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Abstract Introduction Transgender women are at increased risk of acquiring HIV. Earlier studies reported lower retention in HIV care, antiretroviral therapy uptake, adherence and viral suppression. We assessed the stages of the HIV care continuum of transgender women in the Netherlands over an 11‐year period. In addition, we assessed new HIV diagnoses and late presentation, as well as disengagement from care, between 2011 and 2021. Methods Using data from the Dutch national ATHENA cohort, we separately assessed viral suppression, as well as time to achieving viral suppression, among transgender women for each year between 2011 and 2021. We also assessed trends in new HIV diagnoses and late presentation (CD4 count of

Measuring the flow properties of fiber-laden fresh concrete poses a substantial challenge because not only the fraction of fibers but also their orientation process during the measurement influence the measured quantities. Numerical simulations of the flow in a ball probe rheometer are used to determine the fiber orientation process during the measurement of the flow properties and its influence on the measured variables. Through analytical considerations and comparison with measurement results, it can be shown that the constitutive law applied can reproduce the real flow behavior very well, taking the fiber orientation into account. At the same time, it is investigated why no orientation influence on the torque is recognizable in the experimental measurement curves, although the orientation process demonstrably exceeds the duration of the measurement process. The results show that fluid inertia is overcome before the recognizable onset of fiber orientation, and the spatially inhomogeneous flow minimises the impact of the orientation process on torque. The simulation model aligns well with experimental outcomes, indicating a linear increase in effective viscosity with increasing fiber volume fraction. The findings can be used to accurately measure the objective material parameters of the orientation-considering constitutive law using ball probe rheometers, so that an accurate prediction of the flow process of fresh concrete with fibers is made possible, for example for the simulation of formwork fillings.

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that “one-size-fits-all” for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

Abstract Stage‐based demographic methods, such as matrix population models (MPMs), are powerful tools used to address a broad range of fundamental questions in ecology, evolutionary biology and conservation science. Accordingly, MPMs now exist for over 3000 species worldwide. These data are being digitised as an ongoing process and periodically released into two large open‐access online repositories: the COMPADRE Plant Matrix Database and the COMADRE Animal Matrix Database. During the last decade, data archiving and curation of COMPADRE and COMADRE, and subsequent comparative research, have revealed pronounced variation in how MPMs are parameterized and reported. Here, we summarise current issues related to the parameterisation and reporting of MPMs that arise most frequently and outline how they affect MPM construction, analysis, and interpretation. To quantify variation in how MPMs are reported, we present results from a survey identifying key aspects of MPMs that are frequently unreported in manuscripts. We then screen COMPADRE and COMADRE to quantify how often key pieces of information are omitted from manuscripts using MPMs. Over 80% of surveyed researchers (n = 60) state a clear benefit to adopting more standardised methodologies for reporting MPMs. Furthermore, over 85% of the 300 MPMs assessed from COMPADRE and COMADRE omitted one or more elements that are key to their accurate interpretation. Based on these insights, we identify fundamental issues that can arise from MPM construction and communication and provide suggestions to improve clarity, reproducibility and future research utilising MPMs and their required metadata. To fortify reproducibility and empower researchers to take full advantage of their demographic data, we introduce a standardised protocol to present MPMs in publications. This standard is linked to www.compadre‐db.org, so that authors wishing to archive their MPMs can do so prior to submission of publications, following examples from other open‐access repositories such as DRYAD, Figshare and Zenodo. Combining and standardising MPMs parameterized from populations around the globe and across the tree of life opens up powerful research opportunities in evolutionary biology, ecology and conservation research. However, this potential can only be fully realised by adopting standardised methods to ensure reproducibility.

IntroductionBreast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study.Methods and analysesPatients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated.RegistrationThe study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221).

