Insulin Determines Transforming Growth Factor ß Effects on Hepatocyte Nuclear Factor 4α Transcription in Hepatocytes.

Loss of hepatocyte nuclear factor 4α (HNF4α) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasing mortality. Loss of HNF4α expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-ß. However, details of how HNF4α is suppressed are largely unknown to date. Herein, TGF-ß did not directly inhibit HNF4α but contributed to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4α promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein α (C/EBPα) binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4α expressed both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lacked either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibited C/EBPα transcription. Long-term TGF-ß incubation resulted in C/EBPα depletion, which abrogated HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter was abolished by insulin. Two-thirds of patients without C/EBPα lacked membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, these data indicate that hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.

The impact of long-term care interventions on healthcare utilisation among older persons: a scoping review of reviews.

BACKGROUND: As the ageing population grows, the demand for long-term care (LTC) services will rise, concurrently amplifying healthcare utilisation. This review aims to examine and consolidate information on LTC interventions that influence healthcare utilisation among older persons. METHODS: A scoping review was performed through a systematic search in PubMed, EBSCO CINAHL, EBM Reviews - Cochrane Database of Systematic Reviews, Embase, APA PsycInfo, EBM Reviews - Health Technology Assessment, and EBM Reviews - NHS Economic Evaluation Database. Systematic reviews with meta-analyses published between 1 January 2010 and 2 June 2022 among older persons aged 60 and above were included. The characteristics of LTC interventions were mapped to the World Health Organization (WHO) Healthy Ageing Framework. The effect sizes of healthcare utilisations for LTC interventions were recalculated using a random-effects model. The methodological quality was assessed with the AMSTAR-2 checklist, while the quality of evidence for each association was evaluated using GRADE. RESULTS: Thirty-seven meta-analyses were included. The most prominent domain of the healthy ageing framework was managing chronic conditions. One hundred twelve associations between various LTC interventions and healthcare utilisations were identified, with 22 associations impacting healthcare utilisation. Four interventions were supported by suggestive or convincing evidence. Preventive home visits were found to reduce hospital admission (OR: 0.73, 95% CI: 0.59, 0.91, p = 0.005), caregiver integration during discharge planning (OR: 0.68, 95% CI: 0.57, 0.81, p < 0.001), and continuity of care (OR: 0.76, 95% CI: 0.61, 0.95, p = 0.018) reduced hospital readmission, and perioperative geriatric interventions reduced the length of hospital stay (MD: -1.50, 95% CI: -2.24, -0.76, p < 0.001). None of the associations impacted emergency department visits, medication use, and primary care utilisations with convincing evidence. Most reviews received low methodological quality. CONCLUSION: The findings suggest that LTC interventions could benefit from transitioning to a community-based setting involving a multidisciplinary team, including carers. The spectrum of services should incorporate a comprehensive assessment to ensure continuous care.

Analysis of duration of different stages of surgery in posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) patients: comparison between severe versus non-severe AIS.

PURPOSE: Prolonged surgical duration in severe adolescent idiopathic scoliosis (AIS) patients is associated with increased blood loss and perioperative complications. The aim of this study was to compare the duration of each stage of posterior spinal fusion (PSF) in severe AIS (Cobb angle ≥ 90°) with non-severe AIS patients. This analysis will identify the most time-consuming stage of PSF and help surgeons formulate strategies to shorten operative time. METHODS: Retrospective study whereby 90 AIS patients (Lenke type 2, 3, 4, and 6) who underwent PSF from 2019 to 2023 were recruited. Twenty-five severe AIS patients were categorized in Gp1 and 65 non-severe AIS patients in Gp2. Propensity score matching (PSM) with one-to-one with nearest neighbor matching (match tolerance 0.05) was performed. Outcomes measured via operation duration of each stage of surgery, blood loss, number of screws, fusion levels and screw density. RESULTS: Twenty-five patients from each group were matched. Total operative time was significantly higher in Gp1 (168.2 ± 30.8 vs. 133.3 ± 24.0 min, p < 0.001). The lengthiest stage was screw insertion which took 58.5 ± 13.4 min in Gp1 and 44.7 ± 13.7 min in Gp2 (p = 0.001). Screw insertion contributed 39.5% of the overall increased surgical duration in Gp1. Intraoperative blood loss (1022.2 ± 412.5 vs. 714.2 ± 206.7 mL, p = 0.002), number of screws (17.1 ± 1.5 vs. 15.5 ± 1.1, p < 0.001) and fusion level (13.1 ± 0.9 vs. 12.5 ± 1.0, p = 0.026) were significantly higher in Gp1. CONCLUSION: Screw insertion was the most time-consuming stage of PSF and was significantly longer in severe AIS. Adjunct technologies such as CT-guided navigation and robotic-assisted navigation should be considered to reduce screw insertion time in severe AIS.

