Search

A 27-year-old man newly diagnosed with metastatic testicular choriocarcinoma developed a large right perinephric haematoma secondary to a metastatic deposit in his right kidney. His presentation was also complicated by bilateral iliac venous thrombosis and pulmonary embolism identified prior to initiation of chemotherapy. He underwent multiple attempts at angioembolisation of the bleeding vessels and ultimately angioembolisation of the main renal artery had to be performed to control the bleeding. Following resolution and commencement of chemotherapy, the patient also developed spontaneous intracranial haemorrhage requiring craniotomy.

Study treatment disposition

Adverse events

Purpose:Preclinically, AKT kinase inhibition restores drug sensitivity in platinum-resistant tumors. Here the pan-AKT kinase inhibitor afuresertib was given in combination with paclitaxel and carboplatin (PC) in patients with recurrent platinum-resistant epithelial ovarian cancer (PROC) and primary platinum-refractory ovarian cancer (PPROC).Patients and Methods:Part I was a combination 3+3 dose escalation study for recurrent ovarian cancer. Patients received daily continuous oral afuresertib at 50–150 mg/day with intravenous paclitaxel (175 mg/m2) and carboplatin (AUC5) every 3 weeks for six cycles followed by maintenance afuresertib at 125 mg/day until progression or toxicity. Part II was a single-arm evaluation of the clinical activity of this combination in recurrent PROC (Cohort A) or PPROC (Cohort B). Patients received oral afuresertib at the MTD defined in Part I in combination with PC for six cycles, followed by maintenance afuresertib. Primary endpoints were safety and tolerability of afuresertib in combination with PC (Part I, dose escalation), and investigator-assessed overall response rate (ORR) as per RECIST version 1.1 (Part II).Results:Twenty-nine patients enrolled into Part I, and 30 into Part II. Three dose-limiting toxicities of grade 3 rash were observed, one at 125 mg and two at 150 mg afuresertib. The MTD of afuresertib in combination with PC was therefore identified as 125 mg/day. The most common (≥50%) drug-related adverse events observed in Part I of the study were nausea, diarrhea, vomiting, alopecia, fatigue, and neutropenia and, in Part II, were diarrhea, fatigue, nausea, and alopecia. The Part II ORR in the intention to treat patients was 32% [95% confidence interval (CI), 15.9–52.4] by RECIST 1.1 and 52% (95% CI, 31.3–72.2) by GCIG CA125 criteria. Median progression-free survival was 7.1 months (95% CI, 6.3–9.0 months).Conclusions:Afuresertib plus PC demonstrated efficacy in recurrent PROC with the MTD of afuresertib defined as 125 mg/day.

Summary of exposure to afuresertib, paclitaxel and carboplatin

INTRODUCTION: Bone metastases occur frequently in castration-resistant prostate cancer (CRPC) and may lead to skeletal-related events (SREs), including symptomatic skeletal events (SSEs). Bone-modifying agents (BMAs) delay SREs and SSEs. However, the real-world use of BMAs is debated given the absence of demonstrated survival advantage and potential adverse events (AEs). Our retrospective study examined BMA use and SSE rates in Australian patients with CRPC. METHODS: Patients with CRPC and bone metastases were identified from the electronic CRPC Australian Database. Patient characteristics, treatment patterns and AEs were analysed. Descriptive statistics reported baseline characteristics, SSE rates and BMA use. Comparisons between groups used t-tests and Chi-square analyses. Overall survival was calculated by the Kaplan-Meier method. RESULTS: A total of 532 eligible patients were identified with a median age of 73 years (range: 44-97 years). BMAs were prescribed in 232 men (46%), 183 of whom received denosumab. Patients receiving first-line docetaxel for CRPC were more likely to commence BMAs than those receiving abiraterone or enzalutamide (51% vs 31% vs 38%; p = 0.004). SSEs occurred in 148 men (28%), most commonly symptomatic lesions requiring intervention (75%). At the time of initial SSEs, only 28% were receiving BMAs. Patients treated at sites with lower BMA use (

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.

