Search

Abstract Background Healthcare policy implemented during the COVID-19 pandemic may have impacted the health of patients with heart failure. Australian data provide a unique opportunity to examine service disruption independent of significant COVID-19 burden. This study aimed to examine heart failure care during the pandemic in New South Wales (NSW). Methods Analysis of hospital utilisation among patients aged ≥ 18 years with a primary diagnosis of heart failure conducted using linked administrative health records from hospital admission, emergency department, non-admitted services, and mortality data collections. Health service utilisation and outcomes were compared “Pre-pandemic” (PP): 16th March 2018 – 28th August 2019 and “During pandemic” (DP): 16th March 2020 – 28th August 2021. Mortality data were available until December 2021. Results Heart failure-related ED presentations and hospital admissions were similar between the periods (PP = 15,324 vs DP = 15,023 ED presentations, PP = 24,072 vs DP = 23,145 hospital admissions), though rates of admission from ED were lower DP (PP = 12,783/15,324 (83.4% [95% CI 82.8-84.0]) vs DP = 12,230/15,023 (81.4% [95% CI 80.8-82.0%]). There was no difference according to age, sex, rurality, or socioeconomic status. Outpatient volume reduced DP (PP = 44,447 vs DP = 35,801 occasions of service), but telehealth visits increased nearly threefold (PP = 5,978/44,447 (13.4% [95% CI 13.1-13.8%]) vs DP = 15,901/35,801 (44.4% [95% CI 43.9-44.9%]) with highest uptake among the wealthy and those in major cities. Time to heart failure-related ED presentation, hospitalisation or all-cause mortality following index admission was longer DP (PP = 273 [IQR 259, 290] days, DP = 323 [IQR 300, 342] days, HR 0.91 [95% CI 0.88, 0.95]). Conclusions Policies implemented DP had minimal impact on volumes of inpatient heart failure care in NSW hospitals, but there were fewer admissions from ED and reduced volumes of publicly funded outpatient care. A rapid shift from patient-facing to remotely delivered care enabled compliance with restrictions and was associated with increased time to heart failure-related adverse events, but access was not afforded equally across the socio-demographic spectrum.

Abstract Excitotoxicity from the impairment of glutamate uptake constitutes an important mechanism in neurodegenerative diseases such as Alzheimer’s, multiple sclerosis, and Parkinson's disease. Within the eye, excitotoxicity is thought to play a critical role in retinal ganglion cell death in glaucoma, diabetic retinopathy, retinal ischemia, and optic nerve injury, yet how excitotoxic injury impacts different retinal layers is not well understood. Here, we investigated the longitudinal effects of N-methyl-D-aspartate (NMDA)-induced excitotoxic retinal injury in a rat model using deep learning-assisted retinal layer thickness estimation. Before and after unilateral intravitreal NMDA injection in nine adult Long Evans rats, spectral-domain optical coherence tomography (OCT) was used to acquire volumetric retinal images in both eyes over 4 weeks. Ten retinal layers were automatically segmented from the OCT data using our deep learning-based algorithm. Retinal degeneration was evaluated using layer-specific retinal thickness changes at each time point (before, and at 3, 7, and 28 days after NMDA injection). Within the inner retina, our OCT results showed that retinal thinning occurred first in the inner plexiform layer at 3 days after NMDA injection, followed by the inner nuclear layer at 7 days post-injury. In contrast, the retinal nerve fiber layer exhibited an initial thickening 3 days after NMDA injection, followed by normalization and thinning up to 4 weeks post-injury. Our results demonstrated the pathological cascades of NMDA-induced neurotoxicity across different layers of the retina. The early inner plexiform layer thinning suggests early dendritic shrinkage, whereas the initial retinal nerve fiber layer thickening before subsequent normalization and thinning indicates early inflammation before axonal loss and cell death. These findings implicate the inner plexiform layer as an early imaging biomarker of excitotoxic retinal degeneration, whereas caution is warranted when interpreting the ganglion cell complex combining retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses in conventional OCT measures. Deep learning-assisted retinal layer segmentation and longitudinal OCT monitoring can help evaluate the different phases of retinal layer damage upon excitotoxicity.

