Citations

Lung adenocarcinoma (LUAD) is the most prevalent form of non–small cell lung cancer (NSCLC) and a leading cause of cancer death. Immune checkpoint inhibitors (ICIs) of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling induce tumor regressions in a subset of LUAD, but many LUAD tumors exhibit resistance to ICI therapy. Here, we identified Prkci as a major determinant of response to ICI in a syngeneic mouse model of oncogenic mutant Kras / Trp53 loss (KP)–driven LUAD. Protein kinase Cι (PKCι)–dependent KP tumors exhibited resistance to anti–PD-1 antibody therapy (α-PD-1), whereas KP tumors in which Prkci was genetically deleted (KPI tumors) were highly responsive. Prkci- dependent resistance to α-PD-1 was characterized by enhanced infiltration of myeloid-derived suppressor cells (MDSCs) and decreased infiltration of CD8 + T cells in response to α-PD-1. Mechanistically, Prkci regulated YAP1-dependent expression of Cxcl5 , which served to attract MDSCs to KP tumors. The PKCι inhibitor auranofin inhibited KP tumor growth and sensitized these tumors to α-PD-1, whereas expression of either Prkci or its downstream effector Cxcl5 in KPI tumors induced intratumoral infiltration of MDSCs and resistance to α-PD-1. PRKCI expression in tumors of patients with LUAD correlated with genomic signatures indicative of high YAP1-mediated transcription, elevated MDSC infiltration and low CD8 + T cell infiltration, and with elevated CXCL5 / 6 expression. Last, PKCι-YAP1 signaling was a biomarker associated with poor response to ICI in patients with LUAD. Our data indicate that immunosuppressive PKCι-YAP1-CXCL5 signaling is a key determinant of response to ICI, and pharmacologic inhibition of PKCι may improve therapeutic response to ICI in patients with LUAD.

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

AbstractGlycogen synthase kinase‐3 α/β is involved in dysregulation of neuronal tau protein in Alzheimer's disease (AD). There is an unmet clinical need for a blood‐brain barrier (BBB) permeable positron emission tomography (PET) probe for imaging of GSK‐3α/β in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [18F]F‐CNBI and [18F]F‐CNPIFE, and evaluated their BBB permeability and affinity towards GSK‐3α/β. [19F]F‐CNPIFE showed higher in‐vitro binding towards GSK‐3α/β (IC50=19.4±2.5 nM; n=3, for GSK‐3α, IC50=19.4±3.8 nM; n=3, for GSK‐3β) compared to [19F]F‐CNBI (IC50=107.6±26.0 nM; n=4, for GSK‐3α, IC50=105.3±18.2 nM; n=3, for GSK‐3β). [18F]F‐CNPIFE showed 9.5‐fold higher brain uptake than [18F]F‐CNBI, in normal FVB/NJ mice, which was increased by additional 1.5‐fold on co‐administration of [19F]F‐CNPIFE with respect to [18F]F‐CNBI. Overall, [18F]F‐CNPIFE is a promising PET probe for GSK‐3α/β imaging and warrants further evaluation in an AD mouse model.

Objectives To assess the safety profile of antegrade mitomycin gel instillation through a percutaneous nephrostomy tube (PCNT) for upper tract urothelial carcinoma (UTUC) with the aim of decreasing morbidity associated with therapy. Patients and Methods Patients undergoing antegrade administration of mitomycin gel via PCNT were retrospectively included for analysis from four tertiary referral centres between 2020 and 2022. The primary outcome was safety profile, as graded by Common Terminology Criteria for Adverse Events (v5.0). Post‐therapy disease burden was assessed by primary disease evaluation (PDE) via ureteroscopy. Results Thirty‐two patients received at least one dose of mitomycin gel via PCNT for UTUC, 29 of whom completed induction and underwent PDE. Thirteen patients (41%) had residual tumour present prior to induction therapy. At a median of 15.0 months following first dose of induction therapy, ureteric stenosis occurred in three patients (9%), all of whom were treated without later recurrence or chronic stenosis. Other adverse events included fatigue (27%), flank pain (19%), urinary tract infection (12%), sepsis (8%) and haematuria (8%). No patients had impaired renal function during follow‐up and there were no treatment‐related deaths. Seventeen patients (59%) had no evidence of disease at PDE and have not experienced recurrence at a median follow‐up of 13.0 months post induction. Conclusions Administration of mitomycin gel via a PCNT offers a low rate of ureteric stenosis, demonstrates a favourable safety profile, and is administered without general anaesthesia.

The continued citation of retracted publications from the medical literature is a well-known and persistent problem. We describe the contexts of ongoing citations to manuscripts that have been retracted from a selection of anesthesiology journals. We also examine how bibliographic databases and publisher websites document the retracted status of these manuscripts. The authors performed an analysis of retracted publications from anesthesiology journals using the Retraction Watch database. We then examined how the retraction information was displayed on bibliographic databases, search engines, and publisher websites. The primary outcome was the context of continued citation after retraction of flawed publications within the specialty of anesthesiology. Secondary outcomes included comparison of the documentation, bibliographic databases, search engines, and publisher websites used in identifying the retracted status of these publications and provision of access to the respective retraction notices. A total of 245 original publications were retracted over a 28-year period from 9 anesthesiology journals. PubMed, compared to the other databases and search engines, was the most consistent (98.8%) in documenting the retracted status of the publications examined, as well as providing a direct link to the retraction notice. From the 211 publications retracted before January 2020, there were 1307 postretraction citations accessed from Scopus. The median number of postretraction citations was 3.5 (range, 0–88, with at least 1 citation in 164 publications) in Scopus. Of the postretraction citations, 80% affirmed the validity of the retracted publications, while only 5.2% of citations acknowledged the retraction or misconduct. In 10.2% of the citations from original research studies, retracted manuscripts appeared to influence the decision to pursue or the methods used in subsequent original research studies. The frequency of citation of the 15 most cited retracted publications declined in a similar pattern during the 10 years after retraction. Citation of manuscripts retracted from anesthesiology journals remains a common occurrence. Technological innovations and application of standards for handling retracted publications, as suggested by coalitions of researchers across the spectrum of scientific investigation, may serve to reduce the persistence of this error.

