STAT3 Inhibits Autocrine IFN Signaling in Type I Conventional Dendritic Cells.

Type I conventional dendritic cells (cDC1s) are an essential Ag-presenting population required for generating adaptive immunity against intracellular pathogens and tumors. While the transcriptional control of cDC1 development is well understood, the mechanisms by which extracellular stimuli regulate cDC1 function remain unclear. We previously demonstrated that the cytokine-responsive transcriptional regulator STAT3 inhibits polyinosinic:polycytidylic acid [poly(I:C)]-induced cDC1 maturation and cDC1-mediated antitumor immunity in murine breast cancer, indicating an intrinsic, suppressive role for STAT3 in cDC1s. To probe transcriptional mechanisms regulating cDC1 function, we generated novel RNA sequencing datasets representing poly(I:C)-, IL-10-, and STAT3-mediated gene expression responses in murine cDC1s. Bioinformatics analyses indicated that poly(I:C) stimulates multiple inflammatory pathways independent of STAT3, while IL-10-activated STAT3 uniquely inhibits the poly(I:C)-induced type I IFN (IFN-I) transcriptional response. We validated this mechanism using purified cDC1s deficient for STAT3 or IFN signaling. Our data reveal IL-10-activated STAT3 suppresses production of IFN-ß and IFN-γ, accrual of tyrosine phosphorylated STAT1, and IFN-stimulated gene expression in cDC1s after poly(I:C) exposure. Moreover, we found that maturation of cDC1s in response to poly(I:C) is dependent on the IFN-I receptor, but not the type II IFN receptor, or IFN-λ. Taken together, we elucidate an essential role for STAT3 in restraining autocrine IFN-I signaling in cDC1s elicited by poly(I:C) stimulation, and we provide novel RNA sequencing datasets that will aid in further delineating inflammatory and anti-inflammatory mechanisms in cDC1s.

A near-deterministic mutational hotspot in Pseudomonas fluorescens is constructed by multiple interacting genomic features.

Mutation - whilst stochastic - is frequently biased toward certain loci. When combined with selection this results in highly repeatable and predictable evolutionary outcomes. Immotile variants of the bacterium Pseudomonas fluorescens (SBW25) possess a 'mutational hotspot' that facilitates repeated occurrences of an identical de novo single nucleotide polymorphism when re-evolving motility, where ≥95% independent lines fix the mutation ntrB A289C. Identifying hotspots of similar potency in other genes and genomic backgrounds would prove valuable for predictive evolutionary models, but to do so we must understand the genomic features that enable such a hotspot to form. Here we reveal that genomic location, local nucleotide sequence, gene strandedness and presence of mismatch repair proteins operate in combination to facilitate the formation of this mutational hotspot. Our study therefore provides a framework for utilising genomic features to predict and identify hotspot positions capable of enforcing near-deterministic evolution.

A Longitudinal Study on the Dynamics of Salmonella enterica Prevalence and Serovar Composition in Beef Cattle Feces and Lymph Nodes and Potential Contributing Sources from the Feedlot Environment.

Salmonella can persist in the feedlot pen environment, acting as a source of transmission among beef cattle. Concurrently, cattle that are colonized with Salmonella can perpetuate contamination of the pen environment through fecal shedding. To study these cyclical dynamics, pen environment and bovine samples were collected for a 7-month longitudinal comparison of Salmonella prevalence, serovar, and antimicrobial resistance profiles. These samples included composite environment, water, and feed from the feedlot pens (n = 30) and cattle (n = 282) feces and subiliac lymph nodes. Salmonella prevalence across all sample types was 57.7%, with the highest prevalence in the pen environment (76.0%) and feces (70.9%). Salmonella was identified in 42.3% of the subiliac lymph nodes. Based on a multilevel mixed-effects logistic regression model, Salmonella prevalence varied significantly (P < 0.05) by collection month for most sample types. Eight Salmonella serovars were identified, and most isolates were pansusceptible, except for a point mutation in the parC gene, associated with fluoroquinolone resistance. There was a proportional difference in serovars Montevideo, Anatum, and Lubbock comparing the environment (37.2, 15.9, and 11.0%, respectively), fecal (27.5, 22.2, and 14.6%, respectively), and lymph node (15.6, 30.2, and 17.7%, respectively) samples. This suggests that the ability of Salmonella to migrate from the pen environment to the cattle host-or vice versa-is serovar specific. The presence of certain serovars also varied by season. Our results provide evidence that Salmonella serovar dynamics differ when comparing environment and host; therefore, developing serovar-specific preharvest environmental Salmonella mitigation strategies should be considered. IMPORTANCE Salmonella contamination of beef products, specifically from the incorporation of bovine lymph nodes into ground beef, remains a food safety concern. Current postharvest Salmonella mitigation techniques do not address Salmonella bacteria that are harbored in the lymph nodes, nor is it well understood how Salmonella invades the lymph nodes. Alternatively, preharvest mitigation techniques that can be applied to the feedlot environment, such as moisture applications, probiotics, or bacteriophage, may reduce Salmonella before dissemination into cattle lymph nodes. However, previous research conducted in cattle feedlots includes study designs that are cross-sectional, are limited to point-in-time sampling, or are limited to sampling of the cattle host, making it difficult to assess the Salmonella interactions between environment and hosts. This longitudinal analysis of the cattle feedlot explores the Salmonella dynamics between the feedlot environment and beef cattle over time to determine the applicability of preharvest environmental treatments.

