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Background Hepatitis C virus (HCV) infection causes substantial morbidity and mortality in Canada and is of concern among First Nations communities. In partnership with the Ontario First Nations HIV/AIDS Education Circle, we described trends in HCV testing and epidemiologic features among Status First Nations people in Ontario. Methods In this retrospective study, we used health administrative databases for 2006-2014 in Ontario with 3 cohorts of Status First Nations people: those tested for HCV for the first time, those who tested positive for HCV antibodies or RNA, and those with no HCV laboratory or testing records. We examined cohort characteristics, and the annual prevalence and incidence of testing and diagnosis of HCV infection. Outcomes were stratified by region, sex and residence within or outside of First Nations communities. Results During the study period, 2423 Status First Nations people were diagnosed with HCV infection, 20 481 received their first test, and 135 185 had no test record. The point prevalence of ever having been tested increased from 6.3 (95% confidence interval [CI] 6.2-6.5) per 100 people in 2006 to 16.2 (95% CI 16.0-16.4) per 100 people in 2014. The point prevalence of diagnosed HCV infection increased from 0.9 (95% CI 0.9-1.0) to 2.0 (95% CI 1.9-2.0) per 100 people. The incidence of first test and of diagnosis increased from 12.1 (95% CI 11.5-12.6) to 21.3 (95% CI 20.5-22.1) per 1000 person-years and from 1.3 (95% CI 1.1-1.5) to 2.3 (95% CI 2.1-2.6) per 1000 person-years, respectively. Testing, diagnosis and prevalence of HCV infection were consistently higher among people living outside of versus within First Nations communities, but larger increases over time were observed among those living within First Nations communities. Interpretation Testing and diagnosis of HCV infection increased from 2006 to 2014 among Status First Nations people in Ontario. Our findings indicate the need for population-level efforts to eliminate hepatitis C in First Nations communities.

Background: Colonization and marginalization have affected the risk for and experience of hepatitis C virus (HCV) infection for First Nations people in Canada. In partnership with the Ontario First Nations HIV/AIDS Education Circle, we estimated the publicly borne health care costs associated with HCV infection among Status First Nations people in Ontario. Methods: In this retrospective matched cohort study, we used linked health administrative databases to identify Status First Nations people in Ontario who tested positive for HCV antibodies or RNA between 2004 and 2014, and Status First Nations people who had no HCV testing records or only a negative test result (control group, matched 2:1 to case participants). We estimated total and net costs (difference between case and control participants) for 4 phases of care: prediagnosis (6 mo before HCV infection diagnosis), initial (after diagnosis), late (liver disease) and terminal (6 mo before death), until death or Dec. 31, 2017, whichever occurred first. We stratified costs by sex and residence within or outside of First Nations communities. All costs were measured in 2018 Canadian dollars. Results: From 2004 to 2014, 2197 people were diagnosed with HCV infection. The mean net total costs per 30 days of HCV infection were $348 (95% confidence interval [CI] $277 to $427) for the prediagnosis phase, $377 (95% CI $288 to $470) for the initial phase, $1768 (95% CI $1153 to $2427) for the late phase and $893 (95% CI −$1114 to $3149) for the terminal phase. After diagnosis of HCV infection, net costs varied considerably among those who resided within compared to outside of First Nations communities. Net costs were higher for females than for males except in the terminal phase. Interpretation: The costs per 30 days of HCV infection among Status First Nations people in Ontario increased substantially with progression to advanced liver disease and finally to death. These estimates will allow for planning and evaluation of provincial and territorial population-specific hepatitis C control efforts.

Aim Expert recommendations for child/adolescent obesity include extensive investigation for weight-related comorbidities, based on body mass index (BMI) percentile cut-offs. This study aimed to estimate the cost of initial investigations for weight-related comorbidities in children/adolescents with obesity, according to international expert guidelines. Methods The annual mean cost of investigations for weight-related comorbidities in children/adolescents was calculated from a health-funder perspective using 2019 cost data obtained from three New Zealand District Health Boards. Prevalence data for child/adolescent obesity (aged 2-14 years) were obtained from the New Zealand Health Survey (2017/2018), and prevalence of weight-related comorbidities requiring further investigation were obtained from a previous New Zealand study of a cohort of children with obesity. Results The cost of initial laboratory screening for weight-related comorbidities per child was NZD 28.36. Based on national prevalence data from 2018/2019 for children with BMI greater than the 98th percentile (obesity cut-off), the total annual cost for initial laboratory screening for weight-related comorbidities in children/adolescents aged 2-14 years with obesity was estimated at NZD 2,665,840. The cost of further investigation in the presence of risk factors was estimated at NZD 2,972,934. Conclusions Investigating weight-related comorbidities in New Zealand according to international expert guidelines is resource-intensive. Ways to further determine who warrants investigation with an individualised approach are required.

Obesity and type 2 diabetes are rapidly increasing in the adolescent population. We sought to determine whether adipokines, specifically leptin, C1q/TNF-related proteins 1 (CTRP1) and CTRP9, and the hepatokine fibroblast growth factor 21 (FGF21), are associated with obesity and hyperglycemia in a cohort of lean and obese adolescents, across the spectrum of glycemia. In an observational, longitudinal study of lean and obese adolescents, we measured fasting laboratory tests, oral glucose tolerance tests, and adipokines including leptin, CTRP1, CTRP9, and FGF21. Participants completed baseline and 2-year follow-up study visits and were categorized as lean (LC, lean control; n = 30), obese normoglycemic (ONG; n = 61), and obese hyperglycemic (OHG; n = 31) adolescents at baseline and lean (n = 8), ONG (n = 18), and OHG (n = 4) at follow-up. Groups were compared using ANOVA and regression analysis, and linear mixed effects modeling was used to test for differences in adipokine levels across baseline and follow-up visits. Results showed that at baseline, leptin was higher in all obese groups (P < 0.001) compared with LC. FGF21 was higher in OHG participants compared with LC (P < 0.001) and ONG (P < 0.001) and positively associated with fasting glucose (P < 0.001), fasting insulin (P < 0.001), Homeostasis Model Assessment-Insulin Resistance Index (HOMA-IR; P < 0.001), and hemoglobin A1c (HbA1c; P = 0.01). CTRP1 was higher in OHG compared with ONG (P = 0.03). CTRP9 was not associated with obesity or hyperglycemia in this pediatric cohort. At 2 years, leptin decreased in ONG (P = 0.003) and FGF21 increased in OHG (P = 0.02), relative to lean controls. Altered adipokine levels are associated with the inflammatory milieu in obese youth with and without hyperglycemia. In adolescence, the novel adipokine CTRP1 was elevated with hyperglycemia, whereas CTRP9 was unchanged in this cohort. NEW & NOTEWORTHY Leptin is higher in obese adolescents and FGF21 is higher in obese hyperglycemic adolescents. The novel adipokine CTRP1 is higher in obese hyperglycemic adolescents, whereas CTRP9 was unchanged in this adolescent cohort.

Ring‐finger protein 213 (RNF213) encodes a protein of unknown function believed to play a role in cellular metabolism and angiogenesis. Gene variants are associated with susceptibility to moyamoya disease. Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in RNF213. These cases highlight the ability of RNF213 to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi‐organ RNF213‐spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C‐terminal RNF213 missense variants.

