Measuring food insecurity among a national sample of children with recurrent acute otitis media.

INTRODUCTION: Acute otitis media is one of the most common reasons for pediatric medical visits in the United States. Additionally, past studies have linked food insecurity and malnutrition with increased infections and worse health outcomes. However, there is a lack of information on the risk factors for food insecurity in specific patient populations, including the pediatric recurrent acute otitis media (RAOM) population. METHODS: The 2011 to 2018 National Health Interview Survey (NHIS) datasets were used to obtain a national estimate of the presentation of food insecurity within pediatric patients with RAOM. Relevant sociodemographic information and prevalence were identified. A multivariable logistic regression model was used to determine sociodemographic risk factors. Calculations were conducted using R with the "survey" package to account for the clustering and sampling of the NHIS. RESULTS: Of 3844 children with RAOM who responded to the food insecurity module, 20.8 % (19.0-22.6 %) were food insecure. Age, race/ethnicity, percentage of federal poverty level status, insurance status, and self-reported health status were significant and were not independent of food insecurity status. Using multivariable regression, this study found the following sociodemographic risk factors: age 6-10 and age > 10 (reference: age 0-2); Black (reference: Non-Hispanic White); 100 % to 200 % and <100 % federal poverty level (reference: >200 % federal poverty level); public insurance or uninsured status (reference: private insurance); and poor to fair self-reported health status (reference: good to excellent). DISCUSSION: Children with RAOM who were older, Black, less insured, living in lower-income households, and of poorer health had a greater association with being food insecure. Due to the frequency of RAOM pediatric visits, identifying at-risk groups as well as incorporating food insecurity screening and food referral programs within clinical practice can enable otolaryngologists to reduce disparities and improve outcomes in a targeted approach.

Outpatient Total Hip Arthroplasty Volume up Nearly 8-Fold After Regulatory Changes With Expanding Demographics and Unchanging Outcomes: A 10-Year Analysis.

BACKGROUND: With the removal of total hip arthroplasty (THA) from the inpatient-only (IPO) lists, the orthopedic landscape across the United States has changed rapidly. Thus, this study aimed to: 1) characterize the change in THA volume for outpatient and inpatient surgeries; 2) elucidate demographical differences before and after removal from the IPO list; and 3) analyze 30-day complications, readmissions, and reoperations. METHODS: The National Surgical Quality Improvement Program database was queried for primary THAs between January 2010 and December 2021. The primary outcome was the annual volume of outpatient and inpatient THAs. Secondary outcomes involved 30-day complications, readmissions, and reoperations. The variables between cohorts were analyzed using goodness-of-fit Chi-square tests with summary statistics. RESULTS: Of the 332,423 THAs between 2010 and 2021, 88% were inpatient THAs (n = 292,974) and 12% were outpatient THAs (n = 39,449). From 2019 to 2021, the volume of inpatient THA decreased by 55% (42,779 to 19,075), while outpatient THA increased by 751% (2,518 to 21,424). Patients who had a THA after 2019 were older (P < .001), more commonly women (P < .001), white (P < .001), and more likely American Society of Anesthesiologists Class III (P < .001). The outpatient cohort had fewer 30-day complications, readmissions, and reoperations. The length of stay for both cohorts decreased until 2019, before increasing in 2020 and 2021 for inpatient THAs, while home discharge and operative time increased for both. CONCLUSIONS: The volume of outpatient THA increased almost eightfold after its removal from the IPO lists in 2020. Despite expanding eligibility with older patients and more comorbidities, 30-day complications, readmissions, and reoperations remain low. These findings support the safe transition to outpatient THA with appropriate patient selection and optimization.

Robotic Assisted Percutaneous Coronary Intervention: Initial Australian Experience.

