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D M Johnson

Publications and source records attributed to D M Johnson.

At least 37 records · Page 2Linked to original sources

In vitro evaluation of broad-spectrum beta-lactams in the philippines medical centers: role of fourth-generation cephalosporins. The Philippines Antimicrobial Resistance Study Group.

Cefepime is a potent broad-spectrum "fourth-generation" cephalosporin. The in vitro activity of cefepime was compared to that of cefpirome, ceftazidime, ceftriaxone, imipenem, and piperacillin/tazobactam in a multilaboratory (nine medical centers) Philippine surveillance project from March through October 1998. A total of 626 Gram-positive and Gram-negative organisms (10 species groups) were tested by the Etest method (AB BIODISK, Solna, Sweden) with results validated by current quality control strain analysis. The overall rank order of usable spectrum of activity was imipenem (4.2% resistance), cefepime (4.5%), cefpirome (5.0%), piperacillin/tazobactam (5.8%) > ceftriaxone (11.2%) > ceftazidime (15.3%), and results did not differ significantly between medical centers. Ceftazidime-resistant Escherichia coli and Klebsiella spp. occurred at rates of 13.3% and 31.1%, respectively, indicating extended-spectrum beta-lactamase (ESBL) activity. Imipenem (100% susceptible), cefepime, and cefpirome (both > or = 97.8% susceptible) were active in vitro against these ESBL phenotypes. Organisms with ceftazidime and/or ceftriaxone-resistant profiles consistent for hyper-production of Amp C cephalosporinases were detected at high rates among the Citrobacter spp. (29.2%) and Enterobacter spp. (45.8%); however, imipenem (100.0% susceptible) and cefepime (98.9%) remained active. Cefepime and imipenem (both 87.5% susceptible) were the most active agents tested against Acinetobacter spp. whereas piperacillin/tazobactam was most effective against P. aeruginosa (80.0% susceptible). Most tested beta-lactams (except ceftazidime) were active versus oxacillin-susceptible staphylococci. These data should be used as a guide for treatment selection with beta-lactam compounds in the Philippines and to serve as a resistance benchmark in comparisons with future studies in this nation.

Bacteria↗

In vitro evaluation of cefepime and other broad-spectrum beta-lactams in Taiwan medical centers. The Taiwan Antimicrobial Resistance Study Group.

The rates of resistance to commonly used antimicrobial agents have been documented to be at alarmingly high levels in Taiwan for both Gram-positive and Gram-negative species. This study was conducted to assess the current resistance patterns in six medical centers strictly controlled using a common MIC methodology and quality assurance measures. Cefepime, a new clinically introduced broad-spectrum "fourth-generation" cephalosporin, was compared to other members in this class including ceftazidime, cefpirome, ceftriaxone, piperacillin/tazobactam, and imipenem. These antimicrobials were tested against ten species groups of common clinical isolates of Enterobacteriaceae, non-enteric Gram-negative bacilli, and oxacillin-susceptible Staphylococcus spp. The results confirmed that extended spectrum beta-lactamase (ESBL) production in Klebsiella spp. (21.7%) and Escherichia coli (16.7%) was common in all medical centers surveyed. Cefepime was more active against these two species as well as against Amp C producing species, indole-positive Proteae, and Acinetobacter species. The activity of cefepime was comparable although slightly less than that of ceftazidime against Serratia spp. and Pseudomonas aeruginosa strains. All or nearly all staphylococci isolates were susceptible to the beta-lactam antimicrobial agents, except for ceftazidime. Overall, these antimicrobial agents had descending spectrums of activity as follows: imipenem > cefepime > cefpirome > piperacillin/tazobactam > ceftazidime > ceftriaxone for the 550 isolates tested. Cefepime seems to be an important broad-spectrum beta-lactam that can be used with confidence against many important pathogens in Taiwan, including those harboring resistance mechanisms. A continued surveillance program seems prudent for this geographic area.

Anti-Bacterial Agents↗

In vitro evaluation of cefepime and other broad-spectrum beta-lactams in eight medical centers in Thailand. The Thailand Antimicrobial Resistance Study Group.

