Analyses of the return on investment of public health interventions: a scoping review and recommendations for future studies.

Return on investment (ROI) analysis is increasingly being used for evaluating the value for money of public health interventions. Given its potential role for informing health policies, it is important that there is a more comprehensive understanding of ROI analysis within the global health field. To address this gap in the literature, we conducted a scoping review of recent research articles reporting an ROI metric for a health intervention within the public sector in any country setting. The database search was limited to literature published in English and studies published between 1 January 2018 and 14 June 2021. Uses and settings where the ROI metric is being applied, key methodological features of the calculations and the types of economic benefits included were extracted. 118 relevant studies were included within this scoping review. We found that ROI analyses of health interventions differed between those that only included fiscal savings (such as prevented medical expenses) and those which incorporated a wider range of benefits (such as monetised health benefits). This highlights the variation in the definition of ROI analyses and supports the finding that ROI analyses are used for a range of different research questions/purposes within the healthcare sector. We also found that the methodologies used in ROI calculations were inconsistent and often poorly reported. This review demonstrates that there is notable variation in the methodology surrounding recent ROI calculations of healthcare interventions, as well as the definition of ROI analysis. We recommend that ROI metrics should be carefully interpreted before they are used to inform policy decisions regarding the allocation of healthcare resources. To improve the consistency of future studies, we also set out recommended use cases for ROI analysis and a reporting checklist.

Bridge Suture for Successful McDonald Emergency Cerclage.

OBJECTIVES: To create awareness about a surgical technique termed bridge suture, which is performed as a pretreatment before a McDonald cerclage is performed on an emergency to treat severe cervical insufficiency. METHODS: Procedures for bridge suture were reviewed in detail and outcomes of 16 patients treated with bridge suture followed by McDonald cerclage were evaluated retrospectively. RESULTS: Using the bridge suture, the edges of uterine cervix were temporarily sutured and the external uterine os was closed, while the hourglass-shaped fetal membranes were concomitantly confined within the cervix; subsequently, a McDonald cerclage was performed. Over a 22-year period, 16 patients with a dilated cervix and bulging fetal membranes were treated using the technique of bridge suture followed by an emergency cerclage. The mean gestational age at cerclage was 22.5 weeks; the mean gestational age at delivery was 30.7 weeks; and the mean interval between cerclage and delivery was 8.2 weeks. In 15 out of 16 cases, cerclage was performed without encountering any complications. No maternal complications, including cervical laceration, were observed. The mean body weight of 17 neonates, including that of a twin, was 1,516 g and of them, 15 neonates survived. CONCLUSION: The important outcome of bridge suture is the replacement of fetal membranes back into the uterine cavity before McDonald's cerclage is performed. Pretreatment with bridge suture may facilitate the performance of a successful emergency cerclage and contribute to good maternal and neonatal outcomes.

Porphyrins and porphines bind strongly and specifically to tRNA, precursor tRNA and to M1 RNA and inhibit the ribonuclease P ribozyme reaction.

Porphyrins and porphines strongly inhibit the action of the RNA subunit of the Escherichia coli ribonuclease P (M1 RNA). Meso-tetrakis(N-methyl-pyridyl)porphine followed linear competitive kinetics with pre-tRNA(Gly1) from E. coli as variable substrate (Ki 0.960 microM). Protoporphyrin IX showed linear competitive inhibition versus pre-tRNA(Gly1) from E. coli (Ki 1.90 microM). Inhibition by meso-tetrakis[4-(trimethylammonio)phenyl]porphine versus pre-tRNA(Gly1) from E. coli followed non-competitive kinetics (Ki 4.1 microM). The porphyrins bound directly to E. coli tRNAVal, E. coli pre-tRNAGly1 and M1 RNA and dissociation constants for the 1:1 complexes were determined using fluorescence spectroscopy. Dissociation constants (microM) against E. coli tRNAVal and E. coli pre-tRNAGly were: meso-tetrakis(N-methyl-pyridyl)porphine 1.21 and 0.170; meso-tetrakis[4-(trimethylammonio)phenyl]porphine, 0.107 and 0.293; protoporphyrin IX, 0.138 and 0.0819. For M1 RNA, dissociation constants were 32.8 nM for meso-tetrakis(N-methyl-pyridyl)porphine and 59.8 nM for meso-tetrakis[4-(trimethylammonio)phenyl]porphine and excitation and emission spectra indicate a binding mode with strong pi-stacking of the porphine nucleus and base pairs in a rigid low-polarity environment. Part of the inhibition of ribonuclease P is from interaction with the pre-tRNA substrate, resulting from porphyrin binding to the D-loop/T-loop region which interfaces with M1 RNA during catalysis, and part from the porphyrin binding to the M1 RNA component.

Escherichia coli tRNAs are resistant to the hyperprocessing reaction of homologous E. coli ribonuclease P ribozyme.