Optimising operating theatre (OT) efficiency while maintaining the standardised patient care in adolescent idiopathic scoliosis (AIS) surgery with the dedicated spine team approach: a specialised spine unit experience.

PURPOSE: To report the efficiency of OT utilisation and perioperative outcomes with a dedicated spine team approach in AIS patients who underwent posterior spinal fusion (PSF) surgeries in a consecutive case operation list. METHODS: Three AIS patients operated in a day (8:00 AM-8:00 PM) by a dedicated spine team were recruited between 2021 and 2022. The dedicated team comprised of three senior spine consultants who operated using a dual attending surgeon strategy, an anaesthetic consultant, dedicated surgical scrub nurses, anaesthesiology nurses, radiographers, and neuromonitoring technicians. Patients were categorised according to the sequence of operation list of the day (Case 1, Case 2, and Case 3). OT efficiency was represented by OT time in five stages (preoperative time, operative time, postoperative time, total OT time, and turnover time). OT time and perioperative outcomes were compared. RESULTS: 102 cases were analysed. On average, Case 1 began at 8:38 AM whereas Case 3 ended by 5:54 PM. OT efficiency was consistent throughout the day of operation with comparable OT time in all five stages between groups (p > 0.05). The mean turnover time was 15.1 ± 13.5 min and the mean operative time was 123.0 ± 28.1 min. Intraoperative arterial blood gas (ABG) parameters were maintained in an optimal range. The complication rate was 2.0% (N = 2/102). CONCLUSION: Consistent OT efficiency was demonstrated with a dedicated spine team approach. Despite performing three AIS cases in a consecutive case operation list, patients' safety was not compromised as perioperative outcomes between groups were comparable.

A comparison between Boston brace and European braces in the treatment of adolescent idiopathic scoliosis (AIS) patients: a systematic review based on the standardised Scoliosis Research Society (SRS) inclusion criteria for brace treatment.

PURPOSE: To compare the Boston brace and European braces using a standardised Scoliosis Research Society (SRS) inclusion criteria for brace treatment as well as consensus recommendations for treatment outcome. METHODS: This was a systematic review that was carried out using MeSH terminology in our search protocol in PubMed, Cochrane Library, Scopus, Clinicaltrials.gov and Web of Science database between 1976 and 29th of Jan 2023. All studies that were included in this review had applied fully/partially the SRS inclusion criteria for brace wear. Outcome measures were divided into primary and secondary outcome measures. RESULTS: 3830 literatures were found in which 176 literatures were deemed relevant to the study once duplicates were removed and titles and abstracts were screened. Of these literatures, only 15 had fulfilled the eligibility criteria and were included in the study. 8 of the studies were Level IV studies, 5 were Level III studies and 2 studies were Level I studies (1 prospective randomised controlled trial (RCT) and 1 Quasi-RCT). The percentage of patients who avoided surgery for European braces ranged from 88 to 100%, whereas for Boston brace ranged from 70 to 94%. When treatment success was assessed based on the final Cobb angle > 45°, approximately 15% of patients treated with European braces had treatment failure. In contrast, 20-63% of patients treated with Boston brace had curves > 45° at skeletal maturity. The BrAIST study used a cut-off point of 50° to define failure of treatment and the rate of treatment failure was 28%. Curve correction was not achieved in most patients (24-51% of patients) who were treated with the Chêneau brace and its derivatives. However, none of the patients treated with Boston brace achieved curve correction. CONCLUSION: Boston brace and European braces were effective in the prevention of surgery. In addition, curve stabilisation was achieved in most studies. Limitation in current literature included lack of studies providing high level of evidence and lack of standardisation in terms of compliance to brace as well as multidisciplinary management of brace wear.

Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure.

BACKGROUND AND AIMS: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS: Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-ß superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. CONCLUSIONS: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.

Astragalin ameliorates renal injury in diabetic mice by modulating mitochondrial quality control via AMPK-dependent PGC1α pathway.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus, and oxidative stress and mitochondrial dysfunction play an important role in this process. It has been shown that aldose reductase (ALR2) catalyzes NADPH-dependent reduction of glucose to sorbitol, resulting in oxidative stress and mitochondrial dysfunction in diabetic patients. Astragalin (AG), a flavonoid extracted from Thesium chinense Turcz., shows an inhibitory activity on ALR2. In this study, we investigated the therapeutic effects of AG against renal injury in streptozocin (STZ)-induced diabetic mouse model. Diabetic mice were orally administered AG (5, 10 mg·kg-1·d-1) for 4 weeks. We showed that AG treatment greatly improved the proteinuria and ameliorated renal pathological damage without affecting the elevated blood glucose in diabetic mice. Furthermore, AG treatment significantly suppressed highly activated ALR2, and reduced oxidative stress in the kidney of diabetic mice and in high glucose and lipids-stimulated HK2 cells in vitro. We demonstrated that AG treatment modulated mitochondrial quality control and ameliorated apoptosis, boosting mitochondrial biogenesis, maintaining mitochondrial dynamic homeostasis, and improving energy metabolism disorder in vivo and in vitro. In high glucose and lipids-stimulated HK2 cells, we found that AG (20 µM) restored the phosphorylation level of AMPK, and upregulated the expression and transcriptional activity of PGC1α, whereas treatment with H2O2, blockade of AMPK with Compound C or knockdown of AMPKα with siRNA abolished the protective effect of AG on mitochondrial function, suggesting that antioxidant effects and activation of AMPK-dependent PGC1α pathway might be the molecular mechanisms underlying the protective effects of AG on mitochondrial quality control. We conclude that AG could be a promising drug candidate for the treatment of diabetic renal injury through activating AMPK.

Prevalence and sociodemographic predictors of high-risk vaginal human papillomavirus infection: findings from a public cervical cancer screening registry.

INTRODUCTION: High-risk human papillomavirus (HPV) screening is vital for early cervical cancer detection and treatment. With the introduction of the national cervical cancer screening programme and screening registry in Malaysia, there is a need to monitor population-based HPV screening uptake and high-risk HPV prevalence as part of cervical cancer surveillance. OBJECTIVE: To determine the prevalence and sociodemographic factors predicting high-risk HPV infection in Malaysia based on a public, community-based cervical cancer screening registry targeting women at risk of getting HPV infection. METHODS: The study used data from the Malaysian cervical cancer screening registry established by the Family Health Development Division from 2019 to 2021. The registry recorded sociodemographic data, HPV test details and results of eligible women who underwent HPV screening at public primary healthcare facilities. A vaginal sample (via self-sampling or assisted by a healthcare provider) was used for DNA extraction for HPV detection and genotyping. Registry data were extracted and analysed to determine prevalence estimates of high-risk HPV infection. Multifactorial logistic regression analysis was conducted to determine predictors of high-risk HPV infection. All analyses were performed using Stata version 14. RESULTS: The programme screened a total of 36,738 women during the study period. Women who attended the screening programme were mainly from urban areas, aged 30-39 years, and of Malay ethnicity. The prevalence of high-risk HPV infection was 4.53% among women screened, with the yearly prevalence ranging from 4.27 to 4.80%. A higher prevalence was observed among urban settling women, those aged 30-49 years, those of Indian ethnicity, and those without children. The results from logistic regression showed that women from urban areas, lower age groups, of Indian or Chinese ethnicity, and who are self-employed were more likely to be infected with high-risk HPV. CONCLUSION: Targeted and robust strategies to reach identified high-risk groups are needed in Malaysia. In addition, the registry has the potential to be expanded for an improved cervical cancer elimination plan. TRIAL REGISTRATION: Trial registration number: NMRR ID-22-00187-DJU.

