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Biomedical subjects

Bernard L Nahlen

Publications and source records attributed to Bernard L Nahlen.

At least 19 recordsLinked to original sources

The burden of malaria mortality among African children in the year 2000.

BACKGROUND: Although malaria is a leading cause of child deaths, few well-documented estimates of its direct and indirect burden exist. Our objective was to estimate the number of deaths directly attributable to malaria among children <5 years old in sub-Saharan Africa for the year 2000. METHODS: We divided the population into six sub-populations and, using results of studies identified in a literature review, estimated a malaria mortality rate for each sub-population. Malaria deaths were estimated by multiplying each sub-population by its corresponding rate. Sensitivity analyses were performed to assess the impact of varying key assumptions. RESULTS: The literature review identified 31 studies from 14 countries in middle Africa and 17 studies and reports from four countries in southern Africa. In 2000, we estimated that approximately 100 million children lived in areas where malaria transmission occurs and that 803 620 (precision estimate: 705 821-901 418) children died from the direct effects of malaria. For all of sub-Saharan Africa, including populations not exposed to malaria, malaria accounted for 18.0% (precision estimate: 15.8-20.2%) of child deaths. These estimates were sensitive to extreme assumptions about the causes of deaths with no known cause. CONCLUSIONS: These estimates, based on the best available data and methods, clearly demonstrate malaria's enormous mortality burden. We emphasize that these estimates are an approximation with many limitations and that the estimates do not account for malaria's large indirect burden. We describe information needs that, if filled, might improve the validity of future estimates.

Africa↗

Evaluation of various methods of maternal placental blood collection for immunology studies.

The collection of maternal placental intervillous blood (IVB), without contamination of fetal blood and with an accurate mononuclear cell profile, is essential for immunological studies of placental malaria and other infectious diseases of the placenta. We have compared five documented methods of IVB collection: perfusion, incision, biopsy, tissue grinding, and puncture (prick) for fetal blood contamination and mononuclear cell profiles using flow cytometry. Twenty-five placentas were obtained from Plasmodium falciparum and human immunodeficiency virus-negative primigravid and secundigravid women delivering at Nyanza Provincial Hospital in Kisumu, western Kenya. Each of the five methods was performed on the same placenta. Fetal red blood cell contamination was significantly lower for the prick and perfusion methods (4.1% and 8.3%, respectively) than for incision (59.5%), biopsy (42.6%), and tissue grinding (19.9%). Significant variation was noted among the five methods in the percentages of monocytes, total T cells, CD4+ and CD8+ T cells, B cells, and NK cells. Further, a pairwise comparison of prick and perfusion, the two methods with low fetal blood contamination, showed that they were not different for fetal red blood cell contamination levels; however, prick yielded significantly higher percentages of CD4 T cells and CD4 memory T cells than perfusion. Collection by prick was determined to be the best method of intervillous blood collection for immunology studies, and perfusion represented the next best method of choice due to high sample volume yield. Overall, in considering the advantages/disadvantages of the two methods with low fetal cell contamination, we conclude that a combination of prick and perfusion is most suitable for immunology studies.

B-Lymphocytes↗

Malaria risk: estimating clinical episodes of malaria.

Estimates of the disease burden caused by malaria are crucial for informing malaria control programmes. Snow and colleagues claim that their estimate of 515 million cases of malaria caused by Plasmodium falciparum globally is up to 50% higher than that reported by the World Health Organization (WHO), and 200% higher for areas outside Africa. However, this comparison refers to the WHO's estimates from 1990 and 1998, and not to the range of 300 million to 500 million that the WHO has used since 2000 (ref. 2). Both groups agree that the burden of malaria disease outside Africa, especially in South Asia, is greater than was estimated in the 1990s.

Animals↗

Relationship of measles vaccination with anaemia and malaria in western Kenya.