AIM Pre-emptive kidney transplantation (PKT) is generally considered the optimal treatment for kidney failure as it minimises dialysis-associated morbidity and mortality and is associated with improved allograft survival. This study aimed to determine rates of paediatric PKT in New Zealand, identify barriers to PKT and consider potential interventions to influence future rates of pre-emptive transplantation. METHODS Children commencing kidney replacement therapy between 2005 and 2017 in New Zealand were included. Descriptive analysis considered those referred late (referral

Men who have sex with men (MSM) use dating applications (apps) to explore various romantic and sexual relationships. This qualitative study aimed to describe HIV-negative MSM's experiences with app usage, the sexual activities arranged accordingly and their experiences in using dating apps to arrange sexual encounters. Thirty-one MSM who were sexually active and who used dating apps were recruited. Individual semi-structured interviews were conducted. Qualitative data were thematically analyzed to outline significant phenomena and perceptions. The factors associated with matching on apps included sex roles, human immunodeficiency virus serostatus and availability of a venue for meetup. Facilitated by these apps, diverse types of sexual encounters were arranged. Condoms were typically used for safer intercourse, except by people who were younger and inexperienced or when drugs were consumed before or during sex (chemsex). Extensive interest in non-penetrative sexual behaviors was expressed by our sample. Searching for post-exposure prophylaxis methods and/or sexual health screenings was common after exposure to risk of infections. Sexually abusive encounters were followed by changes in sex-searching habits and lowered trust in relationship formation. The results of this study are important for the development of appropriate interventions to promote safer sexual practices among HIV-negative MSM dating app users.

Background High-quality estimates of health care costs are required to understand the burden of illness and to inform economic models. We estimated the costs associated with hepatitis C virus (HCV) infection from the public payer perspective in Ontario, Canada. Methods In this population-based retrospective cohort study, we identified patients aged 18-105 years diagnosed with chronic HCV infection in Ontario from 2003 to 2014 using linked administrative data. We allocated the time from diagnosis until death or the end of follow-up (Dec. 31, 2016) to 9 mutually exclusive health states using validated algorithms: no cirrhosis, no cirrhosis (RNA negative) (i.e., cured HCV infection), compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, both decompensated cirrhosis and hepatocellular carcinoma, liver transplantation, terminal (liver-related) and terminal (non-liver-related). We estimated direct medical costs (in 2018 Canadian dollars) per 30 days per health state and used regression models to identify predictors of the costs. Results We identified 48 239 patients with chronic hepatitis C, of whom 30 763 (63.8%) were men and 35 891 (74.4%) were aged 30-59 years at diagnosis. The mean 30-day costs were $798 (95% confidence interval [CI] $780-$816) (n = 43 568) for no cirrhosis, $661 (95% CI $630-$692) (n = 6422) for no cirrhosis (RNA negative), $1487 (95% CI $1375-$1599) (n = 4970) for compensated cirrhosis, $3659 (95% CI $3279-$4039) (n = 3151) for decompensated cirrhosis, $4238 (95% CI $3480-$4996) (n = 550) for hepatocellular carcinoma, $8753 (95% CI $7130-$10 377) (n = 485) for both decompensated cirrhosis and hepatocellular carcinoma, $4539 (95% CI $3746-$5333) (n = 372) for liver transplantation, $11 202 (95% CI $10 645-$11 760) (n = 3201) for terminal (liver-related) and $8801 (95% CI $8331-$9271) (n = 5278) for terminal (non-liver-related) health states. Comorbidity was the most significant predictor of total costs for all health states. Interpretation Our findings suggest that the financial burden of HCV infection is substantially higher than previously estimated in Canada. Our comprehensive, up-to-date cost estimates for clinically defined health states of HCV infection should be useful for future economic evaluations related to this disorder.

Central and peripheral mechanisms are both required for proper control of energy homeostasis. Among circulating plasma proteins, C1q/TNF-related proteins (CTRPs) have recently emerged as important regulators of sugar and fat metabolism. CTRP4, expressed in brain and adipose tissue, is unique among the family members in having two tandem globular C1q domains. We previously showed that central administration of recombinant CTRP4 suppresses food intake, suggesting a central nervous system role in regulating ingestive physiology. Whether this effect is pharmacological or physiological remains unclear. We used a loss-of-function knockout (KO) mouse model to clarify the physiological role of CTRP4. Under basal conditions, CTRP4 deficiency increased serum cholesterol levels and impaired glucose tolerance in male but not female mice fed a control low-fat diet. When challenged with a high-fat diet, male and female KO mice responded differently to weight gain and had different food intake patterns. On an obesogenic diet, male KO mice had similar weight gain as wild-type littermates. When fed ad libitum, KO male mice had greater meal number, shorter intermeal interval, and reduced satiety ratio. Female KO mice, in contrast, had lower body weight and adiposity. In the refeeding period following food deprivation, female KO mice had significantly higher food intake due to longer meal duration and reduced satiety ratio. Collectively, our data provide genetic evidence for a sex-dependent physiological role of CTRP4 in modulating food intake patterns and systemic energy metabolism.

Introduction: Shock index is defined as heart rate divided by systolic blood pressure. It is reported as a predictor of morbidity and mortality in trauma and acute myocardial infarction in previous studies. It may be valuable in evaluation of calcium channel blocker poisoning. The objective of this study is to examine the probability of serious outcome based on first measured shock index in patients who presented to emergency department with calcium channel blocker poisoning. Methods: A retrospective chart review was conducted on calcium channel blocker poisoning cases in Hong Kong Poison Information Centre from 1 July 2008 to 30 June 2017. Shock index was calculated with blood pressure and pulse measurement at emergency department triage. Odds ratios of various variables for major outcome, mortality, intensive care unit admission, length of stay in acute hospital were calculated by multivariate analysis or negative binomial regression where appropriate. The performance of shock index in predicting major outcome was evaluated with receiver operating characteristic curve. Results: A total of 390 cases were identified, of whom 25.1% developed major outcome and 5.6% died. Shock index showed significant association with major outcome (odds ratio: 17.017, 95% confidence interval: 5.521–52.455). The area under the receiver operating characteristic curve for shock index in predicting major outcome was 0.7008 (95% confidence interval: 0.64–0.76). Conclusion: Higher shock index is associated with worse patient outcome in calcium channel blocker poisoning. However, shock index alone is not reliable in predicting patient outcome. Further research is needed before shock index can be incorporated for use in patient management in poisoning with calcium channel blocker or other anti-hypertensives.

For the 6% of breast cancer patients with a diagnosis of stage IV disease, systemic therapy is the cornerstone of treatment, with an unclear role for surgery. Limited evidence exists to delineate treatment methods with regard to hormone receptor and human epidermal growth factor receptor 2 (HER2) status. The National Cancer Database was used to identify 12,838 stage IV breast cancer patients with known hormone receptor and HER2 status from 2010 to 2015. Chi square tests examined subgroup differences between the treatment methods received. Using the Kaplan–Meier method, 5-year overall survival (OS) was assessed. Multivariate Cox proportional hazard models examined factors associated with survival. A survival advantage was noted for patients who received either systemic therapy and surgery (ST + Surg: hazard ratio [HR] 0.723; 95% confidence interval [CI] 0.671–0.779) or systemic therapy, surgery, and radiation (Trimodality: HR 0.640; 95% CI 0.591–0.694) (both p

