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Biomedical subjects

M Opravil

Publications and source records attributed to M Opravil.

At least 55 records · Page 3Linked to original sources
PubMed1999

Highly sensitive methods for quantitation of human immunodeficiency virus type 1 RNA from plasma, cells, and tissues.

Precise and sensitive quantitation of viral RNA in specimens from human immunodeficiency virus (HIV) type 1 (HIV-1)-infected individuals has become an indispensable tool for the monitoring of the efficacy of highly active antiretroviral combination therapy. The present report describes reproducible and efficient protocols with enhanced sensitivity for quantitation of HIV-1 RNA from plasma, peripheral blood mononuclear cells, and tissues with Qiagen silica columns for RNA purification combined with the Roche Amplicor HIV-1 Monitor test for quantitative reverse transcription-PCR (RT-PCR). Extraction of RNA from 0.5 ml of plasma resulted in the detection of fewer than 20 HIV RNA copies/ml of plasma, equivalent to the centrifugation-based boosted RT-PCR assay. Silica extraction of cellular RNA resulted in the detection of fewer than 3 HIV-1 RNA copies/microg of total RNA. These techniques facilitate direct comparisons of viral loads between liquid and cellular specimens. Application of these sensitive methods may improve the assessment of the response to new antiretroviral regimens.

DNA Transposable Elements↗
PubMed1999

A randomized trial of interferon-alpha2a and zidovudine versus bleomycin and zidovudine for AIDS-related Kaposi's sarcoma. Swiss HIV Cohort Study.

The efficacy and toxicity of interferon-alpha2a (9MU/d) and bleomycin (15 mg every 2 weeks), each combined with zidovudine (2x250 mg/d), was compared in a randomized study in 26 men with progressing AIDS-related Kaposi's sarcoma (KS). The median CD4 count was 113/microl. Complete or partial response was achieved in one (8%) of 12 evaluable patients on interferon and in 2 (20%) of 10 patients on bleomycin (P = 0.43) during 4.7 and 5.3 months of treatment, respectively. The tolerability was comparable. During extended follow up, survival time was 24 and 13 months in the interferon and bleomycin arm, respectively. In a multivariate Cox regression analysis, CD4 lymphocytes <200/microl (relative risk 3.74; 95% CI: 1.30-10.8) and randomization to interferon (relative risk 0.37; 95% CI: 0.15-0.90) were significantly predictive of mortality. New AIDS-related events occurred more frequently in patients who had received bleomycin. The antiviral activity of interferon-alpha or the chemotherapy-mediated increase in the risk for opportunistic infections may explain these differences.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Levels of HIV-infected peripheral blood cells remain stable throughout the natural history of HIV-1 infection. Swiss HIV Cohort Study.

OBJECTIVE: To clarify the relationship between the number of provirus-bearing peripheral blood mononuclear cells (PBMC) and HIV-1 disease progression during the natural history of infection. DESIGN: Twenty-four HIV-1-infected subjects with known seroconversion dates and long-term follow-up were retrospectively identified using the Swiss HIV Cohort Database. PBMC specimens from this cohort were retrieved from storage for analysis. METHODS: Infected PBMC equivalents were determined by HIV-1 DNA quantitative competitive (QC)-PCR. The results were analysed with respect to HIV-1 disease stage and compared with a mathematical model of long-term HIV-1 disease progression. RESULTS: PBMC HIV-1 DNA did not correlate with major indices of disease progression, including time following primary infection, time before reaching a CD4 cell count less than 200 x 10(6)/l, and time before death. The number of PBMC harbouring HIV-1 provirus was relatively constant throughout the clinical stages of HIV-1 infection, consistent with simulated data from a mathematical model of long-term HIV-1 infection. We also showed that a biased interpretation of the QC-PCR data may arise when the values are expressed as HIV-1 DNA copies per PBMC or per CD4 cell. CONCLUSIONS: This analysis suggests that levels of provirus-bearing PBMC remain constant during the natural course of HIV-1 infection, whereas plasma virus load typically increases logarithmically during the same period. The hypothesis that plasma virus levels are directly related to the number of infected cells may deserve reconsideration.

