Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence

OBJECTIVE: To assess cardiovascular (CV) safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice. DESIGN: Two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS. METHODS: Serious adverse events, serious adverse reactions (SARs), and non-serious adverse reactions (NSARs) were reported by the treating physicians. CV comorbidities at baseline and throughout the studies were also recorded. RESULTS: The safety analysis set comprised 412 children with NS (29.1% females), with a mean (standard deviation) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. CV comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No CV safety events were recorded in patients with NS. Five CV comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified CV disease, one ruptured abdominal aortic aneurysm and one pulmonary valve stenosis. CONCLUSIONS: GH treatment had a favourable safety profile in patients with NS, including those with CV comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with Noonan syndrome and CV disease

Factors associated with response to growth hormone in pediatric growth disorders: results of a 5-year registry analysis

Context Growth hormone (GH) therapy can increase linear growth in patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS), although outcomes vary by disease state. Objective To assess growth and identify factors associated with growth response with long-term GH therapy. Methods Data from pediatric patients with GHD, TS, NS, and PWS obtained at GH treatment initiation (baseline) and annually for 5 years in the ANSWER Program and NordiNet® IOS were analyzed retrospectively. Height standard deviation score (HSDS) was assessed over time, and multivariate analyses determined variables with significant positive effects on growth outcomes in each patient cohort. Results Data from patients with GHD (n = 12 683), TS (n = 1307), NS (n = 203), and PWS (n = 102) were analyzed. HSDS increased over time during GH treatment in all cohorts. Factors with significant positive effects on ΔHSDS were younger age at GH initiation and lower HSDS at baseline (all cohorts) and higher GH dose (GHD and TS only); sex had no effect in any cohort. The modeling analysis showed that ΔHSDS was greatest in year 1 and attenuated over consecutive years through year 5. Estimated least-squares mean ΔHSDS values at year 5 by cohort were 1.702 (females) and 1.586 (males) in GHD, 1.033 in TS, 1.153 in NS, and 1.392 in PWS. Conclusion Long-term GH therapy results in large increases in HSDS in patients with GHD, TS, NS, and PWS. Greater gains in HSDS can be obtained with higher GH doses and earlier initiation of treatment

Therapeutic effects of peripheral repetitive magnetic stimulation on myofascial pain syndrome

Objective: To evaluate short- and medium-term effects of peripheral repetitive magnetic stimulation (rMS) on myofascial pain. Methods: Eighteen patients who presented with myofascial trigger points (TPs) at the level of the superior trapezius were separated into two groups according to a restricted randomization scheme. Group 1 (n=9) underwent treatment with rMS that consisted of a total of 10 sessions, each lasting 20 min, in which 4000 magnetic stimuli were administered in 5 s trains at 20 Hz at the TP. Group 2 (n=9) received a placebo treatment that consisted of the application of a non-functioning ultrasound therapy device to the TP. Patients were evaluated before treatment, at the end of treatment, and again 1 week and 1 month after the conclusion of the treatment. Clinical evaluation included parameters for measuring pain levels (VAS, NPDVAS and algometry), the myofascial TP characteristics and the range of cervical movement (ROM). Results: The rMS group showed a significant improvement in VAS, NPDVAS, algometry, as well as in the characteristics of the TP after conclusion of treatment. Improvements in the ROM were also present in rotation and controlateral bending. This improvement persisted after 1 month. On the other hand, the placebo group did not show any significant improvement in the tests considered. Conclusions: The results of this study show that peripheral rMS may have positive short- and medium-term therapeutic effects on myofascial pain

Repetitive magnetic stimulation A novel therapeutic approach for myofascial pain syndrome.

