Correlation of Patient-Reported Social Determinants of Health With Census Tract Measures of Socioeconomic Disadvantage in Patients With GI Cancers in Eastern North Carolina.

PURPOSE: Investigating the impact of social determinants of health (SDOHs) on cancer care in large populations relies on census estimates. Routine clinic SDOH screening provides timely patient-level information which could inform best practices. This study evaluated the correlation between patient-reported SDOH needs and population-level census tract measures. METHODS: This was a retrospective cross-sectional study of a cohort of adult patients with GI malignancy screened for SDOHs such as financial insecurity, transportation, and food insecurity during initial outpatient evaluation at East Carolina University (formerly Vidant) Health Medical Center in Greenville, NC (November 2020-July 2021). Primary outcomes included number and severity of identified SDOH needs and area deprivation index (ADI) and census tract measures for each patient. Spearman rank correlations were calculated among patient-level needs and between patient-level needs and similar census tract measures. RESULTS: Of 112 patients screened, 58.9% self-identified as White (n = 66) and 41.1% as Black (n = 46). A total of 50.5% (n = 54) resided in a rural county. The collective median state ADI rank was 7 (IQR, 5-9). The median household income was $38,125 in US dollars (USD) (IQR, $31,436-$48,934 [USD]). Only 12.5% (n = 14) reported a moderate or severe financial need. Among reported needs, financial need moderately correlated with food insecurity (coefficient, 0.46; P < .001) and transportation (coefficient, 0.45; P < .001). Overall, census tract measures and reported needs poorly correlated. Lack of transportation correlated with percentage of households without a vehicle (coefficient, 0.18; P = .03) and limited access to healthy foods (coefficient, 0.18; P = .04). CONCLUSION: Given the poor correlation between reported and census needs, population-level measures may not accurately predict patient-reported needs. These findings highlight the importance of SDOH screening in the clinical setting to reduce health disparities and identify opportunities to improve care delivery.

Single-step, non-surgical placement of permanent low-profile cystostomy tubes in dogs: 10 cases (2018-2023).

OBJECTIVES: Low-profile cystostomy tubes provide an alternative to conventional cystostomy tubes with external tubing. Previously, these have been placed surgically involving coeliotomy, cystotomy and cystopexy, or have been used as replacement tubes in existing stoma sites. The purpose of this study is to describe a technique for, and the outcomes of, single-step, non-surgical low-profile cystostomy tube placement. MATERIALS AND METHODS: All cases that had single-step, non-surgical placement of low-profile cystotomy tube attempted at the authors' institutions were included in this study. Data, including success rates, outcomes and complications, were extracted from the medical records. RESULTS: Ten client-owned dogs were inclided. Single-step, non-surgical placement was successful in eight out of 10 dogs, with placement being unsuccessful in two thus necessitating coeliotomy. The median duration that low-profile cystostomy tubes were in place was 7.0 months (range 4 days to 38 months). Seven of the eight dogs required replacement of their cystostomy tube. Mean time until first tube replacement was 103 days (range 13 to 363 days). CLINICAL SIGNIFICANCE: Single-step, non-surgical placement of a low-profile cystostomy tube is a viable alternative to surgical placement. Lack of cystopexy does not appear to result in complications. Conversion to coeliotomy might be required if tube placement is not successful with this technique. Complications seen with non-surgical tube placement such as inadvertent tube removal were similar to those previously reported for surgically placed tubes.

Per- and polyfluoroalkyl ether acids in well water and blood serum from private well users residing by a fluorochemical facility near Fayetteville, North Carolina.

