Distinguishing risk of curve progression in adolescent idiopathic scoliosis with bone microarchitecture phenotyping: a 6-year longitudinal study.

Low bone mineral density and impaired bone quality have been shown to be important prognostic factors for curve progression in adolescent idiopathic scoliosis (AIS). There is no evidence-based integrative interpretation method to analyze high-resolution peripheral quantitative computed tomography (HR-pQCT) data in AIS. This study aimed to (1) utilize unsupervised machine learning to cluster bone microarchitecture phenotypes on HR-pQCT parameters in girls with AIS, (2) assess the phenotypes' risk of curve progression and progression to surgical threshold at skeletal maturity (primary cohort), and (3) investigate risk of curve progression in a separate cohort of girls with mild AIS whose curve severity did not reach bracing threshold at recruitment (secondary cohort). Patients were followed up prospectively for 6.22 ± 0.33 years in the primary cohort (n = 101). Three bone microarchitecture phenotypes were clustered by fuzzy C-means at time of peripubertal peak height velocity (PHV). Phenotype 1 had normal bone characteristics. Phenotype 2 was characterized by low bone volume and high cortical bone density, and phenotype 3 had low cortical and trabecular bone density and impaired trabecular microarchitecture. The difference in bone quality among the phenotypes was significant at peripubertal PHV and continued to skeletal maturity. Phenotype 3 had significantly increased risk of curve progression to surgical threshold at skeletal maturity (odd ratio [OR] = 4.88; 95% CI, 1.03-28.63). In the secondary cohort (n = 106), both phenotype 2 (adjusted OR = 5.39; 95% CI, 1.47-22.76) and phenotype 3 (adjusted OR = 3.67; 95% CI, 1.05-14.29) had increased risk of curve progression ≥6° with mean follow-up of 3.03 ± 0.16 years. In conclusion, 3 distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT-generated bone parameters at peripubertal PHV in AIS. The bone quality reflected by these phenotypes was found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS.

Adolescent idiopathic scoliosis (AIS) is an abnormal spinal curvature that commonly presents during puberty growth. Evidence has shown that low bone mineral density and impaired bone quality are important risk factors for curve progression in AIS. High-resolution peripheral quantitative computed tomography (HR-pQCT) has improved our understanding of bone quality in AIS. It generates a large amount of quantitative and qualitative bone parameters from a single measurement, but the data are not easy for clinicians to interpret and analyze. This study enrolled girls with AIS and used an unsupervised machine-learning model to analyze their HR-pQCT data at the first clinic visit. The model clustered the patients into 3 bone microarchitecture phenotypes (ie, phenotype 1: normal; phenotype 2: low bone volume and high cortical bone density; and phenotype 3: low cortical and trabecular bone density and impaired trabecular microarchitecture). They were longitudinally followed up for 6 years until skeletal maturity. We observed the 3 phenotypes were persistent and phenotype 3 had a significantly increased risk of curve progression to severity that requires invasive spinal surgery (odds ratio = 4.88, p = .029). The difference in bone quality reflected by these 3 distinct phenotypes could aid clinicians to differentiate risk of curve progression and surgery at early stages of AIS.

Pinpoint: trajectory planning for multi-probe electrophysiology and injections in an interactive web-based 3D environment.

Targeting deep brain structures during electrophysiology and injections requires intensive training and expertise. Even with experience, researchers often can't be certain that a probe is placed precisely in a target location and this complexity scales with the number of simultaneous probes used in an experiment. Here, we present Pinpoint, open-source software that allows for interactive exploration of stereotaxic insertion plans. Once an insertion plan is created, Pinpoint allows users to save these online and share them with collaborators. 3D modeling tools allow users to explore their insertions alongside rig and implant hardware and ensure plans are physically possible. Probes in Pinpoint can be linked to electronic micro-manipulators allowing real-time visualization of current brain region targets alongside neural data. In addition, Pinpoint can control manipulators to automate and parallelize the insertion process. Compared to previously available software, Pinpoint's easy access through web browsers, extensive features, and real-time experiment integration enable more efficient and reproducible recordings.

Genetic insight into the putative causal proteins and druggable targets of osteoporosis: a large-scale proteome-wide mendelian randomization study.