The aim of this study was to evaluate the short, medium and long-term effects of peripheral repetitive magnetic stimulation (rMS) on myofascial pain compared with transcutaneous electrical nerve stimulation ( TENS). Fifty-three subjects with myofascial trigger points (TPs) at the level of the superior trapezius muscle were allocated randomly to three groups. The first group (n = 17) was treated with rMS, the second (n = 18) with TENS and the third (n = 18) received a placebo treatment. Each treatment consisted of ten daily 20-minute sessions. Patients were evaluated before and immediately following treatment, and at one and three months after the end of treatment. Outcome measures were: the "neck pain and disability visual analogue scale" (NPDVAS), an algometric evaluation of pain, an evaluation of the TP characteristics, and the range of cervical bending and rotation contralateral to the affected trapezius muscle. At the end of treatment, the rMS group showed a significant improvement in the NPDVAS, algometry, TP characteristics, and cervical contralateral rotation. This improvement also persisted at one and three months post-therapy. After treatment, the TENS group showed significant improvement in the same outcome measures except for algometry. At the one month follow-up visit, this improvement had returned to non significant levels in all outcome measures with the exception of NPDVAS. No significant effect of TENS was seen at the three-month follow-up visit. The placebo group showed no significant improvement in any measure. Our results strongly suggest that at medium and longer term intervals peripheral rMS may be more effective than TENS for the treatment of myofascial pain

Sub-acute exposure of male guppies (Poecilia reticulata) to environmentally relevant concentrations of PFOA and GenX induces significant changes in the testis transcriptome and reproductive traits

Poly- and perfluoroalkyl substances (PFAS) are frequently detected in the environment and are linked to adverse reproductive health outcomes in humans. Although legacy PFAS have been phased out due to their toxicity, alternative PFAS are increasingly used despite the fact that information on their toxic effects on reproductive traits is particularly scarce. Here, we exposed male guppies (Poecilia reticulata) for a short period (21 days) to an environmentally realistic concentration (1 ppb) of PFOA, a legacy PFAS, and its replacement compound, GenX, to assess their impact on reproductive traits and gene expression. Exposure to PFAS did not impair survival but instead caused sublethal effects. Overall, PFAS exposure caused changes in male sexual behaviour and had detrimental effects on sperm motility. Sublethal variations were also seen at the transcriptional level, with the modulation of genes involved in immune regulation, spermatogenesis, and oxidative stress. We also observed bioaccumulation of PFAS, which was higher for PFOA than for GenX. Our results offer a comprehensive comparison of these two PFAS and shed light on the toxicity of a newly emerging alternative to legacy PFAS. It is therefore evident that even at low concentrations and with short exposure, PFAS can have subtle yet significant effects on behaviour, fertility, and immunity. These findings underscore the potential ramifications of pollution under natural conditions and their impact on fish populations

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status

Introduction: Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated. Methods: This analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-na\uefve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin\uae, Novo Nordisk A/S). Results: A total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was -1.9 (1.1) and -1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses. Conclusions: GHT resulted in improved growth outcomes over 4 years in GHT-na\uefve, pre-pubertal NS patients, irrespective of PTPN11 mutation status

Long-term safety and efficacy of Omnitrope(®) in adults with growth hormone deficiency: Italian interim analysis of the PATRO Adults study

To report the long-term effectiveness and safety of the recombinant human growth hormone Omnitrope(®), a somatropin biosimilar to Genotropin(®), in Italian patients with growth hormone deficiency (GHD) enrolled in the PATRO Adults study.METHODS: The PATRO Adults study is an ongoing observational, longitudinal, non-interventional global post-marketing surveillance study, conducted in several European countries. The primary endpoint is long-term safety; secondary endpoints include the effectiveness of Omnitrope®, which was assessed using serum insulin-like growth factor-1 levels, body composition, bone mineral density and lipid levels. Here we report the data from the Italian patients enrolled in the study. RESULTS: Sixty-seven patients (mean age 50.4 years, 61.2% male) have been enrolled and have received a mean 45.4 ± 24.3 months of Omnitrope®. A total of 55.2% of patients were reported to have experienced adverse events (AEs), including arthralgia, myalgia, abdominal distension and hypoaesthesia, and 4.5% had adverse drug reactions. Fourteen serious AEs have been recorded; none of these are considered related to the study drug. The effectiveness of Omnitrope® was similar to other available somatropin preparations. CONCLUSIONS: This study confirms the effectiveness and safety of Omnitrope® in adult patients with GHD in Italy. However, due to the limited size of the study population, these results need to be further confirmed by the global PATRO Adults study