Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

Early Versus Late Feeding After Percutaneous Endoscopic Gastrostomy Placement in Trauma and Burn.

INTRODUCTION: Timing to resume feeds after percutaneous endoscopic gastrostomy (PEG) placement continues to vary among US trauma surgeons. The purpose of this study was to assess differences in meeting nutritional therapy goals and adverse outcomes with early versus late enteral feeding after PEG placement. METHODS: This retrospective review included 364 trauma and burn patients who underwent PEG placement. Data included patient characteristics, time to initiate feeds, rate feeds were resumed, % feed volume goals on postoperative days 0-7, and complications. Statistical analysis was performed comparing two groups (feeds ≤ 6 h versus > 6 h) and three subgroups (< 4 h, 4-6 h, ≥ 6 h) based on data quartiles. Chi-square/Fisher's exact test, independent-samples t-test, and one-way analysis of variance were used to analyze the data. RESULTS: Mean time to initiate feeds after PEG was 5.48 ± 4.79 h. Burn patients received early feeds in a larger proportion. A larger proportion of trauma patients received late feeds. The mean % of goal feed volume met on postoperative day 0 was higher in the early feeding group versus the late (P < 0.001). There were no differences in adverse events, even after subgroup analysis of those who received feeds < 4 h after PEG placement. CONCLUSIONS: Patients with early initiation of feeds after PEG placement achieve a higher percentage of goals on day 0 without an increased rate of adverse events. Unfortunately, patients routinely fall short of their target tube feeding goals.

Construction and characterization of a novel miniaturized filamentous phagemid for targeted mammalian gene transfer.

BACKGROUND: As simplistic proteinaceous carriers of genetic material, phages offer great potential as targeted vectors for mammalian transgene delivery. The filamentous phage M13 is a single-stranded DNA phage with attractive characteristics for gene delivery, including a theoretically unlimited DNA carrying capacity, amenability to tropism modification via phage display, and a well-characterized genome that is easy to genetically modify. The bacterial backbone in gene transfer plasmids consists of elements only necessary for amplification in prokaryotes, and, as such, are superfluous in the mammalian cell. These problematic elements include antibiotic resistance genes, which can disseminate antibiotic resistance, and CpG motifs, which are inflammatory in animals and can lead to transgene silencing. RESULTS: Here, we examined how M13-based phagemids could be improved for transgene delivery by removing the bacterial backbone. A transgene cassette was flanked by isolated initiation and termination elements from the phage origin of replication. Phage proteins provided in trans by a helper would replicate only the cassette, without any bacterial backbone. The rescue efficiency of "miniphagemids" from these split origins was equal to, if not greater than, isogenic "full phagemids" arising from intact origins. The type of cassette encoded by the miniphagemid as well as the choice of host strain constrained the efficiency of phagemid rescue. CONCLUSIONS: The use of two separated domains of the f1 ori improves upon a single wildtype origin while still resulting in high titres of miniphagemid gene transfer vectors. Highly pure lysates of miniaturized phagemids could be rapidly obtained in a straightforward procedure without additional downstream processing.

Enteral ferric citrate absorption is dependent on the iron transport protein ferroportin.

Ferric citrate is approved as an iron replacement product in patients with non-dialysis chronic kidney disease and iron deficiency anemia. Ferric citrate-delivered iron is enterally absorbed, but the specific mechanisms involved have not been evaluated, including the possibilities of conventional, transcellular ferroportin-mediated absorption and/or citrate-mediated paracellular absorption. Here, we first demonstrate the efficacy of ferric citrate in high hepcidin models, including Tmprss6 knockout mice (characterized by iron-refractory iron deficiency anemia) with and without adenine diet-induced chronic kidney disease. Next, to assess whether or not enteral ferric citrate absorption is dependent on ferroportin, we evaluated the effects of ferric citrate in a tamoxifen-inducible, enterocyte-specific ferroportin knockout murine model (Villin-Cre-ERT2, Fpnflox/flox). In this model, ferroportin deletion was efficient, as tamoxifen injection induced a 4000-fold decrease in duodenum ferroportin mRNA expression, with undetectable ferroportin protein on Western blot of duodenal enterocytes, resulting in a severe iron deficiency anemia phenotype. In ferroportin-deficient mice, three weeks of 1% ferric citrate dietary supplementation, a dose that prevented iron deficiency in control mice, did not improve iron status or rescue the iron deficiency anemia phenotype. We repeated the conditional ferroportin knockout experiment in the setting of uremia, using an adenine nephropathy model, where three weeks of 1% ferric citrate dietary supplementation again failed to improve iron status or rescue the iron deficiency anemia phenotype. Thus, our data suggest that enteral ferric citrate absorption is dependent on conventional enterocyte iron transport by ferroportin and that, in these models, significant paracellular absorption does not occur.

