Implementation Challenges of T Visa Eligibility for Human Trafficking Survivors: A Role for Social Work.

The passage of the Victims of Trafficking and Violence Protection Act of 2000 (TVPA) and subsequent creation of a residency process for nonresident survivors of human trafficking (the T Visa) are notable milestones in the United States' effort to address the problem of human trafficking and provide essential supports to trafficking survivors. However, current implementation of the statute's eligibility criteria for accessing entitlements and protections contributes to a potential for retraumatization, further traumatization, and other continued harms to survivors. The present article explores the structural and conceptual limitations of current T Visa policy and of recent annual policy guidance materials as important contributors to these policy implementation problems. Resulting problems are identified as an ambiguity of definitions and thresholds, a narrow conceptualization of victimhood, and the contradictory relationship between protection and prosecution. This article then utilizes a trauma-informed social policy framework to identify multisystemic action steps for social workers to address these limitations and improve the T Visa process for trafficking survivors. These actions steps provide an essential road map for closing the gap between the policy goals of the TVPA and its current implementation.

A Process for the Design and Development of Novel Bone Morphogenetic Protein-7 (BMP-7) Mimetics With an Example: THR-184.

Growth Factors have been evaluated as therapeutic targets for the treatment of a broad spectrum of diseases. Because they are proteins with pleiotropic effects, the quest to harness their beneficial effects has presented challenges. Most Growth Factors operate at the extracellular-receptor level and have natural feedback mechanisms that modulate their effects. As proteins, they are difficult and expensive to manufacture. Frequently proteins must be administered parenterally, may invoke an immune response, and may be neutralized by naturally occurring inhibitors. To circumvent these limitations, we have undertaken an effort to develop mimetics for the Bone Morphogenetic Protein (BMP) signaling pathway effects that incorporate the beneficial effects, eliminate the deleterious effects, and thereby create effective drug-like compounds.To this end, we have designed and tested a family of small peptide BMP mimetics. The design used the three-dimensional structure of BMP-7 to identify likely active surface regions. Lead sequences were then optimized based on in vitro assays that examine the selective binding to BMP receptors, demonstrate the phosphorylation of Smad-1,5,8, detect anti-apoptosis and anti-inflammation, and block the epithelial to mesenchymal transition (EMT) in renal tubular epithelial cells. These sequences were further optimized using in vivo assays of the attenuation of acute kidney injury in a rat-model of unilateral clamp ischemic reperfusion. This process uses a Structure Variance Analysis algorithm (SVA) to identify structure/activity relationships. One member of this family, THR-184, is an agonist of BMP signaling and a potent antagonist of TGFß signaling. This small peptide mimetic inhibits inflammation, apoptosis, fibrosis and reverses epithelial to mesenchymal transition (EMT) by regulating multiple signaling pathways involved in the cellular injury of multiple organs. Its effects have been shown to control Acute Kidney Injury (AKI). THR-184 has progressed through phase I and II clinical trials for the prevention of Cardio-Vascular Surgery (CVS) associated AKI. This work provides a roadmap for the development of other growth factor mimetics and demonstrates how we might harness their therapeutic potential.

Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.

BACKGROUND: Low donor heart availability underscores the need to identify all potentially transplantable organs. We sought to determine whether pre-emptive administration of pangenotypic direct-acting antiviral therapy can safely prevent the development of chronic hepatitis C virus (HCV) infection in uninfected recipients of HCV-infected donor hearts. METHODS: Patients were recruited for this an open-label, single-centre, proof-of-concept study from Nov 1, 2017, to Nov 30, 2018. Following enrolment, the recipient's status on the heart transplantation waiting list was updated to reflect a willingness to accept either an HCV-positive or HCV-negative heart donor. Patients who underwent transplantation with a viraemic donor heart, as determined by nucleic acid testing (NAT), received pre-emptive oral glecaprevir-pibrentasvir before transport to the operating room followed by an 8-week course of glecaprevir-pibrentasvir after transplantation. Patients receiving HCV antibody-positive donor hearts without detectable circulating HCV RNA were followed using a reactive approach and started glecaprevir-pibrentasvir only if they developed viraemia. The primary outcome was achievement of sustained virological response 12 weeks after completion of glecaprevir-pibrentasvir therapy (SVR12). Patients were followed from study enrolment to 1 year after transplantation. This is an interim analysis, initiated after all enrolled patients reached the primary outcome. Results reflect data from Nov 1, 2017, to May 30, 2019. This trial is registered with ClinicalTrials.gov, number NCT03208244. FINDINGS: 55 patients were assessed for eligibility and 52 consented to enrolment. 25 patients underwent heart transplantation with HCV-positive donor hearts (20 NAT-positive, five NAT-negative), three of whom underwent simultaneous heart-kidney transplantation. All 20 recipients of NAT-positive hearts tolerated glecaprevir-pibrentasvir and showed rapid viral suppression (median time to clearance 3·5 days, IQR 0·0-8·3), with the subsequent achievement of SVR12 by all 20. The five recipients of NAT-negative grafts did not become viraemic. Median pre-transplant waiting time for patients following enrolment in the HCV protocol was 20 days (IQR 8-57). Patient and allograft survival were 100% at a median follow-up of 10·7 months (range 6·5-18·0). INTERPRETATION: Pre-emptive administration of glecaprevir-pibrentasvir therapy results in expedited organ transplantation, rapid HCV suppression, prevention of chronic HCV infection, and excellent early allograft function in patients receiving HCV-infected donor hearts. Long-term outcomes are not yet known. FUNDING: American Association for the Study of Liver Diseases, National Institutes of Health, and the Massachusetts General Hospital.

