Functional outcome after selective dorsal rhizotomy: a retrospective case control study.

PURPOSE: This study examines long-term benefit on functional outcomes and quality of life after selective dorsal rhizotomy (SDR) in children with spastic diplegia in Hong Kong. METHOD: This is a case control study. Individuals with spastic diplegia who were at 6 to 12 years post-SDR were recruited. Age, gender, cognition, and Gross Motor Function Classification System level-matched individuals with spastic diplegia who had not undergone SDR were recruited as controls. Outcome measures included physical level, functional level, physiological level, and quality of life. All data were compared by independent t-test. RESULTS: Individuals post-SDR (n = 15) demonstrated a significantly better range of ankle dorsiflexion in knee extension by - 5.7 ± 10.9° than the control group (n = 12). No other significant differences were observed. CONCLUSION: SDR is a safe, one-off procedure and provides long-term reduction in spasticity with no major complications. With the heterogeneity, we did not demonstrate between-group differences in long-term functional outcomes.

Enhanced Goat Milk MUFA Quality via Date Pit Supplementation: A Time-Based Pattern Recognition Analysis Utilizing Agricultural Waste Byproduct.

Date pits are agricultural waste byproducts and are available in tons yearly. Milk MUFAs are lipids beneficial for health and sorted out for food product development. This work is aimed at researching the effect of supplementing dairy goats with date pit powder (DPP) as a source of fatty acids (FA), an alternative to enhancing the unsaturated FA in milk and analysed via chemometrics in a 3-month supplementation-based study. Saanen-Boer crossed dairy goats were divided into six groups comprising of control, 10 g and 20 g both for Ajwa DPP (high-quality dates) and Mariami DPP (agricultural waste byproduct), and another 30 g for Mariami DPP only. The supplementation exercise was done daily on each dairy goat. The DPP and milk samples were analysed for its FA profile applying GC-FID and followed by chemometric techniques, namely, PCA and PLS. Results indicated that the n-6/n-3 ratio was the highest for the unsupplemented group compared to the DPP-treated goats with lower n-6/n-3 ratios. The M30 group showcased the most promising health-related class of FAs viewed by 3D PCA and PLS model clustering patterns, in particular monounsaturated FA (MUFA) (C18:1n9c or oleic acid). These results suggest that Mariami DPP supplementation at higher doses and time to lactating Saanen-Boer cross goats can be a means to milk FA quantity and quality enhancement and that chemometrics via pattern recognition can be useful statistical tools when dealing with overwhelming data.

Smoothing tool design and performance during subaperture glass polishing.

During subaperture tool grinding and polishing, overlaps of the tool influence function can result in undesirable mid-spatial frequency (MSF) errors in the form of surface ripples, which are often corrected using a smoothing polishing step. In this study, flat multi-layer smoothing polishing tools are designed and tested to simultaneously (1) reduce or remove MSF errors, (2) minimize surface figure degradation, and (3) maximize the material removal rate. A time-dependent convergence model in which spatial material removal varies with a workpiece-tool height mismatch, combined with a finite element mechanical analysis to determine the interface contact pressure distribution, was developed to evaluate various smoothing tool designs as a function of tool material properties, thicknesses, pad textures, and displacements. An improvement in smoothing tool performance is achieved when the gap pressure constant, h¯ (which describes the inverse rate at which the pressure drops with a workpiece-tool height mismatch), is minimized for smaller spatial scale length surface features (namely, MSF errors) and maximized for large spatial scale length features (i.e., surface figure). Five specific smoothing tool designs were experimentally evaluated. A two-layer smoothing tool using a thin, grooved IC1000 polyurethane pad (with a high elastic modulus, E p a d =360M P a), thicker blue foam (with an intermediate modulus, E f o a m =5.3M P a) underlayer, and an optimized displacement (d t=1m m) provided the best overall performance (namely, high MSF error convergence, minimal surface figure degradation, and high material removal rate).

Imaging in gynecological disease (26): clinical and ultrasound characteristics of benign retroperitoneal pelvic peripheral-nerve-sheath tumors.