Incidence and clinical characteristics of pediatric-onset type 2 diabetes in Hong Kong: The Hong Kong childhood diabetes registry 2008 to 2017.

OBJECTIVE: With increasing prevalence of childhood obesity worldwide, the incidence of pediatric-onset type 2 diabetes (T2D) is also increasing in many countries. We aim to analyze the time trend and incidence of T2D in children in Hong Kong from 2008 to 2017, and to characterize clinical characteristics at diagnosis. METHODS: Data were retrieved from the Hong Kong Childhood Diabetes Registry. All children with T2D diagnosed at the age of less than 18 years from January 1, 2008 to December 31, 2017 and managed in the public health care system were included in this study. RESULTS: In the incident years of 2008-2017 period, 391 children were diagnosed with T2D. The crude incidence rate was 3.42 per 100,000 persons/year [95% confidence interval (CI) 3.08-3.76], which was much higher than that in last registry of 1.27 per 100,000 persons/year in 1997-2007 (P < 0.001).Most children (76%) were asymptomatic and were diagnosed by routine screening. At presentation, a significant proportion presented with co-morbidities including fatty liver (37.9%), dyslipidaemia (35.3%), hypertension (22.5%), and microalbuminuria (12.8%). CONCLUSIONS: The incidence of T2D in children has increased significantly in Hong Kong. Most of them were asymptomatic and picked up on routine health screening. Yet, comorbidities were commonly identified at diagnosis.

Is the search for cerebral palsy 'cures' a reasonable and appropriate goal in the 2020s?

In the field of disability research and advocacy, the notion of 'cures' is contentious. Cerebral palsy (CP) is no exception. In this narrative review, we combine perspectives gained during community consultation undertaken for the Australian and New Zealand Cerebral Palsy Strategy, 2020 with those published in the scientific and grey literature to understand whether 'cures for CP' is a reasonable and appropriate goal. We frame these perspectives through the lens of several ethical principles central to the discussion. These include maintaining hope while also being realistic, sensitivity to sharply different viewpoints amongst people with disability and their families, and responding to community priorities, societal attitudes, and identity. Through this exploration of the literature and perspectives, we arrived at a definition of 'cures for CP' that is pluralized and focuses on functional improvement and/or symptom reduction whilst still acknowledging the potential for neural repair/regeneration strategies.

Predictors of real-world utilisation of docetaxel combined with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer.

BACKGROUND: Docetaxel has emerged as a standard-of-care for metastatic hormone-sensitive prostate cancer (mHSPC). Uptake of docetaxel for mHSPC in Australia has not previously been reported. AIMS: To investigate the real-world uptake of docetaxel in mHSPC and to identify predictors of utilisation of docetaxel in mHSPC. METHODS: Men diagnosed from June 2014 to December 2018 and enrolled in the Prostate Cancer Outcomes Registry-Victoria (PCOR-Vic) were included. Data collected include demographics, diagnosis method and institution, staging investigations and treatments within 12 months of diagnosis. Wilcoxon rank-sum, Chi-squared and trend tests were used to identify predictors of docetaxel utilisation. All predictors were entered as covariates simultaneously into a multivariable logistic regression model. Statistical significance was set at 0.05 (two sided). RESULTS: In all, 1014 men with mHSPC were analysed, 25% of whom received docetaxel with androgen deprivation therapy. Uptake of docetaxel increased from 20% in 2014 to 33% in 2018. Predictors of higher usage of docetaxel were younger age and treatment in a private hospital, with both remaining significant on multivariable analysis. Notably, the proportion of men aged <70 years receiving docetaxel increased from 54% in 2014-2015 to 64% in 2016-2018, while in men aged ≥70 years the comparative figures were 15% and 22% respectively. CONCLUSIONS: Although docetaxel was not used in the majority of cases, there was a clear increase in docetaxel uptake, especially in younger men following publication of the CHAARTED and STAMPEDE trials. Identifying barriers to real-world implementation of pivotal clinical trial data is critical to improving outcomes in mHSPC.

