Parks, Trails, and Greenways for Physical Activity: A Community Guide Systematic Economic Review.

INTRODUCTION: This systematic economic review examined the cost-benefit and cost-effectiveness of park, trail, and greenway infrastructure interventions to increase physical activity or infrastructure use. METHODS: The search period covered the date of inception of publications databases through February 2022. Inclusion was limited to studies that reported cost-benefit or cost-effectiveness outcomes and were based in the U.S. and other high-income countries. Analyses were conducted from March 2022 through December 2022. All monetary values reported are in 2021 U.S. dollars. RESULTS: The search yielded 1 study based in the U.S. and 7 based in other high-income countries, with 1 reporting cost-effectiveness and 7 reporting cost-benefit outcomes. The cost-effectiveness study based in the United Kingdom reported $23,254 per disability-adjusted life year averted. The median benefit-to-cost ratio was 3.1 (interquartile interval=2.9-3.9) on the basis of 7 studies. DISCUSSION: The evidence shows that economic benefits exceed the intervention cost of park, trail, and greenway infrastructure. Given large differences in the size of infrastructure, intervention costs and economic benefits varied substantially across studies. There was insufficient number of studies to determine the cost-effectiveness of these interventions.

Manipulation Under Anesthesia and/or Lysis of Adhesions After Anterior Cruciate Ligament Reconstruction in Female Basketball Players: Does Race Play a Role?

BACKGROUND: Arthrofibrosis can limit function and return to sport after anterior cruciate ligament (ACL) reconstruction. Previously reported risk factors for developing arthrofibrosis after ACL reconstruction include female sex, age <18 years, time from injury to surgery <28 days, concomitant meniscal repair, prolonged immobilization, and genetic factors. There is a lack of evidence regarding whether race plays a significant role. HYPOTHESIS: The risk of undergoing manipulation under anesthesia (MUA) and/or lysis of adhesions (LOA) after primary ACL reconstruction with bone-patellar tendon-bone (BTB) autograft in female basketball players is higher in African American players than in White players. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Using a computerized relational database, the authors identified competitive female basketball players who underwent primary ACL reconstruction with BTB autograft by the senior author over a 13-year period. Data previously entered from examinations and surgical findings were reviewed retrospectively. Univariate statistics and multivariable logistic regression were used to assess the relationship between undergoing subsequent MUA and/or LOA and study predictors. RESULTS: A total of 186 knees (114 African American knees and 72 White knees) met inclusion criteria. The overall rate of MUA and/or LOA was 8.6%. Thirteen African American knees (11.4%) and 3 White knees (4.2%) underwent MUA and/or LOA for treatment of arthrofibrosis. No study predictor was found to have a statistically significant relationship with the rate of MUA and/or LOA on univariate analysis. However, when controlling for body mass index and previously described risk factors (age <18 years, time from injury to surgery ≤28 days, and concomitant meniscal repair) in the logistic regression model, the authors found that MUA and/or LOA was more likely in African American (odds ratio, 4.01 [95% CI, 1.01-15.92]; P = .049) than in White female players and in patients who underwent ACL reconstruction within 28 days of injury (odds ratio, 4.01 [95% CI, 1.18-13.57]; P = .026) compared with those with surgery delayed beyond 28 days. CONCLUSION: In female basketball players, the present study found a statistically significantly increased risk for undergoing MUA and/or LOA after primary ACL reconstruction with BTB autograft in African American females compared with White females and in patients who underwent ACL reconstruction within 28 days of injury.

Biomimetic Shells Endow Sub-50 nm Nanoparticles with Ultrahigh Paclitaxel Payloads for Specific and Robust Chemotherapy.