Abstract Artificial intelligence and machine learning are driving a paradigm shift in medicine, promising data-driven, personalized solutions for managing diabetes and the excess cardiovascular risk it poses. In this comprehensive review of machine learning applications in the care of patients with diabetes at increased cardiovascular risk, we offer a broad overview of various data-driven methods and how they may be leveraged in developing predictive models for personalized care. We review existing as well as expected artificial intelligence solutions in the context of diagnosis, prognostication, phenotyping, and treatment of diabetes and its cardiovascular complications. In addition to discussing the key properties of such models that enable their successful application in complex risk prediction, we define challenges that arise from their misuse and the role of methodological standards in overcoming these limitations. We also identify key issues in equity and bias mitigation in healthcare and discuss how the current regulatory framework should ensure the efficacy and safety of medical artificial intelligence products in transforming cardiovascular care and outcomes in diabetes.

Abstract Multidrug resistance renders treatment failure in a large proportion of head and neck squamous cell carcinoma (HNSCC) patients that require multimodal therapy involving chemotherapy in conjunction with surgery and/or radiotherapy. Molecular events conferring chemoresistance remain unclear. Through transcriptome datamining, 28 genes were subjected to pharmacological and siRNA rescue functional assays on 12 strains of chemoresistant cell lines each against cisplatin, 5-fluorouracil (5FU), paclitaxel (PTX) and docetaxel (DTX). Ten multidrug chemoresistance genes (TOP2A, DNMT1, INHBA, CXCL8, NEK2, FOXO6, VIM, FOXM1B, NR3C1 and BIRC5) were identified. Of these, four genes (TOP2A, DNMT1, INHBA and NEK2) were upregulated in an HNSCC patient cohort (n = 221). Silencing NEK2 abrogated chemoresistance in all drug-resistant cell strains. INHBA and TOP2A were found to confer chemoresistance in majority of the drug-resistant cell strains whereas DNMT1 showed heterogeneous results. Pan-cancer Kaplan-Meier survival analysis on 21 human cancer types revealed significant prognostic values for INHBA and NEK2 in at least 16 cancer types. Drug library screens identified two compounds (Sirodesmin A and Carfilzomib) targeting both INHBA and NEK2 and re-sensitised cisplatin-resistant cells. We have provided the first evidence for NEK2 and INHBA in conferring chemoresistance in HNSCC cells and siRNA gene silencing of either gene abrogated multidrug chemoresistance. The two existing compounds could be repurposed to counteract cisplatin chemoresistance in HNSCC. This finding may lead to novel personalised biomarker-linked therapeutics that can prevent and/or abrogate chemoresistance in HNSCC and other tumour types with elevated NEK2 and INHBA expression. Further investigation is necessary to delineate their signalling mechanisms in tumour chemoresistance.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) is a major cause of financial toxicity, defined as excess financial strain from healthcare, in the US. Identifying factors that put patients at greatest risk can help inform more targeted and cost-effective interventions. Specific social determinants of health (SDOH) such as income are associated with a higher risk of experiencing financial toxicity from healthcare, however, the associations between more comprehensive measures of cumulative social disadvantage and financial toxicity from healthcare are poorly understood. Methods Using the National Health Interview Survey (2013–17), we assessed patients with self-reported ASCVD. We identified 34 discrete SDOH items, across 6 domains: economic stability, education, food poverty, neighborhood conditions, social context, and health systems. To capture the cumulative effect of SDOH, an aggregate score was computed as their sum, and divided into quartiles, the highest (quartile 4) containing the most unfavorable scores. Financial toxicity included presence of: difficulty paying medical bills, and/or delayed/foregone care due to cost, and/or cost-related medication non-adherence. Results Approximately 37% of study participants reported experiencing financial toxicity from healthcare, with a prevalence of 15% among those in SDOH Q1 vs 68% in SDOH Q4. In fully-adjusted regression analyses, individuals in the 2nd, 3rd and 4th quartiles of the aggregate SDOH score had 1.90 (95% CI 1.60, 2.26), 3.66 (95% CI 3.11, 4.35), and 8.18 (95% CI 6.83, 9.79) higher odds of reporting any financial toxicity from healthcare, when compared with participants in the 1st quartile. The associations were consistent in age-stratified analyses, and were also present in analyses restricted to non-economic SDOH domains and to 7 upstream SDOH features. Conclusions An unfavorable SDOH profile was strongly and independently associated with subjective financial toxicity from healthcare. This analysis provides further evidence to support policies and interventions aimed at screening for prevalent financial toxicity and for high financial toxicity risk among socially vulnerable groups.

