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Background: Titanium has been the conventional implant material of choice for fixation in both primary and metastatic spine tumor surgeries (MSTS). However, these implants result in artifact generation during postoperative computed tomography or magnetic resonance imaging, resulting in poor planning of radiotherapy (RT) and suboptimal tumor surveillance. Carbon fiber-reinforced polyetheretherketone (CFR-PEEK) implants have gained momentum for instrumentation in MSTS due to their radiolucent properties. In this study, the perioperative outcomes, postoperative imaging artifacts, and dosimetric data of CFR-PEEK implants to titanium implants were compared to assess for potential benefits in postoperative RT planning in patients undergoing MSTS., Methods: This is a retrospective study involving 62 patients who underwent operations for MSTS. The cohort of CFR-PEEK fixations ( n = 20) was compared with a series of patients operated using titanium implants ( n = 42). Patient-related data, including demographics, tumor pathology and extent of morbidity, intraoperative data, functional outcome, and RT-related data, were recorded for both groups. Primary outcome measures for RT data were amount of artifact generated on postoperative imaging and the time taken to contour them. All patients were followed up postoperatively for a minimum of 2 years or until death, whichever was earlier., Results: Both groups had similar clinical outcomes for pain and overall survival predictability preoperatively ( P = 0.786). The mean number of levels instrumented by titanium screws was 5.69 ± 2.64, while for CFR-PEEK screws it was 4.26 ± 1.05. Mean volume of artifact generated during postoperative computed tomography was 73.4 ± 50.43 mm 3 in the titanium group and 20.0 ± 20.7 mm 3 in the CFR-PEEK group ( P < 0.001). The mean time taken to contour the artifacts was 17.3 ± 5.84 minutes in titanium group and 9.60 ± 7.17 minutes in CFR-PEEK group ( P = 0.049)., Conclusion: Our study confirms that CFR-PEEK screws significantly reduce artifact generation and the time taken to contour them during postoperative RT planning while delivering equivalent clinical and functional outcomes as compared with standard titanium implants., Competing Interests: Declaration of Conflicting Interests : The authors report no conflicts of interest in this work., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2024 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Structural variants (SVs) are significant contributors to inter-individual genetic variation associated with traits and diseases. Current SV studies using whole-genome sequencing (WGS) have a largely Eurocentric composition, with little known about SV diversity in other ancestries, particularly from Asia. Here, we present a WGS catalogue of 73,035 SVs from 8392 Singaporeans of East Asian, Southeast Asian and South Asian ancestries, of which ~65% (47,770 SVs) are novel. We show that Asian populations can be stratified by their global SV patterns and identified 42,239 novel SVs that are specific to Asian populations. 52% of these novel SVs are restricted to one of the three major ancestry groups studied (Indian, Chinese or Malay). We uncovered SVs affecting major clinically actionable loci. Lastly, by identifying SVs in linkage disequilibrium with single-nucleotide variants, we demonstrate the utility of our SV catalogue in the fine-mapping of Asian GWAS variants and identification of potential causative variants. These results augment our knowledge of structural variation across human populations, thereby reducing current ancestry biases in global references of genetic variation afflicting equity, diversity and inclusion in genetic research., (© 2024. The Author(s).)

Aims: To assess colposcopic performance and determine indicators for competency within the new Australian primary human papillomavirus (HPV) cervical screening program., Materials and Methods: A retrospective observational study of 4542 women seen at The Royal Women's Hospital Colposcopy Clinic in Melbourne, from 1 December 2017 to 31 July 2020 after a higher-risk cervical screening test (CST) result., Results: Histological CIN2+ was detected in 25.1% up to two years from first colposcopy visit (FCV). The majority (86.7%) of CIN2+ was detected early within the first six months of presentation. Biopsy rate overall was 96.1% with abnormal colposcopic impression. Of four colposcopists with a lower biopsy rate, only one was able to achieve this early detection rate. Biopsy was also taken in over 30% of cases with negative reflex cytology and normal colposcopy, with CIN2+ detected in 5.0% among positive HPV16/18 and 3.8% with non-16/18 HPV. Positive predictive value