AbstractPurpose The heating characteristics of water-filtered infrared-A (wIRA) radiation were investigated in vivo in two body regions of healthy humans according to the quality standards of the European Society for Hyperthermic Oncology (ESHO) using an irradiance (infrared-A) of 146 W m−2 as recommended for clinical superficial hyperthermia (HT).Methods wIRA was applied to the abdominal wall and lumbar region for 60 min. Skin surface temperature was limited to ≤43 °C. Tissue temperatures were measured invasively at 1-min intervals before, during and after wIRA exposure using five fiber-optical probes at depths of 1–20 mm.Results Significant differences between body regions occurred during the heating-up phase at depths of 5–15 mm. Thermal steady states were reached at depths ≤5 mm after exposures of 5–6 min, and ≤20 mm after 20 min. On average, the minimum requirements of ESHO were exceeded in both regions by the following factors: ≈3 for the heating rate, ≈2 for the specific absorption rate and ≈1.4 for the temperature rise. Tissue depths with T90 ≥ 40 °C and T50 > 41 °C were ≤10 mm, and ≤20 mm for Tmax ≤ 43 °C. The temperature decay time after termination of irradiation was 1–5 min. Corresponding temperatures were ≤42.2 °C for CEM43 and ≤41.8 °C for CEM43T90, i.e., they are inadequate for direct thermal cell killing.Conclusions Thermography-controlled wIRA-HT complies with the ESHO criteria for superficial HT as a radiosensitizer and avoids the risk of thermal skin toxicity.

ABSTRACT The intraerythrocytic malaria parasite Plasmodium falciparum exports hundreds of proteins into the host red blood cell (RBC). Most are targeted to the endoplasmic reticulum (ER) by a stretch of hydrophobic amino acids and cleaved further downstream at a conserved motif called the Plasmodium Export Element (PEXEL) by the ER protease plasmepsin V (PM V). The mature effectors then travel through the secretory pathway to the parasitophorous vacuole (PV) that surrounds the parasite. There, PEXEL proteins are somehow recognized as export-destined proteins, as opposed to PV-resident proteins, and are selectively translocated out into the RBC. The mature N-terminus appears to be important for export. There is conflicting data on whether PM V cleavage is needed for proper export or whether any means of generating the mature N-terminus would suffice. We replaced the PEXEL-containing N-terminal sequence of an exported GFP reporter with a signal peptide sequence and showed that precise cleavage by signal peptidase, generating the proper mature N-terminus, yields export competence. Expressing a construct with only the native ER targeting signal without the PM V cleavage site dramatically decreased the amount of a mature PEXEL reporter, indicating that the hydrophobic stretch lacks an efficient cleavage signal. Therefore, the PEXEL motif functions as a specialized signal cleavage site when appropriately located after an ER targeting sequence. Our data suggest that PM V cleavage and RBC export are two independent events for PEXEL proteins. We also tested and rejected the hypothesis that an alpha-helical mature N-terminus is necessary for export. IMPORTANCE Malaria parasites export hundreds of proteins to the cytoplasm of the host red blood cells for their survival. A five amino acid sequence, called the PEXEL motif, is conserved among many exported proteins and is thought to be a signal for export. However, the motif is cleaved inside the endoplasmic reticulum of the parasite, and mature proteins starting from the fourth PEXEL residue travel to the parasite periphery for export. We showed that the PEXEL motif is dispensable for export as long as identical mature proteins can be efficiently produced via alternative means in the ER. We also showed that the exported and non-exported proteins are differentiated at the parasite periphery based on their mature N-termini; however, any discernible export signal within that region remained cryptic. Our study resolves a longstanding paradox in PEXEL protein trafficking.

Purpose: To evaluate the return to sport and daily activities in addition to clinical outcomes after modification of the Brostöm repair, specifically using suture augmentation for concomitant fixation of both the anterior talofibular ligament and calcaneofibular ligament. Methods: Patients who had grade III ankle sprains and lateral ankle instability, all of whom failed supervised conservative management, were included. Patients underwent a modified Broström procedure consisting of suture augmentation for both the anterior talofibular ligament and calcaneofibular ligament. For clinical outcome evaluation, Foot and Ankle Ability Measure (FAAM) and Karlsson-Peterson Scoring System for Ankle Function questionnaires coupled with questions regarding time of return to sport and level of sports activity were used. Results: Thirty-one patients were included. The differences in preoperative and postoperative FAAM scores for both the Activities of Daily Living subscale and Sports subscale were significant (P < .001). The FAAM Activities of Daily Living score improved from an average of 46.06 preoperatively to 77.49 postoperatively (P < .001, 99% confidence interval, 26.4–36.4). The FAAM Sports score improved from an average of 4 preoperatively to 19.31 postoperatively (P < .001, 99% confidence interval, 11.6–19.0). For the Karlsson-Peterson Scoring System for Ankle Function, the surveyed population reported a mean of 82.74 points out of 100 post-op (standard deviation 20.14). The mean time to return to sport activity was 5.72 months. Mean follow-up time was 24.12 months. Conclusions: This variant Broström procedure with suture anchors and augmentation of both the anterior talofibular ligament and calcaneofibular ligament was effective in helping patients return to their preinjury functionality level in both daily life and sports activity. Level of Clinical Evidence: Level IV, therapeutic case series.

