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Background: Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI; however, there have been almost no new therapeutic modalities since the development of diazoxide. Summary: Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in "developed" countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. Key Messages: This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited. [ABSTRACT FROM AUTHOR]

Improved local diagnosis of focal hyperinsulinism in the COVID-19 era by interstate radiopharmaceutical transport 2013; 98: E1786 - 9. 7 States LJ, Davis JC, Hamel SM, Becker SA, Zhuang H. 18F-6-Fluoro-l-Dopa PET/CT imaging of congenital hyperinsulinism. Interstate transport of SP 18 sp F-DOPA, rather than the infant, resulted in improved patient safety, reduced cost and shorter time to definitive treatment for an infant with focal congenital hyperinsulinism, but is primarily limited by its 8-h expiry window and requires a close collaborative and multidisciplinary approach. [Extracted from the article]

Phosphate therapy transiently increases phosphate concentrations, lowering ionised calcium concentrations, removing the stimulus to synthesise calcitriol and further reducing calcitriol concentrations. Low levels of phosphate are found in almost all types of rickets and is likely to cause the mineralisation defect, irrespective of the underlying pathophysiology. The tubular reabsorption rate of phosphorus (TRP), the maximal tubular reabsorption of phosphorus per glomerular filtration rate (TmP/GFR) and/or the urinary phosphate/creatinine are critical measurements to distinguish rickets due to insufficient intake (e.g. nutritional rickets), from all causes of rickets associated with renal phosphate wasting. Neurosurgical intervention may be required for craniosynostosis or associated complications.3,7 In summary, HR should be considered in cases of rickets presenting with hypophosphataemia, normal 25OHD levels or where Vitamin D treatment does not resolve the clinical, biochemical or radiological derangements. [Extracted from the article]

For neonates with a suspected congenital hypoglycaemia disorder the recommended goal of treatment is to maintain a plasma blood glucose concentration >3.9 mmol/L. Abnormal neurodevelopment occurs equally in hyperinsulinism that is transient, or persistent. Simultaneous measurement of plasma ACTH and cortisol is helpful, and an ACTH stimulation test may be required.2 4 ¶ I KCNJ11 i homozygous variants are causal variants expected to have resulted in severe diffuse hyperinsulinism in both cases. Following near-total pancreatectomy in both cases, Case 1 had persistent hyperinsulinism postoperatively and Case 2 developed secondary diabetes and pancreatic exocrine insufficiency. [Extracted from the article]

Subtotal pancreatectomy to treat the diffuse form of congenital hyperinsulinism (CHI) sometimes requires revisional surgery, with further pancreatic resection. In such operations, the intrapancreatic bile duct is at risk of injury during dissection and resection. A macrosomic male infant male was born following elective induction at 35 weeks' gestation, weighing 3.6kg. His nine-year-old sibling had a history of diazoxide-unresponsive diffuse CHI requiring near-total pancreatectomy at six weeks of age (one-week corrected age). That sibling had biallelic recessive (compound heterozygote) pathogenic ABCC8 variants c.[2041–21G > A]; [3130_3149del]. The same pathogenic variant was identified in utero in this infant, who was also unresponsive to diazoxide. A laparoscopic subtotal pancreatectomy was performed at six weeks of age (one-week corrected age), with a resection margin to the right side of the superior mesenteric/splenic veins and portal vein confluence. The uncinate process was also resected. Histological assessment confirmed diffuse disease. The patient had persisting hypoglycaemia refractory to maximal medical therapies, necessitating a further resection. Due to concerns regarding the exact course of the intrapancreatic bile duct, ICG was injected into the gall bladder at the commencement of the second dissection. This clearly demonstrated the intrapancreatic bile duct during dissection, becoming visible through the overlying pancreatic tissue during re-dissection. Damage to this duct was avoided by its early identification. Intracholecystic injection of indocyanine green may be used to aid identification of, and decrease the risk of intra-operative damage to, the bile duct during pancreatic surgery. [ABSTRACT FROM AUTHOR]