of high-grade colposcopic impression at FCV averaged 66.4% (range: 54.9-81.6% among our colposcopists) and is poorly correlated with early detection rate of CIN2+. Overall accuracy of colposcopy is 84.5% (range: 78.7-90.3%), buoyed by high true negative colposcopic predictions secondary to high rates of negative reflex cytology referral with the new screening algorithm and is also unlikely to be a useful colposcopy indicator., Conclusions: Early detection rate of CIN2+ within the first six months of presentation is a useful measure of colposcopy competency and we would encourage our National Cancer Screening Register to explore this with the participating colposcopists., (© 2024 Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Study Design: Single centre, cross-sectional study., Objectives: The objective is to report the prevalence of spondylolisthesis and retrolisthesis, analyse both conditions in terms of the affected levels and severity, as well as identify their risk factors., Methods: A review of clinical data and radiographic images of consecutive spine patients seen in outpatient clinics over a 1-month period is performed. Images are obtained using the EOS® technology under standardised protocol, and radiographic measurements were performed by 2 independent, blinded spine surgeons. The prevalence of both conditions were shown and categorised based on the spinal level involvement and severity. Associated risk factors were identified., Results: A total of 256 subjects (46.1% males) with 2304 discs from T9/10 to L5/S1 were studied. Their mean age was 52.2(± 18.7) years. The overall prevalence of spondylolisthesis and retrolisthesis was 25.9% and 17.1% respectively. Spondylolisthesis occurs frequently at L4/5(16.3%), and retrolisthesis at L3/4(6.8%). Majority of the patients with spondylolisthesis had a Grade I slip (84.3%), while those with retrolisthesis had a Grade I slip. The presence of spondylolisthesis was found associated with increased age ( P < .001), female gender (OR: 2.310; P = .005), predominantly sitting occupations (OR:2.421; P = .008), higher American Society of Anaesthesiology grades ( P = .001), and lower limb radiculopathy (OR: 2.175; P = .007). Patients with spondylolisthesis had larger Pelvic Incidence ( P < .001), Pelvic Tilt ( P < .001) and Knee alignment angle ( P = .011), but smaller Thoracolumbar junctional angle ( P = .008), Spinocoxa angle ( P = .007). Retrolisthesis was associated with a larger Thoracolumbar junctional angle ( P =.039)., Conclusion: This is the first study that details the prevalence of spondylolisthesis and retrolisthesis simultaneously, using the EOS technology and updated sagittal radiographic parameters. It allows better understanding of both conditions, their mutual relationship, and associated clinical and radiographic risk factors., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Surgical treatment is increasingly the treatment of choice in cancer patients with epidural spinal cord compression and spinal instability. There has also been an evolution in surgical treatment with the advent of minimally invasive surgical (MIS) techniques and separation surgery. This paper aims to investigate the changes in epidemiology, surgical technique, outcomes and complications in the last 17 years in a tertiary referral center in Singapore., Methods: This is a retrospective study of 383 patients with surgically treated spinal metastases treated between January 2005 to January 2022. Patients were divided into 3 groups, patients treated between 2005 - 2010, 2011-2016, and 2017- 2021. Demographic, oncological, surgical, patient outcome and survival data were collected. Statistical analysis with univariate analysis was performed to compare the groups., Results: There was an increase in surgical treatment (87 vs 105 vs 191). Lung, Breast and prostate cancer were the most common tumor types respectively. There was a significant increase in MIS(p<0.001) and Separation surgery (p<0.001). There was also a significant decrease in mean blood loss (1061ml vs 664 ml vs 594ml) (p<0.001) and total transfusion (562ml vs 349ml vs 239ml) (p<0.001). Group 3 patients were more likely to have improved or normal neurology (p=<0.001) and independent ambulatory status(p=0.012). There was no significant change in overall survival., Conclusion: There has been a significant change in our surgical practice with decreased blood loss, transfusion and improved neurological and functional outcomes. Patients should be managed in a multidisciplinary manner and surgical treatment should be recommended when indicated., 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 © 2023 Tan, Hallinan, Lee, Chan, Tan, Ang, Tan, Tan, Sin, Hey, Lau, Thambiah, Wong, Liu and Kumar.)

