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Background: Occupational burnout is a major concern for personal well-being and patient care. We examined burnout among primary care providers (PCPs), medical residents, behavioral health providers (BHPs), nurses, and other clinical and nonclinical primary care team members. Methods: This was a cross-sectional study, nested within a larger randomized trial. Participants completed a validated 9-item burnout measure with 3 domains: depersonalization, emotional exhaustion, and personal accomplishment. Multivariable multilevel linear regression with a random intercept for each practice was used to determine mean differences in burnout across professional roles. Results: Overall burnout rates varied by professional role: PCPs 70%, medical residents 89%, BHPs 59%, nurses 66%, other clinicians 68%, and nonclinical professionals 70%. Compared with nonclinical professionals, residents experienced more burnout in more domains, followed by PCPs. PCPs, residents, and nurses reported significantly worse depersonalization and exhaustion scores. Nonclinical professionals had worse accomplishment scores than all clinical professionals except for residents. This study revealed moderate-to-high levels of burnout among primary care professionals. Discussion: Clinicians may be experiencing aspects of burnout more intensely than their nonclinical colleagues, and this may be most true for residents and PCPs. Based on these variations, interventions to mitigate burnout may need to be tailored by professional role.

To evaluate the characteristics of FACBC PET/CT in detecting recurrent prostate cancer after radiation or prostatectomy. The secondary aim was to determine the impact of FACBC PET/CT on radiation treatment recommendations in men with biochemical recurrence postprostatectomy.This is a single center retrospective study of men who underwent an FACBC PET/CT for rising PSA after definitive prostate cancer therapy. Detection rates in men with recurrence following any definitive treatment were compared at different PSA levels and anatomical sites. Radiotherapy treatment recommendations for patients postprostatectomy based on conventional imaging findings were compared to recommendations based on FACBC PET/CT findings.A total of 103 men underwent imaging with FACBC PET/CT. 74.8% (77) had lesions consistent with sites of prostate cancer recurrence. At PSA thresholds of1, 1-2, and2 ng/mL lesions were detected in 35.5%, 63.6%, and 95.2% of patients respectively (P.001). The most common site of recurrence was outside of the pelvis (37). Detection of extraprostatic or extrapelvic recurrence was observed in 45.5% of men in the PSA tertile1ng/mL. FACBC PET/CT results led to changes to the recommended radiotherapy treatment plan in 44.1% (15/34) of men with recurrence following radical prostatectomy.FACBC PET/CT demonstrated increased detection of recurrent prostate cancer with increasing PSA levels. Most recurrences were found outside the pelvis. Results of FACBC PET/CT changed radiotherapy management decisions in men treated with prostatectomy, supporting its use in localizing sites of disease recurrence in men with prostate cancer.

Gastrojejunal tubes are important feeding devices for children with gastro-esophageal reflux, allowing medication and feeding into the small bowel, and allowing gastric venting to prevent reflux. As with many medical devices, there are multiple manufacturers and designs, including balloon-retained tubes and disc-retained tubes. This study evaluated the cost difference between these two types of gastrojejunal tube. We conducted a 3.5-year retrospective cost evaluation for all pediatric patients undergoing an insertion or change of gastrojejunal tube using a bottom-up micro-costing analysis. We calculated days between encounters and a subsequent cost per day for each patient. A total of 187 children and adolescents were included, with an average age of 9.2 years. They underwent a total of 1,240 encounters, an average of 6.6 encounters per patient during the study period. A total of 82% of these encounters were related to balloon-retained tubes and 18% to disc-retained tubes. The most common reason for an encounter was a routine change (57%), with mechanical complications accounting for 31%. Disc-retained tubes had a longer period between encounters (117.5 days) than balloon-retained tubes (95 days; P=0.038). However, disc-retained tubes cost 6.9 British pound sterling (GBP) per day, which was significantly higher than balloon-retained tubes at 5.2 GBP per day (P

Introduction The natural history of T1b (4-7 cm) or T2a (> 7-10 cm) kidney cancers managed with observation is not well-understood. The aim of our study was to determine if the addition of histologic subtype to a predictive model of overall survival (OS) that includes covariates for competing risks in observed, biopsy-proven, T1b and T2a renal cell carcinomas (RCCs) improves the model’s performance. Materials and Methods We queried the National Cancer Database for patients with biopsy-proven stage T1b or T2a RCC and managed nonoperatively between 2004 and 2015. OS was estimated by Kaplan-Meier curves based on histologic subtype. The concordance index (c-index) from a Cox proportional hazards model was used to estimate the extent to which histologic subtypes predict survival for each stage when included in a model along with competing risks of age, gender, race/ethnicity, insurance status, area-level socioeconomic indicators, Charlson-Deyo index, and tumor grade. Results A total of 937 patients (754 with T1b and 185 with T2a) with biopsy-proven RCC were identified. Kaplan-Meier analysis suggested differences in OS by histologic subtype where sarcomatoid, followed by clear cell, papillary, and chromophobe, had the highest mortality risk at 1, 3, and 5 years. However, there was marginal improvement in the multivariable model of OS using competing risks and histology (c-index, 0.64 and 0.697) compared with competing risks alone (c-index, 0.631 and 0.671) for T1b and T2a RCCs, respectively. Conclusions In patients with T1b or T2a RCC managed with observation, incorporation of histologic subtype into a risk-stratification model to determine prognostic OS did not improve modeling of OS compared with variables representing competing risks. Histologic subtype of observed T1b and T2a RCC appears to have prognostic OS value when not considering competing risks. These findings may impact the usefulness of renal biopsy to inform decision-making when managing patients with T1b and T2a renal tumors with observation.

Objectives Chronic inflammation is independently associated with the incidence and progression of chronic disease. Exercise has been found to reduce chronic inflammation, however the role of exercise intensity (work rate) is unknown. This review aimed to determine the pooled effect of higher- compared to lower-intensity aerobic and resistance exercise on chronic inflammation in adults. Design Systematic review and meta-analysis. Methods Five electronic databases were searched. Intervention trials that assessed the effect of ≥2 different exercise intensities on peripheral markers of chronic inflammation [c-reactive protein (CRP), interleukin (IL)-6, tumour necrosis factor (TNF)-α and IL-10] in adults were included. Random-effect meta-analyses were conducted to calculate the mean difference in change scores between groups [effect size (ES)]. Sub-group analyses were performed to explore the influence of age, chronic disease, body mass index and intervention duration on inflammation heterogeneity. Results Of 3952 studies identified, 27 were included. There were no significant effects of exercise intensity on IL-6 (ES=-0.039, 95%CI=-0.353–0.275; p = 0.806), TNF-α (ES = 0.296, 95%CI=-0.184–0.777; p = 0.227) and IL-10 (ES = 0.007, 95%CI=-0.904–0.919; p = 0.987). A significant pooled ES was observed for higher- versus lower-intensity exercise on CRP concentrations, in studies of middle-aged adults (ES=-0.412, 95%CI=-0.821– -0.004, p = 0.048) or interventions >9 weeks in duration (ES=-0.520, 95%CI=-0.882–-0.159, p = 0.005). Conclusions Exercise intensity did not influence chronic inflammatory response. However, sub-analyses suggest that higher-intensity training may be more efficacious than lower-intensity for middle-aged adults, or when longer duration interventions are implemented (>9 weeks), in the most commonly-reported analyte (CRP).

