17-Hydroxyprogesterone Response to Standard Dose Synacthene Stımulation Test in CYP21A2 Heterozygous Carriers and Non-Carriers in Symptomatic and Asymptomatic Groups: Meta-Analyses

Abstract Background Mobilization failure may occur when the conventional hematopoietic stem cells (HSCs) mobilization agent granulocyte colony-stimulating factor (G-CSF) is used alone, new regimens were developed to improve mobilization efficacy. Multiple studies have been performed to investigate the efficacy of these regimens via animal models, but the results are inconsistent. We aim to compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies. Methods We searched Medline and Embase databases for the eligible animal studies that compared the efficacy of different HSC mobilization regimens. Primary outcome is the number of total colony-forming cells (CFCs) in per milliliter of peripheral blood (/ml PB), and the secondary outcome is the number of Lin− Sca1+ Kit+ (LSK) cells/ml PB. Bayesian network meta-analyses were performed following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) with WinBUGS version 1.4.3. G-CSF-based regimens were classified into the SD (standard dose, 200–250 μg/kg/day) group and the LD (low dose, 100–150 μg/kg/day) group based on doses, and were classified into the short-term (2–3 days) group and the long-term (4–5 days) group based on administration duration. Long-term SD G-CSF was chosen as the reference treatment. Results are presented as the mean differences (MD) with the associated 95% credibility interval (95% CrI) for each regimen. Results We included 95 eligible studies and reviewed the efficacy of 94 mobilization agents. Then 21 studies using the poor mobilizer mice model (C57BL/6 mice) to investigate the efficacy of different mobilization regimens were included for network meta-analysis. Network meta-analyses indicated that compared with long-term SD G-CSF alone, 14 regimens including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, long-term SD G-CSF + EP80031, POL5551, long-term SD G-CSF + AMD3100, AMD1300 + EP80031 and long-term LD G-CSF + meloxicam significantly increased the collections of total CFCs. G-CSF + Me6 ranked first among these regimens in consideration of the number of harvested CFCs/ml PB (MD 2168.0, 95% CrI 2062.0−2272.0). In addition, 7 regimens including long-term SD G-CSF + AMD3100, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, long-term SD G-CSF + ML141, short-term LD G-CSF + ARL67156, and long-term LD G-CSF + meloxicam significantly increased the collections of LSK cells compared with G-CSF alone. Long-term SD G-CSF + AMD3100 ranked first among these regimens in consideration of the number of harvested LSK cells/ml PB (MD 2577.0, 95% CrI 2422.0–2733.0). Conclusions Considering the number of CFC and LSK cells in PB as outcomes, G-CSF plus AMD3100, Me6, EP80031, ML141, FG-4497, IL-33, ARL67156, meloxicam, desipramine, and reboxetine are all promising mobilizing regimens for future investigation.

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What Cut-off Value of 17-Hydroxyprogesterone Should Be an Indication to Perform a 250 µg Cosyntropin Stimulation Test When NCCAH Is Suspected? - a Retrospective Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.204 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A102-A102

Author(s):