OBJECTIVE: To describe the clinical and sonographic characteristics of benign, retroperitoneal, pelvic peripheral-nerve-sheath tumors (PNSTs). METHODS: This was a retrospective study of patients with a benign, retroperitoneal, pelvic PNST who had undergone preoperative ultrasound examination at a single gynecologic oncology center between 1 January 2018 and 31 August 2022. All ultrasound images, videoclips and final histological specimens of benign PNSTs were reviewed side-by-side in order to: describe the ultrasound appearance of the tumors, using the terminology of the International Ovarian Tumor Analysis (IOTA), Morphological Uterus Sonographic Assessment (MUSA) and Vulvar International Tumor Analysis (VITA) groups, following a predefined ultrasound assessment form; describe their origin in relation to nerves and pelvic anatomy; and assess the association between their ultrasound features and histotopography. A review of the literature reporting benign, retroperitoneal, pelvic PNSTs with preoperative ultrasound examination was performed. RESULTS: Five women (mean age, 53 years) with a benign, retroperitoneal, pelvic PNST were identified, four with a schwannoma and one with a neurofibroma, of which all were sporadic and solitary. All patients had good-quality ultrasound images and videoclips and final biopsy of surgically excised tumors, except one patient managed conservatively who had only a core needle biopsy. In all cases, the findings were incidental. The five PNSTs ranged in maximum diameter from 31 to 50 mm. All five PNSTs were solid, moderately vascular tumors, with non-uniform echogenicity, well-circumscribed by hyperechogenic epineurium and with no acoustic shadowing. Most of the masses were round (n = 4 (80%)), and contained small, irregular, anechoic, cystic areas (n = 3 (60%)) and hyperechogenic foci (n = 5 (100%)). In the woman with a schwannoma in whom surgery was not performed, follow-up over a 3-year period showed minimal growth (1.5 mm/year) of the mass. We also summarize the findings of 47 cases of benign retroperitoneal schwannoma and neurofibroma identified in a literature search. CONCLUSIONS: On ultrasound examination, no imaging characteristics differentiate reliably between benign schwannomas and neurofibromas. Moreover, benign PNSTs show some similar features to malignant retroperitoneal tumors. They are solid lesions with intralesional blood vessels and show degenerative changes such as cystic areas and hyperechogenic foci. Therefore, ultrasound-guided biopsy may play a pivotal role in their diagnosis. If confirmed to be benign PNSTs, these tumors can be managed conservatively, with ultrasound surveillance. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Translation and validation of Cerebral Palsy Quality of Life Questionnaire-Teen in Hong Kong Chinese population [CP QoL-Teen (HK)].

Cerebral palsy (CP) is an early onset, non-progressive, neuromotor disorder. Adolescence is the transition from childhood to adulthood when changes in physical and emotional aspects and self-perception occur further imposing an impact to quality of life (QoL) in individuals with CP. Cerebral Palsy Quality of Life (CP QoL) Teen is a questionnaire examining different domains of QoL for adolescents with CP. This study is aimed at translating and validating self-report and proxy-report CP QoL-Teen (HK). Prior approval of translation has been obtained. Forward and backward translations were performed following standardized translation procedures. Participants and their caregivers were asked to complete self-report and proxy-report CP QoL-Teen (HK), and Child Health Questionnaire (CHQ). Internal consistency and test-retest reliability were assessed by Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Concurrent validity was evaluated by Spearman's rank correlation between subscales of CP QoL-Teen (HK) and CHQ as well as expanded and revised version of Gross Motor Function Classification System (GMFCS-E&R). Ninety-six participants completed the study. Of these, twenty participants completed CP QoL-Teen (HK) twice. Cronbach's α of CP QoL-Teen (HK) ranged from 0.84 to 0.95 suggesting excellent internal consistency. Moderate to excellent test-retest reliability were demonstrated in all subscales of CP QoL-Teen (HK) (self-report: ICC = 0.46-0.8; proxy-report: ICC = 0.40-0.72, p < 0.05). Weak to moderate association between subscales of CP QoL-Teen (HK) and CHQ (self-report: rs = 0.24-0.61; proxy-report: rs = - 0.41-0.60) was reported. CONCLUSION: This study showed that CP QoL-Teen (HK) has good psychometric properties. It is a valid and reliable tool to assess quality of life of adolescents with CP. WHAT IS KNOWN: • Cerebral Palsy Quality of life-Teen (CP QoL-Teen) is a validated tool with strong psychometric properties and clinical utility in gauging the QoL in adolescents with CP during their transition from childhood to adulthood when changes in physical and emotional aspects and self-perception occur. Yet, a locally validated tool is lacking in measuring the QoL for adolescents with CP in Hong Kong. WHAT IS NEW: • The Chinese translated version CP QoL-Teen (HK) is a valid and reliable tool to assess quality of life of adolescents with CP tailoring to the local cultural and social background with good psychometric properties being demonstrated.