Background Companion diagnostic (CDx) testing for patients with advanced non‐small cell lung cancer (aNSCLC) identifies patients more likely to benefit from biomarker‐driven treatments. Methods Patients with nonsquamous cell (non‐Sq) aNSCLC from the Flatiron Health database (diagnosed January 1, 2011–May 31, 2018) who had CDx testing were compared with those who had no reported evidence of testing. The association between CDx testing and overall survival was evaluated by unadjusted and adjusted Cox proportional hazards regression models. Logistic regression analysis identified characteristics associated with CDx testing. The revised modified Lung Cancer Prognostic Index and other factors identified a priori were included in the adjusted models. Results A total of 17,555 patients with non‐Sq aNSCLC (CDx, n = 14,732; no CDx, n = 2,823) with mean ± SD age of 67.2 ± 10.0 years were included. Most were insured (91.7%) and white (67.1%). Asian patients and those who were never‐smokers were more likely to undergo CDx testing. Those with CDx testing lived longer than those without (median [95% confidence interval (CI)] survival, 13.04 [12.62–13.40] vs. 6.01 [5.72–6.24] months) and had a decreased mortality risk (adjusted hazard ratio [95% CI], 0.72 [0.69–0.76]). A survival advantage was also seen for patients with CDx testing who received biomarker‐driven first‐line therapy. Conclusion Patients with non‐Sq aNSCLC who had CDx testing had a greater survival benefit than those without, supporting broader use of CDx testing in routine clinical practice to identify patients more likely to benefit from precision medicine. Implications for Practice Companion diagnostic (CDx) testing coupled with biomarker‐driven treatment offers a greater survival benefit for patients with advanced non‐small cell lung cancer (aNSCLC). In this study, patients with nonsquamous aNSCLC from Flatiron Health, a large, real‐world oncology database, with CDx testing had a reduced mortality risk and lived longer than patients without reported evidence of CDx testing; those who received biomarker‐driven therapy as their first line of treatment were likely to survive three times longer than those who did not. These results demonstrate the clinical utility of CDx testing as the first step in treating nonsquamous aNSCLC in real‐world clinical practice., Improved diagnostic and treatment approaches are needed for patients with non‐small cell lung cancer. This article evaluates the testing patterns and outcomes associated with overall companion diagnostic testing in real‐world clinical practice.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications., Graphical abstract

OBJECTIVES To characterize the clinical course and outcome of children with status asthmaticus (SA) admitted to a pediatric intensive care unit (PICU) METHODS: All patients with SA who were admitted to a PICU from January 2003 to December 2018 were reviewed. Polymerase chain reaction (PCR) studies on nasopharyngeal aspirate for respiratory pathogens were performed from 2014 to 2018. RESULTS Sixty-seven SA admissions constituted 2.4% of total PICU admissions (n = 2788). Fifteen (22.4%) children required noninvasive ventilation (NIV), while 7 children (10%) required invasive mechanical ventilation. Nonadherence to prior asthma therapy was common. PCR was positive for enterorvirus/rhinovirus in 84% (16 out of 19) and for any virus in 95% of nasopharyngeal aspirate (NPA) samples of patients between 2014 and 2018. Over the 16-year period, increased utilization of ipratropium bromide, magnesium sulfate and NIV was noted (P

Chronic hepatitis C (CHC) is among the most burdensome infectious diseases in the world. Health utilities are a valuable tool for quantifying this burden and conducting cost-utility analysis.Our study summarizes the available data on utilities in CHC patients. This will facilitate analyses of CHC treatment and elimination strategies.We searched MEDLINE, Embase, and the Cochrane Library for studies measuring utilities in CHC patients. Utilities were pooled by health state and utility instrument using meta-analysis. A further analysis used meta-regression to adjust for the effects of clinical status and methodological variation.Fifty-one clinical studies comprising 15 053 patients were included. Based on the meta-regression, patients' utilities were lower for more severe health states (predicted mean EuroQol-5D-3L utility for mild/moderate CHC: 0.751; compensated cirrhosis: 0.671; hepatocellular carcinoma: 0.662; decompensated cirrhosis: 0.602). Patients receiving interferon-based treatment had lower utilities than those on interferon-free treatment (0.647 vs 0.733). Patients who achieved sustained virologic response (0.786) had higher utilities than those with mild to moderate CHC. Utilities were substantially higher for patients in experimental studies compared to observational studies (coefficient: +0.074, P.05). The time tradeoff instrument was associated with the highest utilities, and the Health Utilities Index 3 was associated with the lowest utilities.Chronic hepatitis C is associated with a significant impairment in global health status, as measured by health utility instruments. Impairment is greater in advanced disease. Experimental study designs yield higher utilities-an effect not previously documented. Curative therapy can alleviate the burden of CHC, although further research is needed in certain areas, such as the long-term impacts of treatment on utilities.

BACKGROUND/AIM Hepatitis C virus (HCV) continues to pose significant public health concerns with approximately 44% of chronically infected Canadians undiagnosed. The current HCV screening in Canada is a two-step diagnosis pathway consisting of anti-HCV testing and HCV ribonucleic acid (RNA) testing. The introduction of HCV point-of-care assays, such as the Xpert HCV viral load finger-stick assay, can facilitate HCV RNA diagnosis during a single visit and provide quick linkage to care. We evaluated the cost-effectiveness of HCV point-of-care testing compared with current HCV screening strategies for injection drug users (IDUs) from a Canadian provincial Ministry of Health perspective. METHODS A state-transition model based on published literature was developed to compare HCV point-of-care assay with the standard-of-care blood screening for a one-time HCV screening and treatment program. It adopted a lifetime time horizon and included health states related to treatment, fibrosis stages, and advanced liver disease clinical states. Outcomes were expressed in costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Sensitivity analyses were conducted to assess the robustness of the model. RESULTS HCV point-of-care assay generated an additional 0.035 QALYs/person at a cost reduction of $21.15 compared with the standard-of-care screening. The results were the most sensitive to the specificity of HCV point-of-care assay. CONCLUSIONS The implementation of HCV point-of-care screening in Canada is likely to be cost-saving for IDUs. Early detection and treatment of undiagnosed individuals can prolong people's life span and save healthcare costs associated with HCV-related complications.

In chronic obesity, activated adipose tissue proinflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here, we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3-days high-fat feeding (3dHFF) and acute obesity reversal [2-wk switch to low-fat diet after 8-wk HFF (8wHFF)] already induced marked changes in whole body fuel utilization. Although adipose tissue expression of classical proinflammatory cytokines (Tnf-α, Ccl2, and Il1b) exhibited no, or only minor, change, C1qtnf6 uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEFs) exhibited increased adipogenic gene expression (Pparg, Fabp4, and Adipoq) and markedly reduced inflammatory genes (Tnf-α, Ccl2, and Il6) compared with wild-type MEFs, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole body and adipose tissue weight gain compared with wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute overnutrition to induce a “physiological inflammatory response” that limits adipose tissue expansion. NEW & NOTEWORTHY CTRP6 (C1qTNF6), a member of adiponectin gene family, regulates inflammation and metabolism in established obesity. Here, short-term high-fat feeding in mice is shown to increase adipose tissue expression of CTRP6 before changes in the expression of classical inflammatory genes occur. Conversely, CTRP6 expression in adipose tissue decreases early in the course of obesity reversal. Gain- and loss-of-function models suggest CTRP6 as a positive regulator of inflammatory cascades, and a negative regulator of adipogenesis and adipose tissue expansion.