Study Design: Retrospective cohort study., Objective: Physicians may be deterred from operating on elderly patients due to fears of poorer outcomes and complications. We aimed to compare the outcomes of surgical treatment of spinal metastases patients aged ≥70-yrs and <70-yrs., Materials and Methods: This is a retrospective study of patients surgically treated for metastatic epidural spinal cord compression and spinal instability between January-2005 to December-2021. Follow-up was till death or minimum 1-year post-surgery. Outcomes included post-operative neurological status, ambulatory status, medical and surgical complications. Two Sample t -test/Mann Whitney U test were used for numerical variables and Pearson Chi-Squared or Fishers Exact test for categorical variables. Survival was presented with a Kaplan-Meier curve. P < .05 was significant., Results: We identified 412 patients of which 29 (7.1%) patients were excluded due to loss to follow-up and previous surgical treatment. 79 (20.6%) were ≥70-yrs. Age ≥70-yrs patients had poorer ECOG scores ( P = .0017) and Charlson Comorbidity Index ( P < .001). No significant difference in modified Tokuhashi score ( P = .393) was observed with significantly more ≥ prostate ( P < .001) and liver ( P = .029) cancer in ≥70-yrs. Improved or maintained normal neurological function ( P = .934), independent ambulatory status ( P = .171), and survival at 6 months ( P = .119) and 12 months ( P = .659) was not significantly different between both groups. Medical ( P = .528) or surgical ( P = .466) complication rates and readmission rates ( P = .800) were similar., Conclusion: ≥70-yrs patients have comparable outcomes to <70-yr old patients with no significant increase in complication rates. Age should not be a determining factor in deciding surgical management of spinal metastases., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Minimally invasive spine surgery (MIS) has revolutionized fixation of thoracolumbar fractures with burst elements. Recent studies have proven that percutaneous pedicle screw instrumentation is as effective as open instrumentation but with reduced intraoperative blood loss and operative duration. Techniques such as short-segment pedicle screw fixation including the fractured vertebra have shown satisfactory radiological correction and functional outcomes, avoiding the need for extensile posterior constructs., Objective: In the present study, the authors our technique utilizing unipedicular index vertebra fixation and manipulation in MIS for thoracolumbar fractures with burst elements. To our knowledge, this technique is not well described in literature as open approaches are often adopted for the above. The authors sought to highlight the 2-year radiological and functional outcomes of 20 consecutive patients who underwent this technique., Methods: A retrospective review of prospectively collected data was conducted on 20 patients with thoracolumbar fractures with burst elements who underwent fixation using our technique. Patient data collected included demographic characteristics, mechanism of injury, associated injuries, neurological deficit at the time of admission, pre- and postoperative neurological evaluation, and length of hospital stay. Radiological investigations included plain radiographs, computed tomography of the spine with reconstruction, and magnetic resonance imaging of the spine, which provided data for radiological fracture classifications such as AO Spine and derivation of Thoracolumbar Injury Classification and Severity Score, as well as preoperative planning. Radiological investigations in the postoperative period were carried out by standing radiographs or EOS whole spine at each postoperative follow-up for up to 2 years. Radiological parameters-vertebral wedge angle, regional kyphosis angle, coronal Cobb angle, and anterior and posterior vertebral body heights-were recorded at preoperative, intraoperative, postoperative, and up to 2-year follow-up. Clinical outcome scores (visual analog score [VAS] and Oswestry Disability Index [ODI]) were also recorded at similar timepoints., Results: Radiological outcomes reflect significant lordotic corrections of the vertebral wedge angles up to 2-year follow-up when compared with preoperative values (intraoperative: P = 0.06; postoperative: P = 0.001; 3 months: P = 0.002; 6 months: P = 0.004; 1 year: P = 0.011; 2 years: P = 0.016). Additionally, significant lordotic corrections of regional kyphosis angles (intraoperative: P = 0.00; postoperative: P = 0.00; 3 months: P = 0.031; 6 months: P = 0.039) and increases in anterior vertebral body heights (postoperative: P = 0.001; 3 months: P = 0.010; 6 months: P = 0.020) at up to 6-month follow-up were found. Preoperatively, median VAS of 85 (range 30-100) and ODI of 90 (range 40-98) were recorded. Statistically significant improvements in VAS and ODI were found across all timepoints when compared with preoperative values, with a mean VAS of 11.5 (SD 4.8) and ODI of 9.9 (SD 4.5) at 2-year follow-up., Conclusion: Surgical management of thoracolumbar fractures with or without neurological deficit has a role in reducing nursing requirements and postoperative morbidity in patients with polytrauma and other associated injuries. Our approach in treating thoracolumbar fractures with burst elements using MIS short-segment fixation and unipedicular screw manipulation technique shows satisfactory radiological correction and high rates of fracture union while reducing approach-related morbidity and improving functional outcomes., Competing Interests: Declaration of Conflicting Interests : The authors report no conflicts of interest in this work., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2023 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Aims: To examine outcomes in women aged 50-74 years after detection of oncogenic human papillomavirus (HPV) at cervical screening., Materials and Methods: A retrospective observational study of 464 women seen in the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020, 292 (62.9%) were positive for HPV16/18 and 172 (37.1%) for HPV (not 16/18)., Results: Fifty-four women (11.6%) had histologically proven CIN2+ including seven cancers, up to two years