Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN):A randomised, two-by-two factorial trial

Background: In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. Methods: In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. Findings: Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05–1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97–1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. Interpretation: In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. Funding: The Netherlands Organization for Health Research and Development

Impaired glucose metabolism in patients with primary aldosteronism is associated with cortisol cosecretion

Primärer Hyperaldosteronismus (PA) gilt als die häufigste endokrinologische Ursache für einen sekundären Hypertonus. Patienten mit PA haben bedingt durch Hypertonie und Aldosteron-Exzess ein höheres Risiko für kardiovaskuläre und metabolische Folgeerkrankungen, wie zum Beispiel Typ 2 Diabetes Mellitus (T2DM). In den letzten Jahren wurde gehäuft eine Cortisol-Kosekretion bei PA-Patienten beobachtet. Diese könnte auch zu den beobachteten Dysregulationen im Glucosestoffwechsel führen Zielstellung: Das Ziel der vorliegenden Untersuchungen war, bei Patienten mit PA und Cortisol-Kosekretion, die Prävalenz von Störungen des Glucosestoffwechsels zu untersuchen und darzustellen. Wir führten bei 161 PA-Patienten des deutschen Conn-Registers bei Einschlussuntersuchung einen oralen Glucosetoleranztest (OGTT), sowie die komplette Testung für einen möglichen Hypercortisolismus (1mg Dexamethason-Suppressionstest (DST), Mitternachtsspeichelcortisol (LSC), Cortisol im 24h-Sammelurin (UFC)) durch. 76 dieser Patienten wurden ein Jahr später zur Folgeuntersuchung erneut untersucht. Eine weitere Analyse erfolgte durch einen Vergleich mit der populationsbasierten Kohorte der „Kooperative Gesundheitsforschung in der Region Augsburg“ (KORA)-F4 Studie. Der Vergleich mit den PA-Patienten erfolgte mittels 1:3 Matching nach Alter, Geschlecht und Kategorie des Body-Mass-Index. 125 der 161 untersuchten PA-Patienten (77,6%) zeigten in mindestens einem der Cushing-Screening Tests eine pathologische Antwort. Von diesen 125 Patienten wurden 6,4% erstmalig mit T2DM diagnostiziert. PA Patienten die eine pathologisches Ergebnis im DST zeigten hatten signifikant höhere 2h-Glucose-Werte im OGTT und wurden signifikant häufiger mit T2DM diagnostiziert als Patienten mit normalem DST (20% vs. 0,8%; p<0,0001) oder KORA Kontrollen (20,6% vs. 5,9%; p=0,022). Bei PA-Patienten ohne Cortisol-Kosekretion, beobachteten wir höhere Werte für homeostatic model assessment of insulin resistance (HOMA-IR). Cortisol-Kosekretion ist eine häufige Erscheinung bei Patienten mit PA und führt zu Dysregulationen des Glucosestoffwechsels, wie einer höheren Prävalenz für T2DM. Bei Patienten mit alleinigem Aldosteron-Überschuss kommt es verstärkt zu einer Insulinresistenz.Primary Aldosteronism (PA) is known to be the most common endocrinological cause for secondary hypertension. Patients with PA are at a higher risk to suffer from cardiovascular and metabolic diseases, including type 2 diabetes mellitus (T2DM). Recent studies suggest a cortisol cosecretion in patients with PA, which could also lead to observed changes in glucose metabolism. The effect of cortisol cosecretion on glucose metabolism has not been investigated so far. Our goal was to evaluate the prevalence of impaired glucose metabolism in patients with PA and cortisol cosecretion. 161 PA patients of the German Conn Registry underwent an oral glucose tolerance test (OGTT) and complete testing for hypercortisolism (including 1mg dexamethasone suppression test (DST), late-night salivary cortisol (LSC) and 24-hour urinary free cortisol (UFC)) at baseline visit. Follow-up was performed one year later in 76 of those patients. In order to further investigate our results, we performed a 1:3 matching by sex, age and body mass index category with a population-based sample from the Cooperative Health Research in the Region of Augsburg (KORA)- F4. 125 (77.6%) of the 161 investigated patients showed a pathological response in at least one of the performed screening tests for hypercortisolism. In those 125 patients we detected T2DM in 6.4%. Patients who showed a pathological response in DST showed significantly higher values for 2-hour- plasma glucose in OGTT and were diagnosed with T2DM significantly more often than patients with normal DST (20% vs. 0.8%; p<0.0001) or matched KORA controls (20.6% vs. 5.9%; p=0.022). In PA patients without cortisol cosecretion we observed higher values for homeostatic-model-assessment of insulin resistance (HOMA-IR). Cortisol cosecretion in PA is a frequent finding and leads to impairment of glucose metabolism, including a higher prevalence of T2DM. Isolated aldosterone excess impairs insulin-resistance

