bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015
Authors: Reece Albert Stuart , Hulse Gary Kenneth 
Published: January 2022

Abstract
Background
Cannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum. We examined these issues including contextual space-time relationships and formal causal inferential analysis in USA.

Methods
State congenital anomaly (CA) rate (CAR) data was taken from the annual reports of the National Birth Defects Prevention Network 2001–2005 to 2011–2015. Substance abuse rates were from the National Survey of Drug Use and Health a nationally representative longitudinal survey of the non-institutionalized US population with 74.1% response rate. Drugs examined were cigarettes, monthly and binge alcohol, monthly cannabis and analgesic and cocaine abuse. Early termination of pregnancy for abortion (ETOPFA) rates were taken from the published literature. Cannabinoid concentrations were from Drug Enforcement Agency. Ethnicity and income data were from the US Census Bureau. Inverse probability weighted (IPW) regressions and geotemporospatial regressions conducted for selected CAs.

Results
Data on 18,328,529 births from an aggregated population of 2,377,483,589 for mid-year analyses 2005–2013 comprehending 12,611 CARs for 62 CAs was assembled and ETOPFA-corrected (ETOPFACAR) where appropriate. E-Values for ETOPFACARs by substance trends were elevated for THC (40 CAs), cannabis (35 CAs), tobacco (11 CAs), cannabidiol (8 CAs), monthly alcohol (5 CAs) and binge alcohol (2 CAs) with minimum E-Values descending from 16.55, 1.55x107, 555.10, 7.53x1019, 9.30 and 32.98. Cardiovascular, gastrointestinal, chromosomal, limb reductions, urinary, face and body wall CAs particularly affected. Highest v. lowest substance use quintile CAR prevalence ratios 2.84 (95%C.I. 2.44, 3.31), 4.85 (4.08, 5.77) and 1.92 (1.63, 2.27) and attributable fraction in exposed 0.28 (0.27, 0.28), 0.57 (0.51, 0.62) and 0.47 (0.38, 0.55) for tobacco, cannabis and cannabidiol. Small intestinal stenosis or atresia and obstructive genitourinary defect were studied in detail in lagged IPW pseudo-randomized causal regressions and spatiotemporal models confirmed the causal role of cannabinoids. Spatiotemporal predictive modelling demonstrated strongly sigmoidal non-linear cannabidiol dose-response power-function relationships (P = 2.83x10−60 and 1.61x10−71 respectively).

Conclusions
Data implicate cannabinoids including cannabidiol in a diverse spectrum of heritable CAs. Sigmoidal non-linear dose-response relationships are of grave concern.
These transgenerational genotoxic, epigenotoxic, chromosomal-toxic putatively causal teratogenic effects strongly indicate tight restrictions on community cannabinoid penetration.
The effect of COVID-19 lockdown on the glycemic control of children with type 1 diabetes
Authors: Hakonen Elina , Varimo Tero , Tuomaala Anna-Kaisa , Miettinen Päivi J. , Pulkkinen Mari-Anne 
Published: January 2022

Abstract
Background
Between March 18th and May 13th 2020, the COVID-19 pandemic outbreak in Finland resulted in the closure of schools and the limitation of daycare (i.e. lockdown). Social distancing changed the daily routines of children with type 1 diabetes (T1D). Healthcare professionals were forced to adapt to the pandemic by replacing physical outpatient visits with virtual visits. However, the influence of the lockdown on glycemic control in these patients remained unknown.

Methods
In this retrospective register study from a pediatric diabetes outpatient clinic, we analyzed the glycemic data of T1D patients (n = 245; aged 4 to 16 years) before and under the lockdown. All the participants used continuous glucose monitoring (rtCGM or iCGM), two-thirds were on insulin pumps (CSII), and one-third on multiple daily insulin injections (MDI) therapy.

Results
In our patient cohort, time in range (TIR, n = 209) and mean glucose levels (n = 214) were similar prior to and under the lockdown (mean change 0.44% [95%CI: -1.1–2.0], p = 0.56 and -0.13 mmol/mol [95%CI: -0.3–0.1], p = 0.17, respectively). However, children treated with CSII improved their glycemic control significantly during the lockdown: TIR improved on average 2.4% [0.6–4.2] (p = 0.010) and mean blood glucose level decreased -0.3 mmol/mol [-0.6-(-0.1)] (p = 0.008). The difference was more pronounced in girls, adolescents and patients using conventional insulin pumps.