Abstract Background Few studies have examined associations between genetic risk for type 2 diabetes (T2D), lifestyle, clinical risk factors, and cardiovascular disease (CVD). We aimed to investigate the association of and potential interactions among genetic risk for T2D, lifestyle behavior, and metabolic risk factors with CVD. Methods A total of 345,217 unrelated participants of white British descent were included in analyses. Genetic risk for T2D was estimated as a genome-wide polygenic risk score constructed from > 6 million genetic variants. A favorable lifestyle was defined in terms of four modifiable lifestyle components, and metabolic health status was determined according to the presence of metabolic syndrome components. Results During a median follow-up of 8.9 years, 21,865 CVD cases (6.3%) were identified. Compared with the low genetic risk group, participants at high genetic risk for T2D had higher rates of overall CVD events, CVD subtypes (coronary artery disease, peripheral artery disease, heart failure, and atrial fibrillation/flutter), and CVD mortality. Individuals at very high genetic risk for T2D had a 35% higher risk of CVD than those with low genetic risk (HR 1.35 [95% CI 1.19 to 1.53]). A significant gradient of increased CVD risk was observed across genetic risk, lifestyle, and metabolic health status (P for trend > 0.001). Those with favorable lifestyle and metabolically healthy status had significantly reduced risk of CVD events regardless of T2D genetic risk. This risk reduction was more apparent in young participants (≤ 50 years). Conclusions Genetic risk for T2D was associated with increased risks of overall CVD, various CVD subtypes, and fatal CVD. Engaging in a healthy lifestyle and maintaining metabolic health may reduce subsequent risk of CVD regardless of genetic risk for T2D.

Abstract Background In pediatric hereditary cystic kidney diseases, epithelial cell defects mostly result from rare, autosomal recessively inherited pathogenic variants in genes encoding proteins of the cilia-centrosome complex. Consequences of individual gene variants on epithelial function are often difficult to predict and can furthermore depend on the patient’s genetic background. Here, we studied urine-derived renal tubular epithelial cells (URECs) from genetically determined, pediatric cohorts of different hereditary cystic kidney diseases, comprising autosomal recessive polycystic kidney disease, nephronophthisis (NPH) and the Bardet Biedl syndrome (BBS). UREC characteristics and behavior in epithelial function-related 3D cell culture were compared in order to identify gene and variant-specific properties and to determine aspects of epithelial (cell) dysfunction. Results UREC preparations from patients (19) and healthy controls (39) were studied in a qualitative and quantitative manner using primary cells cultured for up-to 21 days. In patients with biallelic pathogenic variants in PKHD1 or NPHP genes, we were able to receive satisfactory amounts of URECs of reproducible quality. In BBS patients, UREC yield was lower and more dependent on the individual genotype. In contrast, in UREC preparations derived from healthy controls, no predictable and satisfactory outcome could be established. Considering cell proliferation, tubular origin and epithelial properties in 2D/3D culture conditions, we observed distinct and reproducible epithelial properties of URECs. In particular, the cells from patients carrying PKHD1 variants were characterized by a high incidence of defective morphogenesis of monolayered spheroids—a property proposed to be suitable for corrective intervention. Furthermore, we explored different ways to generate reference cell lines for both—patients and healthy controls—in order to eliminate restrictions in cell number and availability of primary URECs. Conclusions Ex vivo 3D cell culture of primary URECs represents a valuable, non-invasive source to evaluate epithelial cell function in kidney diseases and as such helps to elucidate the functional consequences of rare genetic disorders. In combination with genetically defined control cell lines to be generated in the future, the cultivation of primary URECs could become a relevant tool for testing personalized treatment of epithelial dysfunction in patients with hereditary cystic kidney disease.

