A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells.

CRISPR technologies have begun to revolutionize T cell therapies; however, conventional CRISPR-Cas9 genome-editing tools are limited in their safety, efficacy, and scope. To address these challenges, we developed multiplexed effector guide arrays (MEGA), a platform for programmable and scalable regulation of the T cell transcriptome using the RNA-guided, RNA-targeting activity of CRISPR-Cas13d. MEGA enables quantitative, reversible, and massively multiplexed gene knockdown in primary human T cells without targeting or cutting genomic DNA. Applying MEGA to a model of CAR T cell exhaustion, we robustly suppressed inhibitory receptor upregulation and uncovered paired regulators of T cell function through combinatorial CRISPR screening. We additionally implemented druggable regulation of MEGA to control CAR activation in a receptor-independent manner. Lastly, MEGA enabled multiplexed disruption of immunoregulatory metabolic pathways to enhance CAR T cell fitness and anti-tumor activity in vitro and in vivo. MEGA offers a versatile synthetic toolkit for applications in cancer immunotherapy and beyond.

FOXO1 is a master regulator of memory programming in CAR T cells.

A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2-6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.

Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).

Reporting time toxicity in prospective cancer clinical trials: A scoping review.

PURPOSE: This review aimed to assess the measurement and reporting of time toxicity (i.e., time spent receiving care) within prospective oncologic studies. METHODS: On July 23, 2023, PubMed, Scopus, and Embase were queried for prospective or randomized controlled trials (RCT) from 1984 to 2023 that reported time toxicity as a primary or secondary outcome for oncologic treatments or interventions. Secondary analyses of RCTs were included if they reported time toxicity. The included studies were then evaluated for how they reported and defined time toxicity. RESULTS: The initial query identified 883 records, with 10 studies (3 RCTs, 2 prospective cohort studies, and 5 secondary analyses of RCTs) meeting the final inclusion criteria. Treatment interventions included surgery (n = 5), systemic therapies (n = 4), and specialized palliative care (n = 1). The metric "days alive and out of the hospital" was used by 80% (n = 4) of the surgical studies. Three of the surgical studies did not include time spent receiving ambulatory care within the calculation of time toxicity. "Time spent at home" was assessed by three studies (30%), each using different definitions. The five secondary analyses from RCTs used more comprehensive metrics that included time spent receiving both inpatient and ambulatory care. CONCLUSIONS: Time toxicity is infrequently reported within oncologic clinical trials, with no standardized definition, metric, or methodology. Further research is needed to identify best practices in the measurement and reporting of time toxicity to develop strategies that can be implemented to reduce its burden on patients seeking cancer care.

Preoperative patient factors that predict achieving the minimal clinically important difference following arthroscopic treatment of snapping scapula syndrome.

BACKGROUND: The aim of this study was to define the minimal clinically important difference (MCID) values for patient-reported outcomes (PROs) after arthroscopic treatment of snapping scapula syndrome (SSS) using a distribution-based method, and to identify demographic, clinical, and intraoperative factors significantly associated with the achievement of MCID. It was hypothesized that subjective satisfaction scores after the procedure would be strongly associated with the achievement of MCID thresholds for the PROs and that pain, preoperative response to injection, and a scapulectomy in addition to bursal resection would be predictive of clinically relevant improvement. METHODS: Patients who underwent arthroscopic treatment of SSS between October 2005 and September 2020 with a minimum of 2-year short-term postoperative follow-up were enrolled in this retrospective single-center study. The MCID was calculated using a distribution-based approach for the following PROs: 12-Item Short Form Health Survey (SF-12), American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), Quick Disabilities of the Arm, Shoulder, and Hand questionnaire (QuickDASH), Single Assessment Numeric Evaluation (SANE), and visual analog scale (VAS) pain "today" and "at worst." The association between achievement of the MCID and postoperative subjective satisfaction was investigated, and factors associated with achievement of MCID were determined using bivariate analysis. RESULTS: Of a total of 190 patients assessed for eligibility, 77 patients (38.1 ± 14.3 years; 36 females) were included. Within the study population, statistically significant improvements in postoperative SF-12 physical component summary (PCS) (P < .001) and mental component summary (MCS) (P < 0.034), ASES (P < .001), QuickDASH (P < .001), SANE (P < .001), and VAS pain (P < .001) scores were observed at the minimum 2-year follow-up. The calculated MCID threshold values based on the study population were 5.0 for SF-12 PCS, 5.8 for SF-12 MCS, 11.3 for ASES, -10.5 for QuickDASH, 14.7 for SANE, 1.5 for VAS pain, and 1.7 for VAS pain at worst. Reaching the MCID was strongly associated with postoperative satisfaction (rated on a scale of 1-10). Across the PROs, younger age, favorable preoperative response to injection, partial scapuloplasty or scapulectomy, no prior surgery, and pain and function at baseline were significantly associated with attaining MCID. CONCLUSIONS: Patients who underwent arthroscopic treatment for SSS experienced clinically significant improvements in functional scores, pain, and quality of life. This study demonstrated predictive roles for certain patient-specific factors and diagnostic variables for achieving MCID in PROs, which may help surgeons preoperatively assess the probability of success and manage patient expectations.