Susceptibility of Bacillus subtilis to Zinc Oxide Nanoparticles Treatment.

Aim: With the characteristics such as low toxicity, high total surface, ability to inhibit the growth of pathogenic microorganisms, zinc oxide nanoparticles (ZnO NPs), as one of the metallic nanoparticles, have been chosen as an antibacterial agent to treat various skin infections. The present study was aimed to determine the antibacterial potential of ZnO NPs on Bacillus subtilis, the Gram-positive bacterium that can cause skin and wound infections. Methods: B. subtilis was exposed to 5 to 150 µg/mL of ZnO NPs for 24 h. The parameters employed to evaluate the antimicrobial potential of ZnO NPs were the growth inhibitory effect on B. subtilis, the surface interaction of ZnO NPs on the bacterial cell wall, and also the morphological alterations in B. subtilis induced by ZnO NPs. Results: The results demonstrated a significant (p <0.05) inhibition of ZnO NPs on B. subtilis growth and it was in a dose-dependent manner for all the tested concentrations of ZnO NPs from 5 to 150 µg/mL at 24 h. Fourier transformed infrared (FTIR) spectrum confirmed the involvement of polysaccharides and polypeptides of bacterial cell wall in surface binding of ZnO NPs on bacteria. The scanning electron microscopy (SEM) was used to visualize the morphological changes, B. subtilis illustrated several surface alterations such as distortion of cell membrane, roughening of cell surface, aggregation and bending of cells, as well as, the cell rupture upon interacting with ZnO NPs for 24 h. Conclusion: The results indicated the potential of ZnO NPs to be used as an antibacterial agent against B. subtilis. The findings of the present study might bring insights to incorporate ZnO NPs as an antibacterial agent in the topical applications against the infections caused by B. subtilis.

Understanding the tool influence function during sub-aperture belt-on-wheel glass polishing.

The tool influence function (TIF) during sub-aperture belt-on-wheel polishing has been evaluated as a function of various process conditions (belt use/wear, dwell time, displacement, belt velocity, and wheel modulus and diameter) on fused silica glass workpieces using C e O 2 polishing media. TIF spots are circular or elliptical in shape with a largely flat bottom character. The volumetric removal rate varies significantly with belt use (or wear), stabilizing after ∼15m i n of use. A modified Preston model, where the pressure dependence is adjusted using a different scaling of the wheel modulus (E w0.5), largely predicts the volumetric removal rate over the range of process conditions evaluated. The relatively high volumetric removal rate of 30-60m m 3/h using a fixed C e O 2-in-resin-host belt offers a rapid, and hence, more economical, initial polish of aspheric and freeform optics.

Public sentiment on the global outbreak of monkeypox: an unsupervised machine learning analysis of 352,182 twitter posts.

OBJECTIVES: This study aimed to study the public's sentiments on the current monkeypox outbreaks via an unsupervised machine learning analysis of social media posts. STUDY DESIGN: This was an exploratory analysis of tweets sentiments. METHODS: We extracted original tweets containing the terms 'monkeypox', 'monkey pox' or 'monkey_pox' and posted them in the English language from 6 May 2022 (first case detected in the United Kingdom) to 23 July 2022 (when World Health Organization declared Monkeypox to be a global health emergency). Retweets and duplicate tweets were excluded from study. Bidirectional Encoder Representations from Transformers (BERT) Named Entity Recognition. This was followed by topic modelling (specifically BERTopic) and manual thematic analysis by the study team, with independent reviews of the topic labels and themes. RESULTS: Based on topic modelling and thematic analysis of a total of 352,182 Twitter posts, we derived five topics clustered into three major themes related to the public discourse on the ongoing outbreaks. These include concerns of safety, stigmatisation of minority communities, and a general lack of faith in public institutions. The public sentiments underscore growing (and existing) partisanship, personal health worries in relation to the evolving situation, as well as concerns of the media's portrayal of lesbian, gay, bisexual, transgender and queer and minority communities, which might further stigmatise these groups. CONCLUSIONS: Monkeypox is an emerging infectious disease of public concern. Our study has highlighted important societal issues, including misinformation, political mistrust and anti-gay stigma that should be sensitively considered when designing public health policies to contain the ongoing outbreaks.

Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin.

To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines. The activity of 7-O-methyl analog 7 was reduced 36-fold in OVCAR5 cells and 47-fold and A2780 cells, compared with pironetin. Phenylpironetin (4) was rapidly metabolized by mouse and human liver microsomes. We identified 17 human metabolites for phenyl analog 4 and 14 human metabolites for pironetin. Metabolism occurred at the C12-13 moiety, the α,ß-unsaturated lactone and the side chains of the molecules (C6-C11 segments). The significant extent of oxidative metabolism suggests that it may not be possible to attain a metabolically stable pironetin analog by structural modifications of the parent compound.

Impact of replacing or adding pregnancy-associated plasma protein-A at 11-13 weeks on screening for preterm pre-eclampsia.

OBJECTIVE: To assess whether pregnancy-associated plasma protein-A (PAPP-A) alters or provides equivalent screening performance as placental growth factor (PlGF) when screening for preterm pre-eclampsia (PE) at 11-13 weeks of gestation. METHODS: This was a secondary analysis of a non-intervention screening study of 6546 singleton pregnancies that were screened prospectively for preterm PE in the first trimester between December 2016 and June 2018. Patient-specific risks for preterm PE were estimated by maternal history, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), PlGF and PAPP-A. A competing-risks model with biomarkers expressed as multiples of the median was used. All women and clinicians were blinded to the risk for preterm PE. The performance of screening for preterm PE using PlGF vs PAPP-A vs both PAPP-A and PlGF was assessed by comparing areas under the receiver-operating-characteristics (AUC) curves. McNemar's test was used to compare detection rate at a fixed false-positive rate (FPR) of 10%. RESULTS: PlGF and PAPP-A were measured in 6546 women, of whom 37 developed preterm PE. The AUC and detection rate at 10% FPR using PlGF in combination with maternal history, MAP and UtA-PI were 0.854 and 59.46%, respectively. The respective values were 0.813 and 51.35% when replacing PlGF with PAPP-A and 0.855 and 59.46% when using both PAPP-A and PlGF. Statistically non-significant differences were noted in AUC when replacing PlGF with PAPP-A (ΔAUC, 0.04; P = 0.095) and when using both PAPP-A and PlGF (ΔAUC, 0.002; P = 0.423). However, on an individual case basis, screening using PlGF in conjunction with maternal history, MAP and UtA-PI identified three (8.1%) additional pregnancies that developed preterm PE and that were not identified when replacing PlGF with PAPP-A. Screening using PAPP-A in addition to maternal history and other biomarkers did not identify any additional pregnancies. CONCLUSION: On an individual case basis, adoption of a screening strategy that uses PAPP-A instead of PlGF results in reduced detection of preterm PE, consistent with previous literature. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Understanding and reducing mid-spatial frequency ripples during hemispherical sub-aperture tool glass polishing.

During sub-aperture tool polishing of glass optics, mid-spatial surface ripples are generated because of material removal non-uniformities during tool linear translation (resulting in feed ripples) and tool pathway step overlaps (resulting in pitch ripples). A variety of tool influence function (TIF) spots, trenches, and patches were created to understand and minimize such ripples on fused silica workpieces after polishing with cerium oxide slurry using a rotating hemispherical pad-foam tool. The feed ripple amplitude can be decreased by reducing the non-uniformities in the pad texture and/or by minimizing a derived feed ripple metric (rf=Vmax0.5Vf/Rt) via adjustments in processing parameters. Pitch ripples can be minimized by reducing relative step distance to spot radius ratio (xs/at) and by achieving a flat bottom trench shape cross section or by reducing the material removal per pass. Using the combined methods, an overall ripple error of ∼1.2nm rms has been achieved.

Exploring the diagnostic utility of genome sequencing for fetal congenital heart defects.