BACKGROUND & AIM: Robotic-assisted percutaneous coronary intervention (R-PCI) has been increasingly performed overseas. Initial observations have demonstrated its clinical efficacy and safety with additional potential benefits of more accurate lesion assessment and stent deployment, with reduced radiation exposure to operators and patients. However, data from randomised controlled trials or clinical experience from Australia are lacking. METHODS: This was a single-centre experience of all patients undergoing R-PCI as part of the run-in phase for an upcoming randomised clinical trial (ACTRN12623000480684). All R-PCI procedures were performed using the CorPath GRX robot (Corindus Vascular Robotics, Waltham, Massachusetts, USA). Key inclusion criteria included patients with obstructive coronary disease requiring percutaneous coronary intervention. Major exclusion criteria included ST-elevation myocardial infarction, cardiogenic shock or lesions deemed unsuitable for R-PCI by the operator. Clinical success was defined as residual stenosis <30% without in-hospital major adverse cardiovascular events (MACE). Technical success was defined as the completion of the R-PCI procedure without unplanned manual conversion. Procedural characteristics were compared between early (cases 1-3) and later (cases 4-21) cases. RESULTS: Twenty-one (21) patients with a total of 24 lesions were analysed. The mean age of patients was 66.5 years, and 66% of cases were male. Radial access was used in 18 cases (86%). Most lesions were American Heart Association/American College of Cardiology class B2/C (66%). Clinical success was achieved in 100% with manual conversion required in four cases (19%). No procedural complications or in-hospital MACE occurred. Compared to the early cases, later cases had a statistically significantly shorter fluoroscopy time (44.0mins vs 25.2mins, p<0.007), dose area product (967.3 dGy.cm2 vs 361.0dGy.cm2, p=0.01) and air kerma (2484.3mGy vs 797.4mGy, p=0.009) with no difference in contrast usage (136.7mL vs 131.4mL, p=0.88). CONCLUSIONS: We present the first clinical experience of R-PCI in Australia using the Corindus CorPath GRX robot. We achieved clinical success in all patients and technical success in the majority of cases with no procedural complications or in-hospital MACE. With increasing operator and staff experience, cases required shorter fluoroscopy time and less radiation exposure but similar contrast usage.

Stomatin-like protein 3 modulates the responses of Aδ, but not C fiber bone afferent neurons to noxious mechanical stimulation in an animal model of acute experimental bone pain.

STOML3 is a membrane bound scaffolding protein that has been shown to facilitate the opening of mechanically sensitive ion channels and contribute to noxious mechanical sensation, allodynia and hyperalgesia. In this study, we aimed to determine the role of STOML3 in noxious mechanical sensitivity of bone afferent neurons and carrageenan-induced acute inflammation in the bone. An in vivo, electrophysiological bone-nerve preparation was used to make recordings of the activity and sensitivity of bone afferent neurons that innervate the tibial marrow cavity in anaesthetised rats, in response to noxious mechanical stimuli delivered to the marrow cavity, before and after injection of either the STOML3 oligomerisation inhibitor OB-1 or vehicle, in either naïve animals or animals with carrageenan-induced inflammation of the marrow cavity. A dynamic weight-bearing apparatus was used to measure weight bearing in response to inflammatory pain before and after injection of OB-1 or saline into the tibial marrow cavity in the presence of carrageenan-induced inflammation. Electrophysiological recordings revealed that Aδ, but not C bone afferent neurons have a reduced discharge frequency in response to mechanical stimulation, and that carrageenan-induced sensitisation of Aδ, but not C bone afferent neurons was attenuated by inhibition of STOML3 oligomerisation with OB-1. Animals treated with OB-1 spent a significantly greater amount of time on the limb injected with carrageenan than animals treated with saline. Our findings demonstrate that inhibition of STOML3 oligomerisation reduces inflammatory bone pain by reducing the sensitivity of Aδ bone afferent neurons to mechanical stimulation. Targeting STOML3 may be an effective approach to reduce pain from noxious pressure and/or painful inflammatory pathology in bone.

Normative values of renin and aldosterone in clinically stable preterm neonates.

BACKGROUND: There is a paucity of literature on the normative levels of plasma renin concentration (PRC) and serum aldosterone (SA) in premature neonates. This study aims to provide normative data on PRC and SA levels in preterm neonates in the first 2 weeks after birth and explore associations with maternal, perinatal, or postnatal factors. METHODS: Neonates born at 26- to 34-week gestation were recruited from two neonatal intensive care units in Canada and Australia. The direct renin assay PRC and SA were analyzed on day 1 and days 14-21 after birth to compare across categorical variables and to produce normative values. RESULTS: A total of 262 subjects were enrolled from the Canadian (29%) and Australian (71%) sites. The mean gestational age was 30 weeks, with a mean birth weight of 1457 g. The normative values of PRC and SA for neonates born between 26 + 0 and 29 + 6 weeks and 30 + 0 and 34 + 0 weeks of gestation were produced for day 1 and day 14-21 after birth. Both PRC and SA increased from day 1 to day 14-21. The more premature neonates reached a higher PRC on days 14-21 after birth but exhibited lower SA levels on day 1 after birth. When comparing gender, birth weight, and maternal risk factor categories, no statistical differences in PRC or SA were found. A small but significant decrease in PRC, but not SA, was noted for neonates with placental pathology. CONCLUSIONS: This study produced normative values of PRA and SA in clinically stable preterm neonates that can be referenced for use in clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.