Paediatric thyroid nodules are more likely to be malignant compared with adults. Differentiated thyroid cancer, including papillary thyroid cancer, which accounts for more than 90% of cases, frequently presents as a thyroid nodule with or without cervical lymphadenopathy. The Bethesda System for Reporting Thyroid Cytopathology is well regarded to categorise thyroid nodules; however, false-negative results, particularly in larger nodules (>4 cm) due to sampling errors can occur. [Extracted from the article]

Background: Maturity‐onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 confirmed genes. Estimates of MODY prevalence vary widely, as genetic screening is usually restricted based on clinical features, even in population studies. We aimed to determine prevalence of MODY variants in a large and unselected pediatric diabetes cohort. Methods: MODY variants were assessed using massively parallel sequencing in the population‐based diabetes cohort (n = 1363) of the sole tertiary pediatric diabetes service for Western Australia (population 2.6 million). All individuals were screened, irrespective of clinical features. MODY variants were also assessed in a control cohort (n = 993). Results: DNA and signed consent were available for 821 children. Seventeen children had pathogenic/likely pathogenic variants in MODY genes, two diagnosed with type 2 diabetes, four diagnosed with antibody‐negative type 1 diabetes (T1DM), three diagnosed with antibody‐positive T1DM, and eight previously diagnosed with MODY. Prevalence of MODY variants in the sequenced cohort was 2.1%, compared to 0.3% of controls. Conclusions: This is the first comprehensive study of MODY variants in an unselected population‐based pediatric diabetes cohort. The observed prevalence, increasing access to rapid and affordable genetic screening, and significant clinical implications suggest that genetic screening for MODY could be considered for all children with diabetes, irrespective of other clinical features. [ABSTRACT FROM AUTHOR]

Objective: Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes, with multiple causative genes. Some MODY subtypes can be treated with sulfonylureas instead of insulin, improving glycemic control, complication rates, quality of life (QoL), and costs. Using massively parallel sequencing (MPS), we recently determined the prevalence of pathogenic/likely pathogenic MODY variants in an Australian pediatric diabetes cohort. Here, these data are used to estimate cost-effectiveness of using MPS for MODY in all pediatric diabetes cases compared with standard practice (sequencing limited to individuals with specific clinical features).Research Design and Methods: A Markov decision model was developed to estimate incremental costs and quality-adjusted life-years (QALYs) of MPS screening, modeled over 30 years. We used our observed prevalence of 2.14% compared with 0.7% for standard practice, based on published data. The probabilities and utility weightings of long-term diabetes complications were based on HbA1c and estimated from published data. A series of one-way sensitivity analyses were performed using the net monetary benefit framework.Results: Routine MPS screening for MODY was more effective and less costly than standard care screening, with 26 QALYs gained and 1,016,000 AUD (782,000 USD) saved per 1,000 patients. Cost of screening was fully offset within 10 years. Routine MPS screening remained dominant until MODY prevalence fell to <1.1%.Conclusions: Routine MPS screening for MODY in the pediatric population with diabetes could reduce health system costs and improve patient QoL. Our results make a compelling argument for routine genetic screening in all children with presumed type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

The article presents a case study of ABCC8 mutation in a family having highly suggestive history of maturity onset diabetes of the young. History of the patient included macrosomia at birth in addition to transient neonatal hyperinsulinemic hypoglycemia and polyuria. He experienced mild hypoglycemia with exercise and succeeded in removing his pump for some days without acquiring ketosis.

Insulin gene (INS) mutations cause a rare form of maturity‐onset diabetes of the young (MODY), a heterogeneous group of autosomal dominant diabetes with at least 14 confirmed causative genes. Here, we describe a family with MODY due to a novel INS mutation, detected using massively parallel sequencing (MPS). The proband presented aged 11 years with mild diabetic ketoacidosis. She was negative for IA2 and GAD antibodies. She had a strong family history of diabetes affecting both her two siblings and her mother, none of whom had ketosis but who were considered to have type 1 diabetes and managed on insulin, and her maternal grandfather, who was managed for decades on sulfonylureas. Of note, her younger sister had insulin deficiency but an elevated fasting proinsulin:insulin ratio of 76% (ref 5%‐30%). Sanger sequencing of HNF4A, HNF1A, and HNF1B in the proband was negative. Targeted MPS using a custom‐designed amplicon panel sequenced on an Illumina MiSeq detected a heterozygous INS mutation c.277G>A (p.Glu93Lys). Sanger sequencing confirmed the variant segregated with diabetes within the family. Structural analysis of this variant suggested disruption of a critical hydrogen bond between insulin and the insulin receptor; however, the clinical picture in some individuals also suggested abnormal insulin processing and insulin deficiency. This family has a novel INS mutation and demonstrated variable insulin deficiency. MPS represents an efficient method of MODY diagnosis in families with rarer gene mutations. [ABSTRACT FROM AUTHOR]