Adult↗
PubMed1998

Highly active antiretroviral therapy during early HIV infection reverses T-cell activation and maturation abnormalities. Swiss HIV Cohort Study.

OBJECTIVES: To evaluate the impact of early initiation of highly active antiretroviral therapy (HAART) on disease-induced T-cell activation and maturation abnormalities during asymptomatic HIV infection. DESIGN: A prospective open-label trial of zidovudine, lamivudine and ritonavir in treatment-naive asymptomatic HIV-infected individuals with CD4 cells > or = 400 x 10(6)/l. METHODS: Peripheral blood CD4+ and CD8+ T cells derived from 15 asymptomatic HIV-infected individuals (median baseline CD4+ cells, 608 x 10(6)/l; CD8+ cells, 894 x 10(6)/l; plasma HIV RNA, 3.93 log10 copies/ml) undergoing therapy with zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and ritonavir (600 mg twice daily) were assessed for changes in expression of phenotypic markers of T-cell activation (HLA-DR and CD38) and maturation (CD45RA and CD45RO). At weeks 0, 2, 4, 8, 12, 16, 20 and 24, T-cell subsets were quantified by flow cytometry and plasma HIV viral loads determined using reverse transcription PCR. RESULTS: HAART-induced decrease in plasma HIV RNA levels coincided with a significant reduction in numbers of activated CD4+/HLA-DR+ (maximum change, -36%; P < or = 0.05), CD8+/HLA-DR+ (maximum change, -66%; P < or = 0.005) and CD8+/CD38+ (maximum change, -51%; P < or = 0.01) T cells. A concomitant significant increase in numbers of naive CD4+/CD45RA+ (maximum change, +12%; P < or = 0.005) and memory CD4+/CD45RO+ (maximum change, +6%; P < or = 0.05) T cells was also evident, which contrasted with a significant decrease in memory CD8+/CD45RO+ cells (maximum change, -42%; P < or = 0.005). CONCLUSION: The observed ability of HAART during early asymptomatic HIV infection to initiate rapid reversal of disease-induced T-cell activation and maturation abnormalities, while preserving pretherapy levels of immune function, supports the concept that therapeutic advantage is to be gained by commencing early aggressive antiretroviral therapy.

ADP-ribosyl Cyclase↗
PubMed1998

[Chronic hepatitis B and C in HIV-infected patients].

BACKGROUND AND AIM: This retrospective study examined the prevalence of co-infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) and the frequency of chronic hepatitis in HIV-infected patients with respect to both the different risk groups and the serological results. PATIENTS AND METHODS: All Zurich participants of the Swiss HIV Cohort Study were evaluated who had available results of hepatitis B and C serology and ALT. RESULTS: Of the total 279 patients, 52% belonged to the intravenous drug user, 34% to the homosexual, and 11% to the heterosexual risk category. Serologically, previously acquired infection with HBV alone could be demonstrated in 92 (33%), HCV alone in 9 (3%), and both HBV and HCV in 130 (47%) patients. Only 3% of patients with sexually acquired HIV infection had anti-HCV antibodies, whereas co-infection with HBV and HCV was present in 87% of intravenous drug users. Among the 222 patients with previous HBV contact, 25 (11%) had positive HBsAg and 91 (41%) had "anti-HBc alone", both assumed to represent active HBV infection. 66 (24%) of 279 patients had chronic hepatitis with ALT elevation lasting > or = 6 months. Chronic hepatitis was present in 46% of those with active HBV and HCV co-infection, in 36% of those with HCV infection alone and in 18% of those with active HBV infection alone (P < 0.001). Of the 66 cases of chronic hepatitis, 58 were associated with HCV infection, and only 2 cases had no serological signs of active HBV or HCV infection. CONCLUSION: In patients with sexually acquired HIV infection, HBV had frequently been co-transmitted. In contrast, almost all of those infected by means of intravenous drug use had a co-infection with both HBV and HCV. The latter seems to play the strongest role in the development of chronic hepatitis with persistent ALT elevation. A chronic ALT elevation was almost always associated with serologically active HBV or HCV infection.

Adult↗
PubMed1998

A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study.