Major National Shifts to Outpatient Total Knee Arthroplasties in the United States: A 10-Year Trends Analysis of Procedure Volumes, Complications, and Healthcare Utilizations (2010 to 2020).

BACKGROUND: The removal of total knee arthroplasty (TKA) from inpatient-only lists accelerated changes in orthopaedic surgical practices across the United States. This study aimed to (1) quantify the annual volume of inpatient/outpatient primary TKAs; (2) compare patient characteristics before/after the year 2018; and (3) compare annual trends in 30-day readmissions, 30-day complications, and healthcare utilization parameters for inpatient/outpatient TKAs. METHODS: The National Surgical Quality Improvement Program was reviewed (January 2010 to December 2020) for patients who underwent primary TKA (n = 470,456). The primary outcome was annual volumes of inpatient/outpatient TKA. Secondary outcomes included 30-day readmissions, 30-day reoperations, and 30-day major/minor complications. Demographic characteristics and healthcare utilization parameters (hospital lengths of stay and discharge dispositions) were compared between cohorts via Chi-square goodness-of-fit tests. RESULTS: Overall, 89% had inpatient TKA (n = 416,972) and 11% had outpatient TKA (n = 53,854). Between 2017 and 2020, annual volumes of outpatient TKA increased by 1,925 (1,019 to 20,633), while inpatient TKA decreased by 53% (61,874 to 29,280). Patients who had outpatient TKA after 2018 were older (P < .001), predominantly males (P < .001), more commonly White (P < .001), and had a greater proportion of American Society of Anesthesiologists class III (P < .001). The inpatient cohort had higher rates of 30-day readmissions, reoperations, and complications. Average length of stay and nonhome discharges decreased for both cohorts. CONCLUSION: Outpatient TKA increased 20-fold at NSQIP hospitals. The changes in comorbidity profiles and the increase in volumes of outpatient TKA were not associated with a rise in cumulative 30-day readmissions and complications. Further research and policy endeavors should focus on identifying patients who still require or benefit from inpatient TKA.

Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials.

BACKGROUND: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer. METHODS: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 µg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment. FINDINGS: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups). INTERPRETATION: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient. FUNDING: None.

Assessing Coronary Microvascular Dysfunction in Ischaemic Heart Disease: Little Things Can Make a Big Difference.

The role of coronary microvascular dysfunction (CMD) in the pathogenesis of ischaemic heart disease and in determining long-term prognosis is increasingly recognised. In selected patients, a comprehensive coronary assessment including an assessment of microvascular function may help refine risk stratification and improve patient outcomes. Various non-invasive and invasive techniques have been developed to assess the coronary microcirculation. Many of these tests utilise the indicator-dilution principle to determine coronary or myocardial blood flow. However, these techniques are often limited by their variability and lack of specificity for the coronary microvasculature. Consequently, there is still paucity of data on targeted therapies for CMD and their implications on long-term clinical outcomes, particularly in the setting of non-ST elevation acute coronary syndromes. Recent technical advancements, such as the index of microcirculatory resistance, have largely overcome these limitations and are able to provide novel insights into the assessment and treatment of CMD. This review summarises the currently available techniques for the assessment of CMD and provides an overview of its clinical implications.

A national survey of the enteral feeding practices in Canadian neonatal intensive care units.

AIM: Nutrition affects the growth and neurodevelopmental outcomes of preterm infants, yet controversies exist about the optimal enteral feeding regime. The objective of this study was to compare enteral feeding guidelines in Canadian neonatal intensive care units (NICUs). METHOD: The research team identified key enteral feeding practices of interest. Canadian Neonatal Network site investigators at 30 Level 3 NICUs were contacted to obtain a copy of their 2016 to 2017 feeding guidelines for infants who weighed less than 1,500 g at birth. Each guideline was reviewed to compare recommendations around the selected feeding practices. RESULTS: Five of the 30 NICUs did not have a feeding guideline. The other 25 NICUs used 22 different enteral feeding guidelines. The guidelines in 40% of those NICUs recommend commencing minimal enteral nutrition (MEN) within 24 hours of birth and maintaining that same feeding volume for 24 to 96 hours. In 40% of NICUs, the guideline recommended that MEN be initiated at a volume of 5 to 10 mL/kg/day for infants born at <1,000 g. Guidelines in all 25 NICUs recommend the use of bovine-based human milk fortifier (HMF), and in 56% of NICUs, it is recommended that HMF be initiated at a total fluid intake of 100 mL/kg/day. Guidelines in only 16% of NICUs recommended routine gastric residual checks. Donor milk and probiotics are used in 76% and 72% of the 25 NICUs, respectively. CONCLUSION: This study revealed substantial variability in recommended feeding practices for very low birth weight infants, underscoring the need to establish a national feeding guideline for this vulnerable group.