Erratum: Unified Approach to Polarons and Phonon-Induced Band Structure Renormalization [Phys. Rev. Lett. 129, 076402 (2022)].

This corrects the article DOI: 10.1103/PhysRevLett.129.076402.

Unified Approach to Polarons and Phonon-Induced Band Structure Renormalization.

Ab initio calculations of the phonon-induced band structure renormalization are currently based on the perturbative Allen-Heine theory and its many-body generalizations. These approaches are unsuitable to describe materials where electrons form localized polarons. Here, we develop a self-consistent, many-body Green's function theory of band structure renormalization that incorporates localization and self-trapping. We show that the present approach reduces to the Allen-Heine theory in the weak-coupling limit, and to total energy calculations of self-trapped polarons in the strong-coupling limit. To demonstrate this methodology, we reproduce the path-integral results of Feynman and diagrammatic Monte Carlo calculations for the Fröhlich model at all couplings, and we calculate the zero point renormalization of the band gap of an ionic insulator including polaronic effects.

Severe Lenke 1 and 2 adolescent idiopathic scoliosis had poorer perioperative outcome, higher complication rate, longer fusion and higher operative cost compared to non-severe scoliosis.

PURPOSE: To compare the perioperative outcome and operative cost of posterior spinal fusion (PSF) surgery between severe and non-severe Lenke 1 and 2 adolescent idiopathic scoliosis (AIS) patients. METHODS: A total of 509 AIS patients who underwent single-staged PSF between 2013 and 2020 were reviewed. Fifty-four severe scoliosis patients (Cobb angle ≥ 90°) were categorized into Gp1, and 455 non-severe scoliosis (Cobb angle < 90°) patients into Gp2. Propensity score matching (PSM) analysis using one-to-one nearest neighbor matching and match tolerance of 0.001 were performed. Outcome measures were operative time, intraoperative blood loss (IBL), allogeneic transfusion rate, perioperative complication, length of stay, fusion level, number of screws used, postoperative Cobb angle, correction rate (CR), side bending correction index (SBCI) and operative cost. RESULTS: From the PSM analysis, 35 patients from each group were matched. The operative time was 155.9 ± 41.4 and 130.0 ± 30.3 min for Gp1 and Gp2, respectively (p = 0.004). The IBL was 1349.2 ± 1019.0 and 781.9 ± 325.1 mLs for Gp1 and Gp2, respectively (p = 0.003). Fusion level (12.5 ± 0.8 vs. 11.2 ± 1.3, p < 0.001) and number of screws used (16.4 ± 1.6 vs. 14.6 ± 1.4, p < 0.001) were higher in Gp1. Four perioperative complications were observed in Gp1 compared to none in Gp2 (p < 0.039). Gp1 had larger postoperative Cobb angle (p < 0.001), lower CR (p = 0.005) and higher SBCI (p < 0.001). The operative cost was higher in Gp1 (p < 0.001). CONCLUSIONS: Severe Lenke 1 and 2 AIS patients had poorer perioperative outcome, higher complication rate, longer fusion and higher operative cost than non-severe AIS.

Healthcare provider person-centred practice: relationships between prerequisites, care environment and care processes using structural equation modelling.