Bartosz Domagala ◽

Malgorzata Trofimiuk-Muldner ◽

Anna Krawczyk ◽

Joanna Topor-Kolkowska ◽

Anna Skalniak ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Severe Form ◽

Stimulation Test ◽

Test Results ◽

Mild Phenotype ◽

Secondary Amenorrhea ◽

Stimulation Tests ◽

Microplate Reader ◽

17 Hydroxyprogesterone ◽

Cosyntropin Stimulation Test

Abstract The Nonclassic Congenital Adrenal Hyperplasia (NCCAH) is a less severe form of CAH in which the activity of the 21-hydroxylase is estimated at about 20% to 50%. Cosyntropin stimulation test is the gold diagnostic standard used to test for this condition. The study was aimed at verifying the currently accepted threshold of 17-hydroxyprogesterone (17OHP) level (≥2.0 ng/mL) at which cosyntropin stimulation test should be performed. Material and methods. The study included 343 patients (328 females and 15 males) referred for a cosyntropin stimulation test due to suspected NCCAH. The median age at the time of evaluation was 27 years. Serum 17-OHP was measured with ELISA assay using Ledect96 Microplate Reader. The NCCAH diagnosis was made if cosyntropin-stimulated 17OHP level exceeded 10.0 ng/mL. The ROC curve was determined, and the cut-off point with the highest sensitivity and specificity was established. The study was approved by the Ethics Board of JUMC. Results:. Symptoms, which prompted testing for NCCAH, most often were: hirsutism in 187 patients, irregular menstrual cycles in 178 patients, and acne in 138 patients. A total of 79 patients (77 females and two males) were diagnosed with NCCAH based on cosyntropin stimulation test results. Seventy-one of them had baseline levels of 17OHP≥2.0 ng/mL. The mean age of patients with confirmed NCCAH was 28.86 years. The baseline 17OHP cut-off value that qualified patients best for testing was 2.79 ng/mL in our group, with sensitivity and specificity of 77.2% and 91.3%, respectively. The sensitivity and specificity for a guideline-recommended cut-off point (17OHP ≥2.0 ng/mL) was 86.1% and 76%, respectively. In five of six patients with secondary amenorrhea and a baseline level of 17OHP ≥2.0 ng/mL, NCCAH was confirmed in a cosyntropin stimulation test. Conclusions:. Our results suggest considering an upward shift in the 17OHP threshold at which patients suspected for NCCAH should be referred for further evaluation. This may reduce the number of unnecessary cosyntropin stimulation tests, mainly that patients with mild phenotype (or asymptomatic) frequently may not require any treatment. However, attention should be paid to patients with coexisting secondary amenorrhea and 17OHP levels ≥2.0 ng/mL, which may be a clinical predictor of NCCAH.

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Direct Oral Anticoagulants versus Warfarin in Patients with Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials with Interaction Testing by Age and Sex

Circulation ◽

10.1161/circulationaha.121.056355 ◽

2022 ◽

Author(s):

Anthony P. Carnicelli ◽

Hwanhee Hong ◽

Stuart J. Connolly ◽

John Eikelboom ◽

Robert P. Giugliano ◽

...

Keyword(s):

Major Bleeding ◽

Individual Patient Data ◽

Standard Dose ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Efficacy And Safety ◽

Systemic Embolism ◽

Continuous Covariate ◽

Meta Analyses ◽

Lower Hazard

Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation (AF). Meta-analyses using individual patient data offer significant advantages over study-level data. Methods: We used individual patient data from the COMBINE AF database, which includes all patients randomized in the 4 pivotal trials of DOACs vs warfarin in AF (RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (95% CIs) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. Results: A total of 71,683 patients were included (29,362 on standard-dose DOAC, 13,049 on lower-dose DOAC, 29,272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke/systemic embolism (883/29312 [3.01%] vs 1080/29229 [3.69%]; HR 0.81, 95% CI 0.74-0.89), death (2276/29312 [7.76%] vs 2460/29229 [8.42%]; HR 0.92, 95% CI 0.87-0.97) and intracranial bleeding (184/29270 [0.63%] vs 409/29187 [1.40%]; HR 0.45, 95% CI 0.37-0.56), but no statistically different hazard of major bleeding (1479/29270 [5.05%] vs 1733/29187 [5.94%]; HR 0.86, 95% CI 0.74-1.01), whereas lower-dose DOACs were associated with no statistically different hazard of stroke/systemic embolism (531/13049 [3.96%] vs 1080/29229 [3.69%]; HR 1.06, 95% CI 0.95-1.19) but a lower hazard of intracranial bleeding (55/12985 [0.42%] vs 409/29187 [1.40%]; HR 0.28, 95% CI 0.21-0.37), death (1082/13049 [8.29%] vs 2460/29229 [8.42%]; HR 0.90, 95% CI 0.83-0.97), and major bleeding (564/12985 [4.34%] vs 1733/29187 [5.94%]; HR 0.63, 95% CI 0.45-0.88). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke/systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use (p=0.01) and lower creatinine clearance (p=0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight (p=0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction p=0.02) and lower-dose DOACs (interaction p=0.01) versus warfarin. Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with AF.

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SP519The comparison of the usefulness between Low dose and Standard dose adrenocorticotropin (ACTH) stimulation test in peritoneal dialysis patients

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz103.sp519 ◽

2019 ◽

Vol 34 (Supplement_1) ◽

Author(s):

JIWON RYU ◽

Yun Jung Oh ◽

Chungsik Lee

Keyword(s):

Peritoneal Dialysis ◽

Low Dose ◽

Standard Dose ◽

Stimulation Test ◽

Acth Stimulation Test ◽

Dialysis Patients ◽

Acth Stimulation

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Intradermal versus Intramuscular Administration of Influenza Vaccination: Rapid Review and Meta-analysis

10.1101/2020.10.06.20205989 ◽

2020 ◽

Author(s):

Oluwaseun Egunsola ◽

Fiona Clement ◽

John Taplin ◽

Liza Mastikhina ◽

Joyce W. Li ◽

...