Dynamic Visual Feedback During Junctional Tourniquet Training.

BACKGROUND: This project involved the development and evaluation of a new visual bleeding feedback (VBF) system for tourniquet training. We hypothesized that dynamic VBF during junctional tourniquet training would be helpful and well received by trainees. MATERIALS AND METHODS: We designed the VBF to simulate femoral bleeding. Medical students (n = 15) and emergency medical service (EMS) members (n = 4) were randomized in a single-blind, crossover study to the VBF or without feedback groups. Poststudy surveys assessing VBF usefulness and recommendations were conducted along with participants' reported confidence using a 7-point Likert scale. Data from the different groups were compared using Wilcoxon signed-rank and rank-sum tests. RESULTS: Participants rated the helpfulness of the VBF highly (6.53/7.00) and indicated they were very likely to recommend the VBF simulator to others (6.80/7.00). Pre- and post-VBF confidence were not statistically different (P = 0.59). Likewise, tourniquet application times for VBF and without feedback before crossover were not statistically different (P = 0.63). Although participant confidence did not change significantly from beginning to end of the study (P = 0.46), application time was significantly reduced (P = 0.001). CONCLUSIONS: New tourniquet learners liked our VBF prototype and found it useful. Although confidence did not change over the course of the study for any group, application times improved. Future studies using outcomes of this study will allow us to continue VBF development as well as incorporate other quantitative measures of task performance to elucidate VBF's true benefit and help trainees achieve mastery in junctional tourniquet skills.

CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion.

CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific. These are unusual properties for spliceosome regulatory factors, which typically regulate multiple forms of alternative splicing in a global manner. In breast cancer cells, regulation by CDK12 modulates ALE splicing of the DNA damage response activator ATM and a DNAJB6 isoform that influences cell invasion and tumorigenesis in xenografts. We found that there is a direct correlation between CDK12 levels, DNAJB6 isoform levels and the migration capacity and invasiveness of breast tumor cells. This suggests that CDK12 gene amplification can contribute to the pathogenesis of the cancer.

Clinical and Angiographic Predictors of Mortality in Sudden Cardiac Arrest Patients Having Cardiac Catheterisation: A Single Centre Registry.

BACKGROUND: Immediate cardiac catheterisation (CC) is recommended in ST-elevation myocardial infarction (STEMI) following sudden cardiac arrest (SCA). Guidelines advise urgent CC for SCA patients without-STEMI, at clinician discretion. We examined the clinical and angiographic factors predicting mortality in SCA patients having CC. METHODS: Consecutive SCA patients having CC at Liverpool Hospital, Sydney (January 2011-September 2015) were retrospectively analysed. Patient data were retrieved from hospital records, and angiographic SYNTAX scores (SS) were quantified online. Independent predictors of mortality were derived using multivariate logistic analysis. RESULTS: The study cohort comprised 104 SCA patients; mean age 61±12years, and 79% male. Immediate CC (<2hours post-SCA) was performed in 35% overall. Compared to the without-STEMI subgroup, STEMI patients had more ventricular fibrillation (91 vs 50%; p<0.0001), and higher mean peak serum high-sensitivity troponin-T (8.25±14.7 vs 1.97±6.13 ug/L; p=0.006); in the context of higher median SS (18 vs 6.5; p=0.002) and target-lesion SS (tSS, 10 vs 0; p<0.001). Percutaneous coronary intervention (PCI; 75 vs 23%; p<0.0001) and target vessel revascularisation (11 vs 0%; p=0.005) were more frequent for STEMI. All-cause mortality was 39%, at 1.3±1.5years follow-up. Independent mortality predictors were: delayed CC (HR 4.08), serum lactate >7mmol/L (HR 3.47), and tSS (HR 1.05). CONCLUSIONS: Elevated serum lactate, tSS, and delayed CC, were predictive of longer-term mortality in SCA patients having CC. Late CC in patients without-STEMI suggest scope for improvement in real-world systems of care. Closer scrutiny of target lesion complexity may aid prognostication in SCA survivors.