OBJECTIVE: To explore the short-term effects on surrogate markers for HIV progression of didanosine (ddl) plus stavudine (d4T), with or without hydroxyurea. DESIGN: Randomized, double-blinded, prospective study. SETTING: Swiss HIV Cohort Study. PATIENTS: A total of 144 patients (75% antiretroviral-naive) were studied (mean baseline HIV-1 RNA, 4.53 log10 copies/ml; mean CD4 cell count, 370 x 10(6)/l). INTERVENTION: Patients received ddl (200 mg twice daily) plus d4T (40 mg twice daily), with additional hydroxyurea (500 mg twice daily) or placebo. MAIN OUTCOME MEASURES: The primary endpoint was a reduction of viraemia below 200 copies/ml after 12 weeks. At that time, patients who did not reach the primary endpoint were withdrawn in the hydroxyurea arm, whereas patients in the placebo group had the option of adding hydroxyurea to ddl and d4T. All patients were followed until week 24. RESULTS: After 12 weeks, 54% of the patients randomized to hydroxyurea had viraemia below 200 copies/ml, compared with 28% on placebo (P < 0.001). Using an ultrasensitive assay with a limit of detection of 20 copies/ml, 19% of patients receiving hydroxyurea had viraemia levels below 20 copies/ml, compared with 8% on placebo (P = 0.05). Mean decrease in HIV-1 RNA was 2.3 and 1.7 log10 copies/ml for hydroxyurea and placebo groups, respectively (P = 0.001). Hydroxyurea was found to induce lymphopenia (-124 x 10(6)/l). Increase in CD4 cell counts was +28 x 10(6)/l during hydroxyurea treatment compared with +107 x 10(6)/l on placebo (P = 0.001). CONCLUSIONS: Hydroxyurea improved the antiviral activity of d4T and ddl over a 12-week period, but was associated with a smaller increase in CD4 cell counts due to hydroxyurea-induced lymphopenia.

Adult↗
PubMed1998

Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only. Swiss HIV Cohort Study.

Persons with immune deficiency may present with atypical results in serological tests for hepatitis B virus (HBV). Frozen serum specimens that were sequentially obtained over time from a cohort of 57 HIV-infected patients, all of whom tested positive only for antibody to hepatitis B core antigen (anti-HBcAg), were therefore retested for HBV markers, including HBV DNA. The results were assessed for their time course and correlated with clinical data and alanine aminotransferase (ALT) values. Forty-eight patients were male; intravenous drug users constituted the principal risk group (n = 30), followed by homosexual men (n = 22). Thirty-three persons tested positive for antibody to hepatitis C virus (anti-HCV). During a median of 31 months from the first to the last serum, anti-HBcAg remained the sole marker of HBV infection in 98.2% of the patients. Polymerase chain reaction (PCR) to detect DNA for HBV core and HBV surface gene was positive in 126 (62.4%) and 121 (59.9%) of all 202 serum samples, respectively. Over time, HBV DNA was detected at least once in 51 (89.5%) patients. In contrast, decomplexed hepatitis B surface antigen (HBsAg) was detected at least once in 14 (24.6%) patients. Among patients positive for HBV DNA and negative for anti-HCV, eight (36.4%) of 22 had chronic hepatitis (ALT elevation > or = 6 months) that was attributable only to persisting HBV infection. Similarly, 12 (41.4%) of 29 patients positive for both HBV DNA and anti-HCV had chronic viral hepatitis, but their ALT values were significantly higher. In HIV-infected patients, anti-HBcAg as the sole serological HBV marker detected must be considered indicative of chronic HBV infection and is in part associated with chronic hepatitis and ALT elevation.

Adult↗
PubMed1998

Predictors of unprotected sexual contacts in HIV-infected persons in Switzerland.