Keyword(s):

Adverse Events ◽

Influenza Vaccination ◽

Standard Dose ◽

Meta Analysis ◽

Vaccine Dose ◽

Rapid Review ◽

Cochrane Central Register ◽

Intramuscular Dose ◽

H1n1 Strain ◽

Meta Analyses

AbstractBackgroundVaccinations are essential for prevention of influenza. We synthesized the published literature on the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses compared with full intramuscular doses.MethodsA rapid review of the literature was completed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5th, 2020. All studies comparing intradermal and intramuscular influenza vaccinations were included. Random-effects meta-analyses of immunogenicity and safety outcomes were conducted.ResultsA total of 30 relevant studies were included. Seroconversion rates were equivalent between the 3 mcg, 6 mcg, 7.5 mcg, and 9 mcg intradermal vaccine doses and the 15 mcg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but significantly higher with the 15 mcg intradermal compared with the 15 mcg intramuscular dose, for the H1N1 (RR 1.10, 95% CI: 1.01-1.20) and B strains (RR 1.40, 95% CI: 1.13-1.73). Seroprotection rates for the 9 mcg and 15 mcg intradermal doses were equivalent with the 15 mcg intramuscular dose for all the three strains, except for the 15 mcg intradermal dose for the H1N1 strain which was significantly higher (RR 1.05, 95% CI: 1.01-1.09). Local adverse events were significantly higher with intradermal doses. Fever and chills were significantly higher with the 9 mcg intradermal dose, while all other systemic adverse events were equivalent for all doses.ConclusionReduced dose intradermal influenza vaccination appears to be a reasonable alternative to standard dose intramuscular vaccination because of the similarity in immunogenicity.

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Effectiveness of the MF59-adjuvanted trivalent or quadrivalent seasonal influenza vaccine among adults 65 years of age or older, a systematic review and meta-analysis

10.22541/au.161933909.92394260/v1 ◽

2021 ◽

Author(s):

Brenda Coleman ◽

Ruth Sanderson ◽

Mendel Haag ◽

Ian McGovern

Keyword(s):

Influenza Vaccine ◽

Seasonal Influenza ◽

Standard Dose ◽

Meta Analysis ◽

Grey Literature ◽

Influenza Vaccines ◽

High Dose ◽

Case Control Studies ◽

Cluster Randomized ◽

Meta Analyses

Background: Standard dose seasonal influenza vaccines often produce modest immunogenic responses in adults ≥65 years old. MF59 is intended to elicit a greater magnitude and increased breadth of immune response. Objective: To determine the effectiveness of seasonal MF59-adjuvanted trivalent/quadrivalent influenza vaccine (aTIV/aQIV) relative to no vaccination or vaccination with standard or high dose egg-based influenza vaccines among people ≥65 years old. Methods: Cochrane methodological standards and PRISMA-P guidelines were followed. Real-world evidence from non-interventional studies published in peer reviewed journals and grey literature from 1997 through to July 15, 2020, including cluster-randomized trials, were eligible. Two reviewers independently extracted data and risk of bias was assessed using the ROBINS-I tool. Results: Twenty-one studies conducted during the 2006/07-2019/20 influenza seasons were included in the qualitative review; 16 in the meta-analyses. Meta-analysis of test-negative studies found that aTIV reduced medical encounters due to lab-confirmed influenza with pooled estimates of 40.7% (95% CI: 21.9, 54.9; I2=0%) for general practitioner visits and 58.5% (40.7, 70.9; I2=52.9%) for hospitalized patients. The pooled estimate of VE from case-control studies was 51.3% (39.1, 61.1; I2=0%) against influenza- or pneumonia-related hospitalization. The pooled estimates for the relative VE of aTIV for the prevention of influenza related medical encounters were 13.9% (4.2, 23.5; I2=95.9%) compared with TIV, 13.7% (3.1, 24.2; I2=98.8%) compared with QIV, and 2.8% (-2.9, 8.5; I2=94.5%) compared with HD TIV. Conclusions: Among adults ≥65 years aTIV demonstrated significant absolute VE, improved relative VE compared to non-adjuvanted standard-dose TIV/QIV, and comparable relative VE to high-dose TIV.

