Trends and predictors of Quality of Life in lung cancer survivors.

INTRODUCTION: Health-related quality of life (HR-QoL) is often impaired in lung cancer survivors. To inform personalized survivorship care, we identified associations between HR-QoL scores and patient-, tumor-, and treatment-factors over time. MATERIALS AND METHODS: We evaluated HR-QoL scores provided at diagnosis, 6 months, 1 year, and 2 years from the Yale Lung Cancer Biorepository. HR-QoL was measured via the Functional Assessment of Cancer Therapy - Lung (FACT-L) instrument and available for a subset of patients (n = 513). Analyses were stratified by early-stage (I-II; n = 355) non-small cell lung cancer (NSCLC), advanced stage NSCLC (III-IV; n = 158), and small cell lung cancer (SCLC, n = 21). We used mixed effects modeling and multivariable analysis with covariate adjustment to examine changes in FACT-L from diagnosis to follow-up. Sensitivity analysis was performed including patients with early-stage disease and complete FACT-L scores at both baseline and year 2 (n = 91). RESULTS: The average FACT-L scores at diagnosis in early-stage NSCLC, advanced stage NSCLC, and SCLC were 121.0 (standard deviation (SD) 11.4), 109.2 (18.7), and 98.7 (20.2) respectively. At all timepoints, HR-QoL was higher in patients with early-stage NSCLC (vs advanced-stage disease). In patients with early- and advanced-stage NSCLC, HR-QoL was higher at years 1 and 2 than at diagnosis, though the changes did not meet clinical significance. At NSCLC diagnosis, higher HR-QoL was associated with older age, better performance status, participating in physical activity, adenocarcinoma histology, and (in advanced stage NSCLC) anticipated treatment with chemotherapy. At NSCLC follow-up, HR-QoL was higher in patients with higher BMI and better performance status. DISCUSSION: In patients with newly diagnosed NSCLC, HR-QoL scores are impacted by patient factors, tumor factors, and treatment factors. HR-QoL is higher in patients with early-stage disease. In patients surviving 2 years, HR-QoL was higher at follow-up, though the change did not meet clinical significance. To optimize HR-QoL, lung cancer survivorship teams should prioritize comorbidity management, physical activity, healthy weight maintenance, and treatment-related side effects.

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of CYP2C9, HLA-A and HLA-B with anti-epileptic drugs.

By developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy, the Dutch Pharmacogenetics Working Group (DPWG) aims to advance the implementation of pharmacogenetics (PGx). This guideline outlines the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7-10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine, and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin "essential" for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine, and lamotrigine "beneficial", as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

Head Impact Exposure in Hawaiian High School Football: Influence of Adherence Rates on a Helmetless Tackling and Blocking Training Intervention.

CONTEXT: High school football remains a popular, physically demanding sport despite the known risks for acute brain and neck injury. Impacts to the head also raise concerns about their cumulative effects and long-term health consequences. OBJECTIVE: To examine the effectiveness of a helmetless tackling training program to reduce head impact exposure in football participants. DESIGN: A three-year, quasi-experimental, prospective cohort (clinicaltrials.gov #NCTXXX) study. SETTING: Honolulu (XXX, XXX) area public and private secondary schools with varsity and junior varsity football. PATIENTS OR OTHER PARTICIPANTS: Football participants (n=496) ages 14 to 18 years old. Intervention(s) Participants wore new football helmets furnished with head impact sensor technology. Teams employed a season-long helmetless tackling and blocking intervention in Years 2 and 3 consisting of a 3-phase, systematic progression of 10 instructional drills. MAIN OUTCOME MEASURE(S): Head impact frequency per athlete exposure (ImpAE), location, and impact magnitude per participant intervention adherence levels (60% and 80%). RESULTS: An overall regression analysis revealed a significant negative association between ImpAE and adherence (p=0.003, beta=-1.21, SE=0.41). In year 3, a longitudinal data analysis of weekly ImpAE data resulted in an overall difference between the adherent and non-adherent groups (p=0.040 at 80%; p=0.004 at 60%), mainly due to decreases in top and side impacts. Mean cumulative impact burden for the adherent group (n=131: 2,105.84g ± 219.76,) was significantly (p=0.020) less than the non-adherent group (n=90: 3,158.25g ± 434.80) at the 60% adherence level. CONCLUSIONS: Participants adhering to the intervention on at least a 60% level experienced a 34% to 37% significant reduction in the number of head impacts (per exposure) through the season. These results provide additional evidence that a helmetless tackling and blocking training intervention (utilizing the HuTT® program) reduces head impact exposure in high school football players. Adherence to an intervention is crucial for achieving intended outcomes.