The article discusses the case of a twin boy diagnosed with congenital hyperinsulinism of infancy. Topics discussed include hypoglycemia manifestation of congenital hyperinsulinism of infancy, focal lesion in the pancreas revealed by 18 fluoro-dihydroxy phenylalanine positron emission tomography/computed tomography (PET-CT), and laparoscopic resection of the lesion.

Objective. To assess the effect of combined diazoxide-metformin therapy in obese adolescents treated for craniopharyngioma. Design. A prospective open-label 6-month pilot treatment trial in 9 obese subjects with craniopharyngioma. Diazoxide (2mg/kg divided b.i.d., maximum 200 mg/day) and metformin (1000 mg b.i.d.). Whole body insulin sensitivity index (WBISI) and areaunder- the-curve insulin (AUCins) were calculated. Results. Seven subjects completed: 4M/3F, mean ± SD age 15.4 ± 2.9 years, weight 99.7 ± 26.3 kg, BMI 35.5 ± 5.6 kg/m2, and BMI SDS 2.3 ± 0.3. Two were withdrawn due to vomiting and peripheral edema. Of participants completing the study, the mean ± SD weight gain, BMI, and BMI SDS during the 6 months were reduced compared to the 6 months prestudy (+1.2 ± 5.9 versus +9.5 ± 2.7 kg, P = .004; -0.3 ± 2.3 versus +2.2 ± 1.5 kg/m2, P = .04; -0.04 ± 0.15 versus +0.11 ± 0.08, P = .021, resp.). AUCins correlated with weight loss (r = 0.82, P = .02) and BMI decrease (r = 0.96, P = .009). Conclusion. Combined diazoxide-metformin therapy was associated with reduced weight gain in patients with hypothalamic obesity. AUCins at study commencement predicted effectiveness of the treatment [ABSTRACT FROM AUTHOR]

The authors respond to the comment on a 2019 article by Johnson et al on the cost-effectiveness of routine screening via massive parallel sequencing for maturity-onset diabetes of the young (MODY). They state that specific variant screening costs less than comprehensive initial screening, and that testing of presymptomatic individuals may lead to genetic discrimination. Also noted are time-consuming issues for genetic counseling due to the lack of certainty and unknown penetrance of variants.

The article focuses on the complication posed by Klebsiella pneumoniae bacteraemia to rotavirus gastroenteritis in infants with glucocorticoid deficiency being treated with stress-dose hydrocortisone. Delay in gastroduodenal healing is attributed to glucocorticoids. The most common cause of gastroenteritis is said to be rotavirus. It points out uncertainty in the impact of rotavirus vaccination on such complications as enteric gram-negative (EGN) bacteraemia.

The article highlights a case of differentiated thyroid carcinoma in a 13 year-old girl, which has a history of enlarging thyroid nodule ongoing for 4-months. In the ultrasound assessment, it was found that there was an enlargement of the right lobe of the thyroid gland caused by a cystic and nodular mass lesion. Hashimoto's thryroidtis was seen after a histopathology of the right thyroid lobe and left thyroid lobe was observed, which is most likely caused by the chemical phosphatidylinositol 3-kinase (P13K).

The article describes a case concerning a 12-month old infant girl of Indian descent admitted to the Royal Children's Hospital in Brisbane, Australia because of irritability, failure to bear weight, and hypocalcemia. It states that the radiological images of her wrists and knees were consistent with rickets, while blood tests confirmed that the patient had vitamin D, iron, and vitamin B12 deficiencies. After the quality and variety of the patient's diet was improved, she experienced rapid progression in gross motor development within 6 months.