after first colposcopy visit (FCV): 48 (88.9%) detected at FCV or at excisional treatment (Excision) arranged after no CIN2+ detected at FCV. There was no significant difference (P = 0.14) in proportion of CIN2+ detected between the two groups, 'HPV16/18' (9.9%) or 'HPV (not 16/18)' (14.5%), nor with reflex cytology types. The positive predictive value (PPV) of high-grade impression at colposcopy was 63.6%. There were 243 (52.4%) who had Type 3 transformation zone (TZ3) with 20 CIN2+ detected, 13 at FCV including all three cancers and five at Excision. There were 214 (73.3%) with positive HPV16/18 who had reflex negative cytology, of which seven had CIN2+ including one cancer but only two (1.4%) CIN2+ when their repeat cytology at colposcopy was negative., Conclusions: Most CIN2+ were detected at first colposcopy or at subsequent excision. We would encourage high biopsy rates at colposcopy and vigilance in selection for excisional treatment in TZ3 cases if there is no significant suspicion of high-grade abnormality. There is a need to refine the algorithm for management of persistent HPV16/18 infections with reflex negative cytology to reduce colposcopy referrals in women aged 50 and above., (© 2023 Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Balancing disciplinary knowledge and practical reasoning in problem solving is needed for meaningful learning. In STEM problem solving, science subject matter with associated practices often appears distant to learners due to its abstract nature. Consequently, learners experience difficulties making meaningful connections between science and their daily experiences. Applying Dewey's idea of practical and science inquiry and Bereiter's idea of referent-centred and problem-centred knowledge, we examine how integrated STEM problem solving offers opportunities for learners to shuttle between practical and science inquiry and the kinds of knowledge that result from each form of inquiry. We hypothesize that connecting science inquiry with practical inquiry narrows the gap between science and everyday experiences to overcome isolation and fragmentation of science learning. In this study, we examine classroom talk as students engage in problem solving to increase crop yield. Qualitative content analysis of the utterances of six classes of 113 eighth graders and their teachers were conducted for 3 hours of video recordings. Analysis showed an almost equal amount of science and practical inquiry talk. Teachers and students applied their everyday experiences to generate solutions. Science talk was at the basic level of facts and was used to explain reasons for specific design considerations. There was little evidence of higher-level scientific conceptual knowledge being applied. Our observations suggest opportunities for more intentional connections of science to practical problem solving, if we intend to apply higher-order scientific knowledge in problem solving. Deliberate application and reference to scientific knowledge could improve the quality of solutions generated., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

Asian populations are under-represented in human genomics research. Here, we characterize clinically significant genetic variation in 9051 genomes representing East Asian, South Asian, and severely under-represented Austronesian-speaking Southeast Asian ancestries. We observe disparate genetic risk burden attributable to ancestry-specific recurrent variants and identify individuals with variants specific to ancestries discordant to their self-reported ethnicity, mostly due to cryptic admixture. About 27% of severe recessive disorder genes with appreciable carrier frequencies in Asians are missed by carrier screening panels, and we estimate 0.5% Asian couples at-risk of having an affected child. Prevalence of medically-actionable variant carriers is 3.4% and a further 1.6% harbour variants with potential for pathogenic classification upon additional clinical/experimental evidence. We profile 23 pharmacogenes with high-confidence gene-drug associations and find 22.4% of Asians at-risk of Centers for Disease Control and Prevention Tier 1 genetic conditions concurrently harbour pharmacogenetic variants with actionable phenotypes, highlighting the benefits of pre-emptive pharmacogenomics. Our findings illuminate the diversity in genetic disease epidemiology and opportunities for precision medicine for a large, diverse Asian population., (© 2022. The Author(s).)

Background: Long non-coding RNAs (lncRNAs) are involved in the development of hepatocellular carcinoma (HCC). We aimed to investigate the function of LINC01146 in HCC., Methods: The expression of LINC01146 in HCC tissues was explored via The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and was verified using quantitative real-time polymerase chain reaction (qRT-PCR) in our HCC cohort. Kaplan-Meier analysis was used to assess the relationship between LINC01146 and the prognosis of HCC patients. Cell Counting Kit 8, colony formation assays, Transwell assays, flow cytometric assays, and tumour formation models in nude mice were conducted to reveal the effects of LINC01146 on HCC cells both in vitro and in vivo. Bioinformatic methods were used to explore the possible potential pathways of LINC01146 in HCC., Results: LINC01146 was significantly decreased in HCC tissues compared with adjacent normal tissues and was found to be related to the clinical presentations of malignancy and the poor prognosis of HCC patients. Overexpression of LINC01146 inhibited the proliferation, migration, and invasion of HCC cells in vitro, while promoting their apoptosis. In contrast, downregulation of LINC01146 exerted the opposite effects on HCC cells in vitro. In addition, overexpression of LINC01146 significantly inhibited tumour growth, while downregulation of LINC01146 promoted tumour growth in vivo. Furthermore, the coexpressed genes of LINC01146 were mainly involved in the "metabolic pathway" and "complement and coagulation cascade pathway"., Conclusion: LINC01146 expression was found to be decreased in HCC tissues and associated with the prognosis of HCC patients. It may serve as a cancer suppressor and prognostic biomarker in HCC., (© 2021. The Author(s).)

