Wide-Field Calcium Imaging of Dynamic Cortical Networks during Locomotion.

Motor behavior results in complex exchanges of motor and sensory information across cortical regions. Therefore, fully understanding the cerebral cortex's role in motor behavior requires a mesoscopic-level description of the cortical regions engaged, their functional interactions, and how these functional interactions change with behavioral state. Mesoscopic Ca2+ imaging through transparent polymer skulls in mice reveals elevated activation of the dorsal cerebral cortex during locomotion. Using the correlations between the time series of Ca2+ fluorescence from 28 regions (nodes) obtained using spatial independent component analysis (sICA), we examined the changes in functional connectivity of the cortex from rest to locomotion with a goal of understanding the changes to the cortical functional state that facilitate locomotion. Both the transitions from rest to locomotion and from locomotion to rest show marked increases in correlation among most nodes. However, once a steady state of continued locomotion is reached, many nodes, including primary motor and somatosensory nodes, show decreases in correlations, while retrosplenial and the most anterior nodes of the secondary motor cortex show increases. These results highlight the changes in functional connectivity in the cerebral cortex, representing a series of changes in the cortical state from rest to locomotion and on return to rest.

Peripheral Skeletal Muscle Impairment in Children After Treatment for Leukemia and Lymphoma.

Exercise intolerance is a common adverse effect of childhood cancer, contributing to impaired health and well-being. While reduced aerobic fitness has been attributed to central cardiovascular deficiencies, the involvement of peripheral musculature has not been investigated. We studied peripheral muscle function in children following cancer treatment using noninvasive phosphorus-31 magnetic resonance spectroscopy. Ten acute lymphoblastic leukemia (ALL) and 1 lymphoma patient 8 to 18 years of age who completed treatment 6 to 36 months prior and 11 healthy controls participated in the study. Phosphorus-31 magnetic resonance spectroscopy was used to characterize muscle bioenergetics at rest and following an in-magnet knee-extension exercise. Exercise capacity was evaluated using a submaximal graded treadmill test. Both analysis of variance and Cohen d were used as statistical methods to determine the statistical significance and magnitude of differences, respectively, on these parameters between the patient and control groups. The patients treated for ALL and lymphoma exhibited lower anaerobic function ( P =0.14, d =0.72), slower metabolic recovery ( P =0.08, d =0.93), and lower mechanical muscle power ( d =1.09) during exercise compared with healthy controls. Patients demonstrated lower estimated VO 2peak (41.61±5.97 vs. 47.71±9.99 mL/min/kg, P =0.11, d =0.76), lower minutes of physical activity (58.3±35.3 vs. 114.8±79.3 min, P =0.12, d =0.99) and higher minutes of inactivity (107.3±74.0 vs. 43.5±48.3 min, d =1.04, P <0.05). Children treated for ALL and lymphoma exhibit altered peripheral skeletal muscle metabolism during exercise. Both deconditioning and direct effects of chemotherapy likely contribute to exercise intolerance in this population.

MUREs: a new member of the URE-CURE family of research opportunities for undergrads.

Undergraduate research experiences are important for the development of scientific identity, appreciation of authentic research, and improvement of persistence toward science careers. We identified a gap in experiential research opportunities for undergraduate Biology students who were seeking a formal yet small-scale research experience that was unique to their own interests and career aspirations. These opportunities may be especially worthwhile for of science, technology, engineering, and mathematics (STEM) students aspiring to nonresearch scientific careers (i.e., medicine, dentistry, forensics, and communication) and underrepresented STEM students. Here, we reflect on the use of small-scale, individualized undergraduate research experiences that are based on established methods. These experiences have helped to fill this gap and create problem-centered learning opportunities for undergraduate students that are as unique as the students themselves.

Impaired vascular function in exercising anovulatory premenopausal women is associated with low bone mineral density.

