Study reporting quality among interventions to reduce antibiotic use is a barrier to evidence-informed policymaking on antimicrobial resistance: systematic review.

BACKGROUND: Countries are currently seeking evidence-informed policy options to address antimicrobial resistance (AMR). While rigorous evaluations of AMR interventions are the ideal, they are far from the current reality. Additionally, poor reporting and documentation of AMR interventions impede efforts to use evidence to inform future evaluations and policy interventions. OBJECTIVES: To critically evaluate reporting quality gaps in AMR intervention research. METHODS: To evaluate the reporting quality of studies, we conducted a descriptive synthesis and comparative analysis of studies that were included in a recent systematic review of government policy interventions aiming to reduce human antimicrobial use. Reporting quality was assessed using the SQUIRE 2.0 checklist of 18 items for reporting system-level interventions to improve healthcare. Two reviewers independently applied the checklist to 66 studies identified in the systematic review. RESULTS: None of the studies included complete information on all 18 SQUIRE items (median score = 10, IQR = 8-11). Reporting quality varied across SQUIRE items, with 3% to 100% of studies reporting the recommended information for each SQUIRE item. Only 20% of studies reported the elements of the intervention in sufficient detail for replication and only 24% reported the mechanism through which the intervention was expected to work. CONCLUSIONS: Gaps in the reporting of impact evaluations pose challenges for interpreting and replicating study results. Failure to improve reporting practice of policy evaluations is likely to impede efforts to tackle the growing health, social and economic threats posed by AMR.

Strengthening the science of addressing antimicrobial resistance: a framework for planning, conducting and disseminating antimicrobial resistance intervention research.

Antimicrobial resistance (AMR) has the potential to threaten tens of millions of lives and poses major global economic and development challenges. As the AMR threat grows, it is increasingly important to strengthen the scientific evidence base on AMR policy interventions, to learn from existing policies and programmes, and to integrate scientific evidence into the global AMR response.While rigorous evaluations of AMR policy interventions are the ideal, they are far from the current reality. To strengthen this evidence base, we describe a framework for planning, conducting and disseminating research on AMR policy interventions. The framework identifies challenges in AMR research, areas for enhanced coordination and cooperation with decision-makers, and best practices in the design of impact evaluations for AMR policies.This framework offers a path forward, enabling increased local and global cooperation, and overcoming common limitations in existing research on AMR policy interventions.

Nursing practice and global refugee migration: initial impressions from an Intergovernmental-Academic Partnership.

AIM: This report from the field describes impressions of the initial impact of bilateral, multi-sectoral field-based activities undertaken to strengthen International Organization for Migration/United Nations Migration Agency and US-based nurses' capacity to address complex clinical, social and cultural challenges experienced by refugees in resettlement. Authors comment on the defined and thorough health assessment process that refugees go through prior to resettlement, and focus on the essential nursing role in the health assessment process and continuum of care. The development of the interdisciplinary and collaborative partnership is described as well as next steps to move the partnership forward. BACKGROUND: In 2017, International Organization for Migration/United Nations Migration Agency and the University of Minnesota, guided by experts from the United States Centers for Disease Control and Prevention, began a unique bilateral Intergovernmental-Academic partnership to enhance the health care of refugees. A key component was to strengthen nursing care of refugees through the standardization of clinical practice and nursing leadership. SOURCES OF EVIDENCE: Listening sessions, direct interaction between International Organization for Migration/United Nations Migration Agency and US-based refugee resettlement stakeholders, patterns in resettlement. CONCLUSION AND IMPLICATIONS FOR NURSING AND HEALTH POLICY: The report highlights the potential public health impact of a bilateral and collaborative initiative that develops and bridges key points in the migration and health trajectory of people with refugee status. Separated by geography, context and scope of work, health professionals in different roles in varied worldwide settings with a spectrum of resources may not fully understand the work of each other. Project activities were a platform through which US-based and internationally based nurses established mutuality, reciprocity and equity as partners. By strengthening systems and resources, the partnership reinforces the abilities of nurses who engage in this important work, to optimize health and wellbeing of people with refugee status.