To determine if apparent diffusion coefficients (ADC) can discriminate between posterior fossa brain tumours on a multicentre basis. A total of 124 paediatric patients with posterior fossa tumours (including 55 Medulloblastomas, 36 Pilocytic Astrocytomas and 26 Ependymomas) were scanned using diffusion weighted imaging across 12 different hospitals using a total of 18 different scanners. Apparent diffusion coefficient maps were produced and histogram data was extracted from tumour regions of interest. Total histograms and histogram metrics (mean, variance, skew, kurtosis and 10th, 20th and 50th quantiles) were used as data input for classifiers with accuracy determined by tenfold cross validation. Mean ADC values from the tumour regions of interest differed between tumour types, (ANOVA P −3 mm2 s−1 with sensitivity 80.8% and specificity 80.0%. Overall classification for the ADC histogram metrics were 85% using Naïve Bayes and 84% for Random Forest classifiers. The most commonly occurring posterior fossa paediatric brain tumours can be classified using Apparent Diffusion Coefficient histogram values to a high accuracy on a multicentre basis.

Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7–14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile. Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.

Cellular dedifferentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anticancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in ARID1A represent one of the most frequent molecular alterations in human cancers. ARID1A mutations occur in approximately 10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here, we demonstrate that loss of ARID1A promotes an epithelial–mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo. Although loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibit potential as a biomarker for patients with PDAC who may benefit by HSP90-targeting drugs treatment. Significance: This study identifies ARID1A loss as a promising biomarker for the identification of PDAC tumors that are potentially responsive to treatment with proteotoxic agents.

Background and Purpose: The factors associated with recovery of language domains after stroke remain uncertain. We described recovery of overall-language-ability, auditory comprehension, naming, and functional-communication across participants’ age, sex, and aphasia chronicity in a large, multilingual, international aphasia dataset. Methods: Individual participant data meta-analysis of systematically sourced aphasia datasets described overall-language ability using the Western Aphasia Battery Aphasia-Quotient; auditory comprehension by Aachen Aphasia Test (AAT) Token Test; naming by Boston Naming Test and functional-communication by AAT Spontaneous-Speech Communication subscale. Multivariable analyses regressed absolute score-changes from baseline across language domains onto covariates identified a priori in randomized controlled trials and all study types. Change-from-baseline scores were presented as estimates of means and 95% CIs. Heterogeneity was described using relative variance. Risk of bias was considered at dataset and meta-analysis level. Results: Assessments at baseline (median=43.6 weeks poststroke; interquartile range [4–165.1]) and first-follow-up (median=10 weeks from baseline; interquartile range [3–26]) were available for n=943 on overall-language ability, n=1056 on auditory comprehension, n=791 on naming and n=974 on functional-communication. Younger age ( Conclusions: Earlier intervention for poststroke aphasia was crucial to maximize language recovery across a range of language domains, although recovery continued to be observed to a lesser extent beyond 6 months poststroke.

Few studies to date have examined the utility of the Personality Assessment Inventory (PAI) in predicting aggressive behaviour among those deemed ‘not criminally responsible on account of a mental ...

PURPOSE In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473 ). METHODS We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B). RESULTS Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed. CONCLUSION In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.

Immune thrombocytopenia (ITP) is a rare paraneoplastic syndrome of solid tumor malignancies. In previously described cases of renal cell carcinoma (RCC) associated with secondary ITP, treatment has consisted of nephrectomy, splenectomy, and corticosteroids. Here, we describe a case of metastatic RCC presenting with a right ventricular mass and subsequent development of secondary ITP. The clinical course was complicated by recurrent severe thrombocytopenia despite treatment with corticosteroids, rituximab, and thrombopoietin receptor agonists, precluding cancer-directed therapy and anticoagulation. Further study is needed to determine the optimal management strategy for malignancy-associated ITP.

Objective:To explore explicit beliefs about the controllability of obesity and the internalisation of negative weight-related stereotypes among public health trainees.Design:Cross-sectional online survey assessing explicit beliefs about the controllability of obesity using the Beliefs About Obese Persons Scale (BAOP) and internalisation of weight bias using the Modified Weight Bias Internalization Scale (WBIS-M). Bivariate associations between BAOP and WBIS-M scores and demographic characteristics were examined using t tests or ANOVA with post hoc Tukey’s tests.Setting:School of Public Health at a large, Midwestern University.Participants:Public health students (n 322).Results:Relative to students who identified as male, those who identified as female had a stronger belief that obesity is not within the control of the individual (P = 0·03), yet had more internalisation of weight bias (P < 0·01). Greater weight bias internalisation was also seen among students who perceived themselves to be of a higher weight status (P < 0·001) and those who were at risk for food insecurity (P < 0·01).Conclusions:Public health trainees may be more attuned to the complexities of weight relative to trainees in other health-related fields, but are still susceptible to internalisation of negative weight-related stereotypes.

The objective of this study was to assess the rate of discordance between clinical and pathologic tumor size for women with stage IB1 cervical cancer (FIGO 2009 criteria), assess risk factors for discordance, and determine the impact of discordance on oncologic outcomes.This was a secondary analysis of a prior multi-institutional retrospective review of patients diagnosed with stage IB1 (FIGO 2009 staging) cervical cancer undergoing radical hysterectomy between 2010 and 2017. Demographic, clinicopathologic, and oncologic data were collected. Pathologic upstaging was defined as having a preoperative diagnosis of stage IB1 cervical cancer with pathology demonstrating a tumor size4 cm. Demographic and clinicopathologic data was compared using chi-square, fisher exact or 2-sided t-test. Survival was estimated using the Kaplan-Meier method.Of the 630 patients, 77 (12%) were upstaged. Patients who were upstaged had lower rates of preoperative conization (p .001) or preoperative tumor sizes ≤2 cm (p .001). Upstaged patients had increased odds of deep stromal invasion, lymphovascular space invasion, positive margins and positive lymph nodes. Almost 88% of upstaged patients received adjuvant therapy compared to 29% of patients with tumors ≤4 cm (odds 18.49, 95% CI 8.99-37.94). Finally, pathologic upstaging was associated with an increased hazard of recurrence (hazard ratio [HR] 1.95, 95% CI 1.03-3.67) and all-cause death (HR 2.31, 95% CI 1.04-5.11).Pathologic upstaging in stage IB1 cervical cancer is relatively common. Upstaging is associated with an 18-fold increased risk of receipt of adjuvant therapy. Patients undergoing preoperative conization and those with tumors2 cm had lower risks of upstaging. Improvement in preoperative assessment of tumor size may better inform primary treatment decisions.