Bacterial ribonuclease P RNA ribozyme can do the hyperprocessing reaction, the internal cleavage reaction of some floppy eukaryotic tRNAs. The hyperprocessing reaction can be used as a detection tool to examine the stability of the cloverleaf shape of tRNA. Until now, the hyperprocessing reaction has been observed in the heterologous combination of eukaryotic tRNAs and bacterial RNase P enzymes. In this paper, we examined the hyperprocessing reaction of Escherichia coli tRNAs by homologous E. coli RNase P, to find that these homologous tRNAs were resistant to the toxic hyperprocessing reaction. Our results display the evidence for molecular co-evolution between homologous tRNAs and RNase P in the bacterium E. coli.

Long-term continuous versus intermittent cyclosporin: therapy for psoriasis.

A multicenter randomized controlled study was conducted to assess the long-term efficacy and safety of cyclosporin A therapy for psoriasis using either a continuous or an intermittent regimen. Initially, both regimens consisted of 3-5 mg/kg/day administration of CyA. Once remission was obtained, CyA dose was maintained between 0.5 and 3 mg/kg/day under the continuous regimen, while under the intermittent regimen, CyA dose was tapered off and, when necessary, topical corticosteroids were used until relapse occurred. Thirty-one patients were followed for at least 48 months (mean follow-up period: 55.9+/-4.6 months): 15 received continuous therapy, and 16 received intermittent therapy. With both regimens, the PASI (Psoriasis Area and Severity Index) score was maintained at 5-12 points throughout the follow-up period. The score was decreased by more than 70% from baseline with both regimens: the responses between them were not significantly different. However, overall control of psoriasis, as assessed from the averaged PASI score, was better in the patients receiving continuous therapy. Although the overall frequency of adverse reactions was similar for the two regimens, cancer occurred in two patients on continuous therapy (gastric cancer and hepatocellular carcinoma in one patient each). We could not, however, definitely attribute the cancers in the two patients to continuous therapy itself. There was a significantly higher incidence of renal impairment in elderly patients receiving either regimen when compared with younger patients. In conclusion, CyA administered to psoriasis patients under both regimens exhibited long-term efficacy and tolerability. Despite a lower overall efficacy, it seems proper to conclude that intermittent therapy is more useful than continuous therapy due to the occurrence of malignancies with continuous therapy. Further investigation is required to determine whether intermittent therapy is really safer than continuous therapy, and, if so, how it should be designed to minimize long-term adverse reactions and achieve overall control comparable to that of continuous CyA therapy.

High-concentration (20 mug/g) tacalcitol ointment therapy on refractory psoriasis vulgaris with low response to topical corticosteroids.

The efficacy and safety of the application of high-concentration (20 mug/g) tacalcitol ointment once daily for 12 weeks to psoriasis vulgaris lesions which showed low response to topical corticosteroids, were evaluated in a prospective, multicenter, open-label study. Eighty patients were enrolled in the safety analysis of the test drug, and 54 of the 80 patients in the efficacy analysis. The efficacy rate based on the number of cases graded as "moderate improvement" or better in the final global improvement rating of the 54 cases included in the efficacy analysis, was 88.9% (95% CI: 77.4-95.8%). Significant improvement in erythema, thickness, and scaling was observed from 2 weeks of treatment onward (p < 0.001). Five local adverse reactions (2 events of irritation, 2 events of itching, and 1 event of redness) were observed in 3 of the 80 patients included in the safety analysis. There were no significant changes in mean serum calcium values. Tacalcitol 20 mug/g ointment is concluded to be effective and safe for the treatment of refractory psoriasis vulgaris with low response to topical corticosteroids.

Long-term safety and efficacy of high-concentration (20 microg/g) tacalcitol ointment in psoriasis vulgaris.

A multi-center open prospective research was conducted in order to assess the safety and efficacy of tacalcitol 20 microg/g ointment once daily (maximum 10 g/day) in the long-term treatment of psoriasis vulgaris. For the 74 subjects included in the 54-week efficacy analysis, the mean PASI score at the beginning of the study was 22.49 10.20 (mean SD), which was 5.73 6.04 after 54 weeks. A significant decrease (p < 0.001) in the mean PASI score was seen after 1 week of application, and the score remained almost constant after 18 weeks through 54 weeks. Twenty-five local adverse drug reactions were noticed in 16 of the 154 subjects included in the safety analysis. No increase in the incidence of severe adverse drug reactions was seen in the long-term administration of tacalcitol 20 microg/g ointment. Although a significant decrease in the intact parathyroid hormone (PTH) and 1alpha,25-(OH)2D3 was observed, the homeostasis of the corrected serum calcium was maintained. Tacalcitol 20 microg/g ointment, applied once daily at doses of up to 10 g/day (200 microg tacalcitol), is safe and effective, even in long-term administration, in the treatment of patients with psoriasis vulgaris. Serum calcium should be monitored in patients with decreased renal function and other suspected impairment of calcium metabolism, before and during the treatment with tacalcitol 20 microg/g ointment.

