PubMed Health⌕ Search

Biomedical subjects

D Chiu

Publications and source records attributed to D Chiu.

At least 19 recordsLinked to original sources

A Java application for tissue section image analysis.

The medical industry has taken advantage of Java and Java technologies over the past few years, in large part due to the language's platform-independence and object-oriented structure. As such, Java provides powerful and effective tools for developing tissue section analysis software. The background and execution of this development are discussed in this publication. Object-oriented structure allows for the creation of "Slide", "Unit", and "Cell" objects to simulate the corresponding real-world objects. Different functions may then be created to perform various tasks on these objects, thus facilitating the development of the software package as a whole. At the current time, substantial parts of the initially planned functionality have been implemented. Getafics 1.0 is fully operational and currently supports a variety of research projects; however, there are certain features of the software that currently introduce unnecessary complexity and inefficiency. In the future, we hope to include features that obviate these problems.

Cytological Techniques↗

Supportive care management of brain metastases: what is known and what we need to know. Conference proceedings of the National Cancer Institute of Canada (NCIC) Workshop on Symptom Control in Radiation Oncology.

OBJECTIVES: To review the results of published randomised controlled trials in the treatment of brain metastases and, from the knowledge gained from these trials, to identify potential study questions. MATERIALS AND METHODS: The literature was searched for randomised controlled trials that dealt with the management of brain metastases. Potential research questions were identified on the basis of the results of the literature review. RESULTS: A number of research questions were identified. In the context of the NCIC Symptom Control Group, a trial of supportive care alone vs supportive care and whole-brain radiotherapy (WBRT) in a subset of patients with the diagnosis of brain metastases was deemed to be of highest priority. We discussed a number of issues relating to the feasibility of such a trial. CONCLUSIONS: The optimal management of brain metastases remains elusive. Despite the results of numerous randomised controlled trials, many questions remain unanswered. The magnitude of benefit using WBRT above supportive care alone is uncertain. A trial of supportive care alone vs supportive care and WBRT may be successful once target population, feasibility and methodological issues are thoroughly solved.

Brain Neoplasms↗

Generating mouse models of retinal disease using ENU mutagenesis.

We used the chemical mutagen, N-ethyl-N-nitrosourea, to induce random point mutations in the germline of the mouse strain C57BL/6 in order to generate models of retinal diseases. 1163 mutagenised first generation mice produced using this approach were examined for eye abnormalities. Approximately one-third (412) presented with some form of ocular abnormality. Most changes were unilateral and confined to the anterior segment of the eye. Less than 10% (44) of identified changes affected the posterior segment of the eye. 21 mice with varying ocular abnormalities, including 17 with retinal changes, were bred to produce second generation mice to confirm genetic inheritance. Genetic inheritance was confirmed in several of these lines including three with retinal changes.

Animals↗

A high-resolution map of human chromosome 12.

Our sequence-tagged site-content map of chromosome 12 is now integrated with the whole-genome fingerprinting effort. It provides accurate and nearly complete bacterial clone coverage of chromosome 12. We propose that this integrated mapping protocol serves as a model for constructing physical maps for entire genomes.

Chromosomes, Artificial, Bacterial↗

Safety of intra-arterial thrombolysis in the postoperative period.