Ethacrynic acid and piriprost as enhancers of cytotoxicity in drug resistant and sensitive cell lines.

Ethacrynic acid and piriprost (6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1) have been shown to potentiate the cytotoxic activity of chlorambucil in rat and human tumor cell lines. Walker 256 rat breast carcinoma cells (WS), with acquired resistance to nitrogen mustards (WR), and two human colon carcinoma cell lines, HT 29 and BE, were sensitized to chlorambucil when either ethacrynic acid or piriprost was administered at the same time as the alkylating agent. Both as single agents and in combination with chlorambucil, there was inhibition of glutathione S-transferase activity as measured with 1-chloro-2,4-dinitrobenzene as a substrate. A depletion in intracellular glutathione was also evident following ethacrynic acid alone or in combination with chlorambucil. Thus, diuretic plant phenols or prostaglandin analogues may have potential therapeutic utility in combination with alkylating agents.

Glutathione S-transferases in normal and malignant human colon tissue.

This study focuses on the GST composition of a tissue intrinsically resistant to chemotherapy, the human colon. GSTs were purified from matched pairs of colon tissue (normal and tumor) using glutathione affinity chromatography. The mean GST activity of colon tumors was 1.5-fold higher than that of normal tissue, with tumors of the sigmoid colon showing the greatest increase (2.3-fold). Two-dimensional gel electrophoresis and Western blot analysis of purified enzymes demonstrated the presence of all three GST classes (alpha, mu and pi) in colon, with GST pi being both the predominant isozyme in normal and malignant tissues. The level of alpha class subunits was the same in normal and tumor tissues, while the mu class subunits were decreased in tumors. A protein copurifying with GSTs from both normal and tumor tissue did not crossreact with GST antibodies, but instead reacted with a polyclonal antibody to glyoxylase I. This enzyme existed as a dimer in its native state. Upon boiling, monomeric subunits were produced with a molecular mass of 22.6 kDa and an isoelectric point more acidic than GST pi. Increased amounts of glyoxylase I were also found in tumor vs. normal colon. The apparent elevated levels of these glutathione-associated detoxifying enzymes in colon tumors may contribute to their intrinsic drug resistance.

Glutathione S-transferases in human prostate.

A number of human prostatic tissue biopsies have been analyzed for glutathione S-transferase activity, using 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate. Samples from nine patients (age range 61-90) with benign prostatic hypertrophy who had received no prior chemotherapy had a mean glutathione S-transferase activity of 137 +/- 44 nmol/min per mg with a range of 97-237. A qualitative comparison of the glutathione S-transferase of normal prostate and benign prostatic hypertrophy samples was carried out. Approximately 260-fold purification was achieved using glutathione-Sepharose affinity chromatography, with glutathione S-transferase accounting for approximately 0.19-0.33% of the total protein. Substrate specificity determinations suggested similar, but not identical, glutathione S-transferase subunits in normal prostate and benign prostatic hypertrophy. One- and two-dimensional electrophoresis (isoelectric focusing and 12.5% SDS-polyacrylamide gel electrophoresis) identified at least seven stained polypeptides in the purified glutathione S-transferase preparations. These ranged in Mr from approximately 24,000 to 28,500 and in pI from near neutral to basic. Western blot analysis using polyclonal antibodies raised against rat liver glutathione S-transferase suggested crossreactivity with five of the human isoenzymes in both normal prostate and benign prostatic hypertrophy. One of the glutathione S-transferases, present in both normal prostate and benign prostatic hypertrophy, had an Mr of approx. 24,000 and a near-neutral pI and crossreacted immunologically with a polyclonal antibody raised against human placental glutathione S-transferase (Yf, subunit 7 or pi). These data suggest that four glutathione S-transferases are expressed in human prostate, with subunits from each of the major classes alpha, mu and pi. These are characterized as Ya, Yb, Yb' and Yf (analogous alternative nomenclature subunits 1, 3, 4 and 7).

