Differential effects of 11 years of long-term injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in comparison with untreated controls: real-world data from a controlled registry study.

BACKGROUND AND SIGNIFICANCE: Obesity is a chronic disease, warranting long-term medical intervention. We evaluated effects of testosterone (T) therapy (Th) in men with T deficiency with normal weight, overweight and obesity on anthropometric and metabolic parameters, compared with untreated men. METHODS: Hypogonadal men (n = 823) with total T ≤ 12.1 nmol/L (age: 60.6 ± 7.0 years) participated in an ongoing registry study. Among these men 474 (57.6%) were obese, 286 (34.8%) overweight and 63 (7.7%) had normal weight. T undecanoate injections were administered to 428 men and 395 remained untreated. Anthropometric and metabolic parameters were measured at least twice a year and changes adjusted for confounding factors to account for baseline differences between groups. RESULTS: Long-term TTh in hypogonadal men, irrespective of weight at baseline, produced improvements in body weight, waist circumference (WC) and body mass index (BMI). Furthermore, TTh decreased fasting blood glucose and HbA1c and improved lipid profiles. Gradual decreases in blood pressure (systolic and diastolic) and pulse pressure occurred in men treated with T in each group. Marked reductions in mortality and major cardiovascular events were recorded in men receiving TTh. CONCLUSIONS: Our findings demonstrate that TTh produces reductions in weight, WC, and BMI. There were 77 (19.5%) deaths in the untreated groups and 23 (5.4%) in the T-groups. Based on these findings we suggest that long-term TTh in overweight and obese hypogonadal men produces progressive and sustained clinically meaningful weight loss and that TTh may contribute to reductions in mortality and incident major adverse cardiovascular events.

THYROID DYSFUNCTION IN AN AIDS PATIENT.

OBJECTIVE: Highly active antiretroviral therapy (HAART) is involved in the potential pathogenic mechanisms linking thyroid autoimmunity with immune restoration.The objective is to emphasize the emergence of autoimmune thyroid disease in a HIV patient long period after restoration of immune competence, unlinked to the immune reconstitution inflammatory syndrome (IRIS) occurring shortly after HAART initiation.We report a case of acute autoimmune thyroiditis with thyrotoxicosis in a patient with stage C3 HIV infection, who had been under HAART for more than 7 years.From the beginning there was a good immune response to the regimen, due to a good adherence and compliance (over 90%). Nine months after HAART initiation the viral load was undetectable (under 34 copies/µL) and the CD4 count reached 645 cells/mm3 (within normal range) after one year of treatment. Eight years after HAART initiation, based on clinical and laboratory findings, autoimmune thyroiditis was diagnosed. At this time immune competence with a normal CD4 count and a CD4/CD8 ratio over 1 was achieved. The chronic inflammation status of an HIV infection is the reason that autoimmunity appears outside the IRIS period. Treatment was initiated with antithyroid drugs.Thyroid function should be monitored periodically in HIV patients undergoing HAART. Future observations must be made for HIV related thyroid disorders using new classifications and studies with a larger number of patients.

Comparison of outcomes after endovascular and open repair of abdominal aortic aneurysms in low-risk patients.