Graduate medical education-led continuous assessment of burnout and learning environments to improve residents' wellbeing.

BACKGROUND: Promoting residents' wellbeing and decreasing burnout is a focus of Graduate Medical Education (GME). A supportive clinical learning environment is required to optimize residents' wellness and learning. OBJECTIVE: To determine if longitudinal assessments of burnout and learning environment as perceived by residents combined with applying continuous quality Model for Improvement and serial Plan, Do, Study, Act (PDSA) cycles to test interventions would improve residents' burnout. METHODS: From November 2017 to January 2020, 271 GME residents in internal medicine, general surgery, psychiatry, emergency medicine, family medicine and obstetrics and gynecology, were assessed over five cycles by Maslach Burnout Inventory (MBI), and by clinical learning environment factors (which included personal/social relationships, self-defined burnout, program burnout support, program back-up support, clinical supervision by faculty, and sleep difficulties). The results of the MBI and clinical learning environment factors were observed and analyzed to determine and develop indicated Institutional and individual program interventions using a Plan, Do, Study, Act process with each of the five cycles. RESULTS: The response rate was 78.34%. MBI parameters for all GME residents improved over time but were not statistically significant. Residents' positive perception of the clinical supervision by faculty was significantly and independently associated with improved MBI scores, while residents' self-defined burnout; and impaired personal relations perceptions were independently significantly associated with adverse MBI scores on liner regression. For all GME, significant improvements improved over time in residents' perception of impaired personal relationships (p < 0.001), self-defined burnout (p = 0.013), program burn-out support (p = 0.002) and program back-up support (p = 0.028). For the Internal Medicine Residency program, there were statistically significant improvements in all three MBI factors (p < 0.001) and in clinical learning environment measures (p = 0.006 to < 0.001). Interventions introduced during the PDSA cycles included organization-directed interventions (such as: faculty and administrative leadership recruitment, workflow interventions and residents' schedule optimization), and individual interventions (such as: selfcare, mentoring and resilience training). CONCLUSION: In our study, for all GME residents, clinical learning environment factors in contrast to MBI factors showed significant improvements. Residents' positive perception of the clinical learning environment was associated with improved burnout measures. Residents in separate programs responded differently with one program reaching significance in all MBI and clinical learning environment factors measured. Continuous wellbeing assessment of all GME residents and introduction of Institutional and individual program interventions was accomplished.

Cancer clinical trial vs real-world outcomes for standard of care first-line treatment in the advanced disease setting.

Clinical trials have strict eligibility criteria, potentially limiting external validity. However, while often discussed this has seldom been explored, particularly across cancer types and at variable time frames posttrial completion. We examined comprehensive registry data (January 2014 to June 2019) for standard first-line treatments for metastatic colorectal cancer (CRC), advanced pancreatic cancer (PC), metastatic HER2-amplified breast cancer (BC) and castrate-resistant prostate cancer (CaP). Registry patient characteristics and outcomes were compared to the practice-changing trial. Registry patients were older than the matched trial cohort by a median of 2-6 years (all P = <.01) for the CRC, BC and PC cohorts. The proportion of Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 patients was lower for CRC (94.1% vs 99.2%, P = .001) and BC (94.9% vs 99.3%, P = .001). Progression-free survival (PFS) for registry patients was similar to the trial patients or significantly longer (CaP, Hazard Ratio [HR] = 0.65, P = <.001). Overall survival (OS) was also similar or significantly longer (CaP, HR 0.49, P = <.001). In conclusion, despite real-world patients sometimes being older or having inferior PS to trial cohorts, the survival outcomes achieved were consistently equal or superior to those reported for the same treatment in the trial. We suggest that this is potentially due to optimised use of each treatment over time, improved multidisciplinary care and increased postprogression options. We can reassure clinicians and patients that outcomes matching or exceeding those reported in trials are possible. The potential for survival gains over time should routinely be factored into future trial statistical plans.

