the Public Health England economic model: 'A return on investment tool for falls prevention programmes in older people based in the community'., Results: Findings from the research show that under the suggested health intervention, there was a 58% reduction in the number of falls. Furthermore, the results also demonstrate that Dance to Health offers a potential cost saving of more than £196m over a 2-year period, of which £158m is a potential cost saving for the NHS., Conclusions: The evidence outlines that Dance to Health offers the health system a cost-effective means to address the issue of older people's falls and most importantly a method that produces strong results in terms of falls prevention., (Copyright © 2021 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

We generated three human induced pluripotent stem cell (hiPSC) sublines from human dermal fibroblasts (HDF) (MZT05) generated from a skin biopsy donated from a previously fertile woman. The skin biopsy was broadly consented for generating hiPSC lines for biomedical research, including unique consent specifically for studying human fertility, infertility and germ cell differentiation. hiPSCs were reprogrammed using Sendai virus vectors and were subsequently positive for markers of self-renewal. Pluripotency was further verified using PluriTest analysis and in vitro differentiation was tested using Taqman Real-Time PCR assays. These sublines serve as controls for hiPSC research projects aimed at understanding the cell and molecular regulation of female fertility., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Three induced pluripotent stem cell sublines (hiPSCs) were generated from human dermal human dermal fibroblasts (HDFs) derived from a human skin punch biopsy. The biopsy was donated from a woman with known infertility due to ovarian failure. The hiPSC sublines were created using Sendai virus vectors and were positive for markers of self-renewal including OCT4, NANOG, TRA-1-81 and SSEA-4. Pluripotency was verified using PluriTest analysis and in vitro differentiation using Taqman Real-Time PCR assays for somatic lineage markers. This participant's monozygotic twin sister also donated a skin-punch biopsy, whose resulting hiPSC lines were published previously as a resource., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aim: To describe the birth prevalence, temporal trends, and clinical outcomes of twins, triplets, or quadruplets with cerebral palsy (CP)., Method: This was a cross-sectional study using data for twins, triplets, and quadruplets with prenatally or perinatally acquired CP and pooled from the Surveillance of Cerebral Palsy in Europe network (born 1992-2009) and Australian Cerebral Palsy Register (born 1993-2009). Children were at least 4 years old at time of registration. Children born in regions with population ascertainment and available denominator data were included in prevalence calculations (n=1033 twins, 81 triplets, and 11 quadruplets). Clinical data from children registered in all participating registers were described, including 2163 twins (56% male), 187 triplets (59% male), and 20 quadruplets (45% male)., Results: The birth prevalence of CP was higher with increasing plurality (twins 6.5 per 1000 live births [95% confidence interval {CI} 6.1-6.9], triplets 17.1 [95% CI 13.6-21.2], quadruplets 50.7 [95% CI 25.6-88.9]); however, prevalence by gestational age was similar across all pluralities. Between 1992-1994 and 2007-2009, prevalence of CP among twins declined (p=0.001) but prevalence of CP among triplets did not change significantly over time (p=0.55). The distributions of Gross Motor Function Classification System, epilepsy, and impairments of intellect, vision, and hearing were similar regardless of plurality., Interpretation: The data combined from two CP register networks indicated that triplets and quadruplets had increased risk of CP compared to twins. The higher prevalence of CP in triplets and quadruplets is due to their higher risk of preterm birth. Prevalence of CP among twins significantly declined in Europe and Australia. Clinical outcomes were similar for all multiple births., (© 2021 Mac Keith Press.)

Background: The COVID-19 pandemic resulted in significant uncertainty and disruption to many aspects of daily living, including physical activity, socialization opportunities, and access to healthcare services. Under these conditions, at-risk older adults are even more likely to be inactive and isolated, leading to potential exacerbation of musculoskeletal and chronic conditions and emotional distress. This case study provides an overview of our experience and best practices developed during our shift from onsite programming to virtual. Methodology: HSS utilized varied online approaches, including phone/video conference classes, webinars, on-demand videos and email campaigns to successfully transition programs. Due to this shift, HSS changed its evaluation to an online approach, using a mixed method to adequately assess the impact of programs. Results: Between April and August 2020, our virtual programs reached 428,766 participants, resulting in a 10,807% increase in program reach. Most participants assessed were 60 years or older (72%) and reported knowledge (85%) and self-management skills (83%) gained as well as high program satisfaction (90%). Analyses of program data did not show any statistical significant difference in self-reported health outcomes. However, qualitative results showed virtual programming helped to foster social connectivity during COVID-19, helped to build a daily routine, and positively impacted mental and physical health. Conclusion: Shifting to virtual programming in the face of the pandemic enabled us to deliver effective programs affording our community the opportunity to stay physically active and socially connected despite the quarantine orders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sanchez-Villagomez, Zurlini, Wimmer, Roberts, Trieu, McGrath, Wiesel, Ologhobo, Goldsmith and Robbins.)