OBJECTIVES HIV-exposed uninfected (HEU) infants exhibit altered vaccine responses and an increased mortality compared with HIV-unexposed infants. Here, vaccine responses in HEU and HIV-unexposed cord blood monocytes (CBMs) were assessed following Bacillus Calmette--Guerin (BCG) treatment. DESIGN Innate responses to in-vitro BCG treatment were assessed through transcriptional profiling using CBMs obtained from a Nigerian cohort of HIV-infected and uninfected women. METHODS HIV-unexposed (n = 9) and HEU (n = 10) infant CBMs were treated with BCG and transcriptionally profiled with the Nanostring nCounter platform. Differential expression and pathway enrichment analyses were performed, and transcripts were identified with enhanced or dampened BCG responses. RESULTS Following BCG stimulation, several pathways associated with inflammatory gene expression were upregulated irrespective of HIV exposure status. Both HIV-unexposed and HEU monocytes increased expression of several cytokines characteristic of innate BCG responses, including IL1β, TNFα, and IL-6. Using differential expression analysis, we identified genes significantly upregulated in HEU compared with HIV-unexposed monocytes including monocyte chemokine CCL7 and anti-inflammatory cytokine TNFAIP6. In contrast, genes significantly upregulated in HIV-unexposed compared with HEU monocytes include chemokine CCL3 and cytokine IL23A, both of which influence anti-mycobacterial T-cell responses. Finally, two genes, which regulate prostaglandin production, CSF2 and PTGS2, were also more significantly upregulated in the HIV-unexposed cord blood indicating that inflammatory mediators are suppressed in the HEU infants. CONCLUSION HEU monocytes exhibit altered induction of several key innate immune responses, providing mechanistic insights into dysregulated innate response pathways that can be therapeutically targeted to improve vaccine responses in HEU infants.

Periodic water impoundment and seasonal flood events result in a 30 m water level fluctuation zone (WLFZ) in the Three Gorges Reservoir Region (TGRR), China. In order to assess the occurrence, sources and seasonal variation of airborne carbonaceous pollutants, a total of thirty-nine PM2.5 samples, twenty-two from August 2017 (summer: low water level ~135m) and seventeen from January 2018 (winter: high water level ~175m) were collected consecutively at a rural site in WLFZ in the TGRR. The results showed that OC, EC, char, soot, 16 PAHs and n-alkanes were higher in winter (mean: 9.17 μg/m3, 4.69 μg/m3, 4.25 μg/m3, 0.45 μg/m3, 19.8 ng/m3 and 210 ng/m3, respectively) than in summer (mean: 6.55 μg/m3, 1.70 μg/m3, 1.37 μg/m3, 0.32 μg/m3, 6.13 ng/m3 and 79.1 ng/m3, respectively). Compositional differences suggested air-soil/plant exchange as a source for 2-3-rings PAHs in summer and biomass burning for 4-5-rings in winter. Diagnostic ratios and PCA suggested more vehicular emission for PAHs in summer. Plant waxes contributed 18.2% and 26.2% of the n-alkanes in summer and winter, respectively, implying a relatively greater contribution from petroleum residues. The specific ratios and relative abundance of hopanes and steranes indicated mixed sources from both vehicle exhaust and petroleum residue; and petroleum residues contribute more steranes in summer compared with winter. As revealing basic information on the formation mechanism of carbonaceous aerosols, this study could contribute to a further understanding of their environmental geochemical behavior in the WLFZ of TGRR.

In response to the Covid-19 pandemic, health care systems worldwide canceled or delayed elective surgeries, outpatient procedures, and clinic appointments. Although such measures may have been necessary to preserve medical resources and to prevent potential exposures early in the pandemic, moving forward, the indirect effects of such an extensive medical shutdown must not outweigh the direct harms of Covid-19. In this essay, we argue for the reopening of evidence-based health care with assurance provided to patients about the safety and necessity of high-value vaccinations, screenings, therapeutics, and procedures. To ensure that virtually all non-Covid-related services do not come to a halt again, health care systems and physician practices must preemptively increase their capacity, secure adequate personal protective equipment to safeguard health care personnel, and develop a measured approach to reclosing such routine health care, should it become necessary in the future.

The authors examine the associations of generational affiliation on empathy and burnout in a sample of millennial (born between 1982 and 2000) and Generation X (born between 1965 and 1981) residents and fellows. At a single large institution during the 2013–2014 academic year, residents and fellows were asked to complete the Jefferson Scale of Physician Empathy and Maslach Burnout Inventory (MBI). Responses were combined with GME database content. Multivariable regression analysis included generation affiliation, race, gender, and post-graduate year (PGY) as covariates. The study sample included 388 millennial (mean age = 29.3) and 200 Generation X trainees (mean age = 34.6), with the response rate being 96.5%. Groups were statistically different by gender (p

Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus H2O2, is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox-/- gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox-/- mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.

Introduction: To evaluate overall survival (OS) of T1a kidney cancers stratified by histologic subtype and curative treatment including partial nephrectomy (PN), percutaneous ablation (PA), and radical nephrectomy (RN). Materials and Methods: We queried the National Cancer Data Base (2004–2015) for patients with T1a kidney cancers who were treated surgically. OS was estimated by Kaplan-Meier curves based on histologic subtype and management. Cox proportional regression models were used to determine whether histologic subtypes and management procedure predicted OS. Results: 46,014 T1a kidney cancers met inclusion criteria. Kaplan Meier curves demonstrated differences in OS by treatment for clear cell, papillary, chromophobe, and cystic histologic subtypes (all p