Amelioration of chronic kidney disease-associated anemia by vadadustat in mice is not dependent on erythroferrone.

Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies.

A snapshot of the λ T4rII exclusion (Rex) phenotype in Escherichia coli.

The lambda (λ) T4rII exclusion (Rex) phenotype is defined as the inability of T4rII to propagate in Escherichia coli lysogenized by bacteriophage λ. The Rex system requires the presence of two lambda immunity genes, rexA and rexB, to exclude T4 (rIIA-rIIB) from plating on a lawn of E. coli λ lysogens. The onset of the Rex phenotype by T4rII infection imparts a harsh cellular environment that prevents T4rII superinfection while killing the majority of the cell population. Since the discovery of this powerful exclusion system in 1955 by Seymour Benzer, few mechanistic models have been proposed to explain the process of Rex activation and the physiological manifestations associated with Rex onset. For the first time, key host proteins have recently been linked to Rex, including σE, σS, TolA, and other membrane proteins. Together with the known Rex system components, the RII proteins of bacteriophage T4 and the Rex proteins from bacteriophage λ, we are closer than ever to solving the mystery that has eluded investigators for over six decades. Here, we review the fundamental Rex components in light of this new knowledge.

Real-world use of first-generation antiandrogens: impact on patient outcomes and subsequent therapies in metastatic castration-resistant prostate cancer.

OBJECTIVES: To investigate the recent real-world use of first-generation antiandrogens (FGAs) in metastatic castration-resistant prostate cancer (mCRPC) using a retrospective multicentre cohort study. PATIENTS AND METHODS: The electronic CRPC Australian Database (ePAD) was interrogated to identify patients with mCRPC. Clinicopathological features, treatment and outcome data, stratified by FGA use, were retrieved and reported through descriptive statistics. Survival analyses were calculated using the Kaplan-Meier method and groups compared using log-rank tests. Factors influencing overall survival (OS) were analysed using Cox proportional hazards regression model. RESULTS: We identified 634 patients with mCRPC, enrolled in ePAD between January 2016 and March 2019, including 322 (51%) who received FGAs. The median follow-up was 21.9 months. Patients treated with FGAs were more likely to have lower International Society of Urological Pathologists (ISUP) grade group (P = 0.04), longer median time to CRPC (25.6 vs 16.0 months, P < 0.001), and were less likely to have visceral metastases (5.0% vs 11.2%, P = 0.005) or to have received upfront docetaxel (P < 0.001). A ≥50% reduction from pre-treatment prostate-specific antigen (PSA) level (PSA50 response) during FGA treatment occurred in 119 (37%) patients and was independently associated with improved OS (hazard ratio 0.233, P < 0.001). Prior FGA treatment did not significantly influence the selection of subsequent life-prolonging treatments for mCRPC or their PSA50 response rates. CONCLUSION: In our present cohort, FGAs were commonly used in lower-risk mCRPC and their use did not significantly influence the choice or duration of subsequent systemic therapy. A PSA50 response to FGA therapy was an independent favourable prognostic marker associated with improved OS.

Secondary analysis of change in physical function after exercise intervention in older adults with hyperkyphosis and low physical function.

