In this review, we summarize our current understanding of the pathophysiology of fragility fractures that occur for the first time during pregnancy and lactation, and provide guidance on appropriate ...investigations and treatment strategies. Most affected women will have had no prior bone density reading, and so the extent of bone loss that may have occurred during pregnancy or lactation is uncertain. During pregnancy, intestinal calcium absorption doubles in order to meet the fetal demand for calcium, but if maternal intake of calcium is insufficient to meet the combined needs of the mother and baby, the maternal skeleton will undergo resorption during the third trimester. During lactation, several hormonal changes, independent of maternal calcium intake, program a 5–10 % loss of trabecular mineral content in order to provide calcium to milk. After weaning the baby, the maternal skeleton is normally restored to its prior mineral content and strength. This physiological bone resorption during reproduction does not normally cause fractures; instead, women who do fracture are more likely to have additional secondary causes of bone loss and fragility. Transient osteoporosis of the hip may affect one or both femoral heads during pregnancy but it involves localized edema and not skeletal resorption. Case reports have described the use of calcitonin, bisphosphonates, strontium ranelate, teriparatide, vertebroplasty, and kyphoplasty to treat post-partum vertebral fractures. However, the need for such treatments is uncertain given that a progressive increase in bone mass subsequently occurs in most women who present with a fracture during pregnancy or lactation.
Aims
This study investigated the efficacy and tolerability of empagliflozin as add‐on to pioglitazone ± metformin in patients with type 2 diabetes (T2DM).
Methods
Patients with HbA1c ≥7 and ≤10% were ...randomized and treated with once daily empagliflozin 10 mg (n = 165), empagliflozin 25 mg (n = 168) or placebo (n = 165) as add‐on to pioglitazone ± metformin for 24 weeks. Endpoints included changes from baseline in HbA1c (primary endpoint), fasting plasma glucose (FPG) and body weight at week 24.
Results
Adjusted mean ± standard error changes in HbA1c were −0.6 ± 0.07% and −0.7 ± 0.07% with empagliflozin 10 mg and 25 mg, respectively, vs. −0.1 ± 0.07% with placebo (both p < 0.001). More patients with HbA1c ≥7% at baseline achieved HbA1c <7% with empagliflozin 10 mg (23.8%) and 25 mg (30.0%) vs. placebo (7.7%) (both p < 0.001). FPG decreased with empagliflozin (−0.94 mmol/l for 10 mg and −1.22 mmol/l for 25 mg) and increased with placebo (+0.36 mmol/l; both p < 0.001). Adjusted mean ± standard error changes in weight were −1.62 ± 0.21 kg and −1.47 ± 0.21 kg with empagliflozin 10 mg and 25 mg, respectively, vs. +0.34 ± 0.21 kg with placebo (both p < 0.001). Similar proportions of patients reported adverse events with empagliflozin (67.3–71.4%) and placebo (72.7%). Confirmed hypoglycaemia was reported by 1.2–2.4% of patients on empagliflozin and 1.8% on placebo.
Conclusion
Empagliflozin 10 mg and 25 mg once daily for 24 weeks as add‐on to pioglitazone ± metformin reduced HbA1c, FPG and weight and were well tolerated in patients with T2DM.
Background
The National Early Warning Score (NEWS) is used to identify deteriorating patients in hospital. NEWS is a better discriminator of outcomes than other early warning scores in acute medical ...admissions, but it has not been evaluated in a surgical population. The study aims were to evaluate the ability of NEWS to discriminate cardiac arrest, death and unanticipated ICU admission in patients admitted to surgical specialties, and to compare the performance of NEWS in admissions to medical and surgical specialties.
Methods
Hospitalwide data over 31 months, from adult inpatients who stayed at least one night or died on the day of admission, were analysed. The data were categorized as elective or non‐elective surgical or medical admissions. The ability of NEWS to discriminate the outcomes above in these different groups was assessed using the area under the receiver operating characteristic curve (AUROC).
Results
There were too few outcomes to permit meaningful comparison of elective admissions, so the analysis was constrained to comparison of non‐elective admissions. NEWS performed equally well, or better, for surgical as for medical patients. For death within 24 h the AUROC for surgical admissions was 0·914 (95 per cent c.i. 0·907 to 0·922), compared with 0·902 (0·898 to 0·905) for medical admissions. For the combined outcome of any of death, cardiac arrest or unanticipated ICU admission, the AUROC was 0·874 (0·868 to 0·880) for surgical admissions and 0·874 (0·871 to 0·877) for medical admissions.
Conclusion
NEWS discriminated deterioration in non‐elective surgical patients at least as well as in non‐elective medical patients.
