Mfsd2a utilizes a flippase mechanism to mediate omega-3 fatty acid lysolipid transport.

Major Facilitator Superfamily Domain containing 2a (Mfsd2a) is a sodium-dependent lysophosphatidylcholine (LPC) transporter expressed at the blood-brain barrier that constitutes the main pathway by which the brain obtains omega-3 fatty acids, such as docosahexanoic acid. Mfsd2a deficiency in humans results in severe microcephaly, underscoring the importance of LPC transport by Mfsd2a for brain development. Biochemical studies and recent cryo-electron microscopy (cryo-EM) structures of Mfsd2a bound to LPC suggest that Mfsd2a transports LPC via an alternating access mechanism between outward-facing and inward-facing conformational states in which the LPC inverts during transport between the outer and inner leaflet of a membrane. However, direct biochemical evidence of flippase activity by Mfsd2a has not been demonstrated and it is not understood how Mfsd2a could invert LPC between the outer and inner leaflet of the membrane in a sodium-dependent manner. Here, we established a unique in vitro assay using recombinant Mfsd2a reconstituted in liposomes that exploits the ability of Mfsd2a to transport lysophosphatidylserine (LPS) coupled with a small molecule LPS binding fluorophore that allowed for monitoring of directional flipping of the LPS headgroup from the outer to the inner liposome membrane. Using this assay, we demonstrate that Mfsd2a flips LPS from the outer to the inner leaflet of a membrane bilayer in a sodium-dependent manner. Furthermore, using cryo-EM structures as guides together with mutagenesis and a cell-based transport assay, we identify amino acid residues important for Mfsd2a activity that likely constitute substrate interaction domains. These studies provide direct biochemical evidence that Mfsd2a functions as a lysolipid flippase.

Spns1 is a lysophospholipid transporter mediating lysosomal phospholipid salvage.

The lysosome is central to the degradation of proteins, carbohydrates, and lipids and their salvage back to the cytosol for reutilization. Lysosomal transporters for amino acids, sugars, and cholesterol have been identified, and the metabolic fates of these molecules in the cytoplasm have been elucidated. Remarkably, it is not known whether lysosomal salvage exists for glycerophospholipids, the major constituents of cellular membranes. By using a transport assay screen against orphan lysosomal transporters, we identified the major facilitator superfamily protein Spns1 that is ubiquitously expressed in all tissues as a proton-dependent lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) transporter, with LPC and LPE being the lysosomal breakdown products of the most abundant eukaryotic phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively. Spns1 deficiency in cells, zebrafish embryos, and mouse liver resulted in lysosomal accumulation of LPC and LPE species with pathological consequences on lysosomal function. Flux analysis using stable isotope-labeled phospholipid apolipoprotein E nanodiscs targeted to lysosomes showed that LPC was transported out of lysosomes in an Spns1-dependent manner and re-esterified back into the cytoplasmic pools of phosphatidylcholine. Our findings identify a phospholipid salvage pathway from lysosomes to the cytosol that is dependent on Spns1 and critical for maintaining normal lysosomal function.

Cost and outcomes of Hospital-based Usual cAre versus Tele-monitor self-directed Rehabilitation (HUATR) in patients with total knee arthroplasty: A randomized, controlled, non-inferiority trial.

OBJECTIVE: To evaluate the clinical efficacy and cost-effectiveness of telemonitored self-directed rehabilitation (TR) compared with hospital-based rehabilitation (HBR) for patients with total knee arthroplasty (TKA). DESIGN: In this randomized, non-inferiority clinical trial, 114 patients with primary TKA who were able to walk independently preoperatively were randomized to receive HBR (n = 58) or TR (n = 56). HBR comprised at least five physical therapy sessions over 10 weeks. TR comprised a therapist-led onboarding session, followed by a 10-week unsupervised home-based exercise program, with asynchronous monitoring of rehabilitation outcomes using a telemonitoring system. The primary outcome was fast-paced gait speed at 12 weeks, with a non-inferiority margin of 0.10 m/s. For economic analysis, quality-adjusted-life-years (QALY) was the primary economic outcome (non-inferiority margin, 0.027 points). RESULTS: In Bayesian analyses, TR had >95% posterior probability of being non-inferior to HBR in gait speed (week-12 adjusted TR-HBR difference, 0.02 m/s; 95%CrI, -0.05 to 0.10 m/s; week-24 difference, 0.01 m/s; 95%CrI, -0.07 to 0.10 m/s) and QALY (0.006 points; 95%CrI, -0.006 to 0.018 points). When evaluated from a societal perspective, TR was associated with lower mean intervention cost (adjusted TR-HBR difference, -S$227; 95%CrI, -112 to -330) after 24 weeks, with 82% probability of being cost-effective compared with HBR at a willingness to pay of S$0/unit of effect for the QALYs. CONCLUSIONS: In patients with uncomplicated TKAs and relatively good preoperative physical function, home-based, self-directed TR was non-inferior to and more cost-effective than HBR over a 24-week follow-up period. TR should be considered for this patient subgroup.