BACKGROUND AND PURPOSE: Limited systemic fibrinolysis and reduced dosage are features of intra-arterial thrombolyis (IAT) that may be advantageous in the treatment of postoperative strokes. However, IAT may increase the risk of surgical bleeding. We sought to determine the safety of postoperative IAT. METHODS: This was a retrospective case series from 6 university hospitals. All cases of IAT within 2 weeks of surgery were identified. Demographics, stroke mechanism, stroke severity, imaging and angiographic findings, time between surgery and lysis, thrombolytic agent used, surgical site bleeding, intracranial bleeding, and mortality rates were determined. Death or complications directly related to IAT were determined. RESULTS: Thirty-six patients (median age, 71.5 years; range, 45 to 85) were identified. Median time from surgery to stroke was 21.5 hours (range, 1 to 120). Open heart surgery was done in 18 (50%), carotid endarterectomy in 6 (17%), craniotomy in 3 (8%), ophthalmologic-ear, nose and throat surgery in 2 (6%), urologic-gynecologic surgery in 4 (11%), orthopedic surgery in 2 (6%), and plastic surgery in 1 (3%). The stroke causes were cardioembolism in 24 (67%), large-vessel atherosclerosis in 4 (11%), dissection in 3 (8%), postendarterectomy occlusion in 4 (11%), and radiation arteriopathy in 1 (3%). Median time to angiogram was 2.5 hours (0.1 to 5.5). Occlusion sites were M1 in 19 (53%), M2 in 9 (25%), internal carotid artery in 5 (14%), basilar artery in 2 (6%), and posterior communicating artery in 1 (3%). Thrombolysis was completed at a median of 4.5 hours (range, 1 to 8.0). Tissue plasminogen activator was used in 19 (53%) and urokinase in 17 (47%). Nine (26%) patients died. Surgical site bleeding occurred in 9 (25%) cases (minor in 6, major in 3). The major surgical bleeds were 2 post-craniotomy intracranial hemorrhages and 1 hemopericardium after coronary artery bypass grafting; all were fatal. Six deaths were non-IAT related: 3 caused by cerebral edema and 3 by systemic causes. Major bleeding complications were significantly more common among patients with craniotomy (P<0.02). CONCLUSIONS: Postoperative IAT carries a risk of bleeding in up to 25% of patients but is usually minor surgical site bleeding. Avoiding IAT in intracranial surgery patients may reduce complications. Mortality rate in this series was similar to that reported in prior IAT trials. IAT remains a viable therapeutic option for postoperative strokes.

Aged↗

Identification of 6 new mutations in the iduronate sulfatase gene. Mutation in brief no. 233. Online.

Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme iduronate-2-sulfatase. We sequenced genomic DNA and RT-PCR products in the iduronate sulfatase (IDS) gene in 6 unrelated patients with Hunter syndrome to assess genotype/phenotype relationships and offer carrier testing where required. Six novel mutations were identified: four missense mutations, one four-base pair deletion (596-599delAACA) and a cryptic splice site mutation. Three of the missense mutations were significant amino acid substitutions (S143F, S491F, E341K) of which the latter two involve amino acids conserved amongst sulfatase enzymes. The patients identified with these mutations all had a severe clinical phenotype. One missense mutation with a minimal amino acid substitution (H342Y), in a non-conserved region of the gene, was associated with a mild clinical phenotype. We identified a novel cryptic splice site (IVS5+934G>A) with some normal (wild type) mRNA processing. We predict that the normal mRNA product confered some residual functional enzyme, resulting in a mild phenotype associated with the absence of overt central nervous system disease.

Gene Deletion↗

Agreement and variability in the interpretation of early CT changes in stroke patients qualifying for intravenous rtPA therapy.

BACKGROUND AND PURPOSE: Ischemic changes identified on CT scans performed in the first few hours after stroke onset, which are thought to possibly represent early cytotoxic edema and development of irreversible injury, may have important implications for subsequent treatment. However, insecurity and conflicting data exist over the ability of clinicians to correctly recognize and interpret these changes. We performed a detailed review of selected baseline CT scans from the NINDS rt-PA Stroke Trial to test agreement among experienced stroke specialists and other physicians on the presence of early CT ischemic changes. METHODS: Seventy baseline CT scans from the NINDS Stroke Trial were read and classified for the presence or absence of various early findings of ischemia by 16 individuals, including NINDS trial investigators, other neurologists, other emergency medicine physicians, and radiology or stroke fellows. CT scans included normal scans and scans from patients who later developed symptomatic intracranial hemorrhage, as well as scans on which the NINDS rt-PA Stroke Trial neuroradiologist identified clear-cut early CT changes. For each CT finding, kappa-statistics were used to assess the proportion of agreement beyond chance. RESULTS: kappa-Values (95% confidence interval [CI]) ranged from 0.20 (-0.20, 0.61) (fair agreement) to 0.41 (0.37, 0.45) (moderate agreement) among the 16 viewers, and the kappa-value was only 0.39 (0.29, 0.49) (fair) in answer to the question "do early CT changes involve more than one third of the MCA [middle cerebral artery] territory?" There was substantial variability within each specialty group and between groups. kappa-Values were only fair to moderate even among physicians experienced in selecting and treating acute stroke patients with rtPA. Observed agreement ranged from 68% to 85%. Physicians agreed on the finding of early CT changes involving >33% of the MCA territory 77% of the time, although the kappa-value of 0.39 suggested only moderate agreement beyond chance. CONCLUSIONS: There is considerable lack of agreement, even among experienced clinicians, in recognizing and quantifying early CT changes. Improved methods of recognizing and quantifying early ischemic brain damage are needed.