BACKGROUND: A fluorochemical facility near Fayetteville, North Carolina, emitted per- and polyfluoroalkyl ether acids (PFEAs), a subgroup of per- and polyfluoroalkyl substances (PFAS), to air. OBJECTIVE: Analyze PFAS in private wells near the facility and in blood from well users to assess relationships between PFEA levels in water and serum. METHODS: In 2019, we recruited private well users into the GenX Exposure Study and collected well water and blood samples. We targeted 26 PFAS (11 PFEAs) in water and 27 PFAS (9 PFEAs) in serum using liquid chromatography-mass spectrometry. We used regression modeling to explore relationships between water and serum PFAS. For the only PFEA detected frequently in water and serum, Nafion byproduct 2, we used generalized estimating equation (GEE) models to assess well water exposure metrics and then adjusted for covariates that may influence Nafion byproduct 2 serum concentrations. RESULTS: We enrolled 153 participants ages 6 and older (median = 56 years) using 84 private wells. Most wells (74%) had ≥6 detectable PFEAs; median ∑PFEAs was 842 ng/L (interquartile range = 197-1760 ng/L). Low molecular weight PFEAs (PMPA, HFPO-DA [GenX], PEPA, PFO2HxA) were frequently detected in well water, had the highest median concentrations, but were not detectable in serum. Nafion byproduct 2 was detected in 73% of wells (median = 14 ng/L) and 56% of serum samples (median = 0.2 ng/mL). Cumulative dose (well concentration × duration at address) was positively associated with Nafion byproduct 2 serum levels and explained the most variability (10%). In the adjusted model, cumulative dose was associated with higher Nafion byproduct 2 serum levels while time outside the home was associated with lower levels. IMPACT: PFAS are a large class of synthetic, fluorinated chemicals. Fluorochemical facilities are important sources of environmental PFAS contamination globally. The fluorochemical industry is producing derivatives of perfluoroalkyl acids, including per- and polyfluoroalkyl ether acids (PFEAs). PFEAs have been detected in various environmental samples but information on PFEA-exposed populations is limited. While serum biomonitoring is often used for PFAS exposure assessment, serum biomarkers were not good measures of long-term exposure to low molecular weight PFEAs in a private well community. Environmental measurements and other approaches besides serum monitoring will be needed to better characterize PFEA exposure.

Long-Term Clinical Outcome of Abdomino-Thoracic Lymphatic Interventions of Traumatic and Non-Traumatic Lymphatic Leakage in Adults.

The aim of this study was to retrospectively evaluate the long-term results of lymphatic interventions in adults with abdomino-thoracic lymphatic pathologies. Management of abdomino-thoracic chylous effusions in adults undergoing X-ray-lymphangiography with or without lymph-vessel embolization (LVE) from 2010-2018 was reviewed. Patients underwent lymphangiography alone when imaging showed normal findings or lymphatic obstruction without leakage or reflux; otherwise, LVE was performed (leakage, reflux, obstruction with leakage or reflux, lymphatic masses). Technical and clinical success, complications, and long-term outcomes were assessed. 78 patients (47 male, median age 56.3 years) were treated for chylous effusions (60.3% traumatic, 39.7% non-traumatic). Lymphangiography showed leakage (48.7%), reflux (14.1%), obstruction (28.2%), lymphatic masses (5.1%), and normal findings (3.8%). Embolization was performed in 49/78 (62.8%) cases. Overall, treatment was clinically successful in 74.4% (mean follow-up of 28 months), with significant differences between LVE and lymphangiography (91.8% vs. 44.8%; p < 0.001), traumatic and non-traumatic etiologies (89.4% vs. 51.6%; p < 0.001), and leakage locations (p = 0.003). The clinical success of LVE did not differ between leakage etiologies or locations. Complications occurred in 5 patients (2/5 needed treatment). Patients survived significantly longer after successful treatment (2679 vs. 927 days; p = 0.044) and without malignancy (3214 vs. 1550 days; p = 0.043). Lymphatic interventions are safe and effective. LVE should be attempted whenever feasible, as success is high (>90%). Successful intervention has a positive effect on patient survival.

Reduced Survival Outcome After Receiving a New Cancer Diagnosis in the Emergency Department: Findings from a Hospital Network in Rural Eastern North Carolina.