Immediate and sustained root caries prevention of fluoride varnish combined with toothpastes: findings of clinical relevance?

DESIGN: An in vitro study to determine the immediate and sustained effect of fluoride varnish and its combination with fluoride toothpastes in preventing the development of root caries. CASE SELECTION: Human root dentine samples (150) were randomly divided into five experimental protocols of 30 specimens each: 1) fluoride varnish (22,600 ppm fluoride and 1-5% CPP-ACP); 2) fluoride varnish followed by Paste One (1100 ppm sodium fluoride and CPP-ACP); 3) fluoride varnish followed by Paste Plus (900 ppm sodium fluoride and CPP-ACP); 4) fluoride varnish followed by Paste One and Paste Plus; and 5) no treatment (control). A layer of varnish was applied to specimens except the control group and was left in situ for 18 h. The varnish layer was removed, and the various toothpaste treatments were initiated. Half of the specimens in each group were assigned to a short-term incubation model in which they were immediately subjected to a 7-day cariogenic challenge consisting of a combination of human saliva and artificial saliva containing 2% sucrose. The other half of the specimens in each group were assigned to the long-term incubation model in which the experimental protocol was continued for 8 weeks before initiating the seven-day cariogenic challenge. The protocols were evaluated by assessing dentine porosity (rhodamine intensity), mineral density, biofilm biomass, and viability assays. DATA ANALYSIS: Confocal laser scanning microscopy was used to determine dentine porosity and Levene's test was used to verify the assumption of equality of variances and normal distribution of errors before two-way ANOVA and the Games-Howell test were carried out at a significance level of 0.05 for both incubation models. Microcomputed tomography was used to determine mineral density with statistical analysis involving Levene's test, two-way ANOVA and Tukey's test at a significance level of 0.05 for both incubation models. Biomass was evaluated using a biofilm biomass assay with analysis of optical density data using Levene's test, ANOVA and Scheffe's test at a significance level of 0.05. RESULTS: For both the short- and long-term incubation models, all the experimental regimes resulted in a statistically significant decrease in dentine porosity and an increase in mineral density when compared to the control group. Fluoride varnish followed by both pastes and fluoride varnish followed by Paste One resulted in a statistically significant decrease in dentine porosity for some depths in both models when compared to fluoride varnish alone. Changes in dentine porosity and mineral density were observed within groups over time. All the experimental regimes demonstrated anti-biofilm effects. Immediate and sustained anti-caries effects were observed for all preventive protocols, with the combination of fluoride varnish and Paste One resulting in superior additional anti-caries effects. CONCLUSIONS: The authors concluded that all protocols demonstrated immediate and sustained anti-caries effects against the development of root caries despite variations in effects over time. The combination of fluoride varnish and Paste One resulted in additional anti-caries effects that were consistently superior, with no additional effects being observed when Paste Plus was added in combination. The authors suggest that, within the study's limitations, topical fluoride varnish seems to have a protective effect on root surfaces for up to eight weeks and that fluoride varnish should be considered as an important adjunct strategy in the prevention of root caries in older adults.

