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Biomedical subjects

B Yip

Publications and source records attributed to B Yip.

At least 19 recordsLinked to original sources
PubMed2006

Multicomponent variance estimation for binary traits in family-based studies.

In biometrical genetic analyses of binary traits, the use of family data overcomes some limitations of twin studies, particularly in terms of sample size and types of genetic or environmental factors that can be estimated. However, because of computational problems, recent methods in the application of generalized linear mixed models for family data structure have limited the ability to handle large data sets with general covariates. In this paper, we investigate the use of the hierarchical likelihood approach to the analysis of binary traits from family data. In a simulation study, the method is shown to be highly accurate for the estimation of both the variance components and fixed regression parameters, even for small family sizes. For illustration, we analyze a real data set of familial aggregation of preeclampsia, a pregnancy-induced hypertension. When possible, the analysis is compared with the exact maximum likelihood approach.

Analysis of Variance↗
PubMed2006

Regimen-dependent variations in adherence to therapy and virological suppression in patients initiating protease inhibitor-based highly active antiretroviral therapy.

OBJECTIVE: To examine differences among four protease inhibitor (PI)-based drug regimens in adherence to therapy and rate of achievement of virological suppression in a cohort of antiretroviral-naive patients initiating highly active antiretroviral therapy (HAART). METHODS: Participants were antiretroviral-naive and were first dispensed combination therapy containing two nucleosides and a ritonavir (RTV)-boosted PI, or unboosted nelfinavir, between 1 January 2000 and 30 September 2003. Logistic regression analysis was used to examine associations between the prescribed PI and other baseline factors associated with being >90% adherent to therapy and then to determine the associations of prescribed drug regimen, adherence to therapy and baseline variables with the odds of achieving two consecutive viral loads of <500 HIV-1 RNA copies/mL. RESULTS A total of 385 subjects were available for analysis. Lopinavir (LPV)/RTV was prescribed for 168 patients (42% of total); 86 (22%) received indinavir (IDV)/RTV; 91 (24%) received nelfinavir (NFV) and 40 (10%) received saquinavir (SQV)/RTV. SQV/RTV-based HAART was associated with reduced adherence to therapy [odds ratio (OR)=0.40; 95% confidence interval (CI) 0.19-0.83]. In multivariate models, IDV/RTV (OR=0.45; 95% CI 0.22-0.92), SQV/RTV (OR=0.18; 95% CI 0.07-0.43) and NFV were associated with reduced odds of achieving virological suppression within 1 year in comparison to LPV/RTV-based therapy. For patients receiving NFV, adjusting for adherence (OR=0.73; 95% CI 0.36-1.47) rendered this association nonsignificant. CONCLUSION: Patients prescribed IDV/RTV, NFV or SQV/RTV were less likely to achieve virological suppression on their first regimen compared with patients prescribed LPV/RTV. Reduced adherence to these therapies only partly explained these observed differences.

Adult↗
PubMed2006

CD4 percentage is an independent predictor of survival in patients starting antiretroviral therapy with absolute CD4 cell counts between 200 and 350 cells/microL.

OBJECTIVE: To determine the prognostic value of baseline CD4 percentage in terms of patient survival in comparison to absolute CD4 cell counts for HIV-positive patients initiating highly active antiretroviral therapy (HAART). METHODS: A population-based cohort study of 1,623 antiretroviral therapy-naïve HIV-positive individuals who initiated HAART between 1 August 1996 and 30 June 2002 was conducted. Cumulative mortality rates were estimated using Kaplan-Meier methods. Cox proportional hazards regression was used to model the effect of baseline CD4 strata and CD4 percentage strata and other prognostic variables on survival. A subgroup analysis was conducted on 417 AIDS-free subjects with baseline CD4 counts between 200 and 350 cells/microL. RESULTS: In multivariate models, low CD4 percentages were associated with increased risk of death [CD4%<5, relative hazard (RH)=4.46; CD4% 5-14, RH=2.43; P<0.01 for both] when compared with those subjects with an initial CD4 fraction of 15% or greater, but had less predictive value than absolute CD4 counts. In subgroup analyses where absolute CD4 strata were not associated with mortality, a baseline CD4 fraction below 15% [RH=2.71; 95% confidence interval (CI) 1.20-6.10], poor adherence to therapy and baseline viral load >100,000 HIV-1 RNA copies/mL were associated with an increased risk of death. CONCLUSION: CD4 percentages below 15% are independent predictors of mortality in AIDS-free patients starting HAART, including those with CD4 counts between 200 and 350 cells/microL. CD4 percentage should be considered for inclusion in guidelines used to determine when to start therapy.