Introduction: There have been a number of recent advances in the management of advanced clear cell renal cell carcinoma (ccRCC). However, the majority of these studies excluded patients with non-clear cell RCC (nccRCC), and optimal management of nccRCC remains unknown. Materials and Methods: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate systemic treatment options in locally advanced or metastatic nccRCC between 2000-2019. Randomized controlled trials, single-arm phase II–IV trials, and prospective analyses of medication access programs were included. The primary outcome measures were progression free survival (PFS), overall survival (OS), and objective response rate (ORR). Results: A total of 31 studies were included in the final analysis. There was the highest level of evidence to support first-line treatment of nccRCC with sunitinib. Additional single-arm trials support the use of other vascular endothelial growth factor (VEGF) inhibitors with axitinib and pazopanib, as well as mammalian target of rapamycin (mTOR) inhibition with temsirolimus or everolimus +/–bevacizumab. Immune checkpoint inhibition has an emerging role in nccRCC, but optimal sequencing of available options is not clear. Prospective data to support the use of newer immunotherapy combinations are lacking. Treatment for collecting duct carcinoma remains platinum-based chemotherapy. Conclusions: The availability of randomized trials in nccRCC is limited, and most studies include outcomes for nccRCC as a group, making conclusions about efficacy by subtype difficult. This systematic review supports consensus guidelines recommending sunitinib or clinical trial enrollment as preferred first-line treatment options for nccRCC, but also suggests a more nuanced approach to management and new options for therapy such as immune checkpoint inhibition.

In the current article, we consider the broad question of “Why is perfectionism antithetical to mindfulness?” and we examine the implications for the treatment of perfectionists suffering from stress-related illnesses and disorders. In addition, we review past research on perfectionism and mindfulness. Finally, we also report two empirical studies with university students evaluating the link between perfectionism and dispositional mindfulness. The findings from these studies demonstrate uniquely that socially prescribed perfectionism and facets of perfectionistic self-presentation are both associated with low mindfulness. Additionally, mindfulness was a mediator of the associations between interpersonal facets of perfectionism and depression in study 2. Collectively, the findings suggest that people who experience pressures to be perfect and who are engaged excessively in extreme self-presentation can benefit substantially from increased mindfulness, but it is particularly difficult for certain perfectionists to develop a state of mindfulness that is not consonant with their personality, temperament, and orientation toward life. The implications for the treatment of distressed perfectionists are discussed.

Gemcitabine and docetaxel combination chemotherapy is the standard of care for patients with unresectable recurrent or metastatic leiomyosarcoma of the uterus. Although they are generally well-tolerated agents, they can also cause severe and life-threatening pulmonary toxicities. Here, we describe a case of grade 4 pneumonitis due to gemcitabine and docetaxel in a 74-year-old woman with recurrent, metastatic uterine leiomyosarcoma. Despite early recognition of chemotherapy-induced lung injury and early administration of corticosteroid, she developed noncardiogenic pulmonary edema, diffuse alveolar hemorrhage, and acute respiratory distress syndrome. She required multiple intubations and a tracheostomy. Physicians should not only be aware of gemcitabine and docetaxel’s potential to cause life-threatening pulmonary injuries but also recognize the variability in clinical presentations and treatment responses, the radiographic findings of these lung toxicities, and the need for early corticosteroid therapy in these cases.

Various previous studies established that the amphiphilic tri-block copolymer known as poloxamer 188 (P188) or Pluronic-F68 can stabilize the plasma membrane following a variety of injuries to multiple mammalian cell types. This characteristic led to proposals for the use of P188 as a therapeutic treatment for various disease states, including muscular dystrophy. Previous studies suggest that P188 increases plasma membrane integrity by resealing plasma membrane disruptions through its affinity for the hydrophobic lipid chains on the lipid bilayer. P188 is one of a large family of copolymers that share the same basic tri-block structure consisting of a middle hydrophobic propylene oxide segment flanked by two hydrophilic ethylene oxide moieties [poly(ethylene oxide)80-poly(propylene oxide)27-poly(ethylene oxide)80]. Despite the similarities of P188 to the other poloxamers in this chemical family, there has been little investigation into the membrane-resealing properties of these other poloxamers. In this study we assessed the resealing properties of poloxamers P181, P124, P182, P234, P108, P407, and P338 on human embryonic kidney 293 (HEK293) cells and isolated muscle from the mdx mouse model of Duchenne muscular dystrophy. Cell membrane injuries from glass bead wounding and multiphoton laser injury show that the majority of poloxamers in our panel improved the plasma membrane resealing of both HEK293 cells and dystrophic muscle fibers. These findings indicate that many tri-block copolymers share characteristics that can increase plasma membrane resealing and that identification of these shared characteristics could help guide design of future therapeutic approaches.

The Ovarian-Adnexal Reporting and Data System (O-RADS) US risk stratification and management system is designed to provide consistent interpretations, to decrease or eliminate ambiguity in US reports resulting in a higher probability of accuracy in assigning risk of malignancy to ovarian and other adnexal masses, and to provide a management recommendation for each risk category. It was developed by an international multidisciplinary committee sponsored by the American College of Radiology and applies the standardized reporting tool for US based on the 2018 published lexicon of the O-RADS US working group. For risk stratification, the O-RADS US system recommends six categories (O-RADS 0-5), incorporating the range of normal to high risk of malignancy. This unique system represents a collaboration between the pattern-based approach commonly used in North America and the widely used, European-based, algorithmic-style International Ovarian Tumor Analysis (IOTA) Assessment of Different Neoplasias in the Adnexa model system, a risk prediction model that has undergone successful prospective and external validation. The pattern approach relies on a subgroup of the most predictive descriptors in the lexicon based on a retrospective review of evidence prospectively obtained in the IOTA phase 1-3 prospective studies and other supporting studies that assist in differentiating management schemes in a variety of almost certainly benign lesions. With O-RADS US working group consensus, guidelines for management in the different risk categories are proposed. Both systems have been stratified to reach the same risk categories and management strategies regardless of which is initially used. At this time, O-RADS US is the only lexicon and classification system that encompasses all risk categories with their associated management schemes.