Abstract Background Polygenic scores—which quantify inherited risk by integrating information from many common sites of DNA variation—may enable a tailored approach to clinical medicine. However, alongside considerable enthusiasm, we and others have highlighted a lack of standardized approaches for score disclosure. Here, we review the landscape of polygenic score reporting and describe a generalizable approach for development of a polygenic score disclosure tool for coronary artery disease. Methods We assembled a working group of clinicians, geneticists, data visualization specialists, and software developers. The group reviewed existing polygenic score reports and then designed a two-page mock report for coronary artery disease. We then conducted a qualitative user-experience study with this report using an interview guide focused on comprehension, experience, and attitudes. Interviews were transcribed and analyzed for themes identification to inform report revision. Results Review of nine existing polygenic score reports from commercial and academic groups demonstrated significant heterogeneity, reinforcing the need for additional efforts to study and standardize score disclosure. Using a newly developed mock score report, we conducted interviews with ten adult individuals (50% females, 70% without prior genetic testing experience, age range 20–70 years) recruited via an online platform. We identified three themes from interviews: (1) visual elements, such as color and simple graphics, enable participants to interpret, relate to, and contextualize their polygenic score, (2) word-based descriptions of risk and polygenic scores presented as percentiles were the best recognized and understood, (3) participants had varying levels of interest in understanding complex genomic information and therefore would benefit from additional resources that can adapt to their individual needs in real time. In response to user feedback, colors used for communicating risk were modified to minimize unintended color associations and odds ratios were removed. All 10 participants expressed interest in receiving a polygenic score report based on their personal genomic information. Conclusions Our findings describe a generalizable approach to develop a polygenic score report understandable by potential patients. Although additional studies are needed across a wider spectrum of patient populations, these results are likely to inform ongoing efforts related to polygenic score disclosure within clinical practice.

Abstract Preliminary reports suggest that the Coronavirus Disease 2019 (COVID− 19) pandemic has led to disproportionate morbidity and mortality among historically disadvantaged populations. We investigate the racial and socioeconomic associations of COVID− 19 hospitalization among 418,794 participants of the UK Biobank, of whom 549 (0.13%) had been hospitalized. Both Black participants (odds ratio 3.7; 95%CI 2.5–5.3) and Asian participants (odds ratio 2.2; 95%CI 1.5–3.2) were at substantially increased risk as compared to White participants. We further observed a striking gradient in COVID− 19 hospitalization rates according to the Townsend Deprivation Index − a composite measure of socioeconomic deprivation − and household income. Adjusting for socioeconomic factors and cardiorespiratory comorbidities led to only modest attenuation of the increased risk in Black participants, adjusted odds ratio 2.4 (95%CI 1.5–3.7). These observations confirm and extend earlier preliminary and lay press reports of higher morbidity in non-White individuals in the context of a large population of participants in a national biobank. The extent to which this increased risk relates to variation in pre-existing comorbidities, differences in testing or hospitalization patterns, or additional disparities in social determinants of health warrants further study.

Abstract Background Childhood pneumonia continues to be a major infectious killer in India. WHO recommended respiratory rate and oxygen saturation (SpO2) measurements are not well implemented in Indian public health outpatient facilities with the result that treatment decision-making rely on subjective assessments from variably trained and supervised healthcare providers. The introduction of a multi-modal pulse oximeter (POx) that gives reliable measurements would mitigate incorrect diagnosis. In light of future potential use of pulse oximeter in peripheral health centres, it becomes important to measure accuracy of respiratory rate and oxygen saturation of such an instrument. The current study measures accuracy of plethysmography based respiratory rate (RR) using a pulse oximeter (Masimo Rad-G) by comparing it with a gold standard (pediatrician) measurement. Study design A cross sectional study was conducted in the OPD and emergency ward of Kalawati Saran Children’s Hospital over a 2 week period wherein a convenience sample of 97 children (2 to 59 months) were assessed by a pediatrician as part of routine assessment alongside independent measure by a consultant using pulse oximeter. The level of agreement between plethymography based RR and pediatrician measure was analyzed along with sensitivity and specificity of fast breathing of plethymography based RR measure. Results Both methods of measurement show strong association (97%, p