C1q/TNF-related protein (CTRP) family comprises fifteen highly conserved secretory proteins with diverse central and peripheral functions. In zebrafish, mouse, and human, CTRP4 is most highly expressed in the brain. We previously showed that CTRP4 is a metabolically responsive regulator of food intake and energy balance, and mice lacking CTRP4 exhibit sexually dimorphic changes in ingestive behaviors and systemic metabolism. Recent single-cell RNA sequencing also revealed Ctrp4/C1qtnf4 expression in diverse neuronal cell types across distinct anatomical brain regions, hinting at additional roles in the central nervous system not previously characterized. To uncover additional central functions of CTRP4, we subjected Ctrp4 knockout (KO) mice to a battery of behavioral tests. Relative to wild-type (WT) littermates, loss of CTRP4 does not alter exploratory, anxiety-, or depressive-like behaviors, motor function and balance, sensorimotor gating, novel object recognition, and spatial memory. While pain-sensing mechanisms in response to thermal stress and mild shock are intact, both male and female Ctrp4 KO mice have increased sensitivity to pain induced by higher-level shock, suggesting altered nociceptive function. Importantly, CTRP4 deficiency impairs hippocampal-dependent associative learning and memory as assessed by trace fear conditioning paradigm. This deficit is sex-dependent, affects only female mice, and is associated with altered expression of learning and memory genes (Arc, c-fos, and Pde4d) in the hippocampus and cortex. Altogether, our behavioral and gene expression analyses have uncovered novel aspects of the CTRP4 function and provided a physiological context to further investigate its mechanism of action in the central and peripheral nervous system.

Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in AR(fl/fl) mice (adLivARKO). We observed normal metabolic function in littermate female Control (AR(fl/fl)) and LivARKO (AR(fl/fl); Cre(+/−)) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Furthermore, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.

Background In a global, phase III, open-label, noninferiority trial (REFLECT), lenvatinib demonstrated noninferiority to sorafenib in overall survival and a statistically significant increase in progression-free survival in patients with unresectable hepatocellular carcinoma (HCC). Recently, lenvatinib became the first agent in more than 10 years to receive approval as first-line therapy for unresectable HCC, along with the previously approved sorafenib. The objective of this study was to determine the comparative cost-effectiveness of lenvatinib and sorafenib as a first-line therapy of unresectable HCC. Materials and methods A state-transition model of unresectable HCC was developed in the form of a cost-utility analysis. The model time horizon was 5 years; the efficacy of the model was informed by the REFLECT trial, and costs and utilities were obtained from published literature. Probabilistic sensitivity analyses and subgroup analyses were performed to test the robustness of the model. Results Lenvatinib dominated sorafenib in the base case analysis. A probabilistic sensitivity analysis indicated that lenvatinib remains a cost-saving measure in 64.87% of the simulations. However, if the cost of sorafenib was reduced by 57%, lenvatinib would no longer be the dominant strategy. Conclusion Lenvatinib offered a similar clinical effectiveness at a lower cost than sorafenib, suggesting that lenvatinib would be a cost-saving alternative in treating unresectable HCC. However, lenvatinib may fail to remain cost-saving if a significantly cheaper generic sorafenib becomes available. Implications for practice This analysis suggests an actionable clinical policy that will achieve cost saving. This cost-utility analysis showed that lenvatinib had a similar clinical effectiveness at a lower cost than sorafenib, indicating that lenvatinib may be a cost-saving measure in patients with unresectable HCC, in which $23,719 could be saved per patient. The introduction of a new therapeutic option for the first time in 10 years in Canada provides an important opportunity for clinicians, researchers, and health care decision-makers to explore potential modifications in recommendations and practice guidelines.

Hypothesis: Dermoscope-guided laser excision is applicable for some cutaneous lesions seen in primary care, particularly those in body flexures or in regions with high blood perfusion. Summary: A male patient presented with an asymptomatic mass behind his left pinna. Polarised dermoscopy revealed signs compatible with malignancy. Excision was difficult owing to the location being concave and the region being one with hyper-perfusion. Dermoscope-guided laser excision was performed. The edge of the lesion and clear margins were marked via dermoscope-guidance. Laser incisions were made following the margins. Dermoscopy confirmed precision of the incision. Upon three laser-dermoscope cycles, the mass separated itself. Laser in coagulation mode achieved haemostasis. Dermoscope-guided laser excision was performed. The edge of the lesion and clear margins were marked via dermoscope-guidance. Laser incisions were made following such margins. Dermoscopy confirmed precision of the incision. Lesion incisions and dermoscopy were then reapplied. Upon three laser-dermoscope cycles, the mass separated itself. Laser in coagulation mode achieved haemostasis. Outcome: The histopathological diagnosis was a pilomatricoma. Healing was uneventful, with minimal scarring. There was no relapse one year post-operatively. Recommendation: Investigations on dermoscope-guided laser incision and other dermoscope-guided surgical procedures in primary care settings can be conducted to evaluate the outcomes of these procedures.

We recently described myonectin (also known as erythroferrone) as a novel skeletal muscle–derived myokine with metabolic functions. Here, we use a genetic mouse model to determine myonectin’s requirement for metabolic homeostasis. Female myonectin-deficient mice had larger gonadal fat pads and developed mild insulin resistance when fed a high-fat diet (HFD) and had reduced food intake during refeeding after an unfed period but were otherwise indistinguishable from wild-type littermates. Male mice lacking myonectin, however, had reduced physical activity when fed ad libitum and in the postprandial state but not during the unfed period. When stressed with an HFD, myonectin-knockout male mice had significantly elevated VLDL–triglyceride (TG) and strikingly impaired lipid clearance from circulation following an oral lipid load. Fat distribution between adipose and liver was also altered in myonectin-deficient male mice fed an HFD. Greater fat storage resulted in significantly enlarged adipocytes and was associated with increased postprandial lipoprotein lipase activity in adipose tissue. Parallel to this was a striking reduction in liver steatosis due to significantly reduced TG accumulation. Liver metabolite profiling revealed additional significant changes in bile acids and 1-carbon metabolism pathways. Combined, our data affirm the physiologic importance of myonectin in regulating local and systemic lipid metabolism.—Little, H. C., Rodriguez, S., Lei, X., Tan, S. Y., Stewart, A. N., Sahagun, A., Sarver, D. C., Wong, G. W. Myonectin deletion promotes adipose fat storage and reduces liver steatosis.

Copper misbalance has been linked to fat accumulation in animals and experimental systems; however, information about copper homeostasis in human obesity is limited. In this study, the copper status of obese individuals was evaluated by measuring their levels of copper and cuproproteins in serum, adipose and hepatic tissues. The analysis of serum trace elements showed significant positive and element-specific correlation between copper and BMI after controlling for gender, age, and ethnicity. Serum copper also positively correlated with leptin, insulin, and the leptin/BMI ratio. When compared to lean controls, obese patients had elevated circulating cuproproteins, such as semucarbazide-sensitive amine oxidase (SSAO) and ceruloplasmin, and higher SSAO activity and copper levels in visceral fat. Although hepatic steatosis reduces copper levels in the liver, obese patients with no or mild steatosis have higher copper content in the liver compared to lean controls. In conclusion, obese patients evaluated in this study had altered copper status. Strong positive correlations of copper levels with BMI and leptin suggest that copper and/or cuproproteins may be functionally linked to fat accumulation.