PURPOSE: Patients whose cancer was found during an Emergency Department (ED) visit often present at later stages when survival outcomes are worse. Limited research has characterized the survival experience of cancer patients who receive their diagnosis through the ED versus those who do not. METHODS: A retrospective cohort study identified all patients presenting to the ED between 2014 and 2015 in a rural, regional hospital system with a visit or resulting admission associated with an oncologic ICD-9 code. The chart was abstracted to determine a new cancer diagnosis versus an existing case. Cox proportional hazards (HR) estimated survival time. Patient and cancer characteristics were compared between those who were newly diagnosed through the ED and patients who were not. FINDINGS: Thirty-nine percent of patients in our sample received their new cancer diagnosis as a result of an ED visit. The median survival was lower in cancer cases diagnosed through the ED (13 vs. 39 months, P < .001), men (20 vs. 32 months, P < .001), and patients aged ≥ 65 (22 months vs. 32 months, P < .001). Factors associated with lower survival were having a type of cancer location other than breast (HR = 1.96; P < .001), followed by being newly diagnosed with cancer through the ED (HR = 1.71; P < .001), and stage IV at diagnosis (HR = 1.70; P < .001). CONCLUSIONS: Patients who received a new cancer diagnosis through the ED and required subsequent hospitalization had shorter overall survival and presented with advanced disease. Future research should address socioeconomic factors that may influence these patterns of cancer presentation.

Towards an Improved Understanding of the Effects of Elevated Progesterone Levels on Human Endometrial Receptivity and Oocyte/Embryo Quality during Assisted Reproductive Technologies.

Ovarian stimulation is an indispensable part of IVF and is employed to produce multiple ovarian follicles. In women who undergo ovarian stimulation with gonadotropins, supraphysiological levels of estradiol, as well as a premature rise in progesterone levels, can be seen on the day of hCG administration. These alterations in hormone levels are associated with reduced embryo implantation and pregnancy rates in IVF cycles with a fresh embryo transfer. This article aims to improve the reader's understanding of the effects of elevated progesterone levels on human endometrial receptivity and oocyte/embryo quality. Based on current clinical data, it appears that the premature rise in progesterone levels exerts minimal or no effects on oocyte/embryo quality, while advancing the histological development of the secretory endometrium and displacing the window of implantation. These clinical findings strongly suggest that reduced implantation and pregnancy rates are the result of a negatively affected endometrium rather than poor oocyte/embryo quality. Understanding the potential negative impact of elevated progesterone levels on the endometrium is crucial to improving implantation rates following a fresh embryo transfer. Clinical studies conducted over the past three decades, many of which have been reviewed here, have greatly advanced our knowledge in this important area.

Prostatitis and prostatic abscessation in dogs: retrospective study of 82 cases.

OBJECTIVES: To describe clinical signs, diagnostics, treatments and outcomes of prostatitis and prostatic abscesses of dogs in a referral population. ANIMALS: Eighty-two dogs diagnosed with prostatitis and/or prostatic abscesses from three referral hospitals. PROCEDURES: Retrospective case series. RESULTS: A total of 82 dogs were included, and the median age was nine years. Acute prostatitis was diagnosed in 63% of cases, chronic prostatitis in 37% of cases and 40% of cases had prostatic abscessation. Prostatomegaly was the most common ultrasonographic finding. Mineralisation was identified in 20% of cases. The results of urine and prostatic bacterial culture were concordant in only 50% of cases. Antimicrobial resistance was encountered commonly, with 29% of cultures resistant to one antimicrobial and 52% resistant to two or more antimicrobials. Abscesses were treated with either antimicrobials alone, ultrasound-guided needle drainage or surgical drainage. CONCLUSIONS AND CLINICAL RELEVANCE: With antimicrobial treatment and castration, the prognosis for canine prostatitis appears good. Prostatic abscessation is commonly encountered and does not appear to infer a worse prognosis and antimicrobials alone, ultrasound-guided needle drainage and surgical drainage all appear to be reasonable treatment options. Antimicrobial resistance is commonly encountered, and the results of urine culture and susceptibility testing are frequently discordant with those from samples from the prostate. Sampling of the prostate is required to confirm a diagnosis and exclude other pathologies such as neoplasia, particularly as mineralisation is seen in a reasonable number of cases of dogs with prostatitis.