Kinetics of hyperprocessing reaction of human tyrosine tRNA by ribonuclease P ribozyme from Escherichia coli.

Human tyrosine tRNA and fly alanine, histidine, and initiator methionine tRNAs are generally cleavable internally by bacterial ribonuclease P ribozyme. The unusual internal cleavage reaction of tRNA, called hyperprocessing, occurs when the cloverleaf structure of the tRNA molecule is denatured to form a double-hair-pin-like structure. The hyperprocessing reaction of these tRNAs requires magnesium ions. We analyzed details of this reaction using human tyrosine tRNA and Escherichia coli RNase P ribozyme. The usual processing reaction occurred efficiently with magnesium at 5 mM, but for the hyperprpocessing reaction, higher concentrations were needed. With such high concentrations, hyperprocessing cleaved both mature tRNA and tRNA precursor as substrates. When mature tRNA was the substrate, the apparent K(M) was almost the same as in the usual reaction, but k(cat) was smaller. These results indicated that the occurrence of hyperprocessing depends on the magnesium ion concentration, and suggested that magnesium ions contribute to the recognition of the shape of the substrate by bacterial RNase P enzymes.

Guide DNA technique in bacterial ribonuclease P reaction for effective processing of tRNA precursor.

Previously, we found that a small (approx. 20-mer) DNA hybridizing to the 5'-leader region of a tRNA precursor enhances the cleavage efficiency in bacterial ribonuclease P reaction. We named this technique the 'guide DNA technique'. Detailed analyses showed that the length of the guide DNA, concentration of the guide DNA and the hybridizing position affected the cleavage efficiency: for an effective cleavage reaction, guide DNA should be designed to hybridize to the region on the cleavage site, should be 20 bases or more in length and should be of high concentration. The presence of a 5'-flanking region in the DNA did not affect the cleavage reaction. The guide DNA technique is a useful tool for effective preparation of mature tRNA molecules in vitro.

Another cut for lysine tRNA: application of the hyperprocessing reaction reveals another stabilization strategy in metazoan lysine tRNAs.

Recently, we revealed that the cloverleaf structure of some eukaryotic tRNAs is not always stable in vitro, and the denatured structures of these tRNAs are sometimes detected in bacterial RNase P reactions. We have designated the unusual internal cleavage reaction of these tRNAs as hyperprocessing. We have developed this hyperprocessing strategy as a useful tool for examining the stability of the tRNA cloverleaf structure. There are some common features in such unstable, hyperprocessible tRNAs, and the criteria for the hyperprocessing reaction of tRNA are extracted. Metazoan initiator methionine tRNAs and lysine tRNAs commonly fit the criteria, and are predicted to be hyperprocessible. The RNase P reactions of two metazoan lysine tRNAs from Homo sapiens and Caenorhabditis elegans, which fit the criteria, resulted in resistance to the internal cleavage reaction, while one bacterial lysine tRNA from Acholeplasma laidlawii, which also fits the criteria, was internally cleaved by the RNase P. The results showed that the metazoan lysine tRNAs examined are very stable without base modifications even under in vitro conditions. We also examined the 3'-half short construct of the human lysine tRNA, and the results showed that this RNA was internally cleaved by the enzyme. The results indicated that the human lysine tRNA has the ability to be hyperprocessed but is structurally stabilized in spite of lacking base modifications. A comparative study suggested, moreover, that the acceptor-stem bases should take part in the stabilization of metazoan lysine tRNAs. Our data strongly suggest that the cloverleaf shape of other metazoan lysine tRNAs should also be stabilized by means of similar strategies to in the case of human tRNA(Lys3).

Porphyrins and porphines inhibit the ribonuclease P reaction in vitro.

Porphyrin has been reported to bind to the T psi C stem of tRNA. This site is also recognized by ribonuclease P, which is essential and ubiquitous endoribonuclease responsible for the maturation of 5' ends of tRNA precursors. Thus, we investigated the effects of porphyrins on the in vitro reaction of ribonuclease P from Escherichia coli. The results showed that some of porphyrins inhibited the reaction more strongly than any other inhibitors reported so far. In addition to the benzimidazole inhibition that we have previously reported, these unusual substrate-binding inhibitions may provide new leads for the novel anti-bacterial reagent design.

Regulation of bacterial RNase P ribozyme reaction by divalent cation and guide DNA.

The RNA subunit of bacterial ribonuclease P (RNase P) is a ribozyme which can cleave a canonical cloverleaf tRNA precursor and a hairpin RNA with a CCA-3' tag sequence as its substrate. With high concentration of Mg ion, the ribozyme as well as holo enzyme internally cleaves certain tRNAs in vitro. We denoted this unusual reaction as hyperprocessing. By controlling magnesium ion concentration for the reaction and also by forcing the RNA shape with external guide DNAs, we could regulate the hyperprocessing reaction by the bacterial RNase P enzymes. These techniques will lead the RNase P ribozyme to more designable and more applicable RNA-cleaving enzyme.