Structure-Activity Relationship of Oxacyclo- and Triazolo-Containing Respiratory Syncytial Virus Polymerase Inhibitors.

Despite the availability of medicines preventing respiratory syncytial virus (RSV) infection, post-exposure treatment options are needed for addressing patient's needs. RSV non-nucleoside polymerase inhibitors (NNI) have emerged as a promising asset for which our group previously disclosed JNJ-8003 with potent in vitro antiviral activity and pronounced in vivo efficacy. In this work, a structural-guided design to modify the linker vector of JNJ-8003 resulted in the identification of 2-oxacyclo pyridine-containing derivatives whose various ring closing strategies are described. In addition, bioisosteric replacement of an amide bond with triazole retained potency, and cryo-electron microscopy (cryo-EM) confirmed binding in the capping domain. Subsequent NMR conformational analysis suggested a correlation between the potency and conformations. Our efforts have fulfilled the aim of identifying linker modifications with maintained biological activity while enriching structural diversity and allowing modulations of other parameters.

Pilot implementation of a telehealth course for health professions students.

OBJECTIVES: This study examined the level of technology proficiency amongst healthcare professions students. Additionally, the study provides an evaluation of the pilot implementation, as well as the effect of a 7-module telehealth course on the level of adoption and future use of telehealth amongst future Australian healthcare workforce. METHODS: Students from four health-sciences departments at the University of Melbourne, Australia, participated in this pilot study by completing the course and an online questionnaire, which included both structured and open-ended questions. The questionnaire included: 12-items on socio-demographic and Internet utilization; 34-items about acceptance and use of telehealth adapted from the Unified Theory of Acceptance and Use of Technology (UTAUT2) questionnaire; and 22-items about confidence in using the Internet and ICT, adapted from Technology Proficiency Self-Assessment Questionnaire for 21st Century Learning (TPSA-C-21). RESULTS: The evaluation included 26 students who expressed confidence in their Internet/ICT skills They showed enthusiasm for telehealth and recognized its potential benefits, but also emphasized the value of face-to-face interactions. They requested information on legal and aspects and additional learning. Post-test assessments indicated improvements in overall acceptance and use attitudes towards telehealth and on six dimensions of the UTAUT2 instrument. Participation in the course indicated improvements in students' overall acceptance and use attitudes and on six of the ten dimensions of the UTAUT2 instrument (p < 0.05). CONCLUSION: This preliminary evaluation indicated that the telehealth course was a positive and enjoyable learning experience for students with appropriate structure and information. The course was successful in improving students' acceptance and use of health technology. The study identified areas in which further development might be required. As such, the course represents a helpful approach for telehealth training among health professions students. Further evaluation with larger samples is required.

Unforeseen plant phenotypic diversity in a dry and grazed world.

Earth harbours an extraordinary plant phenotypic diversity1 that is at risk from ongoing global changes2,3. However, it remains unknown how increasing aridity and livestock grazing pressure-two major drivers of global change4-6-shape the trait covariation that underlies plant phenotypic diversity1,7. Here we assessed how covariation among 20 chemical and morphological traits responds to aridity and grazing pressure within global drylands. Our analysis involved 133,769 trait measurements spanning 1,347 observations of 301 perennial plant species surveyed across 326 plots from 6 continents. Crossing an aridity threshold of approximately 0.7 (close to the transition between semi-arid and arid zones) led to an unexpected 88% increase in trait diversity. This threshold appeared in the presence of grazers, and moved toward lower aridity levels with increasing grazing pressure. Moreover, 57% of observed trait diversity occurred only in the most arid and grazed drylands, highlighting the phenotypic uniqueness of these extreme environments. Our work indicates that drylands act as a global reservoir of plant phenotypic diversity and challenge the pervasive view that harsh environmental conditions reduce plant trait diversity8-10. They also highlight that many alternative strategies may enable plants to cope with increases in environmental stress induced by climate change and land-use intensification.

Predictability in Achieving Target Intervertebral Lordosis Using Personalized Interbody Implants.