In estrogen-deficient post-menopausal women, osteoporosis shares a common link with cardiovascular disease risk, including endothelial dysfunction. The current study sought to examine associations between bone mineral density (BMD) and endothelial function in estrogen-deficient premenopausal women with exercise-associated menstrual disturbances. Recreationally trained women (24.3 ± 0.8 years; overall mean ± SEM) who were estrogen deficient (amenorrheic or eumenorrheic anovulatory cycles; E2Def; n = 13) or estrogen replete (eumenorrheic ovulatory cycles; E2Rep; n = 14) were studied. Total body and lumbar BMD (L1-L4) were determined using dual-energy X-ray absorptiometry. Serum markers of oxidative stress (oxidized low-density lipoprotein; OxLDL), energy deficiency (triiodothyronine), and bone turnover (osteocalcin, c-telopeptide X, P1NP) were assessed. Estrogen exposure was determined by assessing daily urinary estrone-3-glucuronide (E1G) across a monitoring period. Calf blood flow (CBF), an index of endothelial function, was measured using strain-gauge plethysmography. CBF, total body and L1-L4 BMD, triiodothyronine and E1G were lower (P < 0.05), and c-telopeptide crosslinks higher (P < 0.05) in E2Def. Osteocalcin and OxLDL did not differ (P > 0.05) between groups. L1-L4 BMD, osteocalcin, and E1G were the strongest predictors of CBF (R2 =0.615, P < 0.001). CBF was the strongest predictor of L1-L4 BMD (R2 =0.478, P < 0.001). L1-L4 (r = 0.558, P = 0.008) and CBF (r = 0.534, P = 0.004) were independently correlated with E1G. In young recreationally trained premenopausal women with anovulatory menstrual disturbances, low CBF predicts decreased lumbar BMD, suggesting impaired peripheral endothelial function may predict early unfavorable changes in bone metabolism. This finding may be of relevance in the early detection of cardiovascular and bone health decrements in otherwise healthy estrogen-deficient premenopausal women.

Physical activity for children with chronic disease; a narrative review and practical applications.

BACKGROUND: Physical activity (PA) is associated with a diverse range of health benefits. International guidelines suggest that children should be participating in a minimum of 60 min of moderate to vigorous intensity PA per day to achieve these benefits. However, current guidelines are intended for healthy children, and thus may not be applicable to children with a chronic disease. Specifically, the dose of PA and disease specific exercise considerations are not included in these guidelines, leaving such children with few, if any, evidence-based informed suggestions pertaining to PA. Thus, the purpose of this narrative review was to consider current literature in the area of exercise as medicine and provide practical applications for exercise in five prevalent pediatric chronic diseases: respiratory, congenital heart, metabolic, systemic inflammatory/autoimmune, and cancer. METHODS: For each disease, we present the pathophysiology of exercise intolerance, summarize the pediatric exercise intervention research, and provide PA suggestions. RESULTS: Overall, exercise intolerance is prevalent in pediatric chronic disease. PA is important and safe for most children with a chronic disease, however exercise prescription should involve the entire health care team to create an individualized program. CONCLUSIONS: Future research, including a systematic review to create evidence-based guidelines, is needed to better understand the safety and efficacy of exercise among children with chronic disease.

A phase 2, multicenter study investigating ofatumumab and bendamustine combination in patients with untreated or relapsed CLL.

The purpose of this study is to assess the safety and efficacy of the combination of ofatumumab and bendamustine in patients with previously untreated or relapsed chronic lymphocytic leukemia. Patients received IV ofatumumab (cycle 1: 300 mg day 1 and 1,000 mg day 8; cycles 2-6: 1,000 mg on day 1 every 28 days) and IV bendamustine 90 mg m(-2) (previously untreated) or 70 mg m(-2) (relapsed) on days 1 and 2 of each 28-day cycle, for up to 6 cycles. Forty-four previously untreated and 53 relapsed patients were enrolled. Median age was 62.5 years (previously untreated) and 68 years (relapsed); relapsed patients had received a median of 1 (range 1-11) prior therapy. The investigator-assessed overall response rate was 95% (43% complete response [CR]) for the previously untreated, and 74% (11% CR) for the relapsed patients. The regimen was well tolerated with 89% (previously untreated) and 85% (relapsed patients) receiving all 6 cycles. No unexpected toxicities were reported. Grade 3/4 events occurred in 57% of previously untreated, and 72% of relapsed patients. At ∼29 months' follow-up, the median progression-free survival (PFS) was not reached for the previously untreated population, and the 28-month PFS estimate was 72.3%. The median PFS for the relapsed population was 22.5 months (95% CI: 14.0-27.3 months). The combination of ofatumumab and bendamustine was well tolerated and effective in these previously untreated or relapsed populations. Am. J. Hematol. 91:900-906, 2016. © 2016 Wiley Periodicals, Inc.

Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53 × 10(-8), 11q13 near PRDX5, p(rs694739) = 3.71 × 10(-09), 22q11 at YDJC, p(rs181359) = 8.02 × 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99 × 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.

Osteoprotegerin and fractures in men and women with chronic kidney disease.

Fractures are common in men and women with chronic kidney disease (CKD) but the best tool to identify those at high risk is unknown. Increased circulating osteoprotegerin(OPG) is associated with fractures in postmenopausal women. We determined if serum OPG was associated with prevalent fractures (self-reported low trauma fractures since 40 years of age and/or prevalent vertebral fractures identified by radiographs) in men (n = 97) and women (n = 67) with stage 3­5 CKD. Analyses were performed unadjusted and adjusted for stage of CKD. Results are expressed as mean ± standard deviation(SD), and as odds ratio (OR) per SD increase in OPG with 95 % confidence intervals (CI). The mean age was 62.7 ± 16.3 years, and mean weight was 78.9 ± 18.7 kg. Compared to those without fractures, those with fractures(n = 55) were older (p < 0.01). Serum OPG increased as kidney function decreased, and OPG was higher in those with fractures compared to those without (9.42 ± 4.08 vs 8.06 ± 3.11 pmol/L, p = 0.02). After adjusting for stage of CKD, increased OPG was associated with an increased fracture risk (OR 1.13, 95 % CI 1.02­1.25); however, OPG did not discriminate fracture status well (area under the receiver operating characteristic curve 0.61, 95 % CI 0.52­0.70). OPG is associated with fractures in men and women with stage 3­5 CKD; however, the ability of OPG to discriminate fracture status is poor and cannot be used in isolation to assess fracture risk. Further studies should examine the ability of OPG in combination with other risk factors to better discriminate fracture status in men and women with CKD.

Exercise intolerance and the impact of physical activity in children treated with hematopoietic stem cell transplantation.

Hematopoietic stem-cell transplant (SCT) is increasingly used to treat children with cancer, and survival following SCT is improving. One predominant consequence of childhood cancer therapy is increased physical morbidity, which is worse in pediatric SCT recipients compared with children treated with chemotherapy or radiation alone. There are many factors that contribute to exercise intolerance and reduced physical function during the pretransplant, peritransplant, and posttransplant phases. These include side effects from chemotherapy or radiation, excessive immobility due to bed rest, infections, the negative effects of immunosuppressants, and graft vs host disease, all of which can impair cardiorespiratory fitness, muscle strength, and muscle function. Few studies have investigated the effects of exercise in childhood SCT recipients. In a small number of published studies, exercise interventions have been demonstrated to improve cardiorespiratory fitness, preserve or increase muscle mass, and improve muscle strength in children following SCT. The use of exercise as medicine may be a noninvasive and nonpharmaceutical treatment to target physical complications post-SCT. Researchers and health-care professionals should work together to develop exercise prescription guidelines for this unique and important population.

Commentary: Is Wearable Fitness Technology a Medically Approved Device? Yes and No.

Wearable technologies, i.e., activity trackers and fitness watches, are extremely popular and have been increasingly integrated into medical research and clinical practice. To assist in optimizing health, wellness, or medical care, these devices require collaboration between researchers, healthcare providers, and wearable technology companies in order to clarify their clinical capabilities and educate consumers on the utilities and limitations of the wide-ranging wearable devices. Interestingly, activity trackers and fitness watches often track both health/wellness and medical information within the same device. In this commentary, we will focus our discussions regarding wearable technology on (1) defining and explaining the technical differences between tracking health, wellness, and medical information; (2) providing examples of health and wellness compared to medical tracking; (3) describing the potential medical benefits of wearable technology and its applications in clinical populations; and (4) elucidating the potential risks of wearable technology. We conclude that while wearable devices are powerful and informative tools, further research is needed to improve its clinical applications.

Wide-field calcium imaging of cortical activation and functional connectivity in externally- and internally-driven locomotion.