Effective early warning
During pregnancy, female physiology adapts to meet the additional mineral demands of the developing fetus. Meanwhile, the fetus actively transports minerals across the placenta and maintains high ...circulating levels to mineralize the rapidly developing skeleton. Most of this mineral is accreted during the last trimester, including 30 g of calcium, 20 g of phosphate and 0.8 g of magnesium. Given the dependence of calcium homeostasis on vitamin D and calcitriol in the adult and child, it may be expected that vitamin D sufficiency would be even more critical during pregnancy and fetal development. However, the pregnant mother and fetus appear to meet their mineral needs independent of vitamin D. Adaptations in maternal mineral and bone metabolism during pregnancy appear to be invoked independent of maternal vitamin D, while fetal mineral metabolism and skeletal development appear to be protected from vitamin D deficiency and genetic disorders of vitamin D physiology. This review discusses key data from both animal models and human studies to address our current knowledge on the role of vitamin D and calcitriol during pregnancy and fetal development.
In this research, indicator properties of the three recently described diatom ecological guilds (low profile, high profile and motile) and their responses to different stressors and disturbances were ...tested along a temporal gradient. Experiments were run at a standard sampling site in the Torna-stream (Hungary) between 2008 and 2010 using standardized substrata. The low profile guild was dominant during periods with low nutrient (SRP and TN) availability. In contrast, the high profile guild was dominant in resource rich (SRP and SRSi) periods. The motile ecological guild was the most sensitive to the nutrients (TN and SRSi) and some other factors (e.g. temperature, Cl−). Increasing irradiance in spring and summer favored the growth of the high and the low profile guild. Higher resistance to floods favored the adhesion type of the low profile guild enabling their summer peak in terms of relative abundance. During high flood periods, incident light availability apparently sufficed the needs of this guild. Seasonal changes of the diatom ecological guilds and guild diversity were robust and predictable. This study supported that the ecological responses of diatom ecological guilds, despite the apparent simplicity of the grouping method, is strong enough to indicate the temporally changing environmental conditions.
Summary A new Canadian WHO fracture risk assessment (FRAX®) tool to predict 10-year fracture probability was compared with observed 10-year fracture outcomes in a large Canadian population-based ...study (CaMos). The Canadian FRAX tool showed good calibration and discrimination for both hip and major osteoporotic fractures. Introduction The purpose of this study was to validate a new Canadian WHO fracture risk assessment (FRAX®) tool in a prospective, population-based cohort, the Canadian Multicentre Osteoporosis Study (CaMos). Methods A FRAX tool calibrated to the Canadian population was developed by the WHO Collaborating Centre for Metabolic Bone Diseases using national hip fracture and mortality data. Ten-year FRAX probabilities with and without bone mineral density (BMD) were derived for CaMos women (N = 4,778) and men (N = 1,919) and compared with observed fracture outcomes to 10 years (Kaplan-Meier method). Cox proportional hazard models were used to investigate the contribution of individual FRAX variables. Results Mean overall 10-year FRAX probability with BMD for major osteoporotic fractures was not significantly different from the observed value in men predicted 5.4% vs. observed 6.4% (95%CI 5.2-7.5%) and only slightly lower in women predicted 10.8% vs. observed 12.0% (95%CI 11.0-12.9%). FRAX was well calibrated for hip fracture assessment in women predicted 2.7% vs. observed 2.7% (95%CI 2.2-3.2%) but underestimated risk in men predicted 1.3% vs. observed 2.4% (95%CI 1.7-3.1%). FRAX with BMD showed better fracture discrimination than FRAX without BMD or BMD alone. Age, body mass index, prior fragility fracture and femoral neck BMD were significant independent predictors of major osteoporotic fractures; sex, age, prior fragility fracture and femoral neck BMD were significant independent predictors of hip fractures. Conclusion The Canadian FRAX tool provides predictions consistent with observed fracture rates in Canadian women and men, thereby providing a valuable tool for Canadian clinicians assessing patients at risk of fracture.