Poor loading capacity and nonspecific tumor accumulation of current drug delivery system remain the critical challenges that prevent nanomedicine from maximizing therapeutic efficacy in cancer treatment. Herein, poly(ester amide) polymers composed of cationic and hydrophobic segments were formulated with a paclitaxel/human serum albumin (PTX/HSA) complex, as well as free PTX, to construct a core-shell nanoparticle (NP) platform with the interior simultaneously reserving PTX and PTX/HSA complex, while the exterior absorbing the PTX/HSA complex. Following systematic screening, the optimized NPs, namely, APP1i@e NPs, exhibited small particle size (43.95 nm), maximal PTX loading (42.23%), excellent dynamic stability (at least 1 week), and acid-triggered release. In vitro results showed that after being trafficked through caveolae-mediated endocytosis, APP1i@e NPs successfully escaped from endo-/lysosomes and then rapidly released cargos in the acidic cytosol, which continued to enhance cytotoxicity by mitochondrial control of apoptosis and suppression of microtubule dynamics. Longer circulation time and superior targeting efficiency post-intravenous injection confirmed that surface PEGylation imparted APP1i@e NPs with the ability to control their pharmacokinetics and biodistribution. The biomimetic shell design with HSA, which enlarged PTX stock and improved biosafety, made APP1i@e NPs more suitable for in vivo applications. Furthermore, in vivo safety and efficacy demonstrated that APP1i@e NPs effectively inhibited the growth of ovarian xenograft tumors, whereas significantly avoiding toxic issues associated with PTX. APP1i@e NPs with surface PEG coating and biomimetic HSA design, therefore, may provide a remarkable improvement in the therapeutic index of taxanes used in the clinic.

Intracellular Mechanistic Understanding of 2D MoS2 Nanosheets for Anti-Exocytosis-Enhanced Synergistic Cancer Therapy.

Emerging two-dimensional (2D) nanomaterials, such as transition-metal dichalcogenide (TMD) nanosheets (NSs), have shown tremendous potential for use in a wide variety of fields including cancer nanomedicine. The interaction of nanomaterials with biosystems is of critical importance for their safe and efficient application. However, a cellular-level understanding of the nano-bio interactions of these emerging 2D nanomaterials ( i. e., intracellular mechanisms) remains elusive. Here we chose molybdenum disulfide (MoS2) NSs as representative 2D nanomaterials to gain a better understanding of their intracellular mechanisms of action in cancer cells, which play a significant role in both their fate and efficacy. MoS2 NSs were found to be internalized through three pathways: clathrin → early endosomes → lysosomes, caveolae → early endosomes → lysosomes, and macropinocytosis → late endosomes → lysosomes. We also observed autophagy-mediated accumulation in the lysosomes and exocytosis-induced efflux of MoS2 NSs. Based on these findings, we developed a strategy to achieve effective and synergistic in vivo cancer therapy with MoS2 NSs loaded with low doses of drug through inhibiting exocytosis pathway-induced loss. To the best of our knowledge, this is the first systematic experimental report on the nano-bio interaction of 2D nanomaterials in cells and their application for anti-exocytosis-enhanced synergistic cancer therapy.

Intracellular Fate of Nanoparticles with Polydopamine Surface Engineering and a Novel Strategy for Exocytosis-Inhibiting, Lysosome Impairment-Based Cancer Therapy.

Polydopamine (PDA) coating as a bioinspired strategy for nanoparticles (NPs) has been extensively applied in cancer theranostics. However, a cellular-level understanding of nano-biointeraction of these PDA-coated NPs (PDNPs), which drives the fate of them and acts as a critical step to determine their efficacy, still remains unknown. Herein, we utilized the representative mesoporous silica NPs (MSNs) to be coated with PDA and study their nano-bioactivities in cancer cells. HeLa cell line was utilized as a model in this study. The PDNPs were discovered to be internalized through three specific pathways, that is, Caveolae-, Arf6-dependent endocytosis, and Rab34-mediated macropinocytosis (55%, 20% and 37% of uptake inhibition by nystatin, Arf6 knockdown, and rottlerin, respectively). Autophagy-mediated accumulation of PDNPs in lysosomes was observed and the formed PDA shells shedded in the lysosomes. Almost 40% of the NPs were transported out of cells via Rab8/10- and Rab3/26-mediated exocytosis pathways at our tested level. On the basis of these results, a novel combined cancer treatment strategy was further proposed using drug-loaded MSNs-PDA by (i) utilizing naturally intracellular mechanism-controlled PDA shedding for organelle-targeted release of drugs in lysosomes to generate lysosome impairment and (ii) blocking the demonstrated exocytosis pathways for enhanced therapeutic efficacy.