Background: Circular RNAs (circRNAs) have been demonstrated to be closely related to the carcinogenesis of human cancer in recent years. However, the molecular mechanism of circRNAs in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. We aimed to identify critical circRNAs and explore their potential regulatory network in HCC. Methods: The robust rank aggregation (RRA) algorithm and weighted gene co-expression network analysis (WGCNA) were conducted to unearth the differentially expressed circRNAs (DEcircRNAs) in HCC. The expression levels of DEcircRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). A circRNA-miRNA-mRNA regulatory network was constructed by computational biology, and protein-protein interaction (PPI) network, functional enrichment analysis, survival analysis, and infiltrating immune cells analysis were performed to uncover the potential regulatory mechanisms of the network. Results: A total of 22 DEcircRNAs were screened out from four microarray datasets (GSE94508, GSE97332, GSE155949, and GSE164803) utilizing the RRA algorithm. Meanwhile, an HCC-related module containing 404 circRNAs was identified by WGCNA analysis. After intersection, only four circRNAs were recognized in both algorithms. Following qRT-PCR validation, three circRNAs (hsa&#95;circRNA&#95;091581, hsa&#95;circRNA&#95;066568, and hsa&#95;circRNA&#95;105031) were chosen for further analysis. As a result, a circRNA-miRNA-mRNA network containing three circRNAs, 17 miRNAs, and 222 mRNAs was established. Seven core genes ( ESR1 , BUB1 , PRC1 , LOX , CCT5 , YWHAZ , and DDX39B ) were determined from the PPI network of 222 mRNAs, and a circRNA-miRNA-hubgene network was also constructed. Functional enrichment analysis suggested that these seven hub genes were closely correlated with several cancer related pathways. Survival analysis revealed that the expression levels of the seven core genes were significantly associated with the prognosis of HCC patients. In addition, we also found that these seven hub genes were remarkably related to the infiltrating levels of immune cells. Conclusion: Our research identified three pivotal HCC-related circRNAs and provided novel insights into the underlying mechanisms of the circRNA-miRNA-mRNA regulatory network in HCC., 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 © 2022 Mo, Liu, Luo, Tan, Zeng, Zeng, Huang, Li, Liu and Qiu.)

Aim: To examine outcomes in women following cervical screening detection of oncogenic human papillomavirus (HPV), with reflex cytology showing possible high-grade squamous intraepithelial lesion (pHSIL)., Materials and Methods: A retrospective observational study of 523 women seen in the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020., Results: Two hundred eighty-two (53.9%) women had histology-confirmed HSIL, encompassing CIN2 or worse (CIN2+), including seven cancers (1.3%) and two adenocarcinoma in situ (AIS) (0.4%). In 81.2% (229/282) of women with CIN2+, this was detected on cervical biopsy at initial colposcopy, with another 8.9% (25/282) of CIN2+ detected at cervical excision following initial colposcopy and the remaining 9.9% (28/282) at follow-up colposcopy thereafter. When discordant cervical biopsy results were discussed at multidisciplinary meeting (MDM), 66.7% of women with pHSIL cytology upgraded to definite HSIL were found to have CIN2+, but only 20.8% when pHSIL cytology was retained and none when downgraded to low-grade (LSIL) or normal. No significant difference was found in the proportion of CIN2+ based on patient age above or below 40, HPV16 and/or 18 versus non 16/18, or whether discordant findings were reviewed at MDM., Conclusions: We propose a pathway for management of women with positive oncogenic HPV and reflex pHSIL cytology. MDM review is recommended when CIN2+ is not identified on cervical biopsy at initial colposcopy. Conservative management is safe with low risk of CIN2+ when LBC prediction of pHSIL is confirmed or downgraded at MDM with no high-grade change on colposcopy or repeat cytology., (© 2021 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Primary human papillomavirus (HPV) screening was introduced in Australia in December 2017., Aims: Outcomes for women after positive HPV in their cervical screening test (CST)., Materials and Methods: A retrospective observational study of 4458 women seen at the Royal Women's Hospital Colposcopy Clinic from 1 January 2018 to 31 July 2020., Results: HPV16/18 was positive (considered higher-risk CST) in 42.2% of women in the study, 16.6% with reflex possible with high-grade squamous intraepithelial lesions (pHSIL) or worse and 54.9% with normal cytology. There were 24.8% of women with positive HPV16/18 who had histological confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+), 10.3% CIN2+ (including six cancers) among women with reflex negative cytology and 87.7% CIN2+ among women with reflex HSIL cytology. In women with positive HPV (not 16/18), CIN2+ was found in 60.2% with reflex pHSIL or worse cytology (higher risk) and 10.2% with reflex low-grade SIL (LSIL) or normal cytology (intermediate risk). Median waiting time to colposcopy with the intermediate-risk group went up to 181 days. Our colposcopists were able to achieve a positive predictive value (PPV) for CIN2+ of 69.9%, higher than 57.8% PPV in the National Cervical Screening Program (NCSP) 2020 monitoring report. Women with type 3 transformation zone on colposcopy could be followed up with CST if no HSIL was suspected on screening or at colposcopy as their risk of CIN2+ was only 2.5%., Conclusions: Our findings support direct referral to colposcopy for women with higher-risk CST, with all cancers confined to this group. The NCSP recommendation to refer for colposcopy only after three intermediate-risk CST will need monitoring