Background: As most chlamydia cases are asymptomatic, regular testing and timely management may be important for control. We aimed to determine the preferences of people living in Hong Kong for chlamydia testing and management services. Methods: An online panel of sexually active individuals living in Hong Kong completed the survey with two discrete choice experiments (DCEs). The first DCE examined the preferred attributes of a chlamydia testing service (cost, location, appointment time, speed of results, delivery of results and availability of other STI testing). The second DCE examined the preferred attributes of a chlamydia management service (cost, access to patient-delivered partner therapy (PDPT), location, travel time, type of person consulted, and attitude of staff). Results: In total, 520 individuals participated: average age 36·8 years (SD 9·9), 40% males and 66% had a bachelor’s degree or higher. Choosing to test was most influenced by cost, followed by speed of results, delivery of results, extra STI testing, appointment available, and the least important was location of testing. Choosing to attend for management was most influenced by the attitude of staff, followed by cost, who they consult, access to patient-delivered partner therapy, travel time and the least important was treatment location. Conclusion: To design effective chlamydia testing and management services, it is important to be responsive to patient needs and preferences. For people living in Hong Kong, cost and staff attitude were the most important factors for deciding whether to test or be managed for chlamydia, respectively. Funding Information: This research was funded by the Hong Kong Medical Research Fund (18171282). JJO is supported by an Australian National Health and Medical Research Council (NHMRC) Emerging Leadership Investigator Grant (GNT1193955). CKF is supported by an NHMRC Leadership Investigator Grant (GNT1172900). Declaration of Interests: All authors declare there are no conflicts of interest. Ethics Approval Statement: Ethics approval was obtained from the University of Hong Kong Institutional Review Board (UW 19-130).

PURPOSE: In 2018, Medicare issued a national coverage determination (NCD) providing reimbursement for next-generation sequencing (NGS) tests for beneficiaries with advanced or metastatic cancer and no previous NGS testing. We examined the association between NCD implementation and NGS utilization trends in Medicare beneficiaries versus commercially insured patients. METHODS: This was a retrospective study of patients with advanced non–small-cell lung cancer (aNSCLC), metastatic colorectal cancer (mCRC), metastatic breast cancer (mBC), or advanced melanoma with a de novo or recurrent advanced diagnosis from January 1, 2011, through December 30, 2019, using a nationwide US electronic health record–derived deidentified database. Patients were classified by insurance and by advanced diagnosis date. NGS testing was assessed by receipt of first NGS test result ≤ 60 days of advanced diagnosis. Interrupted time series analysis assessed NGS utilization pre- and post-NCD effective date by insurance type. RESULTS: The utilization and repeat NGS testing analysis included 70,290 and 4,295 patients, respectively. Use of NGS rose from < 1% in 2011 to > 45% in Q4 2019 in aNSCLC while remaining < 20% in mBC and advanced melanoma. Among patients with aNSCLC, mCRC, or mBC, NGS testing increased post-NCD versus pre-NCD ( P < .05). There was no significant difference in trends pre- and post-NCD between Medicare beneficiaries and commercially insured patients in any tumor. Repeat NGS testing was similar before the NCD (Medicare v commercial: 24.8% v 28.5%). Post-NCD, fewer Medicare beneficiaries had repeat NGS testing (27.7% v 36.0%; P < .01). CONCLUSION: Trends in NGS utilization significantly changed post-NCD, although the magnitude of change was not significantly different by insurance type, indicating private insurers may also be incorporating NCD guidance. Implementation of the NCD may have limited use of repeat NGS testing in Medicare beneficiaries.

BACKGROUND: Currently, there are no pharmacological options available for the treatment of non-alcoholic steatohepatitis (NASH). In the 18-month interim analysis of an ongoing randomized, placebo-controlled phase 3 trial (REGENERATE), early results demonstrated that obeticholic acid (OCA) 25 mg significantly improved fibrosis with no worsening of NASH among patients with NASH and fibrosis compared with placebo (PBO). This study aimed to assess the potential cost-effectiveness of OCA compared with PBO in NASH patients. METHODS: A state-transition model was developed to perform a cost-utility analysis comparing two treatment strategies, PBO and OCA 25 mg, from a Canadian public payer perspective. The model time horizon was lifetime with annual cycle lengths. Cost and utility parameters were discounted at 1.5% annually. The efficacy data were obtained from the REGENERATE trial, and costs and utilities were derived from other published literature. Probabilistic and deterministic sensitivity analyses were performed to test the robustness of the model. RESULTS: Treatment with OCA led to reductions of 3.58% in decompensated cirrhosis cases, 3.95% in hepatocellular carcinoma, 7.88% in liver transplant, and 6.01% in liver-related death. However, at an annual price of CAD $36,000, OCA failed to be cost-effective compared with PBO at an incremental cost-effectiveness ratio of $815,514 per quality-adjusted life year (QALY). An 88% reduction in drug price to an annual cost of $4,300 would make OCA cost-effective at a willingness-to-pay threshold of $50,000/QALY. CONCLUSIONS: OCA failed to be cost-effective compared with PBO, despite demonstrating clinical benefits due to a high drug cost. A significant price reduction would be needed to make the drug cost-effective.

Background: Chlamydia is common amongst the sexually active population in Hong Kong. As most cases are asymptomatic, partner notification may be helpful in controlling chlamydia. This study examined attitudes towards partner notification for chlamydia among Hong Kong Chinese youths in order to inform a culturally appropriate, patient-empowering sexual health service. Methods: Sixteen individuals (aged 20 to 31) who received a confirmed diagnosis of chlamydia within the previous twelve months of data collection were recruited from two community-based organizations between June and December 2017. Semi-structured individual interviews were conducted by a health psychologist. Results: Nine participants notified a total of eleven current and ex-partners. Seven participants did not notify their sexual partner(s). Our findings revealed how participants struggled with the discrediting sexual aspect of their infection, and how de-sexualizing the infection and selected disclosure facilitated partner notification and social acceptance. Perceived stigma regarding chlamydia however did not dissipate with their disclosure. Participants did not perceive lasting impact of chlamydia on their well-being as they thought they have much control over whether and how to disclose to their (future) partners. All participants agreed there was a pressing need to raise public awareness on this silent but highly prevalent sexually transmitted infection. Conclusions: Our findings illustrate the complex struggle behind communicating about chlamydia to one’s sexual partner and how strategizing the disclosure process served to circumvent embarrassment and foster testing of sexual partners.

We evaluated the impact of insurance status and travel distance on the receipt of total mastectomy without reconstruction (TM) compared to breast conserving surgery with radiation (BCT) for early-stage breast cancer (BC) patients who received care at a single facility. We hypothesized that, lack of insurance and increased travel distance would be predictive of TM over BCT and disparities would vary by different races and/or ethnicities.Using the National Cancer Database from 2010-2017, we examined surgical patients with stage I or II BC, who received care at one facility. Chi-square tests examined subgroup differences by BCT or TM. Multivariable logistic regressions evaluated patient, facility, and pathologic factors associated with the receipt of TM over BCT for the entire cohort and by races and/or ethnicities.Of the 284,202 patients, 70.1% received BCT while 29.9% received TM. After adjustment travel distance60 miles to a treatment facility, and non-insured patients were more likely to receive TM over BCT, when compared to travel distance20 miles and private insurance (all P0.05). Compared to other races and/or ethnicities, African Americans traveling60 miles were 65.4% more likely to receive TM over BCT compared to those traveling20 miles (P.0001). Across all races and/or ethnicities after adjustment, lack of insurance was predictive for receipt of TM over BCT (P0.05).Despite treatment at one facility, increased travel distance and insurance status are independently predictive of the receipt of TM over BCT in patients with early-stage BC. While travel distance is particularly impactful for African Americans, the impact of not having insurance on surgical treatments is universal across all races and/or ethnicities.