Adult↗
PubMed2004

Outpatient pharmacy care and HIV viral load response among patients on HAART.

Adherence to highly active antiretroviral therapy (HAART) is necessary to achieve long-term effectiveness. The impact of HIV/AIDS-specific pharmacy services on patient adherence and HIV viral suppression is currently not well described. This study aimed to compare the impact of differing levels of HIV-pharmacy care on adherence and time to HIV viral suppression among participants on HAART enrolled in a population-based HIV/AIDS drug treatment programme in British Columbia. We performed a retrospective observational study of 788 treatment-naïve patients who started HAART between August 1997 and July 2000 and were followed until 31 March 2002. The degree of outpatient pharmacy care was defined according to pharmacy dispensing site for the participants' first prescription of HAART: highest at the AIDS-tertiary care hospital outpatient pharmacies, intermediate at HIV/AIDS drug treatment programme funded off-site pharmacies and lowest at family physician's offices. Cox-proportional hazard models examined the independent effect of pharmacy dispensing site on time to two consecutive HIV viral suppressions controlling for other prognostic factors including physicians' experience, age, gender, injection drug use, use of therapy containing NNRTI versus PI, adherence >90%, AIDS diagnosis at baseline, baseline CD4 cell count and HIV viral load. The median time on antiretrovirals was 28 months (IQR=14-38). There were 489 (62.1%) participants who obtained their medications from the AIDS-tertiary care outpatient pharmacies; 98 (12.4%) from off-site pharmacies and 201 (25.5%) from their physicians' offices. The proportion of patients exhibiting >90% adherence to treatment was observed to be higher among patients receiving their HAART at the AIDS-tertiary care pharmacies compared to off-site pharmacies and to physicians' offices (70.4, 59.2 and 55.7%, respectively; p=0.0001). After adjusting for other prognostic factors, subjects who were first dispensed medications from the AIDS-tertiary care pharmacy were 1.42 times (CI: 1.10-1.84) more likely to achieve HIV viral suppression than those getting their medications from off-site pharmacies and physicians' offices. Providing regular outpatient pharmacy care is independently associated with improved HIV viral load response through enhanced adherence to HAART. Standardization of pharmacy practices for dispensing HAART may improve outcomes for patients who receive their HIV medications from other non-tertiary care pharmacy sites.

Adolescent↗
PubMed2002

Outcome, functional recovery and unmet needs following acute stroke. Experience of patient follow up at 6 to 9 months in a newly established stroke service.

OBJECTIVE: To assess outcome at six months post stroke and the unmet needs and adherence to the secondary prevention advice among survivors living at home. SETTING: Stroke Rehabilitation Unit (SRU), Hairmyres Hospital and patients homes. SUBJECTS: Survivors living at home who had been managed in the SRU. RESULTS: Of 572 consecutive patients with confirmed acute stroke, 301 were managed in the SRU and 179 of these were reviewed at home between 6 and 9 months post acute stroke incident. One hundred and thirty seven (76%) survivors at home were living with a carer. Sixty-eight (38%) had had no personal contact with their General Practitioner since discharge from hospital, although 83 (46%) had attended or were attending day hospital. Thirty-two individuals (18%) had resumed smoking. One hundred and forty nine survivors (83%) still required assistance with daily living tasks. One hundred and fifteen patients (64%) required medication advice. One hundred and forty one (79%) had health concerns. Eight subjects had returned to paid employment. Issues raised by survivors included a feeling of being abandoned by the healthcare system, poor access to professional psychological support and a fear of further stroke. CONCLUSION: There is a need for continuing patient education, improved support for stroke survivors and more active involvement of Primary Care Services in the care of stroke patients following hospital discharge.

Activities of Daily Living↗
PubMed2001

Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy.