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.

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.

Objective: The mission of this initiative is to get to know each participant behind their diagnoses - through telehealth and home visits - for enhancing the personalized healthcare delivery in chronic disease management. The initiative emphasizes on the management of type 2 diabetes (T2D) , hypertension, chronic kidney disease, COPD, heart failure, and asthma. This abstract focuses on evaluating outcomes relating to T2D. Methods: The evaluation uses a cross-sectional design to summarize the baseline demographic data pertaining to participants and analyze outcomes from June to December 2021. Descriptive statistics were used to study the current outcomes of the initiative. Results: The selected process and impact outcomes are summarized along with demographic information. Conclusion: Many participants increased frequencies on blood glucose and pressure monitoring. These behavioral changes are translated into A1c improvement. Through connecting with participants, their urgent medical needs were met when primary care providers (PCPs) were unavailable, e.g., resolving hypoglycemia episodes, medication titrations for managing hyperglycemia. Findings have shown that this model refines the care delivery for patients with diabetes going beyond the walls of clinics by partnering clinical pharmacists with diabetologists and PCPs at a safety-net clinic system. Disclosure C.F.Young: Advisory Panel; Sanofi-Aventis U.S. S.Wong: None. Funding Sutter Health

The novel betacoronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spread across the globe at an unprecedented rate since its first emergence in Wuhan City, China in December 2019. Scientific communities around the world have been rigorously working to develop a potent vaccine to combat COVID-19 (coronavirus disease 2019), employing conventional and novel vaccine strategies. Gene-based vaccine platforms based on viral vectors, DNA, and RNA, have shown promising results encompassing both humoral and cell-mediated immune responses in previous studies, supporting their implementation for COVID-19 vaccine development. In fact, the U.S. Food and Drug Administration (FDA) recently authorized the emergency use of two RNA-based COVID-19 vaccines. We review current gene-based vaccine candidates proceeding through clinical trials, including their antigenic targets, delivery vehicles, and route of administration. Important features of previous gene-based vaccine developments against other infectious diseases are discussed in guiding the design and development of effective vaccines against COVID-19 and future derivatives., Graphical abstract Unlabelled Image

Despite its historic role in evolving our understanding of modern molecular genetics, the mechanism governing the bacteriophage T4rII exclusion (Rex) phenotype has remained a mystery for over six decades. The Rex system is thought....., The T4rII exclusion (Rex) phenotype is the inability of T4rII mutant bacteriophage to propagate in hosts (Escherichia coli) lysogenized by bacteriophage lambda (λ). The Rex phenotype, triggered by T4rII infection of a rex+ λ lysogen, results in rapid membrane depolarization imposing a harsh cellular environment that resembles stationary phase. Rex “activation” has been proposed as an altruistic cell death system to protect the λ prophage and its host from T4rII superinfection. Although well studied for over 60 years, the mechanism behind Rex still remains unclear. We have identified key nonessential genes involved in this enigmatic exclusion system by examining T4rII infection across a collection of rex+ single-gene knockouts. We further developed a system for rapid, one-step isolation of host mutations that could attenuate/abrogate the Rex phenotype. For the first time, we identified host mutations that influence Rex activity and rex+ host sensitivity to T4rII infection. Among others, notable genes include tolA, ompA, ompF, ompW, ompX, ompT, lpp, mglC, and rpoS. They are critical players in cellular osmotic balance and are part of the stationary phase and/or membrane distress regulons. Based on these findings, we propose a new model that connects Rex to the σS, σE regulons and key membrane proteins.

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.