The introduction of cephalosporins has had an important impact on the resistance rates to several clinically utilized beta-lactam antimicrobial agents. Most Thailand medical centers have not documented the levels of emerging resistant pathogens causing invasive infections. This study shows using reference-quality MIC techniques (Etest, AB BIODISK, Solna, Sweden), that carbapenem), "fourth-generation" cephalosporins (cefepime and cefpirome), and piperacillin/tazobactam were the most active agents tested against Gram-negative bacilli (Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Serratia spp., indole-positive Proteae, Acinetobacter spp., Pseudomonas aeruginosa, and oxacillin-susceptible Staphylococcus spp. when compared to "third-generation" cephalosporins (ceftazidime and ceftriaxone). The rank order of activity for all species was imipenem (2.9% resistant) > cefepime (7.7%) > piperacillin/tazobactam (11.1%) > cefpirome (13.4%) > ceftriaxone (21.1%) > ceftazidime (29.9%). The incidence of extended spectrum beta-lactamase production among E. coli (15.7%) and K. pneumoniae (45.6%) was significant. Cefepime and imipenem were active against the majority of these isolates. The activity of cefepime was also shown to be very good against, 1) organisms capable of producing AmpC enzymes, 2) staphylococci species that were susceptible to oxacillin, and 3) many strains of nonfermentative Gram-negative bacilli. The prevalence of antimicrobial resistance in Thailand seems to be quite high among certain commonly encountered pathogens, and imipenem and cefepime have activity (susceptible and intermediate potency) against > 90% of these organisms.

Anti-Bacterial Agents↗

Assembly of a novel cartilage matrix protein filamentous network: molecular basis of differential requirement of von Willebrand factor A domains.

Cartilage matrix protein (CMP) is the prototype of the newly discovered matrilin family, all of which contain von Willebrand factor A domains. Although the function of matrilins remain unclear, we have shown that, in primary chondrocyte cultures, CMP (matrilin-1) forms a filamentous network, which is made up of two types of filaments, a collagen-dependent one and a collagen-independent one. In this study, we demonstrate that the collagen-independent CMP filaments are enriched in pericellular compartments, extending directly from chondrocyte membranes. Their morphology can be distinguished from that of collagen filaments by immunogold electron microscopy, and mimicked by that of self-assembled purified CMP. The assembly of CMP filaments can occur from transfection of a wild-type CMP transgene alone in skin fibroblasts, which do not produce endogenous CMP. Conversely, assembly of endogenous CMP filaments by chondrocytes can be inhibited specifically by dominant negative CMP transgenes. The two A domains within CMP serve essential but different functions during network formation. Deletion of the A2 domain converts the trimeric CMP into a mixture of monomers, dimers, and trimers, whereas deletion of the A1 domain does not affect the trimeric configuration. This suggests that the A2 domain modulates multimerization of CMP. Absence of either A domain from CMP abolishes its ability to form collagen-independent filaments. In particular, Asp22 in A1 and Asp255 in A2 are essential; double point mutation of these residues disrupts CMP network formation. These residues are part of the metal ion-dependent adhesion sites, thus a metal ion-dependent adhesion site-mediated adhesion mechanism may be applicable to matrilin assembly. Taken together, our data suggest that CMP is a bridging molecule that connects matrix components in cartilage to form an integrated matrix network.

Actin Cytoskeleton↗

In vitro evaluation of sparfloxacin activity and spectrum against 24,940 pathogens isolated in the United States and Canada, the final analysis.