CONTEXT: Current recommendations for initiation of antiretroviral therapy in patients infected with human immunodeficiency virus type 1 (HIV) are based on CD4 T-lymphocyte cell counts and plasma HIV RNA levels. The relative prognostic value of each marker following initiation of therapy has not been fully characterized. OBJECTIVE: To describe rates of disease progression to death and AIDS or death among patients starting triple-drug antiretroviral therapy, stratified by baseline CD4 cell count and HIV RNA levels. DESIGN, SETTING, AND PARTICIPANTS: Population-based analysis of 1219 antiretroviral therapy-naive HIV-positive men and women aged 18 years or older in British Columbia who initiated triple-drug therapy between August 1, 1996, and September 30, 1999. MAIN OUTCOME MEASURE: Cumulative mortality rates from the initiation of triple-drug antiretroviral therapy to September 30, 2000, determined using various CD4 cell and plasma HIV RNA thresholds. RESULTS: As of September 30, 2000, 82 patients had died of AIDS-related causes, for a crude AIDS-related mortality rate of 6.7%. The product limit estimate (SE) of the cumulative mortality rate at 12 months was 2.9% (0.5%). In univariate analyses, a prior diagnosis of acquired immunodeficiency syndrome (AIDS), CD4 cell count, use of protease inhibitors, and HIV RNA level were associated with mortality. There was no difference in mortality by age or sex. Only CD4 cell count remained statistically significant in the multivariate analysis. After controlling for AIDS, protease inhibitor use, and plasma HIV RNA level at baseline, patients with CD4 cell counts of less than 50/microL were 6.67 (95% confidence interval [CI], 3.61-12.34) times and those with counts of 50/microL to 199/microL were 3.41 (95% CI, 1.93-6.03) times more likely to die than those with counts of at least 200/microL. CONCLUSION: Our data demonstrate uniformly low rates of disease progression to death and AIDS or death among patients starting antiretroviral therapy with CD4 cell counts of at least 200/microL. In our study, disease progression to death and AIDS or death was clustered among patients starting therapy with CD4 cell counts less than 200/microL.

Adult↗
PubMed2001

Multiple drug rescue therapy for HIV-infected individuals with prior virologic failure to multiple regimens.

OBJECTIVES: To characterize the antiviral response and tolerability of a multi-drug rescue therapy (MDRT) among heavily pretreated patients. METHODS: Observational study conducted in a single, university-based tertiary referral clinic. Patients (n = 106) who failed several prior regimens started MDRT including at least five antiretroviral (ARV) drugs between August 1997 and June 1998. The most common starting regimen included three nucleoside reverse transcriptase inhibitors and two protease inhibitors, which was prescribed to 45 (42.5%) patients. Virologic response was defined as plasma viral load < 400 copies/ml on at least two consecutive visits. RESULTS: Median prior ARV exposure was seven drugs over a median time of 43 months. Fifty-nine percent of the patients were phenotypically (VIRCO Antivirogram) resistant at baseline to seven or more ARV. Median plasma viral load change following initiation of MDRT was -1.04 log10 copies/ml over a median of 15 months. Using intention-to-treat analysis 40% of patients had plasma viral load values < 400 copies/ml between weeks 47 and 57 of follow-up. Twenty-six patients (25%) experienced severe laboratory abnormalities or subjective adverse drug effects and six of these participants discontinued therapy. CONCLUSION: MDRT induced a substantial antiviral response in this heavily pretreated group of patients despite extensive phenotypic resistance at baseline. Adverse effects were frequent but generally manageable. Our data suggest that relying exclusively on historical, clinical and laboratory evidence may not be sufficient to rule out a possible antiviral response when multiple drug regimens are used in this heavily pretreated patient population.

Adult↗
PubMed2001

Quantitative polymerase chain reaction for the rapid prenatal diagnosis of homozygous alpha-thalassaemia (Hb Barts hydrops fetalis).

A quantitative polymerase chain reaction (Q-PCR) method based on the TaqMan technology has been devised for the prenatal diagnosis of homozygous alpha*-thalassaemia (south-east Asian type deletion). Primers and TaqMan probes were designed to specifically amplify an alpha*-thal chromosomal fragment or a normal alpha-chromosomal fragment. Variations in input target DNA in individual sample wells were normalized by the simultaneous amplification of a beta-actin gene fragment and results expressed as a ratio to that of beta-actin. There was no overlap of the data between the homozygous alpha*-thal, alpha*-thal and normal subjects. Up to 5% maternal DNA (alpha*-thal) contamination did not affect the specificity of the result. In 31 prenatal diagnoses, the result using Q-PCR compared favourably with the gold standard of Southern hybridization of alpha-genes.