BACKGROUND Postoperative radiation therapy (RT) for early-stage Merkel Cell Carcinoma (MCC) decreases the risk of locoregional recurrence and improve overall survival. However, concordance with RT guidelines is unknown. MATERIALS AND METHODS The National Cancer Database was queried for stage I/II MCC patients receiving surgical intervention from 2006-2017. The cohort was stratified by patients who had and did not have indication(s) for adjuvant RT of the primary tumor site based on National Comprehensive Cancer Network guidelines. We captured the use of RT, patient demographics, socioeconomic characteristics, and clinical characteristics. Logistic regression, Kaplan-Meier method, and propensity score weighted Cox proportional hazards model examined associations and survival benefits of RT. RESULTS 2,330 stage I/II MCC patients underwent surgical intervention. 1,858 (79.7%) met National Comprehensive Cancer Network criteria for RT of the primary tumor site, of which 1,062 (57.2%) received RT. 472 (20.3%) did not meet criteria for RT, of which 203 (43.0%) received RT. Five-year overall survival advantage was identified for patients who received RT when it was indicated (P < 0.003). There was no evidence of overall survival advantage when patients received guideline-discordant RT (P = 0.478). CONCLUSIONS Surgical resection with adjuvant RT of the primary tumor site has an overall survival benefit for local MCC when patients meet criteria for RT. This study found a group who received guideline-discordant RT with no survival advantage. Further investigation is warranted to identify the socio-demographic and oncologic reasons for guideline discordance in the treatment of MCC for both under- and over-treatment.

C1q/TNF-related protein 1 (CTRP1) is an endocrine factor with metabolic, cardiovascular, and renal functions. We previously showed that aged Ctrp1-knockout (KO) mice fed a control low-fat diet develop renal hypertrophy and dysfunction. Since aging and obesity adversely affect various organ systems, we hypothesized that aging, in combination with obesity induced by chronic high-fat feeding, would further exacerbate renal dysfunction in CTRP1-deficient animals. To test this, we fed wild-type and Ctrp1-KO mice a high-fat diet for 8 mo or longer. Contrary to our expectation, no differences were observed in blood pressure, heart function, or vascular stiffness between genotypes. Loss of CTRP1, however, resulted in an approximately twofold renal enlargement (relative to body weight), ∼60% increase in urinary total protein content, and elevated pH, and changes in renal gene expression affecting metabolism, signaling, transcription, cell adhesion, solute and metabolite transport, and inflammation. Assessment of glomerular integrity, the extent of podocyte foot process effacement, as well as renal response to water restriction and salt loading did not reveal significant differences between genotypes. Interestingly, blood platelet, white blood cell, neutrophil, lymphocyte, and eosinophil counts were significantly elevated, whereas mean corpuscular volume and hemoglobin were reduced in Ctrp1-KO mice. Cytokine profiling revealed increased circulating levels of CCL17 and TIMP-1 in KO mice. Compared with our previous study, current data suggest that chronic high-fat feeding affects renal phenotypes differently than similarly aged mice fed a control low-fat diet, highlighting a diet-dependent contribution of CTRP1 deficiency to age-related changes in renal structure and function.

Obesity is a major risk factor for SARS-CoV-2 infection and COVID-19 severity. The underlying basis of this association is likely complex in nature. The host-cell receptor angiotensin converting enzyme 2 (ACE2) and the type II transmembrane serine protease (TMPRSS2) are important for viral cell entry. It is unclear whether obesity alters expression of Ace2 and Tmprss2 in the lower respiratory tract. Here, we show that: 1) Ace2 expression is elevated in the lung and trachea of diet-induced obese male mice and reduced in the esophagus of obese female mice relative to lean controls; 2) Tmprss2 expression is increased in the trachea of obese male mice but reduced in the lung and elevated in the trachea of obese female mice relative to lean controls; 3) in chow-fed lean mice, females have higher expression of Ace2 in the lung and esophagus as well as higher Tmprss2 expression in the lung but lower expression in the trachea compared to males; and 4) in diet-induced obese mice, males have higher expression of Ace2 in the trachea and higher expression of Tmprss2 in the lung compared to females, whereas females have higher expression of Tmprss2 in the trachea relative to males. Our data indicate diet- and sex-dependent modulation of Ace2 and Tmprss2 expression in the lower respiratory tract and esophagus. Given the high prevalence of obesity worldwide and a sex-biased mortality rate, we discuss the implications and relevance of our results for COVID-19.

Background Current literature indicates that direct-acting antivirals (DAAs) are cost-effective to treat compensated cirrhotic patients with hepatitis C. Although already funded by public payers, it is unknown whether it is economical to reimburse DAAs within the more advanced decompensated cirrhosis population. Methods A state-transition model was developed to conduct a cost-utility analysis of sofosbuvir-velpatasvir (SOF/VEL) plus ribavirin regimen for 12 weeks. The evaluated cohort had a mean age of 58 years and Child-Turcotte-Pugh (CTP) class B cirrhosis with decompensated symptoms. A scenario analysis was performed on CTP C patients. We used a payer perspective, a lifetime time horizon and a 1.5% annual discount rate. Results While SOF/VEL plus ribavirin treatment for 12 weeks increased costs by $156 676, it provided an extra 4.00 quality-adjusted life years (QALYs) compared to best supportive care (no DAA therapy). With an incremental cost-effectiveness ratio of $39 169 per QALY, SOF/VEL plus ribavirin was determined to be cost-effective at a willingness to pay of $50 000 per QALY. SOF/VEL reduced liver-related deaths and reduced progression to CTP C cirrhosis by 20.4% and 21.9%, respectively. On the contrary, SOF/VEL regimen resulted in increases in liver transplants and hepatocellular carcinoma (HCC) by 54.0% and 42.5%, respectively. Similar results were found for CTP C patients. Conclusion This analysis informs payers that SOF/VEL should continue to be reimbursed in decompensated hepatitis C patients. It also supports the recommendations by the American Association for the Study of Liver Diseases to continue screening for HCC in decompensated cirrhotic patients who have achieved sustained virologic response.

Background Hepatitis C virus (HCV) is a growing public health problem with a large disease burden worldwide. In China many people living with HCV are unaware of their hepatitis status and not connected to care and treatment. Crowdsourcing is a technique that invites the public to create health promotion materials and has been found to increase HIV testing uptake, including in China. This trial aims to evaluate crowdsourcing as a strategy to improve HCV awareness, testing and linkage-to-care in China. Methods A randomized controlled, two-armed trial (RCT) is being conducted in Shenzhen with 1006 participants recruited from primary care sectors of The University of Hong Kong-Shenzhen Hospital. Eligible participants are ≥30 years old; a resident in Shenzhen for at least one month after recruitment; no screening for HCV within the past 12 months and not known to have chronic HCV; and, having a WeChat social media account. Allocation is 1:1. Both groups will be administered a baseline and a follow-up survey (4-week post-enrollment). The intervention group will receive crowdsourcing materials to promote HCV testing once a week for two weeks and feedback will be collected thereafter, while the control group will receive no promotional materials. Feedback collected will be judged by a panel and selected to be implemented to improve the intervention continuously. Those identified positive for HCV antibodies will be referred to gastroenterologists for confirmation and treatment. The primary outcome will be confirmed HCV testing uptake, and secondary outcomes include HCV confirmatory testing and initiation of HCV treatment with follow-ups with specialist providers. Data will be collected on Survey Star@ via mobile devices. Discussion This will be the first study to evaluate the impact of crowdsourcing to improve viral hepatitis testing and linkage-to-care in the health facilities. This RCT will contribute to the existing literature on interventions to improve viral hepatitis testing in primary care setting, and inform future strategies to improve HCV care training for primary care providers in China. Trial registration Chinese Clinical Trial Registry. ChiCTR1900025771. Registered September 7th, 2019, http://www.chictr.org.cn/showprojen.aspx?proj=42788