1 H-magnetic resonance spectroscopy (MRS) provides noninvasive metabolite profiles with the potential to aid the diagnosis of brain tumours. Prospective studies of diagnostic accuracy and comparisons with conventional MRI are lacking. The aim of the current study was to evaluate, prospectively, the diagnostic accuracy of a previously established classifier for diagnosing the three major childhood cerebellar tumours, and to determine added value compared with standard reporting of conventional imaging. Single-voxel MRS (1.5 T, PRESS, TE 30 ms, TR 1500 ms, spectral resolution 1 Hz/point) was acquired prospectively on 39 consecutive cerebellar tumours with histopathological diagnoses of pilocytic astrocytoma, ependymoma or medulloblastoma. Spectra were analysed with LCModel and predefined quality control criteria were applied, leaving 33 cases in the analysis. The MRS diagnostic classifier was applied to this dataset. A retrospective analysis was subsequently undertaken by three radiologists, blind to histopathological diagnosis, to determine the change in diagnostic certainty when sequentially viewing conventional imaging, MRS and a decision support tool, based on the classifier. The overall classifier accuracy, evaluated prospectively, was 91%. Incorrectly classified cases, two anaplastic ependymomas, and a rare histological variant of medulloblastoma, were not well represented in the original training set. On retrospective review of conventional MRI, MRS and the classifier result, all radiologists showed a significant increase (Wilcoxon signed rank test, p

Highlights • Metastatic melanoma to the ovary is uncommon and can occur years after initial diagnosis. • Ovarian metastatic melanoma can mimic various benign lesions on imaging and clinical history is key. • If any suspicion in pregnancy, placenta should be evaluated due to possibility of transplacental transmission., Metastatic melanoma to the ovary is an uncommon presentation. We report a case of metastatic melanoma to the ovary that presented as a growing left adnexal mass during pregnancy and was thought to be benign by imaging and frozen section pathology. Here we discuss the challenges in radiologic and pathologic diagnosis, as well as considerations for the mother and newborn.

PURPOSE To evaluate the safety and efficacy of gemcitabine and cisplatin in combination with the immune checkpoint inhibitor pembrolizumab as neoadjuvant therapy before radical cystectomy (RC) in muscle-invasive bladder cancer. METHODS Patients with clinical T2-4aN0/XM0 muscle-invasive bladder cancer eligible for RC were enrolled. The initial six patients received lead-in pembrolizumab 200 mg once 2 weeks prior to pembrolizumab 200 mg once on day 1, cisplatin 70 mg/m2 once on day 1, and gemcitabine 1,000 mg/m2 once on days 1 and 8 every 21 days for four cycles. This schedule was discontinued for toxicity and subsequent patients received cisplatin 35 mg/m2 once on days 1 and 8 without lead-in pembrolizumab. The primary end point was pathologic downstaging (< pT2N0) with null and alternative hypothesis rates of 35% and 55%, respectively. Secondary end points were toxicity including patient-reported outcomes, complete pathologic response (pT0N0), event-free survival, and overall survival. Association of pathologic downstaging with programmed cell death ligand 1 staining was explored. RESULTS Thirty-nine patients were enrolled between June 2016 and March 2020 (72% cT2, 23% cT3, and 5% cT4a). Patients received a median of four cycles of therapy. All patients underwent RC except one who declined. Twenty-two of 39 patients (56% [95% CI, 40 to 72]) achieved < pT2N0 and 14 of 39 (36% [95% CI, 21 to 53]) achieved pT0N0. Most common adverse events (AEs) of any grade were thrombocytopenia (74%), anemia (69%), neutropenia (67%), and hypomagnesemia (67%). One patient had new-onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab and no patients required steroids for immune-related AEs. Clinicians consistently under-reported AEs when compared with patients. CONCLUSION Neoadjuvant gemcitabine and cisplatin plus pembrolizumab met its primary end point for improved pathologic downstaging and was generally safe. A global study of perioperative chemotherapy plus pembrolizumab or placebo is ongoing.

Saliva secretion requires effective translocation of aquaporin 5 (AQP5) water channel to the salivary glands (SGs) acinar apical membrane. Patients with Sjögren’s syndrome (SS) display abnormal AQP5 localization within acinar cells from SGs that correlate with sicca manifestation and glands hypofunction. Several proteins such as Prolactin-inducible protein (PIP) may regulate AQP5 trafficking as observed in lacrimal glands from mice. However, the role of the AQP5-PIP complex remains poorly understood. In the present study, we show that PIP interacts with AQP5 in vitro and in mice as well as in human SGs and that PIP misexpression correlates with an altered AQP5 distribution at the acinar apical membrane in PIP knockout mice and SS hMSG. Furthermore, our data show that the protein-protein interaction involves the AQP5 C-terminus and the N-terminal of PIP (one molecule of PIP per AQP5 tetramer). In conclusion, our findings highlight for the first time the role of PIP as a protein controlling AQP5 localization in human salivary glands but extend beyond due to the PIP-AQP5 interaction described in lung and breast cancers.

Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti-PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell-autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.

Sjögren’s syndrome (SS) is an exocrinopathy characterized by the hypofunction of salivary glands (SGs). Aquaporin-5 (AQP5), a water channel involved in saliva formation, is aberrantly distributed in SS SG acini and contributes to glandular dysfunction. We aimed to investigate the role of ezrin in AQP5 mislocalization in SS SGs. The AQP5–ezrin interaction was assessed by immunoprecipitation and proteome analysis and by proximity ligation assay in immortalized human SG cells. We demonstrated, for the first time, an interaction between ezrin and AQP5. A model of the complex was derived by computer modeling and in silico docking, suggesting that AQP5 interacts with the ezrin FERM-domain via its C-terminus. The interaction was also investigated in human minor salivary gland (hMSG) acini from SS patients (SICCA-SS), showing that AQP5–ezrin complexes were absent or mislocalized to the basolateral side of SG acini rather than the apical region compared to controls (SICCA-NS). Furthermore, in SICCA-SS hMSG acinar cells, ezrin immunoreactivity was decreased at the acinar apical region and higher at basal or lateral regions, accounting for altered AQP5–ezrin co-localization. Our data reveal that AQP5–ezrin interactions in human SGs could be involved in the regulation of AQP5 trafficking and may contribute to AQP5-altered localization in SS patients

The purpose of the current study is to examine how nonmodifiable sociodemographic, disease, appointment, management, and survey factors correlate with provider rating. This was a retrospective cross-sectional study conducted on 29 857 patient Clinician and Group Consumer Assessment of Healthcare Providers and Systems surveys collected from January 2017 to January 2019 at a tertiary eye center. We included surveys of patients aged 18 years or older, who answered at least 4 of 6 subfield questions, and completed the survey within 90 days of the appointment. The main outcome was the odds of receiving top box score (TBS) of 10/10 on the survey question regarding overall provider rating. The results showed that the variables with higher odds of TBS included higher overall appointment attendance (odds ratio [OR]: 2.66 [95% CI: 1.23-5.75], P = .013); older patient age (OR 2.44 [95% CI: 2.08-2.87], P < .001]; higher percentage of survey questions completed (OR: 2.02 [95% CI: 1.79-2.27], P < .001); better best corrected visual acuity (OR: 1.85 [95% CI: 1.3-2.64], P = .001); optometry clinic visit (OR: 1.25 [95% CI: 1.15-1.36], P < .001); having procedures (OR: 1.19 [95% CI: 1.04-1.36], P = .013), surgery scheduled (OR: 1.18 [95% CI: 1.03-1.36], P = .020], or refraction done (OR: 1.16 [95% CI: 1.08-1.25], P < .001); being seen by male providers (OR: 1.11 [95% CI: 1.04-1.17], P = .001); and having additional eye testing performed (OR: 1.06 [95% CI: 1.00-1.13], P = .048). Variables associated with lower odds of TBS included longer time to complete survey (OR: 0.42 [95% CI: 0.3-0.58], P = .001); new patient encounter (OR: 0.62 [95% CI: 0.58-0.65], P < .001); and glaucoma (OR: 0.66 [95% CI: 0.59-0.75], P < .001), cornea (OR: 0.79 [95% CI: 0.71-0.87], P < .001), or comprehensive clinic visits (OR: 0.86 [95% CI: 0.79-0.94], P < .001). Thus, nonmodifiable factors may affect the provider rating, and these factors should be studied further and accounted for when interpreting the results of patient experience surveys.