Harnessing the BMP signaling pathway to control the formation of cancer stem cells by effects on epithelial-to-mesenchymal transition.

Cancer stem cells (CSCs) persist in tumors as a distinct population and may be causative in metastasis and relapse. CSC-rich tumors are associated with higher rates of metastasis and poor patient prognosis. Targeting CSCs therapeutically is challenging, since they seem to be resistant to standard chemotherapy. We have shown that a novel peptide agonist of bone morphogenetic protein (BMP) signaling, P123, is capable of inhibiting the growth of primary tumor cells by interacting with type I receptors selectively [activin receptor-like kinase 2 (ALK2) and ALK3, but not ALK6] and type II BMP receptors, activating SMAD 1/5/8 signaling and controlling the cell cycle pathway. Furthermore, the compound is capable of blocking transforming growth factor-ß induced epithelial-to-mesenchymal transition (EMT) in primary tumor cells, a critical step for tumor progression and metastasis. In addition, we have investigated the effects of P123 on self-renewal, growth, differentiation (reversal of EMT) and apoptosis of isolated human breast CSCs. We have shown that P123 and BMP-7 reverse the EMT process in human breast CSCs, and inhibit self-renewal and growth. Moreover, compared with single treatment with paclitaxel, co-treatment with paclitaxel and P123 showed an increase in cell apoptosis. Together, these findings suggest that P123 has the therapeutic potential to suppress both bulk tumor cells and CSCs. We believe that P123 represents a new class of drugs that have the potential to eliminate the primary tumor, prevent reoccurrence and metastasis, and enhance the treatment of breast cancer.

Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis.

Molecules associated with the transforming growth factor ß (TGF-ß) superfamily, such as bone morphogenic proteins (BMPs) and TGF-ß, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-ß1-Smad family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis.

Cameraless peritoneal entry in abdominal laparoscopy.

BACKGROUND AND OBJECTIVES: Despite significant advances in laparoscopic instrumentation and techniques, injury to intraabdominal structures remains a potentially serious complication of peritoneal access. Consensus on the best method to obtain peritoneal access is lacking. A safe technique that does not rely on direct visualization of the abdominal layers could shorten the learning curve for surgeons and potentially be adopted by other physicians for a variety of nonsurgical indications for peritoneal entry. METHODS: A prospective series of 99 consecutive patients who underwent upper-abdominal laparoscopic surgery performed by a single surgeon between January 2009 and June 2010 was reviewed. The method used to obtain peritoneal access was the fluid-based peritoneal entry indication technique (C-PET) with the EndoTIP trocar. RESULTS: Successful abdominal entry using C-PET was achieved in 90 (90.9%) of the patients; no trocar-related injuries or other injuries associated with peritoneal access occurred. The mean time from incision to confirmed peritoneal access was 21.4 s (range, 12 to 65). Of the 9 cases in which C-PET did not successfully gain entry, 6 occurred during the first 20 surgeries and only 3 in the final 79. CONCLUSIONS: C-PET is simple, safe, timely, and effective for gaining peritoneal access during laparoscopic abdominal surgeries. In this series, C-PET produced no complications and proved effective across a wide variety of patients, including the obese and those who had had previous surgery. Furthermore, C-PET does not require visual recognition of anatomic layers and potentially could easily be taught to nonsurgeon physicians who perform peritoneal access.

Use of amino-terminal pro-B-type natriuretic peptide to guide outpatient therapy of patients with chronic left ventricular systolic dysfunction.