Conclusions
The glycemic control in T1D children did not deteriorate under the lockdown, and patients on CSII even improved their control, which suggests that social distancing might have allowed families to use the insulin pump more accurately as out-of-home activities were on hold.
Differential microbiological spectrum and resistance pattern in periprosthetic hip joint infections: a matched-cohort analysis comparing direct anterior versus lateral approach
Authors: Aichmair Alexander , Frank Bernhard J. H. , Singer Gabriel , Simon Sebastian , Dominkus Martin , Hofstaetter Jochen G. 
Published: January 2022

Abstract
Background
In recent years, total hip arthroplasty via the direct anterior approach (DAA) has become more common. Little is known on the influence of the surgical approach on the microbiological spectrum and resistance pattern in periprosthetic hip joint infections. The aim of the present study was to evaluate the microbiological spectrum and resistance pattern in periprosthetic hip joint infections comparing the direct anterior versus lateral approach in a matched-cohort analysis at a single institution.

Methods
Patients who underwent revision hip arthroplasty due to PJI following primary total hip arthroplasty with culture positive microbiology were analyzed. In all study patients, both the primary surgery and the revisions surgery were performed at the same institution. Only patients in whom primary surgery was performed via a direct anterior or lateral approach were included (n = 87). A matched cohort analysis was performed to compare the microbiological spectrum and resistance pattern in PJI following direct anterior (n = 36) versus lateral (n = 36) primary THA.

Results
We identified both a significantly different microbiological spectrum and resistance pattern in PJI comparing direct anterior versus lateral approach THA. Cutibacterium avidum was obtained more frequently in the anterior subgroup (22.2% vs. 2.8%, p = 0.028). In the subgroup of infections with Staphylococcus aureus (n = 12), methicillin resistance was detected in 3/5 cases in the direct anterior group versus 0/7 cases in the lateral group (p = 0.045). Overall, Staphylococcus epidermidis was the most common causative microorganism in both groups (direct anterior: 36.1%; lateral: 27.8%, p = 0.448).

Conclusion
The present study indicates a potential influence of the localization of the skin incision in THA on the microbiological spectrum and resistance pattern in PJI. Cutibacterium avidum seemed to be a more common causative microorganism in PJI in patients who underwent direct anterior compared to lateral approach THA.
Single-dose SARS-CoV-2 vaccinations with either BNT162b2 or AZD1222 induce disparate Th1 responses and IgA production
Authors: Müller Michael , Volzke Johann , Subin Behnam , Müller Silke , Sombetzki Martina , Reisinger Emil C. , Müller-Hilke Brigitte 
Published: January 2022

Abstract
Background
While vaccination programs against the severe acute respiratory syndrome virus 2 (SARS-CoV-2) are globally ongoing, disparate strategies for the deployment of spike antigen show varying effectiveness.

Methods
In order to explore this phenomenon, we sought to compare the early immune responses against AZD1222 and BNT162b2. SARS-CoV-2 seronegative participants received a single dose of either vaccine and were analyzed for immune cell, effector T cell, and antibody dynamics.

Results
AZD1222 induced transient leukopenia and major changes among innate and adaptive subpopulations. Both vaccines induced spike protein-specific effector T cells which were dominated by type 1 helper T cell responses following AZD1222 vaccination. A significant reduction of anti-inflammatory T cells upon re-stimulation was also restricted to AZD1222 vaccinees. While IgM and IgG were the dominant isotypes elicited by AZD1222, BNT162b2 led to a significant production of IgG and IgA.