OBJECTIVE: Mild viral illness, including that following immunization with live attenuated measles virus (LAMV), has been associated with transient decreases in haemoglobin (Hb) and cellular immune response that may persist for several weeks. In areas of intense malaria transmission, such as western Kenya, infants experience a progressive drop in Hb until age 9-10 months and one-third may have Hb < 8 g/dl. These children may be at risk of developing severe anaemia with further haematological insult. The objective of this paper was to determine if immunization with LAMV was associated with increased risk of transient anaemia and malaria infection. METHODS: Data from previous cross-sectional surveys (n = 5970) and one cohort study (n = 546) conducted among pre-school children were analyzed retrospectively. RESULTS: Measles vaccination coverage between 12 and 23 months of age ranged from 44.8% to 62.7%. Hb concentrations in children aged 6-23 months with documented measles immunization within the previous 14 or 30 days (n = 103) were similar to those with no history of measles immunization in the previous 90 days (n = 996); mean differences [95% confidence interval (CI)] by 30 days were: in cross-sectional surveys, -0.49 g/dl (-1.12, 0.14); in the cohort study, -0.032 g/dl (-0.52, 0.46). Similarly, the risk of malaria parasitemia or severe to moderate anaemia did not differ. CONCLUSION: These data do not suggest that the transient decrease in Hb and cellular immune response after immunization with LAMV results in clinically significant changes in the risk of subsequent severe to moderate anaemia or malaria in young children living in malaria-endemic regions.

Anemia↗

Placental malaria diminishes development of antibody responses to Plasmodium falciparum epitopes in infants residing in an area of western Kenya where P. falciparum is endemic.

To determine the effect of placental malaria (PM) infection on the development of antibody responses to malaria in infants, we measured immunoglobulin G levels to seven different Plasmodium falciparum epitopes by using plasma samples collected at monthly intervals from infants born to mothers with and without PM. Overall, PM was associated with diminished antibody levels to all of the epitopes tested, especially with infants aged >or=4 to 12 months, and the difference was statistically significant for four of the seven epitopes (P<0.0035). These findings suggest that PM can negatively influence the development of immune responses to malaria in infants.

Animals↗

Immunohistological characterization of macrophage migration inhibitory factor expression in Plasmodium falciparum-infected placentas.

Previously, we have shown that macrophage migration inhibitory factor (MIF) was highly elevated in the placental intervillous blood (IVB) of Plasmodium falciparum-infected women. Here, we compared the expression of MIF in placental tissues obtained from P. falciparum-infected and -uninfected women. Immunoperoxidase staining showed a consistent pattern of MIF expression in syncytiotrophoblasts, extravillous trophoblasts, IVB mononuclear cells, and amniotic epithelial cells, irrespective of their malaria infection status. Cytotrophoblast, villous stroma, and Hofbauer cells showed focal staining. Only amniotic epithelial and IVB mononuclear cells from P. falciparum-infected placentas exhibited significantly higher level of MIF expression than uninfected placentas. Stimulation of syncytilized human trophoblast BeWo cells with P. falciparum-infected erythrocytes that were selected to bind these cells resulted in significant increases in MIF secretion, whereas control erythrocytes, lipopolysaccharides, and synthetic beta-hematin had minimal effect. These findings suggest that placental malaria modulates MIF expression in different placental compartments.

Animals↗

Malaria attributable to the HIV-1 epidemic, sub-Saharan Africa.

We assessed the impact of HIV-1 on malaria in the sub-Saharan African population. Relative risks for malaria in HIV-infected persons, derived from literature review, were applied to the HIV-infected population in each country, by age group, stratum of CD4 cell count, and urban versus rural residence. Distributions of CD4 counts among HIV-infected persons were modeled assuming a linear decline in CD4 after seroconversion. Averaged across 41 countries, the impact of HIV-1 was limited (although quantitatively uncertain) because of the different geographic distributions and contrasting age patterns of the 2 diseases. However, in Botswana, Zimbabwe, Swaziland, South Africa, and Namibia, the incidence of clinical malaria increased by < or =28% (95% confidence interval [CI] 14%-47%) and death increased by < or =114% (95% CI 37%-188%). These effects were due to high HIV-1 prevalence in rural areas and the locally unstable nature of malaria transmission that results in a high proportion of adult cases.

AIDS-Related Opportunistic Infections↗

Factors associated with hemoglobin concentrations in pre-school children in Western Kenya: cross-sectional studies.