Antagonism of the osteoclast vitronectin receptor with an orally active nonpeptide inhibitor prevents cancellous bone loss in the ovariectomized rat.

An orally active, nonpeptide Arg-Gly-Asp (RGD) mimetic alpha(v)beta3 antagonist, (S)-3-Oxo-8-[2-[6-(methylamino)-pyridin-2-yl]-1-ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid (compound 1), has been generated, which prevented net bone loss and inhibited cancellous bone turnover in vivo. The compound binds alpha(v)beta3 and the closely related integrin alpha(v)beta5 with low nanomolar affinity but binds only weakly to the related integrins alpha(IIb)beta3, and alpha5beta1. Compound 1 inhibited alpha(v)beta3-mediated cell adhesion with an IC50 = 3 nM. More importantly, the compound inhibited human osteoclast-mediated bone resorption in vitro with an IC50 = 11 nM. In vivo, compound 1 inhibited bone resorption in a dose-dependent fashion, in the acute thyroparathyroidectomized (TPTX) rat model of bone resorption with a circulating EC50 approximately 20 microM. When dosed orally at 30 mg/kg twice a day (b.i.d.) in the chronic ovariectomy (OVX)-induced rat model of osteopenia, compound 1 also prevented bone loss. At doses ranging from 3 to 30 mg/kg b.i.d., compound 1 partially prevented the OVX-induced increase in urinary deoxypyridinoline. In addition, the compound prevented the OVX-induced reduction in cancellous bone volume (BV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), as assessed by quantitative microcomputerized tomography (microCT) and static histomorphometry. Furthermore, both the 10-mg/kg and 30-mg/kg doses of compound prevented the OVX-induced increase in bone turnover, as measured by percent osteoid perimeter (%O.Pm). Together, these data indicate that the alpha(v)beta3 antagonist compound 1 inhibits OVX-induced bone loss. Mechanistically, compound 1 prevents bone loss in vivo by inhibiting osteoclast-mediated bone resorption, ultimately preventing cancellous bone turnover.

Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate.

Cathepsin K is a cysteine protease that plays an essential role in osteoclast-mediated degradation of the organic matrix of bone. Knockout of the enzyme in mice, as well as lack of functional enzyme in the human condition pycnodysostosis, results in osteopetrosis. These results suggests that inhibition of the human enzyme may provide protection from bone loss in states of elevated bone turnover, such as postmenopausal osteoporosis. To test this theory, we have produced a small molecule inhibitor of human cathepsin K, SB-357114, that potently and selectively inhibits this enzyme (Ki = 0.16 nM). This compound potently inhibited cathepsin activity in situ, in human osteoclasts (inhibitor concentration [IC]50 = 70 nM) as well as bone resorption mediated by human osteoclasts in vitro (IC50 = 29 nM). Using SB-357114, we evaluated the effect of inhibition of cathepsin K on bone resorption in vivo using a nonhuman primate model of postmenopausal bone loss in which the active form of cathepsin K is identical to the human orthologue. A gonadotropin-releasing hormone agonist (GnRHa) was used to render cynomolgus monkeys estrogen deficient, which led to an increase in bone turnover. Treatment with SB-357114 (12 mg/kg subcutaneously) resulted in a significant reduction in serum markers of bone resorption relative to untreated controls. The effect was observed 1.5 h after the first dose and was maintained for 24 h. After 5 days of dosing, the reductions in N-terminal telopeptides (NTx) and C-terminal telopeptides (CTx) of type I collagen were 61% and 67%, respectively. A decrease in serum osteocalcin of 22% was also observed. These data show that inhibition of cathepsin K results in a significant reduction of bone resorption in vivo and provide further evidence that this may be a viable approach to the treatment of postmenopausal osteoporosis.

Effect of melatonin on human skin color.