BACKGROUND: Lumbar lordosis distribution has become a pivotal factor in re-establishing the foundational alignment of the lumbar spine. This can directly influence overall sagittal alignment, leading to improved long-term outcomes for patients. Despite the wide availability of hyperlordotic stock cages intended to achieve optimal postoperative alignment, there is a lack of correlation between the lordotic shape of a cage and the resultant intervertebral alignment. Recently, personalized spine surgery has witnessed significant advancements, including 3D-printed personalized interbody implants, which are customized to the surgeon's treatment and alignment goals. This study evaluates the reliability of 3D-printed patient-specific interbody implants to achieve the planned postoperative intervertebral alignment. METHODS: This is a retrospective study of 217 patients with spinal deformity or degenerative conditions. Patients were included if they received 3D-printed personalized interbody implants. The desired intervertebral lordosis (IVL) angle was prescribed into the device design for each personalized interbody (IVL goal). Standing postoperative radiographs were measured, and the IVL offset was calculated as IVL achieved minus IVL goal. RESULTS: In this patient population, 365 personalized interbodies were implanted, including 145 anterior lumbar interbody fusions (ALIFs), 99 lateral lumbar interbody fusions (LLIFs), and 121 transforaminal lumbar interbody fusions. Among the 365 treated levels, IVL offset was 1.1° ± 4.4° (mean ± SD). IVL was achieved within 5° of the plan in 299 levels (81.9%). IVL offset depended on the approach of the lumbar interbody fusion and was achieved within 5° for 85.9% of LLIF, 82.6% of transforaminal lumbar interbody fusions and 78.6% of ALIFs. Ten levels (2.7%) missed the planned IVL by >10°. ALIF and LLIF levels in which the plan was missed by more than 5° tended to be overcorrected. CONCLUSIONS: This study supports the use of 3D-printed personalized interbody implants to achieve planned sagittal intervertebral alignment. CLINICAL RELEVANCE: Personalized interbody implants can consistently achieve IVL goals and potentially impact foundational lumbar alignment.

Mismatch Between Pelvic Incidence and Lumbar Lordosis After Personalized Interbody Fusion: The Importance of Preoperative Planning and Alignment in Degenerative Spine Diseases.

BACKGROUND: Emerging data have highlighted the significance of planning and aligning total and segmental lumbar lordosis with pelvic morphology when performing short-segment fusion with the goal of reducing the risk of adjacent segment disease while also decreasing spine-related disability. This study evaluates the impact of personalized interbody implants in restoring pelvic incidence-lumbar lordosis (PI-LL) mismatch compared with a similar study using stock interbody implants. METHODS: This multicenter retrospective analysis assessed radiographic pre- and postoperative spinopelvic alignment (PI-LL) in patients who underwent 1- or 2-level lumbar fusions with personalized interbody implants for degenerative (nondeformity) indications. The aim was to assess the incidence of malalignment (PI-LL ≥ 10°) both before and after fusion surgery and to determine the rate of alignment preservation and/or correction in this population. RESULTS: There were 135 patients included in this study. Of 83 patients who were aligned preoperatively, alignment was preserved in 76 (91.6%) and worsened in 7 (8.4%). Among the 52 preoperatively malaligned patients, alignment was restored in 23 (44.2%), and 29 (55.8%) were not fully corrected. Among patients who were preoperatively aligned, there was no statistically significant difference in either the "preserved" or "worsened" groups between stock devices and personalized interbody devices. In contrast, among patients who were preoperatively malaligned, there was a statistically significant increase in the "restored" group (P = 0.046) and a statistically significant decrease in the "worsened" groups in patients with personalized interbodies compared with historical stock device data (P < 0.05). CONCLUSIONS: Compared with a historical cohort with stock implants, personalized interbody implants in short-segment fusions have shown a statistically significant improvement in restoring patients to normative PI-LL. Using 3-dimensional preoperative planning combined with personalized implants provides an important tool for planning and achieving improvement in spinopelvic parameters.

Changes in Alignment at Untreated Vertebral Levels Following Short-Segment Fusion Using Personalized Interbody Cages: Leveraging Personalized Medicine to Reduce the Risk of Reoperation.