Actins↗
PubMed2000

Full suppression of viral load is needed to achieve an optimal CD4 cell count response among patients on triple drug antiretroviral therapy.

OBJECTIVE: To characterize the relationship between plasma viral load (pVL) suppression and triple drug antiretroviral therapy, and the accompanying changes in CD4 cell counts. METHOD: Retrospective study of 465 participants in a HIV/AIDS Treatment Program who initiated triple drug therapy between August 1996 and May 1998. Participants were divided into three groups according to their pVL response: (i) non-responders (NR; n = 112) exhibited pVL persistently > 500 copies/ml over the study period; (ii) partial responders (PR; n = 100) achieved a pVL < 100 copies/ml at least once and subsequently rebounded to > 500 copies/ml; and (iii) full responders (FR; n = 253) achieved a pVL < 500 copies/ml and sustained this level for the remainder of the study period. For each group, the accompanying changes in absolute and fractional CD4 cell counts were evaluated. RESULTS: The median net change in pVL per person from baseline to the end of the observation period was -0.37, -2.27, and -2.56 log10 copies/ml for NR, PR and FR, respectively. During weeks 68-83, the median CD4 cell count (x 10(6) cells/l) was 150 [interquartile range (IQR) 90-370], 380 (IQR 300-480) and 525 (IQR 305-705) for NR, PR and FR, respectively. Median changes in CD4 cells (x 10(6) cells/l) were -20 (IQR -90 to 40), 150 (IQR 30-250) and 240 (IQR 110-365) for NR, PR, and FR, respectively. The net percentage change in CD4 cells per person was 0% (IQR -34-31), 54% (IQR 6-160), and 83% (IQR 39-173) for NR, PR, and FR, respectively. By weeks 68-83, the median fractional CD4 cells was 0.16 (IQR 0.07-0.22), 0.22 (IQR 0.15-0.28), and 0.26 (IQR 0.17-0.34) for NR, PR and FR respectively. CONCLUSIONS: An optimal CD4 cell count response appears to be coupled with continued pVL suppression. Our data indicate that maximal suppression of viral replication should remain the primary goal of therapy.

Adult↗
PubMed2000

Depressive symptoms decline among persons on HIV protease inhibitors.

OBJECTIVE: To ascertain whether initiation of protease inhibitors was associated with a change in depressive symptoms among persons infected with HIV. METHODS: Study subjects included men and women who were enrolled in the HIV/AIDS Drug Treatment Program and who had completed an annual participant survey before and after initiating triple combination therapy with a protease inhibitor. Depressive symptoms were assessed using the Centre for Epidemiologic Studies-Depression scale (CES-D). Statistical analyses to determine the change in CES-D total and subscale scores before and after protease inhibitor use were conducted using parametric and multivariate methods. RESULTS: Our analysis was restricted to 453 participants. Of these 234 (52%) were depressed at baseline (CES-D score > or = 16). Compared with nondepressed participants, depressed participants were slightly younger (p = .048), less likely to be employed (p < .001) and more likely to have an annual income less than $10,000 per annum (p < .001). After adjusting for CD4 count, employment status, income, age, and CES-D total or subscale score at baseline, we found a significant improvement in total scale score (p = .001) and depressive mood (p = .002), positive affects (p = .005), and somatic symptoms (p = .011) subscale scores at follow-up. There was no significant change in the interpersonal relations score over the study period. CONCLUSION: Our findings indicate that in addition to conferring impressive clinical benefits, protease inhibitor use is associated with a significant improvement in HIV-positive individuals' mental health.

Adult↗
PubMed2000

Determinants of hospital admission among HIV-positive people in British Columbia.