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

Several systemic therapies have demonstrated a survival advantage in metastatic castration resistant prostate cancer (mCRPC). Access to these medications varies significantly worldwide. In Australia until recently, patients must have received docetaxel first, unless unsuitable for chemotherapy, despite no evidence suggesting superiority over androgen receptor signalling inhibitors (ARSIs). Our study investigated real-world systemic treatment patterns in Australian patients with mCRPC.The electronic CRPC Australian Database (ePAD) was interrogated to identify mCRPC patients. Clinicopathological features, treatment and outcome data, stratified by first-line systemic therapies, were extracted. Comparisons between groups utilised Kruskal-Wallis tests and Chi-Square analyses. Time-to-event data were calculated using Kaplan-Meier methods and groups compared using log-rank tests. Factors influencing overall survival (OS) and time to treatment failure (TTF) were analysed through Cox proportional hazards regression models.We identified 578 patients who received first-line systemic therapy for mCRPC. Enzalutamide (ENZ) was most commonly prescribed (In our real-world population, ENZ and AA were common first-line systemic therapy choices, particularly among older patients and those with poorer performance status. Patients receiving ENZ and AA demonstrated superior TTF compared to DOC, while OS was not statistically different. Our findings highlight the important role of ARSIs, given the variability of access worldwide.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Early forms of toothbrush have been in existence since 3000 BC. Several changes have happened since then, it has evolved from a‘chew stick’, into a bristle toothbrush, then a battery-operated toothbrush. Tooth brushing has been our primary way of cleaning theoral cavity and its structures to maintain good oral hygiene. However, prolonged brushing can be abrasive to one’s existing restorationand prosthesis increasing the surface roughness, leaving the resins vulnerable to damage and plaque accumulation. This study aims toevaluate the effect of tooth brushing using a manual toothbrush and a battery-operated toothbrush to the surface roughness ofcomposite resin restorations and denture base acrylic resin. Composite specimens and denture base acrylic specimens showed varyingwear and surface roughness with several variables taken into consideration such as brushing force, brushing stroke, dentifrice, type ofbristle, and type of toothbrush used. The expected result is that the specimens brushed using the battery-operated toothbrush withapplied toothpaste will have greater wear and surface roughness.

The human body is a large reservoir for bacterial viruses known as bacteriophages (phages), which participate in dynamic interactions with their bacterial and human hosts that ultimately affect human health. The current growing interest in human resident phages is paralleled by new uses of phages, including the design of engineered phages for therapeutic applications. Despite the increasing number of clinical trials being conducted, the understanding of the interaction of phages and mammalian cells and tissues is still largely unknown. The presence of phages in compartments within the body previously considered purely sterile, suggests that phages possess a unique capability of bypassing anatomical and physiological barriers characterized by varying degrees of selectivity and permeability. This review will discuss the direct evidence of the accumulation of bacteriophages in various tissues, focusing on the unique capability of phages to traverse relatively impermeable barriers in mammals and its relevance to its current applications in therapy.

Hypertension is a common problem and a major risk factor for cardiovascular disease. It is unclear whether efforts to control blood pressure (BP) known to be effective in integrated healthcare systems can be successfully implemented in an academic setting. We describe our experience implementing a multistep quality improvement program within an academic general medicine practice aimed at improving BP among patients with uncontrolled hypertension. Ensuring medical assistants were correctly measuring BP provided the basis for accurate data entry into the electronic medical record (EMR); our EMR-based registry data allowed us to feedback primary care provider (PCP) level data on BP control for panel management, which resulted in improvements in BP for a substantial proportion of patients, particularly for those with more practice visits. However, due to PCP, patient, and system barriers, our initial attempt to integrate a pharmacist into our team for hypertension management was only successful for a small number of patients who engaged in pharmacist in-person visits. Future improvement efforts will focus on addressing the barriers to more intensive BP management, integrating lessons from this experience. As chronic disease management shifts to a population-based model, team change will be a necessary component for achieving clinical improvement.

