Effectiveness of tapentadol prolonged release (PR) compared with oxycodone/naloxone PR for the management of severe chronic low back pain with a neuropathic component: a randomized, controlled, open‐label, phase 3b/4sStudy

[Abstract] OBJECTIVE: To evaluate the effectiveness of tapentadol prolonged release (PR) vs. oxycodone/naloxone PR in non-opioid-pretreated patients with severe chronic low back pain with a neuropathic pain component. METHODS: Eligible patients (average pain intensity [numerical rating scale-3 (NRS-3)] ≥6; painDETECT positive/unclear) were randomized to twice-daily tapentadol PR 50 mg or oxycodone/naloxone PR 10 mg/5 mg. After a 21-day titration (maximum twice-daily doses: tapentadol PR 250 mg, or oxycodone/naloxone PR 40 mg/20 mg plus oxycodone PR 10 mg), target doses were continued for 9 weeks. The primary effectiveness endpoint was the change in NRS-3 from baseline to final evaluation; the exact repeated confidence interval (RCI) for tapentadol PR minus oxycodone/naloxone PR was used to establish noninferiority (upper limit <1.3) and superiority (confirmatory analyses). RESULTS: For the primary effectiveness endpoint, tapentadol PR was noninferior to oxycodone/naloxone PR (97.5% RCI: [-1.820, -0.184]; P < 0.001). This exact RCI also yielded evidence of superiority for tapentadol PR vs. oxycodone/naloxone PR (significantly greater reduction in pain intensity; P = 0.003). Improvements (baseline to final evaluation) in painDETECT and Neuropathic Pain Symptom Inventory scores were significantly greater with tapentadol PR vs. oxycodone/naloxone PR (all P ≤ 0.005). CONCLUSIONS: The study was formally shown to be positive and demonstrated, in the primary effectiveness endpoint, the noninferiority for tapentadol PR vs. oxycodone/naloxone PR. The effectiveness of tapentadol PR was superior to that of oxycodone/naloxone PR by means of clinical relevance and statistical significance (confirmatory evidence of superiority). Tapentadol PR was associated with significantly greater improvements in neuropathic pain-related symptoms and global health status than oxycodone/naloxone PR and with a significantly better gastrointestinal tolerability profile. Tapentadol PR may be considered a first-line option for managing severe chronic low back pain with a neuropathic pain component

THE PUBLIC ACCOUNTABILITY MODEL OF THE UNITED BANTEN PEOPLE'S SOCIAL SECURITY (JAMSOSRATU) AT THE BANTEN PROVINCE SOCIAL SERVICE

The focus of this research is on the public accountability of Banten Bersatau Social Security (Jamsosratu) at the Banten Province Social Service. The approach in this research is carried out by exploring the issue of public accountability which aims to obtain a clear picture of the accountability of Jamsosratu at the Social Service of Banten Province. The research method used is descriptive qualitative method by observing and exploring the behavior of the object under study and to find a comprehensive and in-depth picture of the object under study, and theory is used as an approach to research problems with data sources consisting of primary data sources and secondary data through observation. , documentation analysis, in-depth interviews and data validity were carried out using triangulation techniques through checks, checks and confirmations between the results of observations, analysis of documentation and interview results. The results show that the 5 (five) dimensions of Jamsosratu's public accountability at the Social Service of Banten Province which include the dimensions: 1) law and honesty, 2) program, 3) managerial, 4) policy and 5) financial, all of which must exist or not. In addition, there are factors that become obstacles and hinder the process of preparing Jamsosratu's public accountability, including employees who lack commitment, lack of capability, and the lack of optimal leadership roles in realizing public accountability. The public accountability model of the United Banten People's Social Security (Jamsosratu) which is effective at the Banten Province Social Service is the system model. The effectiveness of Jamsosratu's public accountability is determined by the dimensions of accountability: 1) law and honesty, 2) managerial, 3) program, 4) policy, 5) financial, 6) professionalism, and 7) code of ethics. The seven dimensions must exist, be implemented and integrated with supervision and control from the leadership. Modification of the theory that researchers put forward, namely by adding 2 (two) dimensions, namely 1) Dimensions of Professionalism, and 2) Dimensions of the code of ethics. And this is a finding in this study (Novelty). The findings of this study greatly strengthen accountability and can be used as a basis for integrated organizational performance in Jamsosratu public accountability reporting at the Banten Province Social Service. The substance of this study, that the Jamsosratu public accountability at the Social Service of Banten Province is effectively determined by the dimensions: 1) law and honesty, 2) program, 3) managerial, 4) policy and 5) financial, 6) professionalism, 7) code of ethics, can be implemented with an accountability system model that is integrated with a public accountability reporting system with the public interest of the people of Banten Province which is transparent and democratic. Keywords: Public Accountability, Social Security, Social Servic

