Estrogens regulate early embryonic development of the olfactory sensory system via estrogen-responsive glia.

Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour.

E-cigarette vapor renders neutrophils dysfunctional due to filamentous actin accumulation.

BACKGROUND: Electronic cigarette (e-cigarette) use continues to rise despite concerns of long-term effects, especially the risk of developing lung diseases such as chronic obstructive pulmonary disease. Neutrophils are central to the pathogenesis of chronic obstructive pulmonary disease, with changes in phenotype and function implicated in tissue damage. OBJECTIVE: We sought to measure the impact of direct exposure to nicotine-containing and nicotine-free e-cigarette vapor on human neutrophil function and phenotype. METHODS: Neutrophils were isolated from the whole blood of self-reported nonsmoking, nonvaping healthy volunteers. Neutrophils were exposed to 40 puffs of e-cigarette vapor generated from e-cigarette devices using flavorless e-cigarette liquids with and without nicotine before functions, deformability, and phenotype were assessed. RESULTS: Neutrophil surface marker expression was altered, with CD62L and CXCR2 expression significantly reduced in neutrophils treated with e-cigarette vapor containing nicotine. Neutrophil migration to IL-8, phagocytosis of Escherichia coli and Staphylococcus aureus pHrodo bioparticles, oxidative burst response, and phorbol 12-myristate 13-acetate-stimulated neutrophil extracellular trap formation were all significantly reduced by e-cigarette vapor treatments, independent of nicotine content. E-cigarette vapor induced increased levels of baseline polymerized filamentous actin levels in the cytoplasm, compared with untreated controls. CONCLUSIONS: The significant reduction in effector neutrophil functions after exposure to high-power e-cigarette devices, even in the absence of nicotine, is associated with excessive filamentous actin polymerization. This highlights the potentially damaging impact of vaping on respiratory health and reinforces the urgency of research to uncover the long-term health implications of e-cigarettes.

Coupling Photoresponsive Transmembrane Ion Transport with Transition Metal Catalysis.

Artificial ion transporters have been explored both as tools for studying fundamental ion transport processes and as potential therapeutics for cancer and channelopathies. Here we demonstrate that synthetic transporters may also be used to regulate the transport of catalytic metal ions across lipid membranes and thus control chemical reactivity inside lipid-bound compartments. We show that acyclic lipophilic pyridyltriazoles enable Pd(II) cations to be transported from the external aqueous phase across the lipid bilayer and into the interior of large unilamellar vesicles. In situ reduction generates Pd(0) species, which catalyze the generation of a fluorescent product. Photocaging the Pd(II) transporter allows for photoactivation of the transport process and hence photocontrol over the internal catalysis process. This work demonstrates that artificial transporters enable control over catalysis inside artificial cell-like systems, which could form the basis of biocompatible nanoreactors for applications such as drug synthesis and delivery or to mediate phototargeted catalyst delivery into cells.

Comparison of Loss of Bone Height Following Total Ankle Arthroplasty Versus Tibiotalocalcaneal Arthrodesis.

Ankle arthrodesis and total ankle arthroplasty are both well-accepted surgical treatment options for end-stage ankle arthrosis. However, total ankle arthroplasty has gained popularity as the survivability of implants is improving. It is understood that there is loss of bone height following tibiotalocalcaneal arthrodesis, but to our knowledge, this has not been investigated in the setting of total ankle arthroplasty. A retrospective radiographic review was conducted over a 5-year period. We investigated all patients who underwent a tibiotalocalcaneal arthrodesis or total ankle arthroplasty for treatment of ankle arthritis by a single fellowship-trained orthopedic surgeon. The anterior and posterior height measurements were measured on preoperative and postoperative lateral radiographs. Differences between preoperative and postoperative heights were analyzed through a series of analyses of covariance. One hundred and thirty-three patients and 143 operative extremities were included: 71 operative extremities in the tibiotalocalcaneal arthrodesis group (mean age 55.5 ± 13.3 years, BMI 32.2 ± 7.9) and 72 in the total ankle arthroplasty group (mean age 65.4 ± 9.5 years, BMI 30.7 ± 6.4). Statistical analysis demonstrated a loss of height in the tibiotalocalcaneal arthrodesis group, and an increased anterior and posterior height in the total ankle arthroplasty group. However, when comparing the arthroplasty group and arthrodesis group only the anterior height measurement reached statistical significance when stratified by gender (p < .001). The potential change in height is an important factor to consider during surgical planning as a limb length discrepancy may result.