Is it possible to slow the rate of ageing, or do biological constraints limit its plasticity? We test the 'invariant rate of ageing' hypothesis, which posits that the rate of ageing is relatively fixed within species, with a collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.

Purpose Tumor perfusion is considered to be the principal factor determining the build-up of therapeutically effective thermal fields. This assumes that malignancies have lower perfusions than their homologous tissues. This assumption, however, ignores the fact that several tumor types have higher perfusions than their healthy counterparts. Additionally, flow changes upon hyperthermia (39–43 °C) are non-predictable and extremely heterogeneous. Therefore, modeling temperature distribution further requires a more robust parameter, different in malignancies and healthy tissues, i.e., water content (Cw), which highly determines thermal properties upon electromagnetic irradiation.Method Systematic literature reviews of Cw and specific heat capacities (cp) were conducted up to 28 February 2022, providing an updated, comprehensive data overview based on original manuscripts, reviews and databases.Results Cw- and cp-values of cancers and their corresponding healthy tissues are presented. Strong correlations between these two parameters are described. In general, malignant tumors have distinctly higher Cw values than their homologous tissues. With increasing Cw in low-water-content normal tissues (80 wt.%), cp rises linearly from 3.6 to 3.9 J·g–1·K–1. Cancers contain up to 27% more water than their tissues of origin and must be considered as ‘high-capacitance-tissues’.Conclusions Hyperhydration of cancers result in higher cp-values, causing cancers to be better heat reservoirs than corresponding normal tissues upon electromagnetic irradiation. Reliable, tissue-/cancer-specific cp values must be considered when modeling temperature distributions in hyperthermic treatment.

Abstract Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.

Background: Tumor hypoxia worsens the prognosis of head-and-neck squamous cell carcinoma (HNSCC) patients, and plasma hypoxia markers may be used as biomarkers for radiotherapy personalization. We therefore investigated the role of the hypoxia-associated plasma proteins osteopontin, galectin-3, vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) as surrogate markers for imaging-based tumor hypoxia. Methods: Serial blood samples of HNSCC patients receiving chemoradiation within a prospective trial were analyzed for osteopontin, galectin-3, VEGF and CTGF concentrations. Tumor hypoxia was quantified in treatment weeks 0, 2 and 5 using [18F]FMISO PET/CT. The association between PET-defined hypoxia and the plasma markers was determined using Pearson’s correlation analyses. Receiver-operating characteristic analyses were conducted to reveal the diagnostic value of the hypoxia markers. Results: Baseline osteopontin (r = 0.579, p 1 mL in week 2 exhibited increased VEGF (p

Theories about biological limits to life span and evolutionary shaping of human longevity depend on facts about mortality at extreme ages, but these facts have remained a matter of debate. Do hazard curves typically level out into high plateaus eventually, as seen in other species, or do exponential increases persist? In this study, we estimated hazard rates from data on all inhabitants of Italy aged 105 and older between 2009 and 2015 (born 1896-1910), a total of 3836 documented cases. We observed level hazard curves, which were essentially constant beyond age 105. Our estimates are free from artifacts of aggregation that limited earlier studies and provide the best evidence to date for the existence of extreme-age mortality plateaus in humans.

The ‘invariant rate of ageing’ hypothesis suggests that the rate of ageing tends to be constant within species. Here, Colchero et al. find support for the hypothesis across primates, including humans, suggesting biological constraints on the rate of ageing.

