Evaluation of clinical performance and safety for the rechargeable InterStim Micro device in overactive bladder subjects: 6-month results from the global postmarket ELITE study.

AIMS: Sacral neuromodulation (SNM) is an advanced therapy option for the treatment of overactive bladder (OAB), nonobstructive urinary retention, and fecal incontinence. The aim of this ongoing prospective, multicenter, global, postmarket study is to confirm safety and clinical performance of the InterStimTM Micro system for SNM in all indications. Reported here are the results for the OAB cohort through 6-month follow-up. METHODS: Eligible OAB subjects that had a successful therapy evaluation were enrolled after implant of an InterStim Micro implantable pulse generator (IPG). Subjects completed voiding diaries and the Overactive Bladder Quality of Life questionnaire (OAB-q) at baseline and follow-up visits occurring at 3 months and 6 months postimplant. Safety was evaluated as device-, procedure-, or therapy-related adverse events. The primary objective for the OAB cohort was to demonstrate an improvement in OAB-q Health Related Quality of Life (HRQL) total score at 3 months postimplant compared to baseline. RESULTS: Sixty-eight OAB subjects were enrolled and implanted with an InterStim Micro IPG. Of those, 67 and 66 subjects completed the 3- and 6-month follow-up visits, respectively. The OAB-q HRQL demonstrated a statistically significant improvement from baseline to 3-month follow-up with an average increase of 33 ± 24 points (n = 67, p < 0.001). The change was also observed at 6-months with an average increase of 31 ± 23 points (n = 65) compared to baseline. Eighty-two percent of subjects achieved the minimally important difference in HRQL score at 3- and 6-month, respectively, with a change of 10 points or greater. The majority of subjects reported that their bladder condition was better at 3-month (92.5%, 62/67) and 6-month (89%, 59/66) compared to before they were treated with SNM therapy delivered by the InterStim Micro system. For subjects with urgency urinary incontinence (UUI), the average change from baseline to follow-up in UUI episodes/day was -3.6 (95% CI: -4.7, -2.6; n = 62) at 3-month and -3.7 (95% CI: -4.7, -2.7; n = 61) at 6-month. Among subjects with urgency-frequency (UF), the average change from baseline to follow up in voids/day was -4.5 (95% CI: -6.3, -2.7; n = 52) at 3-months and -4.4 (95% CI: -6.0, -2.7; n = 52) at 6-month. The cumulative incidence of device-, procedure-, or therapy- related adverse events was 7.4% (5/68). Out of these five related adverse events, there was one serious adverse event (1.5%, implant site pain) at the time of database snapshot. CONCLUSIONS: These data confirm the safety and clinical performance of the InterStim Micro device for subjects with OAB by demonstrating a significant improvement in OAB-q HRQL score at 3-month. Similar improvements were observed at 6 months in addition to an incidence of adverse events that is comparable to previously reported rates for SNM.

Management of Cancer-Related Pain With Intrathecal Drug Delivery: A Systematic Review and Meta-Analysis of Clinical Studies.

BACKGROUND: Despite increased attention paid to assessment and management, pain continues to be a prevalent and undertreated symptom in patients with cancer. Intrathecal drug delivery (IDD) is a therapeutic option that allows targeted delivery of analgesics to the intrathecal space. OBJECTIVE: The aim of this review was to examine the efficacy of managing cancer-related pain with IDD. Secondary objectives included the effects of IDD on systemic opioid use and infection rates. EVIDENCE REVIEW: A systematic search of the literature published between 1990 and 2019 was performed to identify studies evaluating the efficacy and/or safety of IDD with external or implanted pumps in patients with cancer-related pain. Data were extracted and meta-analyses performed to determine the mean changes in pain levels at short-, mid-, and long-term intervals; changes in opioid (oral morphine equivalent [OME]) daily dose; and infection rates. Changes were assessed compared with baseline. FINDINGS: Pain levels were decreased from baseline: On a 0 to 10 scale, mean differences were -4.34 (95% CI [-4.93 to -3.75], p < 0.001) at 4 to 5 weeks; -4.34 (95% CI [-5.07 to -3.62], p < 0.001) at 6 to 12 weeks; and -3.32 (95% CI [-4.60 to -2.04], p < 0.001) at >6 months. Weighted mean OME consumption was reduced by 308.24 (SE = 22.72) mg/d. Weighted mean infection rates were ∼3% for external and implanted pumps. CONCLUSIONS: Meta-analyses show a statistically significant and sustained decrease in cancer pain with IDD, compared with baseline. Systemic opioid consumption was reduced on average by >50% after IDD. Infection rates were comparable with other indications.

White, brown, and bone marrow adipose tissue behavior in DHEA-induced PCOS mice.