Erratum: A Numerical Scheme for Anisotropic Reactive Nonlinear Viscoelasticity.

This erratum corrects a mistake in a sub-component of the numerical algorithm proposed in our recent study for modeling anisotropic reactive nonlinear viscoelasticity (doi:10.1115/1.4054983), for the special case where multiple weak bond families may be recruited with loading. This correction overcomes a non-physical response noted under uniaxial cyclical loading.

Socioecological factors influencing physical activity engagement for women across the menopausal transition: a systematic review.

IMPORTANCE: Physical activity during menopause can be effective in reducing the physiological changes associated with reproductive aging that increase risks for noncommunicable diseases, yet many women do not meet the recommendations for physical activity. OBJECTIVE: This study aimed to synthesize factors influencing physical activity for women across menopausal transition phases using a socioecological approach. EVIDENCE REVIEW: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis was used to systematically search 10 databases between 2001 and 2021. A comprehensive search strategy was used to identify studies on physical activity of women in various stages of menopause. A socioecological model was used to categorize the reported barriers and enablers. FINDINGS: Twenty studies met the inclusion criteria. The findings highlight several intrapersonal barriers such as existing health complaints versus enablers such as awareness of the health benefits of physical activity during menopause. Ensuring women's safety, preventing injury, and enhancing exercise self-efficacy were important components of programs. Social support was also an important enabler of women's engagement in activities. CONCLUSIONS AND RELEVANCE: Several barriers and enablers were identified and can inform practitioners and future interventions to encourage physical activity among women in various stages of menopause. For instance, when encouraging physical activity during menopause, practitioners should consider other health complaints, safety, and injury prevention while discussing the benefits of physical activity related to managing menopausal symptoms. There was a lack of theoretically informed studies exploring the barriers and enablers to physical activity for women in various stages of menopause; thus, research designs may not have fully accounted for influences. Future research that combines socioecological and individual theories of behavior is needed to comprehensively understand the complexity of physical activity among women across the menopausal transition.

Continuum Growth Mechanics: Reconciling Two Common Frameworks.

The objective of this study was to investigate whether the two most common growth mechanics modeling frameworks, the constrained-mixture growth model and the kinematic growth model, could be reconciled mathematically. The purpose of this effort was to provide practical guidelines for potential users of these modeling frameworks. Results showed that the kinematic growth model is mathematically consistent with a special form of the constrained-mixture growth model, where only one generation of a growing solid exists at any given time, overturning its entire solid mass at each instant of growth in order to adopt the reference configuration dictated by the growth deformation. The thermodynamics of the kinematic growth model, along with the specialized constrained-mixture growth model, requires a cellular supply of chemical energy to allow deposition of solid mass under a stressed state. A back-of-the-envelope calculation shows that the amount of chemical energy required to sustain biological growth under these models is negligibly small, when compared to the amount of energy normally consumed daily by the human body. In conclusion, this study successfully reconciled the two most popular growth theories for biological growth and explained the special circumstances under which the constrained-mixture growth model reduces to the kinematic growth model.

Distraction osteogenesis in combined sequential use of external fixation and nailing (lengthening and then nailing): An experimental study in rabbits.