with the LSIL triage group., (© 2021 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background Context: Ossification of the posterior longitudinal ligament (OPLL) is a progressive, debilitating disease most commonly affecting the cervical spine. When compared to other degenerative pathologies, OPLL procedures carry a significantly higher risk of complications owing to increased case complexity and technical difficulties. Most previous studies have focused on functional outcomes and few have reported on risk factors for postoperative complications in OPLL patients., Purpose: To identify clinical and radiological risk factors of surgical complications following treatment for cervical OPLL STUDY DESIGN: Retrospective review PATIENT SAMPLE: One hundred thirty-one patients with cervical myelopathy secondary to OPLL who underwent surgical decompression with complete 2-year follow-up., Outcome Measures: Surgical and medical postoperative complications were analyzed. Revision surgery rates and mortality rates were recorded., Methods: Clinical, surgical, and radiological characteristics were collected for each patient. Complications within 30 days were identified. Univariate and multivariate analysis were performed to identify risk factors for surgical complications., Results: There were 39 (29.8%) surgical complications in the cohort, which included C5 palsy (7.6%), dural tear (3.1%), surgical site infection (3.1%), and epidural hematoma (1.5%). 2-year revision and mortality rates were 4.6% and 2.3%, respectively. Univariate analysis revealed that blood loss ≥750mL (OR 3.42, p=0.028), operative duration ≥5.5 hours (OR 3.16, p=0.008), hill-type OPLL (OR 3.08, p=0.011), K-line (-) OPLL (OR 5.39, p<0.001), and presence of a double-layer sign (OR 3.79, p=0.002) were significant risk factors. In multivariate analysis, only hill-type OPLL (OR 2.61, p=0.048) and K-line (-) OPLL (OR 2.98, p=0.031) were found to be significant. Patients with both hill-type and K-line (-) OPLL had a 3.5 times risk of developing surgical complications (p=0.009)., Conclusions: Patients with OPLL have a higher risk of perioperative surgical complications if they had a hill-shaped OPLL and K-line (-) OPLL on preoperative imaging studies. To the best of the authors' knowledge, this study is the first to link hill-type and K-line (-) OPLL morphology as risk factors for perioperative surgical complications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Single cell genomics offers an unprecedented resolution to interrogate genetic heterogeneity in a patient's tumour at the intercellular level. However, the DNA yield per cell is insufficient for today's sequencing library preparation protocols. This necessitates DNA amplification which is a key source of experimental noise. We provide an evaluation of two protocols using micro-fluidics based amplification for whole exome sequencing, which is an experimental scenario commonly used in single cell genomics. The results highlight their respective biases and relative strengths in identification of single nucleotide variations. Towards this end, we introduce a workflow SoVaTSiC, which allows for quality evaluation and somatic variant identification of single cell data. As proof of concept, the framework was applied to study a lung adenocarcinoma tumour. The analysis provides insights into tumour phylogeny by identifying key mutational events in lung adenocarcinoma evolution. The consequence of this inference is supported by the histology of the tumour and demonstrates usefulness of the approach., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Study Design: A cross-sectional study on a randomly selected prospective cohort of patients presenting to a single tertiary spine center., Objective: The aim of this study was to describe the clinical and radiographic parameters of patients with S- and C-shaped thoracolumbar sagittal spinal profiles, and to identify predictors of these profiles in a natural, relaxed sitting posture., Summary of Background Data: Sagittal realignment in adult spinal deformity surgery has to consider the sitting profile to minimize the risks of junctional failure. Persistence of an S-shaped sagittal profile in the natural, relaxed sitting posture may reflect a lesser need to accommodate for this posture during surgical realignment., Methods: Consecutive patients with low back pain underwent whole body anteroposterior and lateral radiographs in both standing and sitting. Baseline clinical data of patients and radiographic parameters of both standing and sitting sagittal profiles were compared using χ, unpaired t tests, and Wilcoxon rank-sum test. Subsequently, using stepwise multivariate logistic regression analysis, predictors of S-shaped curves were identified while adjusting for confounders., Results: Of the 120 patients included, 54.2% had S-shaped curves when sitting. The most common diagnoses were lumbar spondylosis (26.7%) and degenerative spondylolisthesis (26.7%). When comparing between patients with S- and C-shaped spines in the sitting posture, only diagnoses of degenerative spondylolisthesis (odds ratio [OR], 5.44; P = 0.01) and degenerative scoliosis (OR, 2.00; P = 0.039), and pelvic incidence (PI) >52.5° (OR, 5.48; P = 0.008), were predictive of an S-shaped sitting sagittal spinal alignment on multivariate analysis., Conclusion: Stiffer lumbar curves (eg, patients with degenerative spondylolisthesis and degenerative scoliosis) or those who have a predilection for an S-shaped standing sagittal profile when sitting (eg, high PI) may be more amenable to fusion in accordance with previously studied sagittal realignment targets. In contrast, more flexible curves may benefit from less aggressive lordotic realignment to prevent potential junctional failures., Level of Evidence: 3.