The contribution of diet and genotype to iron status in women:a classical twin study

This is the first published report examining the combined effect of diet and genotype on body iron content using a classical twin study design. The aim of this study was to determine the relative contribution of genetic and environmental factors in determining iron status. The population was comprised of 200 BMI- and age-matched pairs of MZ and DZ healthy twins, characterised for habitual diet and 15 iron-related candidate genetic markers. Variance components analysis demonstrated that the heritability of serum ferritin (SF) and soluble transferrin receptor was 44% and 54% respectively. Measured single nucleotide polymorphisms explained 5% and selected dietary factors 6% of the variance in iron status; there was a negative association between calcium intake and body iron (p = 0.02) and SF (p = 0.04)

Mechanisms of PTPσ-Mediated Presynaptic Differentiation

Formation of synapses between neurons depends in part on binding between axonal and dendritic cell surface synaptic organizing proteins, which recruit components of the developing presynaptic and postsynaptic specializations. One of these presynaptic organizing molecules is protein tyrosine phosphatase σ (PTPσ). Although the protein domains involved in adhesion between PTPσ and its postsynaptic binding partners are known, the mechanisms by which it signals into the presynaptic neuron to recruit synaptic vesicles and other necessary components for regulated transmitter release are not well understood. One attractive candidate to mediate this function is liprin-α, a scaffolding protein with well-established roles at the synapse. We systematically mutated residues of the PTPσ intracellular region (ICR) and used the yeast dihydrofolate reductase (DHFR) protein complementation assay to screen for disrupted interactions between these mutant forms of PTPσ and its various binding partners. Using a molecular replacement strategy, we show that disrupting the interaction between PTPσ and liprin-α, but not between PTPσ and itself or another binding partner, caskin, abolishes presynaptic differentiation. Furthermore, phosphatase activity of PTPσ and binding to extracellular heparan sulfate (HS) proteoglycans are dispensable for presynaptic induction. Previous reports have suggested that binding between PTPσ and liprin-α is mediated by the PTPσ membrane-distal phosphatase-like domain. However, we provide evidence here that both of the PTPσ phosphatase-like domains mediate binding to liprin-α and are required for PTPσ-mediated presynaptic differentiation. These findings further our understanding of the mechanistic basis by which PTPσ acts as a presynaptic organizer

Maternal multiple micronutrient supplementation and other biomedical and socioenvironmental infl uences on children’s cognition at age 9–12 years in Indonesia: follow-up of the SUMMIT randomised trial

Background Brain and cognitive development during the fi rst 1000 days from conception are aff ected by multiple biomedical and socioenvironmental determinants including nutrition, health, nurturing, and stimulation. An improved understanding of the long-term infl uence of these factors is needed to prioritise public health investments to optimise human development. Methods We did a follow-up study of the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind, cluster-randomised trial of maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA) in Indonesia. Of 27 356 live infants from birth to 3 months of age in 2001–04, we re-enrolled 19 274 (70%) children at age 9–12 years, and randomly selected 2879 from the 18 230 who were attending school at a known location. Of these, 574 children were oversampled from mothers who were anaemic or malnourished at SUMMIT enrolment. We assessed the eff ects of MMN and associations of biomedical (ie, maternal and child anthropometry and haemoglobin and preterm birth) and socioenvironmental determinants (ie, parental education, socioeconomic status, home environment, and maternal depression) on general intellectual ability, declarative memory, procedural memory, executive function, academic achievement, fi ne motor dexterity, and socioemotional health. The SUMMIT trial was registered, number ISRCTN34151616. Findings Children of mothers given MMN had a mean score of 0·11 SD (95% CI 0·01–0·20, p=0·0319) higher in procedural memory than those given IFA, equivalent to the increase in scores with half a year of schooling. Children of anaemic mothers in the MMN group scored 0·18 SD (0·06–0·31, p=0·0047) higher in general intellectual ability, similar to the increase with 1 year of schooling. Overall, 18 of 21 tests showed a positive coeffi cient of MMN versus IFA (p=0·0431) with eff ect sizes from 0·00–0·18 SD. In multiple regression models, socioenvironmental determinants had coeffi cients of 0·00–0·43 SD and 22 of 35 tests were signifi cant at the 95% CI level, whereas biomedical coeffi cients were 0·00–0·10 SD and eight of 56 tests were signifi cant, indicating larger and more consistent impact of socioenvironmental factors (p<0·0001). Interpretation Maternal MMN had long-term benefi ts for child cognitive development at 9–12 years of age, thereby supporting its role in early childhood development, and policy change toward MMN. The stronger association of socioenvironmental determinants with improved cognition suggests present reproductive, maternal, neonatal, and child health programmes focused on biomedical determinants might not suffi ciently enhance child cognition, and that programmes addressing socioenvironmental determinants are essential to achieve thriving populations