Limb lengthening relies on the process of distraction osteogenesis. The active periosteal bone formation has been detected in clinical practice with a lengthening and then nail (LATN) technique but has not been confirmed by experimental studies to date. The aim of this study is to compare the tissue regeneration of the distraction regenerate during tibial lengthening in rabbits using a LATN technique. This study was performed on 54 mature rabbits of the Soviet Chinchilla breed, which were divided into three groups of 18 animals. In group 1 (control), the tibia was lengthened in an external fixator. In group 2, the LATN technique was modeled and in group 3, lengthening over nail (LON) was modeled. The total duration of the experiment was 45 days. On the 10th, 15th, 20th, 30th, and 45th day X-ray, computed tomography and morphological studies were performed. In the experimental groups (2 and 3), a more pronounced periosteal bone formation in the area of regenerate was noted when compared to group 1. In group 2 (LATN), wide cortical plates were formed from the intermediate and periosteal areas. In this group, the maximum densitometric density values were noted. Endosteal bone formation was preserved in all groups. The LON and LATN techniques, when compared with the classical Ilizarov lengthening, do not demonstrate any deficiency in the tissue regeneration of the bone tissue at the regenerate sites. The most powerful bone structures are formed with the sequential use of the external fixation and nailing (LATN).

Diagnostic accuracy of tongue swab testing on two automated tuberculosis diagnostic platforms, Cepheid Xpert MTB/RIF Ultra and Molbio Truenat MTB Ultima.

Tongue dorsum swabbing is a potential alternative to sputum collection for tuberculosis (TB) testing. Previous studies showed that Cepheid Xpert MTB/RIF Ultra (Xpert Ultra) can detect Mycobacterium tuberculosis DNA on tongue swabs stored in buffer, with 72% sensitivity and 100% specificity relative to a sputum microbiological reference standard (sputum MRS). The present study evaluated a more convenient sample collection protocol (dry swab storage), combined with streamlined sample processing protocols, for evaluating two commercial TB diagnostic tests: Xpert Ultra and Molbio Truenat MTB Ultima (MTB Ultima). Copan FLOQSwabs were self-collected or collected by study workers from 321 participants in Western Cape, South Africa. All participants had symptoms suggestive of TB, and 245 of them had sputum MRS-confirmed TB (by sputum MGIT culture and/or Xpert Ultra). One tongue swab per participant was tested on Xpert Ultra, and another tongue swab was tested with MTB Ultima. Xpert Ultra was 75.5% sensitive and 100% specific relative to sputum MRS, similar to previous methods that used swabs stored in buffer. MTB Ultima was 71.6% sensitive and 96.9% specific relative to sputum MRS. When sample lysates that were false-negative or invalid by MTB Ultima were frozen, thawed, and re-tested, MTB Ultima sensitivity rose to 79.1%. Both tests were more sensitive with swabs from participants with higher sputum Xpert Ultra semi-quantitative results. Although additional development could improve diagnostic accuracy, these results further support tongue swabs as easy-to-collect samples for TB testing. IMPORTANCE: Tongue dorsum swabbing is a promising alternative to sputum collection for tuberculosis (TB) testing. Our results lend further support for tongue swabs as exceptionally easy-to-collect samples for high-throughput TB testing.

Simulating Cerebral Edema and Ischemia After Traumatic Acute Subdural Hematoma Using Triphasic Swelling Biomechanics.

Poor outcome following traumatic acute subdural hematoma (ASDH) is associated with the severity of the primary injury and secondary injury including cerebral edema and ischemia. However, the underlying secondary injury mechanism contributing to elevated intracranial pressure (ICP) and high mortality rate remains unclear. Cerebral edema occurs in response to the exposure of the intracellular fixed charge density (FCD) after cell death, causing ICP to increase. The increased ICP from swollen tissue compresses blood vessels in adjacent tissue, restricting blood flow and leading to ischemic damage. We hypothesize that the mass occupying effect of ASDH exacerbates the ischemic injury, leading to ICP elevation, which is an indicator of high mortality rate in the clinic. Using FEBio (febio.org) and triphasic swelling biomechanics, this study modeled clinically relevant ASDHs and simulated post-traumatic brain swelling and ischemia to predict ICP. Results showed that common convexity ASDH significantly increased ICP by exacerbating ischemic injury, and surgical removal of the convexity ASDH may control ICP by preventing ischemia progression. However, in cases where the primary injury is very severe, surgical intervention alone may not effectively decrease ICP, as the contribution of the hematoma to the elevated ICP is insignificant. In addition, interhemispheric ASDH, located between the cerebral hemispheres, does not significantly exacerbate ischemia, supporting the conservative surgical management generally recommended for interhemispheric ASDH. The joint effect of the mass occupying effect of the blood clot and resulting ischemia contributes to elevated ICP which may increase mortality. Our novel approach may improve the fidelity of predicting patient outcome after motor vehicle crashes and traumatic brain injuries due to other causes.