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Radioimmunoassay for 21-deoxycortisol: clinical applications

Acta Endocrinologica ◽

10.1530/acta.0.1080537 ◽

1985 ◽

Vol 108 (4) ◽

pp. 537-544 ◽

Cited By ~ 9

Author(s):

B. Gueux ◽

J. Fiet ◽

M. T. Pham-Huu-Trung ◽

J. M. Villette ◽

M. Gourmelen ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Normal Subjects ◽

Ethyl Acetate Fraction ◽

Adrenal Hyperplasia ◽

Acth Stimulation ◽

Hydroxylase Deficiency ◽

Androgen Excess ◽

Heterozygous Carriers ◽

17 Hydroxyprogesterone ◽

21 Hydroxylase Deficiency

Abstract. A radioimmunoassay for 21-deoxycortisol is described. The immunogen, 21-deoxycortisol-3-(O-carboxymethyl) oxime-bovine serum albumin, was prepared, the antisera raised against it were studied and the reliability of the assay was checked. The antiserum selected cross-reacted with 11-deoxycortisol (0.08%), corticosterone (0.25%), cortisol (0.6%) and 17-hydroxyprogesterone (1.6%). 21-deoxycortisol was separated by celite partition chromatography and eluted in the 70/30 (v/v) isooctane/ethyl acetate fraction together with 11-deoxycortisol and corticosterone. The radioimmunoassay was used to measure 21-deoxycortisol in the plasma of normal subjects and patients with androgen excess. In normal subjects, men (0.19 ng/ml ± 0.08) and women (0.18 ng/ml ± 0.09) had similar basal levels (mean ± sd). One hour after ACTH stimulation, these levels were increased by a factor of 3.5. In 7 patients treated for classical congenital adrenal hyperplasia associated with 21-hydroxylase deficiency, basal values varied between 9.1 and 39.9 ng/ml (measured at 8 a.m.). In 7 untreated women with lateonset congenital adrenal hyperplasia (with 21-hydroxylase deficiency), ACTH-stimulated levels were increased to between 9 and 25.5 ng/ml. In 14 heterozygous carriers of 21-hydroxylase deficiency, diagnosed by HLA genotyping, all ACTH-stimulated levels were well above the highest corresponding levels in normal subjects, whereas 17-hydroxyprogesterone levels remained within the normal range in 9 of the cases.

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Comparable Survival in Newly Diagnosed Multiple Myeloma (MM) after VAD Induction with High Dose Therapy Using Melphalan 140mg/M2 + TBI 12 Gy (MEL+TBI) Versus Standard Therapy with VBMCP and No Benefit from Interferon (IFN) Maintenance: Final Clinical Results of Intergroup Trial S9321 in the Context of IFM 90 and MRC VII Trials.

Blood ◽

10.1182/blood.v104.11.539.539 ◽

2004 ◽

Vol 104 (11) ◽

pp. 539-539 ◽

Cited By ~ 12

Author(s):

John Crowley ◽

Rafael Fonseca ◽

Phillip Greipp ◽

McCoy Jason ◽

Barlogie Bart

Keyword(s):

Randomized Clinical Trials ◽

Standard Dose ◽

Dose Intensity ◽

Clinical Results ◽

High Dose ◽

Newly Diagnosed ◽

Dose Therapy ◽

Meta Analyses ◽

To Receive

Abstract ECOG, CALGB and SWOG (coordinating group) enrolled 899 patients with newly diagnosed MM to receive VAD x 4 (813 were considered eligible), followed by randomization to PBSC-supported MEL-TBI (n=261) versus VBMCP (n=255), using CTX 4.5g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or MEL-TBI were randomized to IFN (n=121) or no maintenance (n=121). With a median follow-up of alive patients of 60 mos, median EFS and OS from 1st randomization were 25 and 62 mos for MEL-TBI and 21 and 53 mos for VBMCP (p=.14 for EFS, p=.87 for OS). EFS and OS from IFN randomization were also identical at 23/59 mos for IFN versus 18/74 mos for observation (p=.2/.6). 87 VBMCP failures received salvage autotransplants, with a post-relapse median survival of 24 mos which was similar to the 27 mos observed among the remaining 83 VBMCP failures managed with standard salvage therapies. When examined in the context of 2 other randomized trials (IFM 90, MRC VII), OS from baseline of S932, limited to patients <60 yr (as in IFM 90 + MRC VII), is intermediate between the high dose arms of IFM 90/MRC VII and the standard dose arms of these two trials (randomization at baseline) (Figure 1). OS from the time of randomization to high or standard dose therapy on S9321 (again restricted to age <60 yr) was similar to OS timed from transplant for the high dose arms of IFM 90 and MRC VII. (Figure 2). Figure Figure The comparable outcome after high- versus standard-dose therapies on S9321, interpreted in the context of 2 other published randomized clinical trials, may relate to (1) higher dose intensity with VBMCP than with other standard regimens or (2) a detrimental effect of TBI in S9321. We conclude that with the current follow-up MEL-TBI is no better than VAD/VBMCP with the option of salvage transplant and that IFN maintenance is of no benefit in this maintenance setting. Data from this trial will be provided to MRC to be included in their on-going meta-analyses of high-dose therapies and IFN maintenance.