Collaborative model of care between orthopaedics and allied healthcare professionals (CONNACT) in knee osteoarthritis: Effectiveness-implementation hybrid randomized controlled trial of a community-based, multidisciplinary, stratified intervention.

OBJECTIVE: To compare the clinical and cost effectiveness of the Collaborative Model of Care between Orthopaedics and Allied Healthcare Professionals (CONNACT), a community-based, stratified, multidisciplinary intervention consisting of exercise, education, psychological and nutrition delivered through a chronic care model to usual hospital care in adults with knee osteoarthritis (OA). METHODS: Pragmatic, parallel-arm, single-blinded superiority RCT trial. Community-dwelling, ambulant adults with knee OA (Kellgren-Lawrence grade > 1; Knee Injury and OA Outcome Score (KOOS4) ≤75) were enrolled. Primary outcome was KOOS4 at 12-months; secondary outcomes included: quality of life, physical performance measures, symptom satisfaction, psychological outcomes, dietary habits, and global perceived effect. Intention-to-treat analysis using generalized linear model (GLM) and regression modeling were conducted. Economic evaluation through a societal approach was embedded. RESULTS: 110 participants (55 control, 55 intervention) were randomized. No between-group difference found for the primary outcome (MD [95%CI]: -1.86 [-9.11. 5.38]), although both groups demonstrated within-group improvement over 12-months. Among the secondary outcomes, the CONNACT group demonstrated superior dietary change (12 months) and physical performance measures (3 months), and global perceived effect (6 months). While there was no between-group difference in total cost, significant productivity gains (reduced indirect cost) were seen in the CONNACT group. CONCLUSION: CONNACT was not superior to usual care at 1 year. Further efforts are needed to understand the underlying contextual and implementation factors in order to further improve and refine such community-based, stratified care models moving forward. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03809975. Registered January 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03809975.

Is Kinesiophobia Associated With Quality of Life, Level of Physical Activity, and Function in Older Adults With Knee Osteoarthritis?

BACKGROUND: Beyond knee pain itself, the fear of movement, also known as kinesiophobia, recently has been proposed as a potential factor contributing to disability and functional limitation in patients with knee osteoarthritis (OA). Nevertheless, the available evidence on the association of kinesiophobia with patient-reported outcome measures (PROMs) in knee OA remains limited. QUESTIONS/PURPOSES: Among patients with nonoperatively treated knee OA, we asked: (1) Is kinesiophobia associated with decreased quality of life (QoL), functional outcomes, and physical activity? (2) What are the patient disease and psychosocial demographic factors associated with kinesiophobia? METHODS: This was a multicenter, cross-sectional study of 406 general orthopaedic patients from two urban, referral-based tertiary hospitals in Singapore under a single healthcare group who received nonoperative treatment for knee OA. Between July 2020 and January 2022, a total of 1541 patients were treated for knee OA nonoperatively. Based on that, 60% (923) of patients were rejected due to refusal to participate in the study, 3% (52) of patients were enrolled but did not show up for their appointments for data collection, and a further 10% (160) had incomplete data sets, leaving 26% (406) for this study's analysis. The mean age of patients was 64 ± 8 years, 69% were women, and 81% were Chinese. The level of kinesiophobia in patients was measured using the Brief Fear of Movement scale, a validated 6-item questionnaire ranging from a score of 6 to 24 to measure kinesiophobia in OA, with higher scores representing higher levels of kinesiophobia. In terms of PROMs, the QoL and functional level of patients were measured using the QoL and activities of daily living (ADL) components of the widely validated 12-item Knee Injury and Osteoarthritis Outcome Score (KOOS-12). The KOOS-12 is a questionnaire consisting of 12 items encompassing three domains (QoL, ADL, and pain), with each item ranging from 0 to 4 and higher scores representing worse outcomes. The University of California, Los Angeles (UCLA) Activity Scale was used to measure the level of physical activity in patients. The UCLA score is a descriptive 10-level activity scale ranging from a score of 1 to 10, with higher scores representing greater physical activity levels. A directed acyclic graph, which is a relationship map used to depict and visualize the confounders between the studied variables, was used to identify the confounders between kinesiophobia and PROMs (QoL, function, and physical activity). An ordinal regression model was used to explore: (1) the association between kinesiophobia (as measured using the Brief Fear of Movement scale) and PROMs (as measured using KOOS QoL, KOOS ADL, and the UCLA Activity Scale), adjusting for key confounders such as age, gender, pain, side of arthritis, OA duration/severity, and psychosocial factors (for example, depression, anxiety, and education levels), and (2) the association between kinesiophobia (Brief Fear of Movement scale) and various patient disease and psychosocial demographic factors. RESULTS: After accounting for confounders, greater kinesiophobia (higher Brief Fear of Movement scores) was associated with lower QoL (KOOS QoL score adjusted IQR OR 0.69 [95% confidence interval (CI) 0.53 to 0.90]; p = 0.007) and lower physical activity (UCLA score adjusted IQR OR 0.68 [95% CI 0.52 to 0.90]; p = 0.007); however, there was no association between kinesiophobia and function (KOOS ADL score adjusted IQR OR 0.90 [95% CI 0.70 to 1.17]; p = 0.45). After adjusting for age, gender, OA duration, pain, and BMI, higher levels of anxiety (Patient Health Questionnaire 2 [PHQ-2] anxiety score adjusted OR 2.49 [95% CI 1.36 to 4.58]; p = 0.003) and depression (PHQ-2 depression score adjusted OR 3.38 [95% CI 1.73 to 6.62]; p < 0.001) were associated with higher levels of kinesiophobia. Education level, OA disease severity, side of arthritis (unilateral versus bilateral), and history of previous injury or surgery on the knee were not associated with kinesiophobia. CONCLUSION: Clinicians should assess for kinesiophobia and other psychological comorbidities such as depression and anxiety at the point of initial evaluation and subsequent follow-up of knee OA with simple validated tools like the Brief Fear of Movement scale (kinesiophobia) in the clinic. This allows for clinicians to identify high-risk individuals and offer evidence-based treatment such as cognitive behavioral therapies with a multidisciplinary team, including a physical therapist and psychologist, to manage these psychological comorbidities and improve outcomes in patients with knee OA. While kinesiophobia was found to be associated with poorer QoL and physical activity, future studies including larger observational cohort studies should be conducted to determine causal and prognostic relationships between kinesiophobia and outcomes in knee OA. LEVEL OF EVIDENCE: Level III, prognostic study.