Toward more rigorous and informative nutritional epidemiology: The rational space between dismissal and defense of the status quo.

To date, nutritional epidemiology has relied heavily on relatively weak methods including simple observational designs and substandard measurements. Despite low internal validity and other sources of bias, claims of causality are made commonly in this literature. Nutritional epidemiology investigations can be improved through greater scientific rigor and adherence to scientific reporting commensurate with research methods used. Some commentators advocate jettisoning nutritional epidemiology entirely, perhaps believing improvements are impossible. Still others support only normative refinements. But neither abolition nor minor tweaks are appropriate. Nutritional epidemiology, in its present state, offers utility, yet also needs marked, reformational renovation. Changing the status quo will require ongoing, unflinching scrutiny of research questions, practices, and reporting-and a willingness to admit that "good enough" is no longer good enough. As such, a workshop entitled "Toward more rigorous and informative nutritional epidemiology: the rational space between dismissal and defense of the status quo" was held from July 15 to August 14, 2020. This virtual symposium focused on: (1) Stronger Designs, (2) Stronger Measurement, (3) Stronger Analyses, and (4) Stronger Execution and Reporting. Participants from several leading academic institutions explored existing, evolving, and new better practices, tools, and techniques to collaboratively advance specific recommendations for strengthening nutritional epidemiology.

Economic evaluation of robotic and laparoscopic paraesophageal hernia repair.

BACKGROUND: Robotic approach in paraesophageal hernia (PEH) repair may improve outcomes over laparoscopic approach, though at additional cost. This study aimed to compare cost-effectiveness of robotic and laparoscopic PEH repair. METHODS: A decision tree was created analyzing cost-effectiveness of robotic and laparoscopic PEH repair. Costs were obtained from 2021 Medicare data and were accumulated within 60 months after surgery. Effectiveness was measured in quality-adjusted life-years (QALYs). Branch-point probabilities and costs of robotic surgery consumables were obtained from published literature. The primary outcome of interest was incremental cost-effectiveness ratio (ICER). One-way, two-way, and probabilistic sensitivity analyses were performed. A secondary analysis including attributable capital and maintenance costs of robotic surgery was conducted as well. RESULTS: Laparoscopic repair yielded 3.660 QALYs at $35,843.82. Robotic repair yielded 3.661 QALYs at $36,342.57, with an ICER of $779,488.62/QALY. Robotic repair was favored when rates of open conversion and symptom recurrence were low, or with reduced cost of robotic instruments. A probabilistic sensitivity analysis favored laparoscopic repair in 100% of simulations. When accounting for costs of robotic technology, robotic approach was preferred only in unrealistic clinical scenarios. CONCLUSIONS: Laparoscopic repair is likely more cost-effective for most institutions, though results were relatively similar. With experienced surgeons who surpass the initial learning curve, robotic surgery may improve outcomes enough to be cost-effective, but only when excluding capital and maintenance fees.

Association of self-reported use of cannabis for the purpose of improving physical, mental, and sleep health with problematic cannabis use risk.

BACKGROUND: Little is known about health-focused cannabis use purposes and their associations with risk for problematic cannabis use. This cross-sectional study examined three broad cannabis use purposes and association with risk for problematic use among young adult cannabis users who report using for > 1 health reasons. METHODS: Young adults completed an electronic survey as part of an ongoing study on substance use and health. Those who self-reported past 6-month use of ≥ 1 cannabis products-smoking, vaping, dabbing, eating, and blunts-were included in the analysis. Their purposes for use were coded into three categories: sleep, mental, and physical health. Problematic cannabis use (PCU) was measured with the three-level structure Cannabis Abuse Screening Test (CAST-3). Adjusted multivariable regression models were used to estimate use purposes associated with with problematic cannabis use at the p < 0.05 level. RESULTS: Participants (n = 954) were mostly female (63.94%) and Hispanic (54.93%). Mental health was the most endorsed reason (73.38%) for use among study sample. Among participants, 36.3% were classified as being at severe risk (CAST-3 score ≥ 8). There was a significant association between PCU risk and reporting cannabis use for physical health (p < 0.01), mental health, and sleep health (p < 0.01) purposes. Those who used cannabis for physical heath purposes had about four times the risk (adjusted relative risk ratio (aRRR) = 4.38, 95% CI = 3.06-6.69), those who used for mental health had about three times the risk (aRRR = 2.81, 95% CI = 1.86-4.72), and those who used for sleep health had almost two times the risk (aRRR = 1.83, 95% CI = 1.17-2.63) for severe PCU. CONCLUSION: All cannabis use purposes examined increased risk of problematic cannabis use. Physical health use purposes was associated with highest PCU risk. This study demonstrates the risk for cannabis use disorder associated with self-medicating with cannabis.