BACKGROUND: An abnormal postoperative lordosis distribution index (LDI), which quantifies the ratio between the lordosis at L4 to S1 and the lordosis at L1 to S1, contributes to the development of adjacent segment disease and increased revision rates in patients undergoing short-segment lumbar intervertebral fusions. Incorporating preoperative spinopelvic parameters and LDI into the surgical plan for short-segment fusion is important for guiding alignment restoration and preserving normal preoperative alignment in unfused segments. This study examined changes in LDI, segmental lordosis, and lordosis of the unfused levels in patients treated with personalized interbody cage (PIC) implants. METHODS: This retrospective study evaluated radiographic measurements from 111 consecutively treated patients diagnosed with degenerative spinal conditions and treated with a short-segment fusion of L4 to L5, L5 to S1, or L4 to S1 using PIC implant(s) within 6 months of the fusion procedure. Comparisons of intervertebral lordosis for treated and untreated levels as well as LDI pre- and postoperatively were performed. RESULTS: In patients with a preoperative hypolordotic distribution (LDI < 50%), statistically significant increases were found in LDI postoperatively, approaching the normal LDI range (LDI 50%-80%). Likewise, patients with hyperlordotic distribution preoperatively (LDI > 80%) experienced a decrease in LDI postoperatively, trending toward the normal range, although the changes were not statistically significant. Intervertebral lordosis for the L5 to S1 level increased significantly following the placement of a PIC in the normal and hypolordotic LDI groups. Changes in intervertebral lordosis for L5 to S1 were not significant for patients with preoperative hyperlordotic LDI. Reciprocal changes in intervertebral lordosis at L1 to L4 were not observed in any groups. CONCLUSIONS: PIC implants may provide a benefit for patients, particularly those with hypolordotic distributions preoperatively. They have the potential to further improve patient outcomes by helping surgeons to achieve patient-specific lordosis goals, which may help to reduce the risk of adjacent segment disease and revisions in patients undergoing short-segment lumbar intervertebral fusions. CLINICAL RELEVANCE: Personalized implants can help surgeons achieve patient-specific alignment goals, potentially prevent adjacent segment disease, and reduce long-term reinterventions.

Tomographic Assessment of Fusion Rate, Implant-Endplate Contact Area, Subsidence, and Alignment With Lumbar Personalized Interbody Implants at 1-Year Follow-Up.

BACKGROUND: Incongruity between irregularly shaped vertebral endplates and the uniform surfaces of stock interbody fusion cages has been identified as contributing to cage subsidence, pseudarthrosis, and unpredictable alignment. Advances in manufacturing techniques have driven the development of personalized interbody cages (PICs) that can match individual endplate morphology and provide the exact shape and size needed to fill the disc space and achieve the planned correction. This study used computed tomography (CT) imaging to evaluate the implant-endplate contact area, fusion, subsidence, and achievement of planned alignment correction in patients receiving PIC devices. METHODS: This retrospective study included patients treated for adult spinal deformity at a single site and implanted with PIC devices at L4 to L5 or L5 to S1 for segmental stabilization and alignment correction, who received 1-year postoperative CT images as part of their standard of care. An evaluation using 3-dimensional thin-section scans was conducted. Implant-endplate contact and signs of fusion were assessed in each CT slice across both endplates. The degree of subsidence as well as measures of segmental and global lumbar alignment were also assessed. RESULTS: Fifteen patients were included in the study, with a mean age of 68.2 years. Follow-up ranged between 9 and 14 months. Twenty-six total lumbar levels were implanted; 20 with PIC devices via the anterior lumbar interbody fusion approach, 2 with stock cages via the anterior lumbar interbody fusion approach, and 4 with PIC devices via the transforaminal lumbar interbody fusion approach. CT analysis of PIC-implanted levels found an overall implant-endplate contact area ratio of 93.9%, a subsidence rate of 4.5%, a fusion rate of 100%, and satisfactory segmental and global lumbar correction compared with the preoperative plan. CONCLUSIONS: PIC implants can provide nearly complete contact with endplate surfaces regardless of the individual endplate morphology. Subsidence, fusion, and alignment assessments in this tomographic study illustrated results consistent with the benefits of a personalized interbody implant.

Spinal Cord Injury Associated Disease of the Skeleton, an Unresolved Problem with Need for Multimodal Interventions.

Spinal cord injury is associated with skeletal unloading, sedentary behavior, decreases in skeletal muscle mass, and exercise intolerance, which results in rapid and severe bone loss. To date, monotherapy with physical interventions such as weight-bearing in standing frames, computer-controlled electrically stimulated cycling and ambulation exercise, and low-intensity vibration are unsuccessful in maintaining bone density after SCI. Strategies to maintain bone density with commonly used osteoporosis medications also fail to provide a significant clinical benefit, potentially due to a unique pathology of bone deterioration in SCI. In this review, the available data is discussed on evaluating and monitoring bone loss, fracture, and physical and pharmacological therapeutic approaches to SCI-associated disease of the skeleton. The treatment of SCI-associated disease of the skeleton, the implications for clinical management, and areas of need are considered for future investigation.

