Category: Statistics

Alzheimers Dement. 2024 Apr 4. doi: 10.1002/alz.13806. Online ahead of print.

ABSTRACT

INTRODUCTION: Fundamental questions remain about the key mechanisms that initiate Alzheimer’s disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock-in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan.

METHODS: CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non-invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures.

RESULTS: Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non-carriers. Analysis of brain revealed alterations in several enzyme-substrate interactions within the gamma secretase complex prior to adulthood.

DISCUSSION: Marmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate-specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression.

HIGHLIGHTS: We report the successful generation of genetically engineered marmosets harboring knock-in point mutations in the PSEN1 gene. PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD-related biomarkers. Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate-specific mechanisms that drive disease progression.

PMID:38574388 | DOI:10.1002/alz.13806

J Natl Cancer Inst. 2024 Apr 4:djae078. doi: 10.1093/jnci/djae078. Online ahead of print.

ABSTRACT

BACKGROUND: We examined whether the association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of defective MMR (dMMR)-related tumor mutational signatures (TMSs).

METHODS: We used data from 227,916 men and women who participated in the Nurses’ Health Study (1980-2016), the Nurses’ Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2016). Dietary data was collected every 4 years through validated food frequency questionnaires. Relative contributions of two dMMR-related TMSs (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC cases. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the TMSs. All statistical tests were 2-sided.

RESULTS: We documented 825 incident CRC cases with available TMS data over 26-36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (P-heterogeneitytrend = 0.02) compared to tumors with lower contributions of this TMS. Compared with nondrinkers, drinkers with ≥15 g/d of alcohol had a high risk of c-dMMRb/SBS26-high CRC [multivariable-adjusted HR: 2.43 (95% CI: 1.55-3.82)], but not c-dMMRb/SBS26-low CRC [0.86 (95% CI: 0.57-1.28)] or c-dMMRb/SBS26-moderate CRC [1.14 (95% CI: 0.76-1.71)]. No significant differential associations were observed for c-dMMRa/SBS15 (P-heterogeneitytrend = 0.41).

CONCLUSIONS: High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.

PMID:38574386 | DOI:10.1093/jnci/djae078

Health Secur. 2024 Apr 4. doi: 10.1089/hs.2023.0099. Online ahead of print.

ABSTRACT

The surveillance and identification of emerging, reemerging, and unknown infectious disease pathogens is essential to national public health preparedness and relies on fluidity, coordination, and interconnectivity between public and private pathogen surveillance systems and networks. Developing a national sentinel surveillance network with existing resources and infrastructure could increase efficiency, accelerate the identification of emerging public health threats, and support coordinated intervention strategies that reduce morbidity and mortality. However, implementing and sustaining programs to detect emerging and reemerging pathogens in humans using advanced molecular methods, such as metagenomic sequencing, requires making large investments in testing equipment and developing networks of clinicians, laboratory scientists, and bioinformaticians. In this study, we sought to gain an understanding of how federal government agencies currently support such pathogen agnostic testing of human specimens in the United States. We conducted a landscape analysis of federal agency websites for publicly accessible information on the availability and type of pathogen agnostic testing and details on flow of clinical specimens and data. The website analysis was supplemented by an expert review of results with representatives from the federal agencies. Operating divisions within the US Department of Health and Human Services and the US Department of Veterans Affairs have developed and sustained extensive clinical and research networks to obtain patient specimens and perform metagenomic sequencing. Metagenomic facilities supported by US agencies were not equally geographically distributed across the United States. Although many entities have work dedicated to metagenomics and/or support emerging infectious disease surveillance specimen collection, there was minimal formal collaboration across agencies.

PMID:38574329 | DOI:10.1089/hs.2023.0099

J Clin Oncol. 2024 Apr 4:JCO2302235. doi: 10.1200/JCO.23.02235. Online ahead of print.

ABSTRACT

PURPOSE: To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery.

METHODS: Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m² and G 50 mg/m² were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0.

RESULTS: Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment.

CONCLUSION: Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.

PMID:38574312 | DOI:10.1200/JCO.23.02235

J Laparoendosc Adv Surg Tech A. 2024 Apr 4. doi: 10.1089/lap.2023.0472. Online ahead of print.

