A µ-opioid receptor modulator that works cooperatively with naloxone.

The µ-opioid receptor (µOR) is a well-established target for analgesia1, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo.

Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum.

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurological and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is poorly understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric type A (GABAA) receptors. Here, we show that Hsp47 enhances the functional surface expression of GABAA receptors in rat neurons and human HEK293T cells. Furthermore, molecular mechanism study demonstrates that Hsp47 acts after BiP (Gene: HSPA5) and preferentially binds the folded conformation of GABAA receptors without inducing the unfolded protein response in HEK293T cells. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAA receptors. Overexpressing Hsp47 is sufficient to correct the surface expression and function of epilepsy-associated GABAA receptor variants in HEK293T cells. Hsp47 also promotes the surface trafficking of other Cys-loop receptors, including nicotinic acetylcholine receptors and serotonin type 3 receptors in HEK293T cells. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 plays a critical and general role in the maturation of multi-subunit Cys-loop neuroreceptors.

Identification of a subpopulation of highly adherent endothelial cells for seeding synthetic vascular grafts.

OBJECTIVE: There is an unmet clinical need for alternatives to autologous vessel grafts. Small-diameter (<6mm) synthetic vascular grafts are not suitable because of unacceptable patency rates. This mainly occurs due to the lack of an endothelial cell (EC) monolayer to prevent platelet activation, thrombosis, and intimal hyperplasia. There are no reliable methods to endothelialize small-diameter grafts, as most seeded ECs are lost due to exposure to fluid shear stress (SS) after implantation. The goal of this work is to determine if EC loss is a random process or if it is possible to predict which cells are more likely to remain adherent. METHODS: In initial studies, we sorted ECs using fluid SS and identified a subpopulation of ECs that are more likely to resist detachment. We use RNA-sequencing (RNA-seq) to examine gene expression of adherent ECs compared to the whole population. Using fluorescence activated cell sorting (FACS), we sorted ECs based on the expression level of a candidate marker and studied their retention in small-diameter vascular grafts in vitro. RESULTS: Transcriptomic analysis revealed that fibronectin leucine rich transmembrane protein 2 (FLRT2), encoding protein FLRT2, is downregulated in the ECs that are more likely to resist detachment. When seeded onto vascular grafts and exposed to SS, ECs expressing low levels of FLRT2 exhibit 59.2±7.4% retention compared to 24.5±6.1% retention for the remainder of the EC population. CONCLUSIONS: For the first time, we show EC detachment is not an entirely random process. This provides validation for the concept that we can seed small-diameter vascular grafts only with highly adherent ECs to maintain a stable endothelium and improve graft patency rates.

Anterior cervical hybrid constructs reduce superior adjacent segment burden compared to multilevel anterior cervical discectomy and fusion.

Background: Traditional surgical treatment for symptomatic cervical degenerative disc disease is anterior cervical discectomy and fusion (ACDF), yet the increased risk of adjacent segment degeneration (ASD) requiring additional surgery exists and may result in limiting long-term surgical success when it occurs. Disc arthroplasty can preserve or restore physiologic range of motion (ROM), decreasing adjacent level stress and subsequent surgery. For patients with multilevel pathology requiring at least a 1-level fusion, interest is growing in anterior cervical hybrid (ACH) surgery as a partial motion-preserving procedure to decrease the adjacent level burden. This radiographic study compares postoperative superior adjacent segment motion between ACH and ACDF. Secondarily, total global motion, construct motion, inferior adjacent segment motion, and sagittal alignment parameters were compared. Methods: This is a single-center, multi-surgeon, retrospective cohort study of 2- and 3-level ACH and ACDF cases between 2013 and 2021. Degrees of motion were analyzed on flexion/extension views using Cobb angles to measure global (C2-C7) construct and adjacent segment lordosis. Neutral lateral X-rays were analyzed for alignment parameters, including global lordosis, cervical sagittal vertical axis (cSVA), and T1 slope (T1S). Differences were determined by independent t-test and Fisher's exact test. Results: Of 100 patients, 38% were 2-level cases (47% ACH, 53% ACDF) and 62% were 3-level cases: (52% ACH, 48% ACDF). Postoperatively, superior adjacent segment motion increased with ACDF and decreased with ACH (-1.3°±5.3° ACH, 1.6°±4.6° ACDF, P=0.005). Postoperatively, the ACH group had greater ROM across the construct (16.3°±8.7° ACH, 4.7°±3.3° ACDF, P<0.001) and total global ROM (38.0°±12.8° ACH, 28.0°±11.1° ACDF, P<0.001). ACH resulted in a significant reduction of motion loss across the construct (-10.0°±11.7° ACH, -18.1°±10.8° ACDF, P<0.001). Postoperative alignment restoration was similar between both cohorts (-2.61°±8.36° ACH, 0.04°±12.24° ACDF, P=0.21). Conclusions: Compared to ACDF, hybrid constructs partially preserved motion across operative levels and had greater postoperative global ROM without increasing superior adjacent segment mobility or sacrificing alignment restoration. This supports the consideration of ACH in patients with multilevel degenerative cervical pathology requiring at least a 1-level fusion and suggests a propensity for long-term success by reducing the superior adjacent segment burden.