Bacterial cell wall dynamics have been implicated as important determinants of cellular physiology, stress tolerance, and virulence. In
, the cell wall is composed primarily of a rhamnose-glucose ...polysaccharide (RGP) linked to the peptidoglycan. Despite extensive studies describing its formation and composition, the potential roles for RGP in
biology have not been well investigated. The present study characterizes the impact of RGP disruption as a result of the deletion of
, the gene encoding a rhamnosyltransferase involved in the construction of the core polyrhamnose backbone of RGP. The Δ
mutant strain displayed an overall reduced fitness compared to the wild type, with heightened sensitivities to various stress-inducing culture conditions and an inability to tolerate acid challenge. The loss of
caused a perturbation of membrane-associated functions known to be critical for aciduricity, a hallmark of
acid tolerance. The proton gradient across the membrane was disrupted, and the Δ
mutant strain was unable to induce activity of the F
F
ATPase in cultures grown under low-pH conditions. Further, the virulence potential of
was also drastically reduced following the deletion of
The Δ
mutant strain produced significantly less robust biofilms, indicating an impairment in its ability to adhere to hydroxyapatite surfaces. Additionally, the Δ
mutant lost competitive fitness against oral peroxigenic streptococci, and it displayed significantly attenuated virulence in an
infection model. Collectively, these results highlight a critical function of the RGP in the maintenance of overall stress tolerance and virulence traits in
The cell wall of
, the bacterium most commonly associated with tooth decay, is abundant in rhamnose-glucose polysaccharides (RGP). While these structures are antigenically distinct to
, the process by which they are formed and the enzymes leading to their construction are well conserved among streptococci. The present study describes the consequences of the loss of RgpF, a rhamnosyltransferase involved in RGP construction. The deletion of
resulted in severe ablation of the organism's overall fitness, culminating in significantly attenuated virulence. Our data demonstrate an important link between the RGP and cell wall physiology of
, affecting critical features used by the organism to cause disease and providing a potential novel target for inhibiting the pathogenesis of
.
Summary
Objective
To determine whether sclerostin is associated with fasting glucose, insulin levels, insulin resistance or increased risk of incident type 2 diabetes.
Background
Type 2 diabetic ...patients have a higher risk of fractures. Recent studies suggest sclerostin, a regulator of osteoblast activity, is associated with diabetes.
Materials and methods
Sclerostin levels were obtained from 1778 individuals with no history of type 2 diabetes participating in the population‐based Canadian Multicentre Osteoporosis Study (CaMos) cohort. Participants were followed until diagnosis of type 2 diabetes, death or end of the study period (31 December 2013). The relationship of sclerostin with fasting glucose, insulin levels and homoeostatic model assessment‐insulin resistance (HOMA‐IR) was studied in linear regression models. Cox proportional hazards models were used to determine the association of sclerostin levels and the risk of incident type 2 diabetes during a mean 7·5 years of follow‐up.
Results
Fasting glucose, fasting insulin levels and HOMA‐IR were weakly correlated with sclerostin levels (Spearman's correlation coefficient: 0·11, P < 0·05; −0·09, P < 0·05; and −0·07, P = 0·02, respectively). Multiple linear regression analyses confirmed a significant association between sclerostin and fasting insulin and HOMA‐IR but no significant association with fasting glucose levels. Sclerostin levels were not found to be significantly associated with the risk of incident type 2 diabetes (HR: 1·30; 95% CI: 0·37–4·57).
Conclusions
We observed an association between sclerostin levels with fasting insulin levels and HOMA‐IR, but there was no clear association with type 2 diabetes risk. Further studies are needed to understand the role of sclerostin in type 2 diabetes.
Interleukin-22 (IL-22) is a cytokine with epithelial reparative and regenerative properties that is produced by Th22 cells and by other immune cell subsets. Therefore, we explored the hypothesis that ...disruption of the gut barrier during HIV infection involves dysregulation of these cells in the gastrointestinal mucosa. Sigmoid IL-22-producing T cell and Th22 cells were dramatically depleted during chronic HIV infection, epithelial integrity was compromised, and microbial translocation was increased. These alterations were reversed after long-term antiretroviral therapy. While all mucosal IL-22-producing T-cell subsets were also depleted very early during HIV infection, at these early stages IL-22 production by non-T-cell populations (including NKp44+ cells) was increased and gut epithelial integrity was maintained. Circulating Th22 cells expressed a higher level of the HIV co-receptor/binding molecules CCR5 and α4β7 than CD4+ T-cell subsets in HIV-uninfected participants, but this was not the case after HIV infection. Finally, recombinant IL-22 was protective against HIV and tumor necrosis factor-α-induced gut epithelial damage in a validated in vitro gut epithelial system. We conclude that reduced IL-22 production and Th22 depletion in the gut mucosa are important factors in HIV mucosal immunopathogenesis.
Summary
In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction ...compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways.
Introduction
Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture.
Methods
A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models.
Results
There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate,
n
= 599, alendronate,
n
= 498, and risedronate
n
= 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks pairwise HR, 0.66 (95% CI, 0.48–0.91) while the less potent non-n-BP, etidronate, was not pairwise HR: 0.89 (95% CI, 0.66–1.20). A direct comparison between n-BP and etidronate (
n
= 340 pairs) also suggested a better survival for n-BP paired HR, 0.47 (95%CI, (95% CI, 031–0.70) for n-BP vs. etidronate.
Conclusion
Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.
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