Predictors of sexual risk behavior with regular and casual partners among HIV-infected heterosexual and gay persons were addressed. Sociodemographic data as well as self- and interviewer-reported data on sexual behavior were obtained from 117 asymptomatic HIV-infected persons enrolled in the Zurich part of the Swiss HIV Cohort Study (SHCS). Participants who reported sexual intercourse at least once (vaginal and/or anal) without condom use in the 6 months prior to interview were considered to have risk behavior. Sexual risk behavior was analyzed separately in contacts with regular and casual partners. In the 6-month preinterview period, 92% (108 of 117) of the HIV-infected study population reported sexual contacts, and 30/117 (26%) had at least one unprotected vaginal and/or anal contact. Among 93 persons using condoms, 25% of the heterosexual and 10% of the homosexual participants reported breakage of the condom. The main predictor for unprotected sexual behavior with regular partners was an elevated number of contacts. Predictors for sexual risk behavior with casual partners were the combination of alcohol and sexual encounters and the change of sexual behavior since the epidemic of AIDS. These findings did not differ between persons with hetero- and homosexual behavior. Considering that these contacts may have passed the virus on to the seronegative population, that the probability of unsafe sex increased with the growing number of contacts, and that the number of condom breakages was remarkable, it is imperative that this group be educated and motivated to take the active role in insisting on safer sex practices in each encounter.

Adult↗
PubMed1998

Improvement in immune function due to treatment with indinavir despite severe immune deficiency.

To study the virological, immunological and clinical effects of the protease inhibitor indinavir in human immunodeficiency virus (HIV)-infected patients with CD4 counts < 50 cells/mm3, indinavir was added to prior treatment with nucleoside analogues in a prospective open-label study in 23 HIV-infected patients with median CD4 count of 10 cells/mm3 and median serum HIV-1 RNA load of 27,508 copies/ml. Addition of indinavir induced a decrease in HIV-1 RNA levels to < 400 copies/ml in 15 patients that was maintained until week 36 of the study in 8 (35%) patients. The median increase in CD4 cell counts was 92 cells/mm3 (range 55-258 cells/mm3) and in CD8 counts was 245 cells/mm3 (range 51-1552 cells/mm3) at week 30. The treatment induced a significant CD8 T cell expansion, consisting in the first 6 weeks of predominantly memory CD45RO+ cells and followed by expansion of naive cells from week 12 on, and a significant decrease in the proportion of activated CD8/CD38 cells. In addition, significant increases in T cell proliferation following stimulation with phytohaemagglutinin and significant decreases in the rates of spontaneous apoptosis of CD4+ and CD8+ T cells were observed. In conclusion, the addition of indinavir induced restoration of both memory and naive CD8 T cells. Corresponding evidence of improving T cell function, as assessed by enhanced lymphoproliferative capacity and diminished propensity to undergo apoptosis, provides evidence for treatment-induced regeneration of immune function even in patients with severe immunodeficiency.

Adult↗
PubMed1998

Prediction of HIV-1 RNA suppression and its durability during treatment with zidovudine/lamivudine.

To predict the probability of long-term viral suppression during treatment with zidovudine and lamivudine, human immunodeficiency virus type 1 (HIV-1) RNA values were retrospectively pooled for 1083 patients from six randomized, double-blind clinical trials. All analyses of HIV-1 RNA were obtained using the Roche Amplicor assay or its earlier prototype. Time to loss of response was evaluated by Kaplan-Meier analysis; Cox proportional hazards models were used to assess the influence of baseline variables. Among 523 patients with < or = 6 months of prior zidovudine treatment, the probability of HIV-1 RNA suppression below 400 copies/ml at 48 weeks was 71% in those with baseline HIV-1 RNA < 5000 copies/ml, but only 14% in those with HIV-1 RNA between 50,000 and 200,000 copies/ml. Among 560 patients with > 6 months of prior zidovudine treatment, the rates of sustained viral suppression were lower, but also significantly associated with the baseline HIV-1 RNA. Multivariate analyses showed no independent effect of CD4 cell count, age, sex, race, or CDC disease stage on the probability of sustained HIV-1 RNA suppression. When patients with < or = 6 months of prior therapy were stratified based on the magnitude of HIV-1 RNA nadir achieved during treatment, those who reached a nadir of < 400 copies/ml retained this response for significantly longer time periods than the ones who only achieved partial viral suppression. In conclusion, baseline HIV-1 RNA levels and the duration of prior zidovudine therapy strongly predict the antiretroviral efficacy of zidovudine/lamivudine. The baseline parameters should influence the choice of the antiretroviral regimen.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Didanosine plus stavudine with or without hydroxyurea in HIV-1-infected patients: 1 year follow-up. Swiss HIV Cohort Study.