Sparfloxacin, a recently marketed oral fluoroquinolone, was tested against 24,940 recent clinical strains isolated from blood stream and respiratory tract cultures at 187 hospitals in the USA and Canada. Sparfloxacin activity was compared with 5 to 13 antimicrobial agents using either Etest (AB BIODISK, Solna, Sweden) and a reference broth microdilution or a standardized disk diffusion method. When applying recommended MIC breakpoint criteria of sparfloxacin susceptibility (< or = 0.5 microgram/mL) for Streptococcus pneumoniae (4,410 strains) and other Streptococcus spp. (554 isolates), 93% and 88% were inhibited, respectively. Furthermore, at < or = 1 microgram/mL sparfloxacin susceptibility rates for streptococci increased to 98% overall and 99.3% for S. pneumoniae. In contrast, only 46% and 68% of pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/mL; susceptible at < or = 1 microgram/mL) and penicillin (MIC90, 1.5 microgram/mL; susceptible at < or = 0.06 microgram/mL), respectively. Differences between regions in the USA for rates of penicillin-resistant pneumococcal strains were observed (greatest resistances in southeast and midwest), but results indicate that the sparfloxacin potency was not adversely influenced (MIC90, 0.5 microgram/mL). Also pneumococcal isolates from the lower respiratory tract were more resistant to penicillin and other beta-lactams. Nearly all Haemophilus species and Moraxella catarrhalis strains, including those harboring beta-lactamases, were susceptible to tested fluoroquinolones (sparfloxacin, ciprofloxacin), amoxicillin/clavulanic acid, and newer oral cephalosporins. Sparfloxacin was very active against oxacillin-susceptible Staphylococcus aureus (MIC90, 0.12 microgram/mL; 96-97% susceptible), Klebsiella spp. (MIC90 0.12 microgram/mL), and other tested enteric bacilli (92-95% susceptible). Comparisons between the broth microdilution MIC and disk diffusion interpretive results demonstrated excellent intermethod susceptibility category agreement (> 95%) using current sparfloxacin breakpoints, but some compounds (cefpodoxime disk diffusion tests for S. aureus) may require modifications. These results demonstrate that new Gram-positive focused fluoroquinolones (sparfloxacin) possess an excellent in vitro activity and spectrum against pathogens that cause respiratory tract infections. This spectrum of activity includes strains resistant to other antimicrobial classes, including the oral cephalosporins, macrolides, amoxicillin/clavulanic acid, and earlier fluoroquinolones (ciprofloxacin, ofloxacin). Overall, sparfloxacin inhibited 89% to nearly 100% of the isolates (species variable) tested against those species against which it has Food and Drug Administration indications for clinical use.

Anti-Infective Agents↗

Combinations of orally administered beta-lactams to maximize spectrum and activity against drug-resistant respiratory tract pathogens: I. Synergy studies of amoxicillin and cefixime with Streptococcus pneumoniae.

Streptococcus pneumoniae strains have emerged that are resistant to penicillin (MICs >0.06 microg/mL) and many other beta-lactams. However, some older compounds such as amoxicillin have potency against these pneumococci with altered penicillin-binding proteins, but are labile to beta-lactamases produced by other prevalent respiratory tract pathogens. The interactions of amoxicillin with an enzyme-stable cephalosporin (cefixime) with a long elimination half-life were examined by the checkerboard dilution method versus 39 S. pneumoniae strains (13 resistant, 15 intermediate, and 11 susceptible to penicillin). Among 24 strains with evaluable drug interaction tests, 17 (71%) demonstrated partial or complete synergy. This favorable interaction produces a cefixime susceptibility category change from resistant or intermediate to susceptible for 16 of 28 strains (57%), when combined with < or = 1 microg/mL amoxicillin. Thus, the use of two currently available oral beta-lactams (amoxicillin twice a day + cefixime once a day; three total doses) appears to be a potential alternative treatment with greater spectrum for community-acquired respiratory tract infections pending clinical trial results.

Administration, Oral↗

In vitro antimicrobial activity and MIC quality control guidelines of RPR 106972 (RPR 112808/RPR106950): a novel orally administered streptogramin combination. The Quality Control Study Group.

