Government political structure and violent death rates: A longitudinal analysis of forty-three countries, 1960-2008.

OBJECTIVES: Currently, little is known regarding the effect of regime type on mortality on a global level. The purpose of this study is to examine the effect of regime type on the rates of violent deaths (homicide, suicide, and combined rates). METHODS: Three measures of democracy were used to quantify regime type, the independent variable. Homicide and suicide rates were obtained from the World Health Organization. Multivariate conditional fixed-effects models were run to examine associations between regime characteristics and logged rates of homicide, suicide, and violent deaths. Models were adjusted for unemployment and economic inequality. RESULTS: Nations that scored higher on democracy indices, especially emerging democracies, experienced increased mortality due to violence. Homicide and suicide were divergent, showing a different time course and decreasing statistical power as a combined variable. Unemployment and inequality were associated with higher violence-related mortality. CONCLUSIONS: Homicide and suicide appear to be more prevalent in democracies. Future analyses should examine which aspects of democracies lead to higher rates of violent death and should seek to use independently collected mortality data.

A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

Preliminary evaluation of treatment outcomes at a military intensive outpatient program.

Recent U.S. Army policy has established intensive outpatient programs at several installations as part of a comprehensive behavioral health system of care. This study presents retrospective program evaluation data from a case series without randomization or a control group at 1 recently established intensive outpatient program for active duty service members at a joint military installation. Out of 240 patients referred to the program at 1 installation, 200 enrolled in treatment. Of these, 169 completed treatment in a Skills & Resiliency Track (n = 97), Trauma Track (n = 34), or both (Combined Track; n = 38). Patients completed measures of posttraumatic stress symptoms and general distress throughout program enrollment. First year preliminary results show significant decreases in distress for those in the Skills & Resiliency and Combined groups. Trauma group patients showed significant decreases in posttraumatic stress symptoms. Patients in the Skills & Resiliency and Combined groups showed significant decreases in rates of psychiatric hospitalization. These results show potential for treating high-risk or treatment-resistant patients in a half-day intensive outpatient program. Lessons learned and recommendations for establishing intensive outpatient programming for the military are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Transforming Our World: Implementing the 2030 Agenda Through Sustainable Development Goal Indicators.

The United Nations' 2030 Agenda for Sustainable Development recognizes violence as a threat to sustainability. To serve as a context, we provide an overview of the Sustainable Development Goals as they relate to violence prevention by including a summary of key documents informing violence prevention efforts by the World Health Organization (WHO) and Violence Prevention Alliance (VPA) partners. After consultation with the United Nations (UN) Inter-Agency Expert Group on Sustainable Development Goal Indicators (IAEG-SDG), we select specific targets and indicators, featuring them in a summary table. Using the diverse expertise of the authors, we assign attributes that characterize the focus and nature of these indicators. We hope that this will serve as a preliminary framework for understanding these accountability metrics. We include a brief analysis of the target indicators and how they relate to promising practices in violence prevention.

A case for studying country regimes in the public health model of violence.

Many national and international institutions advocate approaching violence as a problem in public health and preventive medicine, in a manner similar to the way we address other disabling and life-threatening pathologies such as cancer, diabetes, and heart disease. Prevention by a health model requires an ecological perspective. Previous work has found evidence that economic factors, including unemployment and relative poverty, as well as political culture and values, may affect violent death rates, including homicide and suicide. Nevertheless, wider political analyses of the effects that different regimes have on these variables have been notably absent, for understandable reasons given the sheer complexity of patterns of governance throughout the world. In view of the importance and scale of the problem, and implications of the United Nations' 2030 Agenda for Sustainable Development, we feel it is nevertheless important to bring regime types into the conversation of factors that can influence violent death.

The calcitonin and glucocorticoids combination: mechanistic insights into their class-effect synergy in experimental arthritis.

INTRODUCTION: Previous work reported the anti-arthritic synergy afforded by combining calcitonin (CT) and glucocorticoids (GC). Here we focus on the pairing of elcatonin (eCT) and dexamethasone (Dex), querying whether: i) this was a class-effect action; ii) mechanistic insights could be unveiled; iii) the synergy affected canonical GC adverse effects. METHODS: Using the rat collagen-induced arthritis model, different combinations of eCT and Dex, were administered from disease onset to peak (day 11 to 18). Macroscopic disease score was monitored throughout, with biochemical and histological analyses conducted on plasma and tissues at day 18. The effect on acute hyperglycaemia and liver enzyme message were also assessed. RESULTS: Whilst eCT alone was inactive, it synergised at 1 µg/kg with low doses of Dex (7.5 or 15 µg/kg) to yield an anti-arthritic efficacy equivalent to a 4- to 7-fold higher Dex dose. Mechanistically, the anti-arthritic synergy corresponded to a marked attenuation in RA-relevant analytes. CXCL5 expression, in both plasma and joint, was markedly inhibited by the co-therapy. Finally, co-administration of eCT did not exacerbate metrics of GC adverse effects, and rescued some of them. CONCLUSIONS: We present evidence of a class-effect action for the anti-arthritic synergy of CT/GC combination, underpinned by the powerful inhibition of joint destruction markers. Furthermore, we identify CXCL5 as a marker for the combination therapy with potential diagnostic and prognostic utility. Substantial GC dose reduction, together with the absence of exacerbated adverse effects, indicated a significant clinical potential for this co-therapy in RA and beyond.