Cerebrovascular Disorders↗

Interaction of antioxidants and their implication in genetic anemia.

The generation of reactive oxygen species (ROS) is a steady-state cellular event in respiring cells. Their production can be grossly amplified in response to a variety of pathophysiological conditions such as inflammation, immunologic disorders, hypoxia, hyperoxia, metabolism of drug or alcohol, exposure to UV or therapeutic radiation, and deficiency in antioxidant vitamins. Uncontrolled production of ROS often leads to damage of cellular macromolecules (DNA, protein, and lipids) and other small antioxidant molecules. A number of major cellular defense mechanisms exist to neutralize and combat the damaging effects of these reactive substances. The enzymic system functions by direct or sequential removal of ROS (superoxide dismutase, catalase, and glutathione peroxidase), thereby terminating their activities. Metal binding proteins, targeted to bind iron and copper ions, ensure that these Fenton metals are cryptic. Nonenzymic defense consists of scavenging molecules that are endogenously produced (GSH, ubiquinols, uric acid) or those derived from the diet (vitamins C and E, lipoic acid, selenium, riboflavin, zinc, and the carotenoids). These antioxidant nutrients occupy distinct cellular compartments and among them, there are active recycling. For example, oxidized vitamin E (tocopheroxy radical) has been shown to be regenerated by ascorbate, GSH, lipoic acid, or ubiquinols. GSH disulfides (GSSG) can be regenerated by GSSG reductase (a riboflavin-dependent protein), and enzymic pathways have been identified for the recycling of ascorbate radical and dehydroascorbate. The electrons that are used to fuel these recycling reactions (NADH and NADPH) are ultimately derived from the oxidation of foods. Sickle cell anemia, thalassemia, and glucose-6-phosphate-dehydrogenase deficiency are all hereditary disorders with higher potential for oxidative damage due to chronic redox imbalance in red cells that often results in clinical manifestation of mild to serve hemolysis in patients with these disorders. The release of hemoglobin during hemolysis and the subsequent therapeutic transfusion in some cases lead to systemic iron overloading that further potentiates the generation of ROS. Antioxidant status in anemia will be examined, and the potential application of antioxidant treatment as an adjunct therapy under these conditions will be discussed.

Anemia↗

Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program.

BACKGROUND: Population-based data are unavailable concerning the predictive value of orthostatic hypotension on mortality in ambulatory elderly patients, particularly minority groups. METHODS AND RESULTS: With the use of data from the Honolulu Heart Program's fourth examination (1991 to 1993), orthostatic hypotension was assessed in relation to subsequent 4-year all-cause mortality among a cohort of 3522 Japanese American men 71 to 93 years old. Blood pressure was measured in the supine position and after 3 minutes of standing, with the use of standardized methods. Orthostatic hypotension was defined as a drop in systolic blood pressure (SBP) of >/=20 mm Hg or in diastolic blood pressure of >/=10 mm Hg. Overall prevalence of orthostatic hypotension was 6.9% and increased with age. There was a total of 473 deaths in the cohort over 4 years; of those who died, 52 had orthostatic hypotension. Four-year age-adjusted mortality rates in those with and without orthostatic hypotension were 56.6 and 38.6 per 1000 person-years, respectively. With the use of Cox proportional hazards models, after adjustment for age, smoking, diabetes mellitus, body mass index, physical activity, seated systolic blood pressure, antihypertensive medications, hematocrit, alcohol intake, and prevalent stroke, coronary heart disease and cancer, orthostatic hypotension was a significant independent predictor of 4-year all-cause mortality (relative risk 1.64, 95% CI 1.19 to 2.26). There was a significant linear association between change in systolic blood pressure from supine position to standing and 4-year mortality rates (test for linear trend, P<0.001), suggesting a dose-response relation. CONCLUSIONS: Orthostatic hypotension is relatively uncommon, may be a marker for physical frailty, and is a significant independent predictor of 4-year all-cause mortality in this cohort of elderly ambulatory men.