A cross sectional study exploring the relationship of self-reported physical activity with function, kinesiophobia, self-efficacy and quality of life in an Asian population seeking care for knee osteoarthritis.

BACKGROUND: Physical activity is a guideline-recommended first-line intervention for people with knee osteoarthritis. Physical activity levels, and its potential correlates, is underexplored in Asian populations with knee osteoarthritis. METHODS: Participants enrolled in a longitudinal study in Singapore self-reported physical activity (UCLA activity score), function (Knee Osteoarthritis Outcome Score [KOOS-12]), kinesiophobia (Brief fear of movement [BFOM]), self-efficacy (ASES-8), and quality of life (EQ-5D-5 L). One-Way ANOVA was used to test the difference in outcomes between UCLA categories, while ordinal logistic regression was used to identify the associated factors to physical activity level. RESULTS: Seventy-three percent of all enrolled participants (n = 311/425) reported either inactivity or low physical activity (median 4, IQR 3-5). Significant, weak, positive correlations were observed be-tween UCLA activity score and either KOOS-12 (Spearman's rho: 0.1961; p < 0.001), ASES-8 (0.1983; p = 0.004), or EQ-5D-5 L (0.2078; p < 0.001). A significant, weak, negative correlation was observed between physical activity and BFOM (-0.2183; p < 0.001). Significant differences in function between groups (moderate vs. inactive or low physical activity) were not clinically important. Participants with obesity, from the eldest age category (i.e. ≥75), or who identified as Malay or female, were less physically active than those with a healthy BMI, below the age of 54, or who identified as Chinese or male, respectively. CONCLUSION: Healthcare professionals in Asia should be aware of the large proportion of people with knee osteoarthritis who are either inactive or have low physical activity levels. Screening for, and offering interventions to promote, physical activity and its correlates should be prioritised.

Deltoid tuberosity index for proximal humerus fracture: reliability and a predictor of systemic osteoporosis in an Asian population.

HYPOTHESIS AND BACKGROUND: Fragility fracture of the proximal humerus is a common occurrence. Current literature suggests that poor local bone density is a significant predictor of surgical fixation failure. The deltoid tuberosity index (DTI) is a simple radiographic tool that strongly correlates with local humeral bone mineral density (BMD), aiding surgical planning to consider adjuncts or arthroplasty. However, there is a lack of data in the reliability of assessment of DTI, as well as its correlation to systemic osteoporosis. Our study investigates the reliability of DTI as a predictor of systemic osteoporosis. METHODS: A retrospective cohort of patients with proximal humeral fracture (PHF) treated at a trauma center in Singapore from August 2017 to July 2018 were recruited. Four raters at different levels of varying clinical seniority measured DTI using shoulder radiographs. The dual-energy x-ray absorptiometry (DEXA) BMD scan of the hip and lumbar spine was used to diagnose osteoporosis. Area under the receiver operating characteristic curve analysis was calculated to study the diagnostic utility of DTI for predicting the risk of osteoporosis. RESULTS: Our study sample had 87 patients comprising 18 men and 69 women, mainly of Chinese ethnicity (84%), and with a mean age of 69.7 years (standard deviation 9.52, range 39-92). For assessment of DTI, there was good intrarater reliability among 4 raters (correlation coefficient range 0.805-0.843) and excellent interrater reliability between all raters (intraclass correlation coefficient 0.898, 95% confidence interval [CI] 0.784-0.950, P < .001). Based on the BMD, 55.2% (n = 48) had osteoporosis, with a T score <2.5. The highest correlation of DTI to BMD was with femoral neck density at 0.580. The DTI cutoff of 1.6 had the highest combined sensitivity and false positive rate, with areas under the curve of 0.682 (95% CI 0.564-0.799) for the overall population and 0.706 (95% CI 0.569-0.842) for patients aged <75 years. CONCLUSION: The DTI is a simple and reliable tool and has a strong applicability in clinical practice to enhance preoperative planning in the surgical fixation of PHF. DTI with a cutoff of 1.6 may help prompt clinicians to initiate workup and thus manage underlying osteoporosis.