Idiopathic pulmonary fibrosis in the United States: time to diagnosis and treatment.

OBJECTIVE: Create a timeline of diagnosis and treatment for IPF in the US. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed in collaboration with the OptumLabs Data Warehouse using an administrative claims database of Medicare Fee for Service beneficiaries. Adults 50 and over with IPF were included (2014 to 2019). EXPOSURE: To focus on IPF, the following diagnoses were excluded: post-inflammatory fibrosis, hypersensitivity pneumonitis, rheumatoid arthritis, sarcoidosis, scleroderma, and connective tissue disease. MAIN OUTCOMES AND MEASURES: Data were collected from periods prior, during, and following initial clinical diagnosis of IPF. This included prior respiratory diagnoses, number of respiratory-related hospitalizations, anti-fibrotic and oxygen use, and survival. RESULTS: A total of 44,891 with IPF were identified. The most common diagnoses prior to diagnosis of IPF were upper respiratory infections (47%), acute bronchitis (13%), other respiratory disease (10%), chronic obstructive pulmonary disease and bronchiectasis (7%), and pneumonia (6%). The average time to a diagnosis of IPF was 2.7 years after initial respiratory diagnosis. Half of patients had two or more respiratory-related hospitalizations prior to IPF diagnosis. Also, 37% of patients were prescribed oxygen prior to diagnosis of IPF. These observations suggest delayed diagnosis. We also observed only 10.4% were treated with anti-fibrotics. Overall survival declined each year after diagnosis with median survival of 2.80 years. CONCLUSIONS AND RELEVANCE: Our retrospective cohort demonstrates that IPF is often diagnosed late, usually preceded by other respiratory diagnoses and hospitalizations. Use of available therapies is low and outcomes remain poor.

Evaluation for clinical benefit of metformin in patients with idiopathic pulmonary fibrosis and type 2 diabetes mellitus: a national claims-based cohort analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high morbidity and limited treatment options. Type 2 diabetes mellitus (T2DM) is a common comorbid illness among patients with IPF and is often treated with metformin, the first-line agent in the management of T2DM. There is growing evidence demonstrating metformin's anti-fibrotic properties; however, there is little real-world clinical data regarding its potential effectiveness in IPF. This study aims to evaluate the clinical benefit of metformin in patients with IPF and T2DM. METHODS: This nationwide cohort study used de-identified administrative claims data from OptumLabs® Data Warehouse to identify 3599 adults with IPF and concomitant T2DM between January 1, 2014 and June 30, 2019. Two cohorts were created: a cohort treated with metformin (n = 1377) and a cohort not treated with metformin (n = 2222). A final 1:1 propensity score-matched cohort compared 1100 patients with IPF and T2DM receiving metformin to those with both diagnoses but not receiving metformin; matching accounted for age, sex, race/ethnicity, residence region, year, medications, oxygen use, smoking status, healthcare use, and comorbidities. Outcomes were all-cause mortality (primary) and hospitalizations (secondary). RESULTS: Among 2200 patients with IPF and T2DM included in this matched analysis, metformin therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.36-0.58; p < 0.001) and hospitalizations (HR, 0.82; 95% CI, 0.72-0.93; p = 0.003) compared to patients not receiving metformin. CONCLUSIONS: Among patients with IPF and T2DM, metformin therapy may be associated with improved clinical outcomes. However, further investigation with randomized clinical trials is necessary prior to metformin's broad implementation in the clinical management of IPF.