Chronic Daily House Dust Mite Exposure in Mice is an Effective Model to Quantify the Effect of Pharmacologic Agents on Discrete Stages of Artery Remodeling in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogenous and incurable disease marked by varying degrees of pulmonary vascular remodeling. This vascular remodeling, which includes thickening of the smooth muscle layer (an early finding) and formation of occlusive neointimal lesions (a late finding) in the pulmonary arteries, is a major driver of morbidity and mortality in PH. Available PH therapies consist of vasodilators that do not specifically target lesion formation or expansion and neither prevent progression nor reverse disease. This paucity of curative treatments highlights the need for new drug discovery targeting crucial steps of artery remodeling in PH. The cell dynamics and molecular signals driving neointimal lesion formation have been difficult to elucidate as classic mouse models of PH do not develop neointima. Here, we detail the methods to generate a robust and non-genetic mouse model of PH with medial thickening and neointimal lesion formation in the pulmonary arteries, through chronic exposure to an inflammatory stimulus-house dust mite (HDM). This model rapidly generates human-like pulmonary arterial lesions following a reproducible time course, allowing scrutiny of the cellular and molecular mechanisms controlling each stage of artery remodeling. Further, we outline optimal tissue handling, sectioning, and staining methodologies for detailed quantitative analysis of artery medial thickening and neointimal lesion formation and expansion. Finally, we present a method for staged pharmacologic intervention to identify molecules and pathways required at each step of the pulmonary arterial remodeling process. The advantages of this mouse model of PH over currently available animal models are five-fold. (i) It allows the use of the full range of genetic and single cell tools available in mice to manipulate and study the process of vascular remodeling seen in human disease, including the formation of neointimal lesions in a controlled and cell specific manner. (ii) The vascular lesions develop in a stereotyped manner with predictable timing, allowing for pharmacologic manipulation at discrete stages of vessel remodeling. (iii) It is rapid, with development of PH and vascular remodeling in a timeframe of two to eight weeks. (iv) It uses simple techniques and requires neither surgery, unusual equipment, or extensive personnel training. (v) The staining and quantitation methodologies we present are a significant improvement over those currently in use in the field. We hope that dissemination of this model and the associated detailed methods will speed up the development of novel and more effective PH therapeutics. Graphic abstract: Chronic perivascular inflammation induces medial thickening and neointima formation in pulmonary arteries, following a stereotyped time course, and allowing staged pharmacologic intervention during specific remodeling events, as well as quantitative assessment of vascular changes.

Iron and sulfate reduction structure microbial communities in (sub-)Antarctic sediments.

Permanently cold marine sediments are heavily influenced by increased input of iron as a result of accelerated glacial melt, weathering, and erosion. The impact of such environmental changes on microbial communities in coastal sediments is poorly understood. We investigated geochemical parameters that shape microbial community compositions in anoxic surface sediments of four geochemically differing sites (Annenkov Trough, Church Trough, Cumberland Bay, Drygalski Trough) around South Georgia, Southern Ocean. Sulfate reduction prevails in Church Trough and iron reduction at the other sites, correlating with differing local microbial communities. Within the order Desulfuromonadales, the family Sva1033, not previously recognized for being capable of dissimilatory iron reduction, was detected at rather high relative abundances (up to 5%) while other members of Desulfuromonadales were less abundant (<0.6%). We propose that Sva1033 is capable of performing dissimilatory iron reduction in sediment incubations based on RNA stable isotope probing. Sulfate reducers, who maintain a high relative abundance of up to 30% of bacterial 16S rRNA genes at the iron reduction sites, were also active during iron reduction in the incubations. Thus, concurrent sulfate reduction is possibly masked by cryptic sulfur cycling, i.e., reoxidation or precipitation of produced sulfide at a small or undetectable pool size. Our results show the importance of iron and sulfate reduction, indicated by ferrous iron and sulfide, as processes that shape microbial communities and provide evidence for one of Sva1033's metabolic capabilities in permanently cold marine sediments.