Predictive Factors of Postoperative Pain in Patients With Tibiotalocalcaneal Arthrodesis With an Intramedullary Nail: A Retrospective Review.

Tibiotalocalcaneal arthrodesis has been shown in literature to have good results in regards to low complication rates and deformity correction. While previous studies have investigated functional outcomes and complication rates, no large-scale studies have looked at pain outcomes. The present study performed a retrospective review of 154 extremities to analyze how a patient's comorbidities and characteristics influence pain outcomes following a tibiotalocalcaneal arthrodesis. The present study found an average change of pain from 7.1 to 3.0 in at least a 6 month follow up. We found that a diagnosis of chronic pain and tobacco use had statistically significant less pain improvement compared to patients without chronic pain or current tobacco use. We determined no statistically significant difference in pain outcomes for patients with or without Charcot deformity. Lastly, we found that with older patients there was more pain improvement observed. We physicians can educate current tobacco users of the improved pain outcomes with tobacco cessation prior to surgery. We recommend a multidisciplinary approach for pain in patients with a pre-operative diagnosis of chronic pain and to educate patients on realistic postoperative pain outcomes.

Modular Bioorthogonal Lipid Nanoparticle Modification Platforms for Cardiac Homing.

Lipid nanoparticles (LNPs) are becoming widely adopted as vectors for the delivery of therapeutic payloads but generally lack intrinsic tissue-homing properties. These extracellular vesicle (EV) mimetics can be targeted toward the liver, lung, or spleen via charge modification of their lipid headgroups. Homing to other tissues has only been achieved via covalent surface modification strategies using small-molecule ligands, peptides, or monoclonal antibodies─methods that are challenging to couple with large-scale manufacturing. Herein, we design a novel modular artificial membrane-binding protein (AMBP) platform for the modification of LNPs postformation. The system is composed of two protein modules that can be readily coupled using bioorthogonal chemistry to yield the AMBP. The first is a membrane anchor module comprising a supercharged green fluorescent protein (scGFP) electrostatically conjugated to a dynamic polymer surfactant corona. The second is a functional module containing a cardiac tissue fibronectin homing sequence from the bacterial adhesin CshA. We demonstrate that LNPs modified using the AMBP exhibit a 20-fold increase in uptake by fibronectin-rich C2C12 cells under static conditions and a 10-fold increase under physiologically relevant shear stresses, with no loss of cell viability. Moreover, we show targeted localization of the AMBP-modified LNPs in zebrafish hearts, highlighting their therapeutic potential as a vector for the treatment of cardiac disease and, more generally, as a smart vector.

Epigenomic Blood-Based Early Detection of Pancreatic Cancer Employing Cell-Free DNA.

BACKGROUND & AIMS: Early detection of pancreatic cancer (PaC) can drastically improve survival rates. Approximately 25% of subjects with PaC have type 2 diabetes diagnosed within 3 years prior to the PaC diagnosis, suggesting that subjects with type 2 diabetes are at high risk of occult PaC. We have developed an early-detection PaC test, based on changes in 5-hydroxymethylcytosine (5hmC) signals in cell-free DNA from plasma. METHODS: Blood was collected from 132 subjects with PaC and 528 noncancer subjects to generate epigenomic and genomic feature sets yielding a predictive PaC signal algorithm. The algorithm was validated in a blinded cohort composed of 102 subjects with PaC, 2048 noncancer subjects, and 1524 subjects with non-PaCs. RESULTS: 5hmC differential profiling and additional genomic features enabled the development of a machine learning algorithm capable of distinguishing subjects with PaC from noncancer subjects with high specificity and sensitivity. The algorithm was validated with a sensitivity for early-stage (stage I/II) PaC of 68.3% (95% confidence interval [CI], 51.9%-81.9%) and an overall specificity of 96.9% (95% CI, 96.1%-97.7%). CONCLUSIONS: The PaC detection test showed robust early-stage detection of PaC signal in the studied cohorts with varying type 2 diabetes status. This assay merits further clinical validation for the early detection of PaC in high-risk individuals.

Associations Between General Vaccine Hesitancy and Healthcare Access Among Arkansans.