Background FGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance. Methods 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients. Results Our findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response. Conclusions Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.

In the current article, we describe the development and validation of the Mistake Rumination Scale as a supplement to existing trait and cognitive measures of perfectionism. The Mistake Rumination Scale is a seven-item inventory that taps the tendency to ruminate about a past personal mistake. Psychometric analyses confirmed that the Mistake Rumination Scale consists of one factor assessed with high internal consistency. Analyses established that elevated levels of mistake rumination are associated with trait perfectionism, ruminative brooding, depression, and social anxiety. Moreover, scores on the Mistake Rumination Scale significantly predicted unique variance in depression beyond the variance accounted for by trait perfectionism dimensions, rumination, and automatic thoughts. Overall, our findings attest to the further use of the Mistake Rumination Scale and highlight the tendency of certain perfectionists to suffer from cognitive forms of perfectionism involving overthinking about past mistakes and related imperfections involving the self.

Introduction The flexibility and tunability of metal organic frameworks (MOFs), crystalline porous materials composed of a network of metal ions coordinated by organic ligands, confer their variety of applications as drug delivery systems or as sensing and imaging agents. However, such properties also add to the difficulty in ensuring their safe implementation when interaction with biological systems is considered. Methods In the current study, we used real-time sensorial strategies and cellular-based approaches to allow for fast and effective screening of two MOFs of prevalent use, namely, MIL-160 representative of a hydrophilic and ZIF-8 representative of a hydrophobic framework. The two MOFs were synthesized "in house" and exposed to human bronchial epithelial (BEAS-2B) cells, a pertinent toxicological screening model. Results Analysis allowed evaluation and differentiation of particle-induced cellular effects as well identification of different degrees and routes of toxicity, all in a high-throughput manner. Our results show the importance of performing screening toxicity assessments before introducing MOFs to biomedical applications. Discussion Our proposed screening assays could be extended to a wider variety of cell lines to allow for identification of any deleterious effects of MOFs, with the range of toxic mechanisms to be differentiated based on cell viability, morphology and cell-substrate interactions, respectively. Conclusion Our analysis highlights the importance of considering the physicochemical properties of MOFs when recommending a MOF-based therapeutic option or MOFs implementation in biomedical applications.

Background: In order to provide patient center care, our multiple sclerosis (MS) clinic assesses patient concerns before clinical encounters, first by asking the optional qualitative question “What is the most important thing you what your health-care provider to know today” (most important concern of the patient [MIPC]) and then completing quantitative patient-reported outcome measures (PROMs) including Quality of Life in Neurological Disorders (Neuro-QoL). Both sets of questions are designed to facilitate encounters that address patients’ values and preferences. Objective: Determine whether the qualitative MIPC responses provided unique information not included in PROMs or clinical assessments. Methods: We randomly selected 400 first-time MIPC responders and 400 first-time MIPC nonresponders from 2788 participants in our database. We categorized MIPC responses by content and number of unique concerns and appended them to the Neuro-QoL framework. Nonresponders were compared to those who provided 1 and 2 or more responses. Results: Several MIPCs MS symptoms categories were added to the Neuro-QoL Physical domain. Most important concern of the patients work and cost-of-care categories were added to the Social Domain. Domains regarding treatment satisfaction and disease management were added. Two hundred thirty (58%) MIPC respondents reported 1 concern, 140 (35%) expressed 2 to 6 concerns, and 30 (7%) reported MS-unrelated concerns and not analyzed. Physical symptoms were the most common MIPC (69.9%). Respondents with more concerns were more likely African American, lacked private insurance, and worse disability. Conclusions: Importantly, MIPC responders described idiosyncratic symptoms, disease management, and social concerns not included in the PROMS, suggesting the MIPC question offered patients a unique opportunity to share specific concerns with their providers.

Background With the integration of Objective Structured Clinical Examinations into the Anesthesiology primary board certification process, residency programs may choose to implement Objective Structured Clinical Examinations for resident skill assessment. The aim of this study was to evaluate Objective Structured Clinical Examination-based milestone assessment and compare with Clinical Competency Committee milestone assessment that is based purely on clinical evaluations. Methods An annual Objective Structured Clinical Examination event was used to obtain milestone assessment of clinical anesthesia year 0-clinical anesthesia year 3 residents for selected milestones in patient care, professionalism, and interpersonal/communication skills. The Objective Structured Clinical Examination scenarios were different for each training level. The Clinical Competency Committee evaluated each resident semiannually based on clinical evaluations of resident performance. The Clinical Competency Committee milestone assessments from 2014 to 2016 that were recorded closest to the Objective Structured Clinical Examination event (±3 months) were compared to the Objective Structured Clinical Examination milestone assessments. A total of 35 residents were included in this analysis in 3 different training cohorts: A (graduates 2016, n = 12); B (graduates 2017, n = 10); and C (graduates 2018, n = 13). All residents participated in Objective Structured Clinical Examinations because their clinical anesthesia year 0 year and Clinical Competency Committee milestone data had been reported since December 2014. Results Both assessment techniques indicated a competency growth proportional to the length in training. Despite limited cumulative statistics in this study, average trends in the Objective Structured Clinical Examination-Clinical Competency Committee relationship indicated: (1) a good proportionality in reflecting competency growth; (2) a grade enhancement associated with Clinical Competency Committee assessment, dominated by evaluations of junior residents (clinical anesthesia year 0-clinical anesthesia year 1); and (3) an expectation bias in Clinical Competency Committee assessment, dominated by evaluation of senior residents (clinical anesthesia year 2-clinical anesthesia year 3). Conclusions Our analysis confirms the compatibility of the 2 evaluation methods in reflecting longitudinal growth. The deviation of Objective Structured Clinical Examination assessments versus Clinical Competency Committee assessments suggests that Objective Structured Clinical Examinations may be providing additional or different information on resident performance. Educators might consider using both assessment methods to provide the most reliable and valid competency assessments during residency.