Abstract Background Inherited susceptibility to common, complex diseases may be caused by rare, pathogenic variants (“monogenic”) or by the cumulative effect of numerous common variants (“polygenic”). Comprehensive genome interpretation should enable assessment for both monogenic and polygenic components of inherited risk. The traditional approach requires two distinct genetic testing technologies—high coverage sequencing of known genes to detect monogenic variants and a genome-wide genotyping array followed by imputation to calculate genome-wide polygenic scores (GPSs). We assessed the feasibility and accuracy of using low coverage whole genome sequencing (lcWGS) as an alternative to genotyping arrays to calculate GPSs. Methods First, we performed downsampling and imputation of WGS data from ten individuals to assess concordance with known genotypes. Second, we assessed the correlation between GPSs for 3 common diseases—coronary artery disease (CAD), breast cancer (BC), and atrial fibrillation (AF)—calculated using lcWGS and genotyping array in 184 samples. Third, we assessed concordance of lcWGS-based genotype calls and GPS calculation in 120 individuals with known genotypes, selected to reflect diverse ancestral backgrounds. Fourth, we assessed the relationship between GPSs calculated using lcWGS and disease phenotypes in a cohort of 11,502 individuals of European ancestry. Results We found imputation accuracy r 2 values of greater than 0.90 for all ten samples—including those of African and Ashkenazi Jewish ancestry—with lcWGS data at 0.5×. GPSs calculated using lcWGS and genotyping array followed by imputation in 184 individuals were highly correlated for each of the 3 common diseases (r 2 = 0.93–0.97) with similar score distributions. Using lcWGS data from 120 individuals of diverse ancestral backgrounds, we found similar results with respect to imputation accuracy and GPS correlations. Finally, we calculated GPSs for CAD, BC, and AF using lcWGS in 11,502 individuals of European ancestry, confirming odds ratios per standard deviation increment ranging 1.28 to 1.59, consistent with previous studies. Conclusions lcWGS is an alternative technology to genotyping arrays for common genetic variant assessment and GPS calculation. lcWGS provides comparable imputation accuracy while also overcoming the ascertainment bias inherent to variant selection in genotyping array design.

Abstract Background Pulmonary alveolar proteinosis (PAP) poses a risk of opportunistic infections with a variety of organisms with Nocardia being the most common pathogen followed by mycobacteria and fungi. Case presentation A 7-year-old female child, presented with headache and multiple episodes of vomiting. There was no fever or altered sensorium. On examination, there were no focal deficits or cranial nerve palsies. An MRI brain showed a small T2 hyperintense lesion in the left superior parietal lobe suggestive of an abscess. She was diagnosed as PAP based on CT chest and bronchioloalveolar lavage 7 months earlier and treated with corticosteroids. A left parieto-occipital craniotomy was done with drainage of abscess and abscess wall excision. Histopathology revealed a suppurative lesion with slender septate acute angle branching hyphae which were positive on fungal stains. Culture done on the pus was positive for Aspergillus fumigatus. The patient was treated with voriconazole and stable at 1 year follow-up. Conclusion Opportunistic infections are common in patients diagnosed with PAP. High index of clinical suspicion and early diagnosis are important for favorable outcome.

Abstract Background An electronic frailty index (eFI) has been developed and validated in the UK; it uses data from primary care electronic medical records (EMR) for effective frailty case-finding in primary care. This project examined the convergent validity of the eFI from Canadian primary care EMR data with a validated frailty index based on comprehensive geriatric assessment (FI-CGA), in order to understand its potential use in the Canadian context. Methods A cross-sectional validation study, using data from an integrated primary care research program for seniors living with frailty in Edmonton, AB. Eighty-five patients 65 years of age and older from six primary care physicians’ practices were recruited. Patients were excluded if they were under 65 years of age, did not provide consent to participate in the program, or were living in a long term care facility at the time of enrolment. We used scatter plots to assess linearity and Pearson correlation coefficients to examine correlations. Results Results indicate a strong statistically significant correlation between the eFI and FI-CGA (r = 0.72, 95% CI 0.60–0.81, p