Aged↗

Primary human herpes virus 6 infection transmitted from donor to recipient through bone marrow infusion.

An 8.5-month-old boy with Wiskott-Aldrich syndrome received a sibling matched bone marrow transplant from his healthy non-identical twin brother. The donor had primary human herpes virus 6 (HHV-6) infection around the time of bone marrow donation. The recipient had hepatitis in the first week and then developed fever and rash on day 18. Skin biopsy was shown to have HHV-6 antigen and his peripheral blood leukocytes were HHV-6 DNA positive. He engrafted on day 18 but the ANC dropped from 5.5 x 10(9)/l (day 23) to 0.48 x 10(9)/l (day 34) with persistent HHV-6 DNAemia. Bone marrow on day 35 was positive for HHV-6 DNA. He was treated with G-CSF and ganciclovir with good response. He later had pneumonitis which was treated empirically with foscarnet, ceftazidime and clarithromycin.

Bone Marrow Transplantation↗

Intravenous tissue plasminogen activator for acute ischemic stroke: feasibility, safety, and efficacy in the first year of clinical practice.

BACKGROUND AND PURPOSE: The feasibility, safety, and efficacy of intravenous tissue plasminogen activator (t-PA) for patients with acute ischemic stroke in clinical practice need to be assessed. METHODS: We initiated a prospective open-label study at a university hospital and two community hospitals in Houston, Tex, immediately after the publication of the National Institute of Neurological Disorders and Stroke (NINDS) t-PA study. A total of 30 patients, age 32 to 90 years, were treated with 0.9 mg/kg of intravenous t-PA (maximum dose, 90 mg) within 3 hours of acute ischemic stroke between December 1995 and December 1996. RESULTS: Six percent (6%) of all patients hospitalized with ischemic stroke received intravenous t-PA at the university hospital and 1.1% at the community hospitals. The rates of total, symptomatic, and fatal intracerebral hemorrhage were 10%, 7%, and 3%. Thirty-seven percent (37%) of patients recovered to fully independent function. The average time from stroke onset to emergency department arrival was 57 minutes; emergency department arrival to computed tomography scan 41 minutes; and computed tomography scan to administration of treatment 59 minutes. CONCLUSIONS: When treatment guidelines are carefully followed in an urban hospital setting, intravenous t-PA for acute ischemic stroke is feasible and shows safety and efficacy comparable to the results of the NINDS study.

Activities of Daily Living↗

Clinical features of moyamoya disease in the United States.

BACKGROUND AND PURPOSE: We report the clinical features and longitudinal outcome of the largest cohort of patients with moyamoya disease described from a single institution in the western hemisphere. Moyamoya disease in Asia usually presents with ischemic stroke in children and intracranial hemorrhage in adults. METHODS: Our study population included all patients with moyamoya disease evaluated at a university hospital in Houston, Texas from 1985 through 1995 (n = 35). We used Kaplan-Meier methods to estimate individual and hemispheric stroke risk by treatment status (medical versus surgical). Predictors of neurological outcome were assessed. RESULTS: The ethnic background of our patients was representative of the general population in Texas. The mean age at diagnosis was 32 years (range, 6 to 59 years). Ischemic stroke or transient ischemic attack was the predominant initial symptom in both adults and children. Of the 6 patients with intracranial hemorrhage, 5 had an intraventricular site of hemorrhage. The crude stroke recurrence rate was 10.3% per year in 116 patient-years of follow-up. Twenty patients underwent surgical revascularization, the most common procedure being encephaloduroarteriosynangiosis. The 5-year risk of ipsilateral stroke after synangiosis was 15%, compared with 20% for medical treatment and 22% overall for surgery. CONCLUSIONS: Our observations indicate that moyamoya disease may have a different clinical expression in the United States than in Asia, and may demonstrate a trend toward a lower stroke recurrence rate and better functional outcome after synangiosis.

Adolescent↗

T cell development in mice expressing splice variants of the protein tyrosine phosphatase CD45.