BACKGROUND: In randomized trials endovascular aortic aneurysm repair (EVAR) has been shown to have superior perioperative outcomes compared with open aneurysm repair (OAR). However, outcomes in patients at low risk of complications are unclear and many surgeons still prefer OAR in this cohort. The objective was to analyse perioperative and longer-term outcomes of OAR and EVAR in this low-risk group of patients. METHODS: All elective infrarenal EVARs and OARs in the Vascular Study Group of New England database were reviewed from 2003 to 2014. The Medicare scoring system was used to identity patients at low risk of perioperative complications and death. Perioperative and longer-term outcomes were analysed in this cohort. A Kaplan-Meier plot was constructed for evaluation of longer-term survival. Further propensity matching and multivariable analysis were performed to analyse additional differences between the two groups. RESULTS: Some 1070 patients who underwent EVAR and 476 who had OAR were identified. Mean(s.d.) age was 67·3(5·7) and 65·1(6·3) years respectively (P < 0·001). EVAR was associated with a lower overall perioperative complication rate (4·2 versus 26·5 per cent; P < 0·001). There was no difference in 30-day mortality (0·4 versus 0·6 per cent; P = 0·446). Overall survival at 3 years was similar after EVAR and OAR (92·5 versus 92·1 per cent respectively; P = 0·592). In multivariable analyses there was no difference in freedom from reintervention (odds ratio 1·69, 95 per cent c.i. 0·73 to 3·90; P = 0·220) or survival (hazard ratio 0·85, 0·61 to 1·20; P = 0·353). CONCLUSION: In patients predicted to be at low risk of perioperative death following aneurysm repair, EVAR resulted in fewer perioperative complications than OAR. However, perioperative mortality, reinterventions and survival rates in the longer term appeared similar between endovascular and open repair.

Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies.

BACKGROUND/OBJECTIVES: Long-term testosterone replacement therapy (TRT) up to 5 years has been shown to produce progressive and sustainable weight loss (WL) in hypogonadal men. This study investigated effects of long-term TRT up to 8 years in hypogonadal men with different obesity classes. SUBJECTS/METHODS: From two independent observational registries we identified a total of 411 obese, hypogonadal men receiving TRT in urological clinics. The effects of TRT on anthropometric as well as metabolic parameters were studied for a maximum duration of 8 years, mean follow-up: 6 years. All men received long-acting injections of testosterone undecanoate in 3-monthly intervals. RESULTS: In all three classes of obesity, T therapy produced significant WL, decrease in waist circumference (WC) and body mass index (BMI). In patients with class I obesity, mean weight decreased from 102.6±6.4 to 84.1±4.9 kg, change from baseline: -17.4±0.5 kg and -16.8±0.4%. WC in this group of patients decreased from 106.8±7.4 to 95.1±5.3 cm, change from baseline: -10.6±0.3 cm. BMI decreased from 32.69±1.4 to 27.07±1.57, change from baseline: -5.52±0.15 kg m(-2). In patients with class II obesity, weight decreased from 116.8±6.9 to 91.3±6.3 kg, change from baseline: -25.3±0.5 kg and -21.5±0.4%. WC decreased from 113.5±7.5 to 100.0±5.4 cm, change from baseline: -13.9±0.4 cm. BMI decreased from 37.32±1.45 to 29.49±1.71, change from baseline: -8.15±0.17 kg m(-2). In patients with class III obesity, weight decreased from 129.0±5.6 to 98.9±4.8 kg, change from baseline: -30.5±0.7 kg and -23.6±0.5%. WC decreased from 118.5±5.6 to 103.8±4.9 cm, change from baseline: -14.3±0.4 cm. BMI decreased from 41.93±1.48 to 32.46±1.59, change from baseline -9.96±0.29 kg m(-2). CONCLUSIONS: Testosterone therapy appears to be an effective approach to achieve sustained WL in obese hypogonadal men irrespective of severity of obesity. Based on these findings we suggest that T therapy offers safe and effective treatment strategy of obesity in hypogonadal men.

The effects of proton pump inhibition on patient-reported severity of dyspepsia when receiving dual anti-platelet therapy with clopidogrel and low-dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial.

BACKGROUND: Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patient-reported outcomes is undetermined. AIM: To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo. METHODS: We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial. RESULTS: Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 ± 0.17 vs. 6.40 ± 0.17, P = 0.001, and 10.61 ± 0.07 vs. 11.00 ± 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 ± 0.35 vs. 7.10 ± 0.37, P = 0.020 for pain intensity; 10.36 ± 0.12 vs. 10.93 ± 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up. CONCLUSIONS: In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline.

Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement.

In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.

Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study.