Effectiveness of an online module: climate-change and sustainability in clinical practice.

BACKGROUND: Climate change has significant implications for health, yet healthcare provision itself contributes significant greenhouse gas emission. Medical students need to be prepared to address impacts of the changing environment and fulfil a key role in climate mitigation. Here we evaluate the effectiveness of an online module on climate-change and sustainability in clinical practice designed to achieve learning objectives adapted from previously established sustainable healthcare priority learning outcomes. METHODS: A multi-media, online module was developed, and 3rd and 4th year medical students at Brighton and Sussex Medical School were invited to enrol. Students completed pre- and post-module questionnaires consisting of Likert scale and white space answer questions. Quantitative and qualitative analysis of responses was performed. RESULTS: Forty students enrolled and 33 students completed the module (83% completion rate). There was a significant increase in reported understanding of key concepts related to climate change and sustainability in clinical practice (p < 0.001), with proportion of students indicating good or excellent understanding increasing from between 2 - 21% students to between 91 - 97% students. The majority (97%) of students completed the module within 90 min. All students reported the module was relevant to their training. Thematic analysis of white space responses found students commonly reported they wanted access to more resources related to health and healthcare sustainability, as well as further guidance on how to make practical steps towards reducing the environmental impact within a clinical setting. CONCLUSION: This is the first study to evaluate learner outcomes of an online module in the field of sustainable health and healthcare. Our results suggest that completion of the module was associated with significant improvement in self-assessed knowledge of key concepts in climate health and sustainability. We hope this approach is followed elsewhere to prepare healthcare staff for impacts of climate change and to support improving the environmental sustainability of healthcare delivery. TRIAL REGISTRATION: Study registered with Brighton and Sussex Medical School Research Governance and Ethics Committee (BSMS RGEC). Reference: ER/BSMS3576/8, Date: 4/3/2020.

Techniques and complications of popliteal nerve blocks.

BACKGROUND: Use of popliteal nerve blocks (PNBs) as an alternative or adjunctive therapy to traditional methods of pain control (e.g., systemic or spinal anesthesia and opioids) is increasingly popular in foot and ankle surgery. METHODS: We reviewed online databases for literature on PNBs in foot and ankle surgery to analyze the various techniques and positioning used, the influence of drugs on their efficacy, and possible complications associated with their use. Thirty articles were identified with a predefined search criteria, followed by a review process for relevance. RESULTS: Patient demographics, procedure specifics, and block techniques, such as anesthetic used, can impact the duration and success of a PNB. Administration with ultrasound guidance proved superior to nerve stimulation, and preoperative administration was superior to postoperative administration. CONCLUSIONS: PNBs are an effective method to control postoperative pain with minimal complications, leading to decreased analgesic use, earlier discharge, and higher patient satisfaction. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Indoor PM2.5, VOCs and asthma outcomes: A systematic review in adults and their home environments.

INTRODUCTION: As the amount of time people spend indoors increases globally, exposure to indoor air pollutants has become an important public health concern. Asthma is a complex disease caused and/or exacerbated by increased exposure to diverse chemical, physical and biological exposures from multiple indoor and outdoor sources. This review aims to investigate the relationship between increased indoor PM and VOC concentrations (i.e. objectively measured) and the risk of adult asthma in higher-income countries. METHODS: Eleven databases were systematically searched on the February 1, 2019 and again on the February 2, 2020. Articles were limited to those published since 1990. Reference lists were independently screened by three reviewers and authors were contacted to identify relevant articles. Backwards and forward citation chasing was used to identify further studies. Data were extracted from included studies meeting our eligibility criteria by three reviewers and assessed for quality using the Newcastle-Ottawa scale designed for case-control and cohort studies. RESULTS: Twelve studies were included in a narrative synthesis. We found insufficient evidence to determine the effect of PM2.5 on asthma in the indoor home environment. However, there was strong evidence to suggest that VOCs, especially aromatic compounds, and aliphatic compounds, were associated with increased asthma symptoms. DISCUSSION & CONCLUSION: Although no single exposure appears to be responsible for the development of asthma or its associated symptoms, the use of everyday products may be associated with increased asthma symptoms. To prevent poor health outcomes among the general population, health professionals and industry must make a concerted effort to better inform the general population of the importance of appropriate use of and storage of chemicals within the home as well as better health messaging on product labelling.