Interfacial Electrochemical Lithiation and Dissolution Mechanisms at a Sulfurized Polyacrylonitrile Cathode Surface.

Advances in sulfurized-polyacrylonitrile (SPAN)-based cathode materials promise safer and more efficient lithium-sulfur (Li-S) battery performance. To elucidate electrolyte-cathode interfacial electrochemistry and polysulfide (PS) dissolution, we emulate discharge SPAN reactions via ab initio molecular dynamics (AIMD) simulations. Plausible structures and their lithiation profiles are cross-validated via Raman/IR spectroscopy and density functional theory (DFT). Lithium bis(fluorosulfonyl)imide (LiFSI) plays versatile roles in the Li-SPAN cell electrochemistry, primarily as the major source in forming the cathode-electrolyte interphase (CEI), further verified via X-ray photoelectron spectroscopy and AIMD. Besides being a charge carrier and CEI composer, LiFSI mediates the PS generation processes in SPAN electrochemical lithiation. Analysis of AIMD trajectories during progressive lithiation reveals that, compared to carbonates, ether solvents enable stronger solvation and chemical stabilization for both salt and SPAN structures. Differentiated CEI formation and electrochemical lithiation decomposition pathways and products are profoundly associated with the intrinsic nature of lithium bonding with oxygen and sulfur.

An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study.

AIMS/HYPOTHESIS: People with type 2 diabetes are heterogeneous in their disease trajectory, with some progressing more quickly to insulin initiation than others. Although classical biomarkers such as age, HbA1c and diabetes duration are associated with glycaemic progression, it is unclear how well such variables predict insulin initiation or requirement and whether newly identified markers have added predictive value. METHODS: In two prospective cohort studies as part of IMI-RHAPSODY, we investigated whether clinical variables and three types of molecular markers (metabolites, lipids, proteins) can predict time to insulin requirement using different machine learning approaches (lasso, ridge, GRridge, random forest). Clinical variables included age, sex, HbA1c, HDL-cholesterol and C-peptide. Models were run with unpenalised clinical variables (i.e. always included in the model without weights) or penalised clinical variables, or without clinical variables. Model development was performed in one cohort and the model was applied in a second cohort. Model performance was evaluated using Harrel's C statistic. RESULTS: Of the 585 individuals from the Hoorn Diabetes Care System (DCS) cohort, 69 required insulin during follow-up (1.0-11.4 years); of the 571 individuals in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort, 175 required insulin during follow-up (0.3-11.8 years). Overall, the clinical variables and proteins were selected in the different models most often, followed by the metabolites. The most frequently selected clinical variables were HbA1c (18 of the 36 models, 50%), age (15 models, 41.2%) and C-peptide (15 models, 41.2%). Base models (age, sex, BMI, HbA1c) including only clinical variables performed moderately in both the DCS discovery cohort (C statistic 0.71 [95% CI 0.64, 0.79]) and the GoDARTS replication cohort (C 0.71 [95% CI 0.69, 0.75]). A more extensive model including HDL-cholesterol and C-peptide performed better in both cohorts (DCS, C 0.74 [95% CI 0.67, 0.81]; GoDARTS, C 0.73 [95% CI 0.69, 0.77]). Two proteins, lactadherin and proto-oncogene tyrosine-protein kinase receptor, were most consistently selected and slightly improved model performance. CONCLUSIONS/INTERPRETATION: Using machine learning approaches, we show that insulin requirement risk can be modestly well predicted by predominantly clinical variables. Inclusion of molecular markers improves the prognostic performance beyond that of clinical variables by up to 5%. Such prognostic models could be useful for identifying people with diabetes at high risk of progressing quickly to treatment intensification. DATA AVAILABILITY: Summary statistics of lipidomic, proteomic and metabolomic data are available from a Shiny dashboard at https://rhapdata-app.vital-it.ch .

Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Decreasing microtubule detyrosination modulates Nav1.5 subcellular distribution and restores sodium current in mdx cardiomyocytes.

BACKGROUND: The microtubule (MT) network plays a major role in the transport of the cardiac sodium channel Nav1.5 to the membrane, where the latter associates with interacting proteins such as dystrophin. Alterations in MT dynamics are known to impact on ion channel trafficking. Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, is associated with an increase in MT detyrosination, decreased sodium current (INa), and arrhythmias. Parthenolide (PTL), a compound that decreases MT detyrosination, has shown beneficial effects on cardiac function in DMD, but its impact on INa has not been investigated. METHODS AND RESULTS: Ventricular cardiomyocytes (CMs) from wild-type (WT) and mdx (DMD) mice were incubated with either 10 µM PTL, 20 µM EpoY or DMSO for 3-5 hours, followed by patch-clamp analysis to assess INa and action potential (AP) characteristics in addition to immunofluorescence and stochastic optical reconstruction microscopy (STORM) to investigate MT detyrosination and Nav1.5 cluster size and density, respectively. In accordance with previous studies, we observed increased MT detyrosination, decreased INa and reduced AP upstroke velocity (Vmax) in mdx CMs compared to WT. PTL decreased MT detyrosination and significantly increased INa magnitude (without affecting INa gating properties) and AP Vmax in mdx CMs, but had no effect in WT CMs. Moreover, STORM analysis showed that in mdx CMs, Nav1.5 clusters were decreased not only in the grooves of the lateral membrane (LM; where dystrophin is localized), but also at the LM crests. PTL restored Nav1.5 clusters at the LM crests (but not the grooves), indicating a dystrophin-independent trafficking route to this subcellular domain. Interestingly, Nav1.5 cluster density was also reduced at the intercalated disc (ID) region of mdx CMs, which was restored to WT levels by PTL. Treatment of mdx CMs with EpoY, a specific MT detyrosination inhibitor, also increased INa density, while decreasing the amount of detyrosinated MTs, confirming a direct mechanistic link. CONCLUSIONS: Attenuating MT detyrosination in mdx CMs restored INa and enhanced Nav1.5 localization at the LM crest and ID. Hence, the reduced whole-cell INa density characteristic of mdx CMs is not only the consequence of the lack of dystrophin within the LM grooves, but is also due to reduced Nav1.5 at the LM crest and ID secondary to increased baseline MT detyrosination. Overall, our findings identify MT detyrosination as a potential therapeutic target for modulating INa and subcellular Nav1.5 distribution in pathophysiological conditions.

Therian origin of INSL3/RXFP2-driven testicular descent in mammals.

Introduction: During early development in most male mammals the testes move from a position near the kidneys through the abdomen to eventually reside in the scrotum. The transabdominal phase of this migration is driven by insulin-like peptide 3 (INSL3) which stimulates growth of the gubernaculum, a key ligament connecting the testes with the abdominal wall. While all marsupials, except the marsupial mole (Notoryctes typhlops), have a scrotum and fully descended testes, it is unclear if INSL3 drives this process in marsupials especially given that marsupials have a different mechanism of scrotum determination and position relative to the phallus compared to eutherian mammals. Methods: To understand if INSL3 plays a role in marsupial testicular descent we have sequenced and curated the INSL3 gene and its receptor (RXFP2) in a range of marsupials representing every order. Furthermore, we looked at single cell RNA-seq and qPCR analysis of INSL3 in the fat-tailed dunnart testis (Sminthopsis crassicaudata) to understand the location and timing of expression during development. Results: These data show a strong phylogenetic similarity between marsupial and eutherian orthologues, but not with monotreme INSL3s which were more similar to the ancestral RLN3 gene. We have also shown the genomic location of INSL3, and surrounding genes is conserved in a range of marsupials and eutherians. Single cell RNA-seq and qPCR data show that INSL3 mRNA is expressed specifically in Leydig cells and expressed at higher levels during the testicular descent phase in developing marsupials. Discussion: Together, these data argue strongly for a therian origin of INSL3 mediated testicular descent in mammals and suggests that a coordinated movement of the testes to the abdominal wall may have preceded externalization in marsupials and therian mammals.