Does concomitant thyroid disorder lead to worse outcomes in frozen shoulder? - A systematic review.

BACKGROUND: Frozen shoulder is a common pathology characterized by significant shoulder pain, range of motion limitation and physical disability. There exists a clear association between the prevalence of frozen shoulder and thyroid disease. However, the effects of concomitant thyroid disease on clinical outcomes of frozen shoulder are less well established. This study aims to evaluate if the presence of thyroid disease predisposes to poorer clinical outcomes in patients with frozen shoulder. METHODOLOGY: The study was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and registered with PROSPERO. Two databases (PubMed and Embase) were searched from date of inception to 9 January 2024. Human studies reporting clinical outcomes of patients with concomitant thyroid disorder and frozen shoulder were included. Risk of bias was assessed based on the Quality In Prognosis Studies (QUIPS) tool and quality of evidence was judged based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework in the domains of range of motion, responsiveness to treatment or timeliness of recovery, and multidimensional scoring systems. RESULTS: Seven studies comprising 167,397 subjects (mean age 52.7 to 58 years, female proportion 67.1%), including 49,314 patients with concomitant thyroid disorder and frozen shoulder were included. Amongst the seven included studies: one study reported improved clinical outcomes in patients with concomitant frozen shoulder and hypothyroidism, one study reported that presence of thyroid disorder led to worse outcomes, while the remaining five studies did not demonstrate evidence of statistically worse outcomes in patients with concomitant thyroid disorder. Based on the GRADE framework, there was no consistent prognostic association between thyroid disorder and frozen shoulder in the domains of range of motion, responsiveness to treatment or timeliness of recovery, and multidimensional scoring systems, and the quality of evidence ranged from 'Very Low' to 'Low'. RISK OF BIAS ASSESSMENT: Based on the QUIPS tool, three studies were assessed to have low risk of bias, while four studies were assessed to have moderate risk of bias. CONCLUSION: Though there exists an association between the prevalence of frozen shoulder and thyroid disorder, there is no consistent evidence in available literature to suggest that concomitant thyroid disorder predisposes to worse clinical outcomes.

Evaluating the association of radiographic parameters of proximal humerus fractures managed conservatively with functional outcomes.

INTRODUCTION: Treatment of proximal humerus fractures remains controversial. Understanding the factors that can affect the long-term functional outcomes can aid with management choices. This primary aim of this paper is to evaluate the association of radiographic parameters with functional outcomes. METHODS: Radiographic parameters [Caput-collum-diaphyseal (CCD) angles, Y-scapular angles, and humeral head height (HHH)] were studied. The patients were split into varus and valgus groups based on the CCD angles and retroverted and anteverted groups based on Y-scapular angles. Functional outcome was measured by Oxford Shoulder Score (OSS), Constant Shoulder Score (CSS), and quick Disabilities of Arm, Shoulder and Hand score at 1 year follow-up. Intra- and interrater reliability were measured with the intraclass correlation coefficients (ICCs). Receiver operator curve (ROC) analysis and logistic regression analysis defined the optimal value for abnormalities on radiographic evaluation as an outcome predictor. RESULTS: 111 patients were recruited (mean age 69, 78% female). Median final radiographic assessment was at 7 months. Mean initial/final CCD was 119o /111o (varus, n = 36) and 153o/140o (valgus, n = 75). Mean initial/final Y-scapula angle was 27o/27o (retroversion, n = 101) and 70o/40o (anteversion, n = 9). There was a significant relationship between OSS and final Y-scapular angle in the retroverted group (adj coeff 0.034, p = 0.009) with optimum predictive retroversion angulation of 25o predicting poor functional outcome (OSS < 40), area under the ROC curve of 0.614. Higher initial valgus and retroversion significantly predicted more change in the final angle (adj coeff - 0.349, p = 0.002, adj coeff - 0.527, p < 0.001 respectively). Both intra-rater and inter-rater reliability for the radiographic parameters were excellent (ICC > 0.9). CONCLUSION: Radiographic parameters whilst having excellent reliability, have a limited ability to predict short-term functional recovery. The extent of retroversion is the most important predictor for functional recovery with 25o a cut-off guide. Fractures with a higher initial valgus and retroversion tend to displace more.