In sub-Saharan Africa, the etiology of anemia in early childhood is complex and multifactorial. Three community-based cross-sectional surveys were used to determine the prevalence and severity of anemia. Regression methods were used to compare mean hemoglobin (Hb) concentrations across covariate levels to identify children at risk of low Hb levels in an area with intense malaria transmission. In a random sample of 2,774 children < 36 months old, the prevalence of anemia (Hb < 11g/dL) was 76.1% and 71%, respectively, in villages without and with insecticide-treated bed nets (ITNs); severe-moderate anemia (Hb < 7 g/dL) was observed in 11% (non-ITN) and 8.3% (ITN). The prevalence of anemia, high-density malaria parasitemia (21.7%), microcytosis (34.9%), underweight (21.9%), and diarrhea (54.8%) increased rapidly from age three months onwards and remained high until 35 months of age. Multivariate analyses showed that family size, history of fever, pale body, general body weakness, diarrhea, soil-eating, concurrent fever, stunting, and malaria parasitemia were associated with mean Hb levels. Prevention of severe anemia should start early in infancy and include a combination of micronutrient supplementation, malaria control, and possibly interventions against diarrheal illness.

Anemia↗

Effect of sustained insecticide-treated bed net use on all-cause child mortality in an area of intense perennial malaria transmission in western Kenya.

We present results from a study conducted in western Kenya where all-cause child mortality was assessed among a population with high levels of sustained insecticide-treated bed net (ITN) use for up to six years. Although ITNs were associated with significant reductions in all-cause mortality among infants 1-11 months old, there was no difference in the rate of all-cause mortality among children 12-59 months old with ITNs for 2-4 years, compared historically with children from villages without ITNs, after controlling for seasonality and underlying child mortality across calendar years (adjusted hazard ratio [AHR] = 0.91, 95% confidence interval [CI] = 0.77-1.07). There was no increase in the proportion of child deaths at older ages (12-59 months old) of all child deaths within villages with ITNs for 5-6 years (48.1%) compared historically with villages without ITNs (47.9%), after controlling for seasonality (AHR = 1.03, P = 0.834). We find no evidence that sustained ITN use increased the risk of mortality in older children in this area of intense perennial malaria transmission.

Animals↗

Malaria and nutritional status among pre-school children: results from cross-sectional surveys in western Kenya.

Protein-energy malnutrition (PEM) affects millions of children in the developing world. The relationship between malaria and PEM is controversial. The goal of this study was to evaluate whether undernutrition is associated with increased or decreased malaria attributable morbidity. Three cross-sectional surveys were conducted using insecticide-treated bed nets (ITNs) among children aged 0-36 months living in an area with intense malaria transmission. Data were collected on nutritional status, recent history of clinical illness, socioeconomic status, current malaria infection status, and hemoglobin. In multivariate models, stunted children had more malaria parasitemia (odds ratio [OR] 1.98, P < 0.0001), high-density parasitemia (OR 1.84; P < 0.0001), clinical malaria (OR 1.77; P < 0.06), and severe malarial anemia (OR 2.65; P < 0.0001) than nonstunted children. The association was evident in children with mild-to-moderate (-3 < height-for-age Z-score [HAZ] < -2) and severe stunting (HAZ < -3). The cross-sectional nature of the study limits the interpretation of causality, but the data provide further observational support that the presence of undernutrition, in particular chronic undernutrition, places children at higher, not lower risk of malaria-related morbidity.

Bedding and Linens↗

Polymorphism of Fc receptor IIa for immunoglobulin G is associated with placental malaria in HIV-1-positive women in western Kenya.

BACKGROUND: Genetic polymorphism of the Fc receptor IIa for immunoglobulin (Ig) G (Fc gamma RIIa) determines IgG subclass binding. Previous studies have shown that individuals with the IgG1/3-binding Fc gamma RIIa-Arg/Arg131 genotype are relatively protected against high-density malaria, whereas individuals with the IgG2-binding Fc gamma RIIa-His/His131 genotype are at increased risk for developing cerebral malaria. The present study was undertaken to examine the relationship between Fc gamma RIIa polymorphism and placental malaria (PM) in pregnant women of known human immunodeficiency virus (HIV)-1 status. METHODS: Fc gamma RIIa genotype was determined in 903 pregnant women who had participated in a study designed to assess the effect that PM has on vertical transmission of HIV-1. Fc gamma RIIa polymorphism was assessed in relation to PM. RESULTS: Among HIV-negative women, there was no difference in the distribution of the Fc gamma RIIa polymorphism by PM status. However, among HIV-positive women, the frequency of the Fc gamma RIIa-His/His131 genotype was significantly higher in women with PM than in women without PM (31% vs. 22%, respectively [P=.032]). In multivariate analysis, the adjusted odds ratio for PM in HIV-positive women with the Fc gamma RIIa-His/His131 genotype versus women in the Fc gamma RIIa-His/Arg131 reference group was 1.72 (95% confidence interval, 1.11-2.69 [P=.016]). CONCLUSIONS: The present study suggests that the IgG2-binding Fc gamma RIIa-His/His131 genotype is associated with enhanced susceptibility to PM in HIV-positive women but not in HIV-negative women.