Vocal Cord Paralysis in Pediatric Chiari Malformation: A Systematic Review and Meta-analysis.

OBJECTIVE: Arnold-Chiari Malformation is one possible cause of congenital vocal cord paralysis (VCP). The natural history of VCP in children with Chiari malformation has previously been limited to small case studies. This systematic review seeks to better characterize the prognostic factors that may predict symptom severity and resolution of congenital VCP in children with Arnold-Chiari malformation. We hypothesized that the onset of stridor or VCP at a younger age would be associated with a poorer prognosis and earlier intervention with posterior fossa decompression would be associated with better outcomes. DATA SOURCES: PubMed, Web of Science, Cochrane Library, and bibliographic review. REVIEW METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Database search yielded 866 articles. Study abstracts were reviewed by 2 independent examiners. One hundred and seventy-six studies underwent full-text review. The following were extracted: age at onset of stridor or VCP, Chiari malformation type, laryngoscopy findings, type and timing of neurosurgical intervention, and tracheostomy history. Statistical analyses utilized χ2 tests. RESULTS: Younger age at symptom onset showed statistically significant associations with decreased likelihood for symptom resolution and tracheostomy decannulation. The shorter time interval from symptom onset to neurosurgical intervention was not significantly associated with better outcomes. CONCLUSION: This meta-analysis suggests poorer prognosis in those with earlier-onset symptoms, reinforcing prior case series findings. Additional prospective studies are needed to elucidate the natural history and utility of early intervention in children with vocal cord paralysis secondary to Chiari malformation.

Neutrophils insert elastase into hepatocytes to regulate calcium signaling in alcohol-associated hepatitis.

Neutrophil infiltration occurs in a variety of liver diseases, but it is unclear how neutrophils and hepatocytes interact. Neutrophils generally use granule proteases to digest phagocytosed bacteria and foreign substances or neutralize them in neutrophil extracellular traps. In certain pathological states, granule proteases play a destructive role against the host as well. More recently, non-destructive actions of neutrophil granule proteins have been reported, such as modulation of tissue remodeling and metabolism. Here we report a completely different mechanism by which neutrophils act non-destructively, by inserting granules directly into hepatocytes. Specifically, elastase-containing granules were transferred to hepatocytes where elastase selectively degraded intracellular calcium channels to reduce cell proliferation without cytotoxicity. In response, hepatocytes increased expression of serpin E2 and A3, which inhibited elastase activity. Elastase insertion was seen in patient specimens of alcohol-associated hepatitis, and the relationship between elastase-mediated ITPR2 degradation and reduced cell proliferation was confirmed in mouse models. Moreover, neutrophils from patients with alcohol-associated hepatitis were more prone to degranulation and more potent in reducing calcium channel expression than neutrophils from healthy subjects. This non-destructive and reversible action on hepatocytes defines a previously unrecognized role for neutrophils in the transient regulation of epithelial calcium signaling mechanisms.

Prevalence of Radiographic Hip Dysplasia in the General Adult Population: A Systematic Review.