METHODS: Thirty-one female C57BL/6J mice were divided into four groups: two were treated with subcutaneous dehydroepiandrosterone (DHEA) implants and divided into normal and hypercaloric diet (HFD). Two were control and divided into normal and HFD. Presence of insulin resistance, growth, and adipocyte markers expression of white and brown adipose tissues and growth and inflammatory cytokines expression of bone marrow adipose tissue were evaluated. RESULTS: Hypercaloric diet groups presented higher total weight gain and huge growth in all fat sites, except bone marrow. They also demonstrated greater expression of adipocyte markers in sites of white adipose tissue. DHEA + HFD group showed more insulin intolerance than all other groups. DHEA shows to abrogate AdipoQ expression in all fatty tissues. CONCLUSIONS: DHEA alone does not influence adipose tissue growth, but contributes to increased insulin resistance and influences the expression of adipokines. Proximal MAT showed different behavior from the other fat depot.

The dietary intake of two groups of lactating women in Shanghai during the puerperium.

BACKGROUND AND OBJECTIVES: Lactation is a time of increased nutritional requirements for mothers, and inadequate nutrient intake may have a detrimental effect on a woman's nutritional status. To investigate the dietary intake of two groups of women in Shanghai during the traditional confinement period. METHODS AND STUDY DESIGN: Two groups of women (1) a community dwelling sample (n=92); (2) residents in a Maternity Care Centre (MCC) (n=30), kept a prospective dietary record which was complemented by photographing. This data collection was done on a single day on three occasions in the community group, and for three days on five occasions in the MCC one. The mean nutrient intakes of the two groups were compared at common time points to dietary reference intakes, and the food intake was compared to dietary guidelines. RESULTS: Over half of this population had high body mass indices (BMIs) which reported that an excessive proportion of calories had come from fat intake. The mean intakes of sodium were higher than the recommended. Fruit, vegetable, bean, tuber, and milk intakes were lower than the recommendations. Over 70% of the women failed to meet the Estimated Average Requirement (EAR) for calcium. A notable proportion of all women failed to meet the EAR for vitamin C, thiamin, and riboflavin. Dietary fiber intakes were low, with a group mean intake value less than half the Adequate Intake (AI). CONCLUSIONS: This study on dietary intakes indicates nutritional intake issues may exist among lactating women in Shanghai, particularly in community-dwelling women.

Heat stroke admissions during heat waves in 1,916 US counties for the period from 1999 to 2010 and their effect modifiers.

BACKGROUND: Heat stroke is a serious heat-related illness, especially among older adults. However, little is known regarding the spatiotemporal variation of heat stroke admissions during heat waves and what factors modify the adverse effects. METHODS: We conducted a large-scale national study among 23.5 million Medicare fee-for-service beneficiaries per year residing in 1,916 US counties during 1999-2010. Heat wave days, defined as a period of at least two consecutive days with temperatures exceeding the 97th percentile of that county's temperatures, were matched to non-heat wave days by county and week. We fitted random-effects Poisson regression models to estimate the relative risk (RR) of heat stroke admissions on a heat wave day as compared to a matched non-heat wave day. A variety of effect modifiers were tested including individual-level covariates, community-level covariates, meteorological conditions, and the intensity and duration of the heat wave event. RESULTS: The RR declined substantially from 71.0 (21.3-236.2) in 1999 to 3.5 (1.9-6.5) in 2010, and was highest in the northeast and lowest in the west north central regions of the US. We found a lower RR among counties with higher central air conditioning (AC) prevalence. More severe and longer-lasting heat waves had higher RRs. CONCLUSIONS: Heat stroke hospitalizations associated with heat waves declined dramatically over time, indicating increased resilience to extreme heat among older adults. Considerable risks, however, still remain through 2010, which could be addressed through public health interventions at a regional scale to further increase central AC and monitoring heat waves.

Maternal dietary patterns are associated with human milk composition in Chinese lactating women.