A primate model for the origin of flake technology.

When and how human ancestors first used tools remains unknown, despite intense research into the origins of technology. It has been hypothesized that the evolutionary roots of stone flake technology has its origin in percussive behavior. Before intentional stone flaking, hominins potentially engaged in various percussive behaviors resulting in accidental flake detachments. We refer to this scenario as the 'by-product hypothesis.' In this scenario, repeated detachments of sharp stone fragments eventually resulted in intentional flake production. Here, we tested the circumstances of accidental flake production as a by-product of percussive foraging in wild capuchin monkeys (Sapajus libidinosus) from Brazil, the only nonhuman primate known to habitually produce sharp-edged flakes through a percussive behavior. We conducted field experiments where we tested the potential for accidental flake production during nut cracking. We provided three different types of stone with varied material properties as anvils to assess the circumstances in which accidental production of sharp-edged flakes occurs during nut cracking. A further freehand knapping experiment, with the raw material that exhibited accidental flake detachments, allows a direct comparison of flakes that have been intentionally produced by an experienced knapper and flakes produced during nut cracking by capuchin monkeys. Our results show that raw material quality and morphology significantly affect the rate of sharp-edged flake production as well as the resulting lithic signature of this behavior. In addition, accidental flakes produced during capuchin nut cracking on highly isotropic raw material are similar in many respects to intentionally produced flakes by a human knapper. Our field experiments highlight the fact that nut-cracking behavior can lead to the unintentional production of substantial quantities of sharp-edged flakes and therefore supports the 'by-product hypothesis' as a potential mechanism for the emergence of hominin flake technology.

Cost-effectiveness analysis of infected necrotizing pancreatitis management in an academic setting.

BACKGROUND AND AIMS: Traditional management for infected necrotizing pancreatitis (INP) often utilizes open necrosectomy, which carries high morbidity and complication rates. Thus, minimally invasive strategies have gained favor, specifically step-up approaches utilizing endoscopic or minimally-invasive surgery (MIS); however, the ideal management modality for INP has not been identified. METHODS: A decision tree model was designed to analyze costs and survival associated with open necrosectomy, endoscopic step-up, and MIS step-up protocols for management of INP after 4 weeks of necrosis development with adequate retroperitoneal access. Costs were based on a third-party payer perspective using Medicare reimbursement rates. The model's effectiveness was represented by quality-adjusted life-years (QALYs). Sensitivity analyses were performed to validate results. RESULTS: Endoscopic step-up was the dominant economic strategy with 7.92 QALYs for $90,864.09. Surgical step-up resulted in a decrease of 0.09 QALYs and a cost increase of $10,067.89 while open necrosectomy resulted in a decrease of 0.4 QALYs and an increased cost of $18,407.52 over endoscopic step-up. In 100,000 random-sampling simulations, 65.5% of simulations favored endoscopic step-up. MIS step-up was favored when MIS acute mortality rates fell and when MIS drainage success rates rose. CONCLUSIONS: In our simulated patients with INP, the most cost-effective management strategy is endoscopic step-up. Cost-effectiveness varies with changes in acute mortality and drainage success, which will depend on local expertise.

Racial disparities in minimally invasive esophagectomy and gastrectomy for upper GI malignancies.