Background: Acetabular dysplasia has a wide range of prevalence reported in the literature. This variation is likely due to differences in the population under investigation and studies focusing on cohorts with hip pain and osteoarthritis. There are reports of radiographic hip dysplasia prevalence for adults without hip pain but there is no systematic review of these studies to document the incidence in the general population. The purpose of this systematic review was to provide a full summary of all studies that report prevalence of hip dysplasia in adults without hip pain. Methods: PRISMA guidelines were utilized as an outline for this systematic review. Articles were pulled from PubMed, OVID Medline, Embase, SCOPUS, Cochrane Central Register of Clinical Trials, and clinicaltrials.gov from their inception dates to 1/7/24. Studies were included if participants were asymptomatic and reported rates of prevalence. Results: Fourteen studies were included in this systematic review. There were 10,998 hips from 5,506 participants included in this analysis. The overall prevalence of radiographic hip dysplasia was 2.3%. Eight studies of 5,930 hips reported the prevalence of hip dysplasia by sex. The prevalence rate in these studies was 3.8% in females and 2.7% in males. Conclusion: Acetabular dysplasia based on radiographic measurements is relatively common in the general adult population. Furthermore, females have a higher prevalence rate when compared to males. It is important to recognize the incidence of hip dysplasia in the asymptomatic adult population as we recommend surgical treatment for patients who present with hip pain and dysplasia. Further studies should investigate the natural history of untreated and treated hip dysplasia. Level of Evidence: III.

Toward high-resolution modeling of small molecule-ion channel interactions.

Ion channels are critical drug targets for a range of pathologies, such as epilepsy, pain, itch, autoimmunity, and cardiac arrhythmias. To develop effective and safe therapeutics, it is necessary to design small molecules with high potency and selectivity for specific ion channel subtypes. There has been increasing implementation of structure-guided drug design for the development of small molecules targeting ion channels. We evaluated the performance of two RosettaLigand docking methods, RosettaLigand and GALigandDock, on the structures of known ligand-cation channel complexes. Ligands were docked to voltage-gated sodium (NaV), voltage-gated calcium (CaV), and transient receptor potential vanilloid (TRPV) channel families. For each test case, RosettaLigand and GALigandDock methods frequently sampled a ligand-binding pose within a root mean square deviation (RMSD) of 1-2 Å relative to the experimental ligand coordinates. However, RosettaLigand and GALigandDock scoring functions cannot consistently identify experimental ligand coordinates as top-scoring models. Our study reveals that the proper scoring criteria for RosettaLigand and GALigandDock modeling of ligand-ion channel complexes should be assessed on a case-by-case basis using sufficient ligand and receptor interface sampling, knowledge about state-specific interactions of the ion channel, and inherent receptor site flexibility that could influence ligand binding.

Galacturonic acid-capsaicin prodrug for prolonged nociceptive-selective nerve blockade.

There is an urgent clinical need to develop nerve-blocking agents capable of inducing long duration sensory block without muscle weakness or paralysis to treat post-operative and chronic pain conditions. Here, we report a galacturonic acid-capsaicin (GalA-CAP) prodrug as an effective nociceptive-selective axon blocking agent. Capsaicin selectively acts on nociceptive signaling without motor nerve blockade or disruption of proprioception and touch sensation, and the galacturonic acid moiety enhance prodrug permeability across the restrictive peripheral nerve barriers (PNBs) via carrier-mediated transport by the facilitative glucose transporters (GLUTs). In addition, following prodrug transport across PNBs, the inactive prodrug is converted to active capsaicin through linker hydrolysis, leading to sustained drug release. A single injection of GalA-CAP prodrug at the sciatic nerves of rats led to nociceptive-selective nerve blockade lasting for 234 ± 37 h, which is a sufficient duration to address the most intense period of postsurgical pain. Furthermore, the prodrug markedly mitigated capsaicin-associated side effects, leading to a notable decrease in systemic toxicity, benign local tissue reactions, and diminished burning and irritant effects.

Individualized throughput metric reports for emergency medicine residents: Impact on time to disposition and resident perceptions.