Aim: To describe the major congenital anomalies present in children with postneonatally acquired cerebral palsy (CP), and to compare clinical outcomes and cause of postneonatally acquired CP between children with and without anomalies., Method: Data were linked between total population CP and congenital anomaly registers in five European and three Australian regions for children born 1991 to 2009 (n=468 children with postneonatally acquired CP; 255 males, 213 females). Data were pooled and children classified into mutually exclusive categories based on type of congenital anomaly. The proportion of children with congenital anomalies was calculated. Clinical outcomes and cause of postneonatally acquired CP were compared between children with and without anomalies., Results: Major congenital anomalies were reported in 25.6% (95% confidence interval [CI] 21.7-29.9) of children with postneonatally acquired CP. Cardiac anomalies, often severe, were common and present in 14.5% of children with postneonatally acquired CP. Clinical outcomes were not more severe in children with congenital anomalies than those without anomalies. Cause of postneonatally acquired CP differed with the presence of congenital anomalies, with cerebrovascular accidents predominating in the anomaly group. Congenital anomalies were likely associated with cause of postneonatally acquired CP in 77% of children with anomalies., Interpretation: In this large, international study of children with postneonatally acquired CP, congenital anomalies (particularly cardiac anomalies) were common. Future research should determine specific causal pathways to postneonatally acquired CP that include congenital anomalies to identify opportunities for prevention., What This Paper Adds: One-quarter of children with postneonatally acquired cerebral palsy (CP) have a major congenital anomaly. Cardiac anomalies, often severe, are the most common anomalies. Causes of postneonatally acquired CP differ between children with and without congenital anomalies., (© 2021 Mac Keith Press.)

Aim: To describe the frequency and types of major congenital anomalies present in children with pre- or perinatally acquired cerebral palsy (CP), and compare clinical outcomes for children with and without anomalies., Method: This multi-centre total population collaborative study between Surveillance of Cerebral Palsy in Europe, Australian Cerebral Palsy Register, and European Surveillance of Congenital Anomalies (EUROCAT) involved six European and three Australian regions. Data were linked between each region's CP and congenital anomaly register for children born between 1991 and 2009, and then pooled. Children were classified into mutually exclusive categories based on type of anomaly. Proportions of children with congenital anomalies were calculated, and clinical outcomes compared between children with and without anomalies., Results: Of 8201 children with CP, 22.8% (95% confidence interval [CI] 21.9, 23.8) had a major congenital anomaly. Isolated cerebral anomalies were most common (45.2%), with a further 8.6% having both cerebral and non-cerebral anomalies. Cardiac anomalies only were described in 10.5% of children and anomalies associated with syndromes were also reported: genetic (8.0%), chromosomal (5.7%), and teratogenic (3.0%). Clinical outcomes were more severe for children with CP and congenital anomalies, particularly cerebral anomalies., Interpretation: This large, international study reports major congenital anomalies in nearly one-quarter of children with pre- or perinatally acquired CP. Future research must focus on aetiological pathways to CP that include specific patterns of congenital anomalies., What This Paper Adds: Congenital anomalies were reported in 23% of children with pre- or perinatally acquired cerebral palsy. A higher proportion of children born at or near term had anomalies. The most common type of anomalies were isolated cerebral anomalies. Clinical outcomes were more severe for children with congenital anomalies (particularly cerebral)., (© 2020 Mac Keith Press.)