Author(s): Katzman, Wendy B; Parimi, Neeta; Gladin, Amy; Wong, Shirley; Lane, Nancy E | Abstract: Background and purposeTreatments that prevent worsening kyphosis are important due to the progressive nature of kyphosis with aging. We assessed long-term efficacy of treatment effects after a short-term kyphosis exercise and posture training intervention in a cohort study among older adults with hyperkyphosis, and investigated whether long-term treatment effects differ among males and females.MethodsIn the original kyphosis intervention, 112 older adults enrolled in a waitlist design randomized controlled trial. One hundred three participants, mean age 70.0 (5.7) years and kyphosis 52.0° (7.4°), completed a twice weekly, 3-month, group exercise and posture training intervention, and were eligible to enroll in the follow-up study. We compared (1) change in outcomes pre-/postintervention to change postintervention over the follow-up period, (2) change in outcomes pre-/postintervention and postintervention to follow-up, stratified by sex, and (3) long-term change postintervention to follow-up in males and females. Primary outcome was change in kyphometer-measured thoracic kyphosis. Secondary outcomes were change in lumbar lordosis, objective measures of physical function, self-reported measures of physical activity, and health-related quality of life (HRQoL).Results and discussionForty-three participants, 42% of the eligible cohort, returned for follow-up, a mean 3.0 (0.7) years after completing the original intervention. Participants (27 females and 16 males) were 73.8 (6.1) years old, with mean kyphosis 48.9° (11.9°) at follow-up. Kyphosis declined -1.5° (95% confidence interval [CI]: -3.9° to 1.0°) postintervention to follow-up and this was no different than change pre-/postintervention, P = .173. Lordosis improved 8.9° (95% CI: 6.2° to 11.6°), more than change pre-/postintervention, P l .001. Gait speed measure of physical function increased 0.08 (95% CI: 0.02 to 0.14) m/s, Physical Activity Scale for the Elderly (PASE) measure of physical activity increased 4 (95% CI: -16 to 24) points, and Patient-Reported Outcomes Measurement Information System (PROMIS) mental health T-score measure of HRQoL increased 1.1 (95% CI: -1.0 to 3.1) points, but these improvements were not significantly more than change pre-/postintervention, P g .050. Other measures of physical function (modified Physical Performance Test [PPT], Timed Up and Go, and 6-minute walk) and HRQoL (Scoliosis Research Society [SRS-30] self-image and PROMIS physical function and physical health) declined at follow-up, significantly more than change pre/postintervention, P ≤ .050. Comparing change in outcomes pre-/postintervention and postintervention to follow-up, stratified by sex, both males and females increased lordosis, and decreased modified PPT and 6-minute walk measures of physical function, P l .050. Males and females differed in long-term change postintervention to follow-up. Time loaded standing and PASE improved in females compared with males, P = .008 and P = .092, respectively, and PROMIS mental health, physical health, and physical function declined in females compared with males, P = .073, P = .025, and P = .005, respectively.ConclusionsIn our follow-up study, a mean of 3.0 (0.07) years after a 3-month kyphosis exercise and posture training intervention, kyphosis maintained and did not progress as expected with age. There was long-term improvement in lordosis. Compared with treatment effects from the short-term intervention, gait speed maintained equally well in males and females, while trunk endurance improved in females. Further investigation of long-term benefits of a short-term kyphosis exercise and posture training intervention is warranted.

Multiple life-prolonging therapies are available for metastatic castration-resistant prostate cancer (mCRPC). However, the optimal treatment strategy following progression through standard treatment with docetaxel, androgen receptor signaling inhibitor (ARSI) and cabazitaxel, remains unclear. We aimed to describe treatment patterns in men with mCRPC following progression on standard treatments and determine whether subsequent treatment choice impacts overall survival.Clinicopathologic and treatment data were extracted from the electronic CRPC Australian Database (ePAD) for patients who had received docetaxel, ARSIs and cabazitaxel in any order. Data were analyzed to compare groups that did versus did not receive subsequent systemic therapy. Treatment sequences, median duration of treatment, and median overall survival (mOS) were reported for each treatment group.Ninety-eight eligible patients were identified, with 51 receiving subsequent systemic therapy. Those who received further treatment were younger (68 vs. 71 years, p .01) but did not have any other differences in clinicopathologic features compared to those who received no further treatment. Patients who received upfront docetaxel were more likely to proceed to subsequent treatment (p = .02). Subsequent systemic therapies varied, the most common being carboplatin-based regimens (n = 13, 25.5%) and many patients were rechallenged with ARSI (n = 10, 19.6%) or docetaxel (n = 6, 11.8%). There was no difference in mOS according to subsequent systemic therapy (p = .09).This retrospective multicenter analysis demonstrates the variation in treatment sequences used for mCRPC in the real-world setting. In the absence of high quality, prospective evidence, our results suggest that subsequent treatment choice does not influence survival outcomes and the optimal choice is guided by individual patient and disease-related factors.