Background: Research suggests that quantitative metric reports can improve the clinical performance of emergency physicians; however, few studies have examined their effects on physicians in training. The primary study objective was to assess the effects of providing emergency medicine (EM) residents with individualized throughput metrics with regard to emergency department (ED) disposition times. Methods: We performed a single-center, retrospective, observational study from January 2021 to December 2022 examining ED disposition times before and after providing upper-level EM residents individualized throughput metrics. Residents received monthly reports of three specific metrics averaged over the preceding 6 months: (1) median time from room to discharge order (Rm2Dc), (2) median time from return of all results to discharge order (Rlts2Dc), and (3) median time from room and to consult order for hospitalization (Rm2Hosp). Overall mean values of the three metrics before and during metric sharing were compared via independent t-test and stratified by level of training and time of year. Adjusted analysis was performed to control for temporal differences between study periods. Testing was conducted at α = 0.05 level of significance. Results: A total of 35 unique residents were included in the analysis. Overall, mean disposition times were not significantly different before and during reporting of metrics: Rm2Dc (154.8 min vs. 148.9 min, p = 0.109), Rslt2Dc (46.5 min vs. 45.1 min, p = 0.522), and Rm2Hosp (141.7 min vs. 135.7 min, p = 0.257). Subgroup analysis yielded similar results, aside from a significant decrease in mean Rm2Hosp in the postgraduate year-3 (PGY-3) group (145.8 min vs. 124.1 min, p = 0.004). Analysis with adjusted means yielded results similar to those observed with unadjusted data. Conclusions: Overall, individualized throughput metrics were not correlated with decreased average times to ED disposition for upper-level EM residents; however, in the subset of hospitalized patients seen by PGY-3 residents, we observed a mean decrease of 21.7 min to consultation.

Short-Term Memory Capacity Predicts Willingness to Expend Cognitive Effort for Reward.

We must often decide whether the effort required for a task is worth the reward. Past rodent work suggests that willingness to deploy cognitive effort can be driven by individual differences in perceived reward value, depression, or chronic stress. However, many factors driving cognitive effort deployment-such as short-term memory ability-cannot easily be captured in rodents. Furthermore, we do not fully understand how individual differences in short-term memory ability, depression, chronic stress, and reward anticipation impact cognitive effort deployment for reward. Here, we examined whether these factors predict cognitive effort deployment for higher reward in an online visual short-term memory task. Undergraduate participants were grouped into high and low effort groups (n HighEffort = 348, n LowEffort = 81; n Female = 332, n Male = 92, M Age = 20.37, Range Age = 16-42) based on decisions in this task. After completing a monetary incentive task to measure reward anticipation, participants completed short-term memory task trials where they could choose to encode either fewer (low effort/reward) or more (high effort/reward) squares before reporting whether or not the color of a target square matched the square previously in that location. We found that only greater short-term memory ability predicted whether participants chose a much higher proportion of high versus low effort trials. Drift diffusion modeling showed that high effort group participants were more biased than low effort group participants toward selecting high effort trials. Our findings highlight the role of individual differences in cognitive effort ability in explaining cognitive effort deployment choices.

High-resolution single-particle imaging at 100-200 keV with the Gatan Alpine direct electron detector.

Developments in direct electron detector technology have played a pivotal role in enabling high-resolution structural studies by cryo-EM at 200 and 300 keV. Yet, theory and recent experiments indicate advantages to imaging at 100 keV, energies for which the current detectors have not been optimized. In this study, we evaluated the Gatan Alpine detector, designed for operation at 100 and 200 keV. Compared to the Gatan K3, Alpine demonstrated a significant DQE improvement at these voltages, specifically a ∼ 4-fold improvement at Nyquist at 100 keV. In single-particle cryo-EM experiments, Alpine datasets yielded better than 2 Šresolution reconstructions of apoferritin at 120 and 200 keV on a ThermoFisher Scientific (TFS) Glacios microscope fitted with a non-standard SP-Twin lens. We also achieved a ∼ 3.2 Šresolution reconstruction for a 115 kDa asymmetric protein complex, proving its effectiveness with complex biological samples. In-depth analysis revealed that Alpine reconstructions are comparable to K3 reconstructions at 200 keV, and remarkably, reconstruction from Alpine at 120 keV on a TFS Glacios surpassed all but the 300 keV data from a TFS Titan Krios with GIF/K3. Additionally, we show Alpine's capability for high-resolution data acquisition and screening on lower-end systems by obtaining ∼ 3 Šresolution reconstructions of apoferritin and aldolase at 100 keV and detailed 2D averages of a 55 kDa sample using a side-entry cryo holder. Overall, we show that Gatan Alpine performs well with the standard 200 keV imaging systems and may potentially capture the benefits of lower accelerating voltages, possibly bringing smaller sized particles within the scope of cryo-EM.