BACKGROUND: This study was initiated to evaluate the demographic and clinical determinants of admission to hospital among HIV-positive men and women receiving antiretroviral therapy in British Columbia. METHODS: The analysis was restricted to participants enrolled in the HIV/AIDS Drug Treatment Program between September 1992 and March 1997 who had completed an annual participant survey, had a viral load determination and had signed a consent form allowing electronic access to their inpatient hospital records. A record linkage was conducted with the BC Ministry of Health to obtain all records of hospital admissions from April 1991 to March 1997. Statistical analyses were carried out using parametric and nonparametric methods and multivariate logistic analyses. RESULTS: The study sample comprised 947 participants (859 men, 88 women). Of these, 165 (17%) were admitted to hospital during the study period from May 1, 1996, to Mar. 31, 1997. The median number of admissions was 1 (interquartile range [IQR] 1-2 admissions), and the median length of stay per admission was 3 days (IQR 1-8 days). Admission to hospital was associated with being unemployed (82% of those admitted v. 58% of those not admitted), being an injection drug user (24% v. 17%), reporting a fair or poor health status (46% v. 29%) and having a physician experienced in the management of HIV/AIDS (31% v. 24%). Examination of clinical determinants demonstrated that hospital admission was associated with a previous admission (72% v. 46%), a high viral load (median 74,000 v. 14,000 HIV-1 RNA copies/mL), a low CD4 count (median 0.16 v. 0.27 x 10(9)/L) and an AIDS diagnosis (44% v. 24%). Multivariate logistic regression analysis revealed that being admitted to hospital was independently associated with being unemployed (odds ratio [OR] 2.64, 95% confidence interval [CI] 1.66-4.20), having been previously admitted to hospital (OR 2.30, 95% CI 1.53-3.46), having a high viral load at baseline (OR 1.45, 95% CI 1.16-1.80), being an injection drug user (OR 1.63, 95% CI 1.02-2.62) and having an experienced physician (OR 1.98, 95% CI 1.29-3.03). INTERPRETATION: Hospital admission among participants in this study was found to be associated with marginalization and poor health status.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Determinants of geographic mobility among participants in a population-based HIV/AIDS drug treatment program.

This study was undertaken to determine the geographic distribution and patterns of migration of persons with HIV in British Columbia. Our analysis was restricted to all HIV-positive men and women aged 18 years and over who had completed a participant survey and were enrolled in the HIV/AIDS Drug Treatment Program between September 1992 and September 1997. Patterns of migration were determined by examining participants whose postal code changed between July 1995 and September 1997. Statistical analysis were carried out using both parametric and non-parametric methodologies. Stepwise logistic regression was used to determine baseline predictors of migration. The final multivariate model revealed that residing in a census subdivision with a population less than 100,000, being heterosexual, acquiring HIV through intravenous drug use, and the absence of AIDS at baseline were all independently associated with moving census subdivisions during the period of observation. In summary, our analyses demonstrate the need for the continued study of the evolving geography and migration patterns of persons with HIV.

Adult↗
PubMed2000

Health related quality of life among persons with HIV after the use of protease inhibitors.

OBJECTIVE: This study was conducted to determine the effect of the use of HIV protease inhibitors on the quality of life among persons infected with HIV. METHODS: Subjects were participants in the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program who had completed two annual participant surveys, one prior to initiating therapy with a protease inhibitor and one after. Quality of life was measured using the Medical Outcomes Study Short Form Health Survey (MOS-SF). Statistical analyses were conducted using parametric and multivariate methods. RESULTS: Our analysis was based on 179 HIV-positive individuals. Compared to quality of life at baseline, we found no statistically significant changes in the health perception, pain, physical, role and social functioning MOS-SF subscale scores at follow-up. The measure of mental health was the only component to decline significantly over time. Subanalyses found significant increases in the measures of health perception (p = 0.004), physical (p = 0.037), role (p < 0.001) and social functioning (p = 0.053) for individuals with a low baseline quality of life. For those with a higher quality of life before starting a protease inhibitor containing regimen we observed a significant decline in the subscales of mental health (p = 0.001), physical (p = 0.007), role (p = 0.021) and social functioning (p = 0.003) over the study period. CONCLUSIONS: Our findings indicate that despite strict dosage requirements and adverse side effects associated with protease inhibitor use patients are on the whole maintaining their quality of life after starting on a protease inhibitor containing regimen. Continued follow-up of this cohort will be required to determine the long term implications of these observations.

Adult↗
PubMed2000

Single nucleotide polymorphisms of the factor IX gene for linkage analysis in the southern Chinese population.