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 =

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 i) To investigate the real-world uptake of docetaxel in mHSPC; and ii) 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 includes demographics, diagnosis method and institution, staging investigations, and treatments within 12 months of diagnosis. Wilcoxon rank-sum, chi-square 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 1014 men with mHSPC were analysed, 25% of whom received docetaxel with androgen deprivation therapy (ADT). 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 under 70 receiving docetaxel increased from 54% in 2014-15 to 64% in 2016-18, while in men aged 70 and over the comparative figures were 15% and 22% respectively. Conclusions Although docetaxel was not used in a 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. This article is protected by copyright. All rights reserved.

4560 Background: In the multicenter, open-label, randomized, phase 3 CLEAR study, LEN + PEMBRO had significant PFS and OS benefits, and improved ORR vs SUN in first-line advanced RCC. Herein, we explore efficacy according to selected subgroups and the association between pts’ depth of response and OS. Methods: Pts in the CLEAR study were randomly assigned 1:1:1 to 1 of 3 treatment arms: LEN 20 mg orally QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + everolimus 5 mg orally QD; or SUN 50 mg orally QD (4 weeks on/2 weeks off). We report PFS, OS, and ORR based on IMDC risk group (favorable and intermediate/poor) and presence of a target kidney lesion at baseline (post hoc analysis). Post hoc 6-month landmark analyses assessed the association between tumor shrinkage and OS. Pts who were alive at 6 months were grouped based on maximum tumor shrinkage from baseline or confirmed complete response (CR) up to 6 months. Tumor assessments were performed by independent review committee per RECIST v1.1. Odds ratios were calculated using the Cochran-Mantel-Haenszel method; HRs were based on stratified Cox proportional hazards model. Results: Among 1069 pts randomized in the CLEAR study, 355 were assigned to LEN + PEMBRO and 357 to SUN. Median follow-up was 27 months for the LEN + PEMBRO group and 26 months for the SUN group. PFS favored LEN + PEMBRO (median 22.1 months, n=243) vs SUN (median 5.9 months, n=229) in the IMDC-intermediate/poor subgroup (HR 0.36 [95% CI 0.28-0.47]); and in the IMDC-favorable subgroup (median 28.1 months, n=110 vs median 12.9 months, n=124; HR 0.41 [95% CI 0.28-0.62]). OS favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (HR 0.58 [95% CI 0.42-0.80]); few events were observed in the IMDC-favorable subgroup thus, it was inadequate to evaluate OS. ORR favored LEN + PEMBRO vs SUN in the IMDC-intermediate/poor subgroup (72.4% vs 28.8%; odds ratio 6.60 [95% CI 4.39-9.90]) and the IMDC-favorable subgroup (68.2% vs 50.8%; odds ratio 2.00 [95% CI 1.17-3.42]). In pts with target kidney lesions, PFS, OS, and ORR were improved with LEN+PEMBRO vs SUN (table). The 6-month landmark analysis in the LEN + PEMBRO group showed that the OS rate at 24 months was 100% (95% CI not estimable [NE]-NE) for pts with confirmed CR per RECIST v1.1 and 91.7% (95% CI 53.9-98.8) both for pts with >75% to