Systemic Osteoporosis and Osteopenia Among Periprosthetic Fractures After Total Hip Arthroplasty.

BACKGROUND: Most periprosthetic fractures following total hip arthroplasty (THA) are fragility fractures that qualify patients for osteoporosis diagnoses. However, it remains unknown how many patients were diagnosed who had osteoporosis before injury or received the proper evaluation, diagnosis, and treatment after injury. METHODS: We identified 171 Vancouver B2 (109) and B3 (62) periprosthetic femur fractures treated with a modular fluted tapered stem from 2000 to 2018 at one institution. The mean patient age was 75 years (range, 35 to 94), 50% were women, and the mean BMI was 29 (range, 17 to 60). We identified patients who had osteoporosis or osteopenia diagnoses, a fracture risk assessment tool (FRAX), bone mineral density (BMD) testing, an endocrinology consult, and osteoporosis medications. Age-appropriate BMD testing was defined as no later than one year after the recommended ages of 65 (women) or 70 years (men). The mean follow-up was 11 years (range, 4 to 21). RESULTS: Falls from standing height caused 94% of fractures and thus, by definition, qualified as osteoporosis-defining events. The prevalence of osteoporosis diagnosis increased from 20% before periprosthetic fracture to 39% after (P < 0.001). The prevalence of osteopenia diagnosis increased from 13% before the fracture to 24% after (P < 0.001). The prevalence of either diagnosis increased from 24% before fracture to 44% after (P < 0.001). No patients had documented FRAX scores before fracture, and only 2% had scores after. The prevalence of BMD testing was 21% before fracture and 22% after (P = 0.88). By the end of the final follow-up, only 16% had received age-appropriate BMD testing. The proportion of patients who had endocrinology consults increased from 6% before the fracture to 25% after (P < 0.001). The proportion on bisphosphonate therapy was 19% before fracture and 25% after (P = 0.08). CONCLUSIONS: Although most periprosthetic fractures following THA are fragility fractures that qualify patients for osteoporosis diagnoses, there remain major gaps in diagnosis, screening, endocrinology follow-up, and treatment. Like non-arthroplasty fragility fractures, a systematic approach is needed after periprosthetic fractures.

Interleukin-1ß induces and accelerates human endometrial stromal cell senescence and impairs decidualization via the c-Jun N-terminal kinase pathway.

As the mean age of first-time mothers increases in the industrialized world, inquiries into causes of human reproductive senescence have followed. Rates of ovulatory dysfunction and oocyte aneuploidy parallel chronological age, but poor reproductive outcomes in women older than 35 years are also attributed to endometrial senescence. The current studies, using primary human endometrial stromal cell (ESC) cultures as an in vitro model for endometrial aging, characterize the proinflammatory cytokine, IL-1ß-mediated and passage number-dependent effects on ESC phenotype. ESC senescence was accelerated by incubation with IL-1ß, which was monitored by RNA sequencing, ELISA, immunocytochemistry and Western blotting. Senescence associated secreted phenotype (SASP) proteins, IL-1ß, IL-6, IL-8, TNF-α, MMP3, CCL2, CCL5, and other senescence-associated biomarkers of DNA damage (p16, p21, HMGB1, phospho-γ-histone 2 A.X) were noted to increase directly in response to 0.1 nM IL-1ß stimulation. Production of the corresponding SASP proteins increased further following extended cell passage. Using enzyme inhibitors and siRNA interference, these effects of IL-1ß were found to be mediated via the c-Jun N-terminal kinase (JNK) signaling pathway. Hormone-induced ESC decidualization, classical morphological and biochemical endocrine responses to estradiol, progesterone and cAMP stimulation (prolactin, IGFBP-1, IL-11 and VEGF), were attenuated pari passu with prolonged ESC passaging. The kinetics of differentiation responses varied in a biomarker-specific manner, with IGFBP-1 and VEGF secretion showing the largest and smallest reductions, with respect to cell passage number. ESC hormone responsiveness was most robust when limited to the first six cell passages. Hence, investigation of ESC cultures as a decidualization model should respect this limitation of cell aging. The results support the hypotheses that "inflammaging" contributes to endometrial senescence, disruption of decidualization and impairment of fecundity. IL-1ß and the JNK signaling pathway are pathogenetic targets amenable to pharmacological correction or mitigation with the potential to reduce endometrial stromal senescence and enhance uterine receptivity.