BACKGROUND: Esophageal cancer and gastric cancer are two important causes of upper GI malignancies. Literature has shown that minimally invasive esophagectomies (MIE) and gastrectomies (MIG), have shorter length of stay and fewer complications. However, limited literature exists about the association between race and access to MIE and MIG. This study aims to identify the racial disparities in the different approaches to esophagectomy and gastrectomy. We further evaluate the relationship between the race and postoperative complications. METHODS: This IRB-approved retrospective study utilized data from the American College of Surgeons National Quality Improvement Program. All recorded cases of MIE, MIG, open gastrectomy, and esophagectomy between 2012 and 2019 were isolated. Propensity score matching and univariate analysis was performed to assess the independent effect of black self-identified race on access and outcomes. p < 0.05 was required to achieve statistical significance. RESULTS: 7891 cases of esophagectomy and 5,132 cases of gastrectomy cases were identified. Using Propensity and logistic regression, we identified that black self-reported race is an independent predictor of open approach to gastrectomy (OR 1.6871943, 95% CI 1.431464-1.989829, p < 0.001). Black self-reported race was not predictive of operative approach among esophagectomy patients (OR 0.7942576, 95% CI 0.5698645-1.124228, p = 0.183). In contrast, black self-reported is an independent predictor of postoperative complications among esophagectomy patients only. Esophagectomy patients of black self-reported race were more likely to experience any complication (OR 1.4373437, 95% CI 1.1129239-1.8557096, p = 0.00537), severe complications (OR 1.3818966, 95% CI 1.0653087-1.7888454, p = 0.0144), and death (OR 2.00779762, 95% CI 1.08034921-3.56117535, p = 0.0211) within 30 days of their surgeries. CONCLUSION: Our analysis revealed a significant racial disparity in access to MIG and a higher incidence of post-operative complications amongst esophagectomy patients. Minimally invasive techniques are underutilized in racial minorities. The findings herein warrant further investigation to eliminate barriers and disparities.

Examining protective factors for substance use problems and self-harm behavior during adolescence: A longitudinal co-twin control study.

Sports participation, physical activity, and friendship quality are theorized to have protective effects on the developmental emergence of substance use and self-harm behavior in adolescence, but existing research has been mixed. This ambiguity could reflect, in part, the potential for confounding of observed associations by genetic and environmental factors, which previous research has been unable to rigorously rule out. We used data from the prospective, population-based Child and Adolescent Twin Study in Sweden (n = 18,234 born 1994-2001) and applied a co-twin control design to account for potential genetic and environmental confounding of sports participation, physical activity, and friendship quality (assessed at age 15) as presumed protective factors for adolescent substance use and self-harm behavior (assessed at age 18). While confidence intervals widened to include the null in numerous co-twin control analyses adjusting for childhood psychopathology, parent-reported sports participation and twin-reported positive friendship quality were associated with increased odds of alcohol problems and nicotine use. However, parent-reported sports participation, twin-reported physical activity, and twin-reported friendship quality were associated with decreased odds of self-harm behavior. The findings provide a more nuanced understanding of the risks and benefits of putative protective factors for risky behaviors that emerge during adolescence.

Sexual orientation and adolescent suicide attempt and self-harm: a co-twin control study.

BACKGROUND: Research has demonstrated that individuals who identify as a sexual minority (e.g., gay/lesbian, bisexual) are at increased risk for suicidality-related outcomes. However, previous research is primarily limited by the lack of adjustment for unmeasured (i.e., genetic and environmental) confounding factors and previous psychopathology. METHODS: Using the Child and Adolescent Twin Study in Sweden, we employed a co-twin control design to examine the extent to which the association between sexual orientation and adolescent suicide attempt and self-harm (SA/SH) was independent of genetic and environmental factors shared by twins, as well as measured symptoms of childhood psychopathology. RESULTS: Adolescents who identified as a sexual minority (i.e., gay/lesbian, bisexual, or other sexual orientation) were at two-fold increased odds for SA/SH (OR, 2.01 [95% confidence interval, 1.63-2.49) compared to heterosexual adolescents. When adjusting for all genetic and shared environmental factors that make twins similar and for measured childhood psychopathology, the association remained positive but attenuated to OR, 1.55 (1.11-2.16). CONCLUSIONS: Identifying as a sexual minority was associated with approximately 50% increased odds of SA/SH in adolescence after adjusting for unmeasured genetic and environmental factors shared by twins and for childhood psychopathology. The results support that environmental factors specifically associated with identifying as a sexual minority likely increase risk for SA/SH. Our findings highlight the need to monitor suicidality risk among this group.