Objective: Compare demographics, treatment, and follow-up rates for patients with complaints of vulvovaginitis suggestive of candida infection evaluated via e-visit, face-to-face (F2F) visits, or nurse-administered phone protocol. Methods: Manual review of 150 vaginitis visits of each visit type (e-visit, F2F, and phone protocol) completed between May 5, 2018 through January 31, 2020 by Mayo Clinic patients residing in Minnesota. Outcomes: Comparison between the three visit types of patient characteristics, treatment rates, type of treatment, follow-up rates, and types of follow-up. Results: Patients utilizing phone visits were significantly older than those seeking care via e-visit ( p < 0.0001) or F2F ( p = 0.001) and were more likely to be treated with oral fluconazole than those treated by e-visit ( p < 0.0001) or F2F ( p < 0.0001) encounters. Patients were significantly less likely to receive fungal directed treatment at a F2F visit than an e-visit ( p < 0.0001) or phone encounter ( p < 0.0001). There was no significant difference in follow-up rates between the three groups. Conclusion: Virtual visits (non-F2F) for suspected vulvovaginal candidiasis are unlikely to result in more follow-up visits than F2F encounters; however, prescriptions for antifungals are significantly higher with virtual visits.

Abstract Acute pancreatitis (AP) is a disease characterized by an acute inflammatory phase followed by a convalescent phase. Diabetes mellitus (DM) was historically felt to be a transient phenomenon related to acute inflammation; however, it is increasingly recognized as an important late and chronic complication. There are several challenges that have prevented precisely determining the incidence rate of DM after AP and understanding the underlying mechanisms. The DREAM (Diabetes RElated to Acute Pancreatitis and its Mechanisms) Study is a prospective cohort study designed to address these and other knowledge gaps to provide the evidence needed to screen for, prevent, and treat DM after AP. In the following article, we summarize literature regarding the epidemiology of DM after AP and provide the rationale and an overview of the DREAM study.

Background: Dementia, vascular disease, and cancer increase with age, enabling complex comorbid interactions. Understanding vascular and cancer contributions to dementia risk and neuropathology in oldest-old may improve risk modification and outcomes. Objective: Investigate the contributions of vascular factors and cancer to dementia and neuropathology. Methods: Longitudinal clinicopathologic study of prospectively followed Mayo Clinic participants dying≥95 years-old who underwent autopsy. Participants were stratified by dementia status and compared according to demographics, vascular risk factors, cancer, and neuropathology. Results: Participants (n = 161; 83% female; 99% non-Hispanic whites)≥95 years (95–106 years-old) with/without dementia did not differ based on demographics. APOE ɛ2 frequency was higher in no dementia (20/72 [28%]) versus dementia (11/88 [12%]; p = 0.03), but APOE ɛ4 frequency did not differ. Coronary artery disease was more frequent in no dementia (31/72 [43%]) versus dementia (23/89 [26%]; p = 0.03) associated with 56% lower dementia odds (odds ratio [OR] = 0.44 [confidence interval (CI) = 0.19–0.98]; p = 0.04) and fewer neuritic/diffuse plaques. Diabetes had an 8-fold increase in dementia odds (OR = 8.42 [CI = 1.39–163]; p = 0.02). Diabetes associated with higher cerebrovascular disease (Dickson score; p = 0.05). Cancer associated with 63% lower dementia odds (OR = 0.37 [CI = 0.17–0.78]; p < 0.01) and lower Braak stage (p = 0.01). Conclusion: Cancer exposure in the oldest-old was associated with lower odds of dementia and tangle pathology, whereas history of coronary artery disease was associated with lower odds of dementia and amyloid-β plaque pathology. History of diabetes mellitus was associated with increased odds of dementia and cerebrovascular disease pathology. Cancer-related mechanisms and vascular risk factor reduction strategies may alter dementia risk and neuropathology in oldest-old.

» Periprosthetic joint infection (PJI) following hip hemiarthroplasty (HA) is a devastating complication, incurring immense health-care costs associated with its treatment and placing considerable burden on patients and their families. These patients often require multiple surgical procedures, extended hospitalization, and prolonged antimicrobial therapy. » Notable risk factors include older age, higher American Society of Anesthesiologists (ASA) score, inadequate antibiotic prophylaxis, non-antibiotic-loaded cementation of the femoral implant, longer duration of the surgical procedure, and postoperative drainage and hematoma. » Although the most frequent infecting organisms are gram-positive cocci such as Staphylococcus aureus , there is a higher proportion of patients with gram-negative and polymicrobial infections after hip HA compared with patients who underwent total hip arthroplasty. » Several surgical strategies exist. Regardless of the preferred surgical treatment, successful management of these infections requires a comprehensive surgical debridement focused on eradicating the biofilm followed by appropriate antibiotic therapy. » A multidisciplinary approach led by surgeons familiar with PJI treatment and infectious disease specialists is recommended for all cases of PJI after hip HA to increase the likelihood of treatment success.