Validation of the RETRIEVE (REverse TRIage EVEnts) Criteria for Same Day Return of Non-ST Elevation Acute Coronary Syndrome Patients to Referring Non-PCI Centres.

BACKGROUND: There are continuing bed constraints in percutaneous coronary intervention centres (PCI) so efficient patient triage from referral hospitals is pivotal. To evaluate a strategy of PCI centre (PCIC) bed-sparing we examined return of patients to referral hospitals screened by the RETRIEVE (REverse TRIage EVEnts) criteria and validated its use as a tool for screening suitability for same day transfer of non-ST-elevation acute coronary syndrome (NSTEACS) patients post PCI to their referring non-PCI centre (NPCIC). METHODS: From May 2008 to May 2011, 433 NSTEACS patients were prospectively screened for suitability for same day transfer back to the referring hospital at the completion of PCI. Of these patients, 212 were excluded from same day transfer using the RETRIEVE criteria and 221 patients met the RETRIEVE criteria and were transferred back to their NPCIC. RESULTS: Over the study period, 218 patients (98.6%) had no major adverse events. The primary endpoint (death, arrhythmia, myocardial infarction, major bleeding event, cerebrovascular accident, major vascular site complication, or requirement for return to the PCIC) was seen in only three transferred patients (1.4%). CONCLUSIONS: The RETRIEVE criteria can be used successfully to identify NSTEACS patients suitable for transfer back to NPCIC following PCI. Same day transfer to a NPCIC using the RETRIEVE criteria was associated with very low rates of major complications or repeat transfer and appears to be as safe as routine overnight observation in a PCIC.

FDA Approval Summary: Nivolumab in Advanced Renal Cell Carcinoma After Anti-Angiogenic Therapy and Exploratory Predictive Biomarker Analysis.

On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO, Bristol-Myers Squibb Company) for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. The approval was based on efficacy and safety data demonstrated in an open-label, randomized study of 821 patients with advanced RCC who progressed after at least one anti-angiogenic therapy. Patients were randomized to nivolumab or everolimus and followed for disease progression. The primary end point was overall survival. Subsequent therapies, including everolimus for patients who developed progressive disease on the nivolumab arm, were allowed, but no cross-over was permitted. The median overall survival was 25.0 months on the nivolumab arm and 19.6 months on everolimus arm (hazard ratio: 0.73; 95% confidence interval: 0.60-0.89). The confirmed response rates were 21.5% versus 3.9%; median durations of response were 23.0 versus 13.7 months, and median times to response were 3.0 versus 3.7 months in the nivolumab and everolimus arms, respectively. A statistically significant improvement in progression-free survival was not observed in this trial. The safety profile of nivolumab in renal cell cancer was similar to that in other disease settings. However, the incidence of immune-mediated nephritis appeared to be higher in patients with RCC. The Oncologist 2017;22:311-317 IMPLICATIONS FOR PRACTICE: The overall benefit/risk profile demonstrated in trial CA209025 supported the approval of nivolumab as an additional treatment option for patients with advanced renal cell carcinoma after anti-angiogenic therapy. The use of nivolumab in patients who had received vascular endothelial growth factor-targeted therapy resulted in a 5.4 month improvement in median overall survival compared with the everolimus arm. This difference is statistically significant and clinically meaningful.

Cardiovascular safety of non-insulin pharmacotherapy for type 2 diabetes.

Patients with type 2 diabetes mellitus have a twofold increased risk of cardiovascular mortality compared with non-diabetic individuals. There is a growing awareness that glycemic efficacy of anti-diabetic drugs does not necessarily translate to cardiovascular safety. Over the past few years, there has been a number of trials evaluating the cardiovascular effects of anti-diabetic drugs. In this review, we seek to examine the cardiovascular safety of these agents in major published trials. Metformin has with-stood the test of time and remains the initial drug of choice. The sulfonylureas, despite being the oldest oral anti-diabetic drug, has been linked to adverse cardiovascular events and are gradually being out-classed by the various other second-line agents. The glitazones are contraindicated in heart failure. The incretin-based drugs have been at the fore-front of this era of cardiovascular safety trials and their performances have been reassuring, whereas the meglitinides and the alpha-glucosidase inhibitors still lack cardiovascular outcomes data. The sodium glucose cotransporter-2 inhibitors are an exciting new addition that has demonstrated a potential for cardiovascular benefit. Many of the currently available oral anti-diabetic agents have clinically relevant cardiovascular effects. The optimal approach to the reduction of cardiovascular risk in diabetic patients should focus on aggressive management of the standard cardiovascular risk factors rather than purely on intensive glycemic control.