Previous studies have shown the pineal hormone melatonin to influence mammalian coat color and amphibian skin color when administered exogenously. It has also been suggested that melatonin can be employed effectively to inhibit progress of neoplastic disease in both animals and humans. In the present study, we set out to investigate the effect of melatonin on human skin color in an effort to uncover its mechanism of action as an antimelanoma agent. We followed seven patients receiving orally administered melatonin over a mean duration of 19 months, and four controls who were not receiving melatonin, for an average of 12 months using monthly reflectometry measurements in three sites to determine skin color. There was no significant change in skin color among patients receiving melatonin, and no difference relative to controls. On the basis of these data, we conclude that melatonin has no effect on human skin pigmentation, and that the demonstrated effectiveness of melatonin in mediating malignant melanoma growth is not related to suppression of normal melanogenesis.

Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats.

Idoxifene, a novel selective estrogen receptor modulator, was tested for its effects on bone loss, serum cholesterol, and uterine wet weight and histology in the ovariectomized (Ovx) rat. Idoxifene (0.5 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD). In an intervention study, idoxifene (0.5 and 2.5 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group. Idoxifene reduced total serum cholesterol, which was maximal at 0.5 mg/kg x day. Idoxifene alone displayed minimal uterotrophic activity in Ovx rats and inhibited the agonist activity of estrogen in intact rats. Histologically, myometrial and endometrial atrophy were observed in both idoxifene and vehicle-treated Ovx rats. In this report, we also provide molecular-based evidence to support the observations in vivo of a novel selective estrogen receptor modulator (SERM) mechanism of action in bone and endometrial cells. Idoxifene is an agonist through the estrogen response element (ERE) and exhibits similar postreceptor effects to estrogen in bone-forming osteoblasts. Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis. However, idoxifene differs from estrogen in a tissue-specific manner. In human endometrial cells, where estrogen is a potent agonist through the ERE, idoxifene has negligible agonist activity. Moreover, idoxifene was able to block estrogen induced gene expression in endometrial cells, which is in agreement with the observation in the intact rat study. In the uterus, idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity. Together with its cholesterol lowering effect and lack of uterotrophic activity, these data suggest that idoxifene may be effective in the prevention of osteoporosis and other postmenopausal diseases without producing unwanted estrogenic effects on the endometrium.

Changes in bone turnover following gonadotropin-releasing hormone (GnRH) agonist administration and estrogen treatment in cynomolgus monkeys: a short-term model for evaluation of antiresorptive therapy.

In this study we determine the early time course of estrogen deficiency-induced bone loss in the cynomolgus monkey and examine the potential of this method for evaluating antiresorptive therapies. In two groups of animals, estrogen deficiency was induced by the administration of a gonadotropin-releasing hormone agonist (GnRHa) and bone turnover was measured using biochemical markers. Two weeks after receiving GnRHa, serum estradiol decreased to below the detection limit in most animals and remained there through 6 months or until estrogen replacement started (months 4-6). Relative to untreated animals, urinary deoxypyridinoline (dPyr), as well as C- and N-telopeptides of type I collagen, were significantly elevated 4 weeks after receiving GnRHa. Serum osteocalcin increased in GnRHa-treated animals as early as week 4 and the level was significantly higher than in untreated control animals from weeks 8-24. Estradiol treatment returned all measures of bone turnover to control levels within 2 weeks. The use of biochemical markers as surrogates of bone turnover and loss was validated by measurement of bone mineral density (BMD), which showed a significant reduction at 6 months in estrogen-deficient animals. However, lumbar BMD in animals that received GnRHa and estradiol was similar to that in animals that had not received GnRHa. In conclusion, a monthly depot injection of GnRHa resulted in increased bone turnover due to estrogen deficiency, as early as 4 weeks after treatment. Estrogen administration returned bone turnover to control levels in 2 weeks. This method represents a valid model for evaluating antiresorptive agents in the short term in a nonhuman primate. Furthermore, the data suggest that changes in biochemical markers in response to antiresorptive therapy in humans may be detectable at much earlier timepoints than commonly used.