Conclusions
Our results suggest that the strategy for spike protein delivery impacts on how and to what extent immune priming against the main SARS-CoV-2 antigen proceeds.
Correlation of physical and cognitive impairment in diabetic and hypertensive frail older adults
Authors: Mone Pasquale , Gambardella Jessica , Lombardi Angela , Pansini Antonella , De Gennaro Stefano , Leo Anna Luisa , Famiglietti Michele , Marro Anna , Morgante Maria , Frullone Salvatore , De Luca Antonio , Santulli Gaetano 
Published: January 2022

AbstractBackgroundDiabetes and hypertension are common in older adults and represent established risk factors for frailty. Frailty is a multidimensional condition due to reserve loss and susceptibility to stressors with a high risk of death, hospitalizations, functional and cognitive impairment. Comorbidities such as diabetes and hypertension play a key role in increasing the risk of mortality, hospitalization, and disability. Moreover, frail patients with diabetes and hypertension are known to have an increased risk of cognitive and physical impairment. Nevertheless, no study assessed the correlation between physical and cognitive impairment in frail older adults with diabetes and hypertension.MethodsWe evaluated consecutive frail older patients with diabetes and hypertension who presented at ASL (local health unit of the Italian Ministry of Health) Avellino, Italy, from March 2021 to October 2021. The inclusion criteria were: a previous diagnosis of diabetes and hypertension with no evidence of secondary causes; age > 65 years; a frailty status; Montreal Cognitive Assessment (MoCA) score < 26.Results179 patients successfully completed the study. We found a strong and significant correlation between MoCA score and 5-m gait speed test (r: 0.877; p < 0.001). To further verify our results, we performed a linear multivariate analysis adjusting for potential confounding factors, with MoCA score as dependent variable, which confirmed the significant association with glycemia (p < 0.001).ConclusionsThis is the first study showing a significant correlation between 5-m gait speed test and MoCA score in frail diabetic and hypertensive older adults.
Pilot study on the value of echocardiography combined with lung ultrasound to evaluate COVID-19 pneumonia
Authors: Han Jing , Yang Xi , Xu Wei , Jin Ronghua , Liu Weiyuan , Ding Lei , Meng Sha , Zhang Yuan , Li Jin , Zheng Ying , Li Haowen , Meng Fankun 
Published: January 2022

Abstract
Background
This study aimed to investigate the relationship between echocardiography results and lung ultrasound score (LUS) in coronavirus disease 2019 (COVID-19) pneumonia patients and evaluate the impact of the combined application of these techniques in the evaluation of COVID-19 pneumonia.

Methods
Hospitalized COVID-19 pneumonia patients who underwent daily lung ultrasound and echocardiography were included in this study. Patients with tricuspid regurgitation within three days of admission were enrolled. Moreover, the correlation and differences between their pulmonary artery pressure (PAP) and LUS on days 3, 8, and 13 were analyzed. The inner diameter of the pulmonary artery root as well as the size of the atria and ventricles were also considered.

Results
The PAP on days 3, 8, and 13 of hospitalization was positively correlated with the LUS (r = 0.448, p = 0.003; r = 0.738, p < 0.001; r = 0.325, p = 0.036, respectively). On day 8, the values of both PAP and LUS were higher than on days 3 and 13 (p < 0.01). Similarly, PAP and LUS were significantly increased in 92.9% (39/42) and 90.5% (38/42) of patients, respectively, and at least one of these two values was positive in 97.6% (41/42) of cases. The inner diameters of the right atrium, right ventricle, and pulmonary artery also differed significantly from their corresponding values on days 3 and 13 (p < 0.05).

Conclusions
PAP is positively correlated with LUS in COVID-19 pneumonia. The two values could be combined for a more precise assessment of disease progression and recovery status.
The path to the clinic: a comprehensive review on direct KRASG12C inhibitors
Authors: Kwan Albert K. , Piazza Gary A. , Keeton Adam B. , Leite Caio A. 
Published: January 2022

AbstractTheRASoncogene is both the most frequently mutated oncogene in human cancer and the first confirmed human oncogene to be discovered in 1982. After decades of research, in 2013, the Shokat lab achieved a seminal breakthrough by showing that the activated KRAS isozyme caused by the G12C mutation in theKRASgene can be directly inhibited via a newly unearthed switch II pocket. Building upon this groundbreaking discovery, sotorasib (AMG510) obtained approval by the United States Food and Drug Administration in 2021 to become the first therapy to directly target the KRAS oncoprotein in any KRAS-mutant cancers, particularly those harboring theKRASG12Cmutation. Adagrasib (MRTX849) and other direct KRASG12Cinhibitors are currently being investigated in multiple clinical trials. In this review, we delve into the path leading to the development of this novel KRAS inhibitor, starting with the discovery, structure, and function of the RAS family of oncoproteins. We then examine the clinical relevance of KRAS, especially the KRASG12Cmutation in human cancer, by providing an in-depth analysis of its cancer epidemiology. Finally, we review the preclinical evidence that supported the initial development of the direct KRASG12Cinhibitors and summarize the ongoing clinical trials of all direct KRASG12Cinhibitors.
Penfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases
Authors: Chen Yue-hong , Liu Rong-han , Cui Ya-zhou , Hettinghouse Aubryanna , Fu Wen-yu , Zhang Lei , Zhang Chen , Liu Chuan-ju 
Published: January 2022