Macroalgae degradation promotes microbial iron reduction via electron shuttling in coastal Antarctic sediments.

Colonization of newly ice-free areas by marine benthic organisms intensifies burial of macroalgae detritus in Potter Cove coastal surface sediments (Western Antarctic Peninsula). Thus, fresh and labile macroalgal detritus serves as primary organic matter (OM) source for microbial degradation. Here, we investigated the effects on post-depositional microbial iron reduction in Potter Cove using sediment incubations amended with pulverized macroalgal detritus as OM source, acetate as primary product of OM degradation and lepidocrocite as reactive iron oxide to mimic in situ conditions. Humic substances analogue anthraquinone-2,6-disulfonic acid (AQDS) was also added to some treatments to simulate potential for electron shuttling. Microbial iron reduction was promoted by macroalgae and further enhanced by up to 30-folds with AQDS. Notably, while acetate amendment alone did not stimulate iron reduction, adding macroalgae alone did. Acetate, formate, lactate, butyrate and propionate were detected as fermentation products from macroalgae degradation. By combining 16S rRNA gene sequencing and RNA stable isotope probing, we reconstructed the potential microbial food chain from macroalgae degraders to iron reducers. Psychromonas, Marinifilum, Moritella, and Colwellia were detected as potential fermenters of macroalgae and fermentation products such as lactate. Members of class deltaproteobacteria including Sva1033, Desulfuromonas, and Desulfuromusa together with Arcobacter (former phylum Epsilonbacteraeota, now Campylobacterota) acted as dissimilatory iron reducers. Our findings demonstrate that increasing burial of macroalgal detritus in an Antarctic fjord affected by glacier retreat intensifies early diagenetic processes such as iron reduction. Under scenarios of global warming, the active microbial populations identified above will expand their environmental function, facilitate OM remineralisation, and contribute to an increased release of iron and CO2 from sediments. Such indirect consequences of glacial retreat are often overlooked but might, on a regional scale, be relevant for the assessment of future nutrient and carbon fluxes.

A Genome-wide Association Study Identifies SERPINB10, CRLF3, STX7, LAMP3, IFNG-AS1, and KRT80 As Risk Loci Contributing to Cutaneous Leishmaniasis in Brazil.

BACKGROUND: Our goal was to identify genetic risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. METHODS: Genotyping 2066 CL cases and 2046 controls using Illumina HumanCoreExomeBeadChips provided data for 4 498 586 imputed single-nucleotide variants (SNVs). A genome-wide association study (GWAS) using linear mixed models took account of genetic diversity/ethnicity/admixture. Post-GWAS positional, expression quantitative trait locus (eQTL) and chromatin interaction mapping was performed in Functional Mapping and Annotation (FUMA). Transcriptional data were compared between lesions and normal skin, and cytokines measured using flow cytometry and Bioplex assay. RESULTS: Positional mapping identified 32 genomic loci associated with CL, none achieving genome-wide significance (P < 5 × 10-8). Lead SNVs at 23 loci occurred at protein coding or noncoding RNA genes, 15 with eQTLs for functionally relevant cells/tissues and/or showing differential expression in lesions. Of these, the 6 most plausible genetic risk loci were SERPINB10 (Pimputed_1000G = 2.67 × 10-6), CRLF3 (Pimputed_1000G = 5.12 × 10-6), STX7 (Pimputed_1000G = 6.06 × 10-6), KRT80 (Pimputed_1000G = 6.58 × 10-6), LAMP3 (Pimputed_1000G = 6.54 × 10-6), and IFNG-AS1 (Pimputed_1000G = 1.32 × 10-5). LAMP3 (Padjusted = 9.25 × 10-12; +6-fold), STX7 (Padjusted = 7.62 × 10-3; +1.3-fold), and CRLF3 (Padjusted = 9.19 × 10-9; +1.97-fold) were expressed more highly in CL biopsies compared to normal skin; KRT80 (Padjusted = 3.07 × 10-8; -3-fold) was lower. Multiple cis-eQTLs across SERPINB10 mapped to chromatin interaction regions of transcriptional/enhancer activity in neutrophils, monocytes, B cells, and hematopoietic stem cells. Those at IFNG-AS1 mapped to transcriptional/enhancer regions in T, natural killer, and B cells. The percentage of peripheral blood CD3+ T cells making antigen-specific interferon-γ differed significantly by IFNG-AS1 genotype. CONCLUSIONS: This first GWAS for CL identified multiple genetic risk loci including a novel lead to understanding CL pathogenesis through regulation of interferon-γ by IFNG antisense RNA 1.