Pancreatic Carcinosarcoma Clinical Outcome Analysis of the National Cancer Institute Database.

BACKGROUND: Pancreatic carcinosarcomas (PCS) are rare aggressive biphasic malignancies with a poor prognosis. We aimed to improve the understanding of PCS by analyzing variables that influence the mortality of PCS patients. METHODS: The Surveillance, Epidemiology, and End Results database was queried for cases of PCS from 1973 to 2016. Cases were analyzed for patient demographics, tumor characteristics, and surgical intervention. Kaplan-Meier and Cox regression analyses were applied to investigate the overall survival (OS) and prognostic factors. RESULTS: Thirty-nine cases of PCS were identified along with the disease demographics and characteristics. The majority of patients had a regionally invasive or metastatic disease. There was a significant decrease in OS with the increase of the tumor extension. Conversely, surgery showed to improve OS in the crude analysis, including patients that underwent lymphadenectomy. In addition, the unadjusted Cox regression results showed decreased hazard ratios with a local disease versus distant metastasis and with cancer-directed surgery versus no surgery. Nevertheless, the adjusted Cox regression results revealed that metastatic disease was the only significant predictor of survival. CONCLUSIONS: This population-based study provides some insight to a very rare disease by analyzing 39 cases of PCS. Our finding suggests considering PCS as a nonsurgical disease and reserving surgery solely for patients with a localized disease in combination or after neoadjuvant therapy. Consequently, there is a need to further investigate novel therapies for this aggressive malignancy.

A population-based study of concurrent prescriptions of opioid analgesic and selective serotonin reuptake inhibitor medications during pregnancy and risk for adverse birth outcomes.

BACKGROUND: Pregnant women with painful conditions often have mental health problems, including depression and anxiety. Co-morbid conditions may cause pregnant women to use multiple medications, although safety of such practice is poorly understood. OBJECTIVES: We investigated the influence of combined prescriptions of opioid analgesics and selective serotonin reuptake inhibitors (SSRIs) during pregnancy on two adverse birth outcomes. METHODS: We analysed Swedish population-based births (n = 688 914) between 2007 and 2013. Using national registers, we obtained data on filled medication prescriptions, birth outcomes, and a wide range of parental characteristics. We estimated preterm birth and small-for-gestational-age risk following independent or combined prescriptions of the two medications compared with no filled prescriptions for either medication. We adjusted for confounders using inverse probability of treatment weights. RESULTS: After adjusting for confounders, preterm birth risk was higher among women with opioid analgesic prescriptions only (5.9%; risk ratio [RR] 1.27, 95% confidence interval [CI] 1.22, 1.33), SSRIs only (6.2%; RR 1.34, 95% CI 1.27, 1.42), and both medications (7.8%; RR 1.70, 95% CI 1.47, 1.96) compared with unexposed women (4.6%). The interaction between the medications on preterm birth was small (risk difference [RD] 0.4%, 95% CI -0.8%, 1.6%); relative excess risk due to interaction [RERI] 0.09, 95% CI -0.17, 0.34; RR 1.00, 95% CI 0.85, 1.17). For small for gestational age, risk was approximately 2% across all groups, and there was no interaction between the medications (RD 0.3%, 95% CI -0.4%, 1.1%); RERI 0.15, 95% CI -0.16, 0.47; RR 1.15, 95% CI 0.87, 1.52). CONCLUSIONS: Compared with unexposed pregnancies, those with either medication alone had a small increased risk for preterm birth but no increased risk for small for gestational age. The magnitude of associations with combined exposure to both medications were not greater than the sum of the associations with each medication considered individually.

Cost-effectiveness of palliative emergent surgery versus endoscopic stenting for acute malignant colonic obstruction.