Abstract Background Though the proportion of female Internal Medicine (IM) residents and faculty has increased, there is minimal large scale modern data comparing resident performance by gender. This study sought to examine the effects of resident and faculty gender on resident evaluations. Methods Retrospective observational study over 5 years in a single IM program. IM certifying examination pass rates were obtained from the American Board of IM. Results Four hundred eighty-eight residents (195 women, 293 men), evaluated by 430 attending physicians (163 women, 270 men) were included. Twelve thousand six hundred eighty-one evaluations between 2007 and 2012 were analyzed. Female residents scored higher in two domains (Medical Interviewing, and Interpersonal and Communication Skills) (p

Abstract Background Traditional beliefs of androgen’s stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells. In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed by testing the tumor incidence rate and tumor growth rate of PCa xenografts on nude mice. Methods Different serum testosterone levels were manipulated in male nude/nude athymic mice by orchiectomy or inserting different dosages of T pellets subcutaneously. PCa cells were injected subcutaneously to nude mice and tumor incidence rate and tumor growth rate of PCa xenografts were tested. Results The data demonstrated that low levels of serum T resulted in the highest PCa incidence rate (50%). This PCa incidence rate in mice with low T levels was significantly higher than that in mice treated with higher doses of T (24%, P

Abstract Background Malaria remains an important health problem in India with approximately 1 million cases in 2014. Of these, 7% occurred in the Jharkhand state mainly in the tribal population. Methods This study was conducted in Dumargarhi, a tribal village about 42 km east of Ranchi city, Jharkhand, from May 2014 to September 2016. Four point prevalence surveys were carried out during consecutive high (October–December) and low (June–August) transmission seasons. Malaria cases were recorded from April 2015 to April 2016 through fortnightly visits to the village. Adult mosquito densities were monitored fortnightly by manual catching using suction tube method. Results The study area consists of five hamlets inhabited by 945 individuals living in 164 households as recorded through a house-to-house census survey performed at enrollment. The study population consisted predominantly of the Munda (n = 425, 45%) and Oraon (n = 217, 23%) ethnic groups. Study participants were categorized as per their age 0–5, 6–10, 11–15 and >15 years. There were 99 cases of clinical malaria from April 2015 to April 2016 and all malaria cases confirmed by microscopy were attributed to Plasmodium falciparum (94 cases) and Plasmodium vivax (5 cases), respectively. During the high transmission season the mean density of P. falciparum parasitaemia per age group increased to a peak level of 23,601 parasites/μl in the 6–10 years age group and gradually declined in the adult population. Malaria attack rates, parasite prevalence and density levels in the study population showed a gradual decrease with increasing age. This finding is consistent with the phenomenon of naturally acquired immunity against malaria. Three vector species were detected: Anopheles fluviatilis, Anopheles annularis, and Anopheles culicifacies. The incoherence or complete out of phase pattern of the vector density peaks together with a high prevalence of parasite positive individuals in the study population explains the year-round malaria transmission in the study region. Conclusions The collection of clinical data from a well-characterized tribal cohort from Jharkhand, India, has provided evidence for naturally acquired immunity against malaria in this hyperendemic region. The study also suggests that enforcement of existing control programmes can reduce the malaria burden further.