Primary care physicians recognize the importance of advance care planning (ACP) conversations and report lack of training and time in the office to start them. Previous efforts have shown that ACP is a low-risk high-value intervention for older patients and those with life-limiting illness.To measure the impact of physician coaching and staff training with registered nurse (RN) support and electronic medical record (EMR) enhancements on the initiation of 2000 ACP conversations in primary care.Employing VitalTalkThere was an increase from zero at baseline in the number of ACP conversations and a leveling out of new ACP initiated each month. A total of 7200 ACP conversations were initiated for 31 months in 36 primary care practices, and 29% of conversations had advance directives scanned into the EMR during a 10-month review period. Most ACP conversations were initiated by RN care managers. In 2017, there were 7589 more ACP conversations initiated.By combining two complementary, evidenced-based curricula, providing support of a nurse liaison and designing a summary and alert in the EMR, this program exceeded its goal to initiate 2000 ACP conversations in primary care. Other health systems might consider a similar multicomponent intervention to increase ACP.

Summary Background Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. Methods We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Findings Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. Interpretation While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. Funding None.

Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2–4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and—in the case of PDAC—the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface—where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth—is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities. In an inducible mouse model of pancreatic ductal adenocarcinoma, the signalling defect that underlies 90% of these tumours causes increased cell-surface expression of syndecan 1, leading to misregulation of macropinocytosis, and linking the defective signalling with nutrient-salvage pathways.

The classical pathway of complement (CP) can mediate C3 opsonization of Ags responsible for the costimulation and activation of cognate B lymphocytes. In this manner, the complement system acts as a bridge between the innate and adaptive immune systems critical for establishing a humoral response. However, aberrant complement activation is often observed in autoimmune diseases in which C3 deposition on self-antigens may serve to activate self-reactive B cell clones. In this study, we use BIVV009 (Sutimlimab), a clinical stage, humanized mAb that specifically inhibits the CP-specific serine protease C1s to evaluate the impact of upstream CP antagonism on activation and proliferation of normal and autoimmune human B cells. We report that BIVV009 significantly inhibited complement-mediated activation and proliferation of primary human B cells. Strikingly, CP antagonism suppressed human Ig–induced activation of B cells derived from patients with rheumatoid arthritis. These results suggest that clinical use of CP inhibitors in autoimmune patients may not only block complement-mediated tissue damage, but may also prevent the long-term activation of autoimmune B cells and the production of autoantibodies that contribute to the underlying pathologic condition of these diseases.

Helicobacter pylori is the strongest risk factor for gastric cancer. Initial interactions between H. pylori and its host originate at the microbial-gastric epithelial cell interface, and contact between H. pylori and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic cag+ H. pylori strain, 7.13, recapitulates many features of H. pylori-induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by H. pylori that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from H. pylori-infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by H. pylori infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly up-regulated in vitro, ex vivo in primary human gastric monolayers, and in vivo in gerbil gastric epithelium following infection with H. pylori strain 7.13 in a cag-dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared with gastritis alone. These results indicate that carcinogenic strains of H. pylori induce dramatic and specific changes within the gastric proteome in vivo and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans.

ObjectivesTo determine if linear measurements of adiposity from pre-operative imaging can improve anticipation of surgical difficulty among endometrial cancer patients.MethodsEighty patients with newly diagnosed endometrial cancer were enrolled. Routine pre-operative imaging (MRI or CT) was performed. Radiologic linear measurements of the following were obtained: anterior-to-posterior skin distance; anterior skin to anterior edge of L5 distance (total anterior); anterior peritoneum to anterior edge of L5 distance (visceral obesity); and posterior edge of L5 to posterior skin distance (total posterior). Surgeons completed questionnaires quantifying preoperative anticipated operative difficulty and postoperative reported operative difficulty. The primary objective was to assess for a correlation between linear measurements of visceral fat and reported operative difficulty.ResultsSeventy-nine patients had questionnaires completed, preoperative imaging obtained, and surgery performed. Univariate analysis showed all four linear measurements, body mass index, weight, and anticipated operative difficulty were associated with increased reported operative difficulty (P< 0.05). Multivariate analysis demonstrated that body mass index and linear measurements visceral obesity and total posterior were independently associated with increased reported operative difficulty (P< 0.05). Compared with body mass index, the visceral obesity measurement was more sensitive and specific for predicting increased reported operative difficulty (visceral obesity; sensitivity 54%, specificity 91 %; body mass index; sensitivity 38%, specificity 89%). A difficulty risk model combining body mass index, visceral obesity, and total posterior demonstrated better predictive performance than any individual preoperative variable.ConclusionsSimple linear measurements of visceral fat obtained from preoperative imaging are more predictive than body mass index alone in anticipating surgeon-reported operative difficulty. These easily obtained measurements may assist in preoperative decision making in this challenging patient population.

Adults conserve metabolic energy during walking by minimizing the step-to-step transition work performed by the legs during double support and by utilizing spring-like mechanisms in their legs, but little is known as to whether children utilize these same mechanisms. To gain a better understanding, we studied how children (5-6 years) and adults modulate the mechanical and metabolic demands of walking at their preferred speed, across slow (75%), preferred (100%), and fast (125%) step frequencies. We quantified the 1) positive mass-specific work done by the trailing leg during step-to-step transitions and 2) the leg’s spring-likebehavior during single support. On average, children walked with a 36% greater net cost of transport (COT; J/kg/m) than adults (p=0.03), yet both groups increased their net COT at varying step frequencies. After scaling for speed, children generated ∼2-fold less trailing limb positive scaled mechanical work during the step-to-step transition (p=0.02). Unlike adults, children did not modulate their trailing limb positive work to meet the demands of walking at 75% and 125% of their preferred step frequency. In single support, young children operated their stance limb with much greater compliance than adultsvs. 11.35;p=.023). Our observations suggest that the mechanics of walking in children 5-6 years are fundamentally distinct from the mechanics of walking in adults and may help to explain a child’s higher net COT. These insights have implications for the design of assistive devices for children and suggest that children cannot be simply treated as scaled down versions of adults.

