Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

Age-Specific Associations of Renal Impairment and Cerebral Small Vessel Disease Burden in Chinese with Ischaemic Stroke.

BACKGROUND: Recent studies in Caucasians with transient ischaemic attack or ischaemic stroke have demonstrated significant age-specific associations between cerebral small vessel disease (SVD) burden on magnetic resonance imaging and renal impairment. We aimed to validate these findings in a large cohort of Chinese with ischaemic stroke. METHODS: In 959 Chinese with ischaemic stroke who received a brain magnetic resonance imaging at the University of Hong Kong, we determined the age-specific associations of renal impairment (glomerular filtration rate < 60 mL/min/1.73 m2) with neuroimaging markers of SVD as well as with the SVD score. RESULTS: Although renal impairment was associated with the SVD score in univariate analysis in all patients (odds ratio 1.61, 95% confidence interval 1.24-2.09, P < .0001), these associations were attenuated after adjusting for age and sex (P = .38). Similar findings were noted in patients with ischaemic stroke due to SVD and non-SVD subtypes. However, in 222 of 959 patients aged <60, renal impairment was independently associated with an increasing microbleed (adjusted odds ratio 6.82, 2.26-20.59), subcortical (4.97, 1.62-15.24) periventricular white matter hyperintensity (3.96, 1.08-14.51) and global SVD burden (3.41, 1.16-10.04; all P < .05) even after adjusting for age, sex, and vascular risk factors. Nevertheless, there were no associations between renal impairment and individual neuroimaging markers of SVD nor with the SVD score in patients aged ≥60 after adjusting for age and sex (all P > .05). CONCLUSIONS: In Chinese with ischaemic stroke, renal impairment was independently associated with microbleed, white matter hyperintensity and global SVD burden in individuals aged <60, but not in those aged ≥60, suggesting that there may be shared susceptibilities to premature systemic disease.

Effect of Nurse-Led Review Plus Simulation on Obstetric/Perinatal Nurses' Self-Assessed Knowledge and Confidence.

Simulation may help both novice and experienced clinicians maintain competence in managing high-risk, low-frequency obstetric and perinatal complications and emergencies. Therefore, we designed a pre-/posttest study to determine whether a day of nurse-led lecture plus low-fidelity simulation would increase registered nurses' self-assessed knowledge and confidence in managing five high-risk obstetric/perinatal situations. The Nursing Management of OB/Perinatal Complications & Emergencies (NursOB) scale was distributed to 67 labor/birth and postpartum nurses before and after a simulation training day. Preliminary findings supported validity and reliability of the NursOB scale, but nurses' knowledge and confidence did not improve after the simulation (p < .05). Anecdotally, nurses' interest in competence reviews was reinvigorated, and we gained practical knowledge in simulation delivery. Future simulations could enhance outcome measures, improve drills, and establish criterion-related validity of the NursOB scale. More research is warranted.

A study of the effectiveness of a workplace violence intervention for small retail and service establishments.

OBJECTIVE: Examine the effectiveness of a robbery and violence prevention program in small businesses in Los Angeles. METHODS: Gas/convenience, liquor and grocery stores, bars/restaurants, and motels were enrolled between 1997 and 2000. Intervention businesses (n = 305) were provided training, program implementation materials, and recommendations for a comprehensive security program. Control businesses (n = 96) received neither training nor program materials. RESULTS: Rate ratios comparing intervention to control businesses were 0.90 for violent crime (95% confidence limits [CL] = 0.53, 1.53) and 0.81 for robbery (95% CL = 0.38, 1.73). The reduction in violent crime was concentrated in high-compliance intervention businesses (risk ratio = 0.74, 95% CL = 0.40, 1.36). Low-compliance intervention businesses had practically the same postintervention crime as the control businesses. CONCLUSIONS: Our results suggest that the workplace violence intervention may reduce violent crime among high-risk businesses, especially those with high program compliance.

Validation set correlates of anogenital injury after sexual assault.