RPR 106972 is a novel oral streptogramin combination with reported therapeutic potency against Gram-positive and certain respiratory tract pathogens. MICs for RPR 106972, quinupristin/dalfopristin, and seven comparison drugs were determined by the reference methods against 337 strains selected to define spectrum and potency. RPR 106972 demonstrated antimicrobial activity against oxacillin-susceptible and -resistant Staphylococcus aureus (MIC ranges of 0.12 to 2 micrograms/ml and 0.5 to 2 micrograms/ml, respectively), and coagulase-negative staphylococci were also inhibited by RPR 106972 (MIC90, < or = 0.5 microgram/ml) and quinupristin/dalfopristin (MIC90, < or = 0.25 microgram/ml). Against all streptococcal strains tested (including penicillin-resistant pneumococcus), RPR 106972 was highly active with MIC results at < or = 1 microgram/ml. RPR 106972 inhibited Corynebacterium jeikeium (MIC90, 0.5 microgram/ml). Moraxella catarrhalis (MIC90, 0.25 microgram/ml), and some Haemophilus influenzae (MIC50, 2 micrograms/ml). RPR 106972 and quinupristin/dalfopristin demonstrated little activity against Enterococcus faecalis (MIC90s, 4 to 32 micrograms/ml) as compared to Enterococcus faecium (MIC90s, 0.5 to 1 microgram/ml) and other Enterococcus ssp. (MIC90s, 1 microgram/ml). Studies to establish MIC quality-control guidelines indicated the following ranges: for E. faecalis ATCC 29212, 0.5 to 4 micrograms/ml; for S. aureus ATCC 29213, 0.25 to 1 microgram/ml; and for Streptococcus pneumoniae ATCC 49619, 0.06 to 0.5 microgram/ml. The results of this study indicate that the in vitro activity of RPR 106972 against Gram-positive bacteria and selected Gram-negative respiratory organisms is promising and warrants additional studies of pharmacokinetics, and in vivo infection model dynamics.

Administration, Oral↗

Comparative in vitro assessment of sparfloxacin activity and spectrum using results from over 14,000 pathogens isolated at 190 medical centers in the USA. SPAR Study Group.

Sparfloxacin, a new orally administered fluoroquinolone, was tested against 14,182 clinical strains isolated (generally blood stream and respiratory tract cultures) at nearly 200 hospitals in the United States (USA) and Canada. Sparfloxacin activity was compared with 13 other compounds by Etest (AB BIODISK, Solna, Sweden), broth microdilution, or a standardized disk diffusion method. Using the Food and Drug Administration/product package insert MIC breakpoint for sparfloxacin susceptibility (< or = 0.5 microgram/ml), 94% of Streptococcus pneumoniae (2666 isolates) and 89% of the other streptococci (554 isolates) were susceptible. However, at < or = 1 microgram/ml (the breakpoint for all nonstreptococcal species) sparfloxacin susceptibility rates increased to 100% and 98%, respectively, for the two groups of streptococci. Only 50% and 65% of pneumococci were susceptible to ciprofloxacin (MIC90, 3 micrograms/ml) and penicillin (MIC90, 1.5 micrograms/ml), respectively. Although there were significant differences between regions in the USA in the frequency of penicillin-resistant pneumococcal strains, results indicate that the overall sparfloxacin MIC90 was uniformly at 0.5 microgram/ml. Nearly all (> or = 99%) Haemophilus species and Moraxella catarrhalis, including those harboring beta-lactamases, were susceptible to sparfloxacin, ciprofloxacin, and amoxicillin/clavulanic acid. Only cefprozil and macrolides demonstrated lower potency and spectrum against these two species. Sparfloxacin was active against oxacillin-susceptible Staphylococcus aureus (96 to 97%), Klebsiella spp. (95%), and other tested enteric bacilli (93%). Comparison between broth microdilution MIC and disk diffusion interpretive results for M. catarrhalis, Staphylococcus aureus, and the Enterobacteriaceae showed an absolute intermethod categorical agreement of > 95% using current sparfloxacin breakpoints, in contrast to those of cefpodoxime for S. aureus where a conspicuous discord (98% versus 59%) between methods was discovered. These results demonstrate that sparfloxacin possesses sufficient in vitro activity and spectrum versus pathogens that cause respiratory tract infections (indications), especially strains resistant to other drug classes such as the earlier fluoroquinolones, oral cephalosporins, macrolides, and amoxicillin/clavulanic acid. The sparfloxacin susceptibility breakpoint for streptococci may require modification (< or = 1 microgram/ml) based on the MIC population analysis presented here. A modal MIC (0.38 to 0.5 microgram/ml) was observed at the current breakpoint. Regardless, sparfloxacin inhibited 89% (nonpneumococcal Streptococcus spp.) to 100% (Haemophilus spp., M. catarrhalis) of the isolates tested with a median activity of 97% against indicated species.

Anti-Bacterial Agents↗

A standard test of heat-pain responses using CASE IV.