Mfsd2a-mediated lysolipid transport is important for renal recovery after acute kidney injury.

Acute kidney injury (AKI) is a global public health concern with high mortality and morbidity. In ischemic-reperfusion injury (IRI), a main cause of AKI, the brush border membrane of S3 proximal tubules (PT) is lost to the tubular lumen. How injured tubules reconstitute lost membrane lipids during renal recovery is not known. Here, we identified Mfsd2a, a sodium-dependent lysophosphatidylcholine (LPC) transporter, to be expressed specifically in the basolateral membrane of S3 PT. Using an in vivo activity probe for Mfsd2a, transport activity was found to be specific to the S3 PT. Mice with haploinsufficiency of Mfsd2a exhibited delayed recovery of renal function after acute IRI, with depressed urine osmolality and elevated levels of histological markers of damage, fibrosis, and inflammation, findings corroborated by transcriptomic analysis. Lipidomics revealed a deficiency in docosahexaenoic acid (DHA) containing phospholipids in Mfsd2a haploinsufficiency. Treatment of Mfsd2a haploinsufficient mice with LPC-DHA improved renal function and reduced markers of injury, fibrosis, and inflammation. Additionally, LPC-DHA treatment restored S3 brush border membrane architecture and normalized DHA-containing phospholipid content. These findings indicate that Mfsd2a-mediated transport of LPC-DHA is limiting for renal recovery after AKI and suggest that LPC-DHA could be a promising dietary supplement for improving recovery following AKI.

A systematic review of optimal pharmacokinetic/pharmacodynamic parameters for beta-lactam therapy in infective endocarditis.

BACKGROUND: Beta-lactam antibiotics are the mainstay of therapy for most bacterial causes of infective endocarditis (IE). Traditionally considered as agents with a broad therapeutic index, there is increasing recognition that standard doses may be subtherapeutic or toxic in critically ill patients. Optimizing therapy for efficacy requires a defined pharmacokinetic (PK)/pharmacodynamic (PD) target associated with clinical and microbiological cure. OBJECTIVES: To elucidate the factors that influence beta-lactam PK and PD variability in IE and to examine optimal PK/PD target parameters for therapy. METHODS: The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical and laboratory in vivo animal or human studies examining PK and/or PD of beta-lactam antibiotics in IE were eligible. Ovid MEDLINE, Embase and Cochrane Central Registry were searched using defined terms. The Office of Health Assessment and Translation (OHAT) tool was used for assessing risk of bias. RESULTS: From 2677 abstracts, 62 articles were selected for review and synthesis, comprising: 45 animal studies investigating the broad categories of beta-lactam diffusion into vegetations, PK/PD determinants of outcome, mode of antibiotic delivery and synergistic impact of agents; and 17 human studies totalling 347 participants. Findings supported the importance of time-dependent killing for beta-lactams but heterogeneous data limited the determination of an optimal PK/PD target for IE treatment. CONCLUSION: Beta-lactam PK and PD in endocarditis are variable and specific to the particular antibiotic-organism combination. Time-dependent killing is important, consistent with non-endocarditis studies, but there is little agreement on optimal drug exposure. Clinical studies examining PK/PD targets in endocarditis are required to further inform drug selection and dosing.

Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis.

BACKGROUND: Recent studies suggest that tirzepatide, a dual glucose-dependent insulinotropic-peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA), has significant weight loss effects. This systematic review and meta-analysis aims to assess the efficacy and safety of tirzepatide for weight loss in patients with overweight or obesity. METHODS: Medline, Embase and Cochrane CENTRAL were searched for randomized controlled trials (RCTs) on tirzepatide's weight loss efficacy for these patients. A single arm meta-analysis of proportions estimated primary outcomes, ≥5%, ≥10%, and ≥15% weight loss, and adverse events (AEs); while meta-analysis of means estimated secondary outcomes. Comparative meta-analysis was conducted between tirzepatide and control arms where mean differences and odds ratios were estimated for continuous and dichotomous outcomes respectively. RESULTS: RCTs included in this study revealed that among 5800 patients, 78.22% (95% CI: 72.15% to 83.73%), 55.60% (95% CI: 46.54% to 64.47%), 32.28% (95% CI: 23.17% to 42.12%) achieved ≥5%, ≥10%, and ≥15% weight loss, respectively. Tirzepatide 5 mg demonstrated weight loss superiority relative to placebo (MD: -12.47 kg, 95% CI: -13.94 kg to -11.00 kg) and semaglutide (n = 1409, MD: -1.90 kg, 95% CI: -2.97 kg to -0.83 kg) with dose-dependent increase for 10 mg and 15 mg doses. The comparison between tirzepatide and semaglutide was examined in the SURPASS-2 trial that was included in this systematic review. For AEs, there was increase odds of experiencing gastrointestinal AEs with tirzepatide compared to placebo, but no significant difference with semaglutide. CONCLUSION: Tirzepatide has significant potential as a weight loss drug in patients with overweight and obesity, with little increase in AEs compared to other weight loss drugs. With its ability to concurrently target multiple aspects of metabolic syndrome, it should be considered as the next helm of weight loss therapies.