Six human induced pluripotent stem cell sublines (hiPSCs) were generated from human dermal fibroblasts (HDFs) derived from skin biopsies donated from monozygotic twin women wherein one woman had proven fertility and her sister was infertile due to ovarian failure. Three hiPSC sublines were created from each twin's HDFs. hiPSCs were reprogrammed using Sendai virus vectors and were subsequently positive for markers of self-renewal including OCT4, NANOG, TRA-1-81 and SSEA-4. Pluripotency was further verified using PluriTest. We show here that the hiPSC lines created from the twins are equivalent in measures of pluripotency and self-renewal, despite their differential diagnosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Congestion is the main reason for hospitalization in patients with acute decompensated heart failure and is an important target for therapy. However, achieving complete decongestion can be challenging. Furthermore, residual congestion before discharge from hospital is associated with a high risk of early rehospitalization and death. An improved understanding of the pathophysiology of congestion is of great importance in finding better and more personalized therapies. In this Review, we describe the two different forms of congestion - intravascular congestion and tissue congestion - and hypothesize that differentiating between and specifically treating these two different forms of congestion could improve the outcomes of patients with acute decompensated heart failure. Although the majority of these patients have a combination of both intravascular and tissue congestion, one phenotype can dominate. Each of these two forms of congestion has a different pathophysiology and requires a different diagnostic approach. We provide an overview of novel and established biomarkers, imaging modalities and mechanical techniques for identifying each type of congestion. Treatment with loop diuretics, the current cornerstone of decongestive treatment, reduces circulating blood volume and thereby reduces intravascular congestion. However, the osmolality of the circulating blood decreases with the use of loop diuretics, which might result in less immediate translocation of fluid from the tissues (lungs, abdomen and periphery) to the circulation when the plasma refill rate is exceeded. By contrast, aquaretic drugs (such as vasopressin antagonists) predominantly cause water excretion, which increases the osmolality of the circulating blood, potentially improving translocation of fluid from the tissues to the circulation and thereby relieving tissue congestion.

Aims: Lung congestion in patients with heart failure (HF) has traditionally been treated using interventions that reduce pulmonary capillary hydrostatic pressure. The transient receptor potential vanilloid 4 (TRPV4) channel regulates fluid transit across the pulmonary capillary-interface, and represents a novel target to reduce lung water, independent of pulmonary capillary hypertension. This pilot study examined the safety and potential efficacy of TRPV4 blockade as a novel treatment for HF., Methods and Results: In this randomized, double-blind, placebo-controlled crossover pilot trial, 11 subjects with chronic, compensated HF were treated with a novel TRPV4 antagonist (GSK2798745) or placebo. The primary endpoint was lung diffusing capacity for carbon monoxide (DL CO ) after 7 days of treatment with GSK2798745 as compared to placebo. Secondary endpoints included additional diffusion parameters, spirometry and safety assessments. Compared to placebo, treatment with GSK2798745 resulted in a trend to improvement in DL CO (placebo: -0.336 mL/mmHg/min; GSK2798745: +0.458 mL/mmHg/min; treatment difference: +0.793 mL/mmHg/min; 95% confidence interval: -0.925 to 2.512) that was not statistically significant. GSK2798745 was well-tolerated with no serious adverse events., Conclusion: In this pilot trial, GSK2798745 was found to be safe and well-tolerated, with a trend toward improved gas transfer. Further investigation is warranted in larger studies to determine whether treatment with TRPV4 antagonists or alternative treatments targeting capillary permeability might be effective to improve lung congestion, pulmonary gas transfer and clinical status in patients with acute or chronic HF., (© 2020 European Society of Cardiology.)

Introduction: Cerebral palsy (CP) describes a heterogeneous group of motor disorders resulting from disturbance in the developing brain. CP occurs in approximately 2.1 per 1000 live births in high-income countries, but in low- and middle-income countries (LMICs) the prevalence and severity of CP may be greater and aetiological risk factors different. In Sri Lanka, a LMIC, there have been no epidemiological studies of CP to date. Systematically collected data are required to identify opportunities for primary and secondary prevention, to plan and establish services to support children and adults with CP and their families and to act as a sampling frame for new research. Here we describe a pilot study protocol for a CP register in Sri Lanka., Methods and Analysis: The aim of this study is to establish a CP register in Sri Lanka. We will use different surveillance methodologies in two provinces of Sri Lanka: hospital and community surveillance in the Western Province and community surveillance in the Eastern Province. A common record form will collect demographic, clinical and service data for children with CP <18 years living in these two provinces. Data will be transferred to a secure online data repository and used to describe the epidemiology of CP in these regions. We will describe the strengths and challenges of the surveillance mechanisms and estimate the resources required for ongoing hospital and community based surveillance in the Western and Eastern provinces and to include additional provinces across the country., Ethics and Dissemination: This study has ethical clearance from The University of Kelaniya, National Health Research Council, the Institutional Ethics Review Committee of the Lady Ridgeway Hospital, Colombo South Teaching Hospital and the Director of the North Colombo Teaching Hospital. Results from this research will be disseminated through local and international conferences and through publications in peer-reviewed journals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The recent paper in JAMA alleging that frozen embryo transfer causes twice the risk of childhood cancer in the offspring is an excellent example of the erroneous use of statistical tests (and the misinterpretation of p value) that is common in much of the medical literature, even in very high impact journals. These myths backed by misleading statements of "statistical significance" can cause far-reaching harm to patients and doctors who might not understand the pitfalls of specious statistical testing.