Outcomes for hospitalized patients with idiopathic pulmonary fibrosis treated with antifibrotic medications.

BACKGROUND: Idiopathic Pulmonary Fibrosis is a chronic, progressive interstitial lung disease for which there is no cure. However, lung function decline, hospitalizations, and mortality may be reduced with the use of the antifibrotic medications, nintedanib and pirfenidone. Historical outcomes for hospitalized patients with Idiopathic Pulmonary Fibrosis are grim; however there is a paucity of data since the approval of nintedanib and pirfenidone for treatment. In this study, we aimed to determine the effect of nintedanib and pirfenidone on mortality following respiratory-related hospitalizations, intensive care unit (ICU) admission, and mechanical ventilation. METHODS: Using a large U.S. insurance database, we created a one-to-one propensity score matched cohort of patients with idiopathic pulmonary fibrosis treated and untreated with an antifibrotic who underwent respiratory-related hospitalization between January 1, 2015 and December 31, 2018. Mortality was evaluated at 30 days and end of follow-up (up to 2 years). Subgroup analyses were performed for all patients receiving treatment in an ICU and those receiving invasive and non-invasive mechanical ventilation during the index hospitalization. RESULTS: Antifibrotics were not observed to effect utilization of mechanical ventilation or ICU treatment during the index admission or effect mortality at 30-days. If patients survived hospitalization, mortality was reduced in the treated cohort compared to the untreated cohort when followed up to two years (20.1% vs 47.8%). CONCLUSIONS: Treatment with antifibrotic medications does not appear to directly improve 30-day mortality during or after respiratory-related hospitalizations. Post-hospital discharge, however, ongoing antifibrotic treatment was associated with improved long-term survival.

Genetic rescue of lineage-balanced blood cell production reveals a crucial role for STAT3 antiinflammatory activity in hematopoiesis.

Blood cell formation must be appropriately maintained throughout life to provide robust immune function, hemostasis, and oxygen delivery to tissues, and to prevent disorders that result from over- or underproduction of critical lineages. Persistent inflammation deregulates hematopoiesis by damaging hematopoietic stem and progenitor cells (HSPCs), leading to elevated myeloid cell output and eventual bone marrow failure. Nonetheless, antiinflammatory mechanisms that protect the hematopoietic system are understudied. The transcriptional regulator STAT3 has myriad roles in HSPC-derived populations and nonhematopoietic tissues, including a potent antiinflammatory function in differentiated myeloid cells. STAT3 antiinflammatory activity is facilitated by STAT3-mediated transcriptional repression of Ube2n, which encodes the E2 ubiquitin-conjugating enzyme Ubc13 involved in proinflammatory signaling. Here we demonstrate a crucial role for STAT3 antiinflammatory activity in preservation of HSPCs and lineage-balanced hematopoiesis. Conditional Stat3 removal from the hematopoietic system led to depletion of the bone marrow lineage- Sca-1+ c-Kit+ CD150+ CD48- HSPC subset (LSK CD150+ CD48- cells), myeloid-skewed hematopoiesis, and accrual of DNA damage in HSPCs. These responses were accompanied by intrinsic transcriptional alterations in HSPCs, including deregulation of inflammatory, survival and developmental pathways. Concomitant Ube2n/Ubc13 deletion from Stat3-deficient hematopoietic cells enabled lineage-balanced hematopoiesis, mitigated depletion of bone marrow LSK CD150+ CD48- cells, alleviated HSPC DNA damage, and corrected a majority of aberrant transcriptional responses. These results indicate an intrinsic protective role for STAT3 in the hematopoietic system, and suggest that this is mediated by STAT3-dependent restraint of excessive proinflammatory signaling via Ubc13 modulation.

Crotonylation at serine 46 impairs p53 activity.