Evolution of the Surgical Residency System in Switzerland: An In-Depth Analysis Over 15 Years.

BACKGROUND: The landscape of surgical training has been subject to many changes over the past 15 years. This study examines resident satisfaction, determinants of satisfaction, demographics, working hours and the teaching rate of common operations in a longitudinal fashion with the aim to identify trends, shortcomings and possible ways to improve the current training system. METHODS: The Swiss Medical Association administers an annual survey to all Swiss residents to evaluate the quality of postgraduate medical training (yearly respondents: 687-825, response rate: 68-72%). Teaching rates for general surgical procedures were obtained from the Swiss association for quality management in surgery. RESULTS: During the study period (2003-2018), the number of surgical residents (408-655 (+61%)) and graduates in general surgery per year (42-63 (+50%)) increased disproportionately to the Swiss population. While the 52 working hour restriction was introduced in 2005 reported average weekly working hours did not decline (59.9-58.4 h (-3%)). Workplace satisfaction (6 being highest) rose from 4.3 to 4.6 (+7%). Working climate and leadership culture were the main determinants for resident satisfaction. The proportion of taught basic surgical procedures fell from 24.6 to 18.9% (-23%). CONCLUSIONS: The number of residents and graduates in general surgery has risen markedly. At the same time, the proportion of taught operations is diminishing. Despite the introduction of working hour restrictions, the self-reported hours never reached the limit. The low teaching rate combined with the increasing resident number represents a major challenge to the maintenance of the current training quality.

FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease.

On May 24, 2019, the Food and Drug Administration approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and pediatric patients 12 years and older. Approval was based on Study INCB 18424-271 (REACH-1; NCT02953678), an open-label, single-arm, multicenter trial that included 49 patients with grades 2-4 SR-aGVHD occurring after allogeneic hematopoietic stem cell transplantation. Ruxolitinib was administered at 5 mg twice daily, with dose increases to 10 mg twice daily permitted after 3 days in the absence of toxicity. The Day-28 overall response rate was 57.1% (95% confidence interval [CI]: 42.2-71.2). The median duration of response was 0.5 months (95% CI: 0.3-2.7), and the median time from Day-28 response to either death or need for new therapy for acute GVHD was 5.7 months (95% CI: 2.2 to not estimable). Common adverse reactions included anemia, thrombocytopenia, neutropenia, infections, edema, bleeding, and elevated transaminases. Ruxolitinib is the first drug approved for treatment of SR-aGVHD. IMPLICATIONS FOR PRACTICE: Ruxolitinib is the first Food and Drug Administration-approved treatment for steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. Its approval provides a treatment option for the 60% of those patients who do not respond to steroid therapy.

Defining a cohort of oligometastatic nasopharyngeal carcinoma patients with improved clinical outcomes.

OBJECTIVES: To compare the clinical outcomes of oligometastatic versus widely metastatic NPC patients. MATERIALS AND METHODS: Retrospective review of 157 patients with metastatic NPC at a tertiary hospital was performed. Multivariate analysis was carried out to compare the overall and progression-free survival (OS and PFS) of these two cohorts of NPC patients. The number of organ involvement and discrete metastatic lesions associated with improved OS and PFS were ascertained. RESULTS: Patients with oligometastatic NPC (single organ, less than six discrete metastatic lesions) had a better median OS than patients with widespread metastasis (24.8 versus 12.8 months, P < .001). Similarly, the median PFS of oligometastatic NPC was better than that of polymetastatic NPC (11.7 versus 7.3 months, P < .001). CONCLUSION: Single organ disease with less than six discrete lesions is a good indicator of limited metastatic load in NPC, and is associated with improved survival.