Alleles↗

Sustainability of reductions in malaria transmission and infant mortality in western Kenya with use of insecticide-treated bednets: 4 to 6 years of follow-up.

CONTEXT: Insecticide-treated bednets reduce malaria transmission and child morbidity and mortality in short-term trials, but this impact may not be sustainable. Previous investigators have suggested that bednet use might paradoxically increase mortality in older children through delayed acquisition of immunity to malaria. OBJECTIVES: To determine whether adherence to and public health benefits of insecticide-treated bednets can be sustained over time and whether bednet use during infancy increases all-cause mortality rates in older children in an area of intense perennial malaria transmission. DESIGN AND SETTING: A community randomized controlled trial in western Kenya (phase 1: January 1997 to February 2000) followed by continued surveillance of adherence, entomologic parameters, morbidity indicators, and all-cause mortality (phase 2: April 1999 to February 2002), and extended demographic monitoring (January to December 2002). PARTICIPANTS: A total of 130,000 residents of 221 villages in Asembo and Gem were randomized to receive insecticide-treated bednets at the start of phase 1 (111 villages) or phase 2 (110 villages). MAIN OUTCOME MEASURES: Proportion of children younger than 5 years using insecticide-treated bednets, mean number of Anopheles mosquitoes per house, and all-cause mortality rates. RESULTS: Adherence to bednet use in children younger than 5 years increased from 65.9% in phase 1 to 82.5% in phase 2 (P<.001). After 3 to 4 years of bednet use, the mean number of Anopheles mosquitoes per house in the study area was 77% lower than in a neighboring area without bednets (risk ratio, 0.23; 95% confidence interval [CI], 0.15-0.35). All-cause mortality rates in infants aged 1 to 11 months were significantly reduced in intervention villages during phase 1 (hazard ratio [HR], 0.78; 95% CI, 0.67-0.90); low rates were maintained during phase 2. Mortality rates did not differ during 2002 (after up to 6 years of bednet use) between children from former intervention and former control households born during phase 1 (HR, 1.01; 95% CI, 0.86-1.19). CONCLUSIONS: The public health benefits of insecticide-treated bednets were sustained for up to 6 years. There is no evidence that bednet use from birth increases all-cause mortality in older children in an area of intense perennial transmission of malaria.

Animals↗

Polymorphism of Fc receptor IIa for IgG in infants is associated with susceptibility to perinatal HIV-1 infection.

OBJECTIVE: To evaluate the effect of polymorphism of the Fc gamma receptor IIa, which is associated with differential human IgG subclass binding, on perinatal HIV-1 transmission. METHODS: Fc gamma RIIa genotype was tested in 448 HIV-seropositive mothers and their infants from a cohort study designed to assess the effect of placental malaria on HIV vertical transmission conducted from 1996 to 2001 in western Kenya. Fc gamma RIIa polymorphism was analyzed for associations with susceptibility to perinatal HIV infection and all-cause child mortality in HIV-positive children. RESULTS: Overall, 20% of infants were perinatally infected with HIV. There was no statistically significant association between maternal genotype and perinatal HIV-1 transmission. However, frequency of the infant Fc gamma RIIa His/His131 genotype was higher in HIV-positive compared with HIV-negative infants (35% and 21%, respectively), whereas the distribution was reversed (15% and 28%, respectively) for infants with the Fc gamma RIIa Arg/Arg131 genotype. Multivariate logistic regression controlling for maternal and infant confounding factors demonstrated that the odds of perinatal HIV infection in infants with the Fc gamma RIIa His/His131 versus Fc gamma RIIa His/Arg131 genotypes were significantly higher (adjusted odds ratio, 2.22; 95% confidence interval, 1.23-4.02; P = 0.009). There was no evidence for an association between HIV-positive child all-cause mortality and Fc gamma RIIa genotype. CONCLUSIONS: This study provides the first evidence that the infant Fc gamma RIIa His/His131 genotype is associated with susceptibility to perinatal HIV-1 transmission and further suggests that there is a dose-response relationship for the effect of the Fc gamma RIIa His131 gene on transmission.