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Dose escalation for insufficient response to standard-dose selective serotonin reuptake inhibitors in major depressive disorder

The British Journal of Psychiatry ◽

10.1192/bjp.bp.105.018325 ◽

2006 ◽

Vol 189 (4) ◽

pp. 309-316 ◽

Cited By ~ 46

Author(s):

Henricus G. Ruhé ◽

Jochanan Huyser ◽

Jan A. Swinkels ◽

Aart H. Schene

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Dose Escalation ◽

Randomised Controlled Trials ◽

Selective Serotonin Reuptake Inhibitors ◽

Standard Dose ◽

Controlled Trials ◽

Major Depressive ◽

Randomised Controlled ◽

Meta Analyses

BackgroundAlthough selective serotonin reuptake inhibitors (SSRIs) are frequently used for major depressive disorder, only 50–60% of patients respond to a standard dose. For non-responders, dose escalation is often applied.AimTo systematically review the evidence for dose escalation of SSRIs.MethodA systematic literature search in MEDLINE, EMBASE, CINAHL and PsycInfo was performed. Randomised controlled trials and meta-analyses investigating dose escalation of SSRIs were identified. Relevant articles were retrieved and critically appraised. Results were summarised in an evidence table. Pooling was not justified because of heterogeneity of the identified studies.ResultsEight true dose-escalation studies and three meta-analyses were identified. The available data provided no unequivocal base for dose escalation. Dose escalation before 4 weeks of treatment at a standard dose appeared to be ineffective.ConclusionsDose escalation of SSRIs is equivocally supported by evidence of randomised controlled trials; methodological difficulties in the studies may account for this lack of evidence.

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Effects of ketoconazole in hirsute women

Acta Endocrinologica ◽

10.1530/acta.0.1240019 ◽

1991 ◽

Vol 124 (1) ◽

pp. 19-22 ◽

Cited By ~ 19

Author(s):

Sema Akalin

Keyword(s):

Study Design ◽

Serum Testosterone ◽

Area Ratio ◽

Stimulation Test ◽

Dehydroepiandrosterone Sulphate ◽

Double Blind ◽

Steroid Synthesis ◽

Baseline Serum ◽

Testosterone Levels ◽

17 Hydroxyprogesterone

Abstract. To determine the efficacy of ketoconazole in the treatment of hirsutism, clinical and hormonal effects of this agent were evaluated with a randomized, placebocontrolled, double-blind cross-over study design. Nine hirsute women were given ketoconazole (600 mg/day) or placebo for 6 months and then crossed over. The severity of hirsutism was assessed according to the scale of Ferriman & Gallwey. Baseline serum testosterone, dehydroepiandrosterone sulphate, progesterone, estradiol, basal and stimulated cortisol and 17-alpha hydroxyprogesterone were measured. Blood was also drawn for FSH and LH levels at 0, 30, 60, and 90 min of a GnRH stimulation test. The same parameters were determined following administration of placebo or ketoconazole for 6 months. The pretreatment (28.3±0.9) and post-placebo (27.7±1.4) Ferriman-Gallwey scores were significantly higher than the post-ketoconazole score (16.6±1.3, p≤0.01). Basal and stimulated cortisol levels were not blunted after ketoconazole, but basal and stimulated 17-hydroxyprogesterone levels were significantly higher, indicating sufficient enzymatic inhibition. Serum dehydroepiandrosterone sulphate and testosterone levels were significantly lowered following ketoconazole (p≤0.05). Although E2 levels did not change significantly at any time, E2:testosterone ratios were significantly higher after ketoconazole (p≤0.01), and the LH:FSH area ratio was also significantly greater than 3 after ketoconazole. It is concluded that ketoconazole significantly alleviates hirsutism by inhibiting steroid synthesis.

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