AIM: The goal of this study was to determine if long-term testosterone (T) therapy in men with hypogonadism, henceforth referred to as testosterone deficiency (TD), ameliorates or improves metabolic syndrome (MetS) components. METHODS: We performed a cumulative registry study of 255 men, aged between 33 and 69 years (mean 58.02 ± 6.30) with subnormal plasma total T levels (mean: 9.93 ± 1.38; range: 5.89-12.13 nmol/l) as well as at least mild symptoms of TD assessed by the Aging Males' symptoms scale. All men received treatment with parenteral T undecanoate 1000 mg (Nebido(®) , Bayer Pharma, Berlin, Germany), administered at baseline and 6 weeks and thereafter every 12 weeks for up to 60 months. Lipids, glucose, liver enzymes and haemoglobin A1c analyses were carried out in a commercial laboratory. Anthropometric measurements were also made throughout the study period. RESULTS: Testosterone therapy restored physiological T levels and resulted in reductions in total cholesterol (TC) [7.29 ± 1.03 to 4.87 ± 0.29 mmol/l (281.58 ± 39.8 to 188.12 ± 11.31 mg/dl)], low-density lipoprotein cholesterol [4.24 ± 1.07 to 2.84 ± 0.92 mmol/l (163.79 ± 41.44 to 109.84 ± 35.41 mg/dl)], triglycerides [3.14 ± 0.58 to 2.16 ± 0.13 mmol/l (276.16 ± 51.32 to 189.78 ± 11.33 mg/dl)] and increased high-density lipoprotein levels [1.45 ± 0.46 to 1.52 ± 0.45 mmol/l (56.17 ± 17.79 to 58.85 ± 17.51 mg/dl)] (p < 0.0001 for all). There were marked reductions in systolic and diastolic blood pressure, blood glucose, haemoglobin A1c , C-reactive protein (6.29 ± 7.96 to 1.03 ± 1.87 U/l), alanine aminotransferase and aspartate aminotransferase (p < 0.0001 for all). CONCLUSIONS: Long-term T therapy, at physiological levels, ameliorates MetS components. These findings strongly suggest that T therapy in hypogonadal men may prove useful in reducing the risk of cardiometabolic diseases.

Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Hypogonadism is associated with increased fat mass and reduced muscle mass, which contributes to obesity and health risks, such as cardiovascular disease.Testosterone treatment of hypogonadal men improves muscle mass and reduces fat mass; however, many of these studies are of short duration.Thus, the long-term effects of testosterone on body anthropometry are not known. WHAT THIS STUDY ADDS: Long-term testosterone treatment of hypogonadal men, up to 5 years duration, produced marked and significant decrease in body weight, waist circumference and body mass index. Hypogonadism contributes to reduced muscle mass and increased adiposity. Testosterone treatment ameliorates loss of muscle mass and reduces fat accumulation associated with hypogonadism. In this study, we evaluated the long-term effects of normalizing testosterone (T) levels in hypogonadal men on anthropometric parameters. Open-label, single-center, cumulative, prospective registry study of 261 men (32-84 years, mean 59.5 ± 8.4 years, with T levels ≤12 nmol L-1 [mean: 7.7 ± 2.1]). Among the 261 men on T treatment, we followed up on 260 men for at least 2 years, 237 for 3 years, 195 for 4 years and 163 for at least 5 years. Subjects received parenteral T undecanoate 1000 mg every 12 weeks after an initial interval of 6 weeks. Body weight (BW), waist circumference (WC) and body mass index (BMI) were measured at baseline and yearly after treatment with T. BW decreased from 100.1 ± 14.0 kg to 92.5 ± 11.2 kg and WC was reduced from 107.7 ± 10.0 cm to 99.0 ± 9.1 cm. BMI declined from 31.7 ± 4.4 m kg-2 to 29.4 ± 3.4 m kg-2. All parameters examined were statistically significant vs. baseline and vs. the previous year over 5 years, indicating a continuous weight loss (WL) over the full observation period. The mean per cent WL was 3.2 ± 0.3% after 1 year, 5.6 ± 0.3%, after 2 years, 7.5 ± 0.3% after 3 years, 9.1 ± 0.3% after 4 years and 10.5 ± 0.4% after 5 years. The data obtained from this uncontrolled, observational, registry study suggest that raising serum T to normal physiological levels in hypogonadal men produces consistent loss in BW, WC and BMI. These marked improvements were progressive over the 5 years of the study.