BACKGROUND: Hyperkyphosis is common in older adults and associated with low physical function and reduced health related quality of life (HrQol). Improved kyphosis has been previously established in kyphosis-targeted interventions in randomized controlled trials in older adults with hyperkyphosis; however, evidence for improved physical function is conflicting. Few studies have investigated change in physical function after a targeted kyphosis intervention in older adults with low physical function. The primary aim in this descriptive study was to explore change in physical function after a progressive high-intensity 3-month targeted kyphosis exercise and posture training intervention in older adults with low physical function and hyperkyphosis. Secondary aims were to explore change in HrQol, spinal strength and spinal curvature, and adherence and safety of the intervention. METHODS: In this secondary analysis of the Specialized Center of Research (SCOR) Kyphosis randomized trial, 101 community dwelling older men and women with hyperkyphosis who completed the intervention were divided into a low function group (LFG) and high function group (HFG). Baseline characteristics were compared between LFG and HFG. Physical function, HrQol, spinal strength and spinal curvature (kyphosis and lordosis) pre/post intervention change scores were explored within and between groups. Adherence and adverse events were examined in the LFG and HFG. RESULTS: Twenty-six (26%) older adults were LFG, mean Short Phyiscal Performance Battery (SPPB) 9.62 (SD = 1.17) points. At baseline, the LFG was older than HFG (p = 0.005), experienced more pain, (p = 0.060), had worse physical function and HrQol (p ≤ 0.001), and comparable kyphosis (p = 0.640). SPPB changed 0.62 (95% CI: - 0.20 to 1.44) points in the LFG and - 0.04 (95%CI: - 0.28 to 0.19) points in the HFG, p = 0.020. Gait speed changed 0.04 (95% CI: - 0.02 to 0.10) m/s in the LFG. Kyphosis improved equally in both groups. Adherence to the intervention was 83% in the LFG and 79% in the HFG. There were no adverse events in either group. CONCLUSIONS: Older adults with low physical function and hyperkyphosis may improve physical function after a kyphosis targeted intervention. Older adults with low physical function may safely participate in targeted high-intensity kyphosis exercise and posture training. This observation needs to be confirmed in larger adequately powered studies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01766674 .

Increasing incidence of type 1 diabetes among Hong Kong children and adolescents: The Hong Kong Childhood Diabetes Registry 2008 to 2017.

OBJECTIVE: The incidence of childhood-onset type 1 diabetes (T1D) has been reported to be rising but there is also evidence that it has been attenuated in recent years. We described the time trends and the incidence of T1D in children in Hong Kong from 2008 to 2017 and compared with the previous local registry in 1997 to 2007. METHODS: Data were extracted from the Hong Kong Childhood Diabetes Registry, which was established in 2016. It consists of a retrospective registry (including all childhood diabetes diagnosed in 2008 to 2015) and a prospective registry (including all T1D children diagnosed from 2016 onwards). All T1D children diagnosed at the age of less than 18 years from 1 January 2008 to 31 December 2017 and managed in the public system were included in this study. RESULTS: For the incident years in the 2008 to 2017 period, a total of 498 children with T1D was identified. The crude incidence rate was 4.3 per 100 000 person/year (95% confidence interval 3.96-4.72), which was much higher than the last registry of 2.2 per 100 000 persons/year. Using general linear model, the increment is statistically significant (P = .02). When compared to the last registry, the rate of increment had attenuated, with annual increment in crude incidence in the two periods for T1D <15 years changing from 4.3% to 3.5% (P = .02). CONCLUSIONS: The incidence of T1D children increased significantly in the past two decades in Hong Kong, but the rate of increase had attenuated in recent years.

Impact of access to novel therapies on the initial management of castrate-resistant prostate cancer: an Australian multicentre study.

BACKGROUND: The impact of regulatory approvals of new therapies for castration-resistant prostate cancer (CRPC) in Australia is unclear. AIMS: To determine if changes in novel therapy access in Australia affected how clinicians initially managed men with newly diagnosed CRPC. METHODS: Data from patients diagnosed with CRPC from 2013 to 2016 across three Australian hospitals were retrospectively collected. Baseline clinicopathological factors and initial management decision at the time of CRPC development (early treatment (ET) vs deferred treatment (DT)) were recorded. Categorical variables between cohorts were compared by Chi-squared analysis. Cox regression analysis was performed to assess the impact of CRPC diagnosis year on time to commencing life-prolonging systemic treatment (TTT). RESULTS: Our study identified 137 CRPC patients, with 126 (92%) patients receiving life-prolonging systemic treatment. The median age was 73 years. The initial management decision was DT in 71 (52%) patients and ET in 66 (48%) patients. There was a significant shift from DT to ET during the study period (2013-2014: DT 61% vs ET 33%; 2015-2016: DT 39% vs ET 67%; P = 0.004), with a rise in novel androgen receptor signalling inhibitor use and simultaneous reduction in first-generation antiandrogen use at CRPC development. Each successive CRPC diagnosis year was associated with shorter TTT on univariate analysis (HR: 1.5, 95% CI: 1.3-1.7, P < 0.001). CONCLUSION: Over time, clinicians are favouring earlier introduction of life-prolonging systemic treatment at the development of CRPC. This trend is largely driven by substantial uptake of novel androgen receptor signalling inhibitors as the preferred initial treatment for CRPC patients.