Background Earthworm communities are an important component of soil biodiversity and contribute to a number of ecosystem functions such as soil-nutrient cycling. Taxonomic identification is an essential requirement to assess earthworm biodiversity and functionality. Although morphological identification of species is labour-intensive, it is the most commonly used method due to a lack of cost-efficient alternatives. Molecular approaches to identify earthworms at species and haplotype level such as DNA barcoding are gaining popularity in science but are rarely applied in practice. In contrast to barcoding, the differentiation of PCR products based on their thermal denaturation properties using high-resolution melting (HRM) curve analysis is a fast and cost-efficient molecular closed-tube, post-PCR tool that allows identification of taxa. Methods We developed a HRM curve assay to identify eight earthworm species common to agricultural soils in Central Europe (Allolobophora chlorotica, Aporrectodea caliginosa, Apo. limicola, Apo. longa, Apo. rosea, Lumbricus castaneus, L. rubellus, and L. terrestris). For this, a new primer pair targeting a 158-bp long subregion of the cytochrome c oxidase I (COI) gene was designed. Our HRM assay was further tested for the differentiation of COI haplotypes using 28 individuals of the earthworm species Allo. chlorotica. Furthermore, we developed a novel extraction method for DNA from earthworm tissue that is fast and requires minimal consumables and laboratory equipment. Results The developed HRM curve assay allowed identifying all eight earthworm species. Performing the assay on 28 individuals of the earthworm species Allo. chlorotica enabled the distinction among different COI haplotypes. Furthermore, we successfully developed a rapid, robust, scalable, and inexpensive method for the extraction of earthworm DNA from fresh or frozen tissue. Conclusions HRM curve analysis of COI genes has the potential to identify earthworm species and haplotypes and could complement morphological identification, especially for juvenile or damaged individuals. Our rapid and inexpensive DNA extraction method from earthworm tissue helps to reduce the costs of molecular analyses and thereby promote their application in practice.

(1) Background: Mild hyperthermia (mHT, 39–42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the short term, changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. Sustained TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O2 diffusivities, acidosis- and heat-related enhanced O2 unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O2 tensions in tumors.

Category: Basic Sciences/Biologics; Sports; Trauma Introduction/Purpose: Mesenchymal stem cells (MSCs) have demonstrated promise in augmenting the surgical repair of full thickness tendon tears. Despite this promise, obtaining a therapeutic concentration of MSCs is time-, labor- and resource intensive, and is subject to ever-tightening governmental regulations. Our group recently demonstrated that postoperative mobilization of MSCs from the marrow compartment and into peripheral blood via subcutaneous granulocyte- colony stimulating factor administration enhanced tendon-bone healing in a rat model of surgical repair of a full-thickness supraspinatus tendon tear. We hypothesized that combining postoperative stem cell mobilization with local delivery of a chemokine that stimulates MSC chemotaxis would enhance the surgical repair of a mid-substance Achilles tendon transection. Methods: Following IACUC approval, Achilles tendons were unilaterally frayed via multiple longitudinal scalpel blade nicks in 24 Lewis rats. Tendons were then surgically transected, followed by repair with braided non-absorbable suture in a modified-Kessler pattern. Based on randomization (n=6/group), the tendon anastomosis was coated with a resorbable chitosan hydrogel containing 100 ng of the chemokine, CCL5 (RANTES), or hydrogel without RANTES. Skin closure and anesthesia recovery were then performed; rats were allowed ad libitum activity. Beginning 24 hours postoperatively, rats received a daily subcutaneous injection of either a peripheral blood mobilizing agent, AMD3100 (5 mg/kg), or saline; dosing was repeated at 48 and 72 hours. At the 4- week endpoint, Achilles tendons harvested en bloc. Decalcified histologic sections were stained with H&E and Alcian Blue as well as immunostained for Collagen III, CD163, and CD68. Slides were digitized (40x magnification) and graded by blinded reviewers via modified-Bonar score to assess tendon integrity. Results: Rats that received local application of RANTES-loaded chitosan hydrogel had worse (higher) modified-Bonar subscores with respect to tenocyte morphology, collagen orientation, and ground substance staining, though none of these comparisons were statistically significant (p=0.068, p=0.672, and p=0.407, respectively). Animals that received subcutaneous AMD3100 alone, or in conjunction with RANTES-loaded chitosan hydrogel displayed the best (lowest) total modified Bonar scores, though these comparisons were also not statistically significant (p = 0.498). No significant differences were found with respect to CD163 (p=0.132) and CD68 (p=0.104) staining. Despite a lack of statistical significance, animals that received AMD3100 displayed a higher number of both macrophage subtypes. No differences were found with respect to Collagen III immunostaining (p=0.808). Conclusion: Tendon repair and regeneration remains a significant clinical challenge, which may be aided by MSC transplantation. The mobilization of endogenous marrow-derived MSCs into peripheral blood and subsequent recruitment via local chemokine delivery may be an efficacious way to enhance tendon repair without the need for ex vivo processing. We failed to demonstrate significant effects of stem cell mobilization via AMD3100 injections, and chemokine-directed recruitment, though trends were present indicating that AMD3100 alone may be beneficial. Additional work is required to draw any translatable conclusions from this research.

