Category: Nevin Manimala

J Bone Miner Res. 2024 Jan 4:zjad011. doi: 10.1093/jbmr/zjad011. Online ahead of print.

ABSTRACT

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.

PMID:38477735 | DOI:10.1093/jbmr/zjad011

J Phys Chem A. 2024 Mar 13. doi: 10.1021/acs.jpca.4c01159. Online ahead of print.

ABSTRACT

Single water molecules alone may introduce unusual features into the kinetics and dynamics of chemical reactions. The singly hydrated hydroperoxide anion, HOO^–(H₂O), was found to be a shapeshifting nucleophile, which can be transformed to HO^– solvated by hydrogen peroxide HO^–(HOOH). Herein, we performed direct dynamics simulations of its reaction with methyl iodide to investigate the effect of individual water molecules. In addition to the normal S_N2 product CH₃OOH, the thermodynamically unfavored proton transfer-induced HO^–-S_N2 path (produces CH₃OH) was also observed, contributing ∼4%. The simulated branching ratio of the HO^–-S_N2 path exceeded the statistical estimation (0.6%) based on the free energy barrier difference. The occurrence of the HO^–-S_N2 path was attributed to the shallow entrance channel well before a submerged saddle point, thus providing a region for extensive proton exchange and ultimately leading to the formation of CH₃OH. In comparison, changing the leaving group from Cl to I increased the overall reaction rate as well as the proportion of the HO^–-S_N2 path because the CH₃I system has a smaller internal barrier. This work elucidates the importance of the dynamic effect introduced by a single solvent molecule to alter the product channel and kinetics of typical ion-molecule S_N2 reactions.

PMID:38477711 | DOI:10.1021/acs.jpca.4c01159

Elife. 2024 Mar 13;12:RP88559. doi: 10.7554/eLife.88559.

ABSTRACT

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here, we combine RNA sequencing with selective pharmacological, chemogenetic, and optogenetic manipulations to isolate the contribution of the locus coeruleus-noradrenaline (LC-NA) system to the acute stress response in mice. We reveal that NA release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, and independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC-mediated hippocampal function and offer new molecular targets for understanding how NA impacts brain function in health and disease.

PMID:38477670 | DOI:10.7554/eLife.88559

Int Wound J. 2024 Mar;21(3):e14773. doi: 10.1111/iwj.14773.

ABSTRACT

This study aims to comprehensively compare the effects of unicondylar knee arthroplasty (UKA) and high tibial osteotomy (HTO) on wound infection and pain in patients with medial knee osteoarthritis. A computerized search was conducted in Embase, PubMed, Google Scholar, China National Knowledge Infrastructure, Cochrane Library and Wanfang databases, from database inception to October 2023, for studies comparing UKA and HTO for medial knee osteoarthritis. Studies selection, data extraction and study quality evaluation were independently conducted by two researchers. Stata 17.0 software was employed for data analysis. Overall, 10 studies involving 870 patients with medial knee osteoarthritis were included. It was found that the UKA group had significantly lower wound visual analogue scale scores compared to the HTO group (SMD = -0.53, 95%CI: -0.87 to -0.20, p < 0.001). The incidence of wound infection in the UKA group was higher than in the HTO group (OR = 1.92, 95%CI: 0.65-5.69, p = 0.240), and the incidence of complications was lower (OR = 0.89, 95%CI: 0.52-1.54, p = 0.684), though these differences were not statistically significant. This study indicates that UKA is effective in alleviating postoperative wound pain in medial knee osteoarthritis. However, the rates of postoperative wound infection and complications are comparable to those of HTO. Clinicians should consider factors such as patient age and disease severity in making individualized treatment decisions.

PMID:38477639 | DOI:10.1111/iwj.14773

Med Phys. 2024 Mar 13. doi: 10.1002/mp.17025. Online ahead of print.

ABSTRACT

BACKGROUND: Accurate measurement of ureteral diameters plays a pivotal role in diagnosing and monitoring urinary tract obstruction (UTO). While three-dimensional magnetic resonance urography (3D MRU) represents a significant advancement in imaging, the traditional manual methods for assessing ureteral diameters are characterized by labor-intensive procedures and inherent variability. In the realm of medical image analysis, deep learning has led to a paradigm shift, yet the development of a comprehensive automated tool for the precise segmentation and measurement of ureters in MR images is an unaddressed challenge.

PURPOSE: The ureter was quantitatively measured on 3D MRU images using a deep learning model.