Reliability of sagittal vertical axis measurement and association with measures of age-related hyperkyphosis.

[Purpose] Persons with age-related hyperkyphosis often have concomitant sagittal plane imbalance of the spine. This study investigated the reliability of sagittal vertical axis (SVA) measurement of sagittal balance, association between thoracic Cobb angle of kyphosis and SVA measure of sagittal balance, and compared the degree of SVA in males and females with age-related hyperkyphosis. [Participants and Methods] Measurements of SVA and Cobb angle of kyphosis were obtained from baseline radiographs of 112 community-dwelling males and females, mean age 70.0 (SD=5.7) years with kyphosis ≥40 degrees, recruited for a randomized controlled trial. Spearman correlation coefficients were used to determine associations between SVA and kyphosis, and Wilcoxon nonparametric tests to compare SVA between genders. [Results] SVA was acquired with excellent intra-rater [0.95 (95% CI: 0.88, 0.98)] and inter-rater reliability [0.93 (95% CI: 0.83,0.97)]. There was no significant correlation between Cobb angle of thoracic kyphosis and SVA, (r=-0.05). More males than females had sagittal imbalance (SVA≥5 cm). [Conclusion] In older adults with hyperkyphosis, SVA was a reliable measure of sagittal balance, and more extreme in males. SVA was not associated with Cobb angle of thoracic kyphosis, and could be considered an independent phenotype of age-related hyperkyphosis to be targeted in future intervention trials.

Sex differences in response to targeted kyphosis specific exercise and posture training in community-dwelling older adults: a randomized controlled trial.

BACKGROUND: Hyperkyphosis, an excessive anterior curvature in the thoracic spine, is associated with reduced health status in older adults. Hyperkyphosis is highly prevalent, more common in older women than men. There is no standard intervention to reduce age-related hyperkyphosis. Sex differences in response to a kyphosis-specific exercise intervention are not known. METHODS: We conducted a randomized controlled trial of a targeted kyphosis-specific exercise and postural training program on the primary outcome Cobb angle of kyphosis, and investigated whether the magnitude of change differed between men and women. One hundred twelve participants aged ≥60 years with kyphosis ≥40° were enrolled and randomized to exercise or waitlist control, and 101 participants had analyzable baseline and follow-up radiographs for Cobb angle measurements. A group intervention including 10 participants per group was delivered by a physical therapist, 1-h, twice a week for 3-months. Controls were placed on a waitlist for 3 months before receiving a delayed intervention. Primary outcome was change from baseline to 3-months in Cobb angle measured from standing lateral spine radiographs. Secondary outcomes included change over 3-months in kyphometer-measured kyphosis, physical function and quality of life. Groups were combined for analysis after both received the intervention, and sex differences in response to the intervention were tested with ANOVA. RESULTS: Participants (60 women, 41 men) were 70.0 (SD = 5.7) years old with mean Cobb angle 55.9 (SD = 12.2) degrees at baseline. The active group had higher baseline modified Physical Performance Test scores than control, p = 0.03. Men had greater baseline kyphometer-measured kyphosis, p = 0.09, and higher bone mineral density (BMD), spine strength, more vertebral fractures and diffuse idiopathic skeletal hyperostosis (DISH) than women, p ≤ 0.01. There was no statistically significant difference between groups in change in Cobb at 3-months, p = 0.09, however change in kyphometer-measured kyphosis differed by 4.8 (95% CI:-6.8,-2.7) degrees, p < 0.001, favoring the active group. There were no differences between men and women in change in either kyphosis measurement after intervention, p > 0.1. CONCLUSIONS: A 3-month targeted spine strengthening exercise and posture training program reduced kyphometer-measured, but not radiographic-measured kyphosis. Despite sex differences in baseline kyphosis, BMD, spine strength, fractures and DISH, sex did not affect treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01766674.