Background: Osteoporosis is a major causative factor of the global burden of disease and disability, characterized by low bone mineral density (BMD) and high risks of fracture. We aimed to identify putative causal proteins and druggable targets of osteoporosis. Methods: This study utilized the largest GWAS summary statistics on plasma proteins and estimated heel BMD (eBMD) to identify causal proteins of osteoporosis by mendelian randomization (MR) analysis. Different GWAS datasets were used to validate the results. Multiple sensitivity analyses were conducted to evaluate the robustness of primary MR findings. We have also performed an enrichment analysis for the identified causal proteins and evaluated their druggability. Results: After Bonferroni correction, 67 proteins were identified to be causally associated with estimated BMD (eBMD) (p < 4 × 10-5). We further replicated 38 of the 67 proteins to be associated with total body BMD, lumbar spine BMD, femoral neck BMD as well as fractures, such as RSPO3, IDUA, SMOC2, and LRP4. The findings were supported by sensitivity analyses. Enrichment analysis identified multiple Gene Ontology items, including collagen-containing extracellular matrix (GO:0062023, p = 1.6 × 10-10), collagen binding (GO:0005518, p = 8.6 × 10-5), and extracellular matrix structural constituent (GO:0005201, p = 2.7 × 10-5). Conclusion: The study identified novel putative causal proteins for osteoporosis which may serve as potential early screening biomarkers and druggable targets. Furthermore, the role of plasma proteins involved in collagen binding and extracellular matrix in the development of osteoporosis was highlighted. Further studies are warranted to validate our findings and investigate the underlying mechanism.

Qualitative study exploring heterogeneity in caregiving experiences post-stroke in Singapore.

OBJECTIVE: Stroke, a common illness in older adults, accounts for up to 4% of direct medical costs in developed nations. Informal caregiving contributing a significant proportion of economic burden post-stroke warrants a deeper understanding of the caregiving context to sustain caregiving arrangement. While literature exists describing differences in motivation and preferences of caregivers, limited literature explores differences in caregiving experiences of different types of caregivers (ie, spouse, adult-child, sibling or others). Addressing this gap, our study aimed to explore the caregiving experience of stroke survivors and their family caregivers across different caregiver identities in an Asian setting. DESIGN: Qualitative descriptive study. SETTING: Community setting. PARTICIPANTS: We conducted semi-structured interviews with 26 stroke survivors and 35 caregivers purposively sampled from an outpatient rehabilitation setting, an outpatient clinic and a support organisation. Data were analysed using thematic analysis. OUTCOME MEASURES: Themes including caregiving experience of stroke survivors and their family caregivers across different caregiver identities. RESULTS: Following five themes were reported: caregiver reserve, coping strategies, caregiver burden, competing commitments and role of foreign domestic worker (FDW) in family caregiving. Spouse caregivers were less willing to ask for help, commonly adopted faith-based, and spacing or recharging types of coping, reported emotional strain and shared limited accounts of FDWs. Adult-child caregivers were more willing to ask for help, engaged in alternative care arrangements involving FDWs, commonly adopted action-focussed coping and reported multidimensional caregiver burden. CONCLUSION: Our findings illustrated the heterogeneity in factors affecting caregiving experience across spouse and adult-child caregivers. Practical implications include conducting a needs assessment for caregiver-stroke survivor dyads and providing tailored support, training and information to help caregivers cope better.

Abnormal morphological features of osteocyte lacunae in adolescent idiopathic scoliosis: A large-scale assessment by ultra-high-resolution micro-computed tomography.

AIM: Abnormal osteocyte lacunar morphology in adolescent idiopathic scoliosis (AIS) has been reported while the results were limited by the number of osteocyte lacunae being quantified. The present study aimed to validate previous findings through (a) comparing morphological features of osteocyte lacunae between AIS patients and controls in spine and ilium using a large-scale assessment, and (b) investigating whether there is an association between the acquired morphological features of osteocyte lacunae and disease severity in AIS. METHOD: Trabecular bone tissue of the facet joint of human vertebrae on both concave and convex sides at the apex of the scoliotic curve were collected from 4 AIS and 5 congenital scoliosis (CS) patients, and also at the same anatomic site from 3 non-scoliosis (NS) subjects intraoperatively. Trabecular bone tissue from ilium was obtained from 12 AIS vs 9 NS subjects during surgery. Osteocyte lacunae were assessed using ultra-high-resolution micro-computed tomography. Clinical information such as age, body mass index (BMI) and radiological Cobb angle of the major curve were collected. RESULTS: There was no significant difference between density of osteocyte lacuna and bone volume fraction (BV/TV) between groups. A total of 230,076 and 78,758 osteocyte lacunae from facet joints of apical vertebra of scoliotic curve and iliac bone were included in the analysis, respectively. In facet joint bone biopsies, lacunar stretch (Lc.St) was higher, and lacunar equancy (Lc.Eq), lacunar oblateness (Lc.Ob), and lacunar sphericity (Lc.Sr) were lower in AIS and CS groups when compared with NS group. CA side was associated with higher Lc.St when compared with CX side. In iliac bone biopsies, Lc.Ob was higher and lacunar surface area (Lc.S) was lower in AIS group than NS group. Median values of Lc.St, Lc.Eq and Lc.Sr were significantly associated with radiological Cobb angle with adjustment for age and BMI (R-squared: 0.576, 0.558 and 0.543, respectively). CONCLUSIONS: This large-scale assessment of osteocyte lacunae confirms that AIS osteocyte lacunae are more oblate in iliac bone that is less influenced by asymmetric loading of the deformed spine than the vertebrae. Shape of osteocyte lacunae in iliac bone is associated with radiological Cobb angle of the major curve in AIS patients, suggesting the likelihood of systemic abnormal osteocyte morphology in AIS. Osteocyte lacunae from concave side of scoliotic curves were more stretched in both AIS and CS groups, which is likely secondary to asymmetric mechanical loading.