BACKGROUND: The translation of person-centred care concepts into practice requires fulfilment of necessary components, including person-centred values and practice held by the employees and having a supportive system. The objectives of this study were multifold: firstly, to evaluate the measurement model, secondly, to examine the roles of prerequisite or attributes of healthcare providers and care environment and how they affect delivery of person-centred processes; and finally, to examine the mediating effect of care environment towards the relationship between prerequisite and care processes. METHODS: A cross sectional study was conducted among healthcare providers working in primary care facilities in a state in Malaysia. The Person-centred Practice Inventory-Staff instrument (PCPI-S) was distributed and completed by respondents. The instrument structure, reliability and validity were assessed through confirmatory factor analysis, while the framework's unidirectional hypothesis and the mediation path hypothesis were analysed using structural equation modelling. RESULTS: The overall goodness of fit verifies the original Person-centred Practice Framework, allowing some correlation errors. There were significant relationships between prerequisites of healthcare providers and care environment (ß = 0.826, p < 0.001), as well as between care environment and care processes (ß = 0.785, p < 0.001). This analysis also proved that care environment plays a partial mediating role in the relationship between prerequisites and care processes. CONCLUSIONS: In order to successfully move towards delivering person-centred practice, it is imperative to equip healthcare providers with person-centred values and beliefs, while at the same time transform current work culture to align with person-centred care. This will allow successful delivery of person-centred processes. TRIAL REGISTRATION: NMRR-18-309-40,447.

STAT1 is a key gene in a gene regulatory network related to immune phenotypes in bladder cancer: An integrative analysis of multi-omics data.

The immunophenotype of bladder cancer plays a pivotal role in the prognosis of cancer, but the effect of different epigenetic factors on different immunophenotypes in bladder tumours remains unclear. This study used multi-omics data analysis to provide molecular basis support for different immune phenotypes. Unsupervised cluster analysis revealed distinct subclusters with higher (subcluster B2) or lower cytotoxic immune phenotypes (subcluster A1) related to PD-L1 and IFNG expression. Mutational landscape analyses showed that the mutation level of TP53 in subcluster B1 was highest than other subclusters, and subcluster B1 had a lower frequency of concurrent mutation than subcluster A2. A total of 2364 differentially expressed genes were identified between subclusters A2 and B1, and the main functions of the up-regulated genes in subcluster B1 were enriched in the activation of T cells and other related pathways. We found that STAT1 was a key gene in a gene regulatory network related to immune phenotypes in bladder cancer. Finally, we constructed a prognostic prediction model by LASSO Cox regression which could distinguish high-risk and low-risk cases significantly. In conclusion, the present study addressed a field synopsis between genetic and epigenetic events in immune phenotypes of bladder cancer.

Predictive factors for correction rate in severe idiopathic scoliosis (Cobb angle ≥ 90°): an analysis of 128 patients.

PURPOSE: Knowledge on the factors affecting the correction rate (CR) aids in the surgical planning among severe idiopathic scoliosis (IS) patients. This study aimed to investigate the independent factors affecting CR among patients with severe IS (Cobb angle ≥ 90°) who underwent single-staged posterior spinal fusion (PSF). METHODS: We retrospectively reviewed 128 severe IS patients who underwent single-staged PSF. Factors including age, height, weight, body mass index, Risser sign, Lenke subtypes, preoperative major Cobb angle, side bending major Cobb angle, side bending flexibility (SBF), motion segments of the major curve, AR curve, number of levels fused, screw density, operative time and postoperative major Cobb angle were analysed using linear regression analysis. RESULTS: The mean age was 15.5 ± 4.5 years with mean Risser sign of 3.1 ± 1.6. The mean preoperative Cobb, SBF, postoperative Cobb and CR were 102.8 ± 12.3°, 37.5 ± 13.7%, 44.4 ± 13.5° and 57.2 ± 10.8%, respectively. From stepwise multiple linear regression analysis, SBF, Risser sign and AR curve were the independent predictive factors for CR, with R2 value of 0.345 (p < 0.001). CR can be predicted using the formula: 47.21 + (0.34 × SBF)-(1.47 × Risser sign) + (3.69 × AR), where AR = 1 and non-AR = 0. CONCLUSION: The flexibility of the major curve, Risser sign and AR curve were the most important predictors for CR in a single-staged PSF among patients with severe IS.

Mid-long-term outcome and degeneration of the remaining unfused lumbar intervertebral disc in adolescent idiopathic scoliosis patients who had posterior spinal fusion surgery.