Heat-pain threshold and stimulus response characteristics can be evaluated with graduated heating pulses from a radiant heat source or a contact thermode. Results may be used to: (1) evaluate differences in sensation among anatomical sites, sides of the body, and with development and aging; and (2) provide an end-point for the study of the efficacy of drugs; or to follow the course of sensory alteration in disease (medical practice, epidemiologic studies, and controlled clinical trials). Because there is great variability in how tests of this kind are performed and scored, comparisons of results among medical centers are difficult. To meet this need, we have developed, and here describe, a standardized and validated test of heat-pain. We use both pyramidal and trapezoid-shaped stimuli. The range of stimulus magnitudes we recommend is sufficient to test heat-pain at a sensitive region (the face) of young people and an insensitive region (the foot) of healthy old people. From tests on healthy subjects and patients, we find that neither our previously published forced-choice or 4, 2, and 1 stepping algorithms are suitable for testing heat-pain sensation. We, therefore, introduce the Non-Repeating Ascending with Null Stimuli (NRA-NS) algorithm which performs satisfactorily. The graphed data points of responses to increasingly stronger heat pulses were made up of two components-the no pain (0) response line and the heat-pain response line (> or = 1 numerical scaling of the pain responses graded from 1 [least] to 10 [greatest]). For the pain responses, we found that usually a curve could be fit using a quadratic equation. Using this equation, or interpolation where necessary, it is possible to compute the heat-pain detection threshold (HPDT or HP:0.5), an intermediate heat-pain response (HP:5.0), and the difference between the two (HP:5.0-0.5). Our studies show that a certain time is needed between successive stimuli and tests to minimize changing basal skin temperature or threshold. We also demonstrated that low or high baseline skin temperatures can affect heat-pain responses, therefore, we advocate specific testing conditions. Based on a study of 25 healthy subjects, the reproducibility of the test falls within +/-1 stimulus steps 88% of the time for HP:5.0 and 76% of the time for HP:0.5. The precise approaches employed to make the test standard and reproducible are described. We illustrate that the algorithm and testing system is able to document altered pain threshold with skin abrasion, with intradermal injection of nerve growth factor, and with diabetic polyneuropathy.

Adult↗

Two investigational glycylcyclines, DMG-DMDOT and DMG-MINO. Antimicrobial activity studies against gram-positive species.

DMG-DMDOT (CL-331,002 OR CL-331,928) and DMG-MINO (CL-329,998 or CL-344,677) are two new semisynthetic tetracyclines called glycylcyclines, with a broad spectrum of activity and includes Enterobacteriaceae, Gram-positive cocci, JK diphtheroids, and Bacillus cereus. Potent activity was demonstrated against all Streptococcus spp. strains [minimum inhibitory concentrations] (MIC90S) 0.06-0.25 micrograms/ml) and staphylococci (oxacillin susceptible ans resistant; MIC90S 0.12-2 micrograms/ml). Both glycylcyclines (MIC90, 0.06 micrograms/ml) were more potent than minocycline (MIC90 8 micrograms/ml) against Enterococcus faecium, many of which were vancomycin resistant (116 strains). Organisms with minocycline MICs at > or = 8 micrograms/ml (Staphylococcus aureus, enterococci, beta-hemolytic streptococci, and pneumococci) had glycylcycline MIC results ranging from 0.06 to 0.5 micrograms/ml (e.g., apparent use against existing tetracycline-resistance phenotypes). Drugs in this class appear promising for therapy of infections caused by Gram-positive species now testing resistant to contemporary antimicrobial agents, and further development of compounds in this class is encouraged.

Anti-Bacterial Agents↗

Comparative activity of twelve beta-lactam drugs tested against penicillin-resistant Streptococcus pneumoniae from five medical centers: effects of serum protein and capsular material on potency and spectrum as measured by reference tests.