BACKGROUND: Vaccines provide protection against numerous diseases that can cause serious illness and death. However, vaccine hesitancy threatens to undermine progress in reducing preventable diseases and illness. Vaccine hesitancy has been shown to vary by sociodemographic characteristics. However, studies examining associations between healthcare access and vaccine hesitancy are lacking. OBJECTIVE: Using a statewide random sample of Arkansas adults, we examined the relationship between general vaccine hesitancy and healthcare access. DESIGN: From July 12 to 30, 2021, participants were contacted by landlines and cellular phones using random digit dialing. PARTICIPANTS: A total of 1500 Arkansas adults were surveyed. Black/African American and Hispanic/Latinx adults were oversampled to ensure adequate representation. The survey had a cooperation rate of 20%. MAIN MEASURES: The dependent variable was an ordinal measure of general vaccine hesitancy. Age, gender, race, education, relationship status, and rural/urban residence were included in the model. Healthcare access was measured across four domains: (1) health insurance coverage; (2) having a primary care provider (PCP); (3) forgoing care due to cost; and (4) time since last routine checkup. The relationship between general vaccine hesitancy and healthcare access was modeled using ordinal logistic regression, controlling for sociodemographic characteristics. KEY RESULTS: Mean age was 48.5 years, 51.1% were women, 28% reported a race other than White, and 36.3% held a bachelor's degree or higher. Those with a PCP and those with health insurance had approximately two-thirds the odds of being more hesitant ([OR=0.63, CI=0.47, 0.84] and [OR=0.68; CI=0.49, 0.94]) than those without a PCP and those without health insurance. Participants reporting a routine checkup in the last 2 years were almost half as likely to be more hesitant than those reporting a checkup more than 2 years prior (OR=0.58; CI=0.43, 0.79). CONCLUSIONS: Results suggest improving access to health insurance, PCPs, and routine preventative care services may be critical to reducing vaccine hesitancy.

Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome.

Rationale: Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. Objectives: To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis. Methods: Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors. Recombinant cathepsin S was instilled directly into the lungs of mice. The effects of cathepsin S knockout and pharmacological inhibition were examined in two models of acute lung injury. Protease-activated receptor-1 antagonism was used to test a possible mechanism for cathepsin S-mediated inflammation. Measurements and Main Results: Pulmonary cathepsin S concentrations and activity were elevated in acute respiratory distress syndrome, a phenotype possibly exacerbated by the loss of the endogenous antiprotease cystatin SN. Direct cathepsin S instillation into the lungs induced key pathologies of acute respiratory distress syndrome, including neutrophilia and alveolar leakage. Conversely, in murine models of acute lung injury, genetic knockdown and prophylactic or therapeutic inhibition of cathepsin S reduced neutrophil recruitment and protein leakage. Cathepsin S may partly mediate its pathogenic effects via protease-activated receptor-1, because antagonism of this receptor abrogated cathepsin S-induced airway inflammation. Conclusions: Cathepsin S contributes to acute lung injury and may represent a novel therapeutic target for acute respiratory distress syndrome.

Associations between COVID-19 Death Exposure and COVID-19 Vaccine Hesitancy and Vaccine Uptake.

OBJECTIVES: The aim of the study was to determine the relation between coronavirus disease 2019 (COVID-19) death exposure and COVID-19 vaccine hesitancy and vaccine uptake among Arkansans, controlling for sociodemographic factors. METHODS: Data were collected from a telephone survey administered in Arkansas between July 12 and July 30, 2021 (N = 1500) via random digit dialing of telephone landlines and cellular telephones. Weighted data were used to estimate regressions. RESULTS: Controlling for sociodemographic variables, COVID-19 death exposure was not a significant predictor of COVID-19 vaccine hesitancy (P = 0.423) or COVID-19 vaccine uptake (P = 0.318). Younger individuals, those with lower levels of education, and those who live in rural counties were more likely to be COVID-19 vaccine hesitant. Older individuals, Hispanic/Latinx individuals, those who reported higher levels of education, and those who reported living in urban counties were more likely to have reported receiving the COVID-19 vaccine. CONCLUSIONS: Many efforts to promote COVID-19 vaccines have focused on prosocial norms, including encouraging vaccination to protect the community from COVID-19 infection and death; however, COVID-19 death exposure was not related to COVID-19 vaccine hesitancy or uptake in the present study. Future research should examine whether prosocial messaging is effective in decreasing hesitancy or motivating some individuals to receive the vaccine among those who have been exposed to COVID-19 deaths.