OBJECTIVES: Dietary patterns are a useful tool to study the impact of overall maternal diet on human milk (HM) composition beyond single foods or nutrients. The present study aimed to identify dietary patterns among Chinese lactating women and assess their associations with HM macronutrient composition. METHODS: Dietary intake data and HM samples were collected from 122 Chinese mothers at three to five study visits during the first 52 d postpartum. Dietary patterns were derived using principal component analysis. Cross-sectional associations of dietary patterns and HM macronutrients were assessed using multivariable linear regression models adjusted for total energy intake. All analyses were done separately for colostrum (postpartum days 0-7) and mature milk (postpartum days 8-52). RESULTS: Four dietary patterns were identified: high-in-animal-foods, high-in-eggs, high-in-plant-foods, and high-in-fruits. Compared with the lowest tertile (T1), participants in the highest tertile (T3) of the high-in-animal-foods and high-in-plant-foods patterns had lower protein (respectively, T3 - T1 = -1.09 g/100 mL, Ptrend = 0.002; T3 - T1 = -0.54 g/100 mL, Ptrend = 0.001) and higher fat (respectively, T3 - T1 = 0.86 g/100 mL, Ptrend = 0.040; T3 - T1 = 0.40 g/100 mL, Ptrend = 0.004) concentrations in colostrum. In contrast, in mature milk the high-in-animal-foods pattern was positively associated with carbohydrates (T3 - T1 = 0.53 g/100 mL, Ptrend = 0.008) and the high-in-plant-foods pattern was negatively associated with fat (T3 - T1 = -0.64 g/100 mL, Ptrend = 0.002). The high-in-eggs pattern was weakly positively associated with protein concentration in mature milk (T3 - T1 = 0.10 g/100 mL, Ptrend = 0.023). CONCLUSIONS: Maternal dietary patterns with high proportions of animal and plant-based foods were associated with higher fat and lower protein concentrations in colostrum. Different associations were found in mature milk. Dietary-pattern analysis provides an opportunity to characterize total diet and may be more predictive of HM composition than single foods or nutrients.

Hyperkyphosis is not dependent on bone mass and quality in the mouse model of Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant disease affecting cardiovascular, ocular and skeletal systems. It is caused by mutations in the fibrillin-1 (FBN1) gene, leading to structural defects of connective tissue and increased activation of TGF-ß. Angiotensin II (ang-II) is involved in TGF-ß activity and in bone mass regulation. Inhibition of TGF-ß signaling by blockage of the ang-II receptor 1 (AT1R) via losartan administration leads to improvement of cardiovascular and pulmonary phenotypes, but has no effect on skeletal phenotype in the haploinsufficient mouse model of MFS mgR, suggesting a distinct mechanism of pathogenesis in the skeletal system. Here we characterized the skeletal phenotypes of the dominant-negative model for MFS mgΔlpn and tested the effect of inhibition of ang-II signaling in improving those phenotypes. As previously shown, heterozygous mice present hyperkyphosis, however we now show that only males also present osteopenia. Inhibition of ang-II production by ramipril minimized the kyphotic deformity, but had no effect on bone microstructure in male mutant animals. Histological analysis revealed increased thickness of the anterior longitudinal ligament (ALL) of the spine in mutant animals (25.8 ± 6.3 vs. 29.7 ± 7.7 µm), coupled with a reduction in type I (164.1 ± 8.7 vs. 139.0 ± 4.4) and increase in type III (86.5 ± 10.2 vs. 140.4 ± 5.6) collagen in the extracellular matrix of this ligament. In addition, we identified in the MFS mice alterations in the erector spinae muscles which presented thinner muscle fibers (1035.0 ± 420.6 vs. 655.6 ± 239.5 µm2) surrounded by increased area of connective tissue (58.17 ± 6.52 vs. 105.0 ± 44.54 µm2). Interestingly, these phenotypes were ameliorated by ramipril treatment. Our results reveal a sex-dependency of bone phenotype in MFS, where females do not present alterations in bone microstructure. More importantly, they indicate that hyperkyphosis is not a result of osteopenia in the MFS mouse model, and suggest that incompetent spine ligaments and muscles are responsible for the development of that phenotype.

Thyrotoxicosis Involves ß2-Adrenoceptor Signaling to Negatively Affect Microarchitecture and Biomechanical Properties of the Femur.