A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat.

Inhibition of the cyteine proteinase, cathepsin K (E.C. 3.4.22.38) has been postulated as a means to control osteoclast-mediated bone resorption. The preferred animal models for evaluation of antiresorptive activity are in the rat. However, the development of compounds that inhibit rat cathepsin K has proven difficult because the human and rat enzymes differ in key residues in the active site. In this study, a potent, nonpeptide inhibitor of rat cathepsin K (K(i) = 4.7 nmol/L), 5-(2-morpholin-4-yl-ethoxy)-benzofuran-2-carboxylic acid ((S)-3-methyl-1-(3-oxo-1-[2-(3-pyridin-2-yl-phenyl)-ethenoyl]-azepan-4-ylcarbanoyl)-butyl)-amide (SB 331750), is described, which is efficacious in rat models of bone resorption. SB 331750 potently inhibited human cathepsin K activity in vitro (K(i) = 0.0048 nmol/L) and was selective for human cathepsin K vs. cathepsins B (K(i) = 100 nmol/L), L (0.48 nmol/L), or S (K(i) = 14.3 nmol/L). In an in situ enzyme assay, SB 331750 inhibited osteoclast-associated cathepsin activity in tissue sections containing human osteoclasts (IC(50) approximately 60 nmol/L) and this translated into potent inhibition of human osteoclast-mediated bone resorption in vitro (IC(50) approximately 30 nmol/L). In vitro, SB 331750 partially, but dose-dependently, prevented the parathyroid hormone-induced hypercalcemia in an acute rat model of bone resorption. To evaluate the ability of SB 331750 to inhibit bone matrix degradation in vivo, it was administered for 4 weeks at 3, 10, or 30 mg/kg, intraperitoneally (i.p.), u.i.d. in the ovariectomized (ovx) rat. Both 10 and 30 mg/kg doses of compound prevented the ovx-induced elevation in urinary deoxypyridinoline and prevented the ovx-induced increase in percent eroded perimeter. Histological evaluation of the bones from compound-treated animals indicated that SB 331750 retarded bone matrix degradation in vivo at all three doses. The inhibition of bone resorption at the 10 and 30 mg/kg doses resulted in prevention of the ovx-induced reduction in percent trabecular area, trabecular number, and increase in trabecular spacing. These effects on bone resorption were also reflected in inhibition of the ovx-induced loss in trabecular bone volume as assessed using microcomputerized tomography (microCT; approximately 60% at 30 mg/kg). Together, these data indicate that the cathepsin K inhibitor, SB 331750, prevented bone resorption in vivo and this inhibition resulted in prevention of ovariectomy-induced loss in trabecular structure.

Synthesis and structure-activity relationships of chiral allosteric modifiers of hemoglobin.

A series of allosteric effectors of hemoglobin, 2-(aryloxy)-2-alkanoic acids, was prepared to investigate the effect of the stereocenter on allosteric activity. The chiral analogues were based on the lead compound, RSR13 (3b), with different alkyl/alkanoic and cycloalkyl/cycloalkanoic groups positioned at the acidic chiral center. Of the 23 racemic molecules synthesized, 5 were selected for resolution based on structure-activity relationships. One chiral analogue, (-)-(1R,2R)-1-[4-[[(3, 5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylcyclopentane carbox ylic acid (11), exhibited greater in vitro activity in hemoglobin solutions than its antipode, racemate, and RSR13. Compound (-)-(1R, 2R)-11 was equipotent with RSR13 in whole blood, is a candidate for in vivo animal studies, and if efficacious and safe has a potential for use in humans. In general, it was found that chirality affects allosteric effector activity with measurable differences observed between enantiomers and the racemates.

Effects of smoking and telic/paratelic dominance on the contingent negative variation (CNV).