The transmembrane protein tyrosine phosphatase CD45 is expressed in multiple isoforms as a result of alternative splicing of variable exons encoding the extracellular domain. CD45 expression is critical for T cell development, and thymocyte maturation is blocked at the immature CD4+ CD8+ double-positive stage in CD45 gene-deficient (CD45 -/-) mice. Moreover, splicing of variable CD45 exons changes during thymocyte selection. To test the role of CD45 extracellular splice variants in T cell selection and development, we introduced CD45RO (a low-m.w. splice variant lacking exons 4, 5, and 6) and CD45ABC (a high-m.w. isoform containing all exons) transgenes under the control of a thymocyte-specific promoter into a CD45 -/- background, generating CD45RO transgene-positive CD45 -/- (CD45RO) and CD45ABC transgene-positive CD45 -/- (CD45ABC) mice. We demonstrate that both CD45 splice isoforms can rescue development of CD4+ and CD8+ TCR-alphabeta+ thymocytes. Neither CD45 isoform rescued positive selection of H-Y TCR transgene thymocytes, and these cells were blocked at a HSA(high) CD69- CD5(low) stage of development. Peripheral T cells from CD45RO and CD45ABC mice proliferated in response to allogeneic stimulator cells and anti-CD3epsilon cross-linking. However, only CD45RO mice, not CD45ABC mice, generated cytotoxic T cell responses and neutralizing, Th cell-dependent IgG Abs after viral infections. In addition, we show that T cells from CD45RO and CD45ABC mice accumulate in lymph nodes but not in the spleen, liver, or skin, indicating that the CD45 phosphatase may control the homing behavior and trafficking of T cells.

Alternative Splicing↗

Association of body mass index with blood pressure in elderly Japanese American men. The Honolulu Heart Program.

Few data are available on the association between body mass index (BMI) and blood pressure in elderly individuals, particularly among minority groups. We studied the cross-sectional association of BMI with systolic and diastolic pressures in 1378 Japanese American men 60 to 82 years of age who were participants in the population-based Third Lipoprotein Examination of the Honolulu Heart Program conducted between 1980 and 1982. When the subjects were divided into 5-year age groups, mean BMI decreased linearly with increasing age. Mean systolic pressure rose from 134.8 mm Hg in the first quintile of BMI to 138 in the second and 141.8 in the third quintiles, with levels of 139.2 and 142 in the fourth and fifth quintiles, respectively (test for trend, P = .083). Mean diastolic pressure rose from 78.1 mm Hg in the lowest quintile of BMI to 83.9 in the highest (test for trend, P = .008). We performed multiple regression analysis, controlling for factors known to influence blood pressure values, including age, physical activity index, alcohol intake, current smoking status, and diabetes mellitus. The association between BMI and both systolic and diastolic pressures remained highly statistically significant in these analyses. These results show that obesity and high blood pressure continue to be highly correlated even in old age and suggest that it may be possible to modify rates of hypertension by changes in body weight.

Age Factors↗

Lack of evidence for rotavirus by polymerase chain reaction/enzyme immunoassay of hepatobiliary samples from children with biliary atresia.

The purpose of this study was to analyze hepatobiliary samples of patients with biliary atresia for rotavirus groups. A, B, and C, because group A rotavirus had been used to produce an animal model of the disease and group C rotavirus had been found in hepatobiliary samples from one group of patients. Biliary remnants and liver tissue from 10 biliary atresia and 14 control patients with other liver diseases were examined for rotavirus groups A, B, and C using nonisotopic, reverse transcriptase polymerase chain reaction enzyme immunoassay. Biliary atresia patients had a median age of 3 mo and were from a confined geographic area. Rotaviral stocks from groups A and C were used as polymerase chain reaction-positive controls. The limits of detection for rotaviral RNA from these two groups were respectively, 5 plaque-forming units and 50 tissue culture infectious doses (ID50). Tissue culture was 100-fold less sensitive for groups A and C than the polymerase chain reaction. The nested nonisotopic probes hybridized in solution only with their homologous target DNAs as determined by the enzyme immunoassay, or by Southern blot hybridization. Although it was possible to detect mRNA from a beta-actin housekeeping gene in all of the hepatobiliary samples, no evidence of rotaviral RNA was found in either the biliary atresia or the negative control group. In conclusion, rotavirus is not a common viral etiology of biliary atresia.

Adolescent↗

Prevalence of dementia in older Japanese-American men in Hawaii: The Honolulu-Asia Aging Study.