The article offers information on several studies related to medicine. One study based on the metabolism of type 1 diabetes (T1D) reveals that T1D is increasing in young children. Another study conducted on chlamydia and gonorrhoea in suspected child sexual abuse reveals that rapid urine tests are required in such case. The last study on treatment of atopic dermatitis reveals that bleach baths are alternative treatment for atopic dermatitis.

The article examines the case of a 9 year-old girl with symptoms typical of hyperthyroidism. These symptoms included weakness, weight loss, irritability, sleeping difficulties, and rapid linear growth. She was diagnosed of Graves' disease and thyroid hormone receptors were seen in chondrocytes and osteoblasts. According to the article, accelerated linear growth may be caused by hyperthyroidism but such growth acceleration has usually been linked to accelerated bone age.

The study aimed to assess the relationship between alanine transaminase (ALT) and proposed aetiological factors in nonalcoholic fatty liver disease (NAFLD). These factors include adiposity, insulin resistance, free fatty acids (FFA), inflammatory cytokines, adipokines and oxidative stress. A cross-sectional comparative study of obese (n=20) and normal weight (n=36) adolescent subjects, aged 12-18 years was conducted. Parameters assessed included alanine aminotransferase, aspartate aminotransferase (AST), adiposity (BMI, waist circumference and Dual Energy X-ray Absorptiometry), homeostasis model of insulin resistance (HOMA-IR), FFA, triglycerides, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), leptin, adiponectin, endogenous antioxidant status (glutathione peroxidase, superoxide dismutase) and oxidative stress (free 8 isoprostane). Of all the subjects, only one (obese) had ALT and AST values above the reference range. For the remainder, the mean ALT of the obese group was higher than that of the control group, although all within the reference range. The geometric means (95% CO were 22.8 (16.7-31.1)"and 14.8 (13.7-16.2) respectively (P=0.011). Independent predictors for ALT were adiposity, FFA and TNF-α, explaining 49% of the variance. In conclusion, obese adolescents may have relatively increased ALT levels compared to normal-weight peers, the majority within the laboratory reference range. Adverse hepatic pathological effects may already be occurring, potentially increasing the risk of NAFLD. Factors postulated to play a role in the aetiology of NAFLD, such as FFA and TNF-α may be determinants from a young age. [ABSTRACT FROM AUTHOR]

The article focuses on a study regarding the dermatological complications of continuous subcutaneous insulin infusion (CSII) in children and adolescents. The study also aimed to determine the relation of the severity of the changes with factors such as duration of CSII use, age and insulin dose. Results showed that there was negative correlation between severity and body mass index (BMI) as well as hemoglobin A (HbA)1c. It notes that scars and erythema were the common complications.