Utility of rapid atrial pacing before and after TAVR with balloon-expandable valve in predicting permanent pacemaker implantation.

BACKGROUND: High-grade or complete atrioventricular block (AVB) requiring permanent pacemaker (PPM) implantation is a known complication of transcatheter aortic valve replacement (TAVR). Wenckebach AVB induced by rapid atrial pacing (RAP) after TAVR was previously demonstrated in an observational analysis to be an independent predictor for PPM. We sought to investigate the utility of both pre- and post-TAVR RAP in predicting PPM implantation. METHODS: In a single-center, prospective study, 421 patients underwent TAVR with balloon-expandable valves (BEV) between April 2020 and August 2021. Intraprocedural RAP was performed in patients without a pre-existing pacemaker, atrial fibrillation/flutter, or intraprocedural complete AVB to assess for RAP-induced Wenckebach AVB. The primary outcome was PPM within 30 days after TAVR. RESULTS: RAP was performed in 253 patients, of whom 91.3% underwent post-TAVR RAP and 61.2% underwent pre-TAVR RAP. The overall PPM implantation rate at 30 days was 9.9%. Although there was a numerically higher rate of PPM at 30 days in patients with RAP-induced Wenckebach AVB, it did not reach statistical significance (13.3% vs. 8.4%, p = 0.23). In a multivariable analysis, RAP-induced Wenckebach was not an independent predictor for PPM implantation at 30 days after TAVR. PPM rates at 30 days were comparable in patients with or without pre-TAVR pacing-induced Wenckebach AVB (11.8% vs. 8.2%, p = 0.51) and post-TAVR pacing-induced Wenckebach AVB (10.2% vs. 5.8%, p = 0.25). CONCLUSION: In patients who underwent TAVR with BEV, there were no statistically significant differences in PPM implantation rates at 30 days regardless of the presence or absence of RAP-induced Wenckebach AVB. Due to conflicting results between the present study and the prior observational analysis, future studies with larger sample sizes are warranted to determine the role of RAP during TAVR as a risk-stratification tool for significant AVB requiring PPM after TAVR.

Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss.

RATIONALE: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive. OBJECTIVE: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype. METHODS AND RESULTS: We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfbret/ret mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfbret/ret brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB. CONCLUSIONS: By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.

Type 2 diabetes mellitus in metabolic-associated fatty liver disease vs. type 2 diabetes mellitus non-alcoholic fatty liver disease: a longitudinal cohort analysis.

INTRODUCTION AND OBJECTIVES: Type 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of "metabolic associated fatty liver disease" (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM. MATERIALS AND METHODS: The current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events. RESULTS: 6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p < 0.001) and all-cause mortality (HR: 1.75, CI: 1.29 to 2.40, p < 0.001). CONCLUSIONS: The identification and treatment of NAFLD in patients with T2DM is a major concern and the premature change to MAFLD results in an over-diagnosis of fatty liver, exaggerated mortality, and morbidity in patients with T2DM. The definition of MAFLD causes further heterogeneity in fatty liver disease/NAFLD.

A Qualitative Study of Psychosocial Factors in Patients With Knee Osteoarthritis: Insights Learned From an Asian Population.