Friend or Foe? Locoregional Therapies and Immunotherapies in the Current Hepatocellular Treatment Landscape.

Over the last several decades, a number of new treatment options for patients with hepatocellular carcinoma (HCC) have been developed. While treatment decisions for some patients remain clear cut, a large numbers of patients have multiple treatment options, and it can be hard for multidisciplinary teams to come to unanimous decisions on which treatment strategy or sequence of treatments is best. This article reviews the available data with regard to two treatment strategies, immunotherapies and locoregional therapies, with a focus on the potential of locoregional therapies to be combined with checkpoint inhibitors to improve outcomes in patients with locally advanced HCC. In this review, the available data on the immunomodulatory effects of locoregional therapies is discussed along with available clinical data on outcomes when the two strategies are combined.

Retrospective Comparison of Isolated Haglund's Deformity Surgery Versus Combined With Gastrocnemius Recession.

Insertional Achilles tendonitis is a common pathology treated by foot and ankle surgeons that may require surgical intervention. Literature has shown good outcomes following detachment and reattachment of the Achilles for removal of the exostosis. However, there is minimal literature showing the impact of adding a gastrocnemius recession to the Haglund's resection. The goal of the present study was to retrospectively review the outcomes of an isolated Haglund's resection versus a Haglund's resection combined with a gastrocnemius recession. A retrospective chart review of 54 operative extremities was performed: 29 with isolated Haglund's resection and 25 with a Strayer gastrocnemius recession. We found similar decreases in pain between the 2 groups, 6.1 to 1.5 and 6.8 to 1.8 in the isolated Haglund's and Strayer's group, respectively. We found decreased postoperative Achilles rupture and reoperation rates in the Strayer group but this did not reach statistical significance. We found a statistically significant decreased rate of wound healing complications in the Strayer group, 4% in the Strayer group and 24% in the isolated procedure. In conclusion, adding a Strayer to a Haglund's resection was found to have a statistically significant decrease in wound complications. We recommend future randomized controlled studies to compare the use of a Strayer procedure on postoperative complications.

Change in Height Following Tibiotalocalcaneal Arthrodesis: Retrospective Radiographic Analysis.

Tibiotalocalcaneal arthrodesis (TTCA) with an intramedullary rod is a viable treatment option for a myriad of pathologies involving the foot and ankle. While the current literature has focused on fixation techniques, deformity correction, and clinical outcomes, we are unaware of any studies specifically examining change in height following a TTCA. In the present study, we retrospectively analyzed radiographs with novel radiographic techniques to determine the change in height from preoperative to postoperative radiographs following TTCA. Patients were divided into 3 categories: Charcot, arthritis, and pes planus as the indication for surgical intervention. We found that Charcot and arthritis had an average decrease in height on anterior and posterior measurements of the height from the distal tibia to the calcaneus, while pes planus had an increase in height. The average Charcot change in height was -12.0 ± 24.4 mm anteriorly and -7.6 ± 15.5 mm posteriorly. The average change in height for the arthritis group was -6.9 ± 6.7 mm anteriorly and -3.8 ± 5.8 mm posteriorly. The pes planus group was found to have an average increase in height 0.5 ± 8.0 mm anteriorly and 2.9 ± 5.8 mm posteriorly. Overall, we found a statistically significant difference in height change between the 3 groups in anterior measurements (p = .012) and posterior measurement (p = .006). We recommend surgeons who perform this procedure to be aware of the potential change in height to better tailor surgical and postoperative care.

Incidence of Nonunion Following First Metatarsophalangeal Joint Arthrodesis for Hallux Valgus Deformity: A Retrospective Analysis of Four Different Constructs.

Arthrodesis of the great toe joint is a valuable procedure for hallux valgus deformities. The primary aim of this study was to determine nonunion rates of a first metatarsophalangeal joint (MTPJ) arthrodesis for bunion deformity. This was a retrospective review of 166 consecutive limbs that underwent a first metatarsal phalangeal joint arthrodesis at Wake Forest Baptist Medical Center (WFBMC). Procedures were performed using 4 different constructs for the arthrodesis. Incidence of nonunion, intermetatarsal correction, infection, and recurrence were measured. Overall, 20 patients (12%) experienced nonunion following a first metatarsophalangeal joint arthrodesis. Eighty-seven patients (86%) of plate and screw patients achieved union while 14 (78%) of crossing screw patients achieved union. The minimum time of follow-up was 3 months and the maximum time was 15.4 months. The mean change in intermetatarsal and hallux valgus angle correction was 3.4° and 20.3°, with no statistical difference based on hardware construct or being diabetic. First metatarsophalangeal joint arthrodesis is a viable option for hallux valgus. However, the results of the present study suggest that there is a lower fusion rate of the first MTPJ using crossing screws for bunion deformities.