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial.

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis.

Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats.

Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture.

Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds.

The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC(50) values below 1.25µM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5'-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.

Dramatic increase in cortical thickness induced by femoral marrow ablation followed by a 3-month treatment with PTH in rats.

We previously reported that following mechanical ablation of the marrow from the midshaft of rat femurs, there is a rapid and abundant but transient growth of bone, and this growth is enhanced and maintained over a 3-week period by the bone anabolic hormone parathyroid hormone (PTH). Here, we asked whether further treatment with PTH or bisphosphonates can extend the half-life of the new bone formed in lieu of marrow. We subjected the left femur of rats to mechanical marrow ablation and treated the animals 5 days a week with PTH for 3 weeks (or with vehicle as a control) to replace the marrow by bone. Some rats were euthanized and used as positive controls or treated with vehicle, PTH, or the bisphosphonate alendronate for a further 9 weeks. We subjected both femurs from each rat to soft X-ray, peripheral quantitative computed tomography (pQCT), micro-computed tomography (microCT), dynamic histomorphometry analysis, and biomechanical testing. We also determined the concentrations of serum osteocalcin to confirm the efficacy of PTH. Treatment with PTH for 3 months dramatically enhanced endosteal and periosteal bone formation, leading to a 30% increase in cortical thickness. In contrast, alendronate protected the bone that had formed in the femoral marrow cavity after marrow ablation and 3 weeks of treatment with PTH but failed to promote endosteal bone growth or to improve the biomechanical properties of ablated femurs. We further asked whether calcium-phosphate cements could potentiate the formation of bone after marrow ablation. Marrow cavities from ablated femurs were filled with one of two calcium-phosphate cements, and rats were treated with PTH or PBS for 84 days. Both cements helped to protect the new bone formed after ablation. To some extent, they promoted the formation of bone after ablation, even in the absence of any anabolic hormone. Our data therefore expand the role of PTH in bone engineering and open new avenues of investigation to the field of regenerative medicine and tissue engineering. Local bone marrow aspiration in conjunction with an anabolic agent, a bisphosphonate, or a calcium-phosphate cement might provide a new platform for rapid preferential site-directed bone growth in areas of high bone loss.

Replacement of bone marrow by bone in rat femurs: the bone bioreactor.

During development and repair of bone, two distinct yet complementary mechanisms, intramembranous and endochondral, mediate new bone formation via osteoblasts. Because mechanical bone marrow ablation leads to the rapid and transient formation of new bone in the marrow cavity, we postulated that parathyroid hormone (PTH), which is a bone anabolic hormone, enhances the formation of new bone that forms after marrow ablation. We subjected the left femur of rats to mechanical marrow ablation, or sham operation, and injected the animals daily with PTH or vehicle for 1, 2, or 3 weeks in a first experiment, then with PTH, parathyroid hormone-related peptide (PTHrP), or vehicle for 3 weeks in a second experiment. We subjected both femurs from each rat to soft X-ray, peripheral quantitative computed tomography, computed tomography on a microscale, and histological analysis, and determined the concentration of serum osteocalcin. In addition, in the second experiment, we determined the serum concentration of calcium, tartrate-resistant acid phosphatase (TRAP), and receptor activator of NF-kappaB ligand (RANKL) at 3 weeks, and subjected femurs to biomechanical testing. Following treatment with PTH or PTHrP for 3 weeks, bone filled the marrow cavity of the shafts whose marrow had been ablated. PTH increased trabecular density in the right femur, but failed to induce bone formation in the medullary region of the right unoperated femoral shafts. The newly formed bone endowed left femoral shafts with improved biomechanical properties when compared to those of right femurs and left femurs from control, sham-operated, and vehicle-treated rats. PTHrP, like PTH, increased serum osteocalcin, but neither increased serum calcium, TRAP, or RANKL at 3 weeks. Our results reveal that the newly formed bone that follows marrow ablation is responsive to PTH, expand the role of PTH in bone, and might open new avenues of investigations to the field of regenerative medicine and tissue engineering. Local bone marrow removal in conjunction with pharmacologic intervention with an anabolic agent might provide a technique for rapid preferential site-directed bone growth in areas of high bone loss.

The Resolve to Stop the Violence Project: transforming an in-house culture of violence through a jail-based programme.