Post-translational modifications (PTMs) play pivotal roles in controlling the stability and activity of the tumor suppressor p53 in response to distinct stressors. Here we report an unexpected finding of a short chain fatty acid modification of p53 in human cells. Crotonic acid (CA) treatment induces p53 crotonylation, but surprisingly reduces its protein, but not mRNA level, leading to inhibition of p53 activity in a dose dependent fashion. Surprisingly this crotonylation targets serine 46, instead of any predicted lysine residues, of p53, as detected in TCEP-probe labeled crotonylation and anti-crotonylated peptide antibody reaction assays. This is further confirmed by substitution of serine 46 with alanine, which abolishes p53 crotonylation in vitro and in cells. CA increases p53-dependent glycolytic activity, and augments cancer cell proliferation in response to metabolic or DNA damage stress. Since serine 46 is only found in human p53, our studies unveil an unconventional PTM unique for human p53, impairing its activity in response to CA. Because CA is likely produced by the gut microbiome, our results also predict that this type of PTM might play a role in early human colorectal neoplasia development by negating p53 activity without mutation of this tumor suppressor gene.

Genetic structure and admixture in sheep from terminal breeds in the United States.

Selection for performance in diverse production settings has resulted in variation across sheep breeds worldwide. Although sheep are an important species to the United States, the current genetic relationship among many terminal sire breeds is not well characterized. Suffolk, Hampshire, Shropshire and Oxford (terminal) and Rambouillet (dual purpose) sheep (n = 248) sampled from different flocks were genotyped using the Applied Biosystems Axiom Ovine Genotyping Array (50K), and additional Shropshire sheep (n = 26) using the Illumina Ovine SNP50 BeadChip. Relationships were investigated by calculating observed heterozygosity, inbreeding coefficients, eigenvalues, pairwise Wright's FST estimates and an identity by state matrix. The mean observed heterozygosity for each breed ranged from 0.30 to 0.35 and was consistent with data reported in other US and Australian sheep. Suffolk from two different regions of the United States (Midwest and West) clustered separately in eigenvalue plots and the rectangular cladogram. Further, divergence was detected between Suffolk from different regions with Wright's FST estimate. Shropshire animals showed the greatest divergence from other terminal breeds in this study. Admixture between breeds was examined using admixture, and based on cross-validation estimates, the best fit number of populations (clusters) was K = 6. The greatest admixture was observed within Hampshire, Suffolk, and Shropshire breeds. When plotting eigenvalues, US terminal breeds clustered separately in comparison with sheep from other locations of the world. Understanding the genetic relationships between terminal sire breeds in sheep will inform us about the potential applicability of markers derived in one breed to other breeds based on relatedness.

PHLD Class Proteins: A Family of New Players in the p53 Network.

The Pleckstrin Homology-like Domain (PHLD) class of proteins are multifunctional proteins. The class is comprised of two families of proteins, PHLDA and PHLDB, each with 3 members. All members of the families possess a pleckstrin homology (PH) domain. Though identified nearly 30 years ago, this class of proteins remains understudied with PHLDA family members receiving most of the research attention. Recent studies have also begun to reveal the functions of the PHLDB family proteins in regulation of p53 and AKT signaling pathways important for cancer and metabolism. This review will discuss current research and offer some prospects on the possible roles of both families in cancer and metabolism.

Presence of Newcastle disease viruses of sub-genotypes Vc and VIn in backyard chickens and in apparently healthy wild birds from Mexico in 2017.

Virulent Newcastle disease viruses (NDV) have been present in Mexico since 1946, and recently, multiple outbreaks have been reported in the country. Here, we characterized eleven NDV isolated from apparently healthy wild birds and backyard chickens in three different locations of Jalisco, Mexico in 2017. Total RNA from NDV was reverse-transcribed, and 1285 nucleotides, which includes 3/4 of the fusion gene, was amplified and sequenced using a long-read MinION sequencing method. The sequences were 99.99-100% identical to the corresponding region obtained using the Illumina MiSeq. Phylogenetic analysis using MinION sequences demonstrated that nine virulent NDV from wild birds belonged to sub-genotypes Vc and VIn, and two backyard chicken isolates were of sub-genotype Vc. The sub-genotype Vc viruses had nucleotide sequence identity that ranged from 97.7 to 98% to a virus of the same sub-genotype isolated from a chicken in Mexico in 2010. Three viruses from pigeons had 96.3-98.7% nucleotide identity to sub-genotype VIn pigeon viruses, commonly referred to as pigeon paramyxovirus, isolated in the USA during 2000-2016. This study demonstrates that viruses of sub-genotype Vc are still present in Mexico, and the detection of this sub-genotype in both chickens and wild birds suggests that transmission among these species may represent a biosecurity risk. This is the first detection and complete genome sequencing of genotype VI NDV from Mexico. In addition, the utilization of an optimized long-read sequencing method for rapid virulence and genotype identification using the Oxford nanopore MinION system is demonstrated.