Concepts from reversal theory, a general theory of motivation, emotion and action, have recently been shown to be relevant to smoking behavior and smoking cessation. One relevant concept is that of telic and paratelic dominance. Individuals who are paratelic-dominant are playful, spontaneous, and prefer high arousal seeking. Those who are telic-dominant are serious, tend to plan ahead, and prefer low arousal. This led to the hypothesis that smoking might increase the amplitude of the contingent negative variation (CNV) in paratelic-dominant smokers more than in telic-dominant smokers. CNV was obtained using a Go/NoGo reaction time task with a 2 s S1-S2 interval and variable intertrial intervals. S1 indicated whether the subject was to respond to S2 or not. Errors were punished with a burst of white noise. Subjects performed the CNV task three times: after being deprived of smoking for at least 4 h; after sham smoking; and after smoking a cigarette of their own brand. Telic-dominant subjects differed from paratelic-dominant subjects in the relative amplitude of early (1 s) and late (2 s) components of the CNV. Smoking did not differentially affect the dominance groups unless gender was taken into account, and the most striking interactions between smoking and dominance groups were noted for the NoGo trials. As expected, smoking decreased the amplitude of the early component of the NoGo CNV for telic-dominant women, but increased it for paratelic-dominant women; no significant differences were found for the late component. In men, smoking increased the late CNV more for telics than for paratelics, while smoking did not differentially affect the early component.

Smoking and EEG power spectra: effects of differences in arousal seeking.

Reversal theory, a general theory of motivation, emotion and action, has recently been shown to predict lapses in smoking cessation. Individuals are less likely to lapse if they are in the telic (serious-minded, arousal avoidant, goal-oriented) state than when they are in the paratelic (playful, arousal seeking, spontaneous) state. The literature indicates that people can smoke in such a way as to either increase or decrease central nervous system arousal; smoking in the telic and paratelic states might therefore differentially affect the resting electroencephalograph, as quantified by Fast Fourier Transform analysis. The basic hypothesis was supported. Theta power was decreased when subjects in the telic state smoked, while beta 2 power was increased when subjects in the paratelic state smoked; the latter finding was, however, true only for men. The results have important implications for research on changing health behaviors and for smoking cessation programs.

Imagery ability in recall of distance and location information.

The role of visual imagery in short-term retention of movement end locations and distances was examined by comparing performances of subjects with extreme scores on the space relations section of the Differential Aptitude Test. Twelve HIGHS and twelve LOWS were tested on reproduction accuracy of six distances and six end locations immediately following presentation a 30-sec rest, a 30 sec imaginal rehearsal condition, and a 30-sec imaginal distraction condition. Initial analysis of the data provided little support for the hypothesis that HIGHS would reproduce criterion locations with more accuracy than LOWS. However, when scores of HIGHS reporting use of an imaginal coding strategy (HIGHS) were compared with LOWS who did not (LOWS), several expected findings were disclosed. HIGHS reproduced end locations with significantly less error in the immediate and imaginal rehearsal conditions, and as expected, accuracy scores for HIGHS and LOWS did not differ for the distance task. The findings suggest that when subjects employ an imaginal coding strategy, visual imagery ability may be an important factor in the retention of location information, but of little functional significance in the recall of distance.

Effects of a specialized prenatal adolescent program on maternal and infant outcomes.

The effects of a specialized prenatal educational program on perinatal outcomes in an urban adolescent maternity term population were examined. Fifty pregnant adolescents attended the program and 50 nonattenders served as controls. All subjects delivered at the same large metropolitan hospital. The data supported the hypotheses predicting that those adolescents exposed to the educational program and their infants would demonstrate fewer perinatal complications than those not exposed to the program. When analyzed by age, attenders and their infants in both groups (13 to 15 and 16 to 18 years of age) had fewer complications than nonattenders. Attenders also demonstrated lower frequencies of several obstetric and postnatal complications than did nonattenders. This study underscores the positive effects a specialized education program can have on adolescent perinatal outcomes.