Background: Thyrotoxicosis increases bone turnover, resulting in net bone loss. Sympathetic nervous system (SNS) activation, via ß2-adrenoceptor (ß2-AR) signaling, also has osteopenic effects. Because thyroid hormones (TH) interact with the SNS to regulate several physiological processes, we hypothesized that this interaction also occurs to regulate bone mass. Previous studies support this hypothesis, as α2-AR knockout (KO) mice are less susceptible to thyrotoxicosis-induced osteopenia. Here, we evaluated whether TH-SNS interactions in bone involve ß2-AR signaling. Methods: Thyrotoxicosis was induced in 120-day-old female and male mice with ß2-AR gene inactivation (ß2-AR-/-) by daily treatment with supraphysiological doses of triiodothyronine (T3) for 12 weeks. The impact of thyrotoxicosis on femoral bone microarchitecture, remodeling, fracture risk, and gene expression of the receptor activator of nuclear factor-kappa-B (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) pathway was evaluated. In addition, the effect of the ß2-AR-specific agonist clenbuterol (CL) on cAMP accumulation was determined in osteoblastic (MC3T3-E1) cells treated with T3 and/or 17ß-estradiol (E2). Results: Thyrotoxicosis negatively affected trabecular bone microarchitecture in wild-type (WT) females, but this effect was milder or nonexistent in ß2-AR-/- animals, whereas the opposite was seen in males. T3 treatment increased the femoral RANKL/OPG mRNA ratio and the endosteal perimeter and medullary area of the diaphysis in WT females and males, but not in ß2-AR-/- mice, suggesting that T3 promotes endosteal resorption in cortical bone, in a mechanism that involves ß2-AR signaling. T3 treatment increased endocortical mineral apposition rate only in WT females but not in ß2-AR-/- mice, suggesting that TH also induce bone formation in a ß2-AR signaling-dependent mechanism. T3 treatment decreased femoral resistance to fracture only in WT females, but not in KO mice. E2 and CL similarly increased cAMP accumulation in MC3T3-E1 cells; whereas T3 alone had no effect, but it completely blocked E2-stimulated cAMP accumulation, suggesting that some T3 effects on bone may involve E2/cAMP signaling in osteoblasts. Conclusions: These findings sustain the hypothesis that T3 interacts with the SNS to regulate bone morphophysiology in a ß2-AR signaling-dependent mechanism. The data also reveal sex as an important modifier of skeletal manifestations of thyrotoxicosis, as well as a modifier of the TH-SNS interactions to control bone microarchitecture, remodeling, and resistance to fracture.

Thyroid Hormone and Skeletal Development.

Thyroid hormone (TH) is essential for skeletal development from the late fetal life to the onset of puberty. During this large window of actions, TH has key roles in endochondral and intramembranous ossifications and in the longitudinal bone growth. There is evidence that TH acts directly in skeletal cells but also indirectly, specially via the growth hormone/insulin-like growth factor-1 axis, to control the linear skeletal growth and maturation. The presence of receptors, plasma membrane transporters, and activating and inactivating enzymes of TH in skeletal cells suggests that direct actions of TH in these cells are crucial for skeletal development, which has been confirmed by several in vitro and in vivo studies, including mouse genetic studies, and clinical studies in patients with resistance to thyroid hormone due to dominant-negative mutations in TH receptors. This review examines progress made on understanding the mechanisms by which TH regulates the skeletal development.

Global Disruption of α2A Adrenoceptor Barely Affects Bone Tissue but Minimizes the Detrimental Effects of Thyrotoxicosis on Cortical Bone.

Evidence shows that sympathetic nervous system (SNS) activation inhibits bone formation and activates bone resorption leading to bone loss. Because thyroid hormone (TH) interacts with the SNS to control several physiological processes, we raised the hypothesis that this interaction also controls bone remodeling. We have previously shown that mice with double-gene inactivation of α2A- and -adrenoceptors (α2A/2C-AR-/-) present high bone mass (HBM) phenotype and resistance to thyrotoxicosis-induced osteopenia, which supports a TH-SNS interaction to control bone mass and suggests that it involves α2-AR signaling. Accordingly, we detected expression of α2A-AR, α2B-AR and α2C-AR in the skeleton, and that triiodothyronine (T3) modulates α2C-AR mRNA expression in the bone. Later, we found that mice with single-gene inactivation of α2C-AR (α2C-AR-/-) present low bone mass in the femur and HBM in the vertebra, but that both skeletal sites are resistant to TH-induce osteopenia, showing that the SNS actions occur in a skeletal site-dependent manner, and that thyrotoxicosis depends on α2C-AR signaling to promote bone loss. To further dissect the specific roles of α2-AR subtypes, in this study, we evaluated the skeletal phenotype of mice with single-gene inactivation of α2A-AR (α2A-AR-/-), and the effect of daily treatment with a supraphysiological dose of T3, for 4 or 12 weeks, on bone microarchitecture and bone resistance to fracture. Micro-computed tomographic (µCT) analysis revealed normal trabecular and cortical bone structure in the femur and vertebra of euthyroid α2A-AR-/- mice. Thyrotoxicosis was more detrimental to femoral trabecular bone in α2A-AR-/- than in WT mice, whereas this bone compartment had been previously shown to present resistance to thyrotoxicosis in α2C-AR-/- mice. Altogether these findings reveal that TH excess depends on α2C-AR signaling to negatively affect femoral trabecular bone. In contrast, thyrotoxicosis was more deleterious to femoral and vertebral cortical bone in WT than in α2A-AR-/- mice, suggesting that α2A-AR signaling contributes to TH actions on cortical bone. These findings further support a TH-SNS interaction to control bone physiology, and suggest that α2A-AR and α2C-AR signaling pathways have key roles in the mechanisms through which thyrotoxicosis promotes its detrimental effects on bone remodeling, structure and resistance to fracture.