Carrier detection and prenatal testing for haemophilia B in Oriental populations have been hampered by the lack of informative markers within the factor IX (FIX) gene. We detected a T/C nucleotide variation at nucleotide 32770 in the poly-A region of the FIX gene in the mother of a haemophilia B child. Analysis of 139 unrelated alleles revealed a heterozygosity rate of 0.193, thus offering an additional marker for linkage analysis. Together with two other polymorphic sites (5' MseI and 3' HhaI) found in Chinese and Thai populations, these polymorphisms were useful in 66% of the families studied.

China↗
PubMed2000

The impact of zidovudine on dementia-free survival in a population of HIV-positive men and women on antiretroviral therapy.

Our objective was to characterize the effect of zidovudine therapy on AIDS dementia complex (dementia) free survival among HIV-infected men and women in a population-based cohort with free access to antiretroviral therapy in the province of British Columbia. Time to diagnosis of dementia among individuals was examined on the basis of zidovudine duration, CD4+ cell count at first treatment, gender, and transmission group [men having sex with men (MSM), intravenous drug users (IDU), heterosexuals]. We restricted the analysis to subjects with CD4+ cells counts within 12 months prior to treatment start date. Among 641 participants eligible for analysis, median duration of follow-up was 3.6 years, under which 86 (9.3%) events of dementia occurred. Participants were less likely to develop dementia with: increased zidovudine exposure (OR=0.26, 95% CI: 0.14-0.49), at least 260 CD4+ cells/mm3 (median) (OR=0.52, 95% CI: 0.34-0.78), and MSM risk group (OR=0.57, 95% CI: 0.35-0.94). Those infected through heterosexual contact had an increased risk (RR=2.04, 95% CI: 1.02-4.07). Using Cox's proportional hazards model, controlling for CD4+ cell count at treatment start date, independent predictors of dementia-free survival were: duration of zidovudine (OR=0.28, 95% CI: 0.15-0.52) and MSM transmission group (OR=0.61, 95% CI: 0.37-1.00). In this observational treatment cohort, factors associated with dementia-free survival include duration of zidovudine (AZT) therapy and MSM transmission group. It is not clear from these data whether the AZT protective effect is exclusive to this agent or whether other therapies might offer a similar protective effect.

AIDS Dementia Complex↗
PubMed2000

The cost effectiveness of antiretroviral regimens for the treatment of HIV/AIDS.

OBJECTIVE: To estimate survival, the number of life-years gained and cost effectiveness of antiretroviral therapy (ART) regimens, denoted as ERA-I [zidovudine + (didanosine or zalcitabine)]; ERA-II [stavudine + (didanosine or zalcitabine) or lamivudine + (zidovudine or didanosine or zalcitabine or stavudine)]; and ERA-III [2 nucleoside reverse transcriptase inhibitors + (1 protease inhibitor or 1 non-nucleoside reverse transcriptase inhibitor)]. DESIGN: Modelling of drug cost, cost of opportunistic diseases and survival of HIV positive men and women in the province of British Columbia who were first prescribed any ART between October 1992 and June 1996. A 'reference cohort' was modelled upon individuals in a longitudinal cohort of homosexual men followed since 1982. PERSPECTIVE AND SETTING: Third-party payer perspective in British Columbia, Canada. PATIENTS: All HIV-positive men and women aged > or =18 years with CD4+ counts < or =350 cells/microL who were enrolled in the province-wide drug treatment programme. MAIN OUTCOME MEASURES: Annual costs, survival and cost-effectiveness ratios of successive ART regimens. RESULTS: Total costs [1997 Canadian dollars ($Can)] at 12 months under ERA-I, -II and -III were $Can4897, $Can6620 and $Can 11 914, respectively. Survival at 12 months under ERA-I, -II and -III was 89.6%, 91.0% and 97.6%, respectively. The annual incremental cost (estimated by the total incremental cost at 12 months) between ERA-II and ERA-I was $Can1723. The incremental cost-effectiveness ratios between ERA-III and ERA-I, and between ERA-III and ERA-II were $Can58 806 and $Can46 971 per life-year gained, respectively. CONCLUSION: We found the cost effectiveness of ERA-III ART regimens well within the range of currently funded therapies for the treatment of other chronic diseases.

Acquired Immunodeficiency Syndrome↗