Is Workload Associated With Oblique Injuries in Professional Baseball Players?

Background: Oblique strains have become a common injury among professional baseball players. The influence of player workload on oblique strains remains unknown. Purpose/Hypothesis: To determine whether workload is a risk factor for oblique strains in professional baseball players. We hypothesized that fewer days of rest, more innings pitched/fielded per game, and more batters faced/plate appearances per game would significantly increase a player's risk of sustaining an oblique strain. Study Design: Case-control study; Level of evidence, 3. Methods: All professional baseball players who sustained an oblique strain between 2011 and 2017 were identified using the Major League Baseball Health and Injury Tracking System. A separate dataset of player usage-days of rest per game, innings pitched or fielded per game, and batters faced or plate appearances per game-was used to determine the workload. We compared these usage variables between player games ≤2, ≤6, ≤12, and >12 weeks before a documented oblique strain with player games from a control group of players with no oblique strains. In a paired analysis, we compared acute (player games ≤2, ≤6, and ≤12 weeks preinjury) versus chronic (player games >12 weeks preinjury) workloads. Results: There were 311 oblique strains in pitchers and 392 oblique strains in position players during the study period. In pitchers, more innings pitched and more batters faced were associated with a subsequent oblique strain (P < .001 for all). In position players, fewer days of rest, more innings fielded, and more plate appearances were associated with a subsequent oblique strain (P < .001 for all). Pitchers who pitched ≥7 innings per game had a 2.4-fold (95% CI, 1.4-4.9) increased risk of subsequent oblique strain compared with those who pitched 1 inning per game. The percentage of position players with a subsequent oblique strain increased by 2.1-fold (95% CI, 1.3-3.5) with >4 plate appearances compared with 1 plate appearance per game. Conclusion: Our analysis demonstrated that workload was associated with an increased risk of sustaining an oblique injury in professional baseball players. High workload over time was more predictive of oblique strains compared to acute increases over chronic baseline workload.

Risk Factors for Progression of Cervical Congenital Scoliosis and Associated Compensatory Curve Behavior.

Background: This study investigated risk factors for progression of deformity in pediatric congenital cervical scoliosis (CCS) and evaluated the correlation between congenital cervical curves and compensatory thoracic and lumbar curves. Methods: Medical records were retrospectively reviewed for 38 pediatric patients with CCS with a minimum 2-year follow-up. Curve progression was defined as >10° increase in cervical coronal curve angle between presentation and last follow-up. Results: A total of 38 patients (16 girls, 22 boys) with a mean age at presentation of 5.6 ± 4.1 years met the inclusion criteria. Sixteen patients (42%) had curve progression with a mean follow-up of 3.1 ± 3.0 years. At presentation, T1 slope was significantly larger among children with progressive deformities (p = 0.041). A total of 18 of the 38 patients with strictly cervical spine deformity were then selected for subanalysis to evaluate the progression of compensatory curves. Cervical major coronal curves were found to significantly correlate with lumbar major coronal curves (r = 0.409), C2 central sacral vertical line (CSVL) (r = 0.407), and C7-CSVL (r = 0.403) (p < 0.05). Thoracic major coronal curves did not significantly correlate with cervical major coronal curves (r = 0.218) (p > 0.05). Conclusion: In conclusion, 42% of osseous CCS curves progressed over time in the overall cohort, and high initial T1 slope was found to be most highly correlated with progression of cervical deformity. Cervical major coronal curves significantly correlated with lumbar curve magnitude but not with thoracic curve size in isolated CCS, possibly due to the increased flexibility of the lumbar spine which may allow greater compensatory balance and thus have a greater correlation with cervical curve magnitude and possibly progression.

Correction to "Effect of Polymer Composition and Morphology on Mechanochemical Activation in Nanostructured Triblock Copolymers".

[This corrects the article DOI: 10.1021/acs.macromol.2c02475.].

Lifestyle-Related Risk Factors and Primary Prevention Strategies for Cardiovascular Diseases in a Middle-Income Country: A Scoping Review and Implication for Future Research.