Acupuncture for primary insomnia: Effectiveness, safety, mechanisms and recommendations for clinical practice.

Primary insomnia (PI) is an increasing concern in modern society. Cognitive-behavioral therapy for insomnia is the first-line recommendation, yet limited availability and cost impede its widespread use. While hypnotics are frequently used, balancing their benefits against the risk of adverse events poses challenges. This review summarizes the clinical and preclinical evidence of acupuncture as a treatment for PI, discussing its potential mechanisms and role in reliving insomnia. Clinical trials show that acupuncture improves subjective sleep quality, fatigue, cognitive impairments, and emotional symptoms with minimal adverse events. It also positively impacts objective sleep processes, including prolonging total sleep time, improving sleep efficiency, reducing sleep onset latency and wake after sleep onset, and enhancing sleep architecture/structure, including increasing N3% and REM%, and decreasing N1%. However, methodological shortcomings in some trials diminish the overall quality of evidence. Animal studies suggest that acupuncture restores circadian rhythms in sleep-deprived rodents and improves their performance in behavioral tests, possibly mediated by various clinical variables and pathways. These may involve neurotransmitters, brain-derived neurotrophic factors, inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, gut microbiota, and other cellular events. While the existing findings support acupuncture as a promising therapeutic strategy for PI, additional high-quality trials are required to validate its benefits.

Navigated Versus Conventional Total Knee Arthroplasty: A Systematic Review and Meta-analysis of Prospective Randomized Controlled Trials.

Background: Recent evidence on the cost-effectiveness of technology in total knee arthroplasty (TKA) demonstrated that navigated computer-assisted methods (N-TKA) is likely to be most cost-effective in the clinical setting. The aim of the current meta-analysis is to compare radiographic, clinical and functional outcomes between conventional TKA (C-TKA) and N-TKA methods. Methods: All prospective randomized controlled trials (pRCTs) comparing primary TKA performed using C-TKA and N-TKA techniques were eligible for inclusion. Radiographic outcomes included postoperative coronal, sagittal and axial component alignment. Clinical outcomes included all-cause revision and aseptic revision. Functional outcomes were analyzed when reported. A random-effects meta-analysis of all available cases was performed. This allowed for all missing data. Results: Normal coronal mechanical alignment of the tibial (p < 0.001) and femoral (p = 0.001) components was achieved more frequently with N-TKA. Normal sagittal mechanical alignment of the tibial component was achieved significantly more with N-TKA (p < 0.010). There was no difference in short-term clinical survivorship (all-cause, p = 0.649; aseptic, p = 0.79) or in functional outcomes reported between groups. There was a clinically significant reduction in the mean C-TKA operative time (87 min, σ = 16.6, 95% CI 76.4-98.8) compared N-TKA (97.6 min, σ = 16.9, 95% CI 86.2-109.1) (p = 0.17). Conclusion: Navigated TKA achieves superior radiographic alignment for femoral and tibial components in both the coronal and sagittal plane. Operative times are 10 min longer in the N-TKA group. Functional outcomes are similar between navigated and conventional groups. Clinical outcomes reported in Level I studies are limited to short-term follow-up so future prospective studies are required.

Pediatric Sport-Related Concussion: Recommendations From the Amsterdam Consensus Statement 2023.