The neural dynamics underlying self-initiated versus sensory driven movements is central to understanding volitional action. Upstream motor cortices are associated with the generation of internally-driven movements over externally-driven. Here we directly compare cortical dynamics during internally- versus externally-driven locomotion using wide-field Ca2+ imaging. We find that secondary motor cortex (M2) plays a larger role in internally-driven spontaneous locomotion transitions, with increased M2 functional connectivity during starting and stopping than in the externally-driven, motorized treadmill locomotion. This is not the case in steady-state walk. In addition, motorized treadmill and spontaneous locomotion are characterized by markedly different patterns of cortical activation and functional connectivity at the different behavior periods. Furthermore, the patterns of fluorescence activation and connectivity are uncorrelated. These experiments reveal widespread and striking differences in the cortical control of internally- and externally-driven locomotion, with M2 playing a major role in the preparation and execution of the self-initiated state.

Wide-field calcium imaging of cortical activation and functional connectivity in externally- and internally-driven locomotion.

The neural dynamics underlying self-initiated versus sensory driven movements is central to understanding volitional action. Upstream motor cortices are associated with the generation of internally-driven movements over externally-driven. Here we directly compare cortical dynamics during internally- versus externally-driven locomotion using wide-field Ca2+ imaging. We find that secondary motor cortex (M2) plays a larger role in internally-driven spontaneous locomotion transitions, with increased M2 functional connectivity during starting and stopping than in the externally-driven, motorized treadmill locomotion. This is not the case in steady-state walk. In addition, motorized treadmill and spontaneous locomotion are characterized by markedly different patterns of cortical activation and functional connectivity at the different behavior periods. Furthermore, the patterns of fluorescence activation and connectivity are uncorrelated. These experiments reveal widespread and striking differences in the cortical control of internally- and externally-driven locomotion, with M2 playing a major role in the preparation and execution of the self-initiated state.

Tests of neuromuscular function are associated with fractures in patients with chronic kidney disease.

BACKGROUND: Fractures are common in individuals with chronic kidney disease (CKD), and tests of neuromuscular function (NMT) discriminate well among fractured and non-fractured patients with Stage 5 CKD on dialysis. The ability of NMT to discriminate fracture status in patients with Stages 3-5 CKD is unknown. METHODS: In this cross-sectional study, we sought to determine in adult patients with Stages 3-5 CKD (eGFR by the Modification of Diet in Renal Disease equation) if NMT [timed up and go (TUG), 6-min walk (6MW) and grip strength] could discriminate fracture status (self-reported low-trauma fractures since age 40 and/or vertebral fractures by morphometry). We conducted logistic regression and receiver-operating characteristic (ROC) curves for each predictor [expressed as area under the ROC curves (AUROC) with 95% confidence intervals (CI)]. RESULTS: Data was available for 125 men and 86 women. The mean age was 63.3 ± 15.5 years, duration of CKD was 96.7 ± 125.3 months and one-third had diabetes. Patients with fractures were older and fell more frequently (P < 0.05). After adjusting for age, weight and sex, for every standard deviation increase in TUG and 6MW, the risk of fracture increased [odds ratio (OR): 1.68; 95% CI: 1.40-2.02] and decreased (OR: 0.53; 95% CI: 0.52-0.54), respectively. Both the TUG and 6MW could discriminate among those with and without fractures (AUROC: 0.90; 95% CI:0.84-0.95, AUROC: 0.87; 95% CI: 0.80-0.94, respectively). CONCLUSIONS: The TUG and 6MW are able to discriminate fracture status in patients with Stages 3-5 CKD. These tests do not require specialized expertise/equipment and are an inexpensive method to assess for the presence of fractures.

Bone and kidney disease: diagnostic and therapeutic implications.

Fractures are common in patients with chronic kidney disease (CKD), but the diagnosis and treatment of bone disease in CKD are difficult due to the multiple etiologies of bone disease in these patients. Noninvasive imaging, including bone mineral density by dual energy x-ray absorptiometry, can be useful in diagnosing osteoporosis in predialysis CKD; however, consensus on the diagnosis of osteoporosis among those with advanced CKD-particularly stage 5 CKD patients on dialysis-is lacking. Treatments approved for osteoporosis in postmenopausal women may be used in patients with stage 1 to 3 CKD. Furthermore, post-hoc analyses show efficacy and safety of oral bisphosphonates, raloxifene, and denosumab in stage 4 CKD for short-term treatment. However, treatment decisions are more difficult in stage 5 CKD. Bone biopsy may be required, and most treatments, if used, would be off label. Overall, the diagnosis and treatment of bone disease in patients with CKD require further research.

Determination of bone architecture and strength in men and women with stage 5 chronic kidney disease.