OBJECTIVES: The aim of this study was to evaluate whether chronic heart failure (HF) therapy guided by concentrations of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is superior to standard of care (SOC) management. BACKGROUND: It is unclear whether standard HF treatment plus a goal of reducing NT-proBNP concentrations improves outcomes compared with standard management alone. METHODS: In a prospective single-center trial, 151 subjects with HF due to left ventricular (LV) systolic dysfunction were randomized to receive either standard HF care plus a goal to reduce NT-proBNP concentrations ≤1,000 pg/ml or SOC management. The primary endpoint was total cardiovascular events between groups compared using generalized estimating equations. Secondary endpoints included effects of NT-proBNP-guided care on patient quality of life as well as cardiac structure and function, assessed with echocardiography. RESULTS: Through a mean follow-up period of 10 ± 3 months, a significant reduction in the primary endpoint of total cardiovascular events was seen in the NT-proBNP arm compared with SOC (58 events vs. 100 events, p = 0.009; logistic odds for events 0.44, p = 0.02); Kaplan-Meier curves demonstrated significant differences in time to first event, favoring NT-proBNP-guided care (p = 0.03). No age interaction was found, with elderly patients benefitting similarly from NT-proBNP-guided care as younger subjects. Compared with SOC, NT-proBNP-guided patients had greater improvements in quality of life, demonstrated greater relative improvements in LV ejection fraction, and had more significant improvements in both LV end-systolic and -diastolic volume indexes. CONCLUSIONS: In patients with HF due to LV systolic dysfunction, NT-proBNP-guided therapy was superior to SOC, with reduced event rates, improved quality of life, and favorable effects on cardiac remodeling. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting; NCT00351390).

Multi-drug resistant E.coli urosepsis in physicians following transrectal ultrasound guided prostate biopsies--three cases including one death.

Three male physicians underwent transrectal ultrasound guided prostate biopsies for elevated prostate-specific antigen levels or irregular digital rectal exam findings. All three of these patients developed urosepsis secondary to multi-drug resistant organisms despite antibiotic prophylaxis. There are increasing reports of infectious complications following prostate biopsy caused by multi-drug resistant organisms. These cases highlight the potentially lethal risks to healthcare workers who are more likely to harbor multi-drug resistant organisms than the general population. Further research into preoperative assessment and appropriate antibiotic prophylaxis in all potentially high risk patients is warranted.

Maternal and fetal risk factors associated with severity of hypospadias: a comparison of mild and severe cases.

OBJECTIVE: To determine maternal and fetal demographic factors which predict the risk of increasing severity of hypospadias. PATIENTS AND METHODS: A population-based study using the Nova Scotia Atlee Perinatal Database was performed. Demographic variables of mothers and boys with hypospadias were obtained from 1980 to 2007 inclusive. Hypospadias was graded by the position of the urinary meatus as glanular, coronal, shaft, or proximal to shaft. Maternal and fetal risk factors for hypospadias severity were compared using logistic regression. RESULTS: The total number of male pregnancy and birth records during the study period was 130,796. The total number of cases of hypospadias was 995, yielding an incidence of 0.76%. The severity of hypospadias was graded as glanular in 428 (77.8%); coronal in 77 (14%); penile shaft in 34 (6.2%); and proximal to the penile shaft in 12 (2.2%). The severity of hypospadias was not graded in 445 cases. Low birth weight, low gestational age and maternal age were associated with increased severity of hypospadias, but only maternal age (P<0.03) when logistic regression was performed. Limitations included self-reporting for some parameters, such as smoking, and lack of data, such as for the use of assisted reproductive technologies. CONCLUSIONS: Advanced maternal age was associated with increased severity of hypospadias in our population.

Hormonal control of second flushing in Douglas-fir shoots.

Spring-flushing, over-wintered buds of Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) produce new buds that may follow various developmental pathways. These include second flushing in early summer or dormancy before flushing during the following spring. Second flushing usually entails an initial release of apical dominance as some of the current-season upper lateral buds grow out. Four hypotheses concerning control of current bud outgrowth in spring-flushing shoots were tested: (1) apically derived auxin in the terminal spring-flushing shoot suppresses lateral bud outgrowth (second flushing); (2) cytokinin (0.5 mM benzyladenine) spray treatments given midway through the spring flush period induce bud formation; (3) similar cytokinin spray treatments induce the outgrowth of existing current lateral buds; and (4) defoliation of the terminal spring-flushing shoot promotes second flushing. Hypothesis 1 was supported by data demonstrating that decapitation-released apical dominance was completely restored by treatment with exogenous auxin (22.5 or 45 mM naphthalene acetic acid) (Thimann-Skoog test). Hypothesis 2 was marginally supported by a small, but significant increase in bud number; and Hypothesis 3 was strongly supported by a large increase in the number of outgrowing buds following cytokinin applications. Defoliation produced similar results to cytokinin application. We conclude that auxin and cytokinin play important repressive and promotive roles, respectively, in the control of second flushing in the terminal spring-flushing Douglas-fir shoot.

Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study.