Poractant alfa and beractant treatment of very premature infants with respiratory distress syndrome.

OBJECTIVE: Comparison of the differences between availability of animal-derived surfactant preparations used to treat premature infants is incomplete. The objective of this study was to assess the short-term treatment efficacy of the two most commonly used surfactant preparations in the United States, beractant (100 mg kg(-1) initial and subsequent doses) and poractant alfa (200 mg kg(-1) initial and 100 mg kg(-1) subsequent doses), in very premature, mechanically ventilated infants <30 weeks gestation with respiratory distress syndrome (RDS). STUDY DESIGN: Inborn infants at two institutions, open label, 1:1, randomized controlled trial. Level of respiratory support for first 72 h of life. Morbidities of prematurity observed during the neonatal intensive care unit hospitalization. RESULT: We studied 52 infants 24 0/7 to 29 6/7 weeks gestation; 25 received poractant alfa (27.1±1.6 weeks, birth weight of 930±231 g) and 27 received beractant (26.7±1.7 weeks, P=0.343 and birth weight 900±271 g, P=0.668). Respiratory support for the first 72 h of life was lower in the poractant alfa than beractant group for mean airway pressure (MAP, P=0.003) and respiratory index (MAP × FiO(2), P=0.032). Infants in the poractant alfa group had a greater number of infants extubated at 48 (13/25 vs 6/27, P=0.027) and 72 h (15/25 vs 8/27, P=0.029) than the beractant group. Although the study was not powered to detect morbidities of prematurity, the prevalence of PDA and air leaks was less in the infants treated with poractant alfa than in those treated with beractant. Rates of bronchopulmonary dysplasia (8/23 vs 11/22, P=0.303) or death (2/25 [corrected] vs 5/27, P=0.272) were similar in the infants treated with poractant alfa and beractant, respectively. CONCLUSION: This study suggests significant short-term benefits to the use of the larger initial dose of poractant alfa than beractant in very premature infants with RDS. Further studies involving a larger number of preterm infants are needed to assess long-term effects.

Patent ductus arteriosus hemodynamics in very premature infants treated with poractant alfa or beractant for respiratory distress syndrome.

OBJECTIVE: Respiratory distress syndrome (RDS), requiring mechanical ventilation and exogenous surfactant treatment, and patent ductus arteriosus (PDA), are common co-morbidities in very premature infants. The effects of intra-tracheal surfactant administration on the cardiovascular and pulmonary systems in very premature infants with RDS and PDAs are not well characterized. We evaluated the effects of poractant alfa and beractant, surfactants with different rapidity of onset and duration of action, in very premature infants with RDS. To assess whether there were differences in PDA hemodynamics in very premature infants with RDS treated with poractant alfa and beractant during the first week of life and to assess whether poractant alfa or beractant had a direct effect on PDAs and PDA hemodynamics following the second dose of surfactant. STUDY DESIGN: We studied 50 in-born, very premature infants with RDS, 24 0 of 7 to 29 6 of 7 weeks gestation, treated with poractant alfa or beractant, in an open label, 1:1, randomized clinical trial. A subgroup of 16 patients with severe RDS, treated with a second dose of surfactant, had echocardiographical assessments before and 20 to 30 min after the second dose of surfactant. RESULT: There were 25 infants treated with poractant alfa (27.1±1.6 weeks, birth weight 930±231 g) and 25 treated with beractant (26.7±1.7 weeks, P=0.407 and birth weight 898±282 g, P=0.666). Clinically significant PDAs were diagnosed and treated in 8 of 25 (32%) of the poractant alfa and 19 of 25 (76%) of the beractant group (P=0.002). Indomethacin treatment was slightly earlier (3.4±2.5 days) in the poractant alfa than in the beractant group (5.1±4.9 days, P=0.038). Right ventricle pressure (RVP)/systolic arterial pressure (SAP) ratio in the first week was slightly lower in the poractant alfa (64±20%) than in the beractant (78±26%, P=0.048) group. Following a second dose of surfactant, neither poractant alfa nor beractant changed PDA flow. These hemodynamic observations were associated with less respiratory support in the poractant alfa group, allowing earlier extubation (13 of 25 at 48 h and 15 of 25 at 72 h), than in the beractant group (6 of 25 at 48 h, P=0.044, and 8 of 25 at 72 h, P=0.049). CONCLUSION: The more rapid improvement in pulmonary function in the poractant alfa-treated infants was associated with a lower RVP/SAP ratio and a corresponding earlier treatment with indomethacin. Neither surfactant had a significant direct effect on PDA hemodynamics. The lower frequency of clinically significant PDAs in the poractant alfa compared with the beractant group may represent an indirect effect of the differences in the pulmonary improvement induced by the two surfactants.