BACKGROUND: Endoscopic stenting has demonstrated value over emergent surgery as a palliative intervention for patients with acute large bowel obstruction due to advanced colorectal cancer. However, concerns regarding high reintervention rates and the risk of perforation have brought into question its cost-effectiveness. METHODS: A decision tree analysis was performed to analyze costs and survival in patients with unresectable or metastatic colorectal cancer who present with acute large bowel obstruction. The model was designed with two treatment arms: self-expanding metallic stent (SEMS) placement and emergent surgery. Costs were derived from medicare reimbursement rates (US$), while effectiveness was represented by quality-adjusted life years (QALYs). The primary outcome measure was the incremental cost-effectiveness ratio (ICER). The model was tested for validation using one-way, two-way, and probabilistic sensitivity analyses. RESULTS: Endoscopic stenting resulted in an average cost of $43,798.06 and 0.68 QALYs. Emergent surgery cost $5865.30 more, while only yielding 0.58 QALYs. This resulted in an ICER of - $58,653.00, indicating that SEMS placement is the dominant strategy. One-way and two-way sensitivity analyses demonstrated that emergent surgery would require an improved survival rate in comparison to endoscopic stenting to become the favored treatment modality. In 100,000 probabilistic simulations, endoscopic stenting was favored 96.3% of the time. CONCLUSIONS: In patients with acute colonic obstruction in the presence of unresectable or metastatic disease, endoscopic stenting is a more cost-effective palliative intervention than emergent surgery. This recommendation would favor surgery over SEMS placement with improved surgical survival, or if the majority of patients undergoing stenting required reintervention.

Revisiting the Factor Structure of Grit: A Commentary on Duckworth and Quinn (2009).

This commentary addresses debate over the factor structure of the Grit Scale in both its original and short forms. Commonly (and in our own work), factor solutions are used to establish dimensionality of the construct being measured. For example, a two-factor hierarchical model was proposed for the Short Grit Scale. It has since been pointed out, correctly, that the specified model cannot be distinguished from a model with two correlated subfactors and no higher-order factor. In this commentary, we acknowledge the mathematical equivalence of these specifications and our error in interpretation. However, we also take the opportunity to admit a more profound correction. It is now clear to us that statistical answers cannot definitively settle certain theoretical riddles, and our argument for grit as a compound of related but distinct dispositions should not have relied so heavily on the optimal factor solution for a questionnaire devised to assess it. Rather, a conceptual question demands a conceptual answer, which we briefly attempt here. We conclude by noting the need for improved operationalizations of the tendency to stay committed to goals for years (passion) while working assiduously toward their achievement (perseverance).

Use of medication for attention-deficit/hyperactivity disorder and risk of unintentional injuries in children and adolescents with co-occurring neurodevelopmental disorders.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often associated with other neurodevelopmental disorders (NDs) and with risky behaviors and adverse health outcomes, including injuries. Treatment with ADHD medication has been associated with reduced risk of injuries. However, it is unknown whether the association is present in individuals with co-occurring NDs. The aim of the present study was to estimate the association between ADHD medication use and unintentional injuries in Sweden in children and adolescents with ADHD, including those with co-occurring NDs. METHODS: Using a linkage of several national registers via the unique personal identification number, we identified individuals with a diagnosis of ADHD and of other NDs, including autism spectrum disorder, intellectual disability, communication disorders, learning disorders and motor disorders. The primary outcome was unintentional injuries. Secondary outcome was traumatic brain injury (TBI). Individuals were followed from January 1st 2006 or their 5th birthday or the date of the first unintentional injury, whichever came last, to December 31st 2013 or their 18th birthday or death, whichever came first. We compared the rate of injuries during periods on-treatment with the rate of injuries during periods off-treatment within the same individual using stratified Cox regression to calculate hazard ratio (HR) with 95% confidence intervals (CIs). RESULTS: For children and adolescents with ADHD (N = 9,421) the rate of any unintentional injuries (HR = 0.85; 95% CI = 0.78-0.92) and TBIs (HR = 0.27; 95% CIs = 0.20-0.38) during medicated periods was lower than during non-medicated periods. Similar results were found among individuals with co-occurring NDs (N = 2,986), for unintentional injuries (HR = 0.88; 95% CI = 0.77-1.01) and for TBIs (HR = 0.27; 95% CI = 0.16-0.44). CONCLUSIONS: Beneficial effects of ADHD medication may extend beyond reduction of ADHD core symptoms to prevention of unintentional injuries in children and adolescents, including individuals with co-occurring NDs.