Staphylococcus aureus intramammary challenge in non-lactating mammary glands stimulated to rapidly grow and develop with estradiol and progesterone.

Intramammary infections (IMI) are prevalent in non-lactating dairy cattle and their occurrence during periods of significant mammary growth and development (i.e. pregnant heifers and dry cows) is believed to interfere with growth, development, and subsequent milk production. However, direct study of IMI impacts on non-lactating but developing mammary glands is lacking. The objectives of this study were to (1) define how IMI affected total and differential mammary secretion somatic cell counts in mammary glands stimulated to rapidly grow using estradiol and progesterone, and (2) characterize changes in mammary morphology in response to IMI. Mammary growth was stimulated in 19 non-pregnant, non-lactating cows and 2 quarters of each cow were subsequently infused with either saline (n = 19) or Staphylococcus aureus (n = 19). Mammary secretions were taken daily until mammary tissues were collected at either 5 or 10 days post-challenge. Staph. aureus quarter secretions yielded greater concentrations of somatic cells than saline quarters and contained a greater proportion of neutrophils. Staph. aureus mammary tissues exhibited higher degrees of immune cell infiltration in luminal and intralobular stroma compartments than saline quarters. Infected tissues also contained reduced areas of epithelium and tended to have greater amounts of intralobular stroma. Results indicate that IMI in non-lactating glands that were stimulated to grow, produced immune cell infiltration into mammary tissues and secretions, which was associated with changes in mammary tissue structure. The observed reduction of mammary epithelium indicates that IMI impair mammary development in rapidly growing mammary glands, which may reduce future reduced milk yields.

Muscle thickness correlates to muscle cross-sectional area in the assessment of strength training-induced hypertrophy.

Muscle thickness (MT) measured by ultrasound has been used to estimate cross-sectional area (measured by CT and MRI) at a single time point. We tested whether MT could be used as a valid marker of MRI determined muscle anatomical cross-sectional area (ACSA) and volume changes following resistance training (RT). Nine healthy, young, male volunteers (24 ± 2 y.o., BMI 24.1 ± 2.8 kg/m2 ) had vastus lateralis (VL) muscle volume (VOL) and ACSAmid (at 50% of femur length, FL) assessed by MRI, and VL MT measured by ultrasound at 50% FL. Measurements were taken at baseline and after 12 weeks of isokinetic RT. Differences between baseline and post-training were assessed by Student's paired t test. The relationships between MRI and ultrasound measurements were tested by Pearson's correlation. After RT, MT increased by 7.5 ± 6.1% (P < .001), ACSAmid by 5.2 ± 5% (P < .001), and VOL by 5.0 ± 6.9% (P < .05) (values: means ± SD). Positive correlations were found, at baseline and 12 weeks, between MT and ACSAmid (r = .82, P < .001 and r = .73, P < .001, respectively), and between MT and VOL (r = .76, P < .001 and r = .73, P < .001, respectively). The % change in MT with training was correlated with % change in ACSAmid (r = .69, P < .01), but not % change in VOL (r = .33, P > .05). These data support evidence that MT is a reliable index of muscle ACSAmid and VOL at a single time point. MT changes following RT are associated with parallel changes in muscle ACSAmid but not with the changes in VOL, highlighting the impact of RT on regional hypertrophy.

Hepatitis C virus-related complications are increasing in women veterans: A national cohort study.