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 in older adults with low physical function and hyperkyphosis.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 SPPB 9.62 (SD=1.17) points. At baseline, the LFG was older than HFG (p=0.005), endorsed more pain, (p=0.060), had worse physical function and HrQol (p≤0.001), and comparable kyphosis (p=0.640). SPPB increased 0.62 (95% CI: -0.20 to 1.44) points in the LFG and decreased 0.04 (95%CI: -0.28 to 0.19) points in the HFG, p=0.020. Gait speed improved 0.04 (95%CI: -0.02 to 0.10) m/s in the LFG. Kyphosis improved equally in both groups. Adherence was similar and there were no adverse events in the LFG or HFG. 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. Clinicaltrials.gov dentifier: NCT01766674

Advances in bionanotechnology aim to develop smart nucleic acid delivery carriers with stimuli-responsive features to overcome challenges such as non-biodegradability, rapid clearance, immune response, and reaching intracellular targets. Peptide-based nanomaterials have become widely used in the field of gene and drug delivery due to their structural versatility and biomimetic properties. Particularly, polypeptide gene vectors that respond to biological stimuli, such as acidic intracellular environments, have promising applications in mediating efficient endosomal escape and drug release. Unfortunately, synthesis strategies for efficient polymerization of acid-labile peptides have been limited due to conditions that fail to preserve acid-degradable functional groups. Stable urethane derivatives of the acid-labile amino acid ketalized serine (kSer) were synthesized and polymerized to a high molecular weight under permissive conditions independent of elevated temperature, restrictive solvents, or an inert atmosphere. A new formulation strategy utilizing solvent-driven self-assembly of poly(kSer) peptides with small interfering RNA (siRNA) was developed, and the resulting poly(kSer)/siRNA complexes were further cross-linked for reinforced stability under physiological conditions. The complexes were highly monodisperse and precisely spherical in morphology, which has significant clinical implications in definitive biodistribution, cellular internalization, and intracellular trafficking patterns. Self-assembled, cross-linked poly(kSer)/siRNA complexes demonstrated efficient nucleic acid encapsulation, internalization, endosomal escape, and acid-triggered cargo release, tackling multiple hurdles in siRNA delivery. The acid-responsive polypeptides and solvent-driven self-assembly strategies demonstrated in this study could be applicable to developing other efficient and safe delivery systems for gene and drug delivery.

Context Diabetes is a complex, chronic condition and managing it can have psychosocial implications for patients, including an impact on relationships with their loved ones and physical wellness. The necessary modifications to daily behaviors can be very overwhelming, thus leading to diabetes-related distress. Objective To investigate the association between diabetes-related distress and perceived social support among people with type 2 diabetes. Methods This cross-sectional study surveyed a population with a lower socioeconomic status (Medi-Cal recipients, which are only given to low-income individuals) in Solano County, California. Patients who had type 2 diabetes mellitus, who were between 40 and 80 years old, and who had a medical appointment in the clinic(s) at least once between December 2015 and December 2016 were included. Patients who could not understand or speak English and patients whose primary care clinicians declined their participation in the study were excluded from the study. Each study participant was recruited at the end of their medical appointment, and the survey instrument in paper form was administered. The Problem Areas in Diabetes (PAID) scale, which indicates diabetes-related distress, and Multidimensional Scale of Perceived Social Support (MSPSS) with 3 subscales (family, friends, and significant others) were used in this study. Multiple linear regression models were used to analyze the associations between PAID and MSPSS surveys. Results For the 101 participants included in our study, multiple linear regression models showed statistically significant association between total MSPSS scores and total PAID scores (β = −.318; 95% CI, .577, −.0581; P=.017) as well as between MSPSS family subscale scores and total PAID scores (β= −.761; 95% CI, −1.35, −.168; P=.012). Among the 3 MSPSS subscales, higher perceived support from family members was found to be significantly associated with lower total PAID scores (β= −.761; 95% CI, −1.35, −.168; P=.012). Conclusion Our findings suggest that a higher level of perceived social support experienced was associated with lower diabetes-related distress among patients with type 2 diabetes. Osteopathic physicians have a central role in providing comprehensive, patient-centered, holistic care, and the attention to social support in chronic disease management can help remove barriers in providing optimal care.