Patterns of care for metastatic renal cell carcinoma in Australia.

OBJECTIVE: To examine the patterns of care and outcomes for metastatic renal cell carcinoma (mRCC) in Australia, where there are limited reimbursed treatment options. In particular, we aim to explore prescribing patterns for first-line systemic treatment, the practice of an initial watchful-waiting approach, and the use of systemic treatments in elderly patients. SUBJECTS/PATIENTS AND METHODS: Patients with mRCC undergoing treatment between 2006 and 2012 were identified from four academic hospitals in Victoria and Australian Capital Territory. Demographic, clinicopathological, treatment, and survival data were recorded by chart review. Descriptive statistics were used to report findings. Survival was estimated by the Kaplan-Meier method and compared using the log-rank test. The study was supported by a grant from Pfizer Australia. RESULTS: Our study identified 212 patients with mRCC for analysis. Patients were predominantly of clear cell histology (75%), Eastern Cooperative Oncology Group performance status <2 (67%) and with favourable/intermediate Memorial Sloan-Kettering Cancer Center risk (68%). The median age at diagnosis was 61 years. In all, 163 (77%) patients received first-line systemic therapy, while 49 (23%) received best supportive care (BSC). The most frequently used first-line treatment was sunitinib (125 patients, 77%). Patients who received sunitinib had a median overall survival (OS) of 27.6 months. In all, 43% of patients who received sunitinib underwent a watchful-waiting period of >90 days before initiating treatment; these patients had a median OS of 56.3 months. Elderly patients (50 patients aged ≥70 years) were more likely to receive BSC alone than younger patients (46% vs 16%, P < 0.001). Of those who received systemic therapy, elderly patients were also more likely to have upfront dose reductions (30% vs 8%, P = 0.03). CONCLUSION: Our study of patients with mRCC treated in Australian centres showed that sunitinib was the most commonly prescribed systemic treatment between 2006 and 2012, associated with survival outcomes similar to pivotal studies. We also found that an initial watchful-waiting approach is commonly adopted without apparent detriment to survival. And finally, we found that age has an impact on the prescribing of systemic therapy.

Prevalence and correlates of suspected nonalcoholic fatty liver disease in Chinese American children.

GOALS: The aim of this study was to evaluate the prevalence and clinical correlates of nonalcoholic fatty liver disease (NAFLD) in children of Chinese immigrants. BACKGROUND: NAFLD is increasing in prevalence and is frequently identified in children. High rates of NAFLD were found in adult Chinese immigrants. However, there are limited data regarding NAFLD in Chinese American children. STUDY: Clinical and laboratory data were collected from 407 children, aged 6 to 18 years, who had routine office visits at a Chinatown medical practice. Children were classified as having suspected NAFLD if common causes of liver disease were excluded, alanine aminotransferase levels exceeded established thresholds (>22.1 IU/L for girls and >25.8 IU/L for boys), and elevated alanine aminotransferase levels were confirmed by repeat measurement. RESULTS: 6.1% of Chinese American children had suspected NAFLD, including 33% of obese children. Seventeen percent of children were overweight, 14% were obese, and 52% had 25-hydroxy vitamin D levels <20 ng/mL. In univariable analysis, children with suspected NAFLD were more frequently male, had higher body mass index percentile and lipid levels, and lower vitamin D levels compared with children without evidence of NAFLD. In multivariable analysis, suspected NAFLD was associated with higher BMI percentile and lower vitamin D levels when adjusting for other factors. CONCLUSIONS: Chinese American children with obesity are at high risk for NAFLD. They should be screened accordingly, including testing for metabolic disorders and low vitamin D levels. Early identification of NAFLD in childhood will allow for intervention with lifestyle modification, providing a means to reduce the prevalence of NAFLD in children and adults.