Exploring xylose metabolism in non-conventional yeasts: kinetic characterization and product accumulation under different aeration conditions.

d-Xylose is a metabolizable carbon source for several non-Saccharomyces species, but not for native strains of S. cerevisiae. For the potential application of xylose-assimilating yeasts in biotechnological processes, a deeper understanding of pentose catabolism is needed. This work aimed to investigate the traits behind xylose utilization in diverse yeast species. The performance of 9 selected xylose-metabolizing yeast strains was evaluated and compared across 3 oxygenation conditions. Oxygenation diversely impacted growth, xylose consumption, and product accumulation. Xylose utilization by ethanol-producing species such as Spathaspora passalidarum and Scheffersomyces stipitis was less affected by oxygen restriction compared with other xylitol-accumulating species such as Meyerozyma guilliermondii, Naganishia liquefaciens, and Yamadazyma sp., for which increased aeration stimulated xylose assimilation considerably. Spathaspora passalidarum exhibited superior conversion of xylose to ethanol and showed the fastest growth and xylose consumption in all 3 conditions. By performing assays under identical conditions for all selected yeasts, we minimize bias in comparisons, providing valuable insight into xylose metabolism and facilitating the development of robust bioprocesses. ONE-SENTENCE SUMMARY: This work aims to expand the knowledge of xylose utilization in different yeast species, with a focus on how oxygenation impacts xylose assimilation.

Evaluating the American Heart Association/American College of Cardiology Guideline-Recommended and Contemporary Pretest Probability Models in a Mixed Asian Cohort: The Contribution of Coronary Artery Calcium.

BACKGROUND: Most pretest probability (PTP) tools for obstructive coronary artery disease (CAD) were Western -developed. The most appropriate PTP models and the contribution of coronary artery calcium score (CACS) in Asian populations remain unknown. In a mixed Asian cohort, we compare 5 PTP models: local assessment of the heart (LAH), CAD Consortium (CAD2), risk factor-weighted clinical likelihood, the American Heart Association/American College of Cardiology and the European Society of Cardiology PTP and 3 extended versions of these models that incorporated CACS: LAH(CACS), CAD2(CACS), and the CACS-clinical likelihood. METHODS AND RESULTS: The study cohort included 771 patients referred for stable chest pain. Obstructive CAD prevalence was 27.5%. Calibration, area under the receiver-operating characteristic curves (AUC) and net reclassification index were evaluated. LAH clinical had the best calibration (χ2 5.8; P=0.12). For CACS models, LAH(CACS) showed least deviation between observed and expected cases (χ2 37.5; P<0.001). There was no difference in AUCs between the LAH clinical (AUC, 0.73 [95% CI, 0.69-0.77]), CAD2 clinical (AUC, 0.72 [95% CI, 0.68-0.76]), risk factor-weighted clinical likelihood (AUC, 0.73 [95% CI: 0.69-0.76) and European Society of Cardiology PTP (AUC, 0.71 [95% CI, 0.67-0.75]). CACS improved discrimination and reclassification of the LAH(CACS) (AUC, 0.88; net reclassification index, 0.46), CAD2(CACS) (AUC, 0.87; net reclassification index, 0.29) and CACS-CL (AUC, 0.87; net reclassification index, 0.25). CONCLUSIONS: In a mixed Asian cohort, Asian-derived LAH models had similar discriminatory performance but better calibration and risk categorization for clinically relevant PTP cutoffs. Incorporating CACS improved discrimination and reclassification. These results support the use of population-matched, CACS-inclusive PTP tools for the prediction of obstructive CAD.

A plasma protein-based risk score to predict hip fractures.

As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined.

Acute Coronary Syndrome at Altitude: Diagnostic Dilemma on Aconcagua Using Point-of-Care Ultrasound.

At the Plaza de Mulas medical tent, located at 4300 m (14,100 ft) along the Normal Route to the 6960 m (22,837 ft) summit of Aconcagua in Argentina, a Korean male in his 50s with no known medical conditions presented with lightheadedness and shortness of breath. He had taken sildenafil and acetazolamide that morning without improvement. Vital signs on arrival were notable for oxygen saturations in the high 60s with basilar crackles on lung auscultation, concerning for high altitude pulmonary edema. The patient was started on oxygen via nasal cannula and given dexamethasone. History was limited secondary to language barriers, but on review of systems the patient noted mild chest pressure. Bedside cardiac echocardiogram was performed, which revealed a septal wall motion abnormality. The patient was therefore given aspirin and clopidogrel and was flown to a lower trailhead, where he was met by local Emergency Medical Services. A 12-lead electrocardiogram revealed an anterior ST-elevation myocardial infarction, and the patient was taken emergently to the catheterization lab in Mendoza and underwent stent placement with a full recovery.

Temporal trends in the contribution of modifiable cardiovascular risk factors to cardiovascular and all-cause mortality in patients undergoing myocardial perfusion imaging in a large city in Brazil.