Fractures are common in men and women with dialysis-dependent chronic kidney disease (stage 5D CKD) and are associated with substantial morbidity and mortality. The clinical utility of dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), noninvasive measures of bone mass and architecture that reflect fracture risk in healthy men and women, is uncertain in patients with stage 5D CKD. This review will outline the epidemiology and etiology of fractures and will summarize the published data that describe the association between fractures, bone mass, and bone strength in stage 5D CKD. Fracture risk assessment in stage 5D CKD is complicated as the etiology of fractures is multifactorial and includes impairments in bone quantity and quality. Cross-sectional data suggest that bone density by DXA is lower among stage 5D CKD patients with fractures compared with those without, and that this may be particularly true at cortical sites. However, DXA does not capture bone microarchitecture and cannot differentiate between cortical and trabecular bone. Some, but not all studies, that measure cortical and trabecular bone by pQCT in stage 5D CKD, demonstrate a preferential decrease in cortical bone; however, these studies are limited by small sample sizes and cross-sectional study design. No studies have reported on longitudinal relationships between bone architecture, strength, and incident fractures in patients with stage 5D CKD. Further research is needed to identify noninvasive measures of bone strength that can be used for fracture risk assessment in stage 5D CKD.

Commentary: Zebrafish as a Model for Osteoporosis-An Approach to Accelerating Progress in Drug and Exercise-Based Treatment.

Osteoporosis (OP) is a degenerative disease characterized by reduced bone strength and increased fracture risk. As the global population continues to age, the prevalence and economic burden of osteoporosis can be expected to rise substantially, but there remain various gaps in the field of OP care. For instance, there is a lack of anti-fracture drugs with proven long-term efficacy. Likewise, though exercise remains widely recommended in OP prevention and management, data regarding the safety and efficacy for patients after vertebral fracture remain limited. This lack of evidence may be due to the cost and inherent difficulties associated with exercise-based OP research. Thus, the current research landscape highlights the need for novel research strategies that accelerate OP drug discovery and allow for the low-cost study of exercise interventions. Here, we outline an example of one strategy, the use of zebrafish, which has emerged as a potential model for the discovery of anti-osteoporosis therapeutics and study of exercise interventions. The strengths, limitations, and potential applications of zebrafish in OP research will be outlined.

Perceived Exertion during Moderate and Vigorous Physical Activity While Mask Wearing: A Quantitative and Qualitative Pilot Study.

There is limited research examining the perception of exertion during exercise while wearing a facemask. The current study examined if mask usage during moderate or vigorous physical activity (MVPA) changed the self-reported perception of exertion. Seventy-two adults (18 years and older) who were physically active before the COVID-19 pandemic completed a questionnaire that assessed exercise habits and perceptions of mask wearing during MVPA. Participants reported their ratings of perceived exertion (RPE, on a scale of 1−10) while exercising. Wearing a mask resulted in higher RPE vs. no mask during both vigorous (8.4 ± 0.2 vs. 7.4 ± 0.1; p < 0.001) and moderate PA (6.6 ± 0.2 vs. 5.6 ± 0.2; p < 0.001). Qualitative analysis revealed mostly negative perceptions of exercising while wearing a mask, including respiratory issues, detriments to cardiovascular endurance, and general discomfort. A total of 40% of participants reported that they stopped exercising in an indoor/public setting because of a mask mandate in their region. Participants reported participating in less vigorous PA (4.7 ± 0.4 vs. 4.0 ± 0.4 h/week; p = 0.046), but not less moderate PA (3.3 ± 0.3 vs. 3.0 ± 0.3 h/week; p = 0.443) pre vs. during the pandemic. Our study suggests that facemask usage during MVPA causes an increase in RPE and may be one reason for a decrease in vigorous PA during the COVID-19 pandemic.

A quasi-experimental examination of weight-reducing dehydration practices in collegiate male rowers.