Purpose: To determine age-adjusted overall success rates for patients undergoing clomiphene citrate only minimal stimulation cycle (mini) in vitro fertilization (IVF) without any gonadotropin administration., Methods: Eight hundred thirty-nine women (mean age: 38.4 ± 0.1 years; 2488 cycles) underwent clomiphene citrate only mini-IVF. Their first oocyte retrieval was between January 2009 and December 2009, with follow-up until December 2014. The cumulative live birth rate (CLBR) per oocyte retrieval cycle started and live birth rate per oocyte was retrospectively analyzed. The basic CLBR was calculated as the number of women who achieved a live birth divided by the total number of women who started oocyte retrieval., Results: The mean number of oocytes retrieved was 1.5. The basic CLBRs for all ages after the first and third cycles were 22.6% and 39.2%, respectively. For ≤ 34 years, 35-37 years, 38-40 years, 41-42 years, and ≥ 43 years, CLBRs after the first and third cycles were 42.5% and 70.1%, 32.9% and 49.1%, 20.0% and 38.6%, 12.6% and 25.2%, and 4.4% and 8.8%, respectively. These rates had a significant relationship with age (P < 0.01). The LBR per oocyte for all ages was 9.6%., Conclusion: Acceptable overall IVF success rates can be achieved in clomiphene citrate only mini-IVF, as well as acceptable LBR. The CLBRs and LBRs per oocyte are evidently influenced by women's age.

Although torsemide's oral bioavailability and half-life theoretically render it a more efficient diuretic than furosemide, the clinical outcomes of torsemide compared with furosemide remain unclear. We performed a systematic review and meta-analysis, including all published studies that compared torsemide and furosemide use in heart failure patients from January 1996 through August 2019. Nineteen studies (9 randomized control trials [RCTs] and 10 observational studies) with a total of 19,280 patients were included. During a mean follow-up duration of 15 months, torsemide was associated with a numerically lower risk of hospitalization due to heart failure (10.6% vs 18.4%; odds ratio [OR] 0.72, 95% confidence interval [CI] [0.51, 1.03], p = 0.07, I 2  = 18%; number needed to treat [NNT] = 23) compared with furosemide. Torsemide was associated with statistically significant more improvement in functional status from New York Heart Association (NYHA) class III/IV to I/II (72.5% vs 58%; OR 2.32, 95% CI (1.32, 4.1), p = 0.004, I 2  = 27%; NNT = 5) and lower risk of cardiac mortality (1.5% vs 4.4%; OR 0.37, 95% CI (0.20, 0.66), p <0.001, I 2  = 0%, NNT = 40) compared with furosemide. However, there was no difference in all-cause mortality or medication side effects between the 2 groups. In conclusion, compared with furosemide, torsemide use was associated with significant more improvement in functional status and lower cardiac mortality; and numerically fewer hospitalizations in patients with heart failure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Congenital anomalies are a strong risk factor for cerebral palsy, particularly for children born at term. This systematic review aimed to address gaps in our understanding of the association between congenital anomalies and cerebral palsy. Eight population-based studies (n = 10 081) were identified. Congenital anomalies were reported in 12% to 32% of children with pre/perinatal brain injury and 20% of children with postneonatal brain injury. Variation between studies included study cohort inclusion criteria and the definitions and classification of included anomalies. The most common cerebral anomalies were microcephaly and hydrocephaly, whereas circulatory system anomalies were the most common noncerebral anomalies. The proportion of congenital anomalies was higher in children born at term than preterm. Synthesizing the highest quality data published, this review identified that congenital anomalies are common in cerebral palsy. New collaborative research, addressing sources of variation, is vital to identify pathways to cerebral palsy that include specific congenital anomalies, and explore opportunities for prevention.

We generated three human induced pluripotent stem cell (hiPSC) sublines from human dermal fibroblasts (HDFs) (MZT04) generated from a skin biopsy donated from a previously fertile woman. The skin biopsy was broadly consented for generating hiPSC lines for biomedical research, including unique consent specifically for studying human fertility, infertility and germ cells. hiPSCs were reprogrammed using Sendai virus vectors and were subsequently positive for markers of self-renewal including OCT4, NANOG, TRA-1-81 and SSEA-4. Pluripotency was further verified using teratomas and PluriTest. These sublines serve as controls for hiPSC research projects aimed at understanding the cell and molecular regulation of female fertility and infertility., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)