Successful salvage chemotherapy and allogeneic transplantation of an acute myeloid leukemia patient with disseminated Fusarium solani infection.

Disseminated Fusarium infection is associated with high mortality in immunocompromised patients. Patients with acute myeloid leukemia (AML) often have an extended duration of neutropenia during intensive induction chemotherapy, consolidation chemotherapy, and hematopoietic stem cell transplantation (SCT). There is no consensus regarding management of invasive disseminated Fusarium infections in the setting of prolonged neutropenia (Tortorano et al., 2014) [1]. We report a case of disseminated Fusarium in a patient with relapsed AML who underwent successful chemotherapy and haplo-identical allogeneic SCT with administration of granulocyte colony stimulating factor (G-CSF) and granulocyte infusions.

The importance of natural killer cell killer immunoglobulin-like receptor-mismatch in transplant outcomes.

PURPOSE OF REVIEW: In recent years, the rules of engagement between natural killer (NK) cells and their targets have become better defined with the identification of an array of NK surface molecules, notably the killer immunoglobulin-like (KIR) receptors and their ligands on target cells through which signals of activation or suppression of NK function are mediated. After allogeneic stem cell transplantation (SCT), the opportunity for NK cell activation can occur both in human leucocyte antigen (HLA) matched and HLA mismatched pairs. Although less well explored in HLA identical transplants, many studies confirm the importance of NK KIR mismatching in the graft-versus-leukemia effect in haploidentical (haplo) SCT and this has stimulated recent research to better define the role of NK mismatching on transplant outcome. In this review, we describe recent progress in identifying favorable and unfavorable NK matching in SCT. RECENT FINDINGS: Recent studies focus less on KIR-HLA mismatching and more on KIR genes as tools to predict alloreactivity via NK licensing and activating KIR. SUMMARY: Current results show that transplant outcomes could be improved by judicious selection of favorable donors.

The Relationship Between Self-Rated Health and Use of Parks and Participation in Recreation Programs, United States, 1991 and 2015.

We examined the relationship between self-rated health and use of parks and recreation program participation by using logistic regression to analyze data from representative national surveys conducted in 1991 and 2015. Neither park use nor program participation were significantly related to self-rated health in 1991; however, both were significantly related in 2015. The growing relationship between use of parks and recreation programs and self-rated health during this period is likely the result of broad national health promotion efforts and provides support for funding of capital and operational expenses for park and recreation services.

Efficacy of Two Techniques in Anterior Cruciate Ligament Reconstruction.

The purpose of this study is to compare failure rate and functional outcome in young, active patients (< 25 years) with two-incision (rear-entry) versus transtibial (all-endoscopic) anterior cruciate ligament (ACL) reconstructions.Utilizing a computerized relational database (Access 2007, Microsoft Inc., Redmond, WA), 480 patients were identified that underwent ACL reconstruction, using a bone-patellar-tendon-bone autograft, by a single surgeon between January 2000 and December 2010 via a transtibial or two-incision technique. Totally, 377 (78.6%) of these patients were less than 25 years of age. Data for each patient were collected at their initial clinic visit, at the time of surgery, and at each follow-up clinic visit and entered into the computerized relational database. Overall, 274 patients (72.7%) underwent ACL reconstruction with a transtibial technique, and 103 patients (27.3%) underwent reconstruction with a two-incision technique. Failures were identified as a 2+ Lachman, 1+ or greater pivot shift, or a KT-1000 arthrometer difference of five or more.In patients < 25 years of age, there were 10 failures (9.7%) out of 103 patients undergoing a two-incision reconstruction and 28 failures (10.2%) out of 274 patients undergoing a transtibial reconstruction (p = 1.000). There was no statistical significance between the failure rate in the two different groups in regards to gender, meniscal tear, activity level, or any other factor that was analyzed.Our study showed no statistical difference between the two-incision technique and the transtibial technique for ACL reconstruction using bone-patellar-tendon-bone autograft with an overall 10.1% failure rate in young, active patients (< 25 years of age). The level of evidence is level IV.