PURPOSE: To investigate mid-long-term effects of the lowest instrumented vertebra (LIV) selection on adolescent idiopathic scoliosis (AIS) patients who had posterior spinal fusion (PSF) surgery. METHODS: Forty-eight patients were recruited. Inclusion criteria were AIS patients who have had PSF surgery more than 10 years ago. Patients were divided into G1: LIV L3 or higher and G2: LIV L4 or lower. MRI evaluation was classified using Pfirrmann grades. Pfirrmann scores were average of Pfirrmann grades for all unfused discs below LIV. SRS-22r, SF-36, Oswestry Disability Index (ODI) and Modified Cincinnati Sports Activity Scale (MCSAS) were used. RESULTS: There were 19 patients in G1 and 29 patients in G2. Demographic parameters showed no significant differences. We found no significant differences in Pfirrmann grades or scores between G1 and G2. There was significant correlation between age and mean Pfirrmann scores (r = 0.546, p < 0.001), Pfirrmann grade for adjacent disc + 1 below LIV (r = 0.475, p = 0.001) and adjacent disc below LIV (r = 0.365, p = 0.011). G2 had significantly lower scores for SRS-22r pain (G1: 4.3 ± 0.5, G2: 4.0 ± 0.6, p = 0.044) and the SF-36 bodily pain (G1: 88.7 ± 12.3, G2: 77.8 ± 18.7, p = 0.018) domains. There were no significant differences in ODI and MCSAS between the two groups. CONCLUSIONS: Patients with fusion to L4 or lower had more significant back pain. However, both groups had similar physical function, self-image, satisfaction with treatment, mental health, and functional sports activity. We did not find any significant association between lumbar discs degeneration and the selection of LIV.

Cross-cultural adaptation and exploratory factor analysis of the Person-centred Practice Inventory - Staff (PCPI-S) questionnaire among Malaysian primary healthcare providers.

BACKGROUND: The Person-centred Practice Inventory-Staff (PCPI-S) instrument was developed to measure healthcare providers' perception towards their person-centred practice. The study aimed to explore the influence of culture, context, language and local practice towards the PCPI-S instrument adaptation process for use among public primary care healthcare providers in Malaysia. METHODS: The original PCPI-S was reviewed and adapted for cultural suitability by an expert committee to ensure conceptual and item equivalence. The instrument was subsequently translated into the local Malay language using the forward-backward translation by two independent native speakers, and modified following pre-tests involving cognitive debriefing interviews. The psychometric properties of the corresponding instrument were determined by assessing the internal consistency, test-retest reliability, and correlation of the instrument, while the underlying structure was analysed using exploratory factor analysis. RESULTS: Review by expert committee found items applicable to local context. Pre-tests on the translated instrument found multiple domains and questions were misinterpreted. Many translations were heavily influenced by culture, context, and language discrepancies. Results of the subsequent pilot study found mean scores for all items ranged from 2.92 to 4.39. Notable ceiling effects were found. Internal consistency was high (Cronbach's alpha > 0.9). Exploratory factor analysis found formation of 11 components as opposed to the original 17 constructs. CONCLUSION: The results of this study provide evidence regarding the reliability and underlying structure of the PCPI-S instrument with regard to primary care practice. Culture, context, language and local practice heavily influenced the adaptation as well as interpretation of the underlying structure and should be given emphasis when translating person-centred into practice.

Perioperative outcome and complications following single-staged Posterior Spinal Fusion (PSF) using pedicle screw instrumentation in Adolescent Idiopathic Scoliosis (AIS): a review of 1057 cases from a single centre.