CD14-positive extracellular vesicles in bronchoalveolar lavage fluid as a new biomarker of acute respiratory distress syndrome.

Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within bronchoalveolar lavage (BAL) fluid of patients with ARDS, and to determine whether BAL EV could be used as a potential biomarker in ARDS. BAL was collected from patients with sepsis with and without ARDS, and from esophagectomy patients postoperatively (of whom a subset later developed ARDS during hospital admission). BAL EVs were characterized with regard to size, number, and cell of origin. Patients with sepsis-related ARDS had significantly higher numbers of CD14+/CD81+ monocyte-derived BAL EV than patients with sepsis without ARDS (P = 0.015). However, the converse was observed in esophagectomy patients who later developed ARDS (P = 0.003). Esophagectomy patients who developed ARDS also had elevated CD31+/CD63+ and CD31+/CD81+ endothelial-derived BAL EV (P ≤ 0.02) compared with esophagectomy patients who did not develop ARDS. Further studies are required to determine whether CD31+ BAL EV may be a predictive biomarker for ARDS in esophagectomy patients. CD14+/CD81+ BAL EV numbers were significantly higher in those patients with sepsis-related ARDS who died during the 30 days following intensive care unit admission (P = 0.027). Thus, CD14+/CD81+ BAL EVs are a potential biomarker for disease severity and mortality in sepsis-related ARDS. These findings provide the impetus to further elucidate the contribution of these EVs to ARDS pathogenesis.

Cigarette smoke exposure and alveolar macrophages: mechanisms for lung disease.

Cigarette smoking is the leading cause of preventable death worldwide. It causes chronic lung disease and predisposes individuals to acute lung injury and pulmonary infection. Alveolar macrophages are sentinel cells strategically positioned in the interface between the airway lumen and the alveolar spaces. These are the most abundant immune cells and are the first line of defence against inhaled particulates and pathogens. Recently, there has been a better understanding about the ontogeny, phenotype and function of alveolar macrophages and their role, not only in phagocytosis, but also in initiating and resolving immune response. Many of the functions of the alveolar macrophage have been shown to be dysregulated following exposure to cigarette smoke. While the mechanisms for these changes remain poorly understood, they are important in the understanding of cigarette smoking-induced lung disease. We review the mechanisms by which smoking influences alveolar macrophage: (1) recruitment, (2) phenotype, (3) immune function (bacterial killing, phagocytosis, proteinase/anti-proteinase release and reactive oxygen species production) and (4) homeostasis (surfactant/lipid processing, iron homeostasis and efferocytosis). Further understanding of the mechanisms of cigarette smoking on alveolar macrophages and other lung monocyte/macrophage populations may allow novel ways of restoring cellular function in those patients who have stopped smoking in order to reduce the risk of subsequent infection or further lung injury.

Four-Year Disease-Free Remission in a Patient With POLE Mutation-Associated Colorectal Cancer Treated Using Anti-PD-1 Therapy.

The stability of the human genome depends upon a delicate balance between replication by high- and low-fidelity DNA polymerases. Aberrant replication by error-prone polymerases or loss of function of high-fidelity polymerases predisposes to genetic instability and, in turn, cancer. DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is responsible for the majority of leading strand synthesis, and mutations in Pol ε have been increasingly associated with various human malignancies. The clinical significance of Pol ε mutations, including how and whether they should influence management decisions, remains poorly understood. In this report, we describe a 24-year-old man with an aggressive stage IV high-grade, poorly differentiated colon carcinoma who experienced a dramatic response to single-agent checkpoint inhibitor immunotherapy after rapidly progressing on standard chemotherapy. His response was complete and durable and has been maintained for more than 48 months. Genetic testing revealed a P286R mutation in the endonuclease domain of POLE and an elevated tumor mutational burden of 126 mutations per megabase, both of which have been previously associated with response to immunotherapy. Interestingly, tumor staining for PD-L1 was negative. This case study highlights the importance of genetic profiling of both early and late-stage cancers, the clinical significance of POLE mutations, and how the interplay between genetic instability and immune-checkpoint blockade can impact clinical decision-making.