Secreted hormones facilitate tissue cross talk to maintain energy balance. We previously described C1q/TNF-related protein 12 (CTRP12) as a novel metabolic hormone. Gain-of-function and partial-deficiency mouse models have highlighted important roles for this fat-derived adipokine in modulating systemic metabolism. Whether CTRP12 is essential and required for metabolic homeostasis is unknown. We show here that homozygous deletion of Ctrp12 gene results in sexually dimorphic phenotypes. Under basal conditions, complete loss of CTRP12 had little impact on male mice, whereas it decreased body weight (driven by reduced lean mass and liver weight) and improved insulin sensitivity in female mice. When challenged with a high-fat diet, Ctrp12 knockout (KO) male mice had decreased energy expenditure, increased weight gain and adiposity, elevated serum TNFα level, and reduced insulin sensitivity. In contrast, female KO mice had reduced weight gain and liver weight. The expression of lipid synthesis and catabolism genes, as well as profibrotic, endoplasmic reticulum stress, and oxidative stress genes were largely unaffected in the adipose tissue of Ctrp12 KO male mice. Despite greater adiposity and insulin resistance, Ctrp12 KO male mice fed an obesogenic diet had lower circulating triglyceride and free fatty acid levels. In contrast, lipid profiles of the leaner female KO mice were not different from those of WT controls. These data suggest that CTRP12 contributes to whole body energy metabolism in genotype-, diet-, and sex-dependent manners, underscoring complex gene-environment interactions influencing metabolic outcomes.

Background Targeted therapy for patients with non–small-cell lung cancer (NSCLC) harboring ROS proto-oncogene 1 (ROS1) rearrangements was approved in 2016. However, little is known about real-world ROS1 testing practices in United States community practice. We aimed to characterize ROS1 testing rates and identify potential barriers to ROS1 testing. Patients and Methods Flatiron Health’s de-identified electronic health record-derived database was used to identify patients diagnosed with advanced NSCLC from July 2016 through December 2018 who received systemic treatment in a community practice setting. ROS1 and other biomarker testing was recorded. Regression analysis identified demographic and clinical characteristics associated with occurrence of ROS1 testing, longer time (≥ 25 days) from diagnosis to ROS1 result, and initiation of therapy prior to ROS1 result. Results Among 11,409 patients, documented ROS1 testing rates increased during the study period in squamous (from 30% to 48%) and nonsquamous (63% to 78%) histologies. Patients who were older, male, black, or with squamous histology, higher Eastern Cooperative Oncology Group score, recurrent disease, or history of smoking were significantly less likely to be tested. Among patients not tested for ROS1, 63% were tested for other biomarkers. Use of next-generation sequencing, older age, Hispanic/Latino ethnicity, squamous histology, de novo disease, and smoking history predicted longer time to test result post-diagnosis. Patients with delayed results were 9.7 times more likely to receive treatment prior to ROS1 test result. Conclusion In real-world practice, some patient subgroups may be less likely to receive timely ROS1 testing and to be identified for potential targeted therapy.

INTRODUCTION: Five-year overall survival rate of breast cancer in low-income countries (LICs) is significantly lower than in high-resource countries. In this study, we explored clinical and pathological factors influencing mortality in a rural community setting in sub-Saharan Africa. METHODS: We performed a retrospective medical review of patients undergoing surgery and chemotherapy for breast cancer at a regional hospital in Ghana from January 2014 through January 2017. Descriptive and survival analysis was done. RESULTS: One hundred and twenty-nine patients were included in the study. The median age at presentation was 51 years. 60.0% of patients presented with poorly differential histological grade III. The most common histological type was invasive ductal carcinoma (83%). Based on assessment of stage using only tumor size and lymph node status, 60% presented at stage 3. Only 25% were tested for hormone receptor proteins and HER2 status. Of these, 57% had triple-negative breast cancer (TNBC). The 3-year overall survival rate was only 52%. A significant proportion of the patients (46%) were lost to follow-up. CONCLUSIONS: The cumulative 3-year survival was 52 %. Despite success in the reduction of cancer mortality in southern and northern Africa, survival in the rural communities of sub-Saharan Africa remains poor. A significantly higher percentage of GIII and TNBC is found in breast cancers seen in Ghana. Late-stage presentation, when combined with limited capacity for accurate diagnosis, cancer subtype analysis, adequate therapy and follow-up, leads to poor outcomes. Future studies should emphasize identification of barriers to care and opportunities for cost-effective and sustainable improvements in the diagnosis and treatment of breast cancer in LICs.

Introduction Several obstacles may delay receipt of targeted treatment in patients with anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC). This study examined the factors associated with delayed initiation of ALK inhibitor (ALKi) treatment and its impact on overall survival (OS) as well as the impact of initiating chemotherapy before biomarker test results. Materials and Methods Advanced NSCLC (aNSCLC) patients selected from the deidentified Flatiron Health electronic health record–derived database were stratified into early- and delayed-use cohorts based on initiation of ALKi treatment relative to time since receiving ALK+ biomarker test results; cohorts were further stratified by timing of chemotherapy initiation relative to availability of ALK+ test results. Prescription-time matching (PTM) was used to examine the effect of delayed ALKi treatment and chemotherapy on survival; Cox proportional hazards models adjusting for baseline characteristics before and after PTM were used to examine factors associated with delayed ALKi treatment and the effects of delayed ALKi treatment and chemotherapy on OS, respectively. Results Comparison of OS between early- and delayed-use cohorts (N = 442 ALK + aNSCLC patients) demonstrated that a >3-week delay in the initiation of ALKi treatment was associated with a >2-fold higher risk of death (adjusted hazard ratio [HR] [95 % CI] 2.05 [1.13, 3.71]. The number of office visits, age factors, and use of chemotherapy were associated with an increased risk of being untreated >3 weeks after ALK+ test results. There were no significant differences in survival outcomes regardless of whether patients received chemotherapy before the ALK+ test result or ALKi treatment (adjusted HR [95 % CI] 1.02 [0.64, 1.63]). Completing the chemotherapy regimen after receiving ALK+ test results did not appear to improve survival (adjusted HR [95 % CI] 0.84 [0.38, 1.9]). Conclusion Initiating ALKi treatment for aNSCLC patients in a timely manner may have a positive impact on survival outcomes.

Purpose Targeted therapy of ALK in patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC) and ALK rearrangements improves outcomes compared with chemotherapy. This study assessed real-world ALK testing patterns among community practices in the United States in patients with advanced (stage IIIB or IV) NSCLC. Methods Patients age ≥ 18 years with two or more visits within the Flatiron Health electronic health record–derived database after January 2011 and diagnosed with stage IIIB or IV NSCLC through May 2017 were included in this analysis. Logistic regression was used to examine the association between demographic and clinical characteristics and testing for ALK rearrangements. Results Of 31,483 patients analyzed from the database, 16,726 patients (53.1%) were tested for ALK rearrangements. ALK testing rates were 66.9% and 18.5% in patients with nonsquamous and squamous histology, respectively. Average ALK testing rates increased over time from 32.4% in 2011 to 62.1% in 2016. Fluorescent in situ hybridization was the most common ALK testing method. Agreement between fluorescent in situ hybridization and other assays ranged from 94.1% to 97.9%. Median (interquartile range) time from laboratory receipt of sample to first ALK test result was 7 (7) days; median time from advanced diagnosis to first ALK test result was 25 (29) days. Patients who were older, male, had a history of smoking, lived in non-Western US regions, and who had recurrent disease or squamous histology were less likely to be tested for ALK. Patients with Medicaid and Medicare insurance were less likely to be tested than patients with commercial insurance. Overall, 21.5% of patients initiated therapy (20.4% chemotherapy) before receiving test results. Conclusion ALK testing rates have increased over time. However, certain subgroups of patients are less likely to be tested, suggesting that additional education on molecular testing is warranted.