METHODS: A retrospective cohort of 445 3D MRU scans (443 patients, 52 ± 18 years; 217 female patients) was collected and split into training, validation, and internal testing cohorts. A 3D V-Net model was trained for urinary tract segmentation, and a post-processing algorithm was developed for ureteral measurements. The accuracy of the segmentation was evaluated using the Dice similarity coefficient (DSC) and volume intraclass correlation coefficient (ICC), with ground truth segmentations provided by experienced radiologists. The external cohort comprised 50 scans (50 patients, 55 ± 21 years; 30 female patients), and the model-predicted ureteral diameter measurements were compared with manual measurements to assess system performance. The various diameter parameters of ureter among the different measurement methods (ground truth, auto-segmentation with automatic diameter extraction, and manual segmentation with automatic diameter extraction) were assessed with Friedman tests and post hoc Dunn test. The effectiveness of the UTO diagnosis was assessed by receiver operating characteristic (ROC) curves and their respective areas under the curve (AUC) between different methods.

RESULTS: In both the internal test and external cohorts, the mean DSC values for bilateral ureters exceeded 0.70. The ICCs for the bilateral ureter volume obtained by comparing the model and manual segmentation were all greater than 0.96 (p < 0.05), except for the right ureter in the internal test cohort, for which the ICC was 0.773 (p < 0.05). The mean DSCs for interobserver and intraobserver reliability were all above 0.97. The maximum diameter of the ureter exhibited no statistically significant differences either in the dilated (p = 0.08) or in the non-dilated (p = 0.32) ureters across the three measurement methods. The AUCs of ground truth, auto-segmentation with automatic diameter extraction, and manual segmentation with automatic diameter extraction in diagnosing UTO were 0.988 (95% CI: 0.934, 1.000), 0.961 (95% CI: 0.893, 0.991), and 0.979 (95% CI: 0.919, 0.998), respectively. There was no statistical difference between AUCs of the different methods (p > 0.05).

CONCLUSION: The proposed deep learning model and post-processing algorithm provide an effective means for the quantitative evaluation of urinary diseases using 3D MRU images.

PMID:38477634 | DOI:10.1002/mp.17025

Health Technol Assess. 2024 Mar;28(10):1-213. doi: 10.3310/MVFR4028.

ABSTRACT

BACKGROUND: The indications for septoplasty are practice-based, rather than evidence-based. In addition, internationally accepted guidelines for the management of nasal obstruction associated with nasal septal deviation are lacking.

OBJECTIVE: The objective was to determine the clinical effectiveness and cost-effectiveness of septoplasty, with or without turbinate reduction, compared with medical management, in the management of nasal obstruction associated with a deviated nasal septum.

DESIGN: This was a multicentre randomised controlled trial comparing septoplasty, with or without turbinate reduction, with defined medical management; it incorporated a mixed-methods process evaluation and an economic evaluation.

SETTING: The trial was set in 17 NHS secondary care hospitals in the UK.

PARTICIPANTS: A total of 378 eligible participants aged > 18 years were recruited.

INTERVENTIONS: Participants were randomised on a 1: 1 basis and stratified by baseline severity and gender to either (1) septoplasty, with or without turbinate surgery (n = 188) or (2) medical management with intranasal steroid spray and saline spray (n = 190).

MAIN OUTCOME MEASURES: The primary outcome was the Sino-nasal Outcome Test-22 items score at 6 months (patient-reported outcome). The secondary outcomes were as follows: patient-reported outcomes – Nasal Obstruction Symptom Evaluation score at 6 and 12 months, Sino-nasal Outcome Test-22 items subscales at 12 months, Double Ordinal Airway Subjective Scale at 6 and 12 months, the Short Form questionnaire-36 items and costs; objective measurements – peak nasal inspiratory flow and rhinospirometry. The number of adverse events experienced was also recorded. A within-trial economic evaluation from an NHS and Personal Social Services perspective estimated the incremental cost per (1) improvement (of ≥ 9 points) in Sino-nasal Outcome Test-22 items score, (2) adverse event avoided and (3) quality-adjusted life-year gained at 12 months. An economic model estimated the incremental cost per quality-adjusted life-year gained at 24 and 36 months. A mixed-methods process evaluation was undertaken to understand/address recruitment issues and examine the acceptability of trial processes and treatment arms.

RESULTS: At the 6-month time point, 307 participants provided primary outcome data (septoplasty, n = 152; medical management, n = 155). An intention-to-treat analysis revealed a greater and more sustained improvement in the primary outcome measure in the surgical arm. The 6-month mean Sino-nasal Outcome Test-22 items scores were -20.0 points lower (better) for participants randomised to septoplasty than for those randomised to medical management [the score for the septoplasty arm was 19.9 and the score for the medical management arm was 39.5 (95% confidence interval -23.6 to -16.4; p < 0.0001)]. This was confirmed by sensitivity analyses and through the analysis of secondary outcomes. Outcomes were statistically significantly related to baseline severity, but not to gender or turbinate reduction. In the surgical and medical management arms, 132 and 95 adverse events occurred, respectively; 14 serious adverse events occurred in the surgical arm and nine in the medical management arm. On average, septoplasty was more costly and more effective in improving Sino-nasal Outcome Test-22 items scores and quality-adjusted life-years than medical management, but incurred a larger number of adverse events. Septoplasty had a 15% probability of being considered cost-effective at 12 months at a £20,000 willingness-to-pay threshold for an additional quality-adjusted life-year. This probability increased to 99% and 100% at 24 and 36 months, respectively.