Acceptability of a perturbation-based balance training programme for falls prevention in older adults:a qualitative study

INTRODUCTION: Perturbation-based balance training (PBT) is reported to effectively reduce falls in older adults and may even be superior compared with various exercise programmes. Due to the nature of the intervention, requiring unpredictable balance perturbations, the question arises whether acceptability is an issue in PBT. OBJECTIVE: To evaluate the acceptability of PBT in older adults with a recent history of falls. DESIGN, METHOD, PARTICIPANTS AND SETTING: This is a qualitative study in which semistructured interviews were conducted in 16 older adults (14 women and 2 men, mean age 73.6±6.0 years) who completed a three-session PBT protocol as part of another study in a university medical centre in the Netherlands. Typical case and purposive sampling strategies were applied. Interviews were based on the theoretical framework of acceptability (TFA) alongside context-specific factors and analysed using a template analysis approach. RESULTS: The results indicate that this PBT protocol is perceived as acceptable by older adults with a recent history of falls and highlight key areas for potential future modifications. Enjoyment of the novel training and technology, being able to feel safe during training, and perceived impact of increased self-efficacy and balance confidence were identified as facilitating factors. Potential issues included initial apprehension or anxiety during training and perceived impact being predominantly psychological instead of physical. Complementary to the TFA one additional theme emerged which described challenges regarding the training setting, such as preference for group training in some participants and travel to the training location. CONCLUSIONS: The results suggest that PBT is perceived acceptable by older adults with a history of falls. Increasing the social aspect of training and sharing the experiences of peers may be considered to enhance acceptability to new participants who initially feel apprehensive or anxious about their ability to participate in future implementation of PBT. TRIAL REGISTRATION NUMBER: The article is linked to a randomised clinical trial registered on https://www.trialregister.nl/trial/7680, NL7680; Results

Acceptability of a perturbation-based balance training programme for falls prevention in older adults: a qualitative study

INTRODUCTION: Perturbation-based balance training (PBT) is reported to effectively reduce falls in older adults and may even be superior compared with various exercise programmes. Due to the nature of the intervention, requiring unpredictable balance perturbations, the question arises whether acceptability is an issue in PBT. OBJECTIVE: To evaluate the acceptability of PBT in older adults with a recent history of falls. DESIGN, METHOD, PARTICIPANTS AND SETTING: This is a qualitative study in which semistructured interviews were conducted in 16 older adults (14 women and 2 men, mean age 73.6±6.0 years) who completed a three-session PBT protocol as part of another study in a university medical centre in the Netherlands. Typical case and purposive sampling strategies were applied. Interviews were based on the theoretical framework of acceptability (TFA) alongside context-specific factors and analysed using a template analysis approach. RESULTS: The results indicate that this PBT protocol is perceived as acceptable by older adults with a recent history of falls and highlight key areas for potential future modifications. Enjoyment of the novel training and technology, being able to feel safe during training, and perceived impact of increased self-efficacy and balance confidence were identified as facilitating factors. Potential issues included initial apprehension or anxiety during training and perceived impact being predominantly psychological instead of physical. Complementary to the TFA one additional theme emerged which described challenges regarding the training setting, such as preference for group training in some participants and travel to the training location. CONCLUSIONS: The results suggest that PBT is perceived acceptable by older adults with a history of falls. Increasing the social aspect of training and sharing the experiences of peers may be considered to enhance acceptability to new participants who initially feel apprehensive or anxious about their ability to participate in future implementation of PBT. TRIAL REGISTRATION NUMBER: The article is linked to a randomised clinical trial registered on https://www.trialregister.nl/trial/7680, NL7680; Results