Abstract
Background
Penfluridol, isolated from an FDA-approved small-molecule drug library as an inhibitor of tumor necrosis factor α (TNFα)-stimulated NF-κB activation, is clinically used to treat chronic schizophrenia and related disorders. This study is aimed to investigate the therapeutic effect of penfluridol on TNFα-stimulated inflammatory autoimmune diseases, particularly inflammatory arthritis.

Methods
Various in vitro studies to confirm the inhibitory effect of penfluridol on TNFα-induced NF-κB activity in bone marrow-derived macrophages or Raw 264.7 macrophage cell line. In vivo studies assessed the therapeutic effects of penfluridol in various disease models, including TNFα transgenic mice, collagen-induced arthritis, DSS-induced colitis, and TNBS-induced colitis. Identification and characterization of the binding of penfluridol to acid sphingomyelinase using bioinformatics and drug affinity responsive target stability assay. Acid sphingomyelinase activity assays to reveal penfluridol-mediated inhibition of acid sphingomyelinase activity. siRNA knockdown experiments to illustrate the dependence of penfluridol’s anti-TNF activity on acid sphingomyelinase.

Results
Penfluridol effectively inhibited TNFα-induced NF-κB activation in vitro and alleviated the severity of arthritis and colitis in vivo. Mechanistic studies revealed that penfluridol bound to acid sphingomyelinase and inhibited its activation. In addition, knockdown of acid sphingomyelinase largely abolished the inhibitory effects of penfluridol on TNFα-induced inflammatory cytokine production. Furthermore, penfluridol suppressed the differentiation of spleen naive CD4+T cells to TH1 and TH17 and inhibited M1 macrophage polarization.

Conclusion
This study provides the rationale for the possible innovative use of penfluridol as a newly identified small-molecule drug for TNFα-driven diseases, such as inflammatory arthritis and colitis.
Cannabinoids in psychiatry: they are here to stay
Authors: Woo Julia Jiyeon , van Reekum Emma , Bhattacharyya Sagnik , Samaan Zainab 
Published: January 2022

SummaryCannabinoids are commonly perceived by the public as safe and effective for improving mental health, despite limited evidence to support their use. We discuss reasons why cannabinoids may be particularly compelling for our patients and provide strategies for how psychiatrists can counsel and educate patients on the evidence regarding cannabinoids.
Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC).
Authors: Barzi Afsaneh , Azad Nilofer Saba , Yang Yan , Tsao-Wei Denice , Rehman Rabia , Fakih Marwan , Iqbal Syma , El-Khoueiry Anthony B. , Millstein Joshua , Jayachandran Priya , Zhang Wu , Lenz Heinz-Josef 
Published: January 2022