BACKGROUND: Most cardiovascular (CV) events stem from modifiable risk factors, but it remains uncertain whether their impact on mortality has decreased in recent years as a result of treatment, particularly in low- and middle-income countries. We evaluated the temporal trends in the population attributable fraction (PAF) of modifiable risk factors to CV mortality in patients undergoing myocardial perfusion imaging (MPI) for suspected coronary artery disease in a large city in Brazil. METHODS: The cohort comprised 25,127 patients without established CV disease undergoing MPI in a referral center in Curitiba, Brazil, from 2010 to 2018. Baseline demographic, clinical and risk factors were prospectively collected. Modifiable risk factors encompassed hypertension, dyslipidemia, diabetes mellitus, sedentary lifestyle, obesity, and smoking. The primary outcome was CV death occurring up to 4 years of follow-up. The PAF of each risk factor was calculated for each triennium using multivariable Cox proportional regression models, adjusting for age, sex and family history of premature coronary disease. RESULTS: Over 9 years, there were 1438 deaths, 444 due to CV causes. In the first triennium, sedentary lifestyle exhibited the highest PAF (49%) for CV death, followed by hypertension (17%), diabetes mellitus (8%) and smoking habit (6%). The PAF for all risk factors combined remained relatively stable thorough the triennia (2010-2012: 57% vs 2013-2015: 64% vs 2016-2018: 47%, p = NS). CONCLUSION: In this large cohort of patients referred to MPI, the PAF of modifiable CV risk factors did not diminish in the last decade, with sedentary lifestyle having the largest contribution for CV mortality. CONDENSED ABSTRACT: This study examinated temporal trends in the impact of modifiable cardiovascular (CV) risk factors on CV and overall mortality in a cohort of 25,127 patients undergoing myocardial perfusion imaging from 2010 to 2018. Sedentary behavior consistently had the greatest impact on both CV and overall mortality, followed by hypertension and diabetes. Smoking had a lesser effect, while obesity showed no independent association with the outcomes. The contributions of these modifiable CV risk factors remained stable over the study period, suggesting that interventions promoting physical activity may be essential in mitigating the burden of CV disease.

Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC.

Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.

Hotspots of biogeochemical activity linked to aridity and plant traits across global drylands.

Perennial plants create productive and biodiverse hotspots, known as fertile islands, beneath their canopies. These hotspots largely determine the structure and functioning of drylands worldwide. Despite their ubiquity, the factors controlling fertile islands under conditions of contrasting grazing by livestock, the most prevalent land use in drylands, remain virtually unknown. Here we evaluated the relative importance of grazing pressure and herbivore type, climate and plant functional traits on 24 soil physical and chemical attributes that represent proxies of key ecosystem services related to decomposition, soil fertility, and soil and water conservation. To do this, we conducted a standardized global survey of 288 plots at 88 sites in 25 countries worldwide. We show that aridity and plant traits are the major factors associated with the magnitude of plant effects on fertile islands in grazed drylands worldwide. Grazing pressure had little influence on the capacity of plants to support fertile islands. Taller and wider shrubs and grasses supported stronger island effects. Stable and functional soils tended to be linked to species-rich sites with taller plants. Together, our findings dispel the notion that grazing pressure or herbivore type are linked to the formation or intensification of fertile islands in drylands. Rather, our study suggests that changes in aridity, and processes that alter island identity and therefore plant traits, will have marked effects on how perennial plants support and maintain the functioning of drylands in a more arid and grazed world.

Simulation in pediatric anesthesiology: current state and visions for the future.

PURPOSE OF REVIEW: Simulation is a well established practice in medicine. This review reflects upon the role of simulation in pediatric anesthesiology in three parts: training anesthesiologists to care for pediatric patients safely and effectively; evaluating and improving systems of care for children; and visions for the future. RECENT FINDINGS: Simulation continues to prove a useful modality to educate both novice and experienced clinicians in the perioperative care of infants and children. It is also a powerful tool to help analyze and improve upon how care is provided to infants and children. Advances in technology and computational power now allow for a greater than ever degree of innovation, accessibility, and focused reflection and debriefing, with an exciting outlook for promising advances in the near future. SUMMARY: Simulation plays a key role in developing and achieving peak performance in the perioperative care of infants and children. Although simulation already has a great impact, its full potential is yet to be harnessed.

Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5 K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P < 1.0 × 10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.

Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. To increase the understanding of the underlying mechanisms, we performed a meta-analysis of the associations between 4860 circulating proteins and risk of fractures using two large cohorts, including 6430 participants with 643 incident hip fractures. We identified 23 proteins/aptamers associated with incident hip fractures. Two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR were most strongly associated with hip fracture risk. High levels of several inflammation-related proteins were also associated with increased hip fracture risk. Pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. Future mechanistic studies should investigate the underlying biology of these novel protein biomarkers which may be potential drug targets.