Abstract Background Red blood cell (RBC) transfusion is frequently employed in both ambulatory and hospital environments with the aim of improving patient functional status. In the ambulatory setting, this practice is particularly common in patients with malignancy due to anemia associated with their cancer therapy. Increasingly, the efficacy of this US$10.5 billion per year practice has been called into question. While it is often standard of care for patients with chemotherapy-induced anemia to receive ambulatory RBC transfusions, it is unclear to what extent such transfusions affect home functional status. It is also unclear whether or not changes in functional status in this population can be objectively quantified using wearable activity monitors. We propose to directly measure the impact of outpatient RBC transfusions on at-home functional status by recording several physiological parameters and quantifiable physical activity metrics, e.g., daily energy expenditure and daily total step count, using the ActiGraph wGT3X-BT. This device is an accelerometer-based wearable activity monitor similar in size to a small watch and is worn at the waist. Study participants will wear the device during the course of their daily activities giving us quantifiable insight into activity levels in the home environment. Methods/design This will be a randomized crossover pilot clinical trial with a participant study duration of 28 days. The crossover nature allows each patient to serve as their own control. Briefly, patients presenting at a tertiary medical center’s Ambulatory Infusion Center (AIC) will be randomized to either: (1) receive an RBC transfusion as scheduled (transfusion) or (2) abstain from the scheduled transfusion (no transfusion). After an appropriate washout period, participants will crossover from the transfusion arm to the no-transfusion arm or vice versa. Activity levels will be recorded continuously throughout the study using an accelerometry monitor. In addition to device data, functional status and health outcomes will be collected via a weekly telephone interview. The primary outcome measure will be daily energy expenditure. Performance metrics, such as step count changes, will also be evaluated. Additional secondary outcome measures will include daily sedentary time and Patient-reported Outcomes Measurement Information System (PROMIS) Global 10 Survey scores. Discussion This trial will provide important information on the feasibility and utility of using accelerometry monitors to directly assess the impact of RBC transfusion on patients’ functional status. The results of the study will inform the merit and methods of a more definitive future trial evaluating the impact of ambulatory RBC transfusions in the target population. Trial registration ClinicalTrials.gov, identifier: NCT02835937 . Registered on 15 July 2016.

Following the publication of this article [1], the authors reported a typesetting error in the “Results” section.

Abstract Background Recent evidence suggests that there may be a bidirectional, physiological link between hypogonadism and metabolic syndrome (MetS), and testosterone replacement therapy (TRT) has been shown to improve some symptoms of MetS in small patient populations. We examined the effect of 12 months of TRT on MetS components in a large cohort of hypogonadal men. Methods Data were obtained from TRiUS (Testim® Registry in the United States), a 12-month, multicenter, prospective observational registry (N = 849) of hypogonadal men prescribed Testim 1% testosterone gel (5-10 g/day). Data analyzed included age, total testosterone (TT), free testosterone (FT), sex hormone-binding globulin (SHBG), and MetS components: waist circumference, blood pressure, fasting blood glucose, plasma triglycerides, and HDL cholesterol. Results Of evaluable patients (581/849) at baseline, 37% were MetS+ (n = 213) and 63% were MetS- (n = 368). MetS+ patients had significantly lower TT (p < 0.0001) and SHBG (p = 0.01) levels. Patients with the lowest quartile TT levels ( Conclusion Hypogonadal MetS+ patients were more likely than their MetS- counterparts to have lower baseline TT levels and present with more comorbid conditions. MetS+ patients and those in the lowest TT quartile showed improvement in some metabolic syndrome components after 12 months of TRT. While it is currently unclear if further cardiometabolic benefit can be seen with longer TRT use in this population, testing for low testosterone may be warranted in MetS+ men with hypogonadal symptoms.

Abstract Background Ankle fractures are common. Management of ankle fractures generally involves a period of immobilisation followed by rehabilitation to reduce pain, stiffness, weakness and swelling. The effects of a rehabilitation program are still unclear. However, it has been shown that important components of rehabilitation programs may not confer additional benefits over exercise alone. The primary aim of this trial is to determine the effectiveness and cost-effectiveness of an exercise-based rehabilitation program after ankle fracture, compared to advice alone. Methods/Design A pragmatic randomised trial will be conducted. Participants will be 342 adults with stiff, painful ankles after ankle fracture treated with immobilisation. They will be randomly allocated using a concealed randomisation procedure to either an Advice or Rehabilitation group. Participants in the Advice group will receive verbal and written advice about exercise at the time of removal of immobilisation. Participants in the Rehabilitation group will be provided with a 4-week rehabilitation program that is designed, monitored and progressed by a physiotherapist, in addition to verbal and written advice. Outcomes will be measured by a blinded assessor at 1, 3 and 6 months. The primary outcomes will be activity limitation and quality-adjusted life years. Discussion This pragmatic trial will determine if a rehabilitation program reduces activity limitation and improves quality of life, compared to advice alone, after immobilisation for ankle fracture.