Tandem cycles of high-dose melphalan and autologous stem cell transplantation increases the response rate in AL amyloidosis.

Clinical outcomes of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation (HDM/SCT) are tightly linked to the achievement of a hematologic complete response (HCR). We conducted a prospective trial to determine whether a second cycle of HDM/SCT could induce HCR in patients in whom the plasma cell dyscrasia persisted following initial treatment with HDM/SCT. Sixty-two patients were enrolled. Nine patients (15%) were removed from the protocol. Of the 53 patients continuing in this study, four died within 100 days of treatment (8%), and 27 (55%) achieved an HCR at 6 months after the first cycle of HDM/SCT. Of the 22 patients who did not achieve an HCR after initial treatment, 17 received a second HDM/SCT, 1 died within 100 days of treatment (6%), while 5 (31%) achieved an HCR. Thus, the HCR rate was 67% (32/48) for surviving patients on study, 60% (32/53) for all patients who received initial cycle of HDM/SCT, and 56% (35/62) by intention-to-treat. The median survival for all patients enrolled on the trial has not yet been reached. Thus, tandem cycles of HDM/SCT can increase the proportion of patients who achieve an HCR.

Clinical effects of erdosteine in the treatment of acute respiratory tract diseases in children.

Erdosteine has positive effects on mucus rheology and transport due to the active metabolite (Metabolite I) which contains a free thiol group. Erdosteine inhibits bacterial adhesiveness and has antioxidant properties. A synergistic effect of erdosteine with various antibiotics has been demonstrated in pharmacological and clinical studies. The present study was multicenter, randomized, double-blind and placebo-controlled. The aims of the study were to compare a combination of erdosteine with amoxicillin against an amoxicillin-placebo combination in pediatric patients with acute lower respiratory tract disease. A total of 158 patients (78 in the erdosteine group and 80 in the placebo group) were treated for 7 +/- 2 days. The efficacy parameters were cough (primary), polypnea, rhonchi, rales and body temperature (all measured at baseline, on Day 3 and at the end of treatment). Safety was assessed by strictly monitoring the occurrence of adverse events and using standard laboratory parameters. The results of the intention-to-treat analysis showed that the severity of cough was decreased by 47% at Day 3 in the erdosteine group with a statistically significant difference compared to placebo, the difference was still significant at the final visit. The decrease in the severity of rales was significantly greater at Day 3 in the erdosteine group than in the placebo group. The incidence of polypnea and rhonchi in the two groups showed similar decreases, an improvement mainly due to the antibiotic. No adverse events occurred and no adverse changes in laboratory parameters were observed. It is concluded that the combination of erdosteine and amoxicillin is a safe medication which is clinically superior to that of the antibiotic combined with placebo, especially in regard to the effects on cough.