A total of 144 human immunodeficiency virus (HIV)-infected patients (mean CD4 cell count, 367 cells/mm3) were included in a double-blind placebo-controlled trial testing the efficacy on surrogate markers of HIV progression of the combination didanosine (2',3'-dideoxyinosine or DDI) plus stavudine (2',3'-didehydro-2',3'-dideoxythymidine or D4T) with or without hydroxyurea. The primary end point was a reduction of HIV RNA levels to below 200 copies/ml after 12 weeks of treatment. The results showed that the triple combination was associated with a more profound decrease in HIV RNA with an increased proportion of patients with viraemia < 200 copies/ml. This effect persisted for the majority of the patients after a 48 week follow-up. In contrast, the increase in CD4 cell counts was less in patients treated with hydroxyurea because of lymphopenia, and adverse events were more frequent in hydroxyurea-treated patients. In conclusion, the addition of hydroxyurea consistently improved the antiviral activity of the didanosine/stavudine combination over a 48 week follow-up. Increased toxicity and decreased effect on CD4 cell counts might inspire caution.

Anti-HIV Agents↗
PubMed1998

[The Swiss HIV Cohort Study--a link between clinical research and medical practice].

The prospective Swiss HIV Cohort Study (SHCS) documents since 1988 epidemiological, clinical and laboratory data of HIV-infected participants. Until the end of 1997, 9447 patients with a total follow-up of 25,584 patient-years have been included. The proportion of women is 27.3% and is rising. The proportion of heterosexually infected patients has been rising since 1992, this group was with 35.6% in 1997 the most frequent transmission category within the newly registered participants. The SHCS is representative for Switzerland since 73% of the 5532 nationwide registered AIDS cases are included in the study. Recently, the SHCS data could demonstrate an impressive reduction in morbidity and mortality due to the improvement in therapy and prophylaxis. The SHCS also serves as a basis for large multicenter studies that aim to evaluate new prophylactic treatments or new antiretroviral strategies. By introducing uniform guidelines for the diagnosis and the treatment of HIV infection, the SHCS has contributed significantly to the high quality of patient care, a goal that must be maintained and further improved in the future. Also important is the recognition of acute HIV infections because early treatment of such patients holds the promise to substantially improve the clinical course.

Acquired Immunodeficiency Syndrome↗
PubMed1998

[Long-term HIV infection and dialysis dependent renal failure in analgesic nephropathy].

We report a case of advanced human immundeficiency virus infection and relapsing urinary tract infections due to analgesic nephropathy. The patient developed an urosepsis with multiorgan dysfunction syndrome and required dialysis. Inspite of this complicated course, for the first time thirteen years after diagnosis of the HIV-infection, an antiretroviral treatment was started, followed by an impressive improvement of quality of life, physical activity and psychological stabilization.

Analgesics↗
PubMed1997

[Meningitis after acute Borrelia burgdorferi infection in HIV infection].

HISTORY AND CLINICAL FINDINGS: A 39-year-old HIV positive patient developed myalgia, headache and cough 4 weeks after a tick bite. His temperature was 37.4 degrees C and a circular pale erythema was noted over the left lower leg. INVESTIGATIONS: C-reactive protein was raised to 120 mg/l, white blood cell count was 5860/microliter, CD4-lymphocyte count 250/microliter. The chest radiogram showed pneumonitic infiltration in the left lower lobe. There were IgM antibodies against Borrelia burgdorferi. TREATMENT AND COURSE: Left lower lobe pneumonia and chronic erythema migrans were diagnosed and he was given oral azithromycin (500 mg on the first day and 250 mg for 4 days). The pneumonia cleared up, but 2 weeks later he developed symptoms of meningitis (496 cells per microliter, 87% lymphocytes, positive Borrelia burgdorferi antibody titer), which quickly and lastingly responded to ceftriaxon (2 g daily by brief infusion for 14 days). CONCLUSION: This immune-compromised HIV-infected patient developed disseminated borreliosis with CNS involvement 2 weeks after the occurrence of chronic erythema migrans. The initial treatment of the latter with azithromycin was unable to prevent the meningitis. It is unlikely that there was a causal connection between the borreliosis and the pneumonia.