BACKGROUND: A patient's experience with knee osteoarthritis (OA) is influenced by many psychosocial contributors that can influence the impact of pain. Such factors are known to explain some of the discordance between objective clinical parameters and patient-reported levels of disability and treatment effectiveness. However, few data are available to help clinicians understand the psychosocial factors that apply to the world's many Asian populations. Insights gained from a qualitative study in such a population may support targeted interventions. QUESTIONS/PURPOSES: In this qualitative study involving a group of Asian patients with knee OA in Singapore, we asked: (1) What psychologic factors contribute to patients' experiences, rehabilitation, and recovery? (2) What social factors contribute to patients' experiences, rehabilitation, and recovery? METHODS: Semistructured interviews eliciting broad patient experiences of managing knee OA were conducted in an urban, referral-based tertiary hospital in central Singapore. Patients were recruited if they met either of the following criteria: Kellgren-Lawrence grade ≥ 3 (minimum of one knee); Knee Injury and Osteoarthritis Outcome Score ≤ 60; or the Pain average (P), interference with Enjoyment of life (E), and interference with General activity (G) (PEG) ≥ 5. All patients had a clinical diagnosis of knee OA, were ambulatory in the community with or without a walking aid, had not undergone partial arthroplasty or TKA, were prescribed nonsurgical treatment, and were conversant in either English or Mandarin. Forty-six patients (30 women and 16 men, mean age 64 years old) were recruited for this study. A thematic analysis with elements of grounded theory and framework analysis was performed using a deductive approach. Psychologic influences specific to patients' behavioral and emotional responses to pain, as well as social factors known to have an impact on the experience of managing knee OA, were identified in the interview transcripts and coded according to established factors from earlier research. An inductive thematic analysis was then applied to the remaining transcripts to identify new themes that emerged from the data. Thematic saturation was attained when study team members agreed data and thematic sufficiency were met in the 46 transcripts. The study team discussed and deemed the 46 transcripts to contain sufficient insights for a reasonably clear understanding of the codes and development of themes to answer the study's research questions. RESULTS: Six main themes related to psychosocial influences on pain emerged. Psychologic factors were "loss of face" because of knee OA, anticipation and avoidance of pain and suffering, and a vicious cycle of negative emotional experiences. The social factors we identified were social and family support, workplace environment and employment uncertainty, and built environment (patients' ability to navigate manmade structures and facilities). CONCLUSION: Psychosocial factors have an important impact on patients' physical, psychologic, and social functioning. Although several of our findings have been addressed previously, the phenomenon of loss of face and the wide spectrum of social and family support dynamics found in our Asian patients with knee OA were new findings. With loss of face, patients were concerned about how others would view the change in them, including movement changes because of knee OA. They appeared to associate the use of walking canes with major disability, loss of respect, and being discriminated against by others, motivating patients to "save face" by dissociating themselves from those stigmas, even at the cost of mobility and independence. An interplay of complex cultural processes (perceived social roles and contributions to family, desire to avoid burdening family, help-seeking behavior, and the preference for unsolicited social support) underpinned by the value of collectivism impacted the behaviors and choices patients exhibited. CLINICAL RELEVANCE: With knowledge about the impact of culturally relevant psychosocial factors on the experience and outcomes of patients with knee OA, clinicians will be able to screen and actively explore these factors more effectively. Especially important themes include pain perception (paying close attention to signs of pain catastrophizing and negative affect), presence of chronic illness shame associated with a diagnosis of knee OA (including the stigma associated with using a walking aid), and level of social support received and contributions of a patient's built environment to kinesiophobia. For patients who are still working, the presence of workplace stressors and management of these stressors should also be explored. Where possible, screening tools that measure psychosocial factors such as pain catastrophizing and emotional distress can also be used as an added layer of screening in busy clinical settings.

Adaptation and validation of the chronic illness-related shame scale among patients with knee osteoarthritis in Singapore.

BACKGROUND: Osteoarthritis (OA) of the knee is one of the most common and disabling conditions worldwide. A neglected aspect of knee OA is its psychosocial impact, such as shame. However, assessment tools to measure shame among patients diagnosed with knee OA are lacking. In this study, the psychometric properties of the Chronic Illness-related Shame Scale (CISS) were evaluated among knee OA patients in Singapore. METHODS: Adaptations were made to CISS for use among the knee OA population. An exploratory factor analysis (EFA) was performed to analyze the factor structure. Cronbach's Alpha and corrected item-total correlations were used to evaluate the internal consistency. Spearman correlation coefficient was used to test the correlation between CISS and Patient Health Questionnaire-4 (PHQ-4) to determine the validity of the instrument. RESULTS: The EFA yielded a one-factor structure, with an eigenvalue of 4.78 explaining 68.25% of variance. Cronbach Alpha was 0.92, which indicated good internal consistency. The Spearman correlation revealed a significant correlation between CISS and PHQ-4. CONCLUSIONS: The adapted CISS is a valid and reliable instrument to measure shame for knee OA patients. Both research and clinical settings can benefit from the use of the adapted CISS for assessing shame among knee OA patients.

Study on proximal humerus evaluation of effective treatment (SPHEER) - what is the effect of rehabilitation compliance on clinical outcomes of proximal humerus fractures.

INTRODUCTION: Proximal humeral fractures (PHFs) are 3rd commonest fragility fractures and cause significant functional impairment. This paper sought to determine impact of rehabilitation compliance on the clinical outcomes for non-surgically managed PHFs, while ascertaining reasons for non-compliance which can be addressed to improve compliance. METHODS: Prospective cohort study of patients undergoing non-surgical treatment for PHFs from August 2017 to April 2020 in a tertiary trauma centre was performed. Data was collected via questionnaire: patient demographic data, PHF injury details, clinical outcome measures, therapist-reported (Sport Injury Rehabilitation Adherence Scale [SIRAS]) and patient-reported (subjective compliance, frequency of exercise) rehabilitation compliance measures. Data was analysed using multiple linear regression model to account for confounding variables. RESULTS: 107 participants attended physical therapy follow-up for mean 137.8 days. 6-week SIRAS strongly predicted 3-month Constant score (p = 0.023; 95%CI = 0.265,3.423), OSS (p = 0.038; 95%CI = 0.049,1.634), flexion ROM (p < 0.001; 95%CI = 2.872,8.982), extension ROM (p = 0.035; 95%CI = 0.097,2.614), abduction ROM (p = 0.002;95%CI = 1.995,8.466) and achievement of functional active ROM at 3-months (p = 0.049; 95%CI = 1.001,1.638). Pain was the top reason impairing rehabilitation compliance from therapist (43.9% at 6-weeks and 20.6% at 3-months) and patient-perspective (33.6% at 6-weeks, 24.3% at 3-months). Author-developed patient-reported compliance measures had good correlation with validated SIRAS score (subjective compliance: p < 0.001 frequency of exercise: p = 0.001). CONCLUSION: Rehabilitation compliance predicts short-term clinical outcomes up to 3-months and potentially 1-year outcomes. Pain control should be optimised to maximise rehabilitation compliance and improve PHF outcomes. There is lack of consensus definition for rehabilitation compliance measures; patient-reported measures used have good correlation to existing validated measures and could serve as a steppingstone for further research. LEVEL OF EVIDENCE: II, cohort study.