OBJECTIVES: Forensic investigators remain unsure exactly why some sexual assault victims display acute injury while others do not. This investigation explores potential reasons for these differential findings among female victims. METHODS: This cross-sectional analysis examined data from consecutive female sexual assault victims, at least 12 years old, who agreed to a forensic exam between November 1, 2002, and November 30, 2006. Exams utilized colposcopy, anoscopy, macrodigital imaging, and toluidine blue dye to delineate anogenital injury (AGI), which was defined as the presence of recorded anogenital abrasions, tears, or ecchymosis. Demographic variables of the victim, including sexual experience and reproductive parity, and assault characteristics were recorded in the database for bivariate and multivariate analysis with AGI. RESULTS: Forty-nine percent of the initial 3,356 patients displayed AGI. Of this total, 2,879 cases included complete data for all variables and were included in the multivariate logistic regression model. A statistically significant increased risk for AGI was noted with: educational status (odds ratio [OR] 1.53, 95% CI = 1.25 to 1.87); vaginal or attempted penetration using penis (OR 2.29, 95% CI = 1.74 to 3.01), finger (OR 1.61, 95% CI = 1.88 to 1.94), or object (OR 3.19, 95% CI = 1.52 to 6.68); anal-penile penetration (OR 2.00, 95% CI = 1.57 to 2.54); alcohol involvement (OR 1.25, 95% CI = 1.04 to 1.50); and virgin status of victim (OR 1.38, 95% CI = 1.11 to 1.71). Victims were less likely to display AGI with a longer postcoital interval (OR 0.50, 95% CI = 0.39 to 0.65) and increased parity (OR 0.76, 95% CI = 0.57 to 0.99). CONCLUSIONS: Approximately half the patients displayed AGI. This rate is higher than earlier studies, but consistent with current investigations utilizing similar injury detection methods. The correlates of injury found reinforce the findings of prior studies, while prompting questions for future study.

Suicides at work: misclassification and prevention implications.

To determine the extent of misclassification of suicides with regard to work-relatedness and the implication for intervention, a matched case-control design was used. Cases were identified from California's master mortality file using ICD 9-CM external cause codes E950-959 and a positive response to the "injury-at-work" designation on the death certificate. Two controls matched on the same external cause of death codes, age, date of death, and county of occurrence were randomly selected. Outcome measures were odds ratios and accuracy assessments. Over 11% of cases and 23% of controls were misclassified. Extrapolation to the United States suggests thousands of suicides are misclassified as to a work-related connection. The findings point to misappropriation of the work-relatedness of suicide and hence, an inaccurate understanding of underlying risk factors and their intervention potential.

Predictors of genitorectal injury in female victims of suspected sexual assault.

OBJECTIVE: Legal decisions in sexual assault cases often hinge on the presence or absence of genitorectal injury. Unfortunately, the forensic literature does not explain why some victims sustain genitorectal injury and others do not. This study explores possible predictors of genitorectal injury in adult female sexual assault victims. METHODS: This retrospective cross-sectional analysis forms the derivation set for a larger planned prospective analysis. The authors extracted data describing consecutive female sexual assault victims who met inclusion criteria between July 1995 and July 1998. Exclusion criteria included male sex, lack of estrogen in females, consensual intercourse within the previous 72 hours, and lack of penetration during the assault. The authors explored associations between genitorectal injury and seven demographic variables, nine assault characteristics, and the time between assault and exam or postcoital interval (PCI). Variables thought to be predictive were incorporated into a logistic regression model. RESULTS: Five hundred forty-eight sexual assault victims were seen during the study time period; 209 of these met the inclusion criteria. Logistic regression controlling for important covariates showed an increase risk of genitorectal injury with a PCI < 24 hours (OR 7.47, 95% CI = 1.78 to 31.35), physical/verbal resistance (OR 5.96, 95% CI = 1.21 to 29.36), rectal penetration (OR 7.47, 95% CI = 1.05 to 53.07), and greater than high school education (OR 7.13, 95% CI = 1.03 to 49.65). CONCLUSIONS: This study presents an important first look at variables that may predict genitorectal injury in sexual assault victims. Future studies that examine more data are needed to corroborate this preliminary derivation set analysis.