ABSTRACT

Background: Life expectancy of patients with rectal cancer is increasing day by day with innovative treatments. Low anterior resection syndrome (LARS), which disrupts the comfort of life in these patients, has become a serious problem. We aimed to evaluate the effect of high ligation (HL) and low ligation (LL) techniques on LARS in rectal cancer surgery performed with the robotic method. Materials and Methods: The data of patients diagnosed with mid-distal rectal cancer between 2016 and 2021 who underwent robotic low anterior resection by the same team in the same center with neoadjuvant chemoradiotherapy were retrospectively evaluated. Patients were divided into two groups as those who underwent HL and LL procedures. Preoperative, 8 weeks after neoadjuvant treatment, 3 and 12 months after ileostomy closure were evaluated. Results: A total of 84 patients (41 HL, 43 LL) were included in the study. There was no statistically significant difference between the demographic characteristics and pathology data of the patients. Although there was a decrease in LARS scores after neoadjuvant treatment, there was a statistically significant difference between the two groups at 3 and 12 months after ileostomy closure (P: .001, P: .015). Conclusions: In patients who underwent robotic low anterior resection, there is a statistically significant difference in the LARS score in the first 1 year with the LL technique compared with that of the HL technique, and the LL technique has superiority in reducing the development of LARS between the two oncologically indistinguishable methods.

PMID:38574307 | DOI:10.1089/lap.2023.0472

JCO Glob Oncol. 2024 Apr;10:e2300379. doi: 10.1200/GO.23.00379.

ABSTRACT

PURPOSE: The aim of this study is to characterize lung cancer treatment clinical trials in Latin America before (January 2001-December 2011) and after (January 2012-December 2021) the organization of major Latin American oncology cooperative groups.

MATERIALS AND METHODS: Interventional clinical trials were identified in ClinicalTrials.gov using the search terms “lung cancer,” country filters for 20 Latin American countries, and study start dates January 1, 2001-December 31, 2011, and January 1, 2012-December 31, 2021. Clinical trials were categorized as either originating in Latin America (LA) or outside Latin America (non-LA) with participation of Latin American countries. Descriptive statistics, two-sided Z-scores, and chi-square analyses with 95% CIs were calculated.

RESULTS: Overall, 273 clinical trials involving Latin American countries between 2001 and 2021 were identified. Comparing 2001-2011 with 2012-2021, there was an increase in total clinical trials (100 v 173; P < .001). Only 9% (26 of 273) of all trials were LA trials. There was a marked decrease in the proportion of LA trials (14% v 7%, P = .058) and estimated enrollment to LA trials (3,245 v 1,190 patients; P < .001). Recruiting of patients with EGFR (29% v 7%; P < .01) and KRAS (18% v 2%; P < .01) driver mutations also decreased. Trial participation was highest in Brazil, Mexico, Argentina, Chile, and Peru and increased over time: Brazil (61 v 108; 77% increase), Mexico (40 v 88; 120% increase), Argentina (50 v 78; 56% increase), Chile (25 v 57; 128% increase), and Peru (14 v 37; 164% increase).

CONCLUSION: There was a significant increase in clinical trial participation by Latin American countries, from 2001-2011 to 2012-2021. However, there were few clinical trials which originated in Latin America or focused on patients with driver mutations.

PMID:38574300 | DOI:10.1200/GO.23.00379

JBJS Rev. 2024 Apr 4;12(4). doi: 10.2106/JBJS.RVW.23.00150. eCollection 2024 Apr 1.

ABSTRACT

BACKGROUND: Vitamin D deficiency is increasingly identified as a predictor of poorer outcomes in musculoskeletal disease affecting as many as 1 in 4 people. This study aimed to evaluate the effect of vitamin D supplementation on outcomes after primary total knee arthroplasty (TKA).

METHODS: A targeted search of terms related to vitamin D and TKA outcomes was performed in PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, American Academy of Orthopaedic Surgeons, and British Orthopaedic Association databases. The results were analyzed using forest plots with I2 heterogeneity statistics and pooled effects with 95% confidence intervals (CIs) and p values. A p < 0.05 was considered statistically significant.

RESULTS: A total of 146,054 patients with 150,107 TKRs were analyzed in 10 studies that complied with the inclusion criteria, of which 3 were suitable for meta-analysis. Of these, 4 of the 10 studies showed that vitamin D deficiency resulted in poorer functional outcome scores (Western Ontario and McMasters Universities Osteoarthritis Index, Knee Society Scoring System, and American Knee Society scores), as well as increased risk of revision surgery, incidence of joint infection, and postoperative stiffness. Meta-analysis of length of hospital stay (LOS) demonstrated a significant increase in LOS in patients with vitamin D deficiency (standardized mean difference, -0.54, 95% CI, -0.69 to -0.38, p < 0.00001). Furthermore, outcomes were improved with vitamin D supplementation in 6 of 10 studies.