Background: Telemedicine for neurological care has been researched and practiced in various ways over the past three decades, but the recent COVID-19 pandemic has rapidly expanded its use and highlighted the need for a synthesis of the existing literature. We aimed to review the methodology and outcomes of previous studies that have evaluated the use of telemedicine in movement disorders. Methods: This scoping review was performed by searching PubMed, Ovid MEDLINE, and CINAHL databases from 1946 to November 2020. Studies that assessed the application of telemedicine for delivering care to patients with a movement disorder were included. We reported the aims and employed methodologies and categorized the outcomes from each study. Results: The search retrieved 228 articles, and 41 studies met the criteria for inclusion in the review. The majority of telemedicine studies were case series or randomized controlled pilot trials, investigating feasibility and acceptability in Parkinson's disease. Even with heterogeneity among outcome measures, they can be categorized into themes, such as feasibility, satisfaction, and efficacy. Conclusions: Telemedicine use has grown rapidly, due to the demands of providing care during a global pandemic. This application of telemedicine has been considered a promising way to expand care in Neurology, although research evaluating the dissemination of its use is dilatory. This review highlights the number of studies that have found telemedicine to be an acceptable and feasible way to deliver care for movement disorders. Further research is needed to expand on harmonization of outcomes, reach, adoption, and long-term use of telemedicine.

Background Patient satisfaction with in-person medical visits includes patient-clinician engagement. However, communication, empathy, and other relationship-centered care measures in virtual visits have not been adequately investigated. Objective This study aims to comprehensively consider patient experience, including relationship-centered care measures, to assess patient satisfaction during virtual visits. Methods We conducted a large survey study with open-ended questions to comprehensively assess patients’ experiences with virtual visits in a diverse patient population. Adults with a virtual visit between June 21, 2017, and July 12, 2017, were invited to complete a survey of 21 Likert-scale items and textboxes for comments following their visit. Factor analysis of the survey items revealed three factors: experience with technology, patient-clinician engagement, and overall satisfaction. Multivariable logistic regression was used to test the associations among the three factors and patient demographics, clinician type, and prior relationship with the clinician. Using qualitative framework analysis, we identified recurrent themes in survey comments, quantitatively coded comments, and computed descriptive statistics of the coded comments. Results A total of 65.7% (426/648) of the patients completed the survey; 64.1% (273/426) of the respondents were women, and the average age was 46 (range 18-86) years. The sample was geographically diverse: 70.2% (299/426) from Ohio, 6.8% (29/426) from Florida, 4.2% (18/426) from Pennsylvania, and 18.7% (80/426) from other states. With regard to insurance coverage, 57.5% (245/426) were undetermined, 23.7% (101/426) had the hospital’s employee health insurance, and 18.7% (80/426) had other private insurance. Types of virtual visits and clinicians varied. Overall, 58.4% (249/426) of patients had an on-demand visit, whereas 41.5% (177/426) had a scheduled visit. A total of 41.8% (178/426) of patients had a virtual visit with a family physician, 20.9% (89/426) with an advanced practice provider, and the rest had a visit with a specialist. Most patients (393/423, 92.9%) agreed that their virtual visit clinician was interested in them as a person, and their virtual visit made it easy to get the care they needed (383/421, 90.9%). A total of 81.9% (344/420) of respondents agreed or strongly agreed that their virtual visit was as good as an in-person visit by a clinician. Having a prior relationship with their virtual visit clinician was associated with less comfort and ease with virtual technology among patients (odds ratio 0.58, 95% CI 0.35-0.98). In terms of technology, patients found the interface easy to use (392/423, 92.7%) and felt comfortable using it (401/423, 94.8%). Technical difficulties were associated with lower odds of overall satisfaction (odds ratio 0.46, 95% CI 0.28-0.76). Conclusions Patient-clinician engagement in virtual visits was comparable with in-person visits. This study supports the value and acceptance of virtual visits. Evaluations of virtual visits should include assessments of technology and patient-clinician engagement, as both are likely to influence patient satisfaction.

Introduction Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear. Patients and methods This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms. Results A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59–2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11–3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45). Conclusion Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.

Introduction South Africa (SA) has the highest number of people living with HIV (PLWH) globally, and a significant burden of alcohol and other drug use (AOD). Although integrating AOD treatment into HIV care may improve antiretroviral therapy (ART) adherence, this is not typically routine practice in SA or other low‐resource settings. Identifying interventions that are feasible and acceptable for implementation is critical to improve HIV and AOD outcomes. Methods A pilot randomized hybrid type 1 effectiveness‐implementation trial (N = 61) was conducted to evaluate the feasibility and acceptability of Khanya, a task‐shared, peer‐delivered behavioral intervention to improve ART adherence and reduce AOD in HIV care in SA. Khanya was compared to enhanced treatment as usual (ETAU), a facilitated referral to on‐site AOD treatment. Implementation outcomes, defined by Proctor’s model, included feasibility, acceptability, appropriateness and fidelity. Primary pilot effectiveness outcomes were ART adherence at post‐treatment (three months) measured via real‐time electronic adherence monitoring, and AOD measured using biomarker and self‐report assessments over six months. Data collection was conducted from August 2018 to April 2020. Results and discussion Ninety‐one percent of participants (n = 56) were retained at six months. The intervention was highly feasible, acceptable, appropriate and delivered with fidelity (>90% of components delivered as intended by the peer). There was a significant treatment‐by‐time interaction for ART adherence (estimate = −0.287 [95% CI = −0.507, −0.066]), revealing a 6.4 percentage point increase in ART adherence in Khanya, and a 22.3 percentage point decline in ETAU. Both groups evidenced significant reductions in alcohol use measured using phosphatidylethanol (PEth) (F(2,101) = 4.16, p = 0.01), significantly decreased likelihood of self‐reported moderate or severe AOD (F(2,104) = 7.02, p = 0.001), and significant declines in alcohol use quantity on the timeline follow‐back (F(2,102) = 21.53, p

Purpose of review Although the set point is one of the best understood weight defense mechanisms, how and when a set point is established and what causes its disruption are not well understood. The purpose of this review is to address these gaps in the literature by exploring studies on the establishment of the set point theory and the underlying metabolic processes that support its existence. Recent findings Research suggests that weight loss achieved through restricted energy intake and increased energy expenditure is difficult to maintain and is often followed by greater weight gain over time. It is hypothesized that such weight gain is driven by an individual's set point, a weight range in which the body seeks to remain by adjusting metabolism (e.g. by moderating energy expenditure based on energy intake in times of diet or energy fluctuation). Similar to adults, weight loss in adolescence results in decreased resting metabolic rate (RMR), and that the RMR remains suppressed even with weight restoration. Summary Recommending weight loss in youth results in metabolic adaptations to restore weight and weight inclusive approaches may be more appropriate to protect their health and wellbeing.