The 6th International Consensus Conference on Concussion in Sport, Amsterdam 2022, addressed sport-related concussion (SRC) in adults, adolescents, and children. We highlight the updated evidence-base and recommendations regarding SRC in children (5-12 years) and adolescents (13-18 years). Prevention strategies demonstrate lower SRC rates with mouthguard use, policy disallowing bodychecking in ice hockey, and neuromuscular training in adolescent rugby. The Sport Concussion Assessment Tools (SCAT) demonstrate robustness with the parent and child symptom scales, with the best diagnostic discrimination within the first 72 hours postinjury. Subacute evaluation (>72 hours) requires a multimodal tool incorporating symptom scales, balance measures, cognitive, oculomotor and vestibular, mental health, and sleep assessment, to which end the Sport Concussion Office Assessment Tools (SCOAT6 [13+] and Child SCOAT6 [8-12]) were developed. Rather than strict rest, early return to light physical activity and reduced screen time facilitate recovery. Cervicovestibular rehabilitation is recommended for adolescents with dizziness, neck pain, and/or headaches for greater than 10 days. Active rehabilitation and collaborative care for adolescents with persisting symptoms for more than 30 days may decrease symptoms. No tests and measures other than standardized and validated symptom rating scales are valid for diagnosing persisting symptoms after concussion. Fluid and imaging biomarkers currently have limited clinical utility in diagnosing or assessing recovery from SRC. Improved paradigms for return to school were developed. The variable nature of disability and differences in evaluating para athletes and those of diverse ethnicity, sex, and gender are discussed, as are ethical considerations and future directions in pediatric SRC research.

Visualization of choroidal vasculature in pigmented mouse eyes from experimental models of AMD.

A variety of techniques exist to investigate retinal and choroidal vascular changes in experimental mouse models of human ocular diseases. While all have specific advantages, a method for evaluating the choroidal vasculature in pigmented mouse eyes has been more challenging especially for whole mount visualization and morphometric analysis. Here we report a simple, reliable technique involving bleaching pigment prior to immunostaining the vasculature in whole mounts of pigmented mouse choroids. Eyes from healthy adult pigmented C57BL/6J mice were used to establish the methodology. The retina and anterior segment were separated from the choroid. The choroid with retinal pigment epithelial cells (RPE) and sclera was soaked in 1% ethylenediaminetetraacetic acid (EDTA) to remove the RPE. Tissues were fixed in 2% paraformaldehyde (PFA) in phosphate-buffered saline (PBS). Choroids were subjected to melanin bleaching with 10% hydrogen peroxide (H2O2) at 55 °C for 90 min, washed in PBS and then immunostained with anti-podocalyxin antibody to label vascular endothelium followed by Cy3-AffiniPure donkey anti-goat IgG at 4 °C overnight. Images of immunostained bleached choroids were captured using a Zeiss 710 confocal microscope. In addition to control eyes, this method was used to analyze the choroids from subretinal sodium iodate (NaIO3) RPE atrophy and laser-induced choroidal neovascularization (CNV) mouse models. The H2O2 pretreatment effectively bleached the melanin, resulting in a transparent choroid. Immunolabeling with podocalyxin antibody following bleaching provided excellent visualization of choroidal vasculature in the flat perspective. In control choroids, the choriocapillaris (CC) displayed different anatomical patterns in peripapillary (PP), mid peripheral (MP) and far peripheral (FP) choroid. Morphometric analysis of the vascular area (VA) revealed that the CC was most dense in the PP region (87.4 ± 4.3% VA) and least dense in FP (79.9 ± 6.7% VA). CC diameters also varied depending on location from 11.4 ± 1.97 mm in PP to 15.1 ± 3.15 mm in FP. In the NaIO3-injected eyes, CC density was significantly reduced in the RPE atrophic regions (50.7 ± 5.8% VA in PP and 45.8 ± 6.17% VA in MP) compared to the far peripheral non-atrophic regions (82.8 ± 3.8% VA). CC diameters were significantly reduced in atrophic regions (6.35 ± 1.02 mm in PP and 6.5 ± 1.2 mm in MP) compared to non-atrophic regions (14.16 ± 2.12 mm). In the laser-induced CNV model, CNV area was 0.26 ± 0.09 mm2 and luminal diameters of CNV vessels were 4.7 ± 0.9 mm. Immunostaining on bleached choroids with anti-podocalyxin antibody provides a simple and reliable tool for visualizing normal and pathologic choroidal vasculature in pigmented mouse eyes for quantitative morphometric analysis. This method will be beneficial for examining and evaluating the effects of various treatment modalities on the choroidal vasculature in mouse models of ocular diseases such as age-related macular degeneration, and degenerative genetic diseases.