Purpose We sought to evaluate features of partial remission (PR) in children with type 1 diabetes mellitus (T1DM) using the insulin-dose adjusted A1c (IDAA1c) definition and to identify risk factors associated with nonremission. Methods Medical records of patients with newly diagnosed T1DM between January 1, 2008, and June 30, 2018, were retrospectively reviewed. Hemoglobin A1c (HbA1c) readings and insulin total daily doses (TDDs) of each patient at each follow-up visit were obtained with IDAA1c values calculated. PR was defined as an IDAA1c score of 9 points or less within 6 months of diagnosis. The trends of HbA1c and TDD within 2 years after diagnosis were compared between remitters and nonremitters. Factors that may predict the occurrence of PR were studied, with their relative risks of nonremission calculated. Results PR occurred in 26 patients (45.6%), including 8 girls and 18 boys, with a median duration of 8 months. The frequency of remission in male patients was significantly higher (P=0.002) and the relative risk of female sex with nonremission was 2.20 (95% confidence interval [CI], 1.24-3.91), which remained significant when adjusted by multivariate regression modeling. The initial HbA1c level at diagnosis was also significantly higher in the nonremission group (P=0.029), with a relative risk of 1.12 (95% CI, 1.01-1.25). Both HbA1c (P=0.012) and TDD (P=0.006) were significantly lower within 2 years after diagnosis among remitters than in nonremitters. TDD was significantly lower in male patients (P=0.029) during the same period, while there was no significant difference in HbA1c level between male and female patients (P=0.163). Conclusion Both the initial HbA1c level at diagnosis and sex were factors associated with the occurrence of PR. Female sex was an independent risk factor of nonremission, likely resulting from a higher insulin requirement in female T1DM patients.

AIM To evaluate the effectiveness of a combined patient empowerment program (PEP) and cognitive training (CT) program on improving glycemic control among older subjects with diabetes and cognitive impairment. METHODS A prospective single blinded, randomized controlled study was carried out in 139 older patients with diabetes aged ≥65 years with memory complaints and recent glycosylated hemoglobin level of 7-9%. They were randomly assigned to either undergo once-weekly PEP combined with CT for 10 weeks (intervention group, N = 73) or receive no intervention (control group, N = 66). All participants were followed up at months 4 and 12 to examine the immediate and long-term effects on glycemic control, cognition, mood and compliance to drug and diabetes self-management. RESULTS The intervention did not significantly reduce glycosylated hemoglobin. The intervention group showed significant progressive improvement in memory over 1 year and executive function improved significantly at month 12. There was no significant change in diabetes self-management activities with the intervention. CONCLUSIONS Combination of PEP and CT did not improve glycemic control or self-care activities in older patients with diabetes and memory complaints but was effective in improving cognitive function in the longer term. Geriatr Gerontol Int 2020; 20: 1164-1170.