CONCLUSION: Vitamin D deficiency results in poorer outcomes of primary TKA, with improved outcomes after supplementation. Further studies should examine the role of preoperative vitamin D screening and/or perioperative supplementation in primary TKA and standardize outcome measures to assess their effect.

LEVEL OF EVIDENCE: Level I/II. See Instructions for Authors for a complete description of levels of evidence.

PMID:38574186 | DOI:10.2106/JBJS.RVW.23.00150

JBJS Rev. 2024 Apr 4;12(4). doi: 10.2106/JBJS.RVW.23.00222. eCollection 2024 Apr 1.

ABSTRACT

BACKGROUND: The anterior cruciate ligament (ACL) is the most commonly injured ligament in the knee. ACL reconstruction (ACLR) proves the standard for treating this injury. However, graft choice and method of fixation remain a heavily debated topic. This study investigates the following: bone-patellar tendon-bone (BPTB) vs. hamstring tendon (HT) autograft, single-bundle vs. double-bundle hamstring graft, and metal vs. bioabsorbable screws in ACLR.

METHODS: A systematic review was performed on PubMed and Google Scholar according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were collected on patient demographics, complications, and functionality scores including International Knee Documentation Committee (IKDC) and Lysholm scores. A systematic review and meta-analysis were conducted with Review Manager. Outcome measurements were determined using forest plots with significant differences considered p < 0.05.

RESULTS: Twenty-five studies were included, accounting for 2,170 patients. No statistically significant difference was appreciated when comparing BPTB to hamstring autografts. Patients who received a double bundle HT autograft exhibited significantly superior outcomes in terms of revision (p = 0.05), failure (p = 0.002), normal pivot shift tests (p = 0.04), and normal IKDC (p = 0.008). When comparing screw types, bioabsorbable screws had a greater Lysholm score (p = 0.01) and lower failure rates for copolymer screws (p = 0.03).

CONCLUSION: Overall, the data collected suggested that BPTB and HT autografts display similar postoperative results. However, if an HT autograft is used, the data suggest a double-bundle graft improves both functionality and decreases the possible complications. Finally, bioabsorbable screws prove superior to metal screws when looking at both functionality and failure rates. Further research into the superior graft type is still needed.

LEVEL OF EVIDENCE: Level II. See Instructions for Authors for a complete description of levels of evidence.

PMID:38574182 | DOI:10.2106/JBJS.RVW.23.00222

PLoS One. 2024 Apr 4;19(4):e0299789. doi: 10.1371/journal.pone.0299789. eCollection 2024.

ABSTRACT

We examined the spatial distribution of Per- and Polyfluoroalkyl Substances (PFAS) in the US drinking water and explored the relationship between PFAS contamination, public water systems (PWS) characteristics, and socioeconomic attributes of the affected communities. Using data from the EPA’s third Unregulated Contaminant Rule, the Census Bureau, and the Bureau of Labor Statistics, we identified spatial contamination hot spots and found that PFAS contamination was correlated with PWSs size, non-surface raw water intake sources, population, and housing density. We also found that non-white communities had less PFAS in drinking water. Lastly, we observed that PFAS contamination varied depending on regional industrial composition. The results showed that drinking water PFAS contamination was an externality of not only some industrial activities but also household consumption.

PMID:38574164 | DOI:10.1371/journal.pone.0299789

Science. 2024 Apr 5;384(6691):48-53. doi: 10.1126/science.adi7877. Epub 2024 Apr 4.

ABSTRACT

Understanding universal aspects of quantum dynamics is an unresolved problem in statistical mechanics. In particular, the spin dynamics of the one-dimensional Heisenberg model were conjectured as to belong to the Kardar-Parisi-Zhang (KPZ) universality class based on the scaling of the infinite-temperature spin-spin correlation function. In a chain of 46 superconducting qubits, we studied the probability distribution of the magnetization transferred across the chain’s center, [Formula: see text]. The first two moments of [Formula: see text] show superdiffusive behavior, a hallmark of KPZ universality. However, the third and fourth moments ruled out the KPZ conjecture and allow for evaluating other theories. Our results highlight the importance of studying higher moments in determining dynamic universality classes and provide insights into universal behavior in quantum systems.

PMID:38574139 | DOI:10.1126/science.adi7877