BACKGROUND: Lightweight rowers commonly utilize weight loss techniques over 24-h before competition to achieve the qualifying weight for racing. The objective was to investigate, using a quasi-experimental design, whether changes in weight resulting from dehydration practices are related to changes in proxies of bodily systems involved in rowing and whether these relationships depend on the dehydration technique used. METHODS: Twelve elite male rowers performed a power test, an incremental VO2max test, and a visuomotor battery following: weight loss via thermal exposure, weight loss via fluid abstinence and then thermal exposure, and no weight loss. The total percent body mass change (%BMC), %BMC attributable to thermal exposure, and %BMC attributable to fluid abstinence were used to predict performance variables. RESULTS: Fluid abstinence but not thermal exposure was related to a lower total wattage produced on a incremental VO2max test (b = 4261.51 W/1%BMC, 95%CI = 1502.68-7020.34), lower wattages required to elicit 2 mmol/L (b = 27.84 W/1%BMC, 95%CI = 14.69-40.99) and 4 mmol/L blood lactate (b = 20.45 W/1%BMC, 95%CI = 8.91-31.99), and slower movement time on a visuomotor task (b = -38.06 ms/1%BMC, 95%CI = -62.09--14.03). CONCLUSIONS: Dehydration related weight changes are associated with reductions in some proxies of bodily systems involved in rowing but depend on the dehydration technique used.

Nemiralisib in Patients with an Acute Exacerbation of COPD: Placebo-Controlled, Dose-Ranging Study.

Background: Management of acute exacerbations of chronic obstructive pulmonary disease (COPD) is sometimes inadequate leading to either prolonged duration and/or an increased risk of recurrent exacerbations in the period following the initial event. Objective: To evaluate the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ inhibitor, in patients experiencing an acute exacerbation of COPD. Patients and Methods: In this double-blind, placebo-controlled study, COPD patients (40-80 years, ≥10 pack-year smoking history, current moderate/severe acute exacerbation of COPD requiring standard-of-care treatment) were randomized to placebo or nemiralisib 12.5 µg, 50 µg, 100 µg, 250 µg, 500 µg, or 750 µg (ratio of 3:1:1:1:1:1:3; N=938) for 12 weeks with an exploratory 12-week follow-up period. The primary endpoint was change from baseline in post-bronchodilator FEV1 at week 12. Key secondary endpoints were rate of re-exacerbations, patient-reported outcomes (Exacerbations of Chronic Pulmonary Disease Tool, COPD Assessment Test, St George's Respiratory Questionnaire-COPD), plasma pharmacokinetics (PK) and safety/tolerability. Results: There was no difference in change from baseline FEV1 at week 12 between the nemiralisib and placebo treatment groups (posterior adjusted median difference, nemiralisib 750 µg and placebo: -0.004L (95% CrI: -0.051L to 0.042L)). Overall, there were also no differences between nemiralisib and placebo in secondary endpoints, including re-exacerbations. Plasma PK increased in a dose proportional manner. The most common adverse event for nemiralisib was post-inhalation cough which appeared to be dose-related. Conclusion: The addition of nemiralisib to standard-of-care treatment for 12 weeks did not improve lung function or re-exacerbations in patients with, and following an acute exacerbation of COPD. However, this study demonstrated that large clinical trials recruiting acutely exacerbating patients can successfully be conducted.

Fracture Risk Assessment in Chronic Kidney Disease, Prospective Testing Under Real World Environments (FRACTURE): a prospective study.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of fracture. Decreased bone mass and disruption of microarchitecture occur early in the course of CKD and worsens with the progressive decline in renal function so that at the time of initiation of dialysis at least 50% of patients have had a fracture. Despite the excess fracture risk, and the associated increases in morbidity and mortality, little is known about the factors that are associated with an increase in fracture risk. Our study aims to identify prognostic factors for bone loss and fractures in patients with stages 3 to 5 CKD. METHODS: This prospective study aims to enroll two hundred and sixty men and women with stages 3 to 5 CKD. Subjects will be followed for 24 months and we will examine the ability of: 1) bone mineral density by dual x-ray absorptiometry at the spine, hip, and radius; 2) volumetric bone density by high resolution peripheral quantitated computed tomography at the radius and tibia; 3) serum markers of bone turnover; 4) bone formation rate by bone biopsy; and 5) muscle strength and balance to predict spine and non-spine fractures, identified by self-report and/or vertebral morphometry. All measurements will be obtained at baseline, at 12 and at 24 months with the exception of bone biopsy, which will be measured once at 12 months. Subjects will be contacted every 4 months to determine if there have been incident fractures or falls. DISCUSSION: This study is one of the first that aims to identify risk factors for fracture in early stage CKD patients. Ultimately, by identifying risk factors for fracture and targeting treatments in this group-before the initiation of renal replacement therapy--we will reduce the burden of disease due to fractures among patients with CKD.