Background: Osteoporosis is a disorder of bone mineralisation occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. This is an updated version of a previous review., Objectives: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis., Search Methods: We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register of references (identified from electronic database searches and hand searches of journals and abstract books) on 5 May 2022. We performed additional searches of PubMed, clinicaltrials.gov and the WHO ICTRP (International Clinical Trials Registry Platform) on 5 May 2022., Selection Criteria: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis., Data Collection and Analysis: Authors independently selected trials, extracted data and assessed risk of bias in included studies. Trial investigators were contacted to obtain missing data. We judged the certainty of the evidence using GRADE., Main Results: We included nine trials with a total of 385 participants (272 adults and 113 children (aged five to 18 years)). Trial durations ranged from six months to two years. Only two of the studies were considered to have a low risk of bias for all the domains.  Bisphosphonates compared to control in people with cystic fibrosis who have not had a lung transplant Seven trials included only adult participants without lung transplants, one trial included both adults and children without lung transplantation (total of 238 adults and 113 children). We analysed adults (n = 238) and children (n = 113) separately. Adults Three trials assessed intravenous bisphosphonates (one assessed pamidronate and two assessed zoledronate) and five trials assessed oral bisphosphonates (one assessed risedronate and four assessed alendronate). Bisphosphonates were compared to either placebo or calcium (with or without additional vitamin D). Data showed no difference between treatment or control groups in new vertebral fractures at 12 months (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.02 to 2.09; 5 trials, 142 participants; very low-certainty evidence) and two trials (44 participants) reported no vertebral fractures at 24 months. There was no difference in non-vertebral fractures at 12 months (OR 2.11, 95% CI 0.18 to 25.35; 4 trials, 95 participants; very low-certainty evidence) and again two trials (44 participants) reported no non-vertebral fractures at 24 months. There was no difference in total fractures between groups at 12 months (OR 0.57, 95% CI 0.13 to 2.50; 5 trials, 142 participants) and no fractures were reported in two trials (44 participants) at 24 months. At 12 months, bisphosphonates may increase bone mineral density at the lumbar spine (mean difference (MD) 6.31, 95% CI 5.39 to 7.22; 6 trials, 171 participants; low-certainty evidence) and at the hip or femur (MD 4.41, 95% 3.44 to 5.37; 5 trials, 155 participants; low-certainty evidence). There was no clear difference in quality of life scores at 12 months (1 trial, 47 participants; low-certainty evidence), but bisphosphonates probably led to more adverse events (bone pain) at 12 months (OR 8.49, 95% CI 3.20 to 22.56; 7 trials, 206 participants; moderate-certainty evidence). Children The single trial in 113 children compared oral alendronate to placebo. We graded all evidence as low certainty. At 12 months we found no difference between treatment and placebo in new vertebral fractures (OR 0.32, 95% CI 0.03 to 3.13; 1 trial, 113 participants) and non-vertebral fractures (OR 0.19, 95% CI 0.01 to 4.04; 1 trial, 113 participants). There was also no difference in total fractures (OR 0.18, 95% CI 0.02 to 1.61; 1 trial, 113 participants). Bisphosphonates may increase bone mineral density at the lumbar spine at 12 months (MD 14.50, 95% CI 12.91 to 16.09). There was no difference in bone or muscle pain (MD 3.00, 95% CI 0.12 to 75.22), fever (MD 3.00, 95% CI 0.12 to 75.22) or gastrointestinal adverse events (OR 0.67, 95% CI 0.20 to 2.26). The trial did not measure bone mineral density at the hip/femur or report on quality of life.  Bisphosphonates compared to control in people with cystic fibrosis who have had a lung transplant One trial of 34 adults who had undergone lung transplantation compared intravenous pamidronate to no bisphosphonate treatment. It did not report at 12 months and we report the 24-month data (not assessed by GRADE). There was no difference in the number of fractures, either vertebral or non-vertebral. However, bone mineral density increased with treatment at the lumbar spine (MD 6.20, 95% CI 4.28 to 8.12) and femur (MD 7.90, 95% CI 5.78 to 10.02). No participants in either group reported either bone pain or fever. The trial did not measure quality of life., Authors' Conclusions: Oral and intravenous bisphosphonates may increase bone mineral density in people with cystic fibrosis, but there are insufficient data to determine whether treatment reduces fractures. Severe bone pain and flu-like symptoms may occur with intravenous bisphosphonates. Before any firm conclusions can be drawn, trials in larger populations, including children, and of longer duration are needed to determine effects on fracture rate and survival. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids can ameliorate or prevent these adverse events. Future trials should also assess gastrointestinal adverse effects associated with oral bisphosphonates., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P < 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G>A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted "benign" variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.

Background: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids., Objectives: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis., Search Methods: We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 13 January 2014.Additional searches of PubMed were performed on 13 January 2014., Selection Criteria: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis., Data Collection and Analysis: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data., Main Results: Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02)., Authors' Conclusions: Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