Upregulation of microRNA-96-5p is associated with adolescent idiopathic scoliosis and low bone mass phenotype.

Bone densitometry revealed low bone mass in patients with adolescent idiopathic scoliosis (AIS) and its prognostic potential to predict curve progression. Recent studies showed differential circulating miRNAs in AIS but their diagnostic potential and links to low bone mass have not been well-documented. The present study aimed to compare miRNA profiles in bone tissues collected from AIS and non-scoliotic subjects, and to explore if the selected miRNA candidates could be useful diagnostic biomarkers for AIS. Microarray analysis identified miR-96-5p being the most upregulated among the candidates. miR-96-5p level was measured in plasma samples from 100 AIS and 52 healthy girls. Our results showed significantly higher plasma levels of miR-96-5p in AIS girls with an area under the curve (AUC) of 0.671 for diagnostic accuracy. A model that was composed of plasma miR-96-5p and patient-specific parameters (age, body weight and years since menarche) gave rise to an improved AUC of 0.752. Ingenuity Pathway Analysis (IPA) indicated functional links between bone metabolic pathways and miR-96-5p. In conclusion, differentially expressed miRNAs in AIS bone and plasma samples represented a new source of disease biomarkers and players in AIS etiopathogenesis, which required further validation study involving AIS patients of both genders with long-term follow-up.

Seeking healthcare services post-stroke: a qualitative descriptive study exploring family caregiver and stroke survivor perspectives in an asian setting.

AIM: Exploration of the healthcare journey post-stroke is incomplete without acknowledging the crucial role of family caregivers. With limited literature documenting the role of caregivers in the healthcare journey post-stroke, we aimed to describe the healthcare experiences of family caregivers and stroke survivors across different caregiver identities in Singapore. METHODS: We conducted a qualitative descriptive study involving semi-structured interviews with transcripts analysed using thematic analysis. 26 stroke survivors and 35 family caregivers purposively sampled from multiple settings. RESULTS: Findings were summarized into seeking care and experience of healthcare encounters. Seeking care comprised of the following themes: factors influencing seeking care, decision to seek care and role of caregiver in seeking care. Experience of healthcare encounters comprised of the following themes: service around the patient, service with care and role of caregiver in healthcare encounters. CONCLUSION: Multi-dimensional role of caregivers in healthcare experience emerged as a major finding. Unique to our Asian context, as per the participants' accounts, family caregivers seemed to be central in healthcare decision-making for stroke survivors, with adult-child caregivers commonly reported being engaged in collaborative decision-making. While spousal caregivers preferred a relational healthcare experience, adult-child caregivers preferred a transactional one. Practical implications include equipping caregivers with skillset to make healthcare decisions, provision of supportive decision-making environment for caregivers and reinforcing communication aspects in the medical, nursing and allied healthcare curriculum to improve healthcare experience.

Support system diversity among family caregivers of stroke survivors: a qualitative study exploring Asian perspectives.