A total of 152 strains of Streptococcus pneumoniae from diverse geographic areas in the United States and with different levels of penicillin resistance were tested against five broad-spectrum cephalosporins, ampicillin, piperacillin, ticarcillin, and three beta-lactamase inhibitor combinations. Also, the effect of human serum proteins on the activity of selected "third-generation" cephalosporins was examined. The overall rank order of activity among the cephalosporins against penicillin-susceptible strains was: ceftriaxone (MIC90, 0.03 microgram/mL) > cefotaxime > ceftizoxime = cefuroxime > ceftazidime (MIC90, 0.5 microgram/mL). Only cefotaxime and ceftriaxone exhibited significant activity against penicillin-intermediate or -resistant isolates. Ampicillin, piperacillin, and penicillin were generally eight- to 16-fold more potent than ticarcillin and no increase in the effectiveness of these agents was observed with the addition of the beta-lactamase inhibitors (clavulanate, sulbactam, tazobactam). Ceftriaxone potency was significantly decreased (> or = four-fold) by the modest addition of 25% pooled human serum proteins and this change modified the rank order of potency against nonpenicillin-susceptible pneumococci to favor cefotaxime (41% resistant versus 71% for ceftriaxone; MICs at > or = 2 micrograms/mL). Induced high-level capsular production had no measurable effect on the MIC results of tested agents. These results confirm the continued activity advantages of cefotaxime and ceftriaxone against various populations of pneumococci compared to other alternative beta-lactams. The predictive value, however, of the utilized breakpoint concentrations of the cephalosporins, remains in question for pneumococcal infections other than those in the central nervous system and at unaltered, "usual" dosing.

Anti-Bacterial Agents↗

In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones.

Two new fluorinated oxazolidinones, U-100592 and U-100766, were evaluated against more than 659 gram-positive and -negative organisms and compared with glycopeptides, erythromycin, clindamycin, clinafloxacin, and chloramphenicol. U-100592 and U-100766 were usually equally potent, but the MICs at which 90% of the isolates are inhibited (MIC90s) of U-100592 for some staphylococci and enterococci were slightly lower than those of U-100766 (1 versus 2 micrograms/ml). The MIC90 of U-100592 and U-100766 for oxacillin-resistant Staphylococcus aureus was 2 micrograms/ml, the same as observed for oxacillin-susceptible strains. The oxazolidinone MICs for other Staphylococcus spp. were < or = 2 micrograms/ml (MIC50, 0.5 to 1 microgram/ml). All enterococci were inhibited by < or = 4 and < or = 2 micrograms of U-100592 and U-100766 per ml, respectively. Against 152 vancomycin-resistant enterococci (five species), both compounds had a narrow range of MICs (0.25 to 2 micrograms/ml) and a MIC90 of 1 microgram/ml. Corynebacterium jeikeium, Bacillus spp., and all tested streptococci were inhibited (< or = 4 micrograms/ml). Members of the family Enterobacteriaceae and other gram-negative bacilli were not susceptible (MIC50, > 64 micrograms/ml) to either oxazolidinone. Three potencies of U-100592 and U-100766 disks were tested (5, 15, and 30 micrograms), and acceptable correlations (r = 0.81 to 0.90) with the measured MICs were observed. Best discrimination of the tentatively susceptible organisms (MICs, < or = 4 micrograms/ml) was demonstrated with the 30-micrograms disk concentration. The oxazolidinones demonstrated a dominant bacteristatic action. These oxazolidinones (U-100592 and U-100766) appear promising for treatment of gram-positive organisms that demonstrate resistance to contemporary therapeutic agents.

Acetamides↗

In vitro efficacy of levofloxacin alone or in combination tested against multi-resistant Pseudomonas aeruginosa strains.

Levofloxacin, the S(-) isomer of ofloxacin, demonstrates in vitro activity against Pseudomonas aeruginosa. To further characterize this activity, levofloxacin was tested against three populations of recent clinical isolates categorized by their resistance patterns to several other anti-pseudomonal agents. Results demonstrate the minimum inhibitory concentrations (MICs) for levofloxacin were generally two- to fourfold higher than for ciprofloxacin. Higher fluoroquinolone MICs were associated with MIC increases in other drugs. Levofloxacin demonstrated cross resistance against ciprofloxacin-resistant strains. Combinations of levofloxacin and several codrugs revealed that the majority of evaluable interactions demonstrated indifferent action. Levofloxacin exhibited enhanced activity (additive or degrees of synergy) principally with piperacillin, aztreonam, or ceftazidime. The synergy and additive rate (21 to 30%) compared favorably with the enhanced interactions observed with gentamicin combined with piperacillin or ceftazidime (27 to 30%). Levofloxacin activity against P. aeruginosa was most comparable to that of ciprofloxacin, which was applicable against > 90% of strains found to be resistant to other classes of antimicrobial agents.

Anti-Bacterial Agents↗