15 Background: Immune check point inhibitors (ICI) are ineffective in MSSCRC. Combination of ICI with targeted agents has the potential to alter the tumor microenvironment and render these tumors vulnerable to ICI. We report the results of the multicenter study of rego and pembro in a diverse patient population with advanced MSSCRC. Methods: This was an investigator-initiated study and enrolled patients (pts) who had failed/were intolerant of chemotherapy at 3 sites. A 3+3 design was used for phase I to evaluate escalating doses of rego (80,120,160, days 1-14/21) in combination with pembro (200m/q3weeks). The primary endpoint was dose limiting toxicities during the first cycle. For phase II, pts received rego at the recommended phase II dose (RP2D) with pembro. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS) and objective response rate (ORR). The study was powered to show an improvement in PFS from 1.9 months (CORRECT data) to 2.85 months. Estimated sample size for phase II was 63 pts. Results: Study started in 7/2019 and accrual completed in 7/2021. Of 73 pts, 10 enrolled in phase I and 63 in phase II. RP2D of rego was 80 mg, days 1-14/21, and 70 pts treated at that dose. As of Sep 14, 11 pts remain on treatment. At baseline, median age was 54 years (23-81), 51% female, 53% white, 19% Asian, 12% black, and 11% Hispanic, median prior lines of therapy 2 (1-5), primary tumor location rectosigmoid/rectal 13%, KRAS mutated 68%, BRAF mutated 5%. Liver metastases was present in 78% of the pts. There was no grade 4 toxicity. The most common grade 3 toxicities were rash (20%), followed by hand-foot syndrome and HTN (7%). Dose modification was required in 14%. The most common reason for discontinuation was disease progression (85%), followed by withdrawal of consent (12%). With a median follow up of 5.3 (range:0.6-24.4) months, median PFS was 2.0 (1.8 -3.5) months, and median OS was 10.9 (5.3-NR) months. In 16 pts (23%), with non-liver metastatic disease PFS was 4.3 (1.9-8.4) months. No objective response was observed. Stable disease was observed in 49% of pts, median duration of stable disease was 2 (0.2-18.8) months. Conclusions: This is the largest trial of combination of ICI + rego in MSSCRC reported to date. The trial didn’t meet its primary endpoint, though the median OS is provocative. Analysis of biomarkers for identification of pts with longer duration of benefit is ongoing. Clinical trial information: NCT03657641.
PD-1 blockade alone for mismatch repair deficient (dMMR) locally advanced rectal cancer.
Authors: Lumish Melissa Amy , Cohen Jenna L. , Stadler Zsofia Kinga , Weiss Jill A , Lamendola-Essel Michelle F. , Yaeger Rona , Segal Neil Howard , El Dika Imane H. , Saltz Leonard B. , Shcherba Marina , Sugarman Ryan , Desai Avni Mukund , Smith Jesse Joshua , Widmar Maria , Pappou Emmanouil , Paty Philip , Garcia-Aguilar Julio , Weiser Martin R. , Diaz Luis A. , Cercek Andrea 
Published: January 2022

16 Background: Total neoadjuvant therapy with induction chemotherapy and chemoradiation (chemoRT) is the standard treatment for locally advanced rectal adenocarcinomas. Mismatch repair deficient (dMMR) rectal tumors respond poorly to neoadjuvant chemotherapy. PD-1 blockade is effective in patients with metastatic dMMR colorectal cancers, but its efficacy has not been established in the neoadjuvant setting. The purpose of this study is to evaluate the clinical benefit of neoadjuvant PD-1 blockade in dMMR locally advanced rectal cancer. Methods: We designed a prospective, single-arm, phase II study in which patients with stage II and III dMMR rectal cancer receive neoadjuvant dostarlimab (anti-PD-1) for a total of 6 months. The co-primary objectives are to determine the overall response rate (ORR) and pathologic complete response (pCR) or clinical complete response rate (cCR) with or without chemoRT. Tumor assessment with endoscopic evaluation is performed at baseline, 6 weeks, 3 months and 6 months; imaging is performed at pretreatment baseline, 3 months and 6 months. Patients with cCR by previously established criteria are eligible for non-operative management without chemoRT. Those with residual disease after neoadjuvant dostarlimab receive standard chemoRT. Following chemoRT, any patient failing to achieve a cCR is then managed surgically. Results: A total of 13 patients have been enrolled, with median age 52 years (range 26-78), 77% female, and 92% with node-positive disease by rectal MRI. The ORR is 100% in the 12 patients who have undergone at least a 3-month evaluation. Seven patients have completed induction therapy and all 7 (100%) have achieved a cCR and are undergoing observation without chemoRT or surgery. The rate of progressive disease thus far is 0%. No patients have required chemoRT or surgery. There have been no serious adverse events. Conclusions: Single agent neoadjuvant PD-1 blockade with dostarlimab is effective and well-tolerated in locally advanced dMMR rectal adenocarcinoma and allows patients to avoid chemoradiation and surgery. This suggests a potential new paradigm for treatment of dMMR locally advanced rectal cancer. Follow up and further patient accrual is ongoing. Clinical trial information: NCT04165772.