Background: Colposcopy has been recommended for all women with recurrent post-coital bleeding (PCB) even if their cervical cytology or co-test (involving oncogenic human papillomavirus (HPV) DNA testing and cytology) are negative., Aims: To determine the risk of cervical cancer and its precursors among women with recurrent PCB with negative cytology or co-test., Materials and Methods: A retrospective analysis of two cohorts of women with PCB referred to a tertiary colposcopy clinic. Cohort (1) (n = 1846) between 1 January 2000 and 31 December 2016 (cytology-based screening) and Cohort (2) (n = 215) from 1 January 2018 to 31 December 2019 after introduction of primary HPV screening., Results: In 1217 (65.9%) women in Cohort (1) referred with negative cytology, there was one cancer (0.08%) and 22 high-grade squamous intraepithelial lesions (HSIL (cervical intraepithelial neoplasia 2/3)) on histopathology. In Cohort (2), there was no cancer or HSIL in 83 women with negative co-tests (negative for oncogenic HPV and cytology). False-negative cytology after a negative referral cytology or co-test was low with 2% of repeat cytology at initial colposcopy showing possible HSIL or worse., Conclusions: Women presenting with PCB and negative cytology alone have a low risk of cancer and could have HPV testing before being triaged to colposcopy. We showed that with the assurance of a negative co-test and the low likelihood of false-negative cytology, these women could avoid colposcopy unless cervical cancer is clinically suspected. There is a need for a larger cohort study to substantiate our findings with more precision., (© 2020 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP., (© 2020 by The American Society of Hematology.)

Background: Test of Cure (ToC), a combination of testing for oncogenic human papillomavirus (HPV) and cytology, at 12 months post-treatment and annually thereafter, was approved in Australia in 2005 for follow-up of women treated for high-grade squamous intraepithelial lesions (HSIL) of the cervix., Aims: To determine among women resident in Victoria, Australia, the compliance with ToC and the incidence of recurrence up to five years after successful ToC., Materials and Methods: A retrospective analysis of women with HSIL (diagnosed at pre-treatment punch biopsy or at excision) who had excisional treatment between 1 January 2007 and 31 December 2011. De-identified data were retrieved from the Victorian Cervical Cytology Registry in Melbourne as at 24 April, 2015. Successful ToC is defined as the occurrence of two consecutive normal (negative) co-tests. Recurrence after treatment is defined by histologically detected HSIL or greater., Results: There were 8478 women who had excisional treatment for HSIL, with 448 (5.5%) experiencing recurrence. Only 2253 (26.6%) women successfully completed ToC, with a decreasing likelihood of ToC completion by time since year of treatment (32.0% in 2007 compared with 20.9% in 2011). Only one (0.08%) woman had HSIL on histology after successful ToC. From the 2007 cohort, 555 (32.0%) women completed ToC successfully and no HSIL recurrence occurred thereafter (median subsequent follow-up period of 4.7 years)., Conclusions: Our study confirmed that women who successfully complete ToC can be returned to five-year routine screening. However, more concerted efforts are needed to ensure that all women treated complete ToC., (© 2020 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Simultaneous identification of multiple single genes and multi-gene prognostic signatures with higher efficacy in liver cancer has rarely been reported. Here, 1,173 genes potentially related to the liver cancer prognosis were mined with Coremine, and the gene expression and survival data in 370 samples for overall survival (OS) and 319 samples for disease-free survival (DFS) were retrieved from The Cancer Genome Atlas. Numerous survival analyses results revealed that 39 genes and 28 genes significantly associated with DFS and OS in liver cancer, including 18 and 12 novel genes that have not been systematically reported in relation to the liver cancer prognosis, respectively. Next, totally 9,139 three-gene combinations (including 816 constructed by 18 novel genes) for predicting DFS and 3,276 three-gene combinations (including 220 constructed by 12 novel genes) for predicting OS were constructed based on the above genes, and the top 15 of these four parts three-gene combinations were selected and shown. Moreover, a huge difference between high and low expression group of these three-gene combination was detected, with median survival difference of DFS up to 65.01 months, and of OS up to 83.57 months. The high or low expression group of these three-gene combinations can predict the longest prognosis of DFS and OS is 71.91 months and 102.66 months, and the shortest is 6.24 months and 13.96 months. Quantitative real-time polymerase chain reaction and immunohistochemistry reconfirmed that three genes F2, GOT2 , and TRPV1 contained in one of the above combinations, are significantly dysregulated in liver cancer tissues, low expression of F2, GOT2 , and TRPV1 is associated with poor prognosis in liver cancer. Overall, we discovered a few novel single genes and multi-gene combinations biomarkers that are closely related to the long-term prognosis of liver cancer, and they can be potential therapeutic targets for liver cancer., (Copyright © 2020 Liu, Liu, Liu, Xiao, Guo, Qin, Wu, Liang, Liang, Li, Zhang, Yang, Luo, Lei, Tan, Yin and Zeng.)