The effect of certolizumab drug concentration and anti-drug antibodies on TNF neutralisation.

OBJECTIVES: Tumour necrosis factor (TNF) inhibitors like certolizumab, elicit an immunogenic response leading to the formation of anti-drug antibodies (ADAs). We sought to mechanistically investigate the relationship between certolizumab concentrations, ADAs, and the effective TNF neutralising capacity in sera of rheumatoid arthritis (RA) patients. TNF neutralising capacity of certolizumab was compared to the neutralising capacity of adalimumab. METHODS: Serum samples were collected from 40 consecutive certolizumab-treated RA patients at baseline and 4, 16, 28 and 52 weeks after treatment initiation [Dutch Trial Register NTR (Nederlands Trial Register) Trial NL2824 no. 2965]. Certolizumab concentration and ADA titre were measured with a certolizumab bridging enzyme-linked immunosorbent assay (ELISA) and a drug-tolerant radioimmunoassay (RIA), respectively. TNF neutralisation by certolizumab and adalimumab, in presence or absence of ADAs, was analysed with the TNF-sensitive WEHI bioassay. RESULTS: Despite a high incidence of ADAs during one year of follow-up (65%; 26/40 patients), certolizumab levels of >10 µg/ml were measured in most patients. The capacity for TNF neutralisation highly correlated with certolizumab serum concentration, whereas no association with ADAs was observed. Similar results were obtained for adalimumab. The relative in vitro neutralising potency was higher for certolizumab compared to adalimumab. CONCLUSIONS: Anti-certolizumab antibodies were detected in a large proportion of patients, but in most cases where ADAs were detected, certolizumab was also present in high concentrations, directly correlating with in vitro neutralising capacity. These results indicate that measurement of certolizumab drug levels, rather than ADAs, have direct clinical significance.

The effect of methotrexate on tumour necrosis factor concentrations in etanercept-treated rheumatoid arthritis patients.

OBJECTIVES: Recently, we demonstrated that early low concentrations of circulating, adalimumab-bound TNF in RA patients treated with adalimumab was associated with future anti-drug antibody formation. Furthermore, low TNF was associated with less frequent baseline MTX use. This is remarkable, because of the anti-inflammatory effects of MTX and a potential inhibiting effect on cytokine production. We hypothesized an indirect effect of non-MTX use on low TNF concentrations via immunogenicity. To investigate the effect of MTX on TNF concentrations independent of anti-drug antibody formation, we measured TNF in RA patients treated with etanercept, a drug with low immunogenicity. METHODS: TNF was quantified in 186 consecutive etanercept-treated RA patients at baseline and at weeks 4, 16 and 28. The dynamics of TNF during etanercept treatment were compared with dynamics recently published for adalimumab. RESULTS: We demonstrated that TNF concentrations at week 4 did not associate with baseline MTX or remission after 28 weeks. Furthermore, median (interquartile range) TNF increased from <112 (<112-<112) pg/ml at baseline to 548 (344-688) pg/ml at week 4 and remained stable at week 16 and 28 [598 (442-756) and 568 (444-755) pg/ml, respectively]. CONCLUSION: Circulating TNF did not associate with MTX usage in etanercept-treated patients. This implies that MTX does not have a direct effect on TNF concentrations in circulation and that the association between early low TNF and non-use of MTX for adalimumab is thus most likely due to anti-drug antibody formation.

Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay.

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a "drug-tolerant" assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of >50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.

Exploring behaviors, treatment beliefs, and barriers to oral chemotherapy adherence among adult leukemia patients in a rural outpatient setting.