Molecular Epidemiology of Coagulase-Negative Staphylococci Causing Sepsis in a Neonatal Intensive Care Unit over an 11-Year Period

Coagulase-negative staphylococci (CoNS) are the major causative microorganisms in neonatal nosocomial sepsis. Previous studies have shown that CoNS sepsis in the neonatal intensive care unit (NICU) is caused by predominant molecular types that are widely distributed among both neonates and staff. Some of these molecular types may persist in the NICU for years. The purpose of the present study was to determine the dynamic behavior of CoNS strains causing sepsis over a prolonged period of time by determining the molecular types of all blood isolates from septicemic infants over a period of 11 years (1991 to 2001). The results show that neonatal CoNS sepsis is increasingly caused by a few predominant molecular clusters. The most striking finding was that in recent years one molecular cluster emerged as the predominant cause of neonatal CoNS sepsis, responsible for no less than 31% (20 of 65) of blood isolates in 2001. Antibiotic resistance, particularly beta-lactam resistance, is probably an important selective force considering the high mecA gene carriage of CoNS blood isolates (70 to 92%). We conclude that neonatal CoNS sepsis is increasingly caused by a limited number of predominant molecular CoNS types and that antibiotic resistance is probably a major selective force

Impaired glucose metabolism in primary aldosteronism is associated with cortisol cosecretion

CONTEXT Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and metabolic risks. Recent studies report glucocorticoid co-secretion as a relevant phenotype of PA, which could contribute to associated risks, including type 2 diabetes mellitus (T2DM). The relationship between autonomous cortisol secretion (ACS) and glucose metabolism in PA has not been investigated. OBJECTIVE To evaluate the prevalence of impaired glucose homeostasis in PA patients according to cortisol co-secretion. METHODS We performed oral-glucose-tolerance-tests (OGTT) and complete testing for hypercortisolism (1mg-dexamethasone-suppression-test (DST), late-night-salivary-cortisol (LNC), 24hour-urinary-free-cortisol (UFC)) in 161 newly diagnosed PA patients of the German Conn Registry. 76 of 161 patients were reevaluated at follow-up. We compared our results to a population-based sample from the KORA-F4 study matched to the PA participants (3:1) by sex, age, and BMI. RESULTS At the time of diagnosis, 125 patients (77.6%) had a pathological response in at least one of the Cushing screening tests; T2DM was diagnosed in 6.4% of these 125 cases. Patients with pathological DST exhibited significantly higher 2h plasma glucose in OGTT and were significantly more often diagnosed with T2DM than patients with normal DST (20% vs. 0.8%, p<0.0001) and matched controls from the KORA study (20.6% vs. 5.9%.; p=0.022). PA patients without ACS tended to have higher homeostatic-model-assessment-of-insulin-resistance (HOMA-IR) than KORA control subjects (p=0.05). CONCLUSION ACS appears frequently in PA patients and is associated with impaired glucose metabolism, which could increase the risk of T2DM. PA itself seems to enhance insulin resistance

Serotypes, genotypes, and antibiotic susceptibility profiles of group B streptococci causing neonatal sepsis and meningitis before and after introduction of antibiotic prophylaxis.

Contains fulltext : 35391.pdf (publisher's version ) (Closed access)We studied the characteristics of strains isolated from neonates with group B streptococci sepsis and meningitis, before and after the introduction of antibiotic prophylaxis in The Netherlands. In 1999, 1 year after this introduction the serotype and genotype distribution and the susceptibility patterns of the GBS strains had not changed. Penicillins remain drugs of first choice to prevent and treat neonatal GBS disease

Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN): a randomised, two-by-two factorial trial

In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05-1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97-1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. The Netherlands Organization for Health Research and Developmen

Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN) : A randomised, two-by-two factorial trial

Background: In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. Methods: In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. Findings: Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05-1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97-1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. Interpretation: In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. Funding: The Netherlands Organization for Health Research and Development