Summary of study A multi-country randomized, placebo-controlled trial of the safety, immunogenicity and efficacy of respiratory syncytial virus (RSV) F-protein nanoparticle vaccine was undertaken in 4,636 pregnant women and their infants. RSV F-protein vaccine was safe and immunogenic in the pregnant women inducing anti-F IgG, palivizumab-competing antibodies and RSV neutralizing antibodies that were transferred to the fetus. Although the primary endpoint of prevention of RSV-specific medically-significant lower respiratory tract infection (MS-LRTI) was not met per protocol criteria for efficacy (i.e. 97.52% lower bound >30%), vaccine efficacy was 39.4% (97.52% CI: -1.0, 63.7%; p=0.0278) in infants 0-90 days age. Furthermore, there was a 58.8% (95% CI 31.9, 75.0%) lower rate of RSV LRTI with severe hypoxemia (secondary endpoint) through to 90 days of age in the expanded intent-to-treat analysis. The number of women needed to be vaccinated to prevent RSV-specific MS-LRTI or LRTI with severe hypoxemia in their infants through to 180 days of life were 88 and 82, respectively. Background RSV is the dominant cause of severe lower respiratory tract infection (LRTI) in infants, with most severe disease concentrated in younger-age infants. Methods Healthy, pregnant women between 28 and 36 weeks gestation, with expected delivery near the start of the RSV season, were randomized to a single intramuscular dose of nanoparticle RSV F-protein vaccine, or placebo in a 2:1 ratio. Their infants were followed for 180 days for medically-significant LRTI (MS-LRTI), LRTI with severe hypoxemia and/or LRTI- hospitalization. RSV detection was performed centrally by PCR. Safety evaluation continued until 364 days age. Results 4,636 women were randomized, with 4,579 live births. Over the first 90 days of life, efficacy against RSV-MS-LRTI was 39.4% (97.52%CI: -1.0, 63.7%; p=0.0278) and 41.4% (95%CI: 5.3, 61.2%) in the per protocol and expanded intent-to-treat (eITT) analyses, respectively. There was a lower rate (efficacy 58.8%; 95%CI 31.9, 75.0% in eITT analysis; not adjusted for multiplicity) of RSV-LRTI with severe hypoxemia in infants of vaccinees through 90 days age. Pneumonia reported as a serious adverse events was 49.4% less common in infants of vaccinees (2.6%) than placebo-recipients through 364 days age. Conclusions Maternal vaccination with RSV F-nanoparticle vaccine was safe and immunogenic. The prespecified primary endpoint success criterion (efficacy 97.5% lower bound ≥30%) was not achieved. However, maternal immunization was associated with reduced risk of RSV-confirmed MS-LRTI and LRTI with severe hypoxemia in early infancy. Trial Registration Number ClinicalTrials.Gov: NCT02624947. Funding statement Funded by Novavax, with supporting grant from the Bill and Melinda Gates Foundation.

Aim Optimal treatment for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) has evolved, with many patients deriving benefit from the addition of docetaxel to androgen deprivation therapy (D-ADT). This study sought to define the therapy used and associated activity following D-ADT. Methods Retrospective analysis of patients with mHSPC treated with one or more cycles of D-ADT who were identified from a prospectively maintained multisite prostate cancer database of patients treated in a community or academic center setting in Australia. The primary endpoint of this study was first-line time to treatment failure (1L TTF) for subsequent treatment of metastatic Castrate Resistant Prostate Cancer (mCRPC), with secondary endpoints of prostate-specific antigen (PSA) reduction >50% and time from 1L to second-line (2L) treatment initiation. Results A total of 93 patients received D-ADT for mHSPC, 85 (91%) had subsequent treatment for mCRPC. Median time to mCRPC (biochemical, clinical or radiographic) had been 14.8 months (95% confidence interval [CI], 11.9-16.5). 1L treatment was enzalutamide 47 patients (55%), abiraterone 23 (27%), cabazitaxel 7 (8%), docetaxel 4 (5%) and other therapies 4 (5%). Median 1L TTF was 6.3 months (95% CI, 4.9-7.6), PSA > 50% reduction was achieved in 32 of 89 patients (36%), median time from 1L to second-line treatment was 7.3 months (1.3-27.4), which did not differ significantly between treatment groups. Conclusions Abiraterone, enzalutamide, cabazitaxel and docetaxel all demonstrate activity following progression on D-ADT. No difference in efficacy was detected between treatment options for mCRPC. Prospective trials investigating the optimal treatment sequence for prostate cancer following progression on D-ADT needed.

Peptide-based biomaterials have been extensively investigated for biomedical applications due to their high structural and functional versatility. Particularly, peptides that can respond to different stimuli, such as pH, redox potential, temperature, light, and enzymes can offer controllable actions in target body locations. Therefore, smart, multifunctional peptide-based nanoparticle (NP) systems that respond to pathological stimuli with the ability to facilitate cellular internalization and enhance cytosolic release via disrupting membranes are of great interest in biomaterials research. This review predominantly focuses on synthetically designed stimuli-responsive peptides that serve different biomedical applications, with emphasis on drug and gene delivery, and touches upon recent advances in membrane-active peptide NPs for enhanced therapeutic activity. The review also provides an outlook on future directions on the maturing field of peptide-based therapeutics.