BACKGROUND: The usual modes of incarceration have not been found to curb violence significantly, even while in custody. A jail-based programme called the Resolve to Stop the Violence Project (RSVP) was created with the hypothesis that immersing men with a history of serious, recent and often multiple violent crimes in an intensive, multi-modal in-house 'culture' would serve as a possible first step to preventing further violence. METHODS: Two years of incident reports were reviewed for the programme dorm and a regular dorm, both typically serving an average of 56 male inmates of similar composition, for historic and between-dorm comparisons. RESULTS: During the year before RSVP began, there were 24 violent incidents serious enough to have constituted felonies had they occurred in the community (roughly three per month) in the 62-bed dorm. During the first month RSVP was in effect there was one such incident; and for the following 12 months, there were none. During that same year, the control dorm that still followed traditional jail practices had 28 violent incidents. CONCLUSIONS: Correctional efforts may improve with the transformation of subcultures into therapeutic communities that facilitate the practice of prosocial skills over attitudes and mores that engender violence.

The Resolve to Stop the Violence Project: reducing violence in the community through a jail-based initiative.

BACKGROUND: The usual modes of incarceration have not been found to curb violent crimes significantly. A jail-based programme called the Resolve to Stop the Violence Project (RSVP) was created with the hypothesis that exposing men with a history of serious, recent and often multiple violent crimes to a certain specifiable set of social, cultural and psychological conditions would reduce the frequency and severity of their violent behaviour. METHODS: Court and criminal records for 1 year following release were reviewed for 101 inmates who had spent 8 weeks or more in the programme and for the same number of those who had spent 8 weeks or more in regular custody. RESULTS: Inmates who participated in RSVP had lower rearrest rates for violent crimes (-46.3 percent, p < 0.05) and spent less time in custody (-42.6 percent, p < 0.05). The decline in violent re-arrests increased with greater lengths of stay (-53.1 percent, p < 0.05 for 12 weeks or more; -82.6 percent, p < 0.05 for 16 weeks or more). CONCLUSIONS: Multilevel, comprehensive prevention approaches that: emphasize making available to violent individuals the kinds of tools they need in order to develop non-violent skills and reality-based sources of self-esteem; increase their capacity to experience feelings of empathy and remorse; and provide opportunities to take responsibility and amend the injuries they have inflicted on others and on the whole community, may play an important role in reducing the cycle of violent crime.

Beyond the prison paradigm: from provoking violence to preventing it by creating "anti-prisons" (residential colleges and therapeutic communities).

Prisons were supposedly created for the purpose of the tertiary prevention of violence (i.e., reducing the frequency and severity of future violence on the part of people who have already become violent). However, there is much evidence that this method of attempting to prevent violence is often, though not always, either ineffectual or counterproductive, in which case it is either a waste of money or actually exacerbates the problem it was ostensibly intended to solve. This article reviews evidence concerning those questions including an analysis of the effect of punishment (one of the main purposes of prisons) on violent behavior. Punishment--the infliction of pain--will be distinguished from restraint (incapacitation, separation from the community). Successful examples of violence prevention in unconventional prison programs, emphasizing therapy and education rather than punishment, and restorative rather than retributive justice, will be summarized, together with evidence that these programs reduce re-incarceration rates so substantially that they actually save the taxpayers more money than they cost, in addition to enhancing the safety of the general public. The position is taken that traditional prisons provoke more violence than they prevent and are so fundamentally flawed that they cannot be reformed; we argue that they should instead be abolished and replaced by "anti-prisons," that is, locked, secure residential colleges, therapeutic communities, and centers for human development. Prisons will come to be seen as a well-meaning experiment that failed, rather like the use of leeches in medicine.

The psychopharmacologic treatment of violent youth.

Aggressive violence has been described as the greatest problem and the most frequent reason for referrals in child and adolescent psychiatry. In this country we have only partially emerged from an epidemic of violence that was really an epidemic of youth violence. Thus it is hardly surprising that psychiatrists are being asked more and more frequently whether psychiatric medications might help to diminish the toll from this behavioral plague. Medications are useful and appropriate for only a small minority of the people who commit serious violence. Even when they are indicated, they can never be the sole treatment modality, but should be supplemented by psychological and social therapies. When the violence is a byproduct or symptom of an underlying mental illness, treating that illness is generally the most effective method of preventing future violence on a long-term basis. However, most violence is not committed by those who are mentally ill, and most of the mentally ill never commit a serious act of violence. That is why many attempts have been made to discover whether there are drugs that diminish the symptom, violence, even when there is no underlying mental illness for which drugs would normally be prescribed. In fact there are several, and their indications and use are reviewed here. Different principles govern the acute short-term emergency treatment of a violent crisis and the long-term treatment of those who are chronically and repetitively violent, and these differences are also summarized here.