Singapore KneE osTeoarthritis CoHort (SKETCH): protocol for a multi-centre prospective cohort study.

BACKGROUND: Knee osteoarthritis (OA) is a leading cause of global disability. The understanding of the role of psychosocial factors in knee OA outcomes is still evolving particularly in an Asian context. The primary aim of this study is to explore psychosocial factors that prognosticate short and long-term clinical outcomes, productivity, and healthcare utilization in patients with knee OA. Secondary aims are to explore the mediation and directional relationships and the role it plays in predicting the discordance between self-reported measures (SRM), physical-performance measures (PPMs) and objective clinical parameters. METHODS: A multi-centre prospective cohort study of community ambulant knee OA patients seeking treatment in the tertiary healthcare institutions in Singapore will be conducted. Patients with secondary arthritis, significant cognitive impairment, severe medical comorbidities or previous knee arthroplasty will be excluded. Primary clinical outcome measure is the Knee injury and OA Outcome Score-12 (KOOS-12). Baseline characteristics include sociodemographic status, arthritis status including symptom duration and radiographic severity, comorbidities and functional status through Charlson Comorbidities Index (CCI), Barthel Index (BI) and Parker Mobility Score (PMS). Psychosocial variables include social support, kinesiophobia, negative affect, self-efficacy, injustice, chronic illness shame and the built environment. Clinical outcomes include quality of life, physical performance, global assessment, satisfaction and physical activity levels. Productivity and healthcare utilization will be assessed by a modified OA Cost and Consequences Questionnaire (OCC-Q) and the Work Productivity and Activity Impairment Questionnaire (WPAI). Variables will be collected at baseline, 4, 12 months and yearly thereafter. Regression, mediation and structural equation modelling will be used for analysis. DISCUSSION: Results will allow contextualization, identification, and phenotyping of the critical (and potentially modifiable) psychosocial parameters that predict positive clinical outcomes in the OA population to guide optimization and refinement of healthcare and community. This will facilitate: 1. identification of high-risk knee OA subpopulations that will likely experience poor outcomes and 2. formulation of targeted multidisciplinary comprehensive approaches to address these psychosocial factors to optimize non-surgical treatment care, maximize functional outcomes and create more value-based care model for knee OA. ETHICS AND DISSEMINATION: The study has been registered under clinicaltrials.gov registry (Identifier: NCT04942236).

Discordance Between Self-Reported and Performance-Based Physical Function in Patients Who Have Knee Osteoarthritis: Associations With Pain Intensity and Negative Affect.

BACKGROUND: Although self-reported measures of physical disability are strong indication criterion for total knee arthroplasty (TKA) in painful knee osteoarthritis (OA), some patients may report greater-than-observed disability. Contributing factors to this discordance are relatively unexplored. We aimed to examine whether pain and negative affect, including anxiety and depression, were associated with the discordance of self-reported measures with performance-based measures (PPM) of physical function. METHODS: We used cross-sectional data (n = 212) from two randomized rehabilitation trials in knee OA. All patients were assessed for knee pain intensity and symptoms of anxiety and depression. Self-reported function was assessed by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) physical-function subscale. Objective performance-based measures (PPMs) of physical function were assessed by timed gait and stair tests. Continuous discordance scores were quantified by the difference in percentiles between WOMAC and PPMs (WOMAC-PPM), where a positive discordance, WOMAC-PPM >0, implied greater perceived than observed disability. RESULTS: Around 1 in 4 patients had >20 percentile units in WOMAC-PPM discordance. In Bayesian regression analyses, knee pain intensity had >99% posterior probability of positive associations with WOMAC-PPM discordance. Among patients awaiting TKA, anxiety intensity had approximately 99% probability of positive associations with discordance, and these associations had >65% probability of exceeding 10 percentile units. In contrast, depression had low (79% to 88%) probability of any association with discordance. CONCLUSION: In patients who have knee OA, a sizable proportion reported substantially greater physical disability than actually observed. Pain and anxiety intensity, but not depression, were meaningful predictors of this discordance. If validated, our findings may help in refining patient selection criteria for TKA.