LIMITATIONS: COVID-19 had an impact on participant-facing data collection from March 2020.

CONCLUSIONS: Septoplasty, with or without turbinate reduction, is more effective than medical management with a nasal steroid and saline spray. Baseline severity predicts the degree of improvement in symptoms. Septoplasty has a low probability of cost-effectiveness at 12 months, but may be considered cost-effective at 24 months. Future work should focus on developing a septoplasty patient decision aid.

TRIAL REGISTRATION: This trial is registered as ISRCTN16168569 and EudraCT 2017-000893-12.

FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/226/07) and is published in full in Health Technology Assessment; Vol. 28, No. 10. See the NIHR Funding and Awards website for further award information.

PMID:38477237 | DOI:10.3310/MVFR4028

Tunis Med. 2024 Dec 5;101(12):912-916.

ABSTRACT

INTRODUCTION: Tunnel enlargement following anterior cruciate ligament (ACL) reconstruction has been frequently reported since the nineties, yet its etiologies remain unclear.

AIM: To elucidate the factors favoring this phenomenon and to investigate its clinical and anatomical consequences.

METHODS: This was a descriptive retrospective study conducted on 37 patients who underwent ACL reconstruction surgery using single-bundle hamstring tendons with fixation using absorbable interference screws at the Traumatology Department of the Kassab National Institute of Orthopedics. The patients were collected between January 2014 and September 2016. Tunnel enlargement, footprint, and tunnel orientation were assessed using standard knee radiographs. At follow-up, patients were evaluated using functional scores (Lysholm, Tegner, and IKDC), clinical examination, and Telos radiographs.

RESULTS: The average global Tunnel enlargement was 51.7% in the femur and 48.88% in the tibia. Femoral tunnel enlargement values were higher than tibial tunnel enlargement at all measurement levels, and it appeared to be a time-evolving phenomenon. Factors favoring tunnel enlargement seemed to include advanced age, male gender, delayed surgery, accelerated rehabilitation protocols, non-compliant placement of transplant footprints, and tunnel horizontalization. Tunnel enlargement did not influence functional scores (Lysholm, Tegner, and IKDC). However, based on the differential study of Telos radiographs, femoral and tibial tunnel enlargement in the lax knees group (38% of cases) was higher than in the stable knees group (62%). Nonetheless, our results were statistically non-significant with respective p-values of 0.584 and 0.53.

CONCLUSION: Several modifiable factors such as delayed surgery, accelerated rehabilitation protocols, incorrect footprint placement, and tunnel orientation appeared to influence the tunnel enlargement phenomenon. However, prospective studies with a larger sample would be necessary to confirm these findings.

PMID:38477200

Tunis Med. 2024 Dec 5;101(12):899-902.

ABSTRACT

INTRODUCTION: The constant increase of both esthetic demands and advancement in materials and technologies have led to the development of guidelines to achieve optimal aesthetic results. These tools are useful to predict the teeth proportion and dimensions. Golden and Red proportion are the most described theories.

AIM: of present study was to evaluate the existence of both Golden and Red proportion in the maxillary anterior teeth among a North-African population.

METHODS: This was an observational study performed at the Fixed Prosthetic department of the dental clinic of Monastir, Tunisia. The study included participants with full intact anterior dentition. Those with diastema or teeth crowding were excluded. For each one, an alginate impression was done. Measures were, including the perceived width and length, have been taken on casts using digital caliper. Width ratios of maxillary lateral incisor to maxillary central incisor and lateral incisor to canine were calculated.

RESULTS: The study included 100 Tunisian participants including 97 females and 21 males. The maxillary central incisors were the largest (8.60±0.58mm) and the longest (99.71±1.14mm). The ratio was 0.89±0.09mm. Anterior teeth dimensions were not statistically not different between males and females. Significant differences were observed between calculated ratios with GP and to each other’s. (p=0).

CONCLUSIONS: Either GP nor RP is applicable amongst the Tunisian Population.

PMID:38477197

Ultrasound Obstet Gynecol. 2024 Mar 13. doi: 10.1002/uog.27643. Online ahead of print.