OBJECTIVE: The diagnostic yield for congenital heart defects (CHD) with routine genetic testing is around 10%-20% when considering pathogenic CNVs or aneuploidies as positive findings. This is a pilot study to investigate the utility of genome sequencing (GS) for prenatal diagnosis of CHD. METHODS: Genome sequencing (GS, 30X) was performed on 13 trios with CHD for which karyotyping and/or chromosomal microarray results were non-diagnostic. RESULTS: Trio GS provided a diagnosis for 4/13 (30.8%) fetuses with complex CHDs and other structural anomalies. Findings included pathogenic or likely pathogenic variants in DNAH5, COL4A1, PTPN11, and KRAS. Of the nine cases without a genetic etiology by GS, we had outcome follow-up data on eight. For five of them (60%), the parents chose to keep the pregnancy. A balanced translocation [46,XX,t(14; 22)(q32.33; q13.31)mat] was detected in a trio with biallelic DNAH5 mutations, which together explained the recurrent fetal situs inversus and dextrocardia that was presumably due to de novo Phelan-McDermid syndrome. A secondary finding of a BRCA2 variant and carrier status of HBB, USH2A, HBA1/HBA2 were detected in the cohort. CONCLUSIONS: GS expands the diagnostic scope of mutation types over conventional testing, revealing the genetic etiology for fetal heart anomalies. Patients without a known genetic abnormality indicated by GS likely opted to keep pregnancy especially if the heart defect could be surgically repaired. We provide evidence to support the application of GS for fetuses with CHD.

Antibiogram data from private hospitals in Hong Kong: 6-year retrospective study.

INTRODUCTION: The surveillance of antibiotic resistance is critical for the establishment of effective control strategies. The antibiotic resistance situations in private hospitals in Hong Kong have not been systematically described. The objective of the study was to analyse antibiogram data from private hospitals and describe the temporal trends of non-susceptibility percentages in this setting. METHODS: This retrospective descriptive study used antibiogram data from all private hospitals in Hong Kong that had been collected annually for 6 years (2014-2019). Data on six targeted bacteria and their corresponding multidrug-resistant organisms were included. RESULTS: The non-susceptibility percentages of isolates remained stable or decreased during the study period: methicillin-resistant Staphylococcus aureus had a stable prevalence of approximately 20%; extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species had stable prevalences of 20% to 30% and 10% to 20%, respectively; multidrug-resistant Acinetobacter species had prevalences of approximately 2% to 8%, which decreased over time; multidrug-resistant Pseudomonas aeruginosa had prevalences of 0.0% to 0.3%; Streptococcus pneumoniae penicillin and macrolide non-susceptibility percentages were 2% to 9% and 71% to 79%, respectively. These values generally were comparable with findings from public hospitals and Residential Care Homes for the Elderly in Hong Kong. However, the prevalences of carbapenem-resistant Enterobacteriaceae, which are increasing in Hong Kong and other nations, were also increasing in our dataset despite their currently low values (<1% for Escherichia coli and <2% for Klebsiella species). CONCLUSION: The antibiotic resistance landscape among private hospitals in Hong Kong is satisfactory overall; there remains a need for surveillance, antibiotic stewardship, and other infection control measures.

[Marginal features of CAD/CAM laminate veneers with different materials and thicknesses].

OBJECTIVE: To analyze the marginal roughness and marginal fitness of chairside computer-aided design and computer-aided manufacturing (CAD/CAM) laminate veneers with different materials and thicknesses, and to provide a reference for the clinical application of laminate veneers. METHODS: The butt-to-butt type laminate veneers were prepared on resin typodonts, the preparations were scanned, and the laminate veneers were manufactured by chairside CAD/CAM equipment. The laminate veneers were divided into four groups (n=9) according to the materials (glass-matrix ceramics and resin-matrix ceramics) and thickness (0.3 mm and 0.5 mm) of the veneers, with a total of 36. The marginal topo-graphies of each laminate veneer were digitally recorded by stereomicroscope, and the marginal rough-nesses of the laminate veneers were determined by ImageJ software. The marginal fitness of the laminate veneers was measured by a fit checker and digital scanning and measuring method. At the same time, the mechanical properties of glass-matrix ceramic and resin-matrix ceramic bars (n=20) were tested by a universal testing device. RESULTS: The marginal roughness of 0.3 mm and 0.5 mm glass-matrix ceramic laminate veneers was (24.48±5.55) µm and (19.06±5.75) µm, respectively, with a statistically significant difference (P < 0.001). The marginal roughness of 0.3 mm and 0.5 mm resin-matrix ceramic laminate veneers was (6.13±1.27) µm and (6.84±2.19) µm, respectively, without a statistically significant difference (P>0.05). The marginal roughness of the glass-matrix ceramic laminate veneers was higher than that of the resin-matrix ceramic laminate veneers with a statistically significant difference (P < 0.001). The marginal fitness of 0.3 mm and 0.5 mm glass-matrix ceramic laminate veneers were (66.30±26.71) µm and (85.48±30.44) µm, respectively. The marginal fitness of 0.3 mm and 0.5 mm resin-matrix ceramic laminate veneers were (56.42±19.27) µm and (58.36±8.33) µm, respectively. There was no statistically significant difference among the 4 groups (P>0.05). For glass-matrix ceramics, the flexural strength was (327.40±54.25) MPa, the flexural modulus was (44.40±4.39) GPa, and the modulus of resilience was (1.24±0.37) MPa. For resin-matrix ceramics, the flexural strength was (173.71±16.61) MPa, the flexural modulus was (11.88±0.51) GPa, and the modulus of resilience was (1.29±0.27) MPa. The flexural strength and modulus of glass-matrix ceramics were significantly higher than those of resin-matrix ceramics (P < 0.001), but there was no statistically significant difference in the modulus of resilience between the two materials (P>0.05). CONCLUSION: The marginal roughness of CAD/CAM glass-matrix ceramic laminate veneers is greater than that of resin-matrix ceramic laminate veneers, but there was no statistically significant difference in marginal fitness among them. Increasing the thickness can reduce the marginal roughness of glass-matrix ceramic laminate veneers, but has no effect on the marginal roughness of resin-matrix ceramic laminate veneers.