Category: Midfoot/Forefoot Introduction/Purpose: An adult flatfoot deformity is a complex pathology that has been attempted to be addressed surgically with a variety of different procedures. Transfer of the flexor tendon has been a cornerstone of the treatment of flatfoot deformity for years. After the procedure, the appearance of the bony correction of the foot is noticeable on radiography, but after surgery when the patient begins to bear the weight the soft tissue laxity affects the achieved bony correction when compared to non- weight bearing images. This study aims to identify the effects of tendon transfer on bony and soft tissue after weight-bearing to better predict what the outcomes of surgery will be. Methods: 29 patients were included. there were 18 patients that underwent tendon transfer as part of their flat foot correction and 11 patients that underwent non-tendon transfer procedure for correction of flat foot deformity. Imaging was performed on patient's weight bearing (WB) and non-weight bearing (NWB) before and after surgery. X-ray measurements included Angles: calcaneal pitch (ML-CP), talo-1st metatarsal (ML-T1MT),talocalcaneal (ML-TC), talar declination (ML-Tdec), calcaneal 1st metatarsal (ML-C1MT) and Distances: talar height (ML-Tal-h), navicular height (ML-Nav-h), 1st cuneiform height (ML-1CN-h), cuboid height (ML-Cub-h), and 1st to 5th metatarsal distance (ML-1CN/5MT) in lateral X-ray and Angles: talonavicular coverage (AP-TN), talar 1st metatarsal (AP-T1MT), talar 2nd metatarsal (AP-T2MT) and Distances: talonavicular uncoverage distance in AP. The differences in measurement between the pre op post op non weight bearing considered as bony correction effect The differences in measurement between the pre op post op weight bearing considered as soft tissue effect. Results: the results from non-weight bearing imaging, tendon transfer had a statistically significant impact on calcaneal pitch (, p=0.026), Talo-1st metatarsal (p=0.048), talar declination ( p=0.038), talar height (p=0.016), navicular height ( p=0.014), 1st cuneiform height (p=0.001), talonavicular coverage (p=0.019), talar-1st metatarsal angle (p=0.015), and talar to 2nd metatarsal angle ( p=0.001). the results from WBimaging, tendon transfer had a statistically significant impact on calcaneal pitch ( p=0.000), calcaneal 1st metatarsal (p=0.02), talar height (35 to 39, p=0.003), navicular height ( p=0.002), 1st cuneiform height (p=0.016), cuboid height ( p=0.016), 1st to 5th The post-op effect calcaneal pitch was 12 degrees of difference in NWB compared to 6 degrees of difference in WB The effect on talar height, navicular height, and 1st cuneiform height was 10mm, 9mm, and 8mm, respectively, in NWBimages. This compares to an effect of 4mm, 6mm, and 4mm, respectively, WB imaging. Conclusion: When comparing NWB to WBimages, the effect of surgery on flat foot correction is consistently less pronounced inWB. there will be a difference between the bony correction and soft tissue correction. there is still a significant soft tissue effect seen in WBimaging. The comparison between NWB, WB changes shows that the soft tissue effect is around 50% of the bony correction on several key measurements. These include calcaneal pitch and talar, navicular, and 1st cuneiform height. These results provide a framework for establishing the soft tissue effect that tendon transfer surgery provides for flat foot correction surgery.