Health-related quality of life (HRQOL) in advanced non-small-cell lung cancer (NSCLC) might be affected by the presence of brain metastasis (BM). We report findings from a prospective observational study that examined HRQOL in patients newly diagnosed with advanced NSCLC, with or without baseline BM, through 1 year of follow-up.Patients starting first-line treatment of stage IIIB/IV NSCLC were prospectively enrolled and consented at 34 US-based community oncology practices. Data on patient-reported outcomes (PROs) were collected once per cycle during treatment, and at each visit after discontinuation. PROs included the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) and Lung Cancer Module (QLQ-LC13), the Lung Cancer Module of the M.D. Anderson Symptom Inventory (MDASI-LC), and the Rotterdam Activity Level Scale (RALS). Linear mixed models were used to examine the effect of baseline BM, including differences in change over time.One hundred forty-five patients provided follow-up PRO data, comprising 1100 individual surveys and 32 PRO end points. The patient group was 58.6% (n = 85) male, and 86.2% (n = 125) Caucasian. Patients with baseline BM were younger (61.3 vs. 65.8 years; P = .040) with more concurrent radiotherapy (59.4% [n = 19] vs. 15.9% [n = 18]; P .0001). Results showed minimal differences in baseline HRQOL. Of the 20 measures that showed significant group differences in HRQOL over time, 18 showed greater deterioration for patients with baseline BM. These 18 measures included all QLQ-C30 composite measures except Global Health Status, all MDASI-LC measures, and the RALS (all P .05). For these measures, the average 1-year deterioration in patients with baseline BM was 19.4%.Newly diagnosed advanced NSCLC patients with baseline BM experienced a significantly faster and clinically meaningful deterioration in PRO-based HRQOL compared with those without baseline BM.

Chronic hepatitis C (CHC) is a leading cause of hepatic fibrosis and cirrhosis. The level of fibrosis is traditionally established by histology, and prognosis is estimated using fibrosis progression rates (FPRs; annual probability of progressing across histological stages). However, newer noninvasive alternatives are quickly replacing biopsy. One alternative, transient elastography (TE), quantifies fibrosis by measuring liver stiffness (LSM). Given these developments, the purpose of this study was (i) to estimate prognosis in treatment-naïve CHC patients using TE-based liver stiffness progression rates (LSPR) as an alternative to FPRs and (ii) to compare consistency between LSPRs and FPRs. A systematic literature search was performed using multiple databases (January 1990 to February 2016). LSPRs were calculated using either a direct method (given the difference in serial LSMs and time elapsed) or an indirect method given a single LSM and the estimated duration of infection and pooled using random-effects meta-analyses. For validation purposes, FPRs were also estimated. Heterogeneity was explored by random-effects meta-regression. Twenty-seven studies reporting on 39 groups of patients (N = 5874) were identified with 35 groups allowing for indirect and 8 for direct estimation of LSPR. The majority (~58%) of patients were HIV/HCV-coinfected. The estimated time-to-cirrhosis based on TE vs biopsy was 39 and 38 years, respectively. In univariate meta-regressions, male sex and HIV were positively and age at assessment, negatively associated with LSPRs. Noninvasive prognosis of HCV is consistent with FPRs in predicting time-to-cirrhosis, but more longitudinal studies of liver stiffness are needed to obtain refined estimates.

Background Mobile technology has become a necessity in the lives of people in many countries. Its characteristics and advantages also make it a potential medium of intervention for people with autism spectrum disorder (ASD). Objective The objective of this review was to evaluate previous evidence, obtained in randomized controlled trials (RCTs), on the effectiveness of using mobile devices as the medium of intervention targeting social and cognitive skills among individuals with ASD. Methods Literature search was conducted on electronic databases including Medline, PsycInfo, PsycArticles, Education Resources Information Centre, and Social Science Citation Index. Only RCTs published in English and after year 2000 were included for this review. Data extraction was carried out by 2 independent reviewers using constant comparative methods. Results Totally 10 RCTs were identified. Most of the findings indicated that mobile devices could be an effective medium of intervention for people with ASD, among which 6 indicated significant intervention effects and 2 showed mixed findings. Effective intervention was more likely to be achieved in the studies that recruited older participants (aged over 9 years), targeting practical skills that could be readily applied in real life, or using pictures or materials that were highly relevant in daily life in the apps or mobile devices. Furthermore, the use of mobile devices was also reported to promote participation in the intervention among individuals with ASD. Conclusions The results suggested that mobile devices could be a promising means for the delivery of interventions targeting people with ASD. Although including a small number of studies was a limitation of this review, the results provided useful implications for designing effective mobile technology–assisted interventions for the ASD population in future studies.

Background Treatment options for patients with platinum-refractory, recurrent, metastatic head and neck squamous cell carcinoma (r/m HNSCC) are limited and prognosis is poor. The recent CheckMate 141 clinical trial demonstrated that nivolumab, an anti-programmed cell death protein 1 monoclonal antibody, was efficacious in extending the median overall survival (OS) in this patient population compared with standard therapies. We conducted a cost-effectiveness analysis to determine whether nivolumab is a cost-effective treatment in this patient population and examined various subgroups to determine for which, if any, the treatment is more cost-effective. Materials and Methods We implemented a state transition model for HNSCC with a patient cohort who had tumor progression 6 months after the last dose of platinum-containing chemotherapy and compared the cost-effectiveness of nivolumab with docetaxel. Treatment effect estimates and adverse event rates were obtained from CheckMate 141. Costs, utilities, and other model inputs were gathered from published sources. We used a Canadian perspective, a 5-year time horizon, and a 1.5% discount rate for the analysis. Results Nivolumab extended mean OS by 4 months compared with docetaxel and resulted in fewer treatment-related adverse events, producing an incremental effectiveness of 0.13 quality-adjusted life years (QALY). The incremental cost of treatment with nivolumab was $18,823. At a willingness-to-pay threshold of $100,000/QALY, nivolumab was not a cost-effective treatment option for r/m HNSCC, with an incremental cost-effectiveness ratio of $144,744/QALY. Nivolumab would be cost-effective if its price was reduced by 20%. Our subgroup analysis seemed to indicate that nivolumab might be cost-effective for tumors with expression of programmed death-ligand 1 >5%. Conclusion We conclude that although nivolumab offers clinical benefit for the treatment of r/m HNSCC over current regimens, it is not cost-effective based on its list price. We have also established a value-based price estimate for nivolumab to be cost-effective in this patient population. Further study is required to draw a definitive conclusion on biomarkers for cost-effectiveness. Implications for Practice In health care settings in which cost considerations are a constraint on choice of therapy, patient selection should be carefully considered to maintain efficiency in the system. Until a biomarker for response to therapy is identified for nivolumab, this medication is unlikely to be cost-effective for most patients with recurrent, metastatic head and neck squamous cell carcinoma.