ABSTRACT

OBJECTIVE: Large-for-gestational-age (LGA) is associated with several adverse maternal and neonatal outcomes. Although many studies have found that early induction of labor (eIOL) in LGA reduces the incidence of shoulder dystocia (SD), no current guidelines recommend this particular strategy, due to concerns about increased rates of cesarean delivery (CD) and neonatal complications. The purpose of this study was to assess whether the timing of IOL in LGA fetuses affects maternal and neonatal outcomes in a single center; and to combine these results with the evidence reported in the literature.

METHODS: This study comprised two parts. The first was a retrospective cohort study that included: consecutive patients with singleton pregnancy, an estimated fetal weight (EFW) ≥90^th percentile on ultrasound (US) between 35+0 and 39+0 weeks of gestation (WG), who were eligible for normal vaginal delivery. The second part was a systematic review of literature and meta-analysis that included the results of the first part as well as all previously reported studies that have compared IOL to expectant management in patients with LGA. The perinatal outcomes were CD, operative vaginal delivery (OVD), SD, brachial plexus palsy, anal sphincter injury, postpartum hemorrhage (PPH), APGAR score, umbilical arterial pH, neonatal intensive care unit (NICU) admission, use of continuous positive airway pressure (CPAP), intracranial hemorrhage (ICH), phototherapy, and bone fracture.

RESULTS: Retrospective cohort: of the 547 patients, 329 (60.1%) were induced and 218 (39.9%) entered spontaneous labor. Following covariate balancing, CD was significantly higher in the IOL group in comparison to the spontaneous labor group. This difference only became apparent beyond 40WG (hazard ratio: 1.9, p=0.030). The difference between both groups for shoulder dystocia was not statistically significant. Systematic review and metanalysis: 17 studies were included in addition to our own results giving a total sample size of 111,300 participants. When IOL was performed <40+0WG, the risk for SD was significantly lower in the IOL group (OR: 0.64, 95%CI: 0.42-0.98, I² =19%). There was no significant difference in CD rate between IOL and expectant management after pooling the results of these 17 studies. However, when removing the studies in which IOL was done exclusively before 40+0WG, the risk for CD in the remaining studies (IOL not exclusively <40+0WG) was significantly higher in the IOL group (odds ratio [OR]: 1.46, 95% confidence interval [95%CI]: 1.02-2.09, I² =56%). There were no statistically significant differences between IOL and expectant management for the remaining perinatal outcomes. Nulliparity, history of CD, and low Bishop score but not methods of induction were independent risk factors for intrapartum CD in patients who were induced for LGA.

CONCLUSION: Timing of IOL in patients with suspected macrosomia significantly impacts perinatal adverse outcomes. IOL has no impact on rates of SD but does increase CD when considered irrespective of gestational age, but it may decrease the risk of SD without increasing the risk of other adverse maternal outcomes, in particular cesarean section when performed before 40+0 WG. (GRADE: Low/Very low). This article is protected by copyright. All rights reserved.

PMID:38477187 | DOI:10.1002/uog.27643

Diabetes Obes Metab. 2024 Mar 13. doi: 10.1111/dom.15543. Online ahead of print.

ABSTRACT

AIMS: To conduct a systematic review and meta-analysis with the aim of synthesizing existing data on the efficacy and safety of topiramate as an adjunctive treatment for reducing second-generation antipsychotic (SGA)-associated weight gain in children aged 4-18 years.

METHODS: We conducted a comprehensive search of PubMed, Embase, PsychNet and Web of Science from time of their inception up to 12 February 2024, including randomized controlled trials that compared SGA treatment with and without topiramate co-administration in children. The primary outcomes were changes in body weight and body mass index (BMI). Heterogeneity was assessed using I² statistics.

RESULTS: This systematic review included five randomized trials, totalling 139 participants (43.9% female; mean [SD] age 11.9 [3.5] years). Four of these trials were included in the meta-analysis, comprising 116 subjects. We found that topiramate was significantly effective both in reducing SGA-associated weight gain, with a mean difference of -2.80 kg (95% confidence interval [CI] -5.28 to -0.31; p = 0.037, I² = 86.7%) and a standardized mean difference (SMD) of -1.33 (95% CI -2.14 to -0.51; p = 0.014, I² = 31.7%), and in reducing BMI change compared to placebo (SMD -1.90, 95% CI -3.09 to -0.70; p = 0.02, I² = 0%). Sedation risk was lower with topiramate than with placebo (odds ratio 0.19, 95% CI 0.11-0.32; p < 0.01, I² = 0%). No significant differences were found in dropouts, any other side effects, and metabolic parameters, such as triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, and glucose. None of the included studies reported assessments on cognitive side effects.

CONCLUSION: This meta-analysis suggests that topiramate is an effective and safe option for mitigating SGA-associated weight gain in children.

PMID:38477159 | DOI:10.1111/dom.15543