Background: Gestational diabetes mellitus (GDM) is associated with a range of adverse pregnancy outcomes for mother and infant. The prevention of GDM using lifestyle interventions has proven difficult. The gut microbiome (the composite of bacteria present in the intestines) influences host inflammatory pathways, glucose and lipid metabolism and, in other settings, alteration of the gut microbiome has been shown to impact on these host responses. Probiotics are one way of altering the gut microbiome but little is known about their use in influencing the metabolic environment of pregnancy., Objectives: To assess the effects of probiotic supplementation when compared with other methods for the prevention of GDM., Search Methods: We searched the Cochrane Pregnancy and childbirth Group's Trials Register (31 August 2013) and reference lists of the articles of retrieved studies., Selection Criteria: Randomised and cluster-randomised trials comparing the use of probiotic supplementation with other methods for the prevention of the development of GDM. Cluster-randomised trials were eligible for inclusion but none were identified. Quasi-randomised and cross-over design studies are not eligible for inclusion in this review. Studies presented only as abstracts with no subsequent full report of study results would also have been excluded., Data Collection and Analysis: Two review authors independently assessed study eligibility, extracted data and assessed risk of bias of included study. Data were checked for accuracy., Main Results: Eleven reports (relating to five possible trials) were found. We included one study (six trial reports) involving 256 women. Four other studies are ongoing.The included trial consisted of three treatment arms: probiotic with dietary intervention, placebo and dietary intervention, and dietary intervention alone; it was at a low risk of bias. The study reported primary outcomes of a reduction in the rate of gestational diabetes mellitus (risk ratio (RR) 0.38, 95% confidence interval (CI) 0.20 to 0.70), with no statistical difference in the rates of miscarriage/intrauterine fetal death (IUFD)/stillbirth/neonatal death (RR 2.00, 95% CI 0.35 to 11.35). Secondary outcomes reported were a reduction in infant birthweight (mean difference (MD) -127.71 g, 95% CI -251.37 to -4.06) in the probiotic group and no clear evidence of increased risk of preterm delivery (RR 3.27, 95% CI 0.44 to 24.43), or caesarean section rate (RR 1.23, 95% CI 0.65 to 2.32). The primary infant outcomes of rates of macrosomia and large-for-gestational age infants were not reported. The following secondary outcomes were not reported: maternal gestational weight gain, pre-eclampsia, and the long-term diagnosis of diabetes mellitus; infant body composition, shoulder dystocia, admission to neonatal intensive care, jaundice, hypoglycaemia and long-term rates of obesity and diabetes mellitus., Authors' Conclusions: One trial has shown a reduction in the rate of GDM when women are randomised to probiotics early in pregnancy but more uncertain evidence of any effect on miscarriage/IUFD/stillbirth/neonatal death. There are no data on macrosomia. At this time, there are insufficient studies to perform a quantitative meta-analysis. Further results are awaited from four ongoing studies.

Background: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids., Objectives: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis., Search Methods: We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 15 February 2012.Additional searches of PubMed were performed on 14 May 2011., Selection Criteria: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis., Data Collection and Analysis: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data., Main Results: Nine trials were identified and seven (with a total of 237 adult participants) were included.Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02)., Authors' Conclusions: Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

Background: Osteoporosis is a bone mineralisation disorder occurring in about one third of adults with cystic fibrosis (CF). Bisphosphonates can increase bone mineral density (BMD) and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids., Objectives: To assess the effects of bisphosphonates on the frequency of fractures, BMD, quality of life, adverse events, trial withdrawals, and survival in people with CF., Search Strategy: We searched the CF and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 29 October 2008.Additional searches of Pubmed were performed on 01 November 2008., Selection Criteria: Randomised controlled trials of at least six months duration studying bisphosphonates in people with CF., Data Collection and Analysis: Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data., Main Results: Seven trials were identified and five (with a total of 145 adult participants) were included.Data were combined when available from four included studies in participants without a lung transplant. This showed that there was no significant reduction in fractures between groups. However, after six months, the percentage change in BMD increased in those on bisphosphonates at the lumbar spine, mean difference (MD) 4.61 (95% confidence interval (CI) 3.90 to 5.32) and at the hip, MD 3.35 (95% CI 1.63 to 5.07); but did not significantly change at the distal forearm, MD -0.49 (95% CI -2.42-1.45). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, BMD increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, MD 6.20 (95% CI 4.28 to 8.12) and femur MD 7.90 (95% CI 5.78 to 10.02)., Authors' Conclusions: Oral and intravenous bisphosphonates increase BMD in people with CF. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Trials in larger populations are needed to determine effects on fracture rate and survival.