Adult↗

Pregnancy interval and delivery outcome among HIV-seropositive and HIV-seronegative women in Kisumu, Kenya.

OBJECTIVE: A short pregnancy interval (PI) has been associated with increased child mortality, but mechanisms are unclear. We studied factors associated with PI and the effect of PI on birthweight and haemoglobin. METHODS: Information was analysed from 2218 multigravidae who were recruited at the prenatal clinic (1758) or in the labour ward (460) of the Provincial Hospital in Kisumu between June 1996 and July 2000 for a study to assess the interaction between placental malaria and vertical HIV transmission. RESULTS: The HIV prevalence was 28.9%. HIV seropositivity, older age, being unmarried, and <8 years of education were associated with a prolonged PI; among all women, a stillbirth, abortion, or death of a liveborn child as outcome of the previous pregnancy, and death of a child other than the last born among HIV-seronegative women, were associated with a shortened PI. No significant effect of short PI (an interval <24 months) on low birth weight (LBW), prematurity, small-for-gestational-age infants or maternal anaemia was evident. An abortion, stillbirth, or death of a liveborn child as outcome of the previous pregnancy was associated at the present delivery with LBW among HIV-seronegative women [adjusted odds ratio (AOR) 3.33, 95% confidence interval (CI) 1.63-6.81], and a low haemoglobin (<11 g/dl) among HIV-seropositive women (AOR 2.01, 95% CI 1.05-4.03 in the third trimester). CONCLUSION: Public health efforts to ensure 'adequate' birth spacing may run contrary to family planning decisions to replace a deceased child and may be spent on prenatal issues like prevention of anaemia, and vertical HIV transmission.

Abortion, Spontaneous↗

Genetic diversity and high proportion of intersubtype recombinants among HIV type 1-infected pregnant women in Kisumu, western Kenya.

The high genetic diversity of HIV-1 continues to complicate effective vaccine development. To better understand the extent of genetic diversity, intersubtype recombinants and their relative contribution to the HIV epidemic in Kenya, we undertook a detailed molecular epidemiological investigation on HIV-1-infected women attending an antenatal clinic in Kisumu, Kenya. Analysis of gag-p24 region from 460 specimens indicated that 310 (67.4%) were A, 94 (20.4%) were D, 28 (6.1%) were C, 9 (2.0%) were A2, 8 (1.7%) were G, and 11 (2.4%) were unclassifiable. Analysis of the env -gp41 region revealed that 326 (70.9%) were A, 85 (18.5%) D, 26 (5.7%) C, 9 (2.0%) each of A2 and G, 4(0.9%) unclassifiable, and 1 (0.2%) CRF02_AG. Parallel analyses of the gag-p24 and env-gp41 regions indicated that 344 (74.8%) were concordant subtypes, while the remaining 116 (25.2%) were discordant subtypes. The most common discordant subtypes were D/A (40, 8.7%), A/D (27, 5.9%), C/A (11, 2.4%), and A/C (8, 1.7%). Further analysis of a 2.1-kb fragment spanning the gag-pol region from 38 selected specimens revealed that 19 were intersubtype recombinants and majority of them were unique recombinant forms. Distribution of concordant and discordant subtypes remained fairly stable over the 4-year period (1996-2000) studied. Comparison of amino acid sequences of gag-p24 and env-gp41 regions with the subtype A consensus sequence or Kenyan candidate vaccine antigen (HIVA) revealed minor variations in the immunodominant epitopes. These data provide further evidence of high genetic diversity, with subtype A as the predominant subtype and a high proportion of intersubtype recombinants in Kenya.

AIDS Serodiagnosis↗

Implementation of intermittent preventive treatment with sulphadoxine-pyrimethamine for control of malaria in pregnancy in Kisumu, western Kenya.