OBJECTIVE: Adherence to oral chemotherapy is essential for patients with chronic myeloid leukemia (CML) and multiple myeloma (MM) to remain in remission. Few studies have used a Likert-type scale to measure medication adherence in CML and MM patients. We applied a validated treatment adherence tool, the ASK-12 (Adherence Starts with Knowledge®) survey, which assessed inconvenience and forgetfulness, treatment beliefs, and medication-taking behaviors recorded on a five-point Likert-type scale at two visits. RESULTS: A medication adherence survey was administered to 42 newly diagnosed or pre-existing CML or MM patients at two outpatient oncology clinics affiliated with an academic medical center in rural eastern North Carolina. Thirty-one patients completed surveys at visit 1 and visit 2 (median 4.5 months apart). Most patients were treated for MM (65%), were non-Hispanic black (68%) and female (58%). Within subscales, mean adherence scores decreased between visits, signaling better adherence. Overall, visit scores were correlated (0.63, p = 0.001). Forgetting to take medication sometimes was the most common reason for non-adherence. Medication costs were not a barrier for MM patients. Greater patient-provider informed decision-making was identified as an opportunity for quality improvement among CML patients. The ASK-12 survey provided a strategy to obtain robust information on medication adherence.

Residency Training in Robotic General Surgery: A Survey of Program Directors.

OBJECTIVE: Robotic surgery continues to expand in minimally invasive surgery; however, the literature is insufficient to understand the current training process for general surgery residents. Therefore, the objectives of this study were to identify the current approach to and perspectives on robotic surgery training. METHODS: An electronic survey was distributed to general surgery program directors identified by the Accreditation Council for Graduate Medical Education website. Multiple choice and open-ended questions regarding current practices and opinions on robotic surgery training in general surgery residency programs were used. RESULTS: 20 program directors were surveyed, a majority being from medium-sized programs (4-7 graduating residents per year). Most respondents (73.68%) had a formal robotic surgery curriculum at their institution, with 63.16% incorporating simulation training. Approximately half of the respondents believe that more time should be dedicated to robotic surgery training (52.63%), with simulation training prior to console use (84.21%). About two-thirds of the respondents (63.16%) believe that a formal robotic surgery curriculum should be established as a part of general surgery residency, with more than half believing that exposure should occur in postgraduate year one (55%). CONCLUSION: A formal robotics curriculum with simulation training and early surgical exposure for general surgery residents should be given consideration in surgical residency training.

Acute Kidney Injury in Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation: Incidence, Risk Factors, and Outcomes.

Acute kidney injury (AKI) is a common adverse event after hematopoietic cell transplantation (HCT). AKI is associated with early death or chronic kidney disease among transplant survivors. However, large-scale pediatric studies based on standardized criteria are lacking. We performed a retrospective analysis of 1057 pediatric patients who received allogeneic HCT to evaluate the incidence and risk factors of AKI according to AKI Network criteria within the first 100 days of HCT. We also determined the effect of AKI on patient survival. The 100-day cumulative incidences of all stages of AKI, stage 3 AKI, and AKI requiring renal replacement therapy (RRT) were 68.2% ± 1.4%, 25.0% ± 1.3%, and 7.6% ± .8%, respectively. Overall survival at 1 year was not different between patients without AKI and those with stage 1 or 2 AKI (66.1% versus 73.4% versus 63.9%, respectively) but was significantly different between patients without AKI and patients with stage 3 AKI with or without RRT requirement (66.1% versus 47.3% versus 7.5%, respectively; P < .001). Age, year of transplantation, donor type, sinusoidal obstruction syndrome (SOS), and acute graft-versus-host disease (GVHD) were independent risk factors for stages 1 through 3 AKI. Age, donor, conditioning regimen, number of HCTs, SOS, and acute GVHD were independent risk factors for AKI requiring RRT. Our study revealed that AKI was a prevalent adverse event, and severe stage 3 AKI, which was associated with reduced survival, was common after pediatric allogeneic HCT. All patients receiving allogeneic HCT, especially those with multiple risk factors, require careful renal monitoring according to standardized criteria to minimize nephrotoxic insults.