BACKGROUND: Caregiving is a global phenomenon which is bound to increase in tandem with the aging population worldwide. Stroke is a condition common in older people that requires complex caregiving necessitating provision of adequate support to the caregivers. Past literature consists of limited accounts of types and organization of support arrangements needed by different caregivers. We aimed to describe the support system of caregivers of stroke survivors in Singapore, highlighting differences across the different caregiver identities (i.e. spouse, adult-child, etc.). METHODS: We conducted a qualitative descriptive study in the community setting involving 61 purposively sampled and recruited stroke survivors and caregivers. Semi-structured interviews were conducted, and transcripts were analysed using thematic analysis. RESULTS: Our findings were summarized across the following 4 themes: 1) cultural influence and caregiving; 2) caregiver support system with the following sub-themes: 2.1) dyadic caregiver support type, 2.2) extended caregiver support type, 2.3.) distributed caregiver support type and 2.4) empowering caregiver support type; 3) breaks in care of stroke survivor and 4) complex relationship dynamics. We operationalized the caregiver support system as comprising of type, people and activities that enable the caregiver to participate in caregiving activities sustainably. While spouse caregivers preferred dyadic and extended support systems positioning themselves in a more central caregiving role, adult-child caregivers preferred distributed support system involving family members with paid caregivers playing a more central role. CONCLUSIONS: Our findings highlight caregiver identity as a surrogate for the differences in the caregiver support systems. Practical implications include imparting relationship-building skills to the stroke survivor-caregiver dyads to sustain dyadic support system and educating clinicians to include differences in caregiving arrangements of stroke survivors in practising family-centred care.

Glioma stem cell maintenance: the role of the microenvironment.

Glioblastomas are highly lethal cancers for which conventional therapies provide only palliation. The cellular heterogeneity of glioblastomas is manifest in genetic and epigenetic variation with both stochastic and hierarchical models informing cellular phenotypes. At the apex of the hierarchy is a self-renewing, tumorigenic, cancer stem cell (CSC). The significance of CSCs is underscored by their resistance to cytotoxic therapies, invasive potential, and promotion of angiogenesis. Thus, targeting CSCs may offer therapeutic benefit and sensitize tumors to conventional treatment, demanding elucidation of CSC regulation. Attention has been paid to intrinsic cellular systems in CSCs, but recognition of extrinsic factors is evolving. Glioma stem cells (GSCs) are enriched in functional niches--prominently the perivascular space and hypoxic regions. These niches provide instructive cues to maintain GSCs and induce cellular plasticity towards a stem-like phenotype. GSC-maintaining niches may therefore offer novel therapeutic targets but also signal additional complexity with perhaps different pools of GSCs governed by different molecular mechanisms that must be targeted for tumor control.

Duration of the interval between the completion of bowel preparation and the start of colonoscopy predicts bowel-preparation quality.

BACKGROUND: Recent studies suggest that colonoscopies done in the morning have better-quality bowel preparations than those done in the afternoon. OBJECTIVE: We aimed to determine how the duration of the interval between the end of the preparation and the start of the colonoscopy affects preparation quality. DESIGN: We prospectively studied consecutive outpatients who had colonoscopies performed at our hospital within a 3-month period. The time of day when the colonoscopy started and the time interval from the last dose of preparation agent to the start of the colonoscopy were recorded. The endoscopist graded the quality of the preparation in the right side of the colon by using a 5-point visual scale. PATIENTS: We studied 378 patients (96% men, mean age 62.2 years) who received preparations of polyethylene glycol electrolyte-based (PEG) and sodium phosphate (SP) solution (71%), oral PEG and magnesium citrate (23%), or SP alone (6%). RESULTS: Compared with patients whose preparations were graded as 2/3/4 (fair/poor/inadequate), those whose preparations were graded as 0/1 (excellent/good) had a significantly shorter interval between the time of the last preparation agent dose and the start of the colonoscopy (P = .013). LIMITATIONS: We used a nonvalidated scale to assess the quality of bowel preparation. CONCLUSIONS: Bowel-preparation quality varies inversely with the duration of the interval between the last dose of the bowel-preparation agent and the start of colonoscopy. This interval appears to be a better predictor of bowel-preparation quality than the time of day when colonoscopy is performed.

Effects of consumer motives on search behavior using internet advertising.

Past studies on uses and gratifications theory suggested that consumer motives affect how they will use media and media contents. Recent advertising research has extended the theory to study the use of Internet advertising. The current study explores the effects of consumer motives on their search behavior using Internet advertising. The study employed a 2 by 2 between-subjects factorial experiment design. A total of 120 subjects were assigned to an experiment condition that contains an Internet advertisement varying by advertising appeals (i.e., rational vs. emotional) and product involvement levels (high vs. low). Consumer search behavior (measured by the depth, breadth, total amount of search), demographics, and motives were collected by post-experiment questionnaires. Because all three dependent variables measuring search behavior were conceptually related to each other, MANCOVA procedures were employed to examine the moderating effects of consumer motives on the dependent variables in four product involvement-advertising appeal conditions. Results indicated that main effects for product involvements and advertising appeals were statistically significant. Univariate ANOVA also showed that advertising appeals and product involvement levels influenced the total amount of search. Three-way interactions among advertising appeals, product involvement levels, and information motive were also statistically significant. Implications and future research directions are discussed.