BACKGROUND: Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with > or =1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from approximately 153 mg/dL at baseline in the 2 atorvastatin groups to approximately 83 mg/dL at 12 months (each P<0.0001) and from 147 to 120 mg/dL in the control group (P<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each P<0.001; P=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each P<0.001; P=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes. CONCLUSIONS: Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.

Vascular basis for the treatment of myocardial ischemia study: trial design and baseline characteristics.

BACKGROUND: Increased low-density lipoprotein (LDL) and oxidized LDL cholesterol levels adversely affect endothelial function in patients with stable coronary artery disease (CAD). Statin drugs are efficacious in primary and secondary prevention of clinical CAD events, but they have not been extensively studied as a treatment for ischemia during routine daily activities or during exercise, indicators of high-risk in patients with stable CAD. The purpose of the Vascular Basis for the Treatment of Myocardial Ischemia study is to determine whether aggressive lowering of LDL cholesterol level with atorvastatin, with or without supplemental antioxidant vitamins C and E, can improve endothelial function and ischemia during ambulatory electrocardiogram (AECG) monitoring and exercise treadmill testing (ETT). METHODS: Patients are eligible when they have ischemia during an ETT and AECG monitoring and when their fasting total cholesterol level is < or =250 mg/dL. Eligible patients are randomized to receive 1 of 3 treatments: intensive atorvastatin to reduce LDL cholesterol level to < or =80 mg/dL, intensive atorvastatin to reduce LDL cholesterol level to < or =80 mg/dL plus antioxidant vitamins C and E, and control of diet and low-dose lovastatin, when needed, to reduce LDL cholesterol level < or = to 130 mg/dL. Patients undergo endothelial function testing, 48-hour AECG monitoring, and ETT at randomization and at 6 and 12 months. RESULTS: A total of 300 patients have been randomized: 101 to receive atorvastatin alone, 103 to receive atorvastatin plus antioxidant vitamins, and 96 to receive placebo. Baseline characteristics are similar across treatment groups. CONCLUSIONS: The Vascular Basis study will provide important insight on the effects of aggressive management of dyslipidemia with statin drugs and antioxidant vitamins in patients with stable but high-risk CAD.

Email recruitment to use web decision support tools for pneumonia.

Application of guidelines to improve clinical decisions for Community Acquired Pneumonia (CAP) patients depends on accurate information about specific facts of each case and on presenting guideline support at the time decisions are being made. We report here on a system designed to solicit information from physicians about their CAP patients in order to classify CAP and present appropriate guidelines for type of care, length of stay, and use of antibiotics. We used elements of three existing information systems to create a achieve these goals: professionals coding diagnoses captured by the existing clinical information system (CIS), email, and web-based decision support tools including a pneumonia severity evaluation tool (SET). The non-secure IS components (email and web) were able to link to information in the CIS using tokens that do not reveal confidential patient-identifiable information. We examined their response to this strategy and the accuracy of pneumonia classification using this approach compared to chart review as a gold standard. On average physicians responded to email solicitations 50% of the time over the 14 month study. Also using this standard, we examined various information triggers for case finding. Professional coding of the primary reason for admission as pneumonia was fairly sensitive as an indicator of CAP. Physician use of the web SET was insensitive but fairly specific. Pneumonia classification using the SET was very reliable compared to experts' chart review using the same algorithm. We examined the distribution of severity of pneumonia for cases of pneumonia found by the various information triggers and for each severity the average length of stay. The distribution found by both chart review and by SET has demonstrated a shift toward more severe cases being admitted compared to only 3 years ago. The length of stay for level of severity is above expectations published by guidelines even for cases of true CAP by chart review. We suggest that the Fine classification system may not adequately describe patients in this setting. Physicians frequently responded that the guidelines presented did not fit their patients.

Photocontrol of flowering and stem extension of the intermediate-day plant Echinacea purpurea.

Intermediate-day plants (IDP) flower most rapidly and completely under intermediate photoperiods (e.g., 12-14 h of light), but few species have been identified and their flowering responses are not well understood. We identified Echinacea purpurea Moench as an IDP and, based on our results, propose a novel mechanism for flowering of IDP. Two genotypes of E. purpurea ('Bravado' and 'Magnus') flowered most completely (>/=79%) and rapidly and at the youngest physiological age under intermediate photoperiods of 13-15 h. Few (/=230% as the photoperiod or NI duration increased, until plants received a saturating duration (at 14 or 1 h, respectively). Flowering was inhibited when 16-h photoperiods were deficient in red (R, 600-700 nm) light, and was promoted when photoperiods were deficient in far-red (FR, 700-800 nm) light. Because of our results, we propose the flowering behavior of IDP such as E. purpurea is composed of two mechanisms: a light-dependent response operating through light-labile (type I) phytochrome in which flowering is inhibited by an LD, and a light-stable (type II) phytochrome (i.e., phyB, D and E) response in which flowering is promoted by a short-night.