Cardiovascular diseases among diffuse large B-cell lymphoma long-term survivors in Asia: a multistate model study.

BACKGROUND: We modeled the clinical course of a cohort of diffuse large B-cell lymphoma (DLBCL) patients with no prior cardiovascular diseases (CVDs) using a multistate modeling framework. PATIENTS AND METHODS: Data on 2600 patients with DLBCL diagnosed between 2000 and 2018 and had received chemotherapy with or without radiotherapy were obtained from a population-wide electronic health database of Hong Kong. We used the Markov illness-death model to quantify the impact of doxorubicin and various risk factors (therapeutic exposure, demographic, comorbidities, cardiovascular risk factors, and lifestyle factors which included smoking) on the clinical course of DLBCL (transitions into incident CVD, lymphoma death, and other causes of death). RESULTS: A total of 613 (23.6%) and 230 (8.8%) of 2600 subjects died of lymphoma and developed incident CVD, respectively. Median follow-up was 7.0 years (interquartile range 3.8-10.8 years). Older ages [hazard ratio (HR) for >75 versus ≤60 years 1.88; 95% confidence interval (CI) 1.25-2.82 and HR for 61-75 versus ≤60 years 1.60; 95% CI 1.12-2.30], hypertension (HR 4.92; 95% CI 2.61-9.26), diabetes (HR 1.43; 95% CI 1.09-1.87), and baseline use of aspirin (HR 5.30; 95% CI 3.93-7.16) were associated with an increased risk of incident CVD. In a subgroup of anticipated higher-risk patients (aged 61-75 years, smoked, had diabetes, and received doxorubicin), we found that they remained on average 7.9 (95% CI 7.2-8.8) years in the DLBCL state and 0.1 (95% CI 0.0-0.4) years in the CVD state, if they could be followed up for 10 years. The brief time in the CVD state is consistent with the high chance of death in patients who developed CVD. Other causes of death have overtaken DLBCL-related death after about 5 years. CONCLUSIONS: In this Asian population-based cohort, we found that incident CVDs can occur soon after DLBCL treatment and continued to occur throughout survivorship. Clinicians are advised to balance the risks and benefits of treatment choices to minimize the risk of CVD.

Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas.

Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet loss of ATRX alone is insufficient to trigger ALT, suggesting that additional cooperating factors are involved. We identify H3.3G34R and IDH1/2 mutations as two such factors in ATRX-mutated glioblastomas. Both mutations are capable of inactivating histone demethylases, and we identify KDM4B as the key demethylase inactivated in ALT. Mouse embryonic stem cells inactivated for ATRX, TP53, TERT and KDM4B (KDM4B knockout or H3.3G34R) show characteristic features of ALT. Conversely, KDM4B over-expression in ALT cancer cells abrogates ALT-associated features. In this work, we demonstrate that inactivation of KDM4B, through H3.3G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in glioblastomas.

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis.

BACKGROUND: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. METHODS: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 µmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. FINDINGS: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016). INTERPRETATION: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. FUNDING: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.