Relationship Between Posterior-Inferior Tibial Slope and Bilateral Noncontact ACL Injury.

Is there a correlation between increased posterior-inferior tibial slope angle and noncontact anterior cruciate ligament (ACL) injury? Does increasing the posterior-inferior tibial slope angle increase the risk of bilateral ACL injury? A computerized relational database (Access 2007; Microsoft Inc, Redmond, Washington) was used to conduct a retrospective review of patients undergoing bilateral or unilateral ACL reconstruction surgery or treatment by a single surgeon between 1995 and 2013. Included in the study were patients with bilateral and unilateral ACL injuries and patellofemoral pain syndrome with no associated ACL deficiency. Exclusion criteria included concomitant ligament injury, previous ACL reconstruction, and previous knee surgery. Also excluded were patients who did not have plain lateral radiographs. Fifty patients were randomly selected from each group. After controlling for age and Tegner activity level, the authors found that the posterior-inferior tibial slope angle was a significant predictor (P=.002) of noncontact ACL injury. Mean posterior-inferior tibial slope angle for the bilateral, unilateral, and control groups was 11.8°±2.3°, 9.3°±2.4°, and 7.5°±2.3°, respectively. In the group with unilateral ACL injury vs the group without ACL deficiency, a 1° increase in posterior-inferior tibial slope angle (P=.03) was associated with a 20% increase in unilateral ACL injury. In those with bilateral ACL injury vs those without ACL deficiency, a 1° increase in posterior-inferior tibial slope angle (P=.001) increased bilateral knee injury by 34%. The difference between the mean angles of the control group without ACL deficiency and both the bilateral injury and unilateral injury cohorts was statistically significant (P=.003). Increased posterior-inferior tibial slope angle is associated with an increased risk of noncontact bilateral and unilateral ACL injury. [Orthopedics. 2017; 40(1):e136-e140.].

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia.

Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine's clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves.

Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia.

Selective depletion (SD) of alloreactive T cells from allogeneic hematopoeitic stem cell transplants to prevent graft-versus-host disease (GVHD) without compromising immune reconstitution and antitumor responses remains a challenge. Here, we demonstrate a novel SD strategy whereby alloreacting T cells are efficiently deleted ex vivo with adenosine. SD was achieved in human leukocyte antigen (HLA) mismatched cocultures by multiple exposures to 2 mmol/l adenosine over 7 days. Adenosine depleted greater than to 90% of alloproliferating T cells in mismatched, haploidentical, and matched sibling pairs while conserving response to third-party antigens. Alloreactive CD4 and CD8 T cells were targeted for depletion while NK and B cells were preserved. Our novel approach also preserved nonalloreactive naive, central, and effector memory T-cell subsets, Tregs, and notably preserved T-cell responses against DNA viruses that contribute to transplant related mortality after allogeneic hematopoeitic stem cell transplants. Additionally, T cells recognizing leukemia-associated antigens were efficiently generated in vitro from the cell product post-SD. This study is the first to demonstrate that adenosine depletion of alloactivated T cells maintains a complete immune cell profile and recall viral responses. Expansion of tumor antigen-specific subsets postdepletion opens the possibility of generating T-cell products capable of graft-versus-tumor responses without causing GVHD.

Novel immunotherapeutic approaches for the treatment of acute leukemia (myeloid and lymphoblastic).