OBJECTIVE: In 1998, the Kenyan Ministry of Health introduced intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine (SP), one treatment dose in the second trimester (16-27 weeks) and one treatment dose between 28 and 34 weeks of gestational age, for the control of malaria in pregnancy. We evaluated the coverage and determinants of receipt of IPT after its introduction in the Provincial Hospital in Kisumu, western Kenya. METHODS: Information on the use of IPT in pregnancy was collected from women who attended the antenatal clinic (ANC) and delivered in the same hospital. In exit interviews, we assessed patterns of IPT use in the ANC. RESULTS: Of 1498 women who delivered between June 1999 and June 2000, 23.7%, 43.4% and 32.9% received > or =2, 1 or no dose of SP, respectively. Late first ANC attendance was the most important factor contributing to incomplete IPT; 45% of the women started attending ANC in the third trimester. More women received at least one tetanus toxoid immunization than at least one dose of IPT (94%vs. 67%, P < 0.05). In exit interviews, 74% correctly associated IPT with treatment of malaria; however, knowledge on the need for the second dose was poor. Three per cent of the administrations were given despite contraindications. The agreement between gestational age by date of last menstrual period and by palpation was low (kappa = 0.1). CONCLUSIONS: Education of pregnant women and ANC staff to increase earlier attendance for ANC has the potential to substantially increase the proportion of women receiving two doses of IPT with SP.

Adult↗

Impact of malaria control on childhood anaemia in Africa -- a quantitative review.

OBJECTIVE: To review the impact of malaria control on haemoglobin (Hb) distributions and anaemia prevalences in children under 5 in malaria-endemic Africa. METHODS: Literature review of community-based studies of insecticide-treated bednets, antimalarial chemoprophylaxis and insecticide residual spraying that reported the impact on childhood anaemia. Anaemia outcomes were standardized by conversion of packed cell volumes into Hb values assuming a fixed threefold difference, and by estimation of anaemia prevalences from mean Hb values by applying normal distributions. Determinants of impact were assessed in multivariate analysis. RESULTS: Across 29 studies, malaria control increased Hb among children by, on average, 0.76 g/dl [95% confidence interval (CI): 0.61-0.91], from a mean baseline level of 10.5 g/dl, after a mean of 1-2 years of intervention. This response corresponded to a relative risk for Hb < 11 g/dl of 0.73 (95% CI: 0.64-0.81) and for Hb < 8 g/dl of 0.40 (95% CI: 0.25-0.55). The anaemia response was positively correlated with the impact on parasitaemia (P = 0.005, P = 0.008 and P = 0.01 for the three outcome measures), but no relationship with the type or duration of malaria intervention was apparent. Impact on the prevalence of Hb < 11 g/dl was larger in sites with a higher baseline parasite prevalence. Although no age pattern in impact was apparent across the studies, some individual trials found larger impacts on anaemia in children aged 6-35 months than in older children. CONCLUSION: In malaria-endemic Africa, malaria control reduces childhood anaemia. Childhood anaemia may be a useful indicator of the burden of malaria and of the progress in malaria control.

Africa↗

Hemozoin differentially regulates proinflammatory cytokine production in human immunodeficiency virus-seropositive and -seronegative women with placental malaria.

Pregnant women are at an increased risk for malarial infection. Plasmodium falciparum accumulates in the placenta and is associated with dysregulated immune function and poor birth outcomes. Malarial pigment (hemozoin) also accumulates in the placenta and may modulate local immune function. In this study, the impact of hemozoin on cytokine production by intervillous blood mononuclear cells from malaria-infected placentas was investigated. There was a dose-dependent, suppressive effect of hemozoin on production of gamma interferon (IFN-gamma), with less of an effect on tumor necrosis factor alpha (TNF-alpha) and interleukin-10, in human immunodeficiency virus-seronegative (HIV(-)) women. In contrast, IFN-gamma and TNF-alpha production tended to increase in HIV-seropositive women with increasing hemozoin levels. Production patterns of cytokines, especially IFN-gamma in HIV(-) women, followed different trends as a function of parasite density and hemozoin level. The findings suggest that the influences of hemozoin accumulation and high-density parasitemia on placental cytokine production are not equivalent and may involve different mechanisms, all of which may operate differently in the context of HIV infection. Cytokine production dysregulated by accumulation of hemozoin or high-density parasitemia may induce pathology and impair protective immunity in HIV-infected and -uninfected women.

Adolescent↗