Background: Adenocarcinoma in situ of cervix is increasingly managed by local excision rather than hysterectomy and this study will ascertain if conservative management by excision alone is adequate., Aims: To evaluate the long-term outcomes of conservative management of adenocarcinoma in situ of cervix, particularly in relation to excisional margin status., Materials and Methods: Retrospective analysis of women diagnosed with adenocarcinoma in situ and their management between 1992 and 2010 retrieved from the Victorian Cervical Cytology Registry, Australia. Failure of conservative treatment is defined by histologically proven adenocarcinoma in situ or adenocarcinoma at follow-up after negative excisional margins., Results: adenocarcinoma in situ of the cervix was managed primarily with cold knife cone biopsy or loop electrosurgical excision of the cervix. Most excisions were in one piece (83.4%) with average depth of 16.1 mm and 21.9% had involved excisional margins. Women with adenocarcinoma in situ on any excisional margin were more likely to have residual or recurrent disease (28.7%) compared with negative excisional margins (4.3%). Residual adenocarcinoma in situ was twice as common if adenocarcinoma in situ was present at endocervical (29.6%) and stromal (23.1%) margins compared with an ectocervical margin (13.6%). Cancer incidence at follow-up was 2.3% for women with positive excisional margins compared to 1.3% with negative margins., Conclusions: Women with adenocarcinoma in situ of cervix can be managed with local excisional procedures, best in single pieces to provide the important information on excisional margins. Adenocarcinoma in situ at endocervical and stromal excisional margins needs re-excision or where appropriate, hysterectomy, while negative excisional margins have a low rate of recurrence and can be followed up with test of cure., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

We present five patients with vibrio necrotising fasciitis, a lethal and disabling disease. Two of these patients had a history of exposure to either warm seawater or raw/live seafood, three had underlying chronic liver disease, and four presented with hypotension and fever. There were three deaths and four patients required intensive care unit stays. Among the two survivors, one had high morbidity. Only one patient met the criteria of Laboratory Risk Indicator for Necrotising Fasciitis score > 6. A clinician should suspect possible vibrio necrotising fasciitis if the following are present: contact with fresh seafood/warm seawater, a known history of chronic liver disease and pain that is out of proportion to cutaneous signs. All patients must be managed via intensive care in high dependency units. We recommend a two-step surgical protocol for patient management involving an initial local debridement, followed by a second-stage radical debridement and skin grafting., (Copyright: © Singapore Medical Association.)

Androgenetic alopecia (AGA) is a common heritable and androgen-dependent hair loss condition in men. Twelve genetic risk loci are known to date, but it is unclear which genes at these loci are relevant for AGA. Dermal papilla cells (DPCs) located in the hair bulb are the main site of androgen activity in the hair follicle. Widely used monolayer-cultured primary DPCs in hair-related studies often lack dermal papilla characteristics. In contrast, immortalized DPCs have high resemblance to intact dermal papilla. We derived immortalized human DPC lines from balding (BAB) and non-balding (BAN) scalp. Both BAB and BAN retained high proportions of dermal papilla signature gene and versican protein expression. We performed expression analysis of BAB and BAN and annotated AGA risk loci with differentially expressed genes. We found evidence for AR but not EDA2R as the candidate gene at the AGA risk locus on chromosome X. Further, our data suggest TWIST1 (twist family basic helix-loop-helix transcription factor 1) and SSPN (sarcospan) to be the functionally relevant AGA genes at the 7p21.1 and 12p12.1 risk loci, respectively. Down-regulated genes in BAB compared to BAN were highly enriched for vasculature-related genes, suggesting that deficiency of DPC from balding scalps in fostering vascularization around the hair follicle may contribute to the development of AGA., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)