In Vivo Characterization of Endogenous Cardiovascular Extracellular Vesicles in Larval and Adult Zebrafish.

Objective: Extracellular vesicles (EVs) facilitate molecular transport across extracellular space, allowing local and systemic signaling during homeostasis and in disease. Extensive studies have described functional roles for EV populations, including during cardiovascular disease, but the in vivo characterization of endogenously produced EVs is still in its infancy. Because of their genetic tractability and live imaging amenability, zebrafish represent an ideal but under-used model to investigate endogenous EVs. We aimed to establish a transgenic zebrafish model to allow the in vivo identification, tracking, and extraction of endogenous EVs produced by different cell types. Approach and Results: Using a membrane-tethered fluorophore reporter system, we show that EVs can be fluorescently labeled in larval and adult zebrafish and demonstrate that multiple cell types including endothelial cells and cardiomyocytes actively produce EVs in vivo. Cell-type specific EVs can be tracked by high spatiotemporal resolution light-sheet live imaging and modified flow cytometry methods allow these EVs to be further evaluated. Additionally, cryo electron microscopy reveals the full morphological diversity of larval and adult EVs. Importantly, we demonstrate the utility of this model by showing that different cell types exchange EVs in the adult heart and that ischemic injury models dynamically alter EV production. Conclusions: We describe a powerful in vivo zebrafish model for the investigation of endogenous EVs in all aspects of cardiovascular biology and pathology. A cell membrane fluorophore labeling approach allows cell-type specific tracing of EV origin without bias toward the expression of individual protein markers and will allow detailed future examination of their function.

Lactate cross-talk in host-pathogen interactions.

Lactate is the main product generated at the end of anaerobic glycolysis or during the Warburg effect and its role as an active signalling molecule is increasingly recognised. Lactate can be released and used by host cells, by pathogens and commensal organisms, thus being essential for the homeostasis of host-microbe interactions. Infection can alter this intricate balance, and the presence of lactate transporters in most human cells including immune cells, as well as in a variety of pathogens (including bacteria, fungi and complex parasites) demonstrates the importance of this metabolite in regulating host-pathogen interactions. This review will cover lactate secretion and sensing in humans and microbes, and will discuss the existing evidence supporting a role for lactate in pathogen growth and persistence, together with lactate's ability to impact the orchestration of effective immune responses. The ubiquitous presence of lactate in the context of infection and the ability of both host cells and pathogens to sense and respond to it, makes manipulation of lactate a potential novel therapeutic strategy. Here, we will discuss the preliminary research that has been carried out in the context of cancer, autoimmunity and inflammation.

Review of Achilles Tendon Reattachment Using Double-Row Knotted and Knotless Techniques in the Management of Insertional Achilles Tendinopathy.

Insertional Achilles tendinopathy represents a chronic degenerative condition affecting the insertion of the Achilles. Surgery is indicated in recalcitrant cases and often involves extensive debridement followed by subsequent repair of the insertion. In the present study, we evaluate the results of knotted and knotless double-row suture systems for Achilles reattachment. Despite the popularity of double-row repairs, there is a relative paucity of clinic data regarding efficacy of the available implants. In a retrospective cohort study, 38 patients (40 Achilles tendons) who received double-row repairs between November 2012 and December 2016 were evaluated. In addition to demographic information, preoperative pain scores and symptom duration were recorded. Perioperative and postoperative records were reviewed, and telephone interviews were conducted to assess patient satisfaction, functional status, postoperative pain, and information regarding surgical complications. At a mean follow-up of 32.5 months, 35 (92.1%) patients reported satisfaction with the outcome. Decreased pain levels were reported in 38 (95%) ankles, with 21 (52.5%) ankles being rated pain-free postoperatively. Of the patients working prior to surgery, 20 (95.2%) were able to return to normal work duties, and all 11 (100%) patients who engaged in sports preoperatively were able to return to the same level of activity. Two patients developed postoperative infections, one of which required operative debridement. No Achilles avulsions were encountered. No significant differences were noted between the 2 operative techniques. Considering the available biomechanical data, along with high patient satisfaction rates and low rate of complications, double-row repair offers a viable option for recalcitrant insertional Achilles tendinopathy.