Category: Ankle; Sports Introduction/Purpose: studies demonstrated that mechanical axis alignment affects the clinical outcome of the chondral repair surgery in the knee. Reduction in stress concentration around chondral defects with HTO has been found to favor cartilage repair in knee surgery. this study aimed to determine the relationship between the tibia mechanical axis alignment and OLT size and location. Methods: 57 patients that underwent OLT repair between 2016-2020 were included. X-rays and MRIs of the ankle were used to collect data on OLT in the study group. X-ray measurements included (a)-measured as distance from where vertical line through center of tibia crosses to center the talar joint in AP view (medial, lateral), (b)- measured as distance from where vertical line through center of tibia crosses to the center talar body in lateral view (ant, post). The coverage angle, TLS, TAS, MA, TI, TTI angles were measured. MRI measurements included distance of the edge of the OLT lesion from the center of the talar surface, in three plans, and for location of the OLT lesion based on the 9-zone grid system. Results: 37.3% of these patients had the mechanical axis of the joint cross posterolaterally, 15.6% anteromedially, 5.9% anterolaterally, and 3.9% posteromedially. 33.3% had the mechanical axis cross posteriorly along the midline of the lateral axis. Using the 9-zone grid to localize lesion location, lesions were most often seen in location 6 (37.3%), location 7 (21.6%), location 9 (21.6%), and location 4 (19.6%). Of note, 36.8% of patients with a posterolateral axis had lesions at location 6 and 26.3% at location 9. For patients with poster joint axis along the midline of the lateral axis, 47.1% had lesions at location 6 and 23.5% at location 7. There is a correlation between Lesion Surface Area and axis location in the AP view (Correlation coefficient: 0.301, P Value: 0.023). we found a significant difference for coverage angle (P

Category: Other; Diabetes Introduction/Purpose: Infections pertaining to orthopaedic surgery play a major role in patient morbidity and increased healthcare-associated expenses. In the setting of foot and ankle surgery for infection, it is common practice to send acid-fast bacilli (AFB) and fungal intraoperative cultures, although there is no standard protocol in place. In this study, the rate of positive AFB and fungal cultures and associated costs in a consecutive series of foot and ankle surgeries was retrospectively assessed. Methods: Under an IRB-approved protocol, CPT codes were used to identify 447 procedures in 320 patients, who underwent foot and ankle surgery for infection by fellowship-trained foot and ankle orthopaedic surgeons at a Level 1, private, academic hospital from 2014 to 2019. A medical records review was performed to collect microbiology and patient demographic data. Materials and labor cost data, which was provided by the institution, was used to quantify a total culture cost. Results: In this series, there were 185 male and 135 female patients with an average age of 57 years (range, 10-105) and average BMI of 31 kg/m 2 (range, 13-56). No patients had positive AFB cultures and 20 patients (7.5%) had positive fungal cultures. There were 434 AFB and 525 fungal cultures performed during these procedures. Based on total cultures performed, there were 0% (0/434) AFB and 5% (26/525) fungal culture positivity rates. The total intra-institutional cost (i.e. labor and materials) for AFB cultures was $23,967. The total labor/materials cost for negative and positive fungal cultures was $12,428 and $2,371, respectively. The total labor/materials cost for all the cultures obtained over the time frame of our study was $38,767. Conclusion: This study highlighted low rates of positive AFB and fungal cultures in the orthopaedic foot and ankle surgery service in a 6-year retrospective review, as well as substantial institutional costs of routine use of intraoperative cultures. While this series included cases from three fellowship-trained foot and ankle orthopaedic surgeons, this study will be expanded to analyze AFB and fungal culturing practices and cost in other orthopaedic subspecialties. Creating and implementing a standardized protocol may achieve cost effectiveness of cultures without diminishing patient outcomes.