Adult↗
PubMed1997

Meta-analysis of prophylactic treatments against Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients.

In a meta-analysis, we examined the efficacy of aerosolized pentamidine, trimethoprim-sulfamethoxazole, and dapsone or dapsone/pyrimethamine for the prevention of Pneumocystis carinii pneumonia and toxoplasma encephalitis in patients with HIV infection. Of 22 trials, 13 compared trimethoprim-sulfamethoxazole with aerosolized pentamidine, nine compared dapsone alone or in combination with pyrimethamine with aerosolized pentamidine, and eight compared trimethoprim-sulfamethoxazole with dapsone/pyrimethamine. In total, 1484 patients were treated with trimethoprim-sulfamethoxazole, 1548 patients with dapsone/pyrimethamine or dapsone, and 1800 patients with aerosolized pentamidine. For dapsone/pyrimethamine versus aerosolized pentamidine, the risk ratio for P. carinii pneumonia was 0.90 (95% confidence interval [CI], 0.71-1.15), and for toxoplasma encephalitis it was 0.72 (95% CI, 0.54-0.97). For trimethoprim-sulfamethoxazole versus aerosolized pentamidine, the risk ratio of P. carinii pneumonia was 0.59 (95% CI, 0.45-0.76), and for toxoplasma encephalitis it was 0.78 (95% CI, 0.55-1.11). For trimethoprim-sulfamethoxazole versus dapsone/pyrimethamine, the risk ratio of P. carinii pneumonia was 0.49 (95% CI, 0.26-0.92), and for toxoplasma encephalitis it was 1.17 (95% CI, 0.68-2.04). Although current evidence does not allow a definitive recommendation, administration of trimethoprim-sulfamethoxazole for prophylaxis of P. carinii pneumonia and toxoplasmosis in patients with HIV infection is consistent with the available data.

AIDS-Related Opportunistic Infections↗
PubMed1997

Change in circulating levels of the chemokines macrophage inflammatory proteins 1 alpha and 11 beta, RANTES, monocyte chemotactic protein-1 and interleukin-16 following treatment of severely immunodeficient HIV-infected individuals with indinavir.

OBJECTIVE: To evaluate the in vivo relationship between HIV replication and circulating levels of the chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, RANTES (acronym for Regulated upon Activation, Normal T-cell Expressed and presumably Secreted), interleukin (IL)-16 and monocyte chemotactic protein (MCP)-1, which have recently been characterized as factors capable of regulating in vitro HIV replication. DESIGN AND METHODS: We have compared changes in plasma HIV-RNA levels and circulating levels of MIP-1 alpha, MIP-1 beta, RANTES, IL-16 and MCP-1 in 20 severely immunodeficient HIV-infected individuals (CD4+ T cells = 14 +/- 3 cells x 10(6)/l; plasma HIV RNA = 4.45 +/- 0.27 log 10 copies/ml) undergoing treatment with the HIV protease inhibitor indinavir that added to pre-existing nucleoside-based therapy. At weeks 0, 2, 6 and 12, viral load was quantified using a commercial reverse-transcription polymerase chain reaction assay, peripheral blood T-cell subpopulations assessed by flow cytometry, and chemokine levels quantified using commercial sandwich enzyme-linked immunosorbent assay kits. RESULTS: Following initiation of indinavir-based therapy, significant decreases in plasma HIV-RNA levels (change = 2.0 +/- 0.75 log 10 copies/ml) were observed in conjunction with significant increases in absolute CD4+ (change = 83 +/- 19 cells x 10(6)/l) and CD8+ (change = 293 +/- 96 cells x 10(6)/l) T-cell numbers. Concomitantly, significant increases in MIP-1 alpha (19% increase), MIP-1 beta (14% increase), RANTES (15% increase) and IL-16 (1213% increase) levels occurred. In contrast, MCP-1 levels decreased significantly (47% decrease). CONCLUSION: The in vivo demonstration of an association between diminishing plasma HIV-RNA levels and the emergence of a circulating chemokine profile capable of inhibiting HIV replication corroborates recent in vitro observations and provides evidence for the restoration of chemokine capacity by HIV protease inhibitor-based therapy.

Acquired Immunodeficiency Syndrome↗