There have been major advances in our understanding of the multiple interactions between malignant cells and the innate and adaptive immune system. While the attention of immunologists has hitherto focused on solid tumors, the specific immunobiology of acute leukemias is now becoming defined. These discoveries have pointed the way to immune interventions building on the established graft-versus-leukemia (GVL) effect from hematopoietic stem-cell transplant (HSCT) and extending immunotherapy beyond HSCT to individuals with acute leukemia with a diversity of immune manipulations early in the course of the leukemia. At present, clinical results are in their infancy. In the coming years larger studies will better define the place of immunotherapy in the management of acute leukemias and lead to treatment approaches that combine conventional chemotherapy, immunotherapy and HSCT to achieve durable cures.

Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study.

BACKGROUND: T-cell large granular lymphocytic leukaemia (T-LGL) is a lymphoproliferative disease that presents with immune-mediated cytopenias and is characterised by clonal expansion of cytotoxic CD3+ CD8+ lymphocytes. Use of methotrexate, ciclosporin, or cyclophosphamide as first therapy improves cytopenias in 50% of patients, but long-term use of these can lead to toxicity. We aimed to explore the activity and safety of alemtuzumab, an anti-CD52 monoclonal antibody, in patients with T-LGL. METHODS: We did this single-arm, phase 2 trial in consecutively enrolled adults with T-LGL referred to the National Institutes of Health in Bethesda, MD, USA. Alemtuzumab was given intravenously at 10 mg per day for 10 days. The primary endpoint was haematological response at 3 months after infusion. A complete response was defined as normalisation of all affected lineages, and a partial response was defined in neutropenic patients as 100% increase in the absolute neutrophil count to more than 5 × 10(8) cells per L, and in those with anaemia, as any increase in haemoglobin of 20 g/L or higher observed in at least two serial measurements 1 week apart and sustained for 1 month or longer without exogenous growth factors support or transfusions. Analysis was by intention to treat. We report results from the first stage of this Simon two-stage design trial; enrolment into the second stage is continuing. This study is registered with ClinicalTrials.gov, number NCT00345345. FINDINGS: From Oct 1, 2006, to March 1, 2015, we enrolled 25 patients with T-LGL. 14 patients (56%; 95% CI 35-76) had a haematological response at 3 months. Four patients with associated myelodysplastic syndrome and two who had received haemopoietic stem cell transplantation had either no response or were not evaluable, meaning 14 (74% [49-91]) of the 19 patients with classic T-LGL responded. All patients had an infusion reaction (24 [96%] patients grade 1-2, one [4%] patient grade 3), which improved with symptomatic therapy. All patients developed lymphopenia, with 22 (88%) patients having grade 3 or 4 lymphopenia. The other most common grade 3 and 4 adverse events were leukopenia (eight [32%]) and neutropenic infections (five [20%]). Seven patients died; all were non-responders. INTERPRETATION: This is the largest and only prospective study of alemtuzumab in patients with T-LGL. The activity reported with a single course of a lymphocytotoxic drug in patients with mainly relapsed and refractory disease suggests that haematological response can be achieved without continued use of oral immunosuppression. FUNDING: National Heart, Lung, and Blood Institute.

Body Mass Index as an Indicator of Associated Intra-articular Injuries in Patients With Anterior Cruciate Ligament Tears.

This study assessed the relationship between body mass index (BMI), anterior cruciate ligament (ACL) injury, and associated meniscal and cartilage injury. Age, ACL classification, and Tegner activity score were considered. A total of 1968 ACL reconstruction patients (2/1/1996 to 5/1/2012) were analyzed. All graft types, age groups, and activity levels were included. A BMI ≥30 correlated with a significant likelihood of medial meniscus tears (p = .022). Patients with a BMI ≥30 were 21.6% more likely to have a medial meniscus tear with an ACL injury. Grade III and IV chondral lesions correlated with a BMI ≥30 (p = .029). Patient's age predicted medial meniscus outcome (p = .013). Patients whose age was >25 had a 25.7% higher risk of medial meniscus tear. Chronic ACL patients were 52.6% more likely to have a meniscus injury. BMI, age, Tegner activity score, and ACL classification are good predictors of medial meniscus injury. Patients with a BMI ≥30 exhibit a greater risk of medial meniscus tear with ACL instability; however, BMI does not significantly contribute to increased chondral damage in ACL-deficient patients.