Category: Ankle; Hindfoot; Sports Introduction/Purpose: Surgical treatment of adult flatfoot deformity has traditionally be driven by tendon transfers and osteotomy. In acquired deformity, injury to the spring ligament and superficial deltoid ligament is common. The procedures mentioned previously do nothing to restore the function of the medial ligament complex. Studies have shown that reconstruction of the medial ligament complex, and thus the medial talonavicular joint, has benefit to patient outcomes. The question still remains of how much correction the medial ligament reconstruction confers on its own. The purpose of this study is to compare isolated medial ligament reconstruction procedures to other flat foot correcting procedures in the treatment of acquired flat foot deformity. Methods: 18 patients were identified that underwent procedure for flatfoot deformity. Of these patients there were 7 patients that underwent isolated medial ligament complex reconstruction and 11 patients that underwent non-tendon transfer procedure for correction of flat foot deformity. Imaging was performed on patient's weight bearing (WB) and non-weight bearing (NWB) before and after surgery. Measurements included Angles: calcaneal pitch, talo-1st metatarsal, talocalcaneal, talar declination, calcaneal 1st metatarsal and Distances: talar height, navicular height, 1st cuneiform height, cuboid height, and 1st to 5th metatarsal distance in lateral X-ray, and Angles: talonavicular coverage, talar 1st metatarsal, talar 2nd metatarsal and Distances: talonavicular uncoverage distance in AP. The differences in measurement between the pre-op and post-op non-weight bearing are considered as bony correction effect while differences between pre-op and post-op weight bearingare considered as soft tissue correction Results: For non-weight bearing; medial ligament reconstruction impact was seen on calcaneal pitch (19 to 35 degrees, p=0.007), 1st cuneiform height (21 to 28mm, p=0.016), talonavicular coverage (6 to 3 degrees, p=0.026), and Talar 1st metatarsal angle (14 to 7 degrees, p=0.008). Other corrections had an impact on calcaneal pitch (15 to 24 degrees, p=0.006), Talo-1st metatarsal angle (11 to 6 degrees, p=0.019), Calcaneal 1st metatarsal (139 to 129 degrees, p=0.044), Talar height (31 to 42mm, p=0.001), navicular height (24 to 34mm, p=0.002), and 1st cuneiform height (18 to 22mm, p=0.016). For weight bearing; reconstruction impact was seen on talocalcaneal angle (36 to 44 degrees, p=0.011), 1st-5thmetatarsal distance (12 to 18mm, p=0.047), and hindfoot moment arm (16 to 6mm, p=0.031). Other corrections had an impact on talar height (34 to 40mm, p=0.028), navicular height (26 to 30mm, p=0.031), cuboid height (p=0.021), and hindfoot alignment angle (17 to 7 degrees, p=0.003). Conclusion: When compared to procedures that only address bony changes in the foot, it is clear from this study that medial ligament repair plays a different, but significant, role in correction of flat foot deformity. Interestingly, the non-weight bearing and weight bearing results show that medial ligament reconstruction affects different aspects of the correction in these two distinct phases. This study serves to suggest that medial ligament reconstruction has a role in the correction of flat foot deformity that is not completely addressed in the more common procedures performed.

Despite the importance of trauma in healthspan and lifespan in humans as well as in non-human species, with one important exception the literature in both gerontology and ecology contains virtually no experimental demographic studies concerned with trauma in any species. We used dietary manipulation [full diet (F) versus sugar-only (S)] to produce four levels of frailty in 55-day old tephritid fruit flies (Anastrepha ludens) that were then subject to the trauma of cage transfer stress (n = 900/sex in each of the 4 treatments). The key results included the following: (1) there is a trauma effect caused by the transfer that depends on previous diet before transfer, new diet after transfer and gender of the fly; (2) males are more vulnerable than females; (3) if initial diet was F, flies are relatively immune against the trauma, and the subsequent diet (F or S) does not matter; (4) however if initial diet was S, then the effect of the trauma depends largely on the diet after the transfer; (5) flies transferred from S to F diets do very well in terms of remaining longevity (i.e. greatest remaining longevity), while flies transferred from S to S diet do poorly (i.e. shortest remaining longevity). We discuss both the strengths and weaknesses of this study and implications of the results.