There are gender-specific variations in the epidemiology and clinical course of hepatitis C virus (HCV) infection. However, few long-term longitudinal studies have examined trends in the incidence and prevalence of serious liver complications among women compared with men with HCV infection. We used the Veterans Administration Corporate Data Warehouse to identify all veterans with positive HCV viraemia from January 2000 to December 2013. We calculated gender-specific annual incidence and prevalence rates of cirrhosis, decompensated cirrhosis and hepatocellular cancer (HCC) adjusting for age, diabetes, HIV and alcohol use. We also calculated the average annual per cent change (AAPC) for each outcome by gender using piecewise linear regression in the Joinpoint software. We identified 264 409 HCV-infected veterans during 2000-2013, of whom 7162 (2.7%) were women. There were statistically significant increases over time in the incidence rates of cirrhosis, decompensated cirrhosis and HCC for both men and women. The annual-adjusted incidence rates of cirrhosis, decompensated cirrhosis and HCC were higher in men than women for all study years. However, these complications increased at a similar rate in both groups. Specifically, the AAPC for cirrhosis was 13.1 and 15.2, while it was 15.6 and 16.9 for decompensated cirrhosis and 21.0 and 25.3 for HCC in men and women, respectively (all test of parallelism not significant). The results were similar in the prevalence analyses, although AAPCs were slightly smaller for each outcome. In conclusion, we found an ongoing upward trend in the incidence and prevalence of HCV complications in this cohort of HCV-infected women. This increase in cirrhosis complications in women with active HCV infection is similar to those in men. With cure from HCV now becoming a reality, most of the projected burden of HCV is potentially preventable. However, benefits of HCV treatment will need to extend to all patients in order to stem the rising tide of HCV complications.

Patient Versus Physician Valuation of Durable Survival Gains: Implications for Value Framework Assessments.

BACKGROUND: Previous research indicates that patients value therapies that provide durable or tail-of-the-curve survival gains, but it is unclear whether physicians share these preferences. OBJECTIVE: To compare patient and physician preferences for treatments with a positive probability of durable survival gains relative to those with fixed survival gains. METHODS: Patients with advanced stage melanoma or lung cancer and the oncologists who treated these patients were surveyed. The primary end point was the share of respondents who selected a therapy with a variable survival profile, with some patients experiencing long-term durable survival and others experiencing much shorter survival, compared to a therapy with a fixed survival duration. Parameter estimation by sequential testing was applied to calculate the length of nonvarying survival that would make respondents indifferent between that survival and therapy with durable survival. RESULTS: The sample comprised 165 patients (lung = 84, melanoma = 81) and 98 physicians. For lung cancer, 65.5% of patients preferred the therapy with a variable survival profile, compared with 40.8% of physicians (Δ = 24.7%; P < 0.001). For melanoma, these figures were 63.0% for patients and 29.7% for physicians (Δ = 33.3%; P < 0.001). Patients' indifference point implied that therapies with a variable survival profile are preferred unless the treatment with fixed survival had 13.6 months (melanoma) or 11.6 months (lung) longer mean survival; physicians would prescribe treatments with a fixed survival if the treatment had 7.5 months (melanoma) or 1.0 month (lung) shorter survival than the variable survival profile. CONCLUSIONS: Patients place a high value on therapies that provide a chance of durable or "tail-of-the-curve" survival, whereas physicians do not. Value frameworks should incorporate measures of tail-of-the-curve survival gains into their methodologies.

Value-Based Payments and Incentives to Improve Care: A Case Study of Patients with Type 2 Diabetes in Medicare Advantage.

OBJECTIVES: To estimate the impact of increased glycated hemoglobin (A1C) monitoring and treatment intensification for patients with type 2 diabetes (T2D) on quality measures and reimbursement within the Medicare Advantage Star (MA Star) program. METHODS: The primary endpoint was the share of patients with T2D with adequate A1C control (A1C ≤ 9%). We conducted a simulation of how increased A1C monitoring and treatment intensification affected this end point using data from the National Health and Nutrition Examination Survey and clinical trials. Using the estimated changes in measured A1C levels, we calculated corresponding changes in the plan-level A1C quality measure, overall star rating, and reimbursement. RESULTS: At baseline, 24.4% of patients with T2D in the average plan had poor A1C control. The share of plans receiving the highest A1C rating increased from 27% at baseline to 49.5% (increased monitoring), 36.2% (intensification), and 57.1% (joint implementation of both interventions). However, overall star ratings increased for only 3.6%, 1.3%, and 4.8% of plans, respectively, by intervention. Projected per-member per-year rebate increases under the MA Star program were $7.71 (monitoring), $2.66 (intensification), and $10.55 (joint implementation). CONCLUSIONS: The simulation showed that increased monitoring and treatment intensification would improve A1C levels; however, the resulting average increases in reimbursement would be small.

Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.