Cardiovascular diseases are the leading cause of death in middle-income countries such as Malaysia. There is a significant gap in knowledge between cardiovascular disease-related risk assessments and interventions in the Malaysian population. In this scoping review, we have determined the status of cardiovascular research in Malaysia by prioritising lifestyle-related risk assessments and interventions. We searched five electronic databases (Ovid MEDLINE, Cochrane Central Register of Controlled Trials, APA PsychINFO, Embase and Scopus) to identify relevant research articles that had been published. The Joanna Briggs Institute and the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews served as a guide for the scoping review. Study selection was made using the Covidence platform, screened, and extracted. Thirty-one studies were included in this review. Studies reviewed reported a significant positive association between physical inactivity, smoking, poor dietary patterns, working hours, clustering of lifestyle risk, and cardiovascular disease risk. Most interventions focused on physical activity and a multimodal lifestyle approach, significantly improving primary and secondary cardiovascular disease-related outcomes. The findings suggest improving lifestyle-related risk assessments and interventions to prevent cardiovascular diseases in this population. It is unclear if these outcomes can translate to higher effectiveness in preventing cardiovascular disease. Nevertheless, intervention using the multifaceted lifestyle approach can improve cardiovascular disease-related outcomes.

Recovery rates of persistent post-COVID-19 olfactory dysfunction using psychophysical assessment: A longitudinal cohort study.

Objectives: Persistent olfactory dysfunction (OD) following loss of smell associated with SARS-CoV-2 infection is a major feature of long COVID. Perspectives on the prevalence of persistent OD predominantly rely on self-reported olfactory function. Few studies have tracked longitudinal rates of recovery using psychophysical assessment among patients presenting for evaluation of persistent OD beyond a window of acute recovery. Data anchored in standardized testing methods are needed to counsel patients who fail to acutely regain their sense of smell. This study aims to quantify the degree of persistent OD in post-COVID-19 patients who experience subjective and psychophysical OD. Methods: We grouped participants presenting for OD evaluation into cohorts based on both subjective and psychophysical olfactory status at a baseline assessment and assessed their olfactory abilities with a visual analogue scale and the Sniffin' Sticks extended test at baseline and 1-year time points. Participants had confirmed a history of COVID-19 by lab evaluation or clinical diagnosis if lab evaluation was not available. Results: Baseline olfactory evaluation was completed by 122 participants, 53 of whom completed the 1-year follow-up assessment. Among participants presenting with perceived OD, 74.5% had confirmed psychophysical OD at baseline, with 55.1% at 1-year follow-up. Participants had reliable trends in self-rated versus psychophysically tested olfactory function at both time points. The total threshold, discrimination, and identification (TDI) score improved by +3.25 points in the cohort with psychophysical OD (p = 0.0005), with this improvement largely attributable to an increase in median threshold scores (+2.75 points; p = 0.0004). Conclusions: OD persists in a significant number of patients who fail to acutely recovery their sense of smell after COVID-19, with many demonstrating lingering deficits at 1-year. Improvements in threshold, but not discrimination or identification, most significantly mediate improvement of total TDI score at follow-up.

Long-term impact of type 2 diabetes onset on dementia incidence rate among New Zealanders with impaired glucose tolerance: A tapered-matched landmark analysis over 25 years.

INTRODUCTION: We aimed to investigate the association between the onset of type 2 diabetes (T2D) and dementia incidence rates (IR) in the population with impaired glucose tolerance (IGT) identified in primary care in New Zealand (NZ) over 25 years. METHODS: Tapered matching and landmark analysis (accounting for immortal bias) were used to control for potential effects of known confounders. The association between T2D onset and 5- and 10-year IR of dementia was estimated by weighted Cox models. RESULTS: The onset of T2D was significantly associated with the 10-year IR of dementia, especially in the socioeconomically deprived, those of non-NZ European ethnicity, those currently smoking, and patients with higher metabolic measures. DISCUSSION: Our findings suggest that the onset of T2D is a significant risk factor for dementia in individuals with IGT. Dementia screening and structured diabetes prevention are vital in the population with IGT, particularly those from deprived or ethnic minority backgrounds. HIGHLIGHTS: Increased dementia incidence rate links with T2D onset in people with IGT. Significant incidence varied by ethnicity, socioeconomic status, and health factors. Results emphasize the diabetes manage and socioeconomic factors on dementia risk. Secondary analysis highlights the key role of vascular health in dementia prevention.