BACKGROUND: There has been a growing interest in using all pedicle screw construct in posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) surgery in recent years. However, studies focusing on perioperative outcome and complications utilizing only pedicle screw system in AIS population are lacking. This study aims to evaluate perioperative outcomes and to determine the prevalence of major and minor complications following single-staged PSF for AIS. METHODS: In this retrospective study of prospectively collected data, 1057 AIS patients operated between 2012 and 2019 were included. Main outcome measures were operative time, intraoperative blood loss, allogeneic blood transfusion rate, length of hospital stay after surgery, complication rate, and mean drop of haemoglobin (Hb) level. We documented the number of fusion levels, screw density, and postoperative radiographic parameters. RESULTS: There were 917 females and 140 males. Majority were Lenke 1 curve type (46.9%). Mean age was 15.6 ± 3.7 years, with mean BMI of 18.6 ± 3.2 kg/m2. Mean operative time was 146.8 ± 49.4 min. Average intraoperative blood loss was 952.9 ± 530.4 ml with allogeneic blood transfusion rate of 5%. Mean screw density was 1.27 ± 0.21 screws per fusion level. Average hospital stay after surgery was 3.5 ± 0.9 days. Twenty-four complications were documented: twelve superficial infections (1.14%), five transient neurological deficits (0.47%), two deep infections (0.19%), two superior mesenteric artery syndrome, and one case each (0.09%) for massive intraoperative blood loss, intraoperative seizure, and lung atelectasis. CONCLUSION: AIS patients treated with single-staged PSF using pedicle screw construct had a 0.95% rate of major complications and 1.32% rate of minor complications. Rate of neurologic complication was 0.47% while non-neurologic postoperative complications was 1.80% with infection being the leading complication at 1.32%.

Distinct mechanisms govern the phosphorylation of different SR protein splicing factors.

Serine-arginine (SR) proteins are essential splicing factors containing a canonical RNA recognition motif (RRM), sometimes followed by a pseudo-RRM, and a C-terminal arginine/serine-rich (RS) domain that undergoes multisite phosphorylation. Phosphorylation regulates the localization and activity of SR proteins, and thus may provide insight into their differential biological roles. The phosphorylation mechanism of the prototypic SRSF1 by serine-arginine protein kinase 1 (SRPK1) has been well-studied, but little is known about the phosphorylation of other SR protein members. In the present study, interaction and kinetic assays unveiled how SRSF1 and the single RRM-containing SRSF3 are phosphorylated by SRPK2, another member of the SRPK family. We showed that a conserved SRPK-specific substrate-docking groove in SRPK2 impacts the binding and phosphorylation of both SR proteins, and the localization of SRSF3. We identified a nonconserved residue within the groove that affects the kinase processivity. We demonstrated that, in contrast to SRSF1, for which SRPK-mediated phosphorylation is confined to the N-terminal region of the RS domain, SRSF3 phosphorylation sites are spread throughout its entire RS domain in vitro Despite this, SRSF3 appears to be hypophosphorylated in cells at steady state. Our results suggest that the absence of a pseudo-RRM renders the single RRM-containing SRSF3 more susceptible to dephosphorylation by phosphatase. These findings suggest that the single RRM- and two RRM-containing SR proteins represent two subclasses of phosphoproteins in which phosphorylation statuses are maintained by unique mechanisms, and pose new directions to explore the distinct roles of SR proteins in vivo.

Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8.

BACKGROUND & AIMS: Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about the mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. METHODS: We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription polymerase chain reaction. We studied mice in which hepatocyte-specific deletion of ß-catenin (Ctnnb1flox/flox mice injected with Adeno-associated virus serotype 8 [AAV8]-TBG-Cre) induces differentiation of LPCs into hepatocytes after a choline-deficient, ethionine-supplemented (CDE) diet. Liver tissues were collected and analyzed by immunohistochemistry and immunoblots. We performed immunohistochemical analyses of liver tissues from patients with compensated or decompensated cirrhosis or acute on chronic liver failure (n = 15). RESULTS: Loss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of ß-catenin impaired differentiation of LPCs into hepatocytes after the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis. CONCLUSIONS: Hdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury after the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.

Inelastic Electron Tunneling in 2H-Ta_{x}Nb_{1-x}Se_{2} Evidenced by Scanning Tunneling Spectroscopy.

We report a detailed study of tunneling spectra measured on 2H-Ta_{x}Nb_{1-x}Se_{2} (x=0∼0.1) single crystals using a low-temperature scanning tunneling microscope. The prominent gaplike feature, which has not been understood for a long time, was found to be accompanied by some "in-gap" fine structures. By investigating the second-derivative spectra and their temperature and magnetic field dependencies, we were able to prove that inelastic electron tunneling is the origin of these features and obtain the Eliashberg function of 2H-Ta_{x}Nb_{1-x}Se_{2} at an atomic scale, providing a potential way to study the local Eliashberg function and the phonon spectra of the related transition-metal dichalcogenides.