OBJECTIVE: To determine prevalence of dementia and its subtypes in Japanese-American men and compare these findings with rates reported for populations in Japan and elsewhere. DESIGN AND SETTING: The Honolulu Heart Program is a prospective population-based study of cardiovascular disease established in 1965. Prevalence estimates were computed from cases identified at the 1991 to 1993 examination. Cognitive performance was assessed using standardized methods, instruments, and diagnostic criteria. PARTICIPANTS: Subjects were 3734 Japanese-American men (80% of surviving cohort) aged 71 through 93 years, living in the community or in institutions. MAIN OUTCOME MEASURES: Age-specific, age-standardized, and cohort prevalence estimates were computed for dementia (all cause) defined by 2 sets of diagnostic criteria and 4 levels of severity. Prevalence levels for Alzheimer disease and vascular dementia were also estimated. RESULTS: Dementia prevalence by Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised ranged from 2.1% in men aged 71 through 74 years to 33.4% in men aged 85 through 93 years. Age-standardized prevalence was 7.6%. Prevalence estimates for the cohort were 9.3% for dementia (all cause), 5.4% for Alzheimer disease (primary or contributing), and 4.2% for vascular dementia (primary or contributing). More than 1 possible cause was found in 26% of cases. The Alzheimer disease/vascular dementia ratio was 1.5 for cases attributed primarily to Alzheimer disease or vascular dementia. CONCLUSIONS: Prevalence of Alzheimer disease in older Japanese-American men in Hawaii appears to be higher than in Japan but similar to European-ancestry populations. Prevalence of vascular dementia appears to be slightly lower than in Japan, but higher than in European-ancestry populations. Further cross-national research with emphasis on standardized diagnostic methods is needed.

Age Distribution↗

Reference values for pulmonary function tests of Japanese-American men aged 71 to 90 years.

Pulmonary function was assessed by spirometry in 3,076 elderly Japanese-American men of the Honolulu Heart Program (HHP) cohort. The assessment was done with a stringent quality assurance program that adhered to American Thoracic Society (ATS) recommendations for spirometry. Less than 6% of the participants were unable to perform three acceptable spirometry maneuvers. A "healthy" subgroup of 528 men between the ages of 71 and 90 yr was identified by excluding almost all smokers and subjects with lung disease and other factors negatively influencing FEV1. Reference equations and normal ranges for FEV1, FVC, and the FEV1/FVC ratio were derived from the healthy group. Use of prediction equations from the Cardiovascular Health Study (CHS) of elderly European-American men consistently overpredicted FVC by 0.3 to 0.4 L and FEV1 by 0.15 L. Men in the HHP were on average 11 cm shorter than those in the CHS. Use of a prediction equation derived from the HHP cohort when the men in the cohort were on average 22.6 yr younger consistently overpredicted FEV1 by 0.2 to 0.3 L. These results underscore the importance of using prediction equations appropriate to the ethnicity, age, and height characteristics of the subjects being studied.

Aged↗

Hypertension in elderly Japanese Americans and adult native Hawaiians.

POPULATION-BASED DATA ON HYPERTENSION IN HAWAII are limited. Two groups for which data from the 1980s exist are Japanese-American men ages 60 to 81 in the Honolulu Heart Program (HHP) and native Hawaiians ages 20 to 59 in the Molokai Heart Study (MHS). In the elderly HHP men, the mean systolic blood pressure (SBP) was higher and the mean diastolic blood pressure (DBP) was lower in the older age groups. In the MHS, both the mean SBP and the mean DBP were higher with increasing age in both sexes. Among Japanese-American men, 53% of those ages 60 to 64 were hypertensive (SBP greater than or equal to 140 mmHg or DBP greater than or equal to 90 mmHg, or taking antihypertensive medications), as were 59% of those ages 65 to 74, and 67% of those ages 75 to 81. Among native Hawaiians, 6% of men and 8% of women ages 20 to 24 were hypertensive, as were 37% of men and 41% of women ages 45 to 54. At ages 55 to 59 the prevalence for men was 31%; and for women, 33%. These data indicate that hypertension is relatively common in both